AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Shamisha Resource Managment, Experts in Recruitment, Pharmaceutical and FMCG Consulting

 breakthrough designation  Comments Off on Shamisha Resource Managment, Experts in Recruitment, Pharmaceutical and FMCG Consulting
Sep 092016
 

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They specialise in Recruitment service in Food/FMCG/ Pharma, with offices in Ahmedabad and Mumbai .We have track record of accurate and prompt service in most ethical manner. I happen to be a Start- up specialist too. I am myself PhD in Pharmaceutical Technology from IIT , BHU and have held top management positions in  leadership role in P&G, Ranbaxy, Teva, Lupin, Novartis, JNJ,Colgate, Pfizer and can assure you of best recruitment solutions.

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Shamisha Resources Management

http://www.shamisha.in/

Shamisha Resources Management is founded by Technocrat Nina Sharma  who holds PhD in Pharmaceutical Sciences from IIT , BHU and has worked in Corporate for 30 years as Technical Head including of Global R&D Centres of Topmost MNC,s.

Shamisha Resources Management is focused on Pharmaceutical Industry and has experise in recruitment service for India and global recruitment.

We have offices in Ahmedabad and Mumbai and have experienced and trained Recruitment consultants who work in most methodical and ethical manner. Our Service standards are very high in promptness and accuracy. We cover technical functions like R&D,QA, RA ,Manufacturing  , Engineering, Project Management , IPR , Pharmacovigilance for both Formulations ,API and Sales and Marketing .We cover small molecules (ANDA) Speciality generics, biosimilars and large molecules. Our accuracy rate of fitment is 100%.Candidates are proposed only after thorough reference, background check and cultural fitment analysis as part of pre-screening programme at our end.

We are start-up specialists and support beyond recruitment solution in guiding on Organization structure and additional inputs for successful start up to operations.

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PRESENTATION, SEE 12 PAGES

 

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http://www.shamisha.in/

Many thanks, Best Regards

Nina Sharma

Nina Sharma
Managing Director at Shamisha Resource Managment

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M Pharm, PhD ( IIT, BHU)PGDMM ( UK)

Recruitment Services –  Standard terms

Pharma Consulting Scope

Managing Director

Shamisha Resources Management, 331-332 Sobo Centre

South Bopal, Ahmedabad 380058

+912717405999/6999/79999

+919974672915,+919820733290

nina1sharma@gmail.com

Mumbai Office  218 Marathon Max LBS Marg, Mulund West 022-40022560/61/62/63/64/65

WEBSITE……http://www.shamisha.in/

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Experience

Managing Director

Shamisha Resource Managment

– Present (1 year 1 month)Mumbai, Ahmedabad

Recruitment/Manpower Consulting, Pharmaceutical and FMCG Consulting , New unit set up , Food and Hospitality

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WEBSITE……http://www.shamisha.in/

Director of Technical Services

Teva Pharma ( PGT Healthcare )

(1 year 11 months)Mumbai Area, India

Director

teva pharma

(2 years)

Director

teva pharma

(2 years)

Senior Vice President QA and Formulations

Biotechnology/Bionutrition

(1 year)

Biosimilars, Bionutrition and Diagnostics QA-Advanced markets

Biosimilars, Bionutrition Formulations R&D

Bionutrition Global Regulatory

Senior Director

JNJ

(1 year 8 months)

Head Tech Development

Novartis Healthcare Pvt Limited

(2 years 5 months)

Director R&D

Pfizer

(1 year)

Senior Manager

Searle India Ltd

(1 year 7 months)

Product Development Manager

Ranbaxy Laboratories

(2 years 7 months)

Product Dev. Manager

Ranbaxy

(3 years)

Product Dev. Manager

Ranbaxy

(3 years)

Product Dev. Manager

Ranbaxy

(3 years)

R&D Manager Healthcare

Proctor &Gamble India

(6 years 8 months)

Education

ABE UK

Ad Dip Buisness Management, Business Management

ABE, UK

HR Advance Dip, HR

Indian Institute of Technology (Banaras Hindu University), Varanasi

M.Pharm,PhD, Pharmacy

Education

M. Pharm ,PhD, Institute of Technology ,BHU
PGDMM , CIM UK

FULL RESUME

DR. NINA SHARMA

M.Pharm (Gold medalist)

PhD (Indian Institute of Technology, IIT, BHU, India), 1985

Post Graduate Diploma in Marketing Management (CIM, UK) 2007

Advanced Diploma in HR Management   (ABE UK) 2008

Advanced Diploma in Business Management (ABE, UK) 2009

(Top Paper Prize Global Award for two papers)

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FORMULATIONS EXPERT

Experienced in top level R&D Operations of Formulation Development, Global Portfolio and ­Resource management with successful  projects completion and Formulation launches   in   various therapeutic categories, for OTC, ANDA and 505(b) (2), NCE and Biosimilars in reputed organizations with repeated track record of achievement

High level Formulation Development skill for LVP.SVP.Tablets, Capsules,Dry Syrup,Liquids, Semisolids for domestic and International markets, QA and Regulatory for USFDA , MCA and semi-regulated markets

Formulation development ,Technology transfer and Production operations ,Quality and compliance expert with track record of successful new products launches  , portfolio expansion, Claims substantiation and Regulatory support, Tech transfer and supply chain transition management ,Project and team leadership to drive successful product launches within time and budget.

In  recent   roles  as Senior Director with Johnson and Johnson ( J&J )  have led  10 million USD  Formulation R &D project  for Early developmentand Late Development ANDA ,manufacturing of clinical supplies  for advanced market  and Integrated drug product development for Emerging markets of China ,Korea, Taiwan and Mexico; Director Technical and Scientific Affairs with Teva Pharma  Assignments with Novartis Healthcare Private Limited as R & D Head India – Global Research & Development Lab for OTC and Pfizer as Director (Head) for Formulation development Global R&D Center for Vet Medicine   were successful   projects in leadership position of Formulation R&D. Expertise in FMCG Sector as Head of Oral care Technology in India Global Formulation R&D Center, Procter and Gamble as R&D Manager Healthcare and Generics in Ranbaxy, Lupin and Searle.

Have published twenty research publications including four in international journals, US andEuropeanPatent holder across the illustrious career path.

Distinction of launching new products in conventional dosage forms, solids, liquids, sterile and semisolids and New Drug delivery systems covering full span of therapeutic area for infectious, psychiatry, cardiology, virology and biotechnology, pain and HIV, well versed with NDDS and Containment strategies.

An effective communicator   with excellent people management/ training skills and strong analytical, problem solving & organizational abilities   with proven track record of efficiently working with global partners.

 

CAREER HIGHLIGHTS

July 2015 to Present: Managing Director Shamisha Resources Management, Ahmedabad and Mumbai

WEBSITE……http://www.shamisha.in/

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Sept 2013 to July 2015– Director Technical Services and Production operation for   Teva Pharma ( Procter &Gamble Teva Joint Venture PGT Healthcare )  , leading a team of 18 Managers /supervisors and Production staff of about 430 by end of 2014, handling commercialization of green field project of 600 crores.

Jan 2012 onwards Gresen Lehmann Group (GLG Singapore) consultant –successfully completed consultancy for Mckinsey, BCG on Pharmaceutical Development

July 2011 to Sep 2011 Senior VP Avesthagen Limited

July 2010 to July 2011 Senior Director Pharmaceutical Development and July 2008 to Feb   2010 Global Formulation   R&D Center at Johnson and Johnson

The responsibilities included set up and start up of Pharmaceutical development organization for Chem Pharm , Global NCE  Pre formulation and Late development for EU and US  and support emerging markets of India , China , Brazil , Mexico .

Asia Drug product development strategy and capability calculations for three Sites, project allocation and transition plan, global SOP, s and processes.

Creating   Road Map of Pharmaceutical Development till 2012 and integration

Since Sept 2005 Jan 2008 Novartis Healthcare Private Limited as Formulation R&D Head India – Global OTC Research &Development

Notable Deliverables

  • Led the effort in setting up the India Lab from Start up to operational build the team through recruitment and training
  • Head count increased to 47, established functions like Product development , Analytical, QA , Regulatory-CMC, Documentation ,CSV , I T   Clinical operations , Facility Management , EHS ,Purchase and administration
  • The Stability centre having 18 chambers can cater to all the four zones including Brazil.
  • Use of LIMS, Empower, SAS and fully validated 21 CFR compliant systems.
  • Product design and submissions for ANDA in advanced market domain.
  • Clinical operations (Phase III) through CRO (Siro, Lotus, and Reliance Life Sciences) in the area of Generic OTC molecules for advanced market. Studies executed by  Protocol preparation , approval ,quality audits and effective relation management , periodic reporting to global Clinical operations at Nyon ( Switzerland )
  • Played a key role in introducing Standard procedures (283 new) to make India Lab compliant with Global Quality operations standard and obtained USFDA Registration   for the Site. The standards introduced by India Site are adopted by two other global sites. Data generation as per USFDA , EMEA , ANVISA and MCA
  • Efficiently led the Information Security and Safety Audits with successful outcome.
  • Distinction of leading the Group Quality Audit which is a tough internal standard to meet and India is the only compliant Lab so far.
  • Planning and control of Revenue and Capital budget for India Site

 

HOLDS THE MERIT OF

  • US FDA Registration ,Twenty eight Pharmaceutical development and Stability testing projects in the area  Conventional Solids , Liquids semi solids and NDDS , Patches
  • Clinical operations, Technical writing, CMC Head count expansions within short time of lab operations.

Instrumental in collaborating with other Global Sites and local management to drive superior results.

  • Conducted successful studies on major global brands like Excedrin, Vibrocil, Theraflu, and Buckleys & Benefiber and applied the Project Management tools, innovative research based on market feedback. Milestones on delivery of Projects completed on time. Global project teams technical resource on global brands like Benefiber, Theraflu
  • Established a successful R&D Centre with high productivity and GMP within short time.

Apr 2004- August 20 05           Pfizer India Limited as Director

  • Planning and budgeting  for new research center in Formulations and API , won 9 million dollar investment (first ever for the Thane Site )
  • Awarded four NCE Enhancement projects in Liquids and solids from Sandwich through bidding process for US and Europe market.
  • Formed the core team of R&D Scientists and Managers
  • Conducted early development studies for NCE molecules, coordinated pharmacokinetic studies on anthelmentics, Doramectin pour on, Selamectin with Praziquantel spot on formulations.
  • Technical liaison with Indian Regulatory Authorities for fast approvals of import of API and formulations.
  • Led the effort in establishing the Organization and formulating plans for expansion
  • Pivotal in establishing linkages across Pfizer, organization processes for reporting and communication, Project management and control systems, and people development.

