DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

Hear Dr Vijay kirpalani speak on: Thursday 26th April 2018 along with ChemSpec India 2018 in Hall 1, NSE, Goregaon, Mumbai, India

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Apr 192018

Vijay Kirpalani

HEAR GREAT DR VIJAY KIRPALANI AT, SEE BELOW

Flow Chemistry Society – India, welcome you to a “free-to-attend” Conference on ” Advances in Chemical Process Technology 2018″ which is being held on: Thursday 26th April 2018 along with ChemSpec India 2018 in Hall 1, NSE, Goregaon, Mumbai, India

Chemspec India 2018, the country’s leading exhibition dedicated to Fine and Speciality Chemicals, takes place for the fourteenth time from 25-26 April 2018

To attend the conferences or know more please contact:
Mr. Kiran Iyer,
M: 91-98201-71374
E: kiran@chemicalweekly.com

//////////////////////#mumbai #conferences #flowchemistry #chemicalprocessing #howto #nse #VIJAYKIRPALANI

The Green ChemisTREE: 20 years after taking root with the 12 principles

green chemistry Comments Off

Apr 192018

The Green ChemisTREE: 20 years after taking root with the 12 principles

Green Chem., 2018, Advance Article
DOI: 10.1039/C8GC00482J, Critical Review

Hanno C. Erythropel, Julie B. Zimmerman, Tamara M. de Winter, Laurene Petitjean, Fjodor Melnikov, Chun Ho Lam, Amanda W. Lounsbury, Karolina E. Mellor, Nina Z. Jankovic, Qingshi Tu, Lauren N. Pincus, Mark M. Falinski, Wenbo Shi, Philip Coish, Desiree L. Plata, Paul T. Anastas
A broad overview of the achievements and emerging areas in the field of Green Chemistry.

The Green ChemisTREE: 20 years after taking root with the 12 principles

Hanno C. Erythropel,^a^b Julie B. Zimmerman,^a^b^c Tamara M. de Winter,^a^c Laurène Petitjean,^a^c Fjodor Melnikov,^a^c Chun Ho Lam,^a^c Amanda W. Lounsbury,^a^b Karolina E. Mellor,^a^c Nina Z. Janković,^a^b Qingshi Tu,^a^b Lauren N. Pincus,^a^c Mark M. Falinski,^a^b Wenbo Shi,^a^b Philip Coish,^a^c Desirée L. Plata^a^b and Paul T. Anastas*^a^b^c^d^e

Author affiliations

* Corresponding authors

^a Center for Green Chemistry and Green Engineering, Yale University, 370 Prospect Str., New Haven, USA
E-mail: paul.anastas@yale.edu

^b Dept. of Chemical and Environmental Engineering, Yale University, 10 Hillhouse Ave., New Haven, USA

^c School of Forestry and Environmental Science, Yale University, 195 Prospect Str., New Haven, USA

^d Dept. of Chemistry, Yale University, 225 Prospect Str., New Haven, USA

^e School of Public Health, Yale University, 60 College Str., New Haven, USA

Abstract

The field of Green Chemistry has seen many scientific discoveries and inventions during the 20 years since the 12 Principles were first published. Inspired by tree diagrams that illustrate diversity of products stemming from raw materials, we present here the Green ChemisTREE as a showcase for the diversity of research and achievements stemming from Green Chemistry. Each branch of the Green ChemisTREE represents one of the 12 Principles, and the leaves represent areas of inquiry and development relevant to that Principle (branch). As such, in this ‘meta-review’, we aim to describe the history and current status of the field of Green Chemistry: by exploring activity within each Principle, by summarizing the benefits of Green Chemistry through robust examples, by discussing tools and metrics available to measure progress towards Green Chemistry, and by outlining knowledge gaps, opportunities, and future challenges for the field.

Hanno C. Erythropel

Julie Zimmerman

ZIMMERMAN LAB

Professor of Chemical & Environmental Engineering & Forestry & Environmental Studies, julie.zimmerman@yale.edu

Tamara M. de Winter

Laurène Petitjean, laurene.petitjean@yale.edu

fjodor.melnikov@yale.edu

Image result for Paul T. Anastas yale Paul T. Anastas,

paul.anastas@yale.edu

//////////////Green ChemisTREE, green chemistry

Catalyst-free and solvent-free hydroboration of aldehydes

ANTHONY CRASTO, spectroscopy, SYNTHESIS Comments Off

Mar 302018

Green Chem., 2018, Advance Article
DOI: 10.1039/C8GC00042E, Communication

Hanna Stachowiak, Joanna Kazmierczak, Krzysztof Kucinski, Grzegorz Hreczycho
For the first time, a general method for catalyst-free and solvent-free hydroboration of various aldehydes has been developed

Catalyst-free and solvent-free hydroboration of aldehydes

Hanna Stachowiak,^a Joanna Kaźmierczak,^a Krzysztof Kuciński^a and Grzegorz Hreczycho*^a

Author affiliations

*Corresponding authors

^aFaculty of Chemistry, Adam Mickiewicz University in Poznań, Umultowska 89b, 61-614 Poznań, Poland
E-mail: g.h@amu.edu.pl

Abstract

A simple catalyst-free and solvent-free method for the hydroboration of various aldehydes bearing a wide array of electron-withdrawing and electron-donating groups was developed. Unlike aldehydes, the addition of boranes to ketones is less efficient and is thus advantageous for the chemoselective reduction of the former ones. It is suggested that the described transformation proceeds with the formation of Lewis acid–base adducts, which facilitates further hydroboration.

4,4,5,5-tetramethyl-2-((4-methylbenzyl)oxy)-1,3,2-dioxaborolane (3b) [1] 4,4,5,5-tetramethyl-2-((4-methylbenzyl)oxy)-1,3,2-dioxaborolane was obtained as colorless oil in 97% yield.

1H NMR (400 MHz, CDCl3) δ (ppm) = 1.29 (s, 12H), 2.36 (s, 3H), 4.91 (s, 2H), 7.17 (d, J = 7.9 Hz, 2H), 7.27-7.30 (m, 2H).

13C NMR (101 MHz, CDCl3) δ (ppm) = 21.3, 24.7, 66.7, 83.0, 127.0, 127.2, 129.1, 129.3, 136.4, 137.1.

11B NMR (128 MHz, CDCl3) δ (ppm) = 22.5.

EA: C14H21BO3 (248.16): calcd.C 67.77; H 8.53; found C 67.66; H 8.47.

11B NMR (128 MHz, CDCl3) δ (ppm) = 22.5.

////////////hydroboration

http://pubs.rsc.org/en/Content/ArticleLanding/2018/GC/C8GC00042E?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Inspiring process innovation via an improved green manufacturing metric: iGAL

green chemistry Comments Off

Mar 292018

Inspiring process innovation via an improved green manufacturing metric: iGAL

Green Chem., 2018, Advance Article
DOI: 10.1039/C8GC00616D, Communication

Inspiring process innovation via an improved green manufacturing metric: iGAL

Frank Roschangar,*^a Yanyan Zhou,^b David J. C. Constable,^c Juan Colberg,^d David P. Dickson,^e Peter J. Dunn,^f Martin D. Eastgate,^g Fabrice Gallou,^h John D. Hayler,ⁱ Stefan G. Koenig,^j Michael E. Kopach,^k David K. Leahy,^l Ingrid Mergelsberg,^m Ulrich Scholz,ⁿ Austin G. Smith,^o Manuel Henry,^p Jason Mulder,^a Jörg Brandenburg,^q Juan R. Dehli,^q Daniel R. Fandrick,^a Keith R. Fandrick,^a Frieder Gnad-Badouin,^q Georg Zerban,^q Klaus Groll,^q Paul T. Anastas,^r Roger A. Sheldon^s^t and Chris H. Senanayake^a

Author affiliations

* Corresponding authors

^a Chemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^b Department of Statistics and Biostatistics, California State University East Bay, Hayward, USA

^c American Chemical Society Green Chemistry Institute, Washington District of Columbia 20036, USA

^d Pharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA

^e Chemical Process R&D, Teva Pharmaceuticals, Malvern, USA

^f Pfizer, Sandwich, UK

^g Chemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA

^h Chemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland

ⁱ API Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK

^j Small Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA

^k Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA

^l Process Chemistry, Takeda Pharmaceuticals International, Cambridge, USA

^m Process Chemistry, Merck, Rahway, USA

ⁿ Chemical Development, Bayer AG – Pharmaceuticals, Wuppertal 42096, Germany

^o Process Development, Amgen, Thousand Oaks, USA

^p Chemical Process Development, Boehringer Ingelheim Pharma GmbH & Co. KG, 88307 Biberach an der Riß, Germany

^q Chemical Process Development, Boehringer Ingelheim Pharma GmbH & Co. KG, 55216 Ingelheim am Rhein, Germany

^r Yale University, New Haven, USA

^s Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa

^t Delft University of Technology, 2628 BL Delft, Netherlands

Abstract

Following our goal to devise a unified green chemistry metric that inspires innovation in sustainable drug manufacturing across the pharmaceutical industry, we herein disclose joint efforts by IQ, the ACS GCI PR and academia, leading to the significantly improved ‘innovation Green Aspiration Level’ (iGAL) methodology. Backed by the statistical analysis of 64 drug manufacturing processes encompassing 703 steps across 12 companies, we find that iGAL affords an excellent proxy for molecular complexity and presents a valuable molecular weight-based ‘fixed’ goal. iGAL thereby accurately captures the impact of green process inventiveness and improvements, making it a useful innovation-driven green metric. We conclude by introducing the comprehensive, yet easy-to-use and readily adaptable Green Chemistry Innovation Scorecard web calculator, whose graphical output clearly and effectively illustrates the impact of innovation on waste reduction during drug manufacture.

Frank Roschangar

Frank Roschangar, PhD MBA

Director – Process Research & Global External Chemistry Management

Boehringer Ingelheim

Yanyan Zhou

Ange Zhou

Professor

California State University, East Bay

David Constable

David J. C. Constable

Juan Colberg

//////////////green manufacturing metric

http://www.rsc.org/suppdata/c8/gc/c8gc00616d/c8gc00616d1.pdf

SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

PATENTS, Uncategorized Comments Off

Mar 142018

Image result for PHARMARESOURCES (SHANGHAI) CO., LTD

SOFOSBUVIR, NEW PATENT, WO 2018032356, Pharmaresources (Shanghai) Co Ltd

WO-2018032356, Pharmaresources (Shanghai) Co Ltd

CHEN, Ping; (CN).
PENG, Shaoping; (CN).
LI, Yinqiang; (CN).
LI, Dafeng; (CN).
DONG, Xuejun; (CN)

Process for the preparation of lactone derivatives and their intermediates are important precursors for the synthesis of anti-hepatitis C virus agents, including sofosbuvir . Represents a first filing from Pharmaresources (Shanghai) Co Ltd and the inventors on this API. Gilead Sciences , following its acquisition of Pharmasset , has developed and launched sofosbuvir, a pure chiral isomer of PSI-7851, a next-generation HCV uracil nucleotide analog polymerase inhibitor prodrug for once-daily oral use.

Hepatitis C virus (HCV) infection represents a global health thereat in need of more effective treatment options. The World Health Organization (WHO) estimates that 130-170 million of individuals worldwide have detectable antibodies to HCV and approximately 60-85％of this population develops into chronic disease, leading to liver cirrhosis (5-25％) and hepatocellular carcinoma (1-3％) and liver failure. While there were existing therapeutics including pegylated interferon- (Peg-IFN) and ribavirin (RBV) , they are suboptimal due to various adverse effects, intolerability, low efficacy and slow response in reducing the viral loads across the multiple genotypes (1-6) of HCV. Therefore, there is an urgent and enormous need to develop more effective and efficacious novel anti-HCV therapies.

During the past decade, there have been a variety of small molecule agents as direct-acting antivirals (DAAs) targeting HCV viral replication via action on both structural and nonstructural proteins (NS3-5) have been launched inmarket or in late-stage clinical development. Among the DAAs reported, Soforsbuvir (brand name Sovaldi) targeting NS5B protein from Gilead was approved by FDA in 2003 for HCV genotypes 2 and 3 (in combination with Ribavin) . In 2014, a combination of Sofosbuvir with viral NS5A inhibitor Ledipasvir (brand name Harvoni) was approved. This combination provides high cure rates in people infected with HCV genotype 1, the most common subtype in the US, Japan, and much of the Europe, without the use of interferon, and irrespective of prior treatment failure or the presence of cirrhosis. Compared to previous treatment, Sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a 2-4 fold reduced duration of therapy.

Sofosbuvir is a prodrug using the ProTide biotechnology strategy. It is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate. The triphosphate serves as a defective substrate for the NS5B protein, which is the viral RNA polymerase, thus acts as an inhibitor of viral RNA synthesis.

Due to the tremendous success in Sorosbuvir-based oral therapy, there remains a need for a more efficient method for making sofosbuvir-like anti-hepatitis C virus agents, including sofosbuvir and intermediates thereof. A variety of methods describing different synthetic approaches for substituted lactone (VI) shown below, a key intermediate for Sofosbuvir and its like anti-viral drugs have been published.

WO2008045419 reported a seven-step synthesis (Scheme 1) for the γ-lactone intermediate. When chiral glyceraldehyde used as the starting material, two new chiral centers were generated following Witting reaction and dihydoxylation. After cyclic sulfonate formed, the fluoro subsititution was introduced stereospecifically by a SN2 reaction with HF-Et3N. Lactonization was achieved under the acid conditions followed by hydroxy protecting step to give the desired intermediate. The main disadvantage of this approach is that considerable quantities of both solid and acidic liquid wastes were produced during the process which is very difficult to handle with (e.x. filtration) and/or contributes to the enviroment pollution upon disposal.

Scheme 1

In a similar process reported in CN105418547A (Scheme 2) , the Witting product was epoxidized followed by ring-opening fluorolation by HF-Et₃N or other fluoro-containing reagents, significant amount of regioisomer was observed which was difficult to remove from the oily mixture.

Scheme 2

US20080145901 reported an enzymetic approach to the γ-lactone intermediate (scheme 3) . Treatment of ethyl 2-fluoro-propinate with chiral glyceraldehyde to form the aldol adducts consisting the mixture of four disteroisomers. The disteroisomers were selectively hydrolyzed by enzyme and the major isomer was obtained. After lactonization and hydroxyl protecting, other two isomers were removed by recrystallization.

WO2008090046 reported a similar synthesis as described in Scheme 3.2-fluoro-propionic acid was converted to diffirent bulky ester or amide and reacted with chiral glyceraldehydes. The mixture of the disteroisomers were purified by recrystallization to obtain the pure isomer. By using the method described in Scheme 3, the γ-lactone can be scale up to kilogram quantities but the de value of the final product can not achieve desired level.

Scheme 3

In WO2014108525, WO2014056442 and CN105111169, diffirent auxiliaries were used in the Aldol Reaction to improve the disteroisomeric selectivity (Scheme 4) . The process was shortened to 3～4 steps and the de value was increase significantly.

Scheme 4

Examples

Example 1： preparation of 2-fluoropropanoyl chloride (3)

Chlorosulfonic acid (660 mL, 10 mol, 20 eq) was added to a solution of phthaloyl dichloride (1.4 L, 10 mol, 20 eq) and ethyl-2-fluoropropanoate (600 g, 5 mol) at room temperature. The solution was heated at 120 ℃ for 4 hs. 2- (R) -fluoropropanoyl chloride was distilled from the reaction mixture under reduced pressure and recovered as a colourless oil (320 g, 58.2％) . ¹H-NMR (CDCl₃， 400 MHz) ： δ 5.08 (dq, J ＝ 48.8, 6.8 Hz, 1 H) , 1.63 (dd, J ＝22.8, 6.8 Hz, 3 H) .

Example 2： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (4)

n-Butyl lithium (2.5 M in hexane, 30 mL, 75 mmol, 1.1 eq) was added to a solution of 4-(R) -4-isopropyl-2-oxazolidinone (8.8 g, 68.2 mmol, 1 eq) in dry THF (80 mL) at -50 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (6.8 mL, 0.9 eq) was added, and the solution was stirred for 4 hs at -50 ℃. The reaction was then quenched with a saturated solution of NH₄Cl (50 mL) , extracted with MTBE (80 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (Hexane/EtOAc＝ 10/1) and recovered as a brown oil (9 g, 74.8％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 6.00 (dm, J ＝ 49.2Hz, 1 H) , 4.27 -4.53 (m, 3 H) , 2.43 (dm, J ＝ 52.6 Hz, 1 H) , 1.63 (td, J ＝ 23.2Hz, 3 H) , 0.92 (dq, J ＝ 17.8 Hz, 6 H) .

[0206]

Example 3： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyloxazolidin-2-one (5)

[0207]

n-Butyl lithium (2.5 M in hexane, 75 mL, 187 mmol, 1.1eq) was added to a solution of 4- (S) -4-isopropyl-2-oxazolidinone (22 g, 170 mmol, 1 eq) in dry THF (200 mL) at -50 ℃ under N₂ atomosphere. After 30 min 2-fuoropropanoyl chloride (17 mL, 153 mmol, 0.9 eq) was added, and the solution was stirred for 1 h at -50 ℃. After the starting material was completely consumed, the reaction was then quenched with a saturated solution of NH₄Cl (125 mL) , extracted with MTBE (200 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc＝ 10/1) and recovered as a brown oil (34 g, 83.3％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 5.93 (dm， J ＝ 48.8 Hz, 1 H) , 4.19 -4.17 (m, 3H) , 2.35 (dm, J ＝ 52.8 Hz , 1 H) , 1.55 (td, J ＝ 23.6 Hz, 3 H) , 0.85 (dq, J ＝ 18 Hz, 6 H) .