 Feb1999-March 2004        Colgate Palmolive India Ltd., General Manager-Oral Care

 Notable Deliverables

  • Technical business support for driving growth in India, Pakistan, Africa and Middle East through new products launches in Oral care technology
  • Managed and coordinated largest Anti caries Clinical trials on Oral formulation with Triclosan and Fluoride conducted in India on 6000 children over a period of 24 months through Dentists
  • Managed and coordinated Multicentre Clinical trials on Whitening Oral care formulations conducted in India for Indian and Australian market
  • Managed and coordinated Clinical trials on formulations with different polishing agents
  • Managed and coordinated Clinical trials on Toothpowder and toothbrushes
  • Effective coordination with Global Research centre for Protocol preparation, approval, servicing of sample, reporting to Global
  • Efficiently liasioned with Government bodies for strategic partnership on future specifications for RM and Finished products pertaining to Oral care.
  • Led the effort to design, develop and Re launch major flagship brands Colgate Dental cream five times, Colgate toothpowder three times and Fresh Energy Gel two variants re-launched three times each to claim back the lost market shares (approximately 900 crores business). Regained the lost market share by nine point
  • Launching of Low cost formula with Cibaca brand name which resulted in increase in 7% Market share, formulation developed indigenously
  • Entry to medium price segment by launching Colgate Herbal
  • Led the efforts in the development of several innovative forms of Oral care including stripe formulations, innovative affordable oral care formulation.
  • Initiated several cost saving projects and implemented margin improvement programs on formulations.
  • Successfully obtained Ayurvedic classification to support pain claim for Herbal dentifrice due for launch.
  • Conducted several training programs for management team of manufacturing locations on Quality as certified trainer.
  • Spearheaded functions for entry into Low and medium price segments retaining the Colgate Global standards, to compete in emerging markets dominated by local players.
  • Herbal segment through launch of Herbal toothpaste
  • Pivotal in designing Consumer qualified products to enter new market segment
  • Efficiently executed Quality improvement programs for raw material across six manufacturing locations in India and Nepal
  • Margin improvement programs on all the major brands like Colgate Dental cream, toothpowder and Gel formulations thereby resulting in huge savings viz. common base Technology for to drive margins, new crystal structure development for Calcium carbonate, process improved for Triclosan manufacture, introduction of liquid form of Sodium lauryl sulphate, powder form of Sodium silicate, use of Natural calcium carbonate in liquid dentifrice
  • Developed self-preservation technique for liquid dentifrice named as Gold standard by Piscataway Research center
  • Merit of introducing Quality standards and Guidelines in India Technology center
  • Participated in designing new plant for toothpaste manufacture
  • Designing Specifications for Bureau of Indian Standards for Toothpaste, toothpowder, Sorbitol and Calcium carbonate
  • Filed one patent on Coated Natural Calcium Carbonate Oral Care Toothpowder Composition
  • Distinction of being committee member on three BIS Committees for PCD 19 for 4 years
  • Received Colgate YCMAD Award for innovation four times
  • Nominated  team members and direct subordinates to win the award 19 times.

Sept ’1997-Jan1999   Searle India Ltd., Senior Manager (Pharmaceutical Development)

Notable Deliverables

·Instrumental in developing, reformulating & launching 12 products within fourteen months. Pivotal in developing

  • New products in area of conventional and specialized delivery system in therapeutic segment of cardiovascular, anti diabetic, gastrointestinal, anti-infective, neurological and biotechnology products.
  • Dosage forms like tablets, capsules, chewable, sustained release, dry syrups, liquid orals, suspensions using resin technology and injectables.
  • Played a key role in setting up a new department for international regulatory submissions, dossiers submitted for twenty molecules to contribute to export business.

July 1994 – Aug 1997   Lupin Laboratories Ltd as Senior Manager (Development)

Notable Deliverables

  • Led the effort in launching New Products Division ,  by developing & launching 8 new Herbal products through a new division of ethically promoted Natural products with 50 Sales personnel
  • Limited Phase III Clinicals for Anxiolytic and Appetite Stimulant formulation managed and coordinated through Clininvent
  • Periodontical Clinicals conducted and managed in Governmental dental College Mumbai
  • Claim support Clinicals on Ayurvedic Uterine tonic (U-Sedate) conducted at KEM Hospital Mumbai and Pune
  • Launched products like natural appetite stimulant, oral care, arthritis, rejuvenation, laxatives and digestive
  • Developed personal care products for export market, shampoos, hair oils, oral rinses, anti ageing cream all herbal/natural in nature
  • Successfully introduced bulk actives for exports, filed international patent on novel process for extraction of Hydroxyl Citric Acid from Garcinia.

 

Dec1991-June 1994 Ranbaxy Laboratories Ltd., as Product Development Manager

Notable Deliverables

  • Successfully developed and launched several conventional and specialty dosage forms as tablets, liquid oral, injectables, creams and led the team of product development scientists for India, Semi regulated markets of CIS , Indonesia , Malyasia and also Europe.
  • Managed and coordinated several BA/BE Studies for anti-infective in Ranbaxy and also Therapeutic Drug Monitoring Lab Mumbai.
  • Pivotal in supporting export market through regulatory submissions, product development and launch in the designated countries.
  • Significantly contributed in documentation for MCA approval.

March 1985-Nov 1991, Procter & Gamble India Ltd., as Research and Development Manager

  • Efficiently developed and launched indigenously developed Herbal products in OTC Category in

candy and syrup base

  • Actively participated in Clinical trials for OTC products (cough syrup)
  • Joining position Research Executive, promoted to Asstt. Manager, further promoted to Manager

Aug 80 -Dec ’84       Indian Institute of Technology, Benares Hindu University as Lecturer

Nov ’78-July ’80       Hamdard College of Pharmacy, University of Delhi as Lecturer

Academic Distinctions

Received Best Girl Student award in High School, University

Merit scholarship National Scholarship CSIR Scholarship –not availed

Memberships : Beureu of Indian Standards 2000-2004, IPA Life Member, CIM Member

Contact details  nina1sharma@gmail.com, 9820733290,9974672915,07940321865,02225797954

Address

Shamisha Resource Management  331-332 Sobo Centre South Bopal Ahmedabad

Ahmedabad  A92 Shaligram 3 Prahladnagar Ahmedabad

Mumbai  1104, Sovereign Hiranandani Gardens Powai Mumbai 400076

////////////Shamisha Resource Managment, Experts in Recruitment, Pharmaceutical ,  FMCG Consulting, NINA SHARMA

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Maralixibat Chloride, ماراليكسيبات كلوريد , 氯马昔巴特 , Мараликсибата хлорид

 breakthrough designation  Comments Off on Maralixibat Chloride, ماراليكسيبات كلوريد , 氯马昔巴特 , Мараликсибата хлорид
Jun 152016
 

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2D chemical structure of 228113-66-4

Maralixibat chloride

Maralixibat Chloride,  ماراليكسيبات كلوريد ,  氯马昔巴特 , Мараликсибата хлорид

SHP625, Maralixibat chloride, Molecular Formula C40-H56-N3-O4-S.Cl, Molecular Weight, 710.4184

4-Aza-1-azoniabicyclo(2.2.2)octane, 1-((4-((4-((4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl)-, chloride (1:1)

1-[4-({4-[(4R,5R)-3,3-Dibutyl-7-(dimethylamino)-4-hydroxy-1,1-dioxido-2,3,4,5-tetrahydro-1-benzothiepin-5-yl]phenoxy}methyl)benzyl]-4-aza-1-azoniabicyclo[2.2.2]octane chloride

4-Aza-1-azoniabicyclo[2.2.2]octane, 1-[[4-[[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-, chloride

(4R.5R)-1- r.4- r _4- .3.3 -Dibutyl-7- (dimethylamino) -2.3 ,4.5- tetrahydro-4-hydroxy-1, l-dioxido-l-benzothiepin-5- yl] henoxy] ethyl] phenyl1methyl] -4-aza-l- azoniabicyclo [2.2.2] octane

(4Rcis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane Chloride Salt

(4R,5R)- 1 -((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -diυxido- 1 -benzithiepin-5-yl)pheπoxy)methyl)phenyl)methyl-4-aza- 1 – azoniabicyclo[2.2.2]octane chloride

Cas: 228113-66-4, Free form 716313-53-0
UNII: V78M04F0XC, LUM 001, Lopixibat chloride, Treatment of Cholestatic Liver Diseases

Inventors James Li, Ching-Cheng Wang, David B. Reitz, Victor Snieckus, Horng-Chih Huang,Andrew J. Carpenter, Less «
Applicant G.D. Searle & Co.

Several drawings of Maralixibat chloride

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ChemSpider 2D Image | maralixibat chloride | C40H56ClN3O4S

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It is well established that agents which inhibit the 20 transport of bile acids across the ileum can also cause a decrease in the level of cholesterol in blood serum. Stedronski, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,” Biochimica et Biophysica Acta, 1210 (1994) 255- 25287, discusses biochemistry, physiology, and known active agents affecting bile acids and cholesterol.

A class of ileal bile acid transport-inhibiting compounds which was recently discovered to be useful for influencing the level of blood serum cholesterol is 30 tetrahydrobenzothiepine-l,l-dioxides (THBDO compounds). (U.S. Patent Application No. 08/816,065)

Some classes of compounds show enhanced potency as pharmaceutical therapeutics after they have been enantiomerically-enriched (see, for example, Richard B. Silverman, The Organic Chemistry of Drug Design and Drug Action, Academic Press, 1992, pp. 76-82) . Therefore, THBDO compounds that have been enantiomerically-enriched are of particular interest.

A class of chemistry useful as intermediates in the preparation of racemic THBDO compounds is tetrahydrobenzothiepine-1-oxides (THBO compounds) . THBDO compounds and THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring. A method of preparing enantiomerically-enriched samples of another phenyl/seven-member fused ring system, the benzothiazepines, is described by Higashikawa (JP 59144777) , where racemic benzothiazepine derivatives are optically resolved on a chromatographic column containing chiral crown ethers as a stationary phase. Although optical resolution is achieved, the Higashikawa method is limited to producing only small quantities of the enantiomerically-enriched benzothiazepine derivatives. Giordano (CA 2068231) reports the cyclization of (2S, 3S) -aminophenylthiopropionates in the presence of a phosphonic acid to produce (2S, 3S) -benzothiazepin-4-ones . However, that preparation is constrained by the need to use enantiomerically-enriched starting materials rather than racemic starting materials. In addition, the Giordano method controls the stereochemistry of the seven-member ring of the benzothiazepin-4-one only at the 2- and 3 -positions. The 4- and 5-positions of the seven-member ring of the benzothiazepin-4-one are not asymmetric centers, and the stereochemistry at these sites therefore cannot be controlled by the Giordano method. A method by which enantiomerically-enriched 1,5- benzothiazepin-3-hydroxy-4 (5H) -one compounds have been produced is through the asymmetric reduction of 1,5- benzothiazepin-3,4 (2H, 5H) -dione compounds, reported by Yamada, et al . (J. Org. Chem. 1996, 61 (24), 8586-8590). The product is obtained by treating the racemic 1,5- benzothiazepin-3,4 (2H, 5H) -dione with the reaction product of an optically active alpha-amino acid and a reducing agent, for example sodium borohydride. Although a product with high optical purity was achieved, the method is limited by the use of a relatively expensive chemical reduction step.

The microbial reduction of racemic 1, 5-benzothiazepin- 3 , 4 (2H, 5H) -dione compounds to produce enantiomerically- enriched 1, 5-benzothiazepin-3-hydroxy-4 (5H) -one compounds is reported by Patel et al . , U.S. Patent 5,559,017. This method is limited by the inherent problems of maintaining a viable and pure bacterial culture of the appropriate species and variety. In addition, that method is limited in scale, producing only microgram quantities of the desired product. Until now, there have been no reported processes for preparing enantiomerically-enriched THBDO compounds or enantiomerically-enriched THBO compounds. Furthermore, there have been no reported processes for controlling the stereochemistry at the 4- and 5-positions of the seven- member rings of THBDO compounds or THBO compounds

FDA Grants Breakthrough Designation to Shire’s Rare GI Therapies

Tue, 06/14/2016

Shire announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for two investigational products for rare diseases: SHP621 (budesonide oral suspension, or BOS) for eosinophilic esophagitis (EoE), and SHP625 (maralixibat) for progressive familial intrahepatic cholestasis type 2 (PFIC2).

“Receiving Breakthrough Therapy Designation on two pipeline products this past week reflects the potential of our strong and innovative pipeline of more than 60 programs,” said Flemming Ornskov, M.D., MPH, and CEO, Shire. “Shire is committed to bringing innovation to the rare and specialty areas we focus on. We persevere to see compounds through the many stages of development through their challenges and successes, and always keep patients with unmet needs top of mind.”

EoE is a serious, chronic and rare disease that stems from an elevated number of eosinophils, a type of white blood cell, that infiltrate the walls of the esophagus. EoE is characterized by an inflammation of the esophagus that may lead to difficulty swallowing (dysphagia). The diagnosed prevalence of EoE ranges from approximately 15-55 cases per 100,000 persons, with high-end estimates reported by studies in Western regions.

PFIC refers to a group of autosomal-recessive liver disorders of childhood that disrupt bile formation and present with cholestasis. The symptoms of PFIC include severe itching of the skin (pruritus), and jaundice. PFIC is estimated to affect 1 in 50,000 to 1 in 100,000 births. PFIC2 is the most common type of PFIC, accounting for around half of cases.