Example 4： preparation of (4R) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (6)

n-Butyl lithium (2.5 M in hexane, 13.5 mL, 33.74 mmol, 1.1 eq) was added to a solution of (R) -4-phenyloxazolidin-2-one (5 g, 30.67 mmol, 1 eq) in dry THF (75 mL) at -50 ℃ under N₂ atomosphere. After 30 minutes, 2-fuoropropanoyl chloride (3.75 g, 33.74 mmol) was added, and the solution was stirred for 1 h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃(sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (4 g, 55％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.35-7.21 (m, 5 H) , 5.99-5.84 (md, 1 H) , 5.42-5.33 (dd, 1 H) , 4.72 (dd, 1 H) , 4.31 (m, 1 H) , 1.50 (m, 3 H) .

Example 5： preparation of (4s) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7)

n-Butyl lithium (2.5 M in hexane, 67.5 mL, 169 mmol, 1.1 eq) was added to a solution of (s) -4-phenyloxazolidin-2-one (25 g, 153 mmol, 1 eq) in dry THF (375 mL) at -60 ℃ under N₂ atomosphere. After 30 min, 2-fuoropropanoyl chloride (18.7 g, 169 mmol) was added, and the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane /EtOAc) and recovered as a brown oil (16.5 g, 45.4％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.36-7.20 (m, 5 H) , 5.95-5.80 (md, 1 H) , 5.42-5.30 (dd, 1 H) , 4.71 (dd, 1 H) , 4.30 (m, 1 H) , 1.51 (m, 3 H) .

Example 6： preparation of (4S) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (8)

n-Butyl lithium (2.5 M in hexane, 54.7 mL, 137 mmol, 1.1eq) was added to a solution of (S) -4-benzyloxazolidin-2-one (22 g, 124 mmol, 1eq) in dry THF (220 mL) at -60 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (15.2 g, 137 mmol) was added dropwisely below -50 ℃ , after adding the solution was stirred for 1h at -50 ℃ to -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The product was purified over silica (hexane/EtOAc) and recovered as a brown oil (25.8 g, 82.7％) . ¹H-NMR(400 MHz, CDCl₃ ) ： δ 7.29-7.13 (m, 5 H) , 6.01-5.81 (qd, 1 H) , 4.71-4.58 (md, 1 H) , 4.29-4.04 (m, 2 H) , 3.32-3.16 (dd, 1 H) , 2.79-2.74 (m, 1 H) , 1.51 (m, 3 H) .

Example 7： preparation of (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (9)

Use the procedure described in Example 6, (R) -4-benzyloxazolidin-2-one as the start material to give the desired compound (4R) -4-benzyl-3- (2-fluoropropanoyl) oxazolidin-2-one (yield: 85％) . ¹H-NMR (400 MHz, CDCl₃ ) ： δ 7.27 -7.12 (m, 5 H) , 6.00-5.83 (qd, 1 H) , 4.72-4.55 (md, 1 H) , 4.27-4.03 (m, 2 H) , 3.32 -3.16 (dd, 1 H) , 2.79 -2.72 (m, 1 H) , 1.53 (m, 3 H) .

[0221]

Example 8： preparation of (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (10)

[0222]

[0223]

n-Butyl lithium (2.5 M in hexane, 48 mL) was added to a solution of (R) -4-isopropyl-5,5-diphenyloxazolidin-2-one (28.1 g) in dry THF (150 mL) at -65 ℃ under N₂ atomosphere. After stirring 30 min at -60 ℃, 2-fuoropropanoyl chloride (16.4 g, 1.5 eq) was added dropwisely below -60 ℃. After adding the solution was stirred for 2 h at -60 ℃. The reaction was then quenched with a saturated solution of NH₄Cl, extracted with EtOAc, washed with NaHCO₃ (sat) , brine and dried over MgSO₄. Solvents were removed under reduced pressure. The crude product was recrystalized in (DCM/PE) to give (4R) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (30 g, 85％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.50 -7.26 (m, 10 H) , 5.89 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.37 (dd, J ＝ 70.8, 3.4 Hz, 1 H) , 2.00 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.70 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.12 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.83 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0224]

Example 9： preparation of (4S) -3- (2-fluoropropanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11)

[0225]

[0226]

Use the procedure described in Example 8 and (S) -4-isopropyl-5, 5-diphenyloxazolidin-2-one as the start material to give the desired compound (4S) -3- (2-fluoropropanoyl) -4-isopropyl- 5,5-diphenyl oxazolidin-2-one (yield: 82％) . ¹H-NMR (CDCl₃, 400 MHz) : δ 7.51 -7.27 (m, 10 H) , 5.90 (ddq, J ＝ 64.4, 49.3, 6.6 Hz, 1 H) , 5.38 (dd, J ＝ 70.8, 3.4 Hz, 1H) , 2.01 (dd, J ＝ 7.3, 3.3 Hz, 1 H) , 1.71 (dd, J ＝ 23.4, 6.7 Hz, 1.5 H) , 1.13 (dd, J ＝ 23.8, 6.6 Hz, 1.5 H) , 0.84 (ddd, J ＝ 28.0, 16.7, 6.9 Hz, 6 H) .

[0227]

Example 10： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12)

[0228]

[0229]

Method A: TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (10.3 mL, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.2 g, yield: 80％, purity: 97.2％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.89 (dddd, J ＝ 17.1, 10.5, 6.5, 0.8 Hz, 1 H) , 5.42 (d, J ＝17.2 Hz, 1 H) , 5.30 (d, J ＝ 10.1 Hz, 1 H) , 4.68 (dd, J ＝ 14.8, 6.5 Hz, 1 H) , 4.44 (d, J ＝ 4.0 Hz, 1 H) , 4.32 (t, J ＝ 8.5 Hz, 1 H) , 4.24 (dd, J ＝ 9.1, 3.4 Hz, 1 H) , 3.61 (d, J ＝ 6.5 Hz, 1 H) , 2.37 (dd, J ＝ 7.0, 4.1 Hz, 1 H) , 1.73 (s, 1.5 H) , 1.67 (s, 1.5 H) , 0.92 (ddd, J ＝ 7.8, 5.6, 2.4 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) : -158.3 ppm.

[0230]

Method B: TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, (-) -spartein (14.5 g, 1.26 eq) was added and the solution was stirred for 2 hs at-78 ℃, then the second batch of TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1eq) was added. After 10 min, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with NH₄Cl (sat 50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (9.4 g, yield: 75％, purity: 96.5％) .

[0231]

Example 11： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (13)

[0232]

[0233]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoy l ) -4-isopropyloxazolidin-2-one (4) (10 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, diisopropylethyl amine (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (10.4 g, yield: 83％, purity: 92.8％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 5.92 (d， J ＝ 1.1 Hz， 1 H) ， 5.44 (d, J ＝ 17.2 Hz, 1 H) , 5.34 -5.28 (m, 1 H) , 4.73 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.43 (m, 1 H) , 4.37 -4.30 (m, 1H) , 4.27 -4.21 (m, 1 H) , 2.43 -2.31 (m, 1H) , 1.77 (s, 1.5 H) , 1.71 (s, 1.5 H) , 0.91 (dd, J ＝ 12.1, 7.0 Hz, 6 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -159.1ppm.

[0234]

Example 12： preparation of (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one

[0235]

[0236]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4S) -4-benzyl-3-(2-fluoro propanoyl) oxazolidin-2-one (8) (12.3 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, TMEDA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at -78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL*2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (13 g, yield: 86％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) ： δ 7.38 -7.27 (m, 3 H) , 7.22 (d, J ＝ 6.8 Hz, 2 H) , 5.96 (dddd, J ＝ 17.0, 10.5, 6.2, 1.2 Hz, 1 H) , 5.47 (d, J ＝ 17.2 Hz, 1 H) , 5.35 (d, J ＝ 10.5 Hz, 1 H) , 4.75 (dd, J ＝ 13.9, 6.2 Hz, 1 H) , 4.66 (td, J ＝ 7.1, 3.6 Hz, 1 H) , 4.23 (dd, J ＝ 16.3, 5.0 Hz, 2 H) , 3.33 (dd, J ＝ 13.3, 3.3 Hz, 1 H) , 2.76 (dd, J ＝13.3, 10.0 Hz, 1 H) , 1.81 (s, 1.5 H) , 1.76 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0237]

Example 13： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0238]

[0239]

TiCl₄ (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoropropanoyl) -4-phenyloxazolidin-2-one (7) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, Et₃N (12.5 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (12 g, yield: 83％, purity: 90.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.43 -7.30 (m, 5 H) , 5.81 (dddd, J ＝ 17.0, 10.5, 6.3, 1.1 Hz, 1 H) , 5.46 (dd, J ＝ 8.4, 5.1 Hz, 1 H) , 5.37 (dt, J ＝ 17.2, 1.2 Hz, 1 H) , 5.23 (d, J ＝ 10.4 Hz, 1 H) , 4.74 (t, J ＝ 8.7 Hz, 1 H) , 4.64 (dd, J ＝ 13.5, 6.3 Hz, 1 H) , 4.31 (dd, J ＝ 8.9, 5.2 Hz, 1 H) , 1.60 (s, 1.5H) , 1.55 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -158.47 ppm.

[0240]

Example 14： preparation of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one

[0241]

[0242]

TiCl₄ (1 M in DCM, 50 mL, 50mmol, 1.1 eq) was added to a solution of (4R) -3- (2-fluoro propan oyl) -4-phenyloxazolidin-2-one (6) (11.6 g, 49.2 mmol, 1 eq) in dry DCM (170 mL) at -78 ℃ under N₂ atomosphere. After 10 min, DIPEA (15.9 g, 2.5 eq) was added and the solution was stirred for 2 hs at-78 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -78℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into DCM (20 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the product was recrystalized in toluene to give the desired compound as a white solid (11.1 g, yield: 77％, purity: 91.5％) . ¹H-NMR (400 MHz, CDCl₃) : δ 7.44 -7.29 (m, 5 H) , 5.74 -5.63 (m, 1 H) , 5.48 (dd, J ＝ 8.4, 5.3 Hz, 1 H) , 5.35 -5.26 (m, 1 H) , 5.15 (d, J ＝ 10.5 Hz, 1 H) , 4.73 (t, 1 H) , 4.52 (dd, J ＝ 14.8, 6.2 Hz, 1 H) , 4.28 (dd, J ＝ 8.9, 5.3 Hz, 1 H) , 1.68 (s, 1.5 H) , 1.63 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -161.93 ppm.

[0243]

Example 15： preparation of (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one

[0244]

[0245]

Method 1: LiHMDS (1 M in THF, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry THF (100 mL) at -20 ℃ under N₂ atomosphere. After 1.5 hs, acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at -20 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (50 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step. m/z (ES+) : 412 [M+H] +.

[0246]

Method 2: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5g, 2eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (40 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (17.82 g, yield: 88％ (Internal standard yield) .

[0247]

Method 3: (n-Bu) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, DIPEA (13 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into EA (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (16.2 g, yield: 80％ (Internal standard yield ) .

[0248]

Method 4: (C₆H₁₂) ₂BOTf (1 M in DCM, 50 mL, 50 mmol, 1.1 eq) was added to a solution of (4S) -3- (2-fluoro propanoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (11) (17.4 g, 49.2 mmol, 1 eq) in dry DCM (100 mL) at 0 ℃ under N₂ atomosphere. After 15 min, 2, 6-lutidine (10.5 g, 2 eq) was added and the solution was stirred for 2 hs at 0 ℃. Then acrylaldehyde (7 mL, 2 eq) was added and the solution was stirred for 1 h at 0 ℃. Then the reaction was quenched with a saturated solution of NH₄Cl (100 mL) . The products were extracted into DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed under reduced pressure and the crude product was used directly in the next step (14.6 g, yield: 80％ (Internal standard yield ) .

[0249]

Example 16： preparation of (3R, 4R, 5R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydro furan-2 (3H) -one

[0250]

Method 1:

[0251]

[0252]

N-Bromosuccinimide (19.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in DME/H₂O (4: 1, 130ml) at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (bromomethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18a) . ¹H-NMR (400 MHz, CDCl₃) : δ 4.62 -4.53 (m, 1 H) , 4.37 (dd, J ＝ 3.0, 1.9 Hz, 1 H) , 3.73 (dd, J ＝ 10.1, 8.7 Hz, 1 H) , 3.60 (ddd, J ＝ 10.1, 5.8, 1.9 Hz, 1 H) , 2.59 (dd, J ＝ 2.5, 1.7 Hz, 1 H) , 1.67 (d, J ＝ 22.7 Hz, 3 H) ； ¹⁹F-NMR (400 MHz, CDCl₃) ： δ -172.248 ppm.

[0253]

Alternative Method 1a: Br₂ (17.6 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in MeCN/H₂O (4: 1, 130 mL) between -5 ℃ to -10 ℃ and stirred for 2 hs . After the reaction was complete, Na₂S₂O₃ (10％, 20 ml) was added and stirred for 0.5 h at rt then separated . The water phase was re-extracted by DCM (50 mL *2) , the combine organic phase was concentrated, dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to used in the next step.

[0254]

Alternative Method 1b: N-chlorosuccinimide (13.3 g, 1.1 eq) was added portionwisely to a solution of (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in 100ml CH3CN at -5 ℃, and stirred for 2 hs . After the reaction was complete, NaHCO₃ (sat, 20 mL) was added and stirred for 0.5 h at rt. The mixture were extracted by DCM (50 mL *2) , washed with brine and dried over MgSO₄. Solvents were removed, the residue dissolved by MTBE (1V) , the solid was filtered off to recover the auxiliary, the filtrate was concentrated to dryness to obtained the (3R, 4R, 5R) -5- (chloromethyl) -3-fluoro-4-hydroxy-3-methyldihydrofuran-2 (3H) -one (18b) , m/z (ES+) : 183 [M+H] +.

[0255]

The related lactone 18a or 18b (0.14eq) was dissolved in EtOH (104 mL) , then KOH (30％in H₂O, 50 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into the mixture and reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (yield: 80～85％) . m/z (ES+) : 165 [M+H] +. ¹H-NMR (400 MHz, MeOD) : δ 4.34 (ddd， J ＝ 8.0， 4.2， 2.3 Hz， 1 H) , 4.02 (ddd, J ＝ 17.6, 15.2, 5.1 Hz, 2 H) , 3.74 (dd, J ＝ 13.0, 4.2 Hz, 1 H) , 1.60 (s, 1.5 H) , 1.54 (s, 1.5 H) ； ¹⁹F-NMR (400 MHz, MeOD) : -172.47 ppm.

[0256]

Method 2:

[0257]

[0258]

Osmium tetroxide (OsO4) (0.1 equiv) was added in one portion to a stirring solution of the (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyloxazolidin-2-one (12) (25.9 g, 100 mmol, 1 eq) in acetone/water (8: 1 ratio) under nitrogen. After 5 min, NMO (N-methylmorpholine N-oxide, 60％by weight in water, 1.1 equiv) was added in one portion and stirred for 24 h. The resulting reaction mixture was concentrated under reduced pressure and immediately purified via column chromatography to obtain the desired lactone (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (21) , yield: 87％, m/z (ES+) : 165 [M+H] +.

[0259]

15.1 g (92.3 mmol) (3R, 4R, 5S) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyl dihydrofuran-2 (3H) -one (21) was dissolved in 25 mL pyridine and 11.1 g (96.9 mmol) methanesulfonyl chloride was slowly added dropwise at -25 degC. It was stirred for a day at -25 deg and a day at -10 deg. After adding 20 mL of ethyl acetate and 20 mL water, the solvent was removed on a rotary evaporator. After neutralization with dilute sodium hydrogen carbonate solution, the solvent was removed in vacuo again, the residue was digested with ethyl acetate, the eluate was dried with magnesium sulfate and concentrated in vacuo to dryness. Recrystallization from ethyl acetate/diethyl ether gave a colorless crystalline product ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate (18c) . Yield: 31 ％.

[0260]

33.8g of ( (2S, 3R, 4R) -4-fluoro-3-hydroxy-4-methyl-5-oxotetrahydrofuran-2-yl) methyl methanesulfonate was disslolved in EtOH (104 mL) , then KOH (16.8 g , 3 eq) in H₂O (52 mL) was added into, the result mixture was reflux for 4 hs. Then HCl (16.7 mL, 12 M) was added into, the mixture was reflux for another 2 hs. The solvent was removed and the residue was recrystalized in toluene to give the desired compound as a white solid (10.5 g, yield: 45％) .

[0261]

Alternative reagents and reactions to those disclosed above can also be employed. For example, 4-methylbenzene-1-sulfonyl chloride can be used instead of methanesulfonyl chloride. Moreover, primary alcohol can be converted to chloro or bromo by using Ph₃P/CCl4, PPh₃P/CBr₄, PPh₃/NCS, PPh₃/NBS, or PPh₃/C₂Cl₆ as a halogenation reagent. The desired product can be obtained in good yields using these reagents and reactions.