According to the FDA, Breakthrough Therapy Designation is granted to a therapy that is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over current standard of care. Under the designation, the FDA provides intensive guidance, organizational commitment involving senior managers, and eligibility for rolling and priority review of the application; this process helps ensure patients have access to therapies as soon as possible, pending approval. Breakthrough Therapy Designation does not guarantee that FDA will ultimately approve BOS for EoE or maralixibat for PFIC2, and the timing of any such approval is uncertain.

“On behalf of patients in the United States with EoE and PFIC2, we are so pleased that the FDA has granted Breakthrough Therapy Designation to BOS and maralixibat,” said Philip J. Vickers, Ph.D., Head of R&D, Shire. “We look forward to working with the agency to continue their development and, pending FDA approval, deliver these therapeutic options to the patients who need them most.”

Source: Shire

Patent

WO 2003022804

It is well established that agents which inhibit the transport of bile acids across the tissue of the ileum can also cause a decrease in the levels of cholesterol in blood serum. Stedronski, in “Interaction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,” Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses biochemistry, physiology, and known active agents surrounding bile acids and cholesterol. Bile acids are actively transported across the tissue of the ileum by an apical sodium co-dependent bile acid transporter (ASBT), alternatively known as an ileal bile acid transporter (IBAT).
A class of ASBT-inhibiting compounds that was recently discovered to be useful for influencing the level of blood serum cholesterol comprises tetrahydrobenzothiepine oxides (THBO compounds, PCT Patent Application No. WO 96/08484). Further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 97/33882.
Additional THBO compounds useful as ASBT inhibitors are described in U.S. Patent No. 5,994,391. Still further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 99/64409. Included in the THBO class are tetrahydrobenzo-thiepine-l -oxides and tetrahydrobenzothiepine- 1,1 -dioxides. THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring.

Published methods for the preparation of THBO compounds include the synthesis through an aromatic sulfone aldehyde intermediate. For example l-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene (29) was cyclized with potassium t-butoxide to form tetrahydrobenzothiepine- 1,1 -dioxide (svn-24) as shown in Eq. 1.

Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the
chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce l-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride.
Phosphorus pentachloride readily hydrolyzes to produce volatile and hazardous hydrogen chloride. The reaction of 2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide and the chlorodiphenylmethane compound required the intermediacy of a cyclic tin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal. The tin compound is expensive and creates a toxic waste stream.
In WO 97/33882 compound syn-24 was dealkylated using boron tribromide to produce the phenol compound 28. Boron tribromide is a corrosive and hazardous material that generates hydrogen bromide gas and requires special handling. Upon hydrolysis, boron tribromide also produces borate salts that are costly and time-consuming to separate and dispose of.

An alternative method of preparing THBO compounds was described in WO
97/33882, wherein a 1,3-propanediol was reacted with thionyl chloride to form a cyclic sulfite compound. The cyclic sulfite compound was oxidized to produce a cyclic sulfate compound. The cyclic sulfate was condensed with a 2-methylthiophenol that had been deprotonated with sodium hydride. The product of the condensation was a (2-methylphenyl) (3′-hydroxypropyl)thioether compound. The thioether compound was oxidized to form an thioether aldehyde compound. The thioether aldehyde compound was further oxidized to form an aldehyde sulfone compound which in turn was cyclized in the presence of potassium t-butoxide to form a 4-hydroxytetrahydrobenzothiepine 1,1 -dioxide compound. This cyclic sulfate route to THBO compounds requires an expensive catalyst. Additionally it requires the use of SOCI2, which in turn requires special equipment to handle.
PCT Patent Application No. WO 97/33882 describes a method by which the phenol compound 28 was reacted at its phenol hydroxyl group to attach a variety of functional groups to the molecule, such as a quaternary ammonium group. For example, (4R,5R)-28 was reacted with l,4-bis(chloromethyl)benzene (?,??’-dichloro-p-xylene) to produce the chloromethyl benzyl- ether (4R,5R)-27. Compound (4R,5R)-27 was treated with diazabicyclo[2.2.2]octane (DABCO) to produce (4R,5R)-l-((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4-hydroxy-l , 1 -dioxido-1 -benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-l-azomabicyclo[2.2.2]octane chloride (41). This method suffers from low yields because of a propensity for two molecules of compound (4R,5R)-28 to react with one molecule of l,4-bis(chloromethyl)benzene to form a bis(benzothiepine) adduct. Once the bis-adduct forms, the reactive chloromethyl group of compound (4R,5R)-27 is not available to react with an amine to form the quaternary ammonium product.

A method of preparing enantiomerically enriched tetrahydrobenzothiepine oxides is described in PCT Patent Application No. WO 99/32478. In that method, an aryl-3- hydroxypropylsulfide compound was oxidized with an asymmetric oxidizing agent, for example (lR (->(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiral aryl-3-hydroxypropylsulfoxide. Reaction of the aryl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfur trioxide pyridine complex yielded an aryl-3-propanalsulfoxide. The aryl- 3-propanalsulfoxide was cyclized with a base such as potassium t-butoxide to
enantioselectively produce a tetrahydrobenzothiepine- 1 -oxide. The tetrahydrobenzothiepine- 1 -oxide was further oxidized to produce a tetrahydrobenzothiepine- 1 , 1 -dioxide. Although this method could produce tetrahydrobenzothiepine- 1,1 -dioxide compounds of high enantiomeric purity, it requires the use of an expensive asymmetric oxidizing agent.
Some 5-amidobenzothiepine compounds and methods to make them are described in

PCT Patent Application Number WO 92/18462.
In Svnlett. 9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-l-buten-4-yl sulfone was treated with tributyl tin hydride and AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1 -dioxide.
In addition to forming the desired ASBT inhibitors, it is also desirable to form such

ASBT inhibitors of higher purity and having lower levels of residual solvent impurities. This is especially so with respect to ASBT inhibitors having a positively charged substituent, for example, the compounds designated as 41 (supra) and 60 (infra).
It is further desirable to provide methods for making such high purity ASBT inhibitors.

Example 11.

Preparation of (4R,5R)- 1 -((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro-4- hydroxy- 1 , 1 -diυxido- 1 -benzithiepin-5-yl)pheπoxy)methyl)phenyl)methyl-4-aza- 1 – azoniabicyclo[2.2.2]octane chloride,
41


41

Ste l. Preparation of (4R.5R1-26.


( 4R, 5R) -26
A 1000 mL 4 neck jacketed Ace reactor flask was fitted with a mechanical stirrer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a 28 mm Teflon turbine agitator. The flask was purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 125 mL of N,N-dimethylacetamide (DMAC). To this was added 4.2 grams of 50% sodium hydroxide. The mixture was heated to 50°C and stiπed for 15 minutes. To the flask was added 8.3 grams of 55 dissolved in 10 mL of DMAC, all at once. The temperature was held at 50°C for 24 hrs. To the flask was added 250 mL of toluene followed by 125 mL of dilution water. The mixture was stiπed for 15 minutes and the layers were then allowed to separate at 50°C. The flask was then charged with 125 mL of saturated sodium chloride solution and stiπed 15 minutes. Layers separated cleanly in 30 seconds at 50°C. Approximately half of the solvent was distilled off under vacuum at 50°C. The residual reaction mixture contained (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.


( 4R, 5R) -27
Toluene was charged back to the reaction mixture of Step 1 and the mixture was cooled to 35°C. To the mixture was then added 7.0 grams of thionyl chloride over 5 minutes. The reaction was exothermic and reached 39°C. The reaction turned cloudy on first addition of thionyl chloride, partially cleared then finally remained cloudy. The mixture was stirred for 0.5 hr and was then washed with 0.25N NaOH. The mixture appeared to form a small amount of solids that diminished on stirring, and the layers cleanly separated. The solvent was distilled to a minimum stir volume under vacuum at 50°C. The residual reaction mixture contained (4R,5R)-27.

Step 3. Preparation of 41.
To the reaction mixture of Step 2 was charged with 350 mL of methyl ethyl ketone (MEK) followed by 10.5 mL water and 6.4 grams of diazabicyclo[2.2.2]octane (DABCO) dissolved in 10 mL of MEK. The mixture was heated to reflux, and HPLC showed <0.5% of (4R,5R)-27. The reaction remained homogenous initially then crystallized at the completion of the reaction. An additional 5.3 mL of water was charged to the flask to redissolve product. Approximately 160 mL of solvent was then distilled off at atmospheric pressure. The mixture started to form crystals after 70 mL of solvent was distilled. Water separated out of distillate indicating a ternary azeotrope between toluene, water and methyl ethyl ketone (MEK). The mixture was then cooled to 25°C. The solids were filtered and washed with 150 mL MEK, and let dry under vacuum at 60°C. Isolated 29.8.0 g of off-white crystalline 4 Example 11a.
Alternate Preparation of (4R,5R)-l-((4-(4-(3,3-dibutyl-7-(dimemylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 – azoniabicyclo[2.2.2]octane chloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanical stiπer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a 28 mm Teflon turbine agitator. The flask is purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 100 mL of N,N-dimethylacetamide (DMAC). The mixture is heated to 50°C and to it is added 4.02 grams of 50% sodium hydroxide. The mixture is stiπed for 30 minutes. To the flask is added 8.7 grams of 55 dissolved in 12.5 mL of DMAC, all at once. The charge vessel is washed with 12.5 mL DMAC and the wash is added to the reactor. The reactor is stiπed for 3 hours. To the reactor is added 0.19 mL of 49.4% aq. NaOH and the mixture is stirred for 2 hours. To the mixture is added 0.9 g DABCO dissolved in 12.5 mL DMAC. The mixture is stiπed 30 to 60 minutes at 50°C. To the flask is added 225 mL of toluene followed by 125 mL of dilution water. The mixture is stiπed for 15 minutes and the layers are then allowed to separate at 50°C. The bottom aqueous layer is removed but any rag layer is retained. The flask is then charged with 175 mL of 5% hydrochloric acid solution and stiπed 15 minutes. Layers are separated at 50°C to remove the bottom aqueous layer, discarding any rag layer with the aqueous layer. Approximately half of the solvent is distilled off under vacuum at a maximum pot temperature of 80°C. The residual reaction mixture contains (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.

Toluene (225 mL) is charged back to the reaction mixture of Step 1 and the mixture is cooled to 30°C. To the mixture is then added 6.7 grams of thionyl chloride over 30 to 45 minutes. The temperature is maintained below 35°C. The reaction turns cloudy on first addition of thionyl chloride, then at about 30 minutes the layers go back together and form a clear mixture. The mixture is stiπed for 0.5 hr and is then charged with 156.6 mL of 4% NaOH wash over a 30 minute period. The addition of the wash is stopped when the pH of the mixture reaches’ 8.0 to 10.0. The bottom aqueous layer is removed at 30°C and any rag layer is retained with the organic layer. To the mixture is charged 175 mL of saturated NaCl wash with agitation. The layers are separated at 30°C and the bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. The solvent is distilled to a minimum stir volume under vacuum at 80°C. The residual reaction mixture contains (4R,5R)-27.

Step 3. Preparation of 41.
To the reaction mixture of Step 2 is charged 325 mL of methyl ethyl ketone (MEK) and 13 mL water. Next, the reactor is charged 6.2 grams of diazabicyclo[2.2.2]octane (DABCO) dissolved in 25 mL of MEK. The mixture is heated to reflux and held for 30 minutes. Approximately 10% of solvent volume is then distilled off. The mixture starts to form crystals during distillation. The mixture is then cooled to 20°C for 1 hour. The off-white crystalline 41 (Form U) is filtered and washed with 50 mL MEK, and let dry under vacuum at 100°C.

Example lib.
Alternate Preparation of (4R,5R)-1 -((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 – azoniabicyclo[2.2.2]octane chloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanical stiπer, a nitrogen inlet, an addition funnel or condenser or distilling head with receiver, a
thermocouple, four internal baffles and a Teflon turbine agitator. The flask is purged with nitrogen gas and charged with 25.0 grams of (4R,5R)-28 and 125 mL of N,N-dimethylacetamide (DMAC). The mixture is heated to 50°C and to it is added 7.11 grams of 30% sodium hydroxide over a period of 15 to 30 minutes with agitation. The mixture is stiπed for 30 minutes. To the flask is added 9.5 grams of solid 55. The reactor is stiπed for 3 hours. To the mixture is added 1.2 g of solid DABCO. The mixture is stiπed 30 to 60 minutes at 50°C. To the flask is added 225 mL of toluene followed by 125 mL of water. The mixture is stirred for 15 minutes and the layers are then allowed to separate at 50°C. The bottom aqueous layer is removed but any rag layer is retained with the organic layer. The flask is then charged with 175 mL of 5% hydrochloric acid solution and stirred 15 minutes. Layers are separated at 50°C to remove the bottom aqueous layer, discarding any rag layer with the aqueous layer. The flask is then charged with 225 mL of water and stirred 15 minutes. The layers are allowed to separate at 50°C. The bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. Approximately half of the solvent is distilled off under vacuum at a maximum pot temperature of 80°C. The residual reaction mixture contains (4R,5R)-26.

Step 2. Preparation of (4R.5RV27.

Toluene (112.5 mL) is charged back to the reaction mixture of Step 1 and the mixture is cooled to 25°C. To the mixture is then added 7.3 grams of thionyl chloride over 15 to 45 minutes. The temperature of the mixture is maintained above 20°C and below 40°C. The reaction turns cloudy on first addition of thionyl chloride, then at about 30 minutes the layers go back together and form a clear mixture. The mixture is then charged with 179.5 mL of 4% NaOH wash over a 30 minute period. The mixture is maintained above 20°C and below 40°C during this time. The addition of the wash is stopped when the pH of the mixture reaches 8.0 to 10.0. The mixture is then allowed to separate at 40°C for at least one hour.

The bottom aqueous layer is removed and any rag layer is retained with the organic layer. To the mixture is charged 200 mL of dilution water. The mixture is stiπed for 15 minutes and then allowed to separate at 40°C for at least one hour. The bottom aqueous layer is removed, discarding any rag layer with the aqueous layer. The solvent is distilled to a minimum stir volume under vacuum at 80°C. The residual reaction mixture contains (4R,5R)-2 .

Step 3. Preparation of 41.
To the reaction mixture of Step 2 is charged 350 mL of methyl ethyl ketone (MEK) and 7 mL water. The mixture is stiπed for 15 minutes and the temperature of the mixture is adjusted to 25°C. Next, the reactor is charged with 6.7 grams of solid
diazabicyclo[2.2.2]octane (DABCO). The mixture is maintained at 25°C for three to four hours. It is then heated to 65°C and maintained at that temperature for 30 minutes. The mixture is then cooled to 25°C for 1 hour. The off-white crystalline 41 (Form II) is filtered and washed with 50 mL MEK, and let dry under vacuum at 100°C.

Example 12.
Alternate preparation of (4R,5R)-1 -((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro- 4-hydroxy- 1 , 1 -dioxido- 1 -benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza- 1 – azoniabicyclo[2.2.2]octane chloride, Form I of 41

(4R,5R)-27 (2.82 kg dry basis, 4.7 mol) was dissolved in MTBE (9.4 L). The solution of (4R,5R)-22 was passed through a 0.2 mm filter cartridge into the feeding vessel. The flask and was rinsed with MTBE (2 x 2.5 L). The obtained solution as passed through the cartridge filter and added to the solution of (4R,5R)-2 in the feeding vessel. DABCO
(diazabicyclo[2.2.2]octane, 0.784 kg, 7.0 mol) was dissolved in MeOH (14.2 L). The DABCO solution was passed through the filter cartridge into the 100 L nitrogen-flushed reactor. The Pyrex bottle and the cartridge filter were rinsed with MeOH (7.5 L) and the solution was added to the reactor. The (4R,5R)-22 solution was added from the feeding vessel into the reactor at 37°C over a period of 10 min, while stirring. Methanol (6.5 L) was added to the Pyrex bottle and via the cartridge filter added to the feeding vessel to rinse the remaining (4R,5R)-2 into the reactor. The reaction mixture was brought to 50-60°C over 10-20 min and stiπed at that temperature for about 1 h. The mixture was cooled to 20-25°C over a period of 1 h. To the reaction mixture, methyl t-butyl ether (MTBE) (42 L) was added over a period of 1 h and stiπed for a minimum of 1 h at 20 – 25°C. The suspension was filtered through a Buchner funnel. The reactor and the filter cake were washed with MTBE (2 x 14 L). The solids were dried on a rotary evaporator in a 20 L flask at 400 – 12 mbar, 40°C, for 22 h. A white crystalline solid was obtained. The yield of 4 . (Form I) was 3.08 kg (2.97 kg dry, 93.8 %) and the purity 99.7 area % (HPLC; Kromasil C 4, 250 x 4.6 mm column; 0.05% TFA in H2O/0.05% TFA in ACN gradient, UV detection at 215 nm).

Example 12a.
Conversion of Form I of Compound 41 into Form II of Compound 41.

To 10.0 grams of Form I of 4 . in a 400 mL jacketed reactor is added 140 mL of MEK. The reactor is stirred (358 φm) for 10 minutes at 23 °C for 10 minutes and the stirring rate is then changed to 178 φm. The suspension is heated to reflux over 1 hour using a programmed temperature ramp (0.95°C/minute) using batch temperature control (cascade mode). The delta Tmaχ is set to 5°C. The mixture is held at reflux for 1 hour. The mixture is cooled to

25°C. After 3 hours at 25°C, a sample of the mixture is collected by filtration. Filtration is rapid (seconds) and the filtrate is clear and colorless. The white solid is dried in a vacuum oven (80°C, 25 in. Hg) to give a white solid. The remainder of the suspension is stirred at 25°C for 18 hours. The mixture is filtered and the cake starts to shrink as the mother liquor reaches the top of the cake. The filtration is stopped and the reactor is rinsed with 14 mL of MEK. The reactor stirrer speed is increased from 100 to 300 φm to rinse the reactor. The rinse is added to the filter and the solid is dried with a rapid air flow for 5 minutes. The solid is dried in a vacuum oven at 25 in. Hg for 84 hours to give Form II of 4

PATENT

WO 2014144650

Scheme 3:

PAPER

Journal of Medicinal Chemistry (2005), 48(18), 5853-5868

Discovery of Potent, Nonsystemic Apical Sodium-Codependent Bile Acid Transporter Inhibitors (Part 2)

Department of Discovery Chemistry and Department of Cardiovascular Disease, Pharmacia, 700 Chesterfield Parkway W, Chesterfield, Missouri 63017, Office of Science and Technology, Chemical Science Division, Pharmacia, 800 Lindbergh Boulevard, Creve Coeur, Missouri 63167, Department of Pharmaceutical Sciences, Pharmacia, Skokie, Illinois, and Department of Chemistry, University of Missouri, St. Louis, Missouri
J. Med. Chem., 2005, 48 (18), pp 5853–5868
DOI: 10.1021/jm0402162

http://pubs.acs.org/doi/abs/10.1021/jm0402162

Abstract

Abstract Image

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure−activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.

compd R IC50 (nM)b hygroscp I wt gain (%)c hygroscp II % wt gain (%)d crystallinitye
74 OCH2C6H4(p)CH2(N+)DB 0.28 1.59 2.1 yes

(4Rcis)-1-[[4-[[4-[3,3-Dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]methyl]phenyl]methyl]-4-aza-1-azoniabicyclo[2.2.2]octane Chloride Salt (74). Following a similar procedure as in General Method B, the title compound 74 was prepared from the corresponding chloromethyl benzyl ether and DABCO as a white solid, mp 223−230 °C (dec); 1H NMR (CDCl3) δ 0.89 (m, 6H), 1.27−1.52 (br m, 10H), 1.63 (m, 1H), 2.20 (m, 1H), 2.81 (s, 6H), 3.06 (ABq, JAB = 15.1 Hz, J = 43.3 Hz, 2H), 3.16 (s, 6H), 3.76 (s, 6H), 4.11 (d, J = 7.7 Hz, 1H), 5.09 (s, 2H), 5.14 (s, 2H), 5.48 (s, 1H), 5.96 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 7.26 (m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.68 (d, J = 7.4 Hz, 2H), 7.87 (d, J = 8.9 Hz, 1H). HRMS calcd for C40H56N3O4S:  674.3992; found, 674.4005. Anal. Calcd for C40H56N3O4S:  ‘ C, 67.62; H, 7.95; N, 5.92; S, 4.51. Found:  C, 67.48; H, 8.32; N, 5.85; S, 4.60.

a All compounds were prepared using method B in Scheme 3.b Taurocholate is transported across the baby hamster kidney cell membrane.c % weight gain in a 25 °C, 57% humidity chamber for 2 weeks.d % weight gain in a 40 °C, 80% humidity chamber for 2 weeks.e Crystallinity as determined by X-ray powder diffraction analysis.f (N+)DB is a DABCO terminal group with the quaternary ammonium attached to the linke

ANY ERROR EMAIL amcrasto@gmail.com, +919323115463

PATENT

https://www.google.com/patents/WO1999032478A1?cl=en

Inventors James Li, Ching-Cheng Wang, David B. Reitz, Victor Snieckus, Horng-Chih Huang,Andrew J. Carpenter,
Applicant G.D. Searle & Co.

Example 10. Preparation of enantiomerically-enriched (4R.5R)-1- r.4- r _4- .3.3 -Dibutyl-7- (dimethylamino) -2.3 ,4.5- tetrahydro-4-hydroxy-1, l-dioxido-l-benzothiepin-5- yl] henoxy] ethyl] phenyl1methyl] -4-aza-l- azoniabicyclo [2.2.2] octane chloride ( (4R,5R) -XXVII) ♦

Figure imgf000053_0001

( (4R,5R) -XXVII) * = chiral center

Step 1. Preparation of 4-flUoro-2- ( (4- methoxyphenyl) methyl) -phenol To a stirred solution of 23.66 g of 95% sodium hydride (0.94 mol) in 600 mL of dry toluene was added 100.0 g of 4- fluorophenol (0.89 mol) at 0°C. The mixture was stirred at 90°C for 1 hour until gas evolution stopped. The mixture was cooled down to room temperature and a solution of 139.71 g of 3 -methoxybenzyl chloride (0.89 mol) in 400 mL of dry toluene was added. After refluxing for 24 hours, the mixture was cooled to room temperature and quenched with 500 mL of water. The organic layer was separated, dried over MgS04, and concentrated under high vacuum. The remaining starting materials were removed by distillation. The crude dark red oil was filtered through a layer of 1 L of silica gel with neat hexane to yield 53.00 g (25.6%) of the product as a pink solid: *H NMR (CDC13) d 3.79 (s, 3H) , 3.90 (s, 2H) , 4.58 (s, IH) , 6.70-6.74 (m, IH) , 6.79-6.88 (m, 4H) , 7.11-7.16 (m, 2H) .

Step 2. Preparation of 4-fluoro-2- ( (4- methoxyphenyl) methyl) -thiophenol

Step 2a. Preparation of thiocarbamate To a stirred solution of 50.00 g (215.30 mmol) of 4- fluoro-2- ( ( -methoxyphenyl) methyl) -phenol in 500 mL of dry DMF was added 11.20 g of 60% sodium hydride dispersion in mineral oil (279.90 mmol) at 2°C. The mixture was allowed to warm to room temperature and 26.61 g of dimethylthiocarbamoyl chloride (215.30 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched with 100 mL of water in an ice bath. The solution was extracted with 500 mL of diethyl ether. The ether solution was washed with 500 mL of water and 500 mL of brine. The ether solution was dried over MgS04 and stripped to dryness. The crude product was filtered through a plug of 500 mL silica gel using 5% ethyl acetate/hexane to yield 48.00 g (69.8%) of the product as a pale white solid: XH NMR (CDC13) d 3.21 (s, 3H) , 3.46 (s, 3H) , 3.80 (s, 3H) , 3.82 (s, 2H) , 6.78-6.86 (m, 3H) , 6.90- 7.00 (m, 2H) , 7.09 (d, J = 8.7 Hz, 2H) .