[0262]

Method 3: Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methyl pent-4-enoyl) -4-isopropyloxazolidin-2-one (13) as starting material provides the desired compound 19 (yield: 63.2％)

[0263]

Method 4： Using a method analogous to that described as hereinabove and (S) -4-benzyl-3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) oxazolidin-2-one (14) as starting material provides the desired compound 19 (yield: 71.8％)

[0264]

Method 5： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-one (15) as the start material gives the desired compound 19 (yield: 65.7％)

[0265]

Method 6： Using a method analogous to that described as hereinabove and (R) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-phenyloxazolidin-2-oneas (16) starting material provides the desired compound 19 (yield: 59.5％)

[0266]

Method 7： Using a method analogous to that described as hereinabove and (S) -3- ( (2R, 3R) -2-fluoro-3-hydroxy-2-methylpent-4-enoyl) -4-isopropyl-5, 5-diphenyloxazolidin-2-one (17) as starting material gives the desired compound 19 (yield: 66.7％)

[0267]

Example 17: preparation of ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetra hydro fur an-2-yl) methyl benzoate

[0268]

[0269]

(3R, 4R) -3-fluoro-4-hydroxy-5- (hydroxymethyl) -3-methyldihydrofuran-2 (3H) -one (19) (25.4 g, 0.154 mol) obtained from example 3 was dissolved in 200 ml of THF. 4- (Dimethylamino) -pyridine (8.2 g, 0.066 mol) and triethylamine (35 g, 0.35 mol) were added and the reaction mixture was cooled to 0 ℃. Benzoyl chloride (46.0 g, 0.33 mol) was added, and the mixture was warmed to 35-40 ℃ in the course of 2 hs. Upon completion of the reaction, water (100 mL) was charged and the mixture was stirred for 30 min. Phases were separated and to the aqueous phase methyl-tert-butyl ether (100 mL) was added and the mixture was stirred for 30 min. Phases were separated and the organic phase was washed with saturated NaCl solution (100 mL) . The combined organic phases were dried over Na₂SO₄ (20 g) filtered and the filtrate was evaporated to dryness. The residue was taken up in iso-propanol (250 mL) and the mixture was warmed to 50 ℃ and stirred for 60 min, then cooled down to 0 ℃ and further stirred for 60 min. The solid was filtered and the wet cake was washed with i-propanol (50 mL) and then dried under vacuum. The title compound ( (3R, 4R) -3- (benzoyloxy) -4-fluoro-4-methyl-5-oxotetrahydrofuran-2-yl) methyl benzoate (47.5 g, 82.6 ％yield) was obtained. ‘H-NMR (CDCl₃, 400 MHz) : 8.10 (d, 7＝7.6 Hz, 2H) , 8.00 (d, 7＝7.6 Hz, 2H) , 7.66 (t, 7＝7.6 Hz, IH) , 7.59 (t, 7＝7.6 Hz, IH) , 7.50 (m, 2H) , 7.43 (m, 2H) , 5.53 (dd, 7＝17.6, 5.6 Hz, IH) , 5.02 (m, IH) , 4.77 (dd, 7＝12.8, 3.6 Hz, IH) , 4.62 (dd, 7＝12.8, 5.2 Hz, IH) , 1.77 (d, 7＝23.2 Hz, 3H) .

///////////////////

Tivozanib, ティボザニブ塩酸塩水和物

EMA, orphan status Comments Off

Mar 142018

ChemSpider 2D Image | Tivozanib | C22H19ClN4O5

Tivozanib

Molecular FormulaC₂₂H₁₉ClN₄O₅
Average mass454.863 Da

AV951

AV951 (KRN951, Tivozanib)

AV-951; AV951;AV 951

AV-951|KRN-951|VEGFR tyrosine kinase inhibitor IV

KRN 951

1-{2-Chloro-4-[(6,7-diméthoxy-4-quinoléinyl)oxy]phényl}-3-(5-méthyl-1,2-oxazol-3-yl)urée

1-{2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl}-3-(5-methyl-1,2-oxazol-3-yl)urea

475108-18-0 [RN] FREE FORM

AV 951

N-(2-chloro-4-((6,7-dimethoxy-4-quinolyl)oxy)phenyl)-N’-(5-methyl-3-isoxazolyl)urea

N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
AV 951
KRN 951
Kil 8951
N-[2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]-N’-(5-methyl-3-isoxazolyl)urea
CAS HCL HYDRATE 682745-41-1
682745-43-3 HCL

Tivozanib (AV-951) is an oral VEGF receptor tyrosine kinase inhibitor. It has completed a pivotal Phase 3 investigation for the treatment of first line (treatment naive) patients with renal cell carcinoma.^[1] The results from this first line study did not lead to FDA approval, but Tivozanib was approved by the EMA in August 2017^[2]

Originally developed at Kirin Brewery, in January 2007 AVEO Pharmaceuticals acquired an exclusive license to develop and commercialize tivozanib in all territories outside of Asia.

In 2010, orphan drug designation was assigned in the E.U. for the treatment of renal cell carcinoma. In 2011, the compound was licensed to Astellas Pharma and AVEO Pharmaceuticals on a worldwide basis for the treatment of cancer

Tivozanib is an orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3 with potential antiangiogenic and antineoplastic activities. Tivozanib binds to and inhibits VEGFRs 1, 2 and 3, which may result in the inhibition of endothelial cell migration and proliferation, inhibition of tumor angiogenesis and tumor cell death. VEGFR tyrosine kinases, frequently overexpressed by a variety of tumor cell types, play a key role in angiogenesis.

Tivozanib was originally developed by Kyowa Hakko Kirin and in 2007 AVEO Pharmaceutical acquired all the rights of the compound outside Asia. In December 2015, AVEO reached an agreement with EUSA Pharma, which acquired exclusive rights to tivozanib for advanced renal cell carcinoma in Europe, South America, Asia, parts of the Middle East and South Africa.

Tivozanib is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 for first-line treatment of patients with advanced renal cell carcinoma in advanced disease or without VEGFR and mTOR inhibitors and progression after cytokine therapy Advanced renal cell carcinoma patients. Fotivda® is an oral capsule containing 890 μg and 1340 μg of Tivozanib per tablet. The recommended dose is 1 day, each 1340μg, taking three weeks, withdrawal for a week.

Image result for tivozanib

Image result for TIVOZANIB EMA

CAS HCL HYDRATE 682745-41-1

ティボザニブ塩酸塩水和物;

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Fotivda is indicated for the first line treatment of adult patients with advanced renal cell carcinoma (RCC) and for adult patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC.

Treatment of advanced renal cell carcinoma

Fotivda : EPAR -Product Information

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004131/human_med_002146.jsp&mid=WC0b01ac058001d124

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004131/WC500239035.pdf

str6

Tivozanib is synthesized in three main steps using well defined starting materials with acceptable specifications.
Adequate in-process controls are applied during the synthesis. The specifications and control methods for intermediate products, starting materials and reagents have been presented. The critical process parameters are duly justified, methodology is presented and control is adequate.
The characterisation of the active substance and its impurities are in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised.
The active substance is packaged in a low-density polyethylene (LDPE) bag which complies with the EC
directive 2002/72/EC and EC 10/2011 as amended.

Product details

NAME	Fotivda
AGENCY PRODUCT NUMBER	EMEA/H/C/004131
ACTIVE SUBSTANCE	tivozanib
INTERNATIONAL NON-PROPRIETARY NAME(INN) OR COMMON NAME	tivozanib hydrochloride monohydrate
THERAPEUTIC AREA	Carcinoma, Renal Cell
ANATOMICAL THERAPEUTIC CHEMICAL (ATC) CODE	L01XE

Publication details

MARKETING-AUTHORISATION HOLDER	EUSA Pharma (UK) Limited
REVISION	0
DATE OF ISSUE OF MARKETING AUTHORISATION VALID THROUGHOUT THE EUROPEAN UNION	24/08/2017

Contact address:

EUSA Pharma (UK) Limited
Breakspear Park, Breakspear Way
Hemel Hempstead, HP2 4TZ
United Kingdom

Mechanism

An oral quinoline urea derivative, tivozanib suppresses angiogenesis by being selectively inhibitory against vascular endothelial growth factor.^[3] It was developed by AVEO Pharmaceuticals.^[4] It is designed to inhibit all three VEGF receptors.^[5]

Results

Phase III results on advanced renal cell carcinoma suggested a 30% or 3 months improvement in median PFS compared to sorafenibbut showed an inferior overall survival rate of the experimental arm versus the control arm.^[5]^[6] The Food and Drug Administration‘s Oncologic Drugs Advisory Committee voted in May 2013 13 to 1 against recommending approval of tivozanib for renal cell carcinoma. The committee felt the drug failed to show a favorable risk-benefit ratio and questioned the equipose of the trial design, which allowed control arm patients who used sorafenib to transition to tivozanib following progression disease but not those on the experimental arm using tivozanib to transition to sorafenib. The application was formally rejected by the FDA in June 2013, saying that approval would require additional clinical studies.^[6]

In 2016 AVEO Oncology published data in conjunction with the ASCO meeting showing a geographical location effect on Overall Survival in the Pivotal PhIII trial^[7]

In 2016 AVEO Oncology announced the start of a second Pivotal PhIII clinical study in Third Line advanced RCC patients. ^[8]

In 2016 EUSA Pharma and AVEO Oncology announced that Tivozanib had been submitted to the European Medicines Agency for review under the Centralised Procedure. ^[9]

In June 2017 the EMA Scientific Committee recommended Tivozanib for approval in Europe, with approval expected in September.^[10]

In August 2017 the European Commission (EC) formally approved Tivozanib in Europe.^[11]

SYNTHESIS

Heterocycles, 92(10), 1882-1887; 2016

CLIP

Image result for tivozanib synthesis

Paper

Heterocycles (2016), 92(10), 1882-1887

Short Paper | Regular issue | Vol 92, No. 10, 2016, pp. 1882 – 1887
Published online: 5th September, 2016

DOI: 10.3987/COM-16-13555

■ A New and Practical Synthesis of Tivozanib

Chunping Zhu, Yongjun Mao,* Han Wang, and Jingli Xu

*College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Rd., Songjiang, Shanghai, 201620, China

Abstract

New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2- en-1-one compound at H2/Ni condition is adopted in good result. Commercial available materials, simple reaction and operation are used, including nitration, condensation, hydrogenation, chlorination and so on, to give the final product in 28.7% yield over six steps and 98.9% purity (HPLC).

Image result for tivozanib

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X15003054

Bioorganic & Medicinal Chemistry Letters

Volume 25, Issue 11, 1 June 2015, Pages 2425-2428

HC-1144 (yield: 69.0% ) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 8.33 (d, J=5.2 Hz, 1H,), 8.17(d, J=9.2 Hz, 1H), 7.47 (s, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.23 (s, 1H), 7.10(m, 1H), 6.47(d, J=5.2 Hz, 1H), 6.28 (brs, 1H), 2.30 (s, 3H). MS (ESI, m/z): 461 [M+H]⁺.

PAPER

J MED CHEM 2005 48 1359

PATENT

WO 2002088110

KUBO, Kazuo; (JP).
SAKAI, Teruyuki; (JP).
NAGAO, Rika; (JP).
FUJIWARA, Yasunari; (JP).
ISOE, Toshiyuki; (JP).
HASEGAWA, Kazumasa; (JP)

Scheme 1 and Scheme 2

Skiing

PATENT

WO 2004035572

MATSUNAGA, Naoki; (JP).
YOSHIDA, Satoshi; (JP).
YOSHINO, Ayako; (JP).
NAKAJIMA, Tatsuo; (JP)

Preparation example: Preparation of N- {2-chloro-1- [(6,7-dimethoxy- 14 1 quinolyl) oxyl] phenyI} – N, – (5-methyl- 3 -isoxazolyl) urea ) Nitration process:

3, 4-Dimethoxyacetophenone (1 500 g) was dissolved in 5:: L 0 ° C of 17% nitric acid (1400 g), and 67% nitric acid (843 0 g) and sodium nitrite g) at a temperature of 5 to 10 ° C. over a period of 2 to 3 hours. After completion of dropping, the mixture was stirred at 5 to 10 ° C. for 1 to 2 hours. Cold water (7. 5 L) was added and after stirring for 30 minutes, filtration and washing with water (30 L). The filtrate was added to water (7. 5 L), neutralized with sodium bicarbonate water, filtered, and washed with water (7 L). The filtrate was dried under reduced pressure to obtain 3, 4-dimethoxy-6-nitroacetophenone (2164 g) (yield = 87.9%).

‘H-NMR (400 MHz, CD C 1 ₃ / p pm); 62. 5 0 (s, 3 H), 3. 9 7 (s, 3H), 3. 9 9 (s, 3 H), 6. 76 (s, 1 H), 7.6 2 (s, 1 H)

(2) Reduction process:

Methanol (5. 4 L), acetic acid (433 g:), 5% palladium / power monobonn (162 g) was added to 3, 4-dimethoxy-6-nitroacetophenone (1082 g) and hydrogen gas The mixture was stirred for 8 hours under pressure (2 Kg / cm 2, 40 ° C. The reaction solution was filtered, washed with methanol (1 L), and the filtrate was neutralized with aqueous sodium hydroxide solution and concentrated under reduced pressure Water (10 L) was added to the concentrate, stirred overnight, filtered and washed with water (7 L) Toluene (4 L) was added to the filtrate, heated to 80 ° C., 1 After stirring for a while, the residue was concentrated under reduced pressure and the residue was filtered, washed with toluene (300 mL), dried under reduced pressure to give 2-amino-4,5-dimethoxa Cetophenone (576 g) was obtained (yield = 6.1%).

‘H-NM (400 MHz, CD C 1 ₃ / p pm); 62. 5 6 (s, 3 H), 3. 84 (s, 3H), 3. 88 (s, 3 H), 6. 10 ( s, 1 H), 7.11 (s, 1 H)

(3) Cyclization step:

Tetrahydrofuran (THF) (5. 3 L) and sodium methoxide (3 1 3 g) were added to 2-amino-4, 5-dimethoxyacetophenone (33 7 g) and the mixture was stirred at 20 ° C for 30 minutes. At 0 ° C, ethyl formate (858 g) was added and stirred at 20 ° C for 1 hour. Water (480 mL) was added at 0 ° C. and neutralized with 1 N hydrochloric acid. After filtering the precipitate, the filtrate was washed with slurry with water (2 L). After filtration, the filtrate was dried under reduced pressure to obtain 6, 7-dimethoxy-141 quinolone (3 52 g) (yield = 8.15%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 8 1 (s, 3 H), 3. 84 (s, 3 H), 5. 94 (d, 1 H), 7. 0 1 (s, 1 H), 7. 43 (s, 1 H), 7. 76 (d, 1 H)

(4) Clovalization process

Toluene (3 L) and phosphorus oxychloride (1300 g) were added to 6, 7-dimethoxy-1-quinolone (105 g), and the mixture was stirred under heating reflux for 1 hour. It was neutralized with aqueous sodium hydroxide solution at 0 ° C. The precipitate was filtered, and then the filtrate was washed with water (10 L) for slurry. After filtering, the filtrate was dried under reduced pressure to obtain 4 1 -chloro- 16, 7-dimethoxyquinoline (928 g) (yield – 87.6 %) _c ‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 63. 9 5 (s, 3 H), 3. 9 6 (s, 3 H), 7. 3 5 (s, 1 H), 7. 43 (s, 1 H) , 7. 54 (d, 1 H), 8. 59 (d, 1 H)

(5) Phenol site introduction step:

4-Amino-3-chlorophenol · HC 1 (990 g) was added to N, N-dimethylacetamide (6. 6 L). Potassium t-butoxide (145 2 g) was added at 0 ° C. and the mixture was stirred at 20 ° C. for 30 minutes. 4-Chloro-6, 7-dimethoxyquinoline (82 5 g) was added thereto, followed by stirring at 115 ° C for 5 hours. After cooling the reaction solution to room temperature, water (8. 3 L) and methanol (8.3 L) were added and the mixture was stirred for 2 hours. After filtration of the precipitate, the filtrate was washed with slurry with water (8. 3 L), filtered, and the filtrate was dried under reduced pressure to give 4- [(4-amino-3-chlorophenol) 6, 7-Dimethoxyquinoline (8 52 g) was obtained (yield = 6 9. 9%).

‘H-NMR (400MH z, DMS 0 – d ₆ / ppm); 63. 9 2 (s, 3 H), 3. 93 (s, 3 H), 5. 4 1 (s, 2 H), 6 (D, 1 H), 6. 89 (d, 1 H), 6. 98 (dd, 1 H), 7. 19 (d, 1 H), 7. 36 (s, 1 H) , 7. 48 (s, 1 H), 8. 43 (d, 1 H)

(6) Ureaization process:

To 3 – amino – 5 – methylisoxazole (377 g), pyridine (1 2 1 5:), N, N – dimethylacetamide (4 L) at 0 ° C was added chlorobutyl carbonate phenyl

(60 1 g) was added dropwise and the mixture was stirred at 20 ° C. for 2 hours. 4- [(4-amino-1-chlorophenol) oxy] -6, 7-dimethoxyquinoline (84 7 g) was added to the reaction solution, and the mixture was stirred at 80 ° C. for 5 hours. The reaction solution was cooled to 5 ° C, then added with MeOH (8. 5 L) and water (8. 5 L) and neutralized with aqueous sodium hydroxide solution. After filtering the precipitate, the filtrate was washed with water (8. 5 L) for slurry. After filtration, the filtrate was dried under reduced pressure to give N- {2-chloro-4- [(6,7-dimethoxy-4-quinolyl) oxy] phenyl] – N, 1- -isoxazolyl) urea (1002 g) was obtained (yield = 86.1%).

‘H-NMR (400 MHz, DMS 0 – d ₆ / ppm); 62.37 (s, 3 H), 3. 92 (s, 3 H), 3. 94 (s, 3 H), 6. 7 (s, 1 H), 7. 48 (s, 1 H), 7 (s, 1 H), 6. 54 (d, . 5 1 (d, 1 H), 8. 2 3 (d, 1 H), 8. 49

(d, 1 H), 8. 77 (s, 1 H), 1 0.16 (s, 1 H)

PATENT

WO 2011060162

WO 2017037220

CN 106967058

CN 104072492

CN 102532116

CN 102408418

PAPER

Advanced Materials Research Vols. 396-398 (2012) pp 1490-1492

Synthesis of the compounds

The synthesis of 6,7-Dimethoxy-4-quinolinone (2a) The 33.7g (0.173mol) of 2-amino-4,5-dimethoxy acetophenone, 150 ml of methanol and 95.5g (0.69mol) of anhydrous potassium carbonate were added to the 500 ml flask and stirred about 1 h at room temperature. Then, the ethyl formate (75.8g, 0.861mol) was dropped the admixture and reactioned about 2 h in the same temperature. The admixture was filtrated and the 35.2 g white powder compound 2a (C11H11NO3) was obtained with the yield of 81.5% and m.p. 124-125. 1H-NMR (DMSO-d6/ppm): δ 3.81 (s, 3H), 3.84 (s,3H), 5.94 (d,1H), 7.01 (s,1H), 7.43 (s,1H), 7.76 (d,1H). ESI-MS: 206 (M+ +1).