Step 2b. Rearrangement and hydrolysis of thiocarbamate to 4-fluoro-2- ( (4 -methoxyphenyl) methyl) -thiophenol A stirred solution of 48.00 g (150.29 mmol) of thiocarbamate (obtained from Step 2a) in 200 mL of diphenyl ether was refluxed at 270°C overnight. The solution was cooled down to room temperature and filtered through 1 L of silica gel with 2 L of hexane to remove phenyl ether. The rearrangement product was washed with 5% ethyl acetate/hexane to give 46.00 g (95.8%) of the product as a pale yellow solid: XH NMR (CDC13) d 3.02 (s, 3H) , 3.10 (s, 3H) , 3.80 (s, 3H) , 4.07 (s, 2H) , 6.82-6.86 (m, 3H) , 6.93 (dt, J = 8.4 Hz, 2.7 Hz, IH) , 7.08 (d, J = 8.7 Hz, 2H) , 7.49 (dd, J = 6.0 Hz, 8.7 Hz, IH) . To a solution of 46.00 g (144.02 mmol) of the rearrangement product (above) in 200 mL of methanol and 200 mL of THF was added 17.28 g of NaOH (432.06 mmol) . The mixture was refluxed under nitrogen overnight . The solvents were evaporated off and 200 mL of water was added. The aqueous solution was washed with 200 mL of diethyl ether twice and placed in an ice bath. The aqueous mixture was acidified to pH 6 with concentrated HCl solution. The solution was extracted with 300 mL of diethyl ether twice. The ether layers were combined, dried over MgS04 and stripped to dryness to afford 27.00 g (75.5%) of the product as a brown oil: XH NMR (CDC13) d 3.24 (s, IH) , 3.80 (s, 3H) , 3.99 (s, 2H) , 6.81-6.87 (m, 4H) , 7.09 (d, J = 8.7 Hz, 2H) , 7.27- 7.33 (m, IH) .

Step 3. Preparation of dibutyl cyclic sulfate

Step 3a. Preparation of 2 , 2-dibutyl-l, 3-propanediol . To a stirred solution of di-butyl-diethylmalonate (Aldrich) (150g, 0.55 mol in dry THF (700ml) in an acetone/dry ice bath was added LAH (1 M THF) 662 ml (1.2 eq. , 0.66 mol) dropwise maintaining the temperature between -20 to 0°C. The reaction was stirred at RT overnight. The reaction was cooled to -20°C and 40 ml of water, and 80 mL of 10% NaOH and 80 ml of water were added dropwise. The resulting suspension was filtered. The filtrate was dried over sodium sulphate and concentrated in vacuo to give diol 598.4 g (yield 95%) as an oil. MS spectra and proton and carbon NMR spectra were consistent with the product.

Step 3b. Preparation of dibutyl cyclic sulfite

A solution of 2 , 2-dibutyl-l, 3-propanediol (103 g, 0.548 0 mol, obtained from Step 3a) and triethylamine (221 g, 2.19 mol) in anhydrous methylene chloride (500 ml) was stirred at 0°C under nitrogen. To the mixture, thionyl chloride (97.8* g, 0.82 mol) was added dropwise and within 5 min the solution turned yellow and then black when the addition was 5 completed within half an hour. The reaction mixture was stirred for 3 hrs. at 0°C. GC showed that there was no starting material left. The mixture was washed with ice water twice then with brine twice . The organic phase was dried over magnesium sulfate and concentrated under vacuum 0 to give 128 g (100%) of the dibutyl cyclic sulfite as a black oil. Mass spectrum (MS) was consistent with the product .

Step 3c. Oxidation of dibutyl cyclic sulfite to 5 dibutyl cyclic sulfate

To a solution of the dibutyl cyclic sulfite (127.5 g , 0.54 mol, obtained from Step 3b) in 600 ml acetonitrile and 500 ml of water cooled in an ice bath under nitrogen was added ruthenium (III) chloride (1 g) and sodium periodate 0 (233 g, 1.08 mol) . The reaction was stirred overnight and the color of the solution turned black. GC showed that there was no starting material left. The mixture was extracted with 300 ml of ether and the ether extract was washed three times with brine. The organic phase was dried over magnesium sulfate and passed through celite. The filtrate was 5 concentrated under vacuum and to give 133 g (97.8%) of the dibutyl cyclic sulfate as an oil. Proton and carbon NMR and MS were consistent with the product.

Step 4. Preparation of aryl-3-hydroxypropylsulfide

10 To a stirred solution of 27.00 g (108.73 mmol) of 4- fluoro-2- ( (4-methoxyphenyl) methyl) thiophenol (obtained from Step 2) in 270 mL of diglyme was added 4.35 g of 60% sodium-, hydride dispersion in mineral oil (108.73 mmol) at 0°C. After gas evolution ceased, 29.94 g (119.60 mmol) of the

15 dibutyl cyclic sulfate (obtained from Step 3c) was added at 0°C and stirred for 10 minutes. The mixture was allowed to warm up to room temperature and stirred overnight. The solvent was evaporated and 200 mL of water was added. The solution was washed with 200 mL of diethyl ether and added

2025 mL of concentrated sulfuric acid to make a 2.0 M solution that was refluxed overnight. The solution was extracted with ethyl acetate and the organic solution was dried over MgS04 and concentrated in vacuo. The crude aryl-3 – hydroxypropylsulfide was purified by silica gel

25 chromatography (Waters Prep 500) using 8% ethyl acetate/hexane to yield 33.00 g (72.5%) of the product as a light brown oil: E NMR (CDC13) d 0.90 (t, J = 7.1 Hz, 6H) , 1.14-1.34 (m, 12H) , 2.82 (s, 2H) , 3.48 (s, 2H) , 3.79 (s, 3H) , 4.10 (s, 2H) , 6.77-6.92 (m, 4H) , 7.09 (d, J = 8.7 Hz,

302H) , 7.41 (dd, J = 8.7 Hz, 5.7 Hz, IH) . Step 5. Preparation of enantiomerically-enriched aryl-3 – hydroxypropylsulfoxide

To a stirred solution of 20.00 g (47.78 mmol) of aryl- 53 -hydroxypropylsulfide (obtained from Step 4) in 1 L of methylene chloride was added 31.50 g of 96% (12?) – ( -) – (8 , 8- dichloro-10-camphor-sulfonyl) oxaziridine (100.34 mmol, Aldrich) at 2°C. After all the oxaziridine dissolved the mixture was placed into a -30 °C freezer for 72 hours. The

10 solvent was evaporated and the crude solid was washed with 1 L of hexane. The white solid was filtered off and the hexane solution was concentrated in vacuo. The crude oil was purified on a silica gel column (Waters Prep 500) using 15% ethyl acetate/hexane to afford 19.00 g (95%) of the

15 enantiomerically-enriched aryl-3 -hydroxypropylsulfoxide as a colorless oil: lH NMR (CDC13) d 0.82-0.98 (m, 6H) , 1.16-1.32 (m, 12H) , 2.29 (d, J – 13.8 Hz, IH) , 2.77 (d, J = 13.5 Hz, IH) , 3.45 (d, J = 12.3 Hz, IH) , 3.69 (d, J = 12.3 Hz, IH) , 3.79 (s, 3H) , 4.02 (q, J = 15.6 Hz, IH) , 6.83-6.93 (m, 3H) ,

207.00 (d, J = 8.1 Hz, 2H) , 7.18-7.23 (m, IH) , 7.99-8.04 (m, IH) . Enantiomeric excess was determined by chiral HPLC on a (2?,2?) -Whelk-0 column using 5% ethanol/hexane as the eluent. It showed to be 78% e.e. with the first eluting peak as the major product.

25

Step 6. Preparation of enantiomerically-enriched aryl-3- propanalsulfoxide

To a stirred solution of 13.27 g of triethylamine (131.16 mmol, Aldrich) in 200 mL dimethyl sulfoxide were

30 added 19.00 g (43.72 mmol) of enantiomerically-enriched aryl-3 -hydroxypropylsulfoxide (obtained from Step 5) and 20.96 g of sulfur trioxide-pyridine (131.16 mmol, Aldrich) at room temperature. After the mixture was stirred at room temperature for 48 hours, 500 mL of water was added to the mixture and stirred vigorously. The mixture was then 5 extracted with 500 mL of ethyl acetate twice. The ethyl acetate layer was separated, dried over MgS04, and concentrated in vacuo. The crude oil was filtered through 500 mL of silica gel using 15% ethyl acetate/hexane to give 17.30 g (91%) of the enantiomerically-enriched aryl-3-

10 propanalsulfoxide as a light orange oil: lE NMR (CDC13) d 0.85-0.95 (m, 6H) , 1.11-1.17 (m, 4H) , 1.21-1.39 (m, 4H) , 1.59-1.76 (m, 4H) , 1.89-1.99 (m, IH) , 2.57 (d, J = 14.1 Hz, IH) , 2.91 (d, J = 13.8 Hz, IH) , 3.79 (s, 3H) , 3.97 (d, J = 15.9 Hz, IH) , 4,12 (d, J = 15.9 Hz, IH) , 6.84-6.89 (m, 3H) ,

157.03 (d, J = 8.4 Hz, 2H) , 7.19 (dt, J = 8.4 Hz, 2.4 Hz, IH) , 8.02 (dd, J = 8.7 Hz, 5.7 Hz, IH) , 9.49 (s, IH) .

Step 7. Preparation of the enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R, 5R)

20 To a stirred solution of 17.30 g (39.99 mmol) of enantiomerically-enriched aryl-3 -propanalsulfoxide (obtained from Step 6) in 300 mL of dry THF at -15°C was added 48 mL of 1.0 M potassium t-butoxide in THF (1.2 equivalents) under nitrogen. The solution was stirred at -15°C for 4 hours.

25 The solution was then quenched with 100 mL of water and neutralized with 4 mL of concentrated HCl solution at 0°C. The THF layer was separated, dried over MgS04, and concentrated in vacuo. The enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (4R,5R) was purified by

30 silica gel chromatography (Waters Prep 500) using 15% ethyl acetate/hexane to give 13.44 g (77.7%) of the product as a white solid: ‘H NMR (CDC13) d 0.87-0.97 (m, 6H) , 1.16-1.32 (m, 4H) , 1.34-1.48 (m, 4H) , 1.50-1.69 (m, 4H) , 1.86-1.96 (m, IH) , 2.88 (d, J = 13.0 Hz, IH) , 3.00 (d, J = 13.0 Hz, IH) , 3.85 (s, 3H) , 4.00 (s, IH) , 4.48 (s, IH) , 6.52 (dd, J = 9.9 5Hz, 2.4 Hz, IH) , 6.94 (d, J = 9 Hz, 2H) , 7.13 (dt, J = 8.4 Hz, 2.4 Hz, IH) , 7.38 (d, J = 8.7 Hz, 2H) , 7.82 (dd, J = 8.7 Hz, 5.7 Hz, IH) .

Step 8. Preparation of enantiomerically-enriched

10 tetrahydrobenzothiepine-1, 1-dioxide (4R, 5R)

To a stirred solution of 13.44 g (31.07 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1-oxide (obtained from Step 7) in 150 mL of methylene chloride was added 9.46 g of 68% m-chloroperoxybenzoic acid (37.28 mmol,

15 Sigma) at 0 °C. After stirring at 0 °C for 2 hours, the mixture was allowed to warm up to room temperature and stirred for 4 hours. 50 mL of saturated Na2S03 was added into the mixture and stirred for 30 minutes. The solution was then neutralized with 50 mL of saturated NaHC03 solution.

20 The methylene chloride layer was separated, dried over MgS04, and concentrated in vacuo to give 13.00 g (97.5%) of the enantiomerically-enriched tetrahydrobenzothiepine-1, 1- dioxide (4R,5R) as a light yellow solid: ‘H NMR (CDC13) d 0.89-0.95 (m, 6H) , 1.09-1.42 (m, 12H) , 2.16-2.26 (m, IH) ,

253.14 (q, J = 15.6 Hz, IH) , 3.87 (s, 3H) , 4.18 (s, IH) , 5.48 (s, IH) , 6.54 (dd, J = 10.2 Hz, 2.4 Hz, IH) , 6.96-7.07 (m, 3H) , 7.40 (d, J = 8.1 Hz, 2H) , 8.11 (dd, J = 8.6 Hz, 5.9 Hz, IH) .

30 Step 9. Preparation of enantiomerically-enriched 7-

(dimethylamino) tetrahydrobenzothiepine-1 , 1-dioxide (4R.5R) – To a solution of 13.00 g (28.98 mmol) of enantiomerically-enriched tetrahydrobenzothiepine-1, 1- dioxide (obtained from Step 8) in 73 mL of dimethylamine (2.0 M in THF, 146 mmol) in a Parr Reactor was added ca . 20 5 mL of neat dimethylamine . The mixture was sealed and stirred at 110 °C overnight, and cooled to ambient temperature. The excess dimethylamine was evaporated. The crude oil was dissolved in 200 mL of ethyl acetate and washed with 100 mL of water, dried over MgS04 and

10 concentrated in vacuo. Purification on a silica gel column (Waters Prep 500) using 20% ethyl acetate/hexane gave 12.43 g (90.5%) of the enantiomerically- enriched 7- (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (4R, 5R) as a colorless solid: *H NMR (CDC13) d 0.87-0.93 (m, 6H) ,

151.10-1.68 (m, 12H) , 2.17-2.25 (m, IH) , 2.81 (s, 6H) , 2.99 (d, J = 15.3 Hz, IH) , 3.15 (d, J = 15.3 Hz, IH) , 3.84 (s, 3H) , 4.11 (d, J = 7.5 Hz, IH) , 5.49 (s, IH) , 5.99 (d, J = 2.4 Hz, IH) , 6.51 (dd, J = 8.7 Hz, 2.4 Hz, IH) , 6.94 (d, J = 8.7 Hz, 2H) , 7.42 (d, J = 8.4 Hz, 2H) , 7.90 (d, J = 8.7 Hz,

20 IH) . The product was determined to have 78% e.e. by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. Recrystallization of this solid from ethyl acetate/hexane gave 1.70 g of the racemic product. The remaining solution was concentrated and recrystallized to

25 give 9.8 g of colorless solid. Enantiomeric excess of this solid was determined by chiral HPLC on a Chiralpak AD column using 5% ethanol/hexane as the eluent. It showed to have 96% e.e with the first eluting peak as the major product.

30 Step 10: Demethylation of 5- (4 ‘ -methoxyphenyl) -7-

(dimethylamino) tetrahydrobenzothiepine-1.1-dioxide (4R, 5R) To a solution of 47 g (99 mmol) of enantiomeric- enriched (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (obtained from Step 9) in 500 mL of methylene chloride at -10 °C was added dropwise a solution of boron tribromide (297 mL, 1M in methylene chloride, 297 mmol), and the resulting solution was stirred cold (-5 °C to 0 °C) for 1 hour or until the reaction was complete. The reaction was cooled in an acetone-dry ice bath at -10 °C, and slowly quenched with 300 mL of water. The mixture was warmed to 10 °C, and further diluted with 300 mL of saturated sodium bicarbonate solution to neutralize the mixture. The aqueous layer was separated and extracted with 300 mL of methylene chloride, and the combined extracts were washed with 200 mL of water, brine, dried over MgS04 and concentrated in vacuo. The residue was dissolved in 500 mL of ethyl acetate and stirred with 50 mL of glacial acetic acid for 30 minutes at ambient temperature. The mixture was washed twice with 200 mL of water, 200 mL of brine, dried over MgS04 and concentrated in vacuo to give the crude 4-hydroxyphenyl intermediate. The solid residue was recrystallized from methylene chloride to give 37.5 g (82%) of the desired (4R, 5R) -5- (4′ – hydoxyphenyl) -7- (dimethylamino) tetrahydrobenzothiepine-1, 1- dioxide as a white solid: *H NMR (CDC13) d 0.84-0.97 (m, 6H) , 1.1-1.5 (m, 10H) , 1.57-1.72 (m, IH) , 2.14-2.28 (m, IH) , 2.83 (s, 6H) , 3.00 (d, J = 15.3 Hz, IH) , 3.16 (d, J – 15.3 Hz, IH) , 4.11 (s, 2H) , 5.48 (s, IH) , 6.02 (d, J – 2.4 Hz, IH) , 6.55 (dd, J = 9, 2.4 Hz, IH) , 6.88 (d, 8 , 7 Hz , 2H) , 7.38 (d, J – 8.7 Hz, 2H) , 7.91 (d, J = 9 Hz, 2H) .

Step 11: Preparation of enantiomerically-enriched chlorobenzyl intermediate Treat a solution of enantiomerically-enriched (4R,5R)- 5- (4′ -hydoxypheny1) -7- (dimethylamino) tetrahydrobenzothiepine-1, 1-dioxide (5.0 g, 10.9 mmol, obtained from Step 10) in acetone (100 mL) at 25 °C under N2 with powdered 5 K2C03 (2.3 g, 16.3 mmol, 1.5 eq.) and a, a’ -dichloro-p-xylene (6.7 g, 38.1 mmol, 3.5 eq.) . Stir the resulting solution at 65 °C for about 48 hours. Cool the reaction mixture to 25 °C and concentrate to 1/5 of original volume. Dissolve the residue in EtOAc (150 mL) and wash with water (2 x 150 mL) .

10 Extract the aqueous layer with EtOAc (2 x 150 mL) and wash the combined organic extracts with saturated aqueous NaCI (2 x 150 mL. Dry the combined extracts with MgS04 and concentrate in vacuo to provide the crude product . Purification by flash chromatography (5.4 x 45 cm silica,

1525-40% EtOAc/hexane) will afford the enantiomerically- enriched chlorobenzyl intermediate .

Step 12: Preparation of enantiomerically-enriched (4R.5R)- 1- r [4- [ [4- [3 , 3-Dibutyl-7- (dimethylamino) -2,3 , 4 , 5-tetrahvdro-

204 -hydroxy-1.1-dioxido-1-benzothiepin-5- yl] phenoxy] methyll phenyl! methyl] -4-aza-l- azoniabicyclo f2.2.2] octane chloride (XXVII)

Treat a solution of the enantiomerically-enriched chlorobenzyl intermediate (4.6 g, 7.7 mmol, obtained from

25 above in Step 11) in acetonitrile (100 mL) at 25 °C under N2 with diazabicyclo [2.2.2] -octane (DABCO, 0.95 g, 8.5 mmol, 1.1 eq.) and stir at 35 °C for 2 hours. Collect the precipitated solid and wash with CH3CN. Recrystallization from CH3OH/Et20 will give the desired title compound (XXVII) .

ANY ERROR,  EMAIL amcrasto@gmail.com, +919323115463

 

///////////FDA, Breakthrough Designation,  Shire, Rare GI Therapies, SHP625, maralixibat, progressive familial intrahepatic , Maralixibat chloride, 228113-66-4, UNII: V78M04F0XC, LUM 001, Lopixibat chloride, cholestasis type 2 (PFIC2), Maralixibat Chloride,  ماراليكسيبات كلوريد ,  氯马昔巴特 , Мараликсибата хлорид

CCCCC1(CS(=O)(=O)c2ccc(cc2[C@H]([C@H]1O)c3ccc(cc3)OCc4ccc(cc4)C[N+]56CCN(CC5)CC6)N(C)C)CCCC.[Cl-]

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The $300,000 Drug

 breakthrough designation  Comments Off on The $300,000 Drug
Jul 192014
 

Kalydeco is truly a wonder drug.

Developed by Vertex Pharmaceuticals, it is the first drug that attacks not just the symptoms but the underlying cause of cystic fibrosis, a genetic lung disease that usually kills victims by the time they reach their 40s. It doesn’t work for every sufferer of the disease, but rather for a small subset — probably around 2,000 people — who have a specific genetic mutation that the drug targets. But for those it helps, it is life changing.  text clipped read at

http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0

Ivacaftor.svg

ivacaftor..kalydeco

read all at

http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0

A drug called Sovaldi, marketed by Gilead Sciences, takes aim at hepatitis C. It is described as a “breakthrough” drug. But each pill costs $1,000

 

sovaldi.sofosbuvir

 

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Dec 102013
 


Sofosbuvir

Sovaldi

M.Wt: 529.45

Formula: C22H29FN3O9P

Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate

A prodrug of 2′-deoxy-2′-alpha-F-2′-beta-C-methyluridine 5′-monophosphate.
GS-7977, PSI-7977

  • GS 7977
  • GS-7977
  • PSI 7977
  • PSI-7977
  • Sofosbuvir
  • Sovaldi
  • UNII-WJ6CA3ZU8B

CAS Registry Number :1190307 -88-0

http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf

Indications: Chronic hepatitis C (HCV GT1, GT2, GT3, GT4)
Mechanism: nucleoside NS5B polymerase inhibitor
approved Time: December 6, 2013
,U.S. Patent Number: 7964580,8415322,8334270,7429572;, patent validity: March 26, 2029 (U.S. Patent No.: 7,964,580 and 8,334,270), April 3, 2025 (U.S. Patent No.: 7,429,572 and 8,415,322)

US patent number 7964580, US patent number 8415322, US patent number 8334270,US patent number 7429572 Patent Expiration Date: March 26, 2029 for US patent number 7964580 and 8334270 (2028 in EU); April 3, 2025 for US patent number 7429572 and 8415322

Sales value (estimated): $ 1.9 billion (2014), 6600000000 USD (2016)

Drug Companies: Gilead Sciences, Inc. (Gilead Sciences)

WASHINGTON, Dec. 6, 2013 (AP) — Federal health officials have approved a highly anticipated hepatitis C drug from Gilead Sciences Inc. that is expected to offer a faster, more palatable cure to millions of people infected with the liver-destroying virus.

The Food and Drug Administration said Friday it approved the pill Sovaldi in combination with older drugs to treat the main forms of hepatitis C that affect U.S. patients.

Current treatments for hepatitis C can take up to a year of therapy and involve weekly injections of a drug that causes flu-like side effects. That approach only cures about three out of four patients. Sovaldi is a daily pill that in clinical trials cured roughly 90 percent of patients in just 12 weeks, when combined with the older drug cocktail.http://www.pharmalive.com/us-approves-breakthrough-hepatitis-c-drug

 

  • The end of October 2013 saw a nod from the FDA given to Gilead’s New Drug Application for Sofosbuvir, a much needed treatment for hepatitis C.
  • As a nucleotide analogue, Sofosbuvir is designed as a once daily treatment.
  • There are roughly 170 million cases of hepatitis C around the world.
  • A report in the Journal of the American Medical Association on August 28, 2013 revealed that the Sofosbuvir and Ribavirin combination treatment effectively cured many patients with the Hepatitis C Virus.
  • The Sofosbuvir and Ribavirin drug combination was void of interferon-based treatments, which  many patients are resistant too.
  • More than 3 million Americans have chronic Hepatitis C Virus, and 22 percent of these patients are African American.

Sofosbuvir (brand names Sovaldi and Virunon) is a drug used for hepatitis C virus (HCV) infection, with a high cure rate.[1][2] It inhibits the RNA polymerase that the hepatitis C virus uses to replicate its RNA. It was discovered at Pharmasset and developed by Gilead Sciences.[3]

Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic Hepatitis C.[4]

In 2013, the FDA approved sofosbuvir in combination with ribavirin (RBV) for oral dual therapy of HCV genotypes 2 and 3, and for triple therapy with injected pegylated interferon (pegIFN) and RBV for treatment-naive patients with HCV genotypes 1 and 4.[4] Sofosbuvir treatment regimens last 12 weeks for genotypes 1, 2 and 4, compared to 24 weeks for treatment of genotype 3. The label furhter states that sofosbuvir in combination with ribavirin may be considered for patients infected with genotype 1 who are interferon-ineligible.[5] Sofosbuvir will cost $84,000 for 12 weeks of treatment and $168,000 for the 24 weeks, which some patient advocates have criticized as unaffordable.