The synthesis of 4-chloro-6,7-dimethoxy-quinoline (2b)The 100 ml of toluene, 15 g (0.103 mol) of phosphorus trichloride and 10.6 g (0.52 mol) compound 2a were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature, filtrated and the solid was dried. The 9.3 g similar white powder compound 2b (C11H10ClNO2 ) was obtained with the yield of 96.9% and m.p.138-140 ℃ . 1H-NMR (DMSO-d6/ppm): δ 3.95 (s,3H) , 3.96 (s,3H), 7.35 (s,1H), 7.43 (s,1H), 7.54 (d,1H), 8.59(d,1H). ESI-MS: 225 (M+ +1).

The synthesis of 4-[(4-Amino-3-phenol) oxy]-6,7-dimethoxy-quinoline (2c) The 60 ml of N, N-dimethylformamide, 8.9g (0.05 mol) of 4-amino-3-chlorophenol hydrochloride, 14.5g (0.105 mol) of potassium carbonate and 8.3 g (0.037 mol) compounds 2b were added to the 250 ml of three bottles, the obtained mixture was refluxed about 2 h. Then, the reaction mixture was cooled to the room temperature and the 100 ml of anhydrous ethanol was added. The obtained mixture was stirred about 1 h and filtrated. The filtered product was then dried under the reduced pressure to give the 8.5 g similar white powder compound 2c (C17H15ClN2O3) with the yield of 69.9%. 1H-NMR (DMSO-d6/ppm): δ 3.92 (s,3H), 3.93 (s,3H), 5.41 (s,2H), 6.41 (d,1H), 6.89 (d,1H), 6.98 (dd,1H), 7.19 (d,1H), 7.36 (s,1H), 7.48 (s,1H), 8.43(d,1H). ESI-MS: 331 (M+ +1).

The synthesis of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl} -N’- (5-methyl-3- isoxazole-yl) urea (2d) The 100 ml of N,N-dimethylformamide, 5.0g (0.051mol) of 3-amino-5- methylisoxa -zole, 7.98 g (0.051mol) of phenyl chloroformate and 17g (0.051mol) compound 2c were added to the 250 ml of three bottles. The mixture was refluxed about 5 h, cooled to room temperature, added the 100 ml of anhydrous ethanol. The obtained mixture was stirred 1 h and filtrated. The filtered product was slurried in water for washing. The slurry was filtered, and the filtered product was then dried under the reduced pressure to give the 20.0g white crystal compound 2d (C22H19ClN4O5) with the yield of 86.1% and the purity of more than 98.5 %. 1H-NMR (DMSO-d6/ppm): δ 2.37 (s,3H), 3.92 (s,3H), 3.94 (s,3H), 6.50 (s,1H), 6.54 (d,1H), 7.26 (dd,1H), 7.39 (s,1H), 7.48 (s,1H), 7.51 (d,1H), 8.23 (d,1H), 8.49 (d,1H), 8.77 (s,1H), 10.16(s,1H). ESI-MS: 456 (M+ +1).

Conclusions Tivozanib was synthesized through the cyclization, chlorinated, condensation reaction with 2-amino-4,5-dimethoxy acetophenone as the starting material. The total yield was 47.5% and the product purity of more than 98.5 %. The synthetic routs and methods of tivozanib are feasible to industrial production owing to the cheap raw materials, mild reaction conditions, stable technology and high yield.

PATENT

https://patents.google.com/patent/CN102532116B/en

Example

[0035] In 250ml three-neck flask, 80ml of chloroform and 22. 0g (0. 16mol) of anhydrous aluminum chloride at room temperature were successively added dropwise l〇.2g (0. 13mol) acetyl chloride, 13.8g (0. i mole) phthalic dimethyl ether, dropwise, stirred at room temperature until the reaction end point (GLC trace). The reaction solution was poured into 500ml diluted hydrochloric acid, with stirring, the organic phase was separated, the aqueous phase was extracted with chloroform and the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 15. Og of white powder Compound Ia (CltlH12O3), mp 48-52 ° C, 83% yield. HKcnT1): 1673,1585,1515,1418 1H-NMR (CDCl3 / ppm):! S 2. 55 (s, 3H), 3.73 (s, 3H), 3.73 (s, 3H), 6.77 (s, lH) , 7.26 (s, lH), 7.31 (s, lH).

[0036] The two 3 Synthesis of 4-dimethoxy-6-nitroacetophenone (Compound lb) Example

[0037] CN 102532116 B specification 4/6

[0038] In 500ml three-neck flask, was added IOOml formic acid and 18g (0 • lmol) compound la, KTC hereinafter 60ml of concentrated nitric acid was added dropwise, dropwise, warmed to 60-70 ° C, stirred for 30min. The reaction mixture was poured into 500ml ice water bath and stirred, suction filtered to give a pale yellow powder 36.9g Compound lb (CltlH11NO5), mp 135-137 ° C, in 82% yield. 1H-NMR (CDCl3 / ppm): S 2. 50 (s, 3H), 3 97 (s, 3H), 3 99 (s, 3H), 6 76 (s, 1H), 7. 62 (… s, 1H).

Example tri-2-amino-4, Synthesis of 5-dimethoxy acetophenone (Compound Ic), [0039] Embodiment

[0041] In 250ml three-neck flask, 36ml of water was added and 7g (0. 125mol) of reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g (0. 025mol) LB compound, stirred for 3h, filtered off with suction, the filtrate is cooled, to give a yellow powder 7g compound Ic (C10H13NO3), mp 106-108 ° C, in 96% yield.1H-NMR (CDCl3Zppm): S 2. 56 (s, 3H), 3.84 (s, 3H), 3.88 (s, 3H), 6.10 (s, lH), 7.11 (s, lH).

Synthesis of four 6, 7-dimethoxy-4-quinolinone (Compound Id), [0042] Example

[0045] A 33. 7g (0 • 173mol) Compound lc, 150ml methanol and 95. 5g (0 • 69mol) of anhydrous potassium carbonate were added to a 500ml three-necked flask, LH stirred at room temperature, was added dropwise 75. 8g (0. 861mol) ethyl, the reaction incubated 2h. Suction filtration and dried, to give 35. 2g of a white powder compound Id (C11H11NO3), mp 124-125 ° C, yield 81.5%. 1H-NMR (DMSO-Cl6Zppm): 8 3.81 (s, 3H), 3.84 (s, 3H), 5.94 (d, 1H), 7.01 (s, 1H), 7.43 (s, lH), 7.76 (d, lH ).

[0046] Example 4- five-chloro-6, 7-dimethoxy-quinoline (compound Ie) Synthesis of

[0047] CN 102532116 B specification 5/6

[0049] The IOOml toluene, 10. 6g (0 • 52mol) Compound Id and 15g (0 • 103mol) phosphorus trichloride force the opening into a 250ml three-necked flask and heated at reflux for 2h, cooled suction filtration and dried to give 9 . 3g white powder compound Ie (C11H10ClNO2), mp 138-14 (TC, yield 87. 6% .1H-NMR (DMS〇-d6 / ppm): 8 3. 95 (s, 3H), 3.96 ( s, 3H), 7.35 (s, lH), 7.43 (s, lH), 7.54 (d, lH), 8.59 (d, lH).

Six 4 [0050] Example – [(4-amino-phenol) oxy] -6, 7-dimethoxy-quinoline (compound If) Synthesis of

[0053] In 250ml three-neck flask, was added 60ml of N, N- dimethylformamide, 8. 9g (0 • 05mol) 4- amino-3-chlorophenol hydrochloride, 14.5g (0.105mol) of potassium carbonate and (0.037 mol) compound le 8.3g, was heated refluxed for 2h. Cooled to room temperature, IOOml ethanol, stirred, filtered off with suction, and dried to give compound 8. 5g If (C17H15ClN2O3), a yield of 69. gQ / jH-NMlUDMSO-dyppm): S 3.92 (s, 3H), 3.93 ( s, 3H), 5.41 (s, 2H), 6.41 (d, 1H), 6.89 (d, 1H), 6.98 (dd, 1H), 7.19 (d, 1H), 7.36 (s, 1H), 7.48 (s , 1H), 8.43 (d, 1H).

-N’- (5- methyl-3-isobutyl – [0054] Example seven N- {[(6,7- dimethoxy-4-quinolyl) oxy] phenyl} -42- chloro oxazolyl) urea (compound Ig) synthesis of

[0056] The IOOml of N, N- dimethylformamide, 5. Og (0.051mol) of 3-amino-5-methylisoxazole, 7. 98g (0 • 051mol) and phenyl chloroformate 17g (0 • 051mol) If a compound was added to 250ml three-necked flask, the reaction was heated at reflux for 5h, cooled to room temperature, ethanol was added IOOml, stirring, filtration, and dried to give 20. Og compound Ig (C22H19ClN4O5), yield 86 . 1%. 1H-NMR (DMS0-d6 / ppm): S 2.37 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.50 (s, lH), 6.54 (d, lH), 7.26 (dd , lH), 7.39 (s, lH), 7.48 (s, lH), 7.51 (d, lH), 8.23 (d, lH), 8.49 (d, lH), 8.77 (s, lH), 10.16 (s, lH).

Claims (3)

translated from Chinese

1. An antitumor drugs Si tivozanib to synthesis, the method as follows: The lOOmL of N, N- dimethylformamide, 5 Og of 3-amino-5-methylisoxazole, 7 . 98g phenyl chloroformate and 17g 4- [(4- amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline was added to 250mL three-necked flask, the reaction was heated at reflux for 5h, cooled to rt, lOOmL ethanol was added, stirred, filtered off with suction, and dried to give 20. Og tivozanib, yield 86.1%, the reaction is:

Wherein the 4- [(4-amino-3-chlorophenol) oxy] -6, 7-dimethoxy-quinoline is obtained by the following synthesis method: in 250mL three-neck flask, was added 60mL of N, N- dimethylformamide, 8. 9g 4- amino-3-chloro-phenol hydrochloride, 14. 5g of potassium carbonate and 8. 3g 4- chloro-6, 7-dimethoxy quinoline, was heated at reflux for 2h cooled to room temperature, 100mL of absolute ethanol was added, stirred, filtered off with suction, and dried to obtain 8. 5g 4 – [(4_-amino-3-chlorophenol) oxy] -6, 7-dimethoxy quinoline, close was 69.9%, the reaction is:

Said 4-chloro-6, 7-dimethoxy-quinoline is obtained by the following synthesis method: A mixture of 100mL of toluene, 10 6g 6, 7- dimethoxy-4-quinolone and 15g trichloride phosphorus is added to 250mL three-necked flask and heated at reflux for 2h, cooled suction filtration, and dried to give an off-white powder 9. 3g 4- chloro-6, 7-dimethoxy quinoline, a yield of 87.6%, the reaction formula:

6, 7-dimethoxy-4-quinolone was synthesized by the following method: 33. 7g 2- amino-4, 5-dimethoxy acetophenone, 150 mL of methanol, and 95. 5g anhydrous potassium carbonate was added to the 500mL three-necked flask, stirred at room temperature LH, 75. 8g of ethyl dropwise, the reaction incubated 2h, filtered off with suction, and dried to give 35. 2g of white powder 6, 7-dimethoxy-4 – quinolinone, a yield of 81.5%, the reaction is:

The 2-amino-4,5-dimethoxy acetophenone is synthesized by the following method: In the 250mL three-neck flask, was added 36mL of water and 7g reduced iron powder was heated and refluxed for LH, was slowly added 5. 6g 3, 4-dimethoxy-6-nitroacetophenone, stirred for 3h, filtered off with suction, the filtrate was cooled to give a yellow powder 7g of 2-amino-4,5-dimethoxy acetophenone, yield 96 %, the reaction is:

2. The synthesis method according to claim 1, wherein: said 3,4-dimethoxy-6-nitroacetophenone is 3, 4-dimethoxy acetophenone nitration obtained by a reaction of reaction formula:

3. The method of synthesis according to claim 2, wherein: said 3,4-dimethoxy acetophenone in the catalyst, to give the phthalimido ether is reacted with acetyl chloride by Friedel The reaction is:

References

Tivozanib is currently being evaluated in the pivotal Phase 3 TIVO-3 trial, a randomized, controlled, multi-center, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced RCC. FDA approval is expected in 2018. A Study of Tivozanib (AV-951), an Oral VEGF Receptor Tyrosine Kinase Inhibitor, in the Treatment of Renal Cell Carcinoma, clinicaltrials.gov
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ivozanib
Names

IUPAC name 1-{2-Chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)urea
Other names AV-951
Identifiers
3D model (JSmol)	Interactive image
ChEMBL	ChEMBL1289494
ChemSpider	8087481
IUPHAR/BPS	6058
KEGG	D09683
PubChem CID	9911830
UNII	172030934T
InChI [show]
SMILES [show]
Properties
Chemical formula	C₂₂H₁₉ClN₄O₅
Molar mass	454.87 g·mol⁻¹
Pharmacology
ATC code	L01XE34 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////Tivozanib, ema 2017, ASP-4130, AV-951, KRN-951, Kil-8951, Fotivda, Tivopath, orphan drug, ティボザニブ塩酸塩水和物,

CC1=CC(=NO1)NC(=O)NC2=C(C=C(C=C2)OC3=C4C=C(C(=CC4=NC=C3)OC)OC)Cl

DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent

PATENTS, Uncategorized Comments Off

Mar 142018

DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent

WO-2018036558-A1 / 2018-03-01

CRYSTAL FORM OF ANDROGEN RECEPTOR ANTAGONIST MEDICATION, PREPARATION METHOD THEREFOR, AND USE

陈敏华 [CN][+]

张炎峰 [CN][+]

李骄洋 [CN][+]

鄢楷强 [CN][+]

刘启月 [CN][+]

张晓宇 [CN]

一种式(I)所示ODM-201的晶型B，其特征在于，其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。

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Novel crystalline forms of an androgen receptor antagonist medication, particularly ODM-201 (also known as darolutamide; designated as Forms B and C), processes for their preparation and compositions comprising them are claimed. Represents a first filing from Crystal Pharmaceutical Co Ltd and the inventors on this API.

Orion and licensee Bayer are codeveloping darolutamide, an androgen receptor antagonist, for treating castration-resistant prostate cancer and metastatic hormone-sensitive prostate cancer.

专利CN102596910B公开了ODM-201的制备方法，但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号：1297538-32-9)所示的晶型I，式(Ia)(CAS号：1976022-48-6)所示的晶型I’和式(Ib)(CAS号：1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道：ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成，即为式(I)所示结构。因此，现有关于ODM-201的晶型只有晶型I报道。

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Prostate cancer has become an important disease threatening the health of men. Its incidence is higher in western countries and shows a year-by-year upward trend. In the past, Asian countries with a lower incidence of the disease have also seen an increase in the number of patients in recent years. Clinical treatment of prostate cancer commonly used methods are surgical resection, radiation therapy and blocking androgen endocrine therapy. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer. Therefore, endocrine therapy has become an effective way to treat prostate cancer. The method includes orchidectomy, estrogen therapy, gonadotropin-releasing hormone analog therapy, gonadotropin-releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonist therapy can be both early treatment of prostate cancer can also be combined Surgery for adjuvant therapy is currently one of the main clinical treatment of prostate cancer. Androgen receptor as a biological target of androgen play an important role in the field of biomedical research.

Clinical trials have shown that exogenous androgen administration to patients with prostate cancer can lead to an exacerbation of the patient’s condition; conversely, if the testicles are removed and the level of androgens in the patient is reduced, the condition is relieved, indicating that androgens contribute to the development of prostate cancer Significant influence. According to receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which is the basis for the application of androgen receptor (AR) antagonist in the treatment of prostate cancer. In vitro experiments have shown that AR antagonists can inhibit prostate cell proliferation and promote apoptosis. Depending on the chemical structure of AR antagonists, they can be divided into steroidal AR antagonists and non-steroidal AR antagonists. Non-steroidal anti-androgen activity is better, there is no steroid-like hormone-like side effects, it is more suitable for the treatment of prostate cancer.

ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used clinically to treat prostate cancer. The binding affinity of ODM-201 to AR was high, with Ki = 11nM and IC50 = 26nM. Ki was the dissociation constant between ODM-201 and AR complex. The smaller the value, the stronger the affinity. half maximal inhibitory concentration “refers to the half-inhibitory concentration measured, indicating that a certain drug or substance (inhibitor) inhibits half the amount of certain biological processes. The lower the value, the stronger the drug’s inhibitory ability. In addition, ODM-201 does not cross the blood-brain barrier and can reduce neurological related side effects such as epilepsy. Bayer Corporation has demonstrated in clinical trials the effectiveness and safety of ODM-201, demonstrating its potential for treating prostate cancer.

The chemical name of ODM-201 is: N – ((S) -l- (3- (3- chloro-4-cyanophenyl) -lH-pyrazol-l-yl) -propan- The chemical name contains the tautomer N – ((S) -1- (3- (3- 4-cyanophenyl) -1H-pyrazol- 1 -yl) -propan-2-yl) -5- (1 -hydroxyethyl) 1297538-32-9, the structural formula is shown in formula (I) :

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The different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, fluidity and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53 -54,57,2000.), Resulting in differences in clinical efficacy. It has been found that new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active ingredients of the medicinal product may give rise to more processing advantages or provide substances with better physical and chemical properties such as better bioavailability, storage stability, ease Processed, purified or used as an intermediate to promote conversion to other crystalline forms. The new crystalline form of the pharmaceutical compound can help improve the performance of the drug and broaden the choice of starting material for the formulation.

Patent CN102596910B discloses the preparation of ODM-201, but does not disclose any crystal form information. Patent WO2016120530A1 discloses a crystalline form I represented by the formula (I) (CAS number: 1297538-32-9), a crystalline form I ‘represented by the formula (Ia) (CAS number: 1976022-48-6) and a compound represented by the formula (CAS No. 1976022-49-7). Document Expert Rev. Anticancer Ther. 15 (9), (2015) It has been reported that ODM-201 is composed of a 1: 1 ratio of (Ia) And (Ib), which is the structure shown in Formula (I), so the only existing crystal form I for ODM-201 is reported.

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However, the lower solubility of Form I and the high hygroscopicity, and the preparation of Form I requires the use of highly toxic acetonitrile solvents, which are carcinogenic in animals and are the second class of solvents that should be controlled during the process development stage. Form I preparation method is more complex, long preparation cycle, the process needs heating, increasing the cost of industrial preparation, is not conducive to industrial production. In order to overcome the above drawbacks, there is still a need in the art for a systematic and comprehensive development of other polymorphs of ODM-201 of formula (I), simplifying the preparation thereof, enabling its pharmacological development and releasing its potential, Preparation of a better formulation of the drug ingredients.

The inventors found through experiments that Form B and Form C of the present invention, and found that Form B and Form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and increased solubility will help to increase the bioavailability of the drug and thereby improve the drug’s druggability. Compared with the prior art, the crystalline forms B and C of the invention have higher solubility and provide favorable conditions for drug development. Compared with the prior art, the crystalline forms B and C of the invention also have lower hygroscopicity. Hydroscopic drug crystal form due to adsorption of more water lead to weight changes, so that the raw material crystal component content is not easy to determine. In addition, the crystalline form of the drug substance absorbs water and lumps due to high hygroscopicity, which affects the particle size distribution of the sample in the formulation process and the homogeneity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample. The crystal form B and the crystal form C have the same moisture content under different humidity conditions, and overcome the disadvantages caused by high hygroscopicity, which is more conducive to the long-term storage of the medicine, reduces the material storage and the quality control cost.

In addition, the present invention provides Form B and Form C of ODM-201 represented by formula (I), which have good stability, excellent flowability, suitable particle size and uniform distribution. The solvent used in the preparation method of crystal form B and crystal form C of the invention has lower toxicity, is conducive to the green industrial production, avoids the pharmaceutical risk brought by the residue of the toxic solvent, and is more conducive to the preparation of the pharmaceutical preparation. The novel crystal type provided by the invention has the advantages of simple operation, no need of heating, short preparation period and cost control in industrialized production. Form B and Form C of the present invention provide new and better choices for the preparation of pharmaceutical formulations containing ODM-201, which are of great significance for drug development.

The problem to be solved by the invention

The main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.

//////////DAROLUTAMIDE, WO 2018036558, 苏州科睿思制药有限公司 , New patent, CRYSTAL

PADELIPORFIN

EMA, Uncategorized Comments Off

Mar 142018

2D chemical structure of 759457-82-4

PADELIPORFIN

759457-82-4; 457P824,

RN: 759457-82-4
UNII: EEO29FZT86

3-[(2S,3S,12R,13R)-8-acetyl-13-ethyl-20-(2-methoxy-2-oxoethyl)-3,7,12,17-tetramethyl-18-(2-sulfoethylcarbamoyl)-2,3,12,13-tetrahydroporphyrin-22,24-diid-2-yl]propanoic acid;palladium(2+)

(SP-4-2)-[(7S,8S,17R,18R)-13-acetyl-18-ethyl-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato (4-)-kN21,kN22,kN23,kN24] palladate(2-)

Palladate(2-), [(7S,8S,17R,18R)-13-acetyl-18-ethyl-7,8-dihydro-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato(4-)-κN²¹,κN²²,κN²³,κN²⁴]-, (SP-4-2)-

Coordination Compound

Other Names

(SP-4-2)-[(7S,8S,17R,18R)-13-Acetyl-18-ethyl-7,8-dihydro-5-(2-methoxy-2-oxoethyl)-2,8,12,17-tetramethyl-3-[[(2-sulfoethyl)amino]carbonyl]-21H,23H-porphine-7-propanoato(4-)-κN²¹,κN²²,κN²³,κN²⁴]palladate(2-)

Molecular Formula:	C₃₇H₄₃N₅O₉PdS
Molecular Weight:	840.257 g/mol

Chemical Formula: C37H41K2N5O9PdS
Molecular Weight: 916.43

cas 698393-30-5

WST11; WST-11; WST 11; Stakel; padeliporfin; palladiumbacteriopheophorbide monolysine taurine.

Tookad : EPAR -Product Information

Tookad : EPAR – Summary for the public

(English only)

29/11/2017

Product details

Pharmacotherapeutic group

Antineoplastic agents

Therapeutic indication

Tookad is indicated as monotherapy for adult patients with previously untreated, unilateral, low risk, adenocarcinoma of the prostate with a life expectancy ≥ 10 years and:

Clinical stage T1c or T2a;
Gleason Score ≤ 6, based on high-resolution biopsy strategies;
PSA ≤ 10 ng/mL;
3 positive cancer cores with a maximum cancer core length of 5 mm in any one core or 1-2 positive cancer cores with ≥ 50 % cancer involvement in any one core or a PSA density ≥ 0.15 ng/mL/cm³.

Name	Tookad
Agency product number	EMEA/H/C/004182
Active substance	padeliporfin di-potassium
International non-proprietary name(INN) or common name	padeliporfin
Therapeutic area	Prostatic Neoplasms
Anatomical therapeutic chemical (ATC) code	L01XD07
Additional monitoring	This medicine is under additional monitoring. This means that it is being monitored even more intensively than other medicines. For more information, see medicines under additional monitoring.

Marketing-authorisation holder	STEBA Biotech S.A
Revision	0
Date of issue of marketing authorisation valid throughout the European Union	10/11/2017

Contact address:

STEBA Biotech S.A
7 place du theatre
L-2613 Luxembourg
Luxembourg

Padeliporfin is a vascular-acting photosensitizer consisting of a water-soluble, palladium-substituted bacteriochlorophyll derivative with potential antineoplastic activity. Upon administration, paldeliporfin is activated locally when the tumor bed is exposed to low-power laser light; reactive oxygen species (ROS) are formed upon activation and ROS-mediated necrosis may occur at the site of interaction between the photosensitizer, light and oxygen. Vascular-targeted photodynamic therapy (VTP) with padeliporfin may allow tumor-site specific cytotoxicity while sparing adjacent normal tissues.

WST-11 (Stakel) is a water-soluble bacteriochlorophyll (chemical structure shown below) derivative coordinated with palldium, which has maximum absorption wavelength in the near infrared (753 nm) and rapid clearance from the body ( t 1/2 = 0.37 hour for a 10-mg/kg drug dose in the rat and t 1/2 = 0.51 hour, 1 hour, and 2.65 hours for 1.25-, 2.5-, and 5-mg/kg drug doses, respectively. It binds to serum albumin and has potent antivascular activity through the generation of hydroxyl radicals when stimulated by the proper light wavelength.

Image result for PADELIPORFIN

Photodynamic therapy (PDT) is a non-surgical treatment of tumors in which non-toxic drugs and non-hazardous photosensitizing irradiation are combined to generate cytotoxic reactive oxygen species in situ. This technique is more selective than the commonly used tumor chemotherapy and radiotherapy. To date, porphyrins have been employed as the primary photosensitizing agents in clinics. However, current sensitizers suffer from several deficiencies that limit their application, including mainly: (1) relatively weak absorption in the visible spectral range which limits the treatment to shallow tumors; (2) accumulation and long retention of the sensitizer in the patient skin, leading to prolonged (days to months) skin phototoxicity; and (3) small or even no differentiation between the PDT effect on illuminated tumor and non-tumor tissues. The drawbacks of current drugs inspired an extensive search for long wavelength absorbing second-generation sensitizers that exhibit better differentiation between their retention in tumor cells and skin or other normal tissues.

In order to optimize the performance of the porphyrin drugs in therapeutics and diagnostics, several porphyrin derivatives have been proposed in which, for example, there is a central metal atom (other than Mg) complexed to the four pyrrole rings, and/or the peripheral substituents of the pyrrole rings are modified and/or the macrocycle is dihydrogenated to chlorophyll derivatives (chlorins) or tetrahydrogenated to bacteriochlorophyll derivatives (bacteriochlorins).

Due to their intense absorption in favorable spectral regions (650-850 nm) and their ready degradation after treatment, chlorophyll and bacteriochlorophyll derivatives have been identified as excellent sensitizers for PDT of tumors and to have superior properties in comparison to porphyrins, but they are less readily available and more difficult to handle.

Bacteriochlorophylls are of potential advantage compared to the chlorophylls because they show intense near-infrared bands, i.e. at considerably longer wavelengths than chlorophyll derivatives.

The spectra, photophysics, and photochemistry of native bacteriochlorophylls (Bchls) have made them optimal light-harvesting molecules with clear advantages over other sensitizers presently used in PDT. In particular, these molecules have a very high extinction coefficient at long wavelengths (λ_max=760-780 nm, ε=(4-10)xl0⁴ M^-1cm^-1), where light penetrates deeply into tissues. They also generate reactive oxygen species (ROS) at a high quantum yield (depending on the central metal).

Under normal delivery conditions, i.e. in the presence of oxygen at room temperature and under normal light conditions, the BChl moieties are labile and have somewhat lower quantum yields for triplet state formation, when compared with, e.g., hematoporphyrin derivative (HPD). However, their possible initiation of biological redox reactions, favorable spectral characteristics and their ready degradation in vivo result in the potential superiority of bacteriochlorophylls over other compounds, e.g. porphyrins and chlorophylls, for PDT therapy and diagnostics and for killing of cells, viruses and bacteria in samples and in living tissue. Chemical modification of bacteriochlorophylls is expected to further improve their properties, but this has been very limited due to lack of suitable methods for the preparation of such modified bacteriochlorophylls .

The biological uptake and PDT efficacy of metal-free derivatives of Bchl have been studied with the objective to manipulate the affinity of the sensitizers to the tumor cellular compartment. Cardinal to this approach is the use of highly lipophilic drugs that may increase the accumulation of the drug in the tumor cells, but also renders its delivery difficult. In addition, the reported biodistribution shows significant phototoxic drug levels in non-tumor tissues over prolonged periods (at least days) after administering the drug.

In applicant’s previous Israel Patent No. 102645 and corresponding EP 0584552, US 5,726,169, US 5,726,169, US 5,955,585 and US 6,147,195, a different approach was taken by the inventors. Highly efficient anti- vascular sensitizers that do not extravasate from the circulation after administration and have short lifetime in the blood were studied. It was expected that the inherent difference between vessels of normal and abnormal tissues such as tumors or other tissues that rely on neovessels, would enable relatively selective destruction of the abnormal tissue. Hence, it was aimed to synthesize Bchl derivatives that are more polar and, hence, have better chance to stay in the vascular compartment, where they convey the primary photodynamic effect. To this end, the geranylgeranyl residue at the C-17 position of Bchl a (Compound 1, depicted in Scheme 1 herein) has been replaced by various residues such as amino acids, peptides, or proteins, which enhance the sensitizer hydrophilicity. One particular derivative, Bchl-Ser (Scheme 1, Compound 1, wherein R is seryl), was found to be water-soluble and highly phototoxic in cell cultures. Following infraperitoneal injection, the Bchl-Ser cleared from the mouse blood and tissues bi-exponentially in a relatively short time (t_1/2~2 and 16 h, respectively). Clearance from the circulation was even faster following intravenous injection. Under the selected treatment protocol (light application within minutes after drug injection), phototoxicity was predominantly conferred to the tumor vasculature (Rosenbach-

Belkin et al., 1996; Zilberstein et al., 2001 and 1997). However, unfortunately, like native Bchl, the Bchl-Ser derivative undergoes rapid photo-oxidation, forming the corresponding 2-desvinyl-2-acetyl-chlorophyllide ester and other products.

To increase the stability of the Bchl derivatives, the central Mg atom was replaced by Pd in the later applicant’s PCT Publication WO 00/33833 and US 6,569,846. This heavy atom was previously shown to markedly increase the oxidation potential of the Bchl macrocycle and, at the same time, to greatly enhance the intersystem-crossing (ISC) rate of the molecule to its triplet state. The metal replacement was performed by direct incorporation of Pd²⁺ ion into a Bpheid molecule, as described in WO 00/33833. Based on the pigment biodistribution and pharmacokinetics, it was assumed that the derivative Pd-Bpheid remained in the circulation for a very short time with practically no extravasation to other tissues, and is therefore a good candidate for vascular-targeting PDT that avoids skin phototoxicity. The treatment effect on the blood vessels was demonstrated by intravital microscopy of treated blood vessels and staining with Evans-Blue. Using a treatment protocol with a minimal drug-to-light interval, Pd-Bpheid (also designated Tookad) was found to be effective in the eradication of different tumors in mice, rats and other animal models and is presently entering Phase I/II clinical trials in patients with prostate cancer that failed radiation therapy (Chen et al, 2002; Schreiber et al., 2002; Koudinova et al., 2003).

Because of its low solubility in aqueous solutions, the clinical use of Pd-Bpheid requires the use of solubilizing agents such as Cremophor that may cause side effects at high doses. It would be highly desirable to render the Pd-Bpheid water-soluble while retaining its physico-chemical properties. Alternatively, it would be desirable to prepare Bchl derivatives that are cytophototoxic and, at the same time, more water-soluble than Pd-Bpheid itself. Such water solubility is expected to further enhance the drug retention in the circulation and, thereby, the aforementioned selectivity. In addition, having no need to use carriers such as detergents or lyposomes, may prevent side effects.

SYNTHESIS

START FROM CAS 17499-98-8, Phorbine, magnesium deriv., Bacteriochlorophyll a_P

PADELIPORFIN

Paper

Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: Synthesis, solubility, phototoxicity and the effect of serum proteins
Photochemistry and Photobiology (2005), 81, (July/Aug.), 983-993

PAPER

Journal of Medicinal Chemistry (2014), 57(1), 223-237

With the knowledge that the dominant photodynamic therapy (PDT) mechanism of 1a (WST09) switched from type 2 to type 1 for 1b (WST11) upon taurine-driven E-ring opening, we hypothesized that taurine-driven E-ring opening of bacteriochlorophyll derivatives and net-charge variations would modulate reactive oxygen species (ROS) photogeneration. Eight bacteriochlorophyll a derivatives were synthesized with varying charges that either contained the E ring (2a–5a) or were synthesized by taurine-driven E-ring opening (2b–5b). Time-dependent density functional theory (TDDFT) modeling showed that all derivatives would be type 2 PDT-active, and ROS-activated fluorescent probes were used to investigate the photogeneration of a combination of type 1 and type 2 PDT ROS in organic- and aqueous-based solutions. These investigations validated our predictive modeling calculations and showed that taurine-driven E-ring opening and increasing negative charge generally enhanced ROS photogeneration in aqueous solutions. We propose that these structure–activity relationships may provide simple strategies for designing bacteriochlorins that efficiently generate ROS upon photoirradiation.

Modulation of Reactive Oxygen Species Photogeneration of Bacteriopheophorbide a Derivatives by Exocyclic E-Ring Opening and Charge Modifications

Áron Roxin†‡, Juan Chen‡, Andrew S. Paton§, Timothy P. Bender§, and Gang Zheng*†‡

^† Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario M5S 3M2, Canada

^‡ Ontario Cancer Institute and Techna Institute, UHN, 101 College Street, Toronto, Ontario M5G 1L7, Canada

^§ Department of Chemical Engineering and Applied Chemistry, University of Toronto, 200 College Street, Toronto, Ontario M5S 3E5, Canada

J. Med. Chem., 2014, 57 (1), pp 223–237

DOI: 10.1021/jm401538h

*Tel: 416-581-7666. Fax 416-581-7667. E-mail: gzheng@uhnresearch.ca.

Palladium 3¹-Oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 13′-(2-Sulfethyl)amide (1b)

……………… The dried crude product was dissolved in 200 μL of DMSO and purified by reverse-phase HPLC. The product was quantified spectrophotometrically, the identity was characterized using ESI+MS and UV–vis spectroscopy, and the purity was found to be >95% using HPLC–MS. This yielded 0.21 mg (250 nmol) of 1b(0.7% yield). ESI+MS: [M]⁺ = 840 m/z. UV–vis (MeOH, λ_max): 748, 517, 385, 332 nm.

PATENT

WO 2004045492

CHEMICAL EXAMPLES

Example 1. Palladium 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide dipotassium salt ( Compound 4)

Nine hundred and thirty five (935) mg of Pd-Bpheid (3) were dissolved in a 1 L round bottom flask with 120 ml of DMSO while stirring under Argon (bubbled in the solution). Taurine (1288 mg) was dissolved in 40 ml of 1M K₂HPO₄ buffer, and the pH of the solution was adjusted to 8.2 (with HCl ). This aqueous solution was added into the DMSO solution while stirring, and the Argon was bubbled in the solution for another 20 minutes. Then the reaction mixture was evaporated at 30°C for 3.5 hours under ~2 mbar and then for another 2 hours at 37°C to a complete dryness. The dry solids were dissolved in 300 ml of MeOH and the colored solution was filtered through cotton wool to get rid of buffer salts and taurine excess.

The progress of the reaction was determined by TLC (R_f of unreacted Pd- Bpheid is 0.8-0.85 and of the reaction (aminolysis) product is 0.08-0.1) and by following the optical absorption spectrum of the reaction mixture after liophylization and resolubihzation in MeOH. The absorption spectrum was characterized by a Q_ytransition shift from 756 nm (for Pd-Bpheid) to 747 nm (for the product 4) and by Q_x shift from 534 nm of Pd-Bpheid to 519 nm (of the product 4). The MeOH was evaporated and the product 4 was purified by HPLC with ODS-A 250X20 S10P μm column (YMC, Japan). Solvent A: 95% 0.005 M phosphate buffer, pH 8.0 and 5% MeOH. Solvent B: 100% MeOH. The dry solid was dissolved in 42 ml of distilled water and injected in portions of 1.5 ml each .

The elution profile is described in Table 1. The product 4_(Scheme 1, see below) was eluted and collected at ~ 9-11 minutes. The main impurities, collected after at 4-7 min (ca 5-10%), corresponded to byproduct(s) with the proposed structure 7. Peaks at 22-25 min (ca 2-5%) possibly corresponded to the iso-form of the main product 4 and untreated Pd-Bpheid residues.

The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified product 4 ]was re-dissolved in ~150 ml MeOH and filtered through cotton wool. The solvent was evaporated again and the solid pigment 4 was stored under Ar in the dark at -20°C. The reaction yield: ~90% (by weight, relative to 3).