Interferon-free therapy for treatment of hepatitis C eliminates the substantial side-effects associated with use of interferon. Up to half of hepatitis C patients cannot tolerate the use of interferon.[6]

 

Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate.[7] Sofosbuvir is anucleotide analog inhibitor of the hepatitis C virus (HCV) polymerase.[8] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.

The New Drug Application for Sofosbuvir was submitted on April 8, 2013 and received the FDA’s Breakthrough Therapy Designation, which grants priority review status to drug candidates that may offer major treatment advantages over existing options.[9]

On 6th December 2013, the U.S. Food and Drug Administration approved sofosbuvir for the treatment of chronic hepatitis C.[10]

Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[11][12] It has shown clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[13]

Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[14][15]

Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir, and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[16] Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.

Sofosbuvir will cost $84,000 for 12 weeks of treatment used for genotype 1 and 2, and $168,000 for the 24 weeks used for genotype 3.[17] This represents a substantial pricing increase from previous treatments consisting of interferon and ribavirin, which cost between $15,000 and $20,000.[18] The price is also significantly higher than that of Johnson & Johnson‘s recently approved drug simeprevir (Olysio), which costs $50,000 and also treats chronic hepatitis C.[18] The high cost of the drug has resulted in a push back from insurance companies and the like, includingExpress Scripts, which has threatened to substitute lower priced competitors, even if those therapies come with a more unfriendly dosing schedule.[18] Other treatments that have recently entered the market have not matched the efficacy of sofosbuvir, however, allowing Gilead to set a higher price until additional competition enters the market.[18] Patient advocates such as Doctors Without Borders have complained about the price, which is particularly difficult for underdeveloped countries to afford.[19]

ChemSpider 2D Image | Sofosbuvir | C22H29FN3O9P

sofosbuvir

  1.  News: United States to approve potent oral drugs for hepatitis C, Sara Reardon, Nature, 30 October 2013
  2.  Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA (October 2010). “Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus”. J. Med. Chem. 53 (19): 7202–18.doi:10.1021/jm100863xPMID 20845908.
  3.  “PSI-7977”. Gilead Sciences.
  4. Tucker M (December 6, 2013). “FDA Approves ‘Game Changer’ Hepatitis C Drug Sofosbuvir”. Medscape.
  5.  “U.S. Food and Drug Administration Approves Gilead’s Sovaldi™ (Sofosbuvir) for the Treatment of Chronic Hepatitis C – See more at: http://www.gilead.com/news/press-releases/2013/12/us-food-and-drug-administration-approves-gileads-sovaldi-sofosbuvir-for-the-treatment-of-chronic-hepatitis-c#sthash.T9uTbSWK.dpuf”. Gilead. December 6, 2013.
  6.  “Sofosbuvir is safer than interferon for hepatitis C patients, say scientists”. News Medical. April 25, 2013.
  7.  Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA (November 2010). “Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977”J. Biol. Chem. 285 (45): 34337–47.doi:10.1074/jbc.M110.161802PMC 2966047PMID 20801890.
  8.  Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
  9.  “FDA Advisory Committee Supports Approval of Gilead’s Sofosbuvir for Chronic Hepatitis C Infection”Drugs.com. October 25, 2013.
  10.  “FDA approves Sovaldi for chronic hepatitis C”FDA New Release. U.S. Food and Drug Administration. 2013-12-06.
  11.  Murphy T (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”.Bloomberg Businessweek.
  12.  Asselah T (January 2014). “Sofosbuvir for the treatment of hepatitis C virus”. Expert Opin Pharmacother 15 (1): 121–30. doi:10.1517/14656566.2014.857656PMID 24289735.
  13.  “AASLD 2012: Sofosbuvir and daclatasvir dual regimen cures most people with HCV genotypes 1, 2, or 3”News. European Liver Patients Association. 2012-11-21.
  14.  AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
  15.  Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (January 2013). “Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C”.N. Engl. J. Med. 368 (1): 34–44. doi:10.1056/NEJMoa1208953PMID 23281974.
  16.  CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
  17.  Campbell T (December 11, 2013). “Gilead’s Sofosbuvir Gets New Name, Price, Headaches”. The Motley Fool.
  18.  Cohen, J. (2013). “Advocates Protest the Cost of a Hepatitis C Cure”. Science 342 (6164): 1302–1303. doi:10.1126/science.342.6164.1302PMID 24337268edit

The chemical structure 

Chemical Structure of Sovaldi_Sofosbuvir_Hepatatis C-Gilead

GS-7977, (S)-isopropyl 2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4- dihydropyrimidin^l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate, available from Gilead Sciences, Inc., is described and claimed in U.S. Patent No. 7,964,580. (See also US 2010/0016251, US 2010/0298257, US 201 1/0251 152 and US 2012/0107278.) GS-7977 has the structure:

 

Figure imgf000013_0001

GS-7977 can be crystalline or amorphous. Examples of preparing crystalline and amorphous forms of GS-7977 are disclosed in US 2010/0298257 (US 12/783,680) and US 201 1/0251 152 (US 13/076,552),

 

 

 

Chemical Synthesis of Sofosbuvir_Sovaldi_GS-7977_PSI-7977_Hepatitis C_Gilead

 

Commerically available isopropylidine protected D-glyceraldehyde was reacted with (carbethoxyethylidene)triphenylmethylphosphorane gave the chiral pentenoate ester YP-1. Permanganate dihydroxylation of YP-1 in acetone gave the D-isomer diol YP-2. The cyclic sulfate YP-3 was obtained by first making the cyclic sulfite with thionyl chloride and then oxidizing to cyclic sulfate with sodium hypochlorite. Fluorination of YP-3 with triethylamine-trihydrofluoride(TEA-3HF) in the presence of triethylamine, followed by the hydrolysis of sulfate ester in the presence of concentrated HCl provided diol YP-4 which was benzoylated to give ribonolactone YP-5. Reduction of YP-5 with Red-Al followed by chlorination with sulfuryl chloride in the presence of catalytic amount of tetrabutylammonium bromide yielded YP-6. The conversion of YP-6 to benzoyl protected 2′-deoxyl-2′-alpha-F-2′-Beta-C-methylcytidine (YP-7) was achieved by using O-trimethyl silyl-N4-benzoylcytosine and stannic chloride. Preparation of the uridine nucleoside YP-8 was accomplished by first heating benzoyl cytidine YP-7 in acetic acid then treating with methoanolic ammonia to provide YP-8 in 78% yield.

The phosphoramidating reagent YP-9 was obtained by first reacting phenyldichlorophosphate with L-Alanine isopropyl ester hydrochloride and then with pentafluorophenol. Isolation of single Sp diastereomer YP-9 was achieved via crystallization-induced dynamic resolution in the presence of 20% MTBE/hexane at room temperature.

The uridine nucleoside YP-8 was treated with tert-butylmagnesium chloride in dry THF, followed by pentafluorophenyl Sp diastereomer YP-9 to furnish the Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate (Sovaldi, sofosbuvir, GS-7977, PSI-7977)。

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US 7429572

US  8415322

US 7964580

US 8334270B

 

WO 2006012440

WO 2011123668

US8334270

/US20080139802

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In US 20050009737 published Jan. 13, 2005, J. Clark discloses fluoro-nucleoside derivatives that inhibit Hepatitis C Virus (HCV) NS5B polymerase. In particular, 4-amino-1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-faran-2-yl)-1H-pyrimidin-2-one (18) was a particularly potent inhibitor of HCV polymerase as well as the polymerase of other Flaviviridae.

 

Figure US20080139802A1-20080612-C00002

 

In WO2006/012440 published Feb. 2, 2006, P. Wang et al disclose processes for the preparation of 18. Introduction of the cytosine is carried out utilizing the Vorbruggen protocol. In US 20060122146 published Jun. 8, 2006, B.-K. Chun et al. disclose and improved procedures for the preparation of the 2-methyl-2-fluoro-lactone 10. In the latter disclosure the nucleobase is glycosylated by reacting with ribofuranosyl acetate which is prepared by reduction of 10 with LiAlH(O-tert-Bu)followed by acetylaton of the intermediate lactol which was treated with an O-trimethylsilyl N4-benzoylcytosine in the presence of SnClto afford the O,O,N-tribenzoylated nucleoside.

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http://www.google.nl/patents/US20080139802

The present process as described in SCHEME A and the following examples contain numerous improvements which have resulted in higher yields of the desired nucleoside. The asymmetric hydroxylation of 22 was discovered to be best carried out with sodium permanganate in the presence of ethylene glycol, sodium bicarbonate in acetone which afforded the diol in 60-64% on pilot plant scale. The sodium permanganate procedure avoids introduction of osmium into the process stream. Further more the stereospecific hydroxylation can be accomplished without using an expensive chiral ligand. The requisite olefin is prepared from (1S,2S)-1,2-bis-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethane-1,2-diol (20) (C. R. Schmid and J. D. Bryant, Org. Syn. 1995 72:6-13) by oxidative cleavage of the diol and treating the resulting aldehyde with 2-(triphenyl-λ5-phosphanylidene)-propionic acid ethyl ester to afford 22.

 

Figure US20080139802A1-20080612-C00005

 

(i) NaIO4, NaHCO3, DCM; (ii) MeC(═PPh3)CO2Et; (iii) acetone-NaMnO(aq), ethylene glycol, NaHCO3, −10 to 0° C.; aq. NaHSO(quench); (iv) i-PrOAc, MeCN, TEA, SOCl2; (v) i-PrOAc, MeCN, NaOCl; (vi) TEA-3HF, TEA; (vii) HCl (aq)-BaCl2-aq; (viii) (PhCO)2O, DMAP, MeCN, (ix) RED-AL/TFE (1:1), DCM; (x) SO2Cl2-TBAB, DCM; (xi) 32, SnCl4-PhCl; (xii) MeOH-MeONa

EXAMPLE 3 (2S,3R)-3-[(4R)-2,2-dimethyl-[1,3]dioxolan-4-yl]-2,3-dihydroxy-2-methyl-propionic acid ethyl ester (24)

 

Figure US20080139802A1-20080612-C00008

 

A suspension of 22 (10 kg, CAS Reg. No. 81997-76-4), ethylene glycol (11.6 kg), solid NaHCO(11.8 kg) and acetone (150 L) is cooled to ca.-15° C. A solution of 36% aqueous NaMnO(19.5 kg) is charged slowly (over 4 h) to the suspension maintaining reaction temperature at or below −10° C. After stirring for 0.5 h at −10° C., an aliquot of the reaction mixture (ca. 5 mL) is quenched with 25% aqueous sodium bisulfite (ca. 15 mL). A portion of resulting slurry is filtered and submitted for GC analysis to check the progress of the reaction. When the reaction is complete, the reaction mixture is quenched by slow addition (over 40 min) of cooled (ca. 0° C.) 25% aqueous NaHSO(60 L). The temperature of the reaction mixture is allowed to reach 4° C. during the quench. CELITE® (ca. 2.5 kg) is then slurried in acetone (8 kg) and added to the dark brown reaction mixture. The resulting slurry is aged at RT to obtain light tan slurry. The slurry is filtered, and the filter cake is washed with acetone (3×39 kg). The combined filtrate is concentrated by vacuum distillation (vacuum approximately 24 inches of Hg; max pot temperature is 32° C.) to remove the acetone. The aqueous concentrate is extracted with EtOAc (3×27 kg), and the combined organic extracts were washed with water (25 L). The organic phase is then concentrated by atmospheric distillation and EtOAc is replaced with toluene. The volume of the batch is adjusted to ca. 20 L. Heptane (62 kg) is added and the batch cooled to ca. 27° C. to initiate crystallization. The batch is then cooled to −10° C. After aging overnight at −10° C., the product is filtered, washed with 10% toluene in heptane and dried at 50° C. under vacuum to afford 6.91 kg (59.5%) of 24 (CARN 81997-76-4) as a white crystalline solid.