The structure of product 4 was confirmed by electrospray mass spectroscopy. (ESI-MS, negative mode, Fig.2), (peaks at 875 (M–K-H), 859 (M–2K-H+Na), 837 (M–2K), 805 (M2K-H-OMe), 719) and 1H-NMR spectrum (Fig. 4 in MeOH-d₄). Table 4 provides the shifts (in ppm units) of the major NMR peaks.

Optical absorption (UN-VIS) spectrum (MeOH): λ, 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50); ε₇₄₇ (MeOH) is 1.2 x 10⁵ mol^-1 cm ^_1.

ΝMR (MeOH-d₄): 9.38 (5-H, s), 8.78 (10-H, s), 8.59 (20-H, s), 5.31 and 4.95 (15¹-CH₂, dd), 4.2-4.4 (7,8,17,18-H, m), 3.88 (15³-Me, s), 3.52 (2¹-Me, s), 3.19 (12¹ -Me, s), 3.09 (3²-Me, s), 1.92-2.41, 1.60-1.75 (17¹, 17²-CH₂, m), 2.19 (8¹-CH₂, m), 1.93 (7¹-Me, d), 1.61 (18¹-Me, d), 1.09 (8²-Me, t), 3.62, 3.05 (CH₂‘s of taurine).

Octanol/water partition ratio is 40:60.

Example 2. Preparation of 3¹-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide dipotassium salt (Compound 5) One hundred and sixty (160) mg of taurine were dissolved in 5 ml of 1M

K₂HPO₄ buffer, and the pH of the solution was adjusted to 8.2. This solution was added to 120 mg of compound 2 dissolved in 15 ml of DMSO, and the reaction and following purification were analogous to those described in previous Example.

Absorption spectrum (MeOH): λ, 750 (1.00), 519 (0.30), 354 (1.18) nm.

ESI-MS (-): 734 (M–2K).

ΝMR (MeOH-d₄): 9.31 (5-H, s), 8.88 (10-H, s), 8.69 (20-H, s), 5.45 and 5.25 (15¹-CH₂, dd), 4.35 (7,18-H, m), 4.06 (8,17-H, m), 4.20 and 3.61 (2-CH₂, m of taurine), 3.83 (15³-Me, s), 3.63 (2¹-Me, s), 3.52 (3-CH₂, m oftaurine), 3.33 (12¹-Me, s), 3.23 (3²-Me, s), 2.47 and 2.16 (17¹-CH₂, m), 2.32 and 2.16 (8¹-CH₂, m), 2.12 and 1.65 (17²-CH₂, m), 1.91 (7¹-Me, d), 1.66 (18¹– Me, d), 1.07 (8²-Me, t).

Octanol/water partition ratio is 60:40.

Example 3. Preparation of copper(II) 3¹-oxo-15-methoxycarbonylmethyl- Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide dipotassium salt (Compound 10)

Fifty (50) mg of compound 5 of Example 2 and 35 mg of copper (II) acetate were dissolved in 40 ml of methanol, and argon was bubbled into solution for 10 minutes. Then 500 mg of palmitoyl ascorbate was added, and the solution was stirred for 30 min. The absorption spectrum was characterized by a Q_y transition shift from 750 nm (for 5) to 768 nm (for the product 10) and by Q_x shift from 519 nm of 5 to 537 nm (of the product 10). Then the reaction mixture was evaporated, re-dissolved in acetone and filtered through cotton wool to get rid of acetate salt excess. The acetone was evaporated and the product was additionally purified by HPLC at the conditions mentioned above with the elution profile, described in Table 2.

The solvent (aqueous methanol) was evaporated under reduced pressure. Then, the purified pigment 10 was re-dissolved in methanol and filtered through cotton wool. The solvent was evaporated again and the solid pigment 10 was stored under Ar in the dark at -20°C. Reaction yield: -90%.

Absorption spectrum (MeOH): λ, 768 (1.00), 537 (0.22), 387 (0.71) and 342 (0.79) nm.

ESI-MS (-): 795 (M–2K).

Octanol/water partition ratio is 40:60.

Example 4. Preparation of zinc 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide dipotassium salt (Compound 11)

Zn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (US Patent No. 5,726,169). Final purification was carried out by HPLC in the same conditions as for compound 5 in Example 2 above.

Absorption spectrum (MeOH): λ, 762 (1.00), 558 (0.26), 390 (0.62) and 355 (0.84) nm.

Octanol/water partition ratio is 50:50.

Example 5. Preparation of manganese(III) 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide dipotassium salt (Compound 12)

Mn insertion into compound 5 was carried out with Zn acetate in acetic acid as previously described (WO 97/19081; US 6,333,319) with some modifications. Thus, fifty (50) mg of compound 5 in 10 ml of DMF were stirred with 220 mg of cadmium acetate and heated under argon atmosphere at 110°C about 15 min (Cd-complex formation is monitored by shifting Q_x transition absorption band from 519 to 585 nm in acetone). Then the reaction mixture was cooled and evaporated. The dry residue was re-dissolved in 15 ml of acetone and stirred with manganese (II) chloride to form the Mn(III)-product 12. The product formation is monitored by shifting Q_x transition band from 585 to 600 nm and Q_y transition band from 768 to 828 nm in acetone. The acetone was evaporated and the product 12 was additionally purified by HPLC in the conditions mentioned in Example 2 above with the elution profile described in Table 3 below where the] solvent system consists of: A – 5% aqueous methanol, B -methanol.

The solvent (aqueous methanol) was evaporated under reduced pressure and the solid pigment 12 was stored under Ar in the dark at -20°C.

Absorption spectrum (MeOH): λ, 828 (1.00), 588 (0.32) and 372 (0.80) nm. Octanol/water partition ratio is 5:95.

Example 6. Preparation of palladium bacteriopheophorbide a 17 -(3-sulfo-1-oxy- succinimide)ester sodium salt (Compound 6)

Fifty (50) mg of Pd-Bpheid (compound 2), 80 mg of N-hydroxy- sulfosuccinimide (sulfoNHS) and 65 mg of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) were mixed in 7 ml of dry DMSO for overnight at room temperature. Then the solvent was evacuated under reduced pressure. The dry residue was re-dissolved in chloroform (ca. 50 ml), filtered from insoluble material, and evaporated. The conversion was ab. 95%) (TLC). The product 6 was used later on without further chromatographic purification. ESI-MS (-): 890 (M–Na).

NMR (CDCl₃): 9.19 (5-H, s), 8.49 (10-H, s), 8.46 (20-H, s), 5.82 (13²-H, s), 4.04- 4.38 (7,8,17,18-H, m), 3.85 (13⁴-Me, s), 3.47 (2¹-Me, s), 3.37 (^-Me, s), 3.09 (3²– Me, s), 1.77 (7¹-Me, d), 1.70 (lδ’-Me, d), 1.10 (8²-Me, t), 4.05 (CH₂ of sNHS), 3.45 (CH ofs NHS).

Example 7. Preparation of palladium bacteriopheophorbide a 17³-(3-sulfopropyl) amide potassium salt (Compound 7)

Ten (10) mg of compound 6 in 1 ml of DMSO was mixed with 20 mg of homotaurine (3-amino-1-propane-sulfonic acid) in 1 ml of 0.1 M K-phosphate buffer, pH 8.0 for overnight. Then the reaction mixture was partitioned in chloroform/water. The organic layer was dried over anhydrous sodium sulfate and evaporated. The dry residue was re-dissolved in chloroform-methanol (19:1) and applied to a chromatographic column with silica. The product 7 was obtained with chloroform-methanol (4:1) elution. The yield was about 80-90%.

ESI-MS (-): 834 (M-K) m/z.

NMR (MeOH-d₄): 9.16 (5-H, s), 8.71 (10-H, s), 8.60 (20-H, s), 6.05 (13²-H, s), 4.51, 4.39, 4.11, 3.98 (7,8,17,18-H, all m), 3.92 (13⁴-Me, s), 3.48 (2¹-Me, s), 3.36 (12¹-Me, s), 3.09 (3²-Me, s), 2.02-2.42 (17¹ arid 17²-CH₂, m), 2.15 ( 8¹-CH₂, q), 1.81 (7¹-Me, d), 1.72 (18¹-Me, d), 1.05 (8²-Me, t), 3.04, 2.68, and 2.32 (CH₂‘s of homotaurine, m).

Example 8. Preparation of palladium 3¹-oxo-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 13 ,17 -di(3-sulfopropyl)amide dipotassium salt (Compound 8)

Ten (10) mg of compound 6 or 7 were dissolved in 3 ml of DMSO, mixed with 100 mg of homotaurine in 1 ml of 0.5 M K-phosphate buffer, pH 8.2, and incubated overnight at room temperature. The solvent was then evacuated under reduced pressure as described above, and the product 8 was purified on HPLC. Yield: 83%.

Absorption spectrum (MeOH): 747 (1.00), 516 (0.13), 384 (0.41), 330 (0.50), ε₇₄₇ =1.3×10⁵ modern^-1.

ESI-MS(-):1011 (M–K), 994 (M–2K+Na),972 (M–2K), 775 (M–2K-CO₂Me-homotaurineNHCH₂CH₂CH₂SO₃), 486 ([M-2K]/2)

NMR (MeOH-d₄): 9.35 (5-H, s), 8.75 (10-H, s), 8.60 (20-H, s), 5.28 and 4.98 (15^-1-CH₂, dd), 4.38, 4.32, 4.22, 4.15 (7,8,17,18-H, all m), 3.85 (15^~3-Me, s), 3.51 (2¹-Me, s), 3.18 (12¹-Me, s), 3.10 (3²-Me, s 2.12-2.41 (17¹-CH₂, m), 2.15-2.34 (8¹-CR₂, m), 1.76-2.02 (17²-CH₂, m), 1.89 (7¹-Me, d), 1.61 (lδ^Me, d), 1.07 (8²-Me, t). 3.82, 3.70,

3.20, 3.10, 2.78, 2.32, 1.90 (CH₂‘s of homotaurine at C-13¹ and C-17³)

Example 9. Palladium 3¹-(3-sulfopropylimino)-15-methoxycarbonylmethyl-Rhodo-bacteriochlorin 13¹,17³-di(3-sulfopropyl)amide tripotassium salt (Compound 9)

Compound 9 was obtained from HPLC as a minor product during synthesis of 8.

Absorption spectrum (MeOH): 729 (1.00), 502 (0.10), 380 (0.69), 328 (0.57).

ESI-MS (30.4.2000): 1171 (M-K+H), 1153 (M–2K-H+Na), 1131 (M-2K), 566 ([M-K]/2), 364 ([M-3K]/3).

NMR (MeOH-d₄): 8.71 (1H), 8.63 (1.5H), 8.23 (0.5H) (5-, 10- and 20-H, all-m), 5.30 and 4.88 (15¹-CH₂, dd), 4.43 and 4.25 (7,8,17,18-H, m), 3.85 (15^~3-Me, s), 3.31 (2¹-Me, s), 3.22 (12¹-Me, s), 3.17 (3²-Me, m), 1.89-2.44 (17¹ and 17²-CH₂, m), 2.25 (8¹-CH₂, m), 1.91 (7¹-Me, s), 1.64 (18¹– Me, s), 1.08 (8²-Me, t), 4.12, 3.56, 3.22, 3.16, 2.80 and 2.68 (CH₂‘s of homotaurine).

Example 10. Palladium 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(2-sulfoethyl)amide, 17³-(N-immunoglobulin G)amide potassium salt (Compound 13)

Ten (10) mg of compound 4 were reacted with 20 mg of sulfo-NHS and 15 mg of EDC in 1 ml of dry DMSO for 1 hour at room temperature, then rabbit IgG (0.6 mg) in PBS (2.5 ml) was added, and the mixture was further incubated overnight at room temperature. The mixture was evaporated to dryness, then re-dissolved in 1 ml of PBS and loaded on Sephadex G-25 column equilibrated with PBS. A colored band was eluted with 4-5 ml of PBS. The pigment/protein ratio in the obtained conjugate 13 was determined by optical density at 753 and 280 mn, respectively, and varied between 0.5/1 to 1/1 of pigment 13/protein.

Example 11. Preparation of palladium 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(2-carboxyethyl)amide dipotassium salt (Compound

The preparation and purification of the title compound 14 were carried out as described in Example 2, by reaction of compound 2 with 3-aminopropionic acid (β-alanine) (150 mg) instead of taurine. Yield: 85%.

Example 12. Preparation of palladium 3¹-oxo-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹-(3-phosphopropyl)amide tripotassium salt (Compound

15)

The preparation and purification of the title compound 15 were carried out as described in Example 2, by reaction of compound 2 with 3 -amino- 1-propanephosphonic acid (180 mg) instead of taurine. Yield: 68%.

Example 13. Palladium 3¹-(3-sulfopropylamino)-15-methoxycarbonylmethyl-Rhodobacteriochlorin 13¹,17³-di(3-sulfopropyl)amide tripotassium salt (Compound 16)

For reduction of the imine group in 3¹-(3-sulfopropylimino) to the correspondent 3¹-(3-sulfopropylamino) group, compound 9 (8 mg) was reacted by stirring with sodium cyanoborohydride (15 mg) in 5 ml of methanol overnight at room temperature. Then the reaction mixture was treated with 0.05 M HCl (5 ml), neutralized with 0.01 M KOH, and evaporated. The title product 16 was purified using HPLC conditions as described in Example 2. Yield: 80-90%).

PATENT

US 7947672

REFERENCES

1: Kessel D, Price M. Evaluation of DADB as a Probe for Singlet Oxygen Formation during Photodynamic Therapy. Photochem Photobiol. 2012 Feb 2. doi: 10.1111/j.1751-1097.2012.01106.x. [Epub ahead of print] PubMed PMID: 22296586.

2: Betrouni N, Lopes R, Puech P, Colin P, Mordon S. A model to estimate the outcome of prostate cancer photodynamic therapy with TOOKAD Soluble WST11. Phys Med Biol. 2011 Aug 7;56(15):4771-83. Epub 2011 Jul 13. PubMed PMID: 21753234.

3: Chevalier S, Anidjar M, Scarlata E, Hamel L, Scherz A, Ficheux H, Borenstein N, Fiette L, Elhilali M. Preclinical study of the novel vascular occluding agent, WST11, for photodynamic therapy of the canine prostate. J Urol. 2011 Jul;186(1):302-9. Epub 2011 May 20. PubMed PMID: 21600602.

4: Dandler J, Wilhelm B, Scheer H. Photochemistry of bacteriochlorophylls in human blood plasma: 1. Pigment stability and light-induced modifications of lipoproteins. Photochem Photobiol. 2010 Mar-Apr;86(2):331-41. Epub 2009 Nov 23. PubMed PMID: 19947966.

5: Dandler J, Scheer H. Inhibition of aggregation of [Pd]-bacteriochlorophyllides in mesoporous silica. Langmuir. 2009 Oct 20;25(20):11988-92. PubMed PMID: 19772311.

6: Ashur I, Goldschmidt R, Pinkas I, Salomon Y, Szewczyk G, Sarna T, Scherz A. Photocatalytic generation of oxygen radicals by the water-soluble bacteriochlorophyll derivative WST11, noncovalently bound to serum albumin. J Phys Chem A. 2009 Jul 16;113(28):8027-37. PubMed PMID: 19545111.

7: Moore CM, Pendse D, Emberton M. Photodynamic therapy for prostate cancer–a review of current status and future promise. Nat Clin Pract Urol. 2009 Jan;6(1):18-30. Review. PubMed PMID: 19132003.

8: Preise D, Oren R, Glinert I, Kalchenko V, Jung S, Scherz A, Salomon Y. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol Immunother. 2009 Jan;58(1):71-84. Epub 2008 May 17. PubMed PMID: 18488222.

9: Fleshker S, Preise D, Kalchenko V, Scherz A, Salomon Y. Prompt assessment of WST11-VTP outcome using luciferase transfected tumors enables second treatment and increase in overall therapeutic rate. Photochem Photobiol. 2008 Sep-Oct;84(5):1231-7. Epub 2008 Apr 8. PubMed PMID: 18399928.

10: Berdugo M, Bejjani RA, Valamanesh F, Savoldelli M, Jeanny JC, Blanc D, Ficheux H, Scherz A, Salomon Y, BenEzra D, Behar-Cohen F. Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes. Invest Ophthalmol Vis Sci. 2008 Apr;49(4):1633-44. PubMed PMID: 18385085.

11: Fabre MA, Fuseau E, Ficheux H. Selection of dosing regimen with WST11 by Monte Carlo simulations, using PK data collected after single IV administration in healthy subjects and population PK modeling. J Pharm Sci. 2007 Dec;96(12):3444-56. PubMed PMID: 17854075.

12: Brandis A, Mazor O, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity and the effect of serum proteins. Photochem Photobiol. 2005 Jul-Aug;81(4):983-93. PubMed PMID: 15839743.

13: Mazor O, Brandis A, Plaks V, Neumark E, Rosenbach-Belkin V, Salomon Y, Scherz A. WST11, a novel water-soluble bacteriochlorophyll derivative; cellular uptake, pharmacokinetics, biodistribution and vascular-targeted photodynamic activity using melanoma tumors as a model. Photochem Photobiol. 2005 Mar-Apr;81(2):342-51. PubMed PMID: 15623318.

14: Plaks V, Posen Y, Mazor O, Brandis A, Scherz A, Salomon Y. Homologous adaptation to oxidative stress induced by the photosensitized Pd-bacteriochlorophyll derivative (WST11) in cultured endothelial cells. J Biol Chem. 2004 Oct 29;279(44):45713-20. Epub 2004 Aug 31. PubMed PMID: 15339936.

////////PADELIPORFIN, WST11, WST-11, WST 11, Stakel, padeliporfin, palladiumbacteriopheophorbide monolysine taurine, EU 2017, EMA 2017

CCC1C(C2=NC1=CC3=C(C(=C([N-]3)C(=C4C(C(C(=N4)C=C5C(=C(C(=C2)[N-]5)C(=O)C)C)C)CCC(=O)O)CC(=O)OC)C(=O)NCCS(=O)(=O)O)C)C.[Pd+2]

Forodesine Hydrochloride

Uncategorized Comments Off

Mar 142018

ChemSpider 2D Image | Forodesine | C11H14N4O4

Forodesine

Molecular FormulaC₁₁H₁₄N₄O₄
Average mass266.253 Da

(2R,3R,4S,5S)-2-(hydroxymethyl)-5-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pyrrolidine-3,4-diol

209799-67-7 [RN]

3,4-pyrrolidinediol, 2-(hydroxymethyl)-5-(4-hydroxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-, (2R,3R,4S,5S)-

4H-Pyrrolo[3,2-d]pyrimidin-4-one, 7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-3,5-dihydro-

7-[(2S,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxyméthyl)-2-pyrrolidinyl]-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

Fodosine

immucillin H

(1S)-1-(9-deazahypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol

(1S)-1,4-dideoxy-4-imino-(9-deazahypoxanthin-9-yl)-D-ribitol

1,4-DIDEOXY-4-AZA-1-(S)-(9-DEAZAHYPOXANTHIN-9-YL)-D-RIBITOL

7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-1,5-dihydropyrrolo[2,3-e]pyrimidin-4-one

7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl]-3,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

8574770 [Beilstein]

BCX1777

BCX-1777 freebase

BCX-1777 freebase;Immucillin-H

BCX-1777|BCX1777|Fodosine® (proposed trade name)|immucillin H|immucillin-H

CAS No. : 284490-13-7

Molecular Formula: C11H15ClN4O4

Average Mass: 302.72 g/mol

Forodesine (INN; also known as Immucillin H; trade names Mundesine and Fodosine) is a transition-state analog inhibitor of purine nucleoside phosphorylase^[1] studied for the treatment of patients with T-cell acute lymphoblastic leukemia (T-ALL) and for treatment of B-cell acute lymphocytic leukemia (B-ALL).

Forodesine was originally discovered by Vern Schramm‘s laboratory at the Albert Einstein College of Medicine in New York and Industrial Research Limited in New Zealand.

Forodesine is being developed by BioCryst Pharmaceuticals. As of 2008, it is currently in phase II clinical trials.^[2].

In 2006, BioCryst entered into a licensing agreement with Mundipharma International Holdings Limited to develop and commercialize forodesine in markets across Europe, Asia, and Australasia for use in oncology.^[3]

In April 2017, forodesine was approved in Japan for the treatment of relapsed/refractory peripheral T-cell lymphoma.^[4]

ema

On 20 September 2010, orphan designation (EU/3/10/780) was granted by the European Commission to Mundipharma Research Limited, United Kingdom, for forodesine for the treatment of chronic lymphocytic leukaemia

EU/3/10/780: Public summary of opinion on orphan designation: Forodesine for the treatment of chronic lymphocytic leukaemia

Active substance	Forodesine hydrochloride
Decision number	P/69/2010
PIP number	EMEA-000785-PIP01-09
Pharmaceutical form(s)	Hard capsule
Condition(s)/indication(s)	Cutaneous T-cell lymphoma (CTCL)
Route(s) of administration	Oral use
PIP applicant	Applicant: Mundipharma Research Ltd E-mail: paediatric@mundipharma-rd.eu Country: United Kingdom Phone: +44 1223424900 Fax: +44 1223426054
Decision type	W: decision granting a waiver in all age groups for the listed condition(s)

P/69/2010: European Medicines Agency decision on the granting of a product specific waiver for forodesine hydrochloride (EMEA-000785-PIP01-09)

What is chronic lymphocytic leukaemia?

Chronic lymphocytic leukaemia (CLL) is cancer of a type of white blood cell called B lymphocytes. In this disease, the lymphocytes multiply too quickly and live for too long, so that there are too many of them circulating in the blood. The cancerous lymphocytes look normal, but they are not fully developed and do not work properly. Over a period of time, the abnormal cells replace the normal white blood cells, red blood cells and platelets (components that help the blood to clot) in the bone marrow (the spongy tissue inside the large bones in the body). CLL is the most common type of leukaemia and mainly affects older people. It is rare in people under the age of 40 years. CLL is a long-term debilitating and life-threatening disease because some patients develop severe infections. What is the estimated number of patients affected by the condition? At the time of designation, CLL affected approximately 3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 152,000 people, and is below the threshold for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

What treatments are available? Treatment for CLL is complex and depends on a number of factors, including the extent of the disease, whether it has been treated before, and the patient’s age, symptoms and general state of health. Patients whose CLL is not causing any symptoms or is only getting worse very slowly may not need

Forodesine Hydrochloride was originally developed by BioCryst Pharmaceuticals and then licensed to Mundipharma and in particular is marketed in Japan under the trade name Mundesine®. Forodesine Hydrochloride is a transitional analogue inhibitor of purine nucleoside phosphorylase (PNP). Mundesine® is approved for the treatment of peripheral T-cell lymphoma (PTCL).

Mundesine® is a capsule that contains 100mg of free Forodesine per capsule. The recommended dose is 300mg orally, twice daily.

In 2004, the compound was eligible for orphan drug treatment for non-Hodgkin’s lymphoma (NHL), chronic myelogenous leukemia (CLL) and hairy cell leukemia, respectively. In 2007, the compound was eligible for the EU orphan drug for the treatment of acute lymphoblastic leukemia (ALL) and cutaneous T-cell lymphoma (CTCL). In 2010, the compound was eligible for EU orphan drug for treatment of CLL. In 2006, the compound obtained Japanese orphan drug eligibility for CTCL treatment.

Forodesine, or 7-[(2S,3S,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-pyrrolidinyl]-l,5-dihydropyrrolo[2,3-e]pyrimidin-4-one, is an inhibitor of purine nucleoside phosphorylase. It is currently in development as a treatment for peripheral T-Cell Lymphoma .

W099/19338 describes a compound genus as a new class of inhibitors of nucleoside metabolism, including Forodesine. The compounds effect as inhibitors of purine nucleoside phosphorylase is taught as efficacious to suppress T-cell function and to treat infections caused by protozoan parasites.

WO00/61783 describes a number of processes for preparing molecules described in W099/19338. Reaction scheme 3 on page 23 of the published application describes a synthesis of Forodesine, characterised by the removal of two acid labile protecting groups in the final step to yield the hydrochloride salt.

Forodesine is a particularly difficult molecule to make on a commercial scale. The current process for manufacture requires a coupling reaction under cryogenic temperature conditions of -55C. Subsequent steps involve the use of a high pressure hydrogenation reaction. Such extreme reaction conditions provide for safety concerns, particularly when conducted on a bulk scale. Further the products of the reaction were extremely challenging to purify. The effect of all this is to require more sophisticated and expensive equipment at the manufacturing plant; all of which add up to an increased cost of goods for patients. Accordingly a new manufacturing process was sought.

Surprisingly a new route has been invented which is shorter, cheaper, less dangerous and provides an increased overall yield whilst still conforming to the required purity profile.

The current manufacturing process is described in Fig 1.

, MeOH, reflux xchange

tallisation

Fig l

Within the diagram, the following acronyms are used, wherein NCS is N-Chlorosuccinimide, OTBDMS is t-butyldimethylsiloxy protecting group, MtBE is methyl t-butyl ether, (BOC)₂0 is di-t-butyldicarbonate and BOC is t-butyloxycarbonyl protecting group,

Particularly problematic in this process is the requirement to conduct the coupling of process step (iii) at exceptionally low temperature. Further challenges are provided by process step (v) the hydrogenation reaction to remove the benxylyoxymethyl (BOM) protecting group, before removing the other acid labile protecting groups.

Conducting hydrogenation reactions with their need for a high pressure environment requires specialist equipment. Such apparatus is expensive, adding to the cost of the materials produced. Despite the use of specialist equipment, safety concerns can never be eradicated. Whilst BOM can, in certain circumstances, be acid labile, treatment of analogues of the molecules described in Fig 1 with acid has always resulted in incomplete removal of the protecting group, leading to a large number of partially deprotected impurities. This makes purification exceptionally difficult as well as reducing the overall yield for the step.

A new improved process has been developed as described in Fig 2:

Toluene

Fig 2

The new route has a number of clear advantages. The coupling reaction (ix) is conducted at a warmer -15°C, rather than the challenging cryogenic conditions of -55°C required previously. It eradicates the hydrogenation step, avoiding the need for dangerous high pressure conditions. It also makes the overall process much quicker and cheaper; not only are the conditions challenging, but the reagents used in large quantities such as palladium are expensive and environmentally challenging.

The classical method to remove a BOM protecting group is by catalytic hydrogenation. It is however known to be unstable in acid conditions. For this reasons there have been previous attempts to remove BOM at the same time as the three acid labile protecting groups. This has always been unsuccessful as treatment with acid typically resulted in incomplete deprotection, leading to a mixture of products. This made for a tricky purification and a reduced yield. Surprisingly under the particular conditions described herein it has been possible to effect the transformation in greater yield and without a difficult purification. The final product is obtained in equal or greater purity than material obtained from the previous route.

PATENT

WO2013158746A1 *

Scheme 13

HO _OH 1 . HCI/Acetone, MeOH OCH,

2. PPh₃, imidazole I

HO (EtO)₂POCH₂CN

OH O O

Ribose Λ 13a

References for preparation of compound 13a:

1. Mishra, Girija Prasad; Rao, Batchu Venkateswara; Tetrahedron: Asymmetry (2011), 22(7), 812-817.

2. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson,

James E; Organic Letters (2011), 13(7), 1594-1597.

3. WO 2010/085377 A2 (incorporated by reference).

4. Yadav, J. S.; Reddy, P. Narayana; Reddy, B. V. Subba; Synlett (2010), (3), 457- 461.

5. Song, Kai; Zheng, Guo-jun; Huaxue Shiji (2010), 32(2), 171-172.

6. Prabhakar, Peddikotla; Rajaram, Singanaboina; Reddy, Dorigondla Kumar;

Shekar, Vanam; Venkateswarlu, Yenamandra; Tetrahedron: Asymmetry (2010), 21(2), 216-221.

7. CN 101182342 A.

8. Baird, Lynton J.; Timmer, Mattie S. M.; Teesdale-Spittle, Paul H.; Harvey, Joanne

E; Journal of Organic Chemistry (2009), 74(6), 2271-2277.

9. Wang, Xiang-cheng; Wang, Gang; Qu, Gang-lian; Huaxue Shijie (2008), 49(4), 226-228.

10. Ivanova, N. A.; Valiullina, Z. R.; Shitikova, O. V.; Miftakhov, M. S; Russian

Journal of Organic Chemistry (2007), 43(5), 742-746.

11. Braga, Fernanda Gambogi; Coimbra, Elaine Soares; Matos, Magnum de Oliveira;

Lino Carmo, Arturene Maria; Cancio, Marisa Damato; da Silva, Adilson David; European Journal of Medicinal Chemistry (2007), 42(4), 530-537.

12. Wender, Paul A.; Bi, F. Christopher; Buschmann, Nicole; Gosselin, Francis; Kan, Cindy; Kee, Jung-Min; Ohmura, Hirofumi; Organic Letters (2006), 8(23), 5373- 5376.

13. Fei, Xiangshu; Wang, Ji-Quan; Miller, Kathy D.; Sledge, George W.; Hutchins, Gary D.; Zheng, Qi-Huang; Nuclear Medicine and Biology (2004), 31(8), 1033- 1041.

14. Abdel-Rahman, Adel A.-H.; Abdel-Megied, Ahmed E.-S.; Goda, Adel E.-S.; Zeid,

Ibrahim F.; El Ashry, El Sayed H; Nucleosides, Nucleotides & Nucleic Acids (2003), 22(11), 2027-2038.

15. Palmer, Andreas M.; Jager, Volker; European Journal of Organic Chemistry

(2001), (7), 1293-1308.

16. Paquette, Leo A.; Bailey, Simon; Journal of Organic Chemistry (1995), 60(24),

7849-56.

17. Classon, Bjoern; Liu, Zhengchun; Samuelsson, Bertil; Journal of Organic

Chemistry (1988), 53(26), 6126-30.

18. Kissman, Henry M.; Baker, B. R; Journal of the American Chemical Society

(1957), 79 5534-40.

References for cyclizations related to preparation of compounds of type 13d:

1. Davies, Stephen G.; Durbin, Matthew J.; Goddard, Euan C; Kelly, Peter M.;

Kurosawa, Wataru; Lee, James A.; Nicholson, Rebecca L.; Price, Paul D.;

Roberts, Paul M.; Russell, Angela J.; Scott, Philip M.; Smith, Andrew D; Organic & Biomolecular Chemistry (2009), 7(4), 761-776.

2. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul M.;

Russell, Angela J.; Savory, Edward D.; Smith, Andrew D.; Thomson, James E; Tetrahedron: Asymmetry (2009), 20(6-8), 758-772.

3. Davies, Stephen G.; Nicholson, Rebecca L.; Price, Paul D.; Roberts, Paul. M.;

Smith, Andrew D; Synlett (2004), (5), 901-903.

4. Brock, E. Anne; Davies, Stephen G.; Lee, James A.; Roberts, Paul M.; Thomson, James E; Organic Letters (2011), 13(7), 1594-1597.

5. Gary B. Evans, Richard H. Furneaux, Andrzej Lewandowicz, Vern L. Schramm, and Peter C. Tyler, Journal of Medicinal Chemistry (2003), 46, 3412-3423.

PATENT

WO 2016110527

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016110527

The invention also provides for the synthesis of a compound of formula (II)

By reacting a compound of Formula (VII)

With di-t-butyldicarbonate.

Preferably the reaction is conducted at -10 to -20°C, in methyl t-butyl ether & heptane

The invention also provides for the synthesis of a compound of formula (VII)

By reacting a compound of Formula (IV)

With a suitable base to form

Before reacting with a compound of Formula (III)

Example 1

Stage 1 Manufacture of (III)

Compound of formula (III) (approx. 130g) in toluene solution is added to a suspension of N-Chlorosuccinimide in toluene at 20°C over a period of 90min. The reaction mixture is stirred at 20°C for 1 hour then chilled to 0°C and stirred for a further hour. The precipitated succinimide by-product is removed by filtration and the filtered solution charged directly to a 45% potassium hydroxide solution (aq) containing

tetrabutylammonium bromide. The reaction mixture is stirred at 0°C and completion of reaction is confirmed by GC analysis. Water is then added to the two-phase mixture to dissolve inorganic precipitates and the toluene product solution is washed with a 28% ammonium hydroxide/acetic acid buffer mixture with sodium chloride added. After phase separation the organic phase solution is stabilised with triethylamine. Magnesium sulfate is added to dry the solution. After filtration, the yield of (III) is determined by R.O.E. and GC purity.

Stage 2 Manufacture of (II)

Stage 2a Lithiation

A suspension of compound of formula (IV) (approx. 200g) in MtBE is chilled to -15°C and treated with /7-Hexyl lithium (2.5M in hexanes) added over 2h, maintaining the reaction mixture at -15°C. The mixture is then stirred for 3h at -15°C.

Stage 2b Coupling with (IV)

After lithiation is complete, a compound formula (III) in toluene solution is added to the reaction mixture maintaining the contents at -15°C. The reaction mixture is then stirred at this temperature for 1.5h.

Stage 2c Boc anhydride quench

A solution of di-t-butyldicarbonate in MtBE is added to the above reaction mixture at -15°C. The solution is stirred for a further 30min.

Workup and Purification

The reaction mixture is quenched by addition of RO water, then filtered. The aqueous layer is separated and run to waste. The organic layer is again washed with water. The organic layer is concentrated to a low volume and solvent replaced by heptane. The mix is stirred for 16h and filtered again.

The solution is passed through a silica gel column and eluted with heptane. The resulting solution is treated with charcoal – stirred for 3h, then filtered. The product (II) is progressed as a solution in heptane to the next stage.

Stage 3 Manufacture of Crude Forodesine (la)

Stage 3 Deprotection with cone. HCI

Concentrated hydrochloric acid is added to (II) in heptane and the mixture stirred. The acid phase is separated off and stirred for 16h at ambient temperature. The solution is then heated to 40°C for 6h. The water is then distilled off under reduced pressure to a minimum volume.

Ethanol is then added to precipitate the crude Forodesine (la) which is isolated by filtration after cooling 0-5°C. It is washed with ethanol and dried in a vacuum oven at 75°C to a constant weight.

Stage 4a Decolourization of crude Forodesine (la) using Ion-Exchange Column

Crude Forodesine (la) is dissolved in water and loaded onto a freshly prepared ion-exchange column containing Dowex 50WX4 resin in the Na⁺ form activated with 30% sodium hydroxide solution. The ion-exchange column is eluted with 4 x lOOmL water followed by 4 x lOOmL 2M HCI. The HCI fractions are collected separately as they contain the desired product. The 2M HCI fractions are combined and concentrated under vacuum with minimum RO water added to dissolve the residue. 1,4-Dioxane is added to the aqueous solution to precipitate the product. The mixture is stirred at 20°C for 1.5h. The product is filtered, washed with 1,4-dioxane and dried in a vacuum oven at 35°C to a constant weight to give decolourised BCX1777.

Stage 4b Recrystallization of Forodesine

Decolourised Forodesine is added to in 0.6M dilute hydrochloric acid and heated to 45°C to dissolve. The resulting solution is hot filtered and washed through with some RO Water. The solution is cooled to 20°C and ethanol added over at least lh. The mixture is then seeded with Forodesine HCI. The resulting slurry is stirred for 8h at 20°C, then cooled to 2°C for a further 1.5h. The product is isolated by filtration, washed twice with cold ethanol then dried in a vacuum oven at 75°C to a constant weight to give a white crystalline Forodesine HCI (approx. 50g).

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one of skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Moreover, all embodiments described herein are considered to be broadly applicable and combinable with any and all other consistent embodiments, as appropriate.

PAPER

Journal of Medicinal Chemistry (2009), 52(4), 1126-1143.