EXAMPLE 4 (3R,4R,5R)-3-Fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-dihydro-furan-2-one (10)

 

Figure US20080139802A1-20080612-C00009

 

steps 1 & 2—A dry, clean vessel was charged with 24 (6.0 kg), isopropyl acetate (28.0 kg), MeCN (3.8 kg) and TEA (5.4 kg). The mixture was cooled to 5-10° C., and thionyl chloride (3.2 kg) was added slowly while cooling the solution to maintain the temperature below 20° C. The mixture was stirred until no starting material was left (GC analysis). The reaction was typically complete within 30 min after addition is complete. To the mixture was added water (9 kg) and after stirring, the mixture was allowed to settle. The aqueous phase was discarded and the organic phase was washed with a mixture of water (8 kg) and saturated NaHCO(4 kg) solution. To the remaining organic phase containing 36 was added MeCN (2.5 kg) and solid NaHCO(3.1 kg). The resulting slurry was cooled to ca. 10° C. Bleach (NaOCl solution, 6.89 wt % aqueous solution, 52.4 kg, 2 eq.) was added slowly while cooling to maintain temperature below 25° C. The mixture was aged with stirring over 90-120 min at 20-25° C., until the reaction was complete (GC analysis). After completion of the reaction, the mixture was cooled to ca. 10° C. and then quenched with aqueous Na2SOsolution (15.1% w/w, 21 kg) while cooling to maintain temperature below 20° C. The quenched reaction mixture was filtered through a cartridge filter to remove inorganic solids. The filtrate was allowed to settle, and phases are separated and the aqueous phase is discarded. The organic layer was washed first with a mixture of water (11 kg) and saturated NaHCOsolution (4.7 kg), then with of saturated NaHCOsolution (5.1 kg). DIPEA (220 mL) was added to the organic phase and the resulting solution was filtered through CELITE® (bag filter) into a clean drum. The reactor was rinsed with isopropyl acetate (7 kg) and the rinse is transferred to the drum. The organic phase was then concentrated under vacuum (25-28 inches of Hg) while maintaining reactor jacket temperature at 45-50° C. to afford 26 as an oil (˜10 L). Additional DIPEA (280 mL) was added and the vacuum distillation was continued (jacket temperature 50-55° C.) until no more distillate was collected. (batch volume ca. 7 L).

step 3—To the concentrated oil from step 2 containing 26 was added TEA (2.34 kg) and TEA-trihydrofluoride (1.63 kg). The mixture was heated to 85° C. for 2 h. The batch was sampled to monitor the progress of the reaction by GC. After the reaction was complete conc. HCl (2.35 kg) was added to the mixture and the resulting mixture heated to ca. 90° C. (small amount of distillate collected). The reaction mixture was stirred at ca. 90° C. for 30 min and then saturated aqueous BaCl2solution (18.8 kg) was added. The resulting suspension was stirred at about 90° C. for 4 h. The resulting mixture was then azeotropically dried under a vacuum (9-10 inches of Hg) by adding slowly n-propanol (119 kg) while distilling off the azeotropic mixture (internal batch temperature ca. 85-90° C.). To the residual suspension was added toluene (33 kg) and vacuum distillation was continued to distill off residual n-propanol (and traces of water) to a minimum volume to afford 28.

step 4—To the residue from step 3 containing 28 was added MeCN (35 kg) and ca. 15 L was distilled out under atmospheric pressure. The reaction mixture was cooled to ca. 10° C. and then benzoyl chloride (8.27 kg) and DMAP (0.14 kg) are added. TEA (5.84 kg) was added slowly to the reaction mixture while cooling to maintain temperature below 40° C. The batch was aged at ca. 20° C. and the progress of the benzoylation is monitored by HPLC. After completion of the reaction, EtOAc (30 kg) was added to the mixture and the resulting suspension is stirred for about 30 min. The reaction mixture was filtered through a CELITE® pad (using a nutsche filter) to remove inorganic salts. The solid cake was washed with EtOAc (38 kg). The combined filtrate and washes were washed successively with water (38 kg), saturated NaHCOsolution (40 kg) and saturated brine (44 kg). The organic phase was polish-filtered (through a cartridge filter) and concentrated under modest vacuum to minimum volume. IPA (77 kg) was added to the concentrate and ca. 25 L of distillate was collected under modest vacuum allowing the internal batch temperature to reach ca. 75° C. at the end of the distillation. The remaining solution was then cooled to ca. 5° C. over 5 h and optionally aged overnight. The precipitate was filtered and washed with of cold (ca. 5° C.) IPA (24 kg). The product was dried under vacuum at 60-70° C. to afford 6.63 kg (70.7% theory of 10 which was 98.2% pure by HPLC.

EXAMPLE 1 Benzoic acid 3-benzoyloxy-5-(4-benzoylamino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-4-methyl-tetrahydro-furan-2-ylmethyl ester (14)

 

Figure US20080139802A1-20080612-C00006

 

Trifluoroethanol (4.08 kg) is added slowly to a cold solution (−15° C.) of RED-AL® solution (12.53 kg) and toluene (21.3 kg) while maintaining the reaction temperature at or below −10° C. After warming up to RT (ca. 20° C.), the modified RED-AL reagent mixture (30.1 kg out of the 37.6 kg prepared) is added slowly to a pre-cooled solution (−15° C.) of fluorolactone dibenzoate 10 (10 kg) in DCM (94.7 kg) while maintaining reaction temperature at or below −10° C. After reduction of the lactone (monitored by in-process HPLC), a catalytic amount of tetrabutylammonium bromide (90 g) is added to the reaction mixture. Sulfiiryl chloride (11.86 kg) is then added while maintaining reaction temperature at or below 0° C. The reaction mixture is then heated to 40° C. until formation of the chloride is complete (ca. 4 h) or warmed to RT (20-25° C.) and stirred over night (ca. 16 h). The reaction mixture is cooled to about 0° C., and water (100 L) is added cautiously while maintaining reaction temperature at or below 15° C. The reaction mixture is then stirred at RT for ca. 1 h to ensure hydrolytic decomposition of excess sulfuryl chloride and the phases are separated. The organic layer is washed with a dilute solution of citric acid (prepared by dissolving 15.5 kg of citric acid in 85 L of water) and then with dilute KOH solution (prepared by dissolving 15 kg of 50% KOH in 100 L of water). The organic phase is then concentrated and solvents are replaced with chlorobenzene (2×150 kg) via atmospheric replacement distillation. The resulting solution containing 30 is dried azeotropically.

A suspension of N-benzoyl cytosine (8.85 kg), ammonium sulfate (0.07 kg) and hexamethyldisilazane (6.6 kg) in chlorobenzene (52.4 kg) is heated to reflux (ca. 135° C.) and stirred (ca. 1 h) until the mixture becomes a clear solution. The reaction mixture is then concentrated in vacuo to obtain 32 as a syrupy liquid. The anhydrous solution of 30 in chlorobenzene (as prepared) and stannic chloride (28.2 kg) is added to this concentrate. The reaction mixture is maintained at about 70° C. until the desired coupling reaction is complete (ca. 10 h) as determined by in-process HPLC. Upon completion, the reaction mixture is cooled to RT and diluted with DCM (121 kg). This solution is added to a suspension of solid NaHCO(47 kg) and CELITE® (9.4 kg) in DCM (100.6 kg). The resulting slurry is cooled to 10-15° C., and water (8.4 kg) is added slowly to quench the reaction mixture. The resulting suspension is very slowly (caution: gas evolution) heated to reflux (ca. 45° C.) and maintained for about 30 min. The slurry is then cooled to ca. 15° C. and filtered. The filter cake is repeatedly reslurried in DCM (4×100 L) and filtered. The combined filtrate is concentrated under atmospheric pressure (the distillate collected in the process is used for reslurrying the filter cake) until the batch temperature rises to about 90° C. and then allowed to cool slowly to about −5° C. The resulting slurry is aged for at least 2 h at −5° C. The precipitated product is filtered and washed with IPA (30 kg+20 kg), and oven-dried in vacuo at about 70° C. to afford 8.8 kg (57.3%) of 1-(2-deoxy-2-fluoro-2-methyl-3-5-O-dibenzoyl-β-D-ribofuranosyl)-N-4-benzoylcytosine (14, CAS Reg No. 817204-32-3) which was 99.3% pure.

EXAMPLE 2 4-Amino-1-(3-fluoro-4-hydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one (18)

 

Figure US20080139802A1-20080612-C00007

 

A slurry of 14 (14.7 kg) in MeOH (92.6 kg) is treated with catalytic amounts of methanolic sodium methoxide (0.275 kg). The reaction mixture is heated to ca. 50° C. and aged (ca. 1 h) until the hydrolysis is complete. The reaction mixture is quenched by addition of isobutyric acid (0.115 kg). The resulting solution is concentrated under moderate vacuum and then residual solvents are replaced with IPA (80 kg). The batch is distilled to a volume of ca. 50 L. The resulting slurry is heated to ca. 80° C. and then cooled slowly to ca. 5° C. and aged (ca. 2 h). The precipitated product is isolated by filtration, washed with IPA (16.8 kg) and dried in an oven at 70° C. in vacuo to afford 6.26 kg (88.9%) of 18 which assayed at 99.43% pure.

 

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https://www.google.com/patents/US8334270

EXAMPLE 4 Preparation of 2′-deoxy-2′-fluoro-2′-C-methyluridine

 

 

2′-Deoxy-2′-fluoro-2′-C-methylcytidine (1.0 g, 1 eq) (Clark, J., et al., J. Med. Chem., 2005, 48, 5504-5508) was dissolved in 10 ml of anhydrous pyridine and concentrated to dryness in vacuo. The resulting syrup was dissolved in 20 ml of anhydrous pyridine under nitrogen and cooled to 0° C. with stirring. The brown solution was treated with benzoyl chloride (1.63 g, 3 eq) dropwise over 10 min. The ice bath was removed and stirring continued for 1.5 h whereby thin-layer chromatography (TLC) showed no remaining starting material. The mixture was quenched by addition of water (0.5 ml) and concentrated to dryness. The residue was dissolved in 50 mL of dichloromethane (DCM) and washed with saturated NaHCOaqueous solution and H2O. The organic phase was dried over NaSOand filtered, concentrated to dryness to give N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, Yield: 91%).

N4,3′,5′-tribenzoyl-2′-Deoxy-2′-fluoro-2′-C-methylcytidine (2.0 g, 1 eq) was refluxed in 80% aqueous AcOH overnight. After cooling and standing at room temperature (15° C.), most of the product precipitated and then was filtered through a sintered funnel. White precipitate was washed with water and co-evaporated with toluene to give a white solid. The filtrate was concentrated and co-evaporated with toluene to give additional product which was washed with water to give a white solid. Combining the two batches of white solid gave 1.50 g of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (Yield: 91%).

To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60%).

 

Example numbers 13-54 and 56-66 are prepared using similar procedures described for examples 5-8. The example number, compound identification, and NMR/MS details are shown below:

 

entry 25
Figure US08334270-20121218-C00063
entry 251H NMR (DMSO-d6) δ 1.13-1.28 (m, 12H), 3.74-3.81 (m, 2H), 3.95-4.08 (m, 1H), 4.20-4.45 (m, 2H), 4.83-4.87 (m, 1H), 5.52-5.58 (m, 1H),5.84-6.15 (m, 3H), 7.17-7.23 (m, 3H), 7.35-7.39 (m, 2H), 7.54-7.57(m, 1H), 11.50 (s. 1H); MS, m/e 530.2 (M + 1)+

 

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Synthesis of diastereomerically pure nucleotide phosphoramidates.

Ross BS, Reddy PG, Zhang HR, Rachakonda S, Sofia MJ.

J Org Chem. 2011 Oct 21;76(20):8311-9. doi: 10.1021/jo201492m. Epub 2011 Sep 26.

The HCV NS5B nucleoside and non-nucleoside inhibitors.

Membreno FE, Lawitz EJ.

Clin Liver Dis. 2011 Aug;15(3):611-26. doi: 10.1016/j.cld.2011.05.003. Review.

Discovery of a β-d-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.

Sofia MJ, Bao D, Chang W, Du J, Nagarathnam D, Rachakonda S, Reddy