Third-Generation Immucillins: Syntheses and Bioactivities of Acyclic Immucillin Inhibitors of Human Purine Nucleoside Phosphorylase

Carbohydrate Chemistry Team, Industrial Research Limited, P.O. Box 31310, Lower Hutt 5040, New Zealand, Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461

J. Med. Chem., 2009, 52 (4), pp 1126–1143

DOI: 10.1021/jm801421q

Publication Date (Web): January 26, 2009

* To whom correspondence should be addressed. Phone: +64-4-9313040. Fax: +64-4-9313055. E-mail: g.evans@irl.cri.nz., †

Carbohydrate Chemistry Team, Industrial Research Limited.

, ‡

Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University.

Abstract Image

References

Jump up^ Kicska GA, Long L, Hörig H, et al. (April 2001). “Immucillin H, a powerful transition-state analog inhibitor of purine nucleoside phosphorylase, selectively inhibits human T lymphocytes”. Proc. Natl. Acad. Sci. U.S.A. 98 (8): 4593–8. Bibcode:2001PNAS…98.4593K. doi:10.1073/pnas.071050798. PMC 31879 . PMID 11287638.
Jump up^ “Complete list of clinical trials for forodesine (BCX-1777) (ClinicalTrials.gov)”. Retrieved 2008-07-22.
Jump up^ “Biocryst Initiates Pivotal Fodosine Phase IIb Clinical Trial In Patients With Relapsed/Refractory T-Lymphoblastic Leukemia/Lymphoma”(Press release). January 16, 2007.
Jump up^ “BioCryst Announces Mundipharma Receives Approval for Mundesine^® in Japan” (Press release). April 3, 2017.

External links

“From cell biology to therapy: forodesine”. Hematology Meeting Reports. 2 (5): 106–111. 2008.
Gore, L; Stelljes, M; Quinones, R (2007). “Forodesine treatment and post-transplant graft-versus-host disease in two patients with acute leukemia: Facilitation of graft-versus-leukemia effect?”. Seminars in Oncology. 34 (6 Suppl 5): S35–9. doi:10.1053/j.seminoncol.2007.11.005. PMID 18086346.
18 December 2006 Fodosine orphan designation by the European Commission for acute lymphoblastic leukaemia.
BioCryst Pharmaceuticals, Inc. have entered into an exclusive license agreement with Mundipharma for develop and commercialize BioCryst’s lead compound, Forodesine.
Birmingham, Alabama – February 2, 2006 Mundipharma will obtain rights in markets across Europe, Asia and Australasia to Forodesine™ in the field of oncology in exchange for a $10 million up-front payment. Furthermore, Mundipharma will commit up to an additional $15 million to assist in the evaluation of Forodesine’s™ therapeutic safety and efficacy profile. BioCryst may also receive future event payments totalling $155 million in addition to royalties on product sales of Forodesine™ by Mundipharma.
News BioCryst provides Fodosine update March 27, 2007. “Voluntarily Placed on Hold by BioCryst (…) we don’t think the final response rate will be as high as 18%”.
The European Commission granted a marketing authorisation valid throughout the European Union for Atriance on 22 August 2007 for acute lymphoblastic leukaemia. What benefit has Atriance shown during the studies? Atriance was shown to be effective in a proportion of the patients in both studies. In the first study, among the 39 children and young adults who se cancer had not responded to two or more previous treatments, five (13%) had a complete response to treatment after a month, with no evidence of disease and normal blood counts. In the second study, among the 28 adults and adolescents with cancer that had not responded to two or more previous tre atments, five (18%) had a complete response to treatment. In both studies, more patients had a partial response to Atriance treatment, with blood counts returning towards normal levels.
Lino Berton collects all the information on Forodesine in www.linoberton.com site, putting them in a row. In 2014 he published the book Qualcosa che non muore where he tells his incredible experience in the closed trial early in 2007.
Il Giornale.it (in Italian). “Come si boicotta un farmaco che funziona”. Dated 08-01-2016.

Forodesine
Clinical data

Trade names	Mundesine and Fodosine
Routes of administration	oral
Identifiers
IUPAC name [show]
CAS Number	209799-67-7
PubChem CID	444499
ChemSpider	392417
UNII	426X066ELK
KEGG	D06596
ChEMBL	CHEMBL218291
Chemical and physical data
Formula	C₁₁H₁₄N₄O₄
Molar mass	266.26 g·mol⁻¹
3D model (JSmol)	Interactive image

/////////Forodesine Hydrochloride, Forodesine, BCX 1777, Immucillin-H, FOSODINE, JAPAN 2017

Elobixibat hydrate, エロビキシバット水和物

Uncategorized Comments Off

Mar 142018

ChemSpider 2D Image | Elobixibat | C36H45N3O7S2

Elobixibat

Molecular FormulaC₃₆H₄₅N₃O₇S₂
Average mass695.888 Da

CAS 439087-18-0 [RN]

A3309

AZD7806

Glycine, N-[(2R)-2-[[2-[[3,3-dibutyl-2,3,4,5-tetrahydro-7-(methylthio)-1,1-dioxido-5-phenyl-1,5-benzothiazepin-8-yl]oxy]acetyl]amino]-2-phenylacetyl]-

N-{(2R)-2-[({[3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylacetyl}glycine

A-3309
AJG-533
AZD-7806

A-3309; AJG-533; Goofice

Elobixibat hydrate

Approved 2018/1/19 Japan pmda

TRADE NAME Goofice to EA Pharma

エロビキシバット水和物

C₃₆H₄₅N₃O₇S₂▪H₂O : 713.9
[1633824-78-8] CAS OF HYDRATE

Image result for Goofice

Gooffice ® tablet 5 mg (hereinafter referred to as Gooffice ® ) is an oral chronic constipation remedy drug containing as active ingredient Erobi vat having bile acid transporter inhibitory action. It is the world’s first bile acid transporter inhibitor.

Elobixibat is an inhibitor of the ileal bile acid transporter (IBAT),^[1] undergoing development in clinical trials for the treatment of chronic constipation and irritable bowel syndrome with constipation (IBS-C).

Mechanism of action

IBAT is the bile acid:sodium symporter responsible for the reuptake of bile acids in the ileum which is the initial step in the enterohepatic circulation. By inhibiting the uptake of bile acids, elobixibat increases the bile acid concentration in the gut, and this accelerates intestinal passage and softens the stool. Following several phase II studies, it is now undergoing phase III trials.^[2]

Drug development

The drug was developed by Albireo AB, who licensed it to Ferring Pharmaceuticals for further development and marketing.^[3] Albireo has partnered with Ajinomoto Pharmaceuticals, giving the Japan-based company the rights to further develop the drug and market it throughout Asia.^[4]

OriginatorAstraZeneca
DeveloperAlbireo Pharma; EA Pharma
Class2 ring heterocyclic compounds; Amides; Carboxylic acids; Laxatives; Small molecules; Sulfides; Sulfones; Thiazepines
Mechanism of ActionSodium-bile acid cotransporter-inhibitors

Orphan Drug StatusNo
New Molecular EntityYes

Highest Development Phases

RegisteredConstipation
DiscontinuedDyslipidaemias; Irritable bowel syndrome

Most Recent Events

Approved 2018/1/19 japan pmda

24 Jan 2018Elobixibat is still in phase II trials for Constipation in Indonesia, South Korea, Taiwan, Thailand and Vietnam (Albireo pipeline, January 2018)
24 Jan 2018Discontinued – Phase-II for Irritable bowel syndrome in USA and Europe (PO) (Alberio pipeline, January 2018)
19 Jan 2018Registered for Constipation in Japan (PO) – First global approval
In 2012, the compound was licensed to Ajinomoto (now EA Pharma) by Albireo for exclusive development and commercialization rights in several Asian countries. At the same year, the product was licensed to Ferring by Albireo worldwide, except Japan and a small number of Asian markets, for development and marketing. However, in 2015, this license between Ferring and Albireo was terminated and Albireo is seeking partner for in the U.S. and Europe. In 2016, Ajinomoto and Mochida signed an agreement on codevelopment and comarketing of the product in Japan.

Elobixibat

Elobixibat is an IBAT inhibitor approved in Japan for the treatment of chronic constipation, the first IBAT inhibitor to be approved anywhere in the world. EA Pharma Co., Ltd., a company formed via a 2016 combination of Eisai’s GI business with Ajinomoto Pharmaceuticals and focused on the gastrointestinal disease space, is the exclusive licensee of elobixibat for the treatment of gastrointestinal disorders in Japan and other select countries in Asia (not including China) and is expected to co-market elobixibat in Japan with Mochida Pharmaceutical Co., Ltd., and to co-promote elobixibat in Japan with Eisai, under the trade name GOOFICE®.

We also believe that elobixibat has potential benefit in the treatment of NASH based on findings on relevant parameters in clinical trials of elobixibat that we previously conducted in patients with chronic constipation and in patients with elevated cholesterol and findings on other parameters relevant to NASH from nonclinical studies that we previously conducted with elobixibat or a different IBAT inhibitor. In particular, in a clinical trial in dyslipidemia patients, elobixibat given for four weeks reduced low-density lipoprotein (LDL) cholesterol, with the occurrence of diarrhea being substantially the same as the placebo group. Also, in other clinical trials in constipated patients, elobixibat given at various doses and for various durations reduced LDL-cholesterol and, in one trial, increased levels of glucagon-like peptide 1 (GLP-1). Moreover, A4250 (an IBAT inhibitor) showed significant improvement (p < 0.05) on the nonalcoholic fatty liver disease activity score in an established model of NASH in mice known as the STAM™ model and improvement in liver inflammation and fibrosis in another preclinical mouse model. We are considering conducting a Phase 2 clinical trial of elobixibat in NASH

These benzothiazepines possess ileal bile acid transport (IBAT) inhibitory activity and accordingly have value in the treatment of disease states associated with hyperlipidaemic conditions and they are useful in methods of treatment of a warm-blooded animal, such as man. The invention also relates to processes for the manufacture of said benzothiazepine derivatives, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit IBAT in a warm-blooded animal, such as man.
It is well-known that hyperlipidaemic conditions associated with elevated
concentrations of total cholesterol and low-density lipoprotein cholesterol are major risk factors for cardiovascular atherosclerotic disease (for instance “Coronary Heart Disease: Reducing the Risk; a Worldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999, 100, 1930-1938 and “Diabetes and Cardiovascular Disease: A Statement for Healthcare Professionals from the American Heart Association” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134-46). Interfering with the circulation of bile acids within the lumen of the intestinal tracts is found to reduce the level of cholesterol. Previous established therapies to reduce the concentration of cholesterol involve, for instance, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or treatment with bile acid binders, such as resins. Frequently used bile acid binders are for instance cholestyramine and cholestipol. One recently proposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissance for Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M; Current Opinion on Lipidology, 1999, 10, 269-74) involved the treatment with substances with an IBAT inhibitory effect.
Re-absorption of bile acid from the gastro-intestinal tract is a normal physiological process which mainly takes place in the ileum by the IBAT mechanism. Inhibitors of EBAT can be used in the treatment of hypercholesterolaemia (see for instance “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolaemic properties”, Biochemica et Biophysica Acta, 1210 (1994) 255- 287). Thus, suitable compounds having such inhibitory IBAT activity are also useful in the treatment of hyperlipidaemic conditions.

Compounds possessing such IBAT inhibitory activity have been described, see for instance the compounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.
A further aspect of this invention relates to the use of the compounds of the invention in the treatment of dyslipidemic conditions and disorders such as hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In addition, these compounds are expected to be useful for the prevention and treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vascular dysfunction, endothelial dysfunction, heart failure, coronary heart diseases, cardiovascular diseases, myocardial infarction, angina pectoris, peripheral vascular diseases, inflammation of cardiovascular tissues such as heart, valves, vasculature, arteries and veins, aneurisms, stenosis, restenosis, vascular plaques, vascular fatty streaks, leukocytes, monocytes and/or macrophage infiltration, intimal thickening, medial thinning, infectious and surgical trauma and vascular thrombosis, stroke and transient ischaemic attacks.

PATENTS

WO 2002050051

https://patentscope.wipo.int/search/en/detail.jsf%3Bjsessionid=4E054324A28B9E2E7C3C73102D1560EC.wapp1?docId=WO2002050051&recNum=237&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22A61K%22%26fq%3DPAF_M%3A%22ASTRAZENECA+AB%22&sortOption=Relevance&maxRec=655

STARKE, Ingemar; (SE).
DAHLSTROM, Mikael; (SE).
BLOMBERG, David; (SE)

ASTRAZENECA

SYNTHESIS

WO 2002050051, WO 1996016051

PATENT

WO 2003051821

WO 2003020710

TW I291951

WO 2013063512

WO 2013063526

US 20140323412

EP 3012252

PATENT

WO 2003020710

https://patents.google.com/patent/WO2003020710A1/und

PATENT

WO 2014174066

WO 02/50051 discloses the compound 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘- [/V-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (elobixibat; lUPAC name: /V-{(2R)-2-[({[3,3-dibutyl-7-(methylthio)-1 ,1 -dioxido-5-phenyl-2,3,4,5-tetrahydro-1 ,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenyl-ethanolyl}glycine). This compound is an ileal bile acid transporter (I BAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases. According to the experimental section of WO 02/50051 , the last synthetic step in the preparation of elobixibat consists of the hydrolysis of a ie f-butoxyl ester under acidic conditions. The crude compound was obtained by evaporation of the reaction mixture under reduced pressure and purification of the residue by preparative HPLC using acetonitrile/ammonium acetate buffer (50:50) as eluent (Example 43). After freeze drying the product, no crystalline material was identified.

Example 1

Preparation of crystal modification I

Toluene (1 1 .78 L) was charged to a 20 L round-bottom flask with stirring and 1 ,1 -dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(/V-{(R)-1 ‘-phenyl-1 ‘-[/\/’-(i-butoxycarbonylmethyl)carbamoyl]-methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1 ,5-benzothiazepine (2.94 kg) was added. Formic acid (4.42 L) was added to the reaction mass at 25-30 °C. The temperature was raised to 1 15-120 °C and stirred for 6 hours. The reaction was monitored by HPLC to assure that not more than 1 % of the starting material remained in the reaction mass. The reaction mass was cooled to 40-43 °C. Purified water (1 1 .78 L) was added while stirring. The reaction mass was further cooled to 25-30 °C and stirred for 15 min.

The layers were separated and the organic layer was filtered through a celite bed (0.5 kg in 3 L of toluene) and the filtrate was collected. The celite bed was washed with toluene (5.9 L), the filtrates were combined and concentrated at 38-40 °C under vacuum. The reaction mass was then cooled to 25-30 °C to obtain a solid.

Ethanol (3.7 L) was charged to a clean round-bottom flask with stirring, and the solid obtained in the previous step was added. The reaction mass was heated to 40-43 °C and stirred at this temperature for 30 min. The reaction mass was then cooled to 25-30 °C over a period of 30 min., and then further cooled to 3-5 °C over a period of 2 h, followed by stirring at this temperature for 14 h. Ethanol (3.7 L) was charged to the reaction mass with stirring, while maintaining the temperature at 0-5 °C, and the reaction mass was then stirred at this temperature for 1 h. The material was then filtered and washed with ethanol (1 .47 L), and vacuum dried for 30 min. The material was dried in a vacuum tray dryer at 37-40 °C for 24 h under nitrogen atmosphere. The material was put in clean double LDPE bags under nitrogen atmosphere and stored in a clean HDPE drum. Yield 1 .56 kg.

Crystal modification I has an XRPD pattern, obtained with CuKal -radiation, with

characteristic peaks at °2Θ positions: 3,1 ± 0.2, 4,4 ± 0.2, 4,9 ± 0.2, 5,2 ± 0.2, 6,0 ± 0.2, 7,4 ± 0.2, 7,6 ± 0.2, 7,8 ± 0.2, 8,2 ± 0.2, 10,0 ± 0.2, 10,5 ± 0.2, 1 1 ,3 ± 0.2, 12,4 ± 0.2, 13,3 ± 0.2, 13,5 ± 0.2, 14,6 ± 0.2, 14,9 ± 0.2, 16,0 ± 0.2, 16,6 ± 0.2, 16,9 ± 0.2, 17,2 ± 0.2, 17,7 ± 0.2, 18,0 ± 0.2, 18,3 ± 0.2, 18,8 ± 0.2, 19,2 ± 0.2, 19,4 ± 0.2, 20,1 ± 0.2, 20,4 ± 0.2, 20,7 ± 0.2, 20,9 ± 0.2, 21 ,1 ± 0.2, 21 ,4 ± 0.2, 21 ,8 ± 0.2, 22,0 ± 0.2, 22,3 ± 0.2, 22,9 ± 0.2, 23,4 ± 0.2, 24,0 ± 0.2, 24,5 ± 0.2, 24,8 ± 0.2, 26,4 ± 0.2,^‘27,1 ± 0.2 and 27,8 ± 0.2. The X-ray powder diffractogram is shown in FIG. 4.

PATENT

WO 2014174066

エロビキシバット水和物
Elobixibat Hydrate

C₃₆H₄₅N₃O₇S₂▪H₂O : 713.9
[1633824-78-8]

References

Jump up^ “INN for A3309 is ELOBIXIBAT”. AlbireoPharma. Archived from the original on 18 January 2012. Retrieved 5 December 2012.
Jump up^ Acosta A, Camilleri M (2014). “Elobixibat and its potential role in chronic idiopathic constipation”. Therap Adv Gastroenterol. 7 (4): 167–75. doi:10.1177/1756283X14528269. PMC 4107709 . PMID 25057297.
Jump up^ Grogan, Kevin. “Ferring acquires rights to Albireo’s bowel drug”. PharmaTimes. Retrieved 23 March 2017.
Jump up^ “Ajinomoto Pharmaceuticals and Albireo Announce Japan and Asia License Agreement for Elobixibat”. Albireo. Retrieved 5 December2012.^{[permanent dead link]}

Elobixibat
Clinical data

Routes of administration	Oral
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name [show]
CAS Number	439087-18-0
PubChem CID	9939892
ChemSpider	8115513
UNII	865UEK4EJC
KEGG	D10796
ChEMBL	CHEMBL3039515
Chemical and physical data
Formula	C₃₆H₄₅N₃O₇S₂
Molar mass	695.89 g/mol
3D model (JSmol)	Interactive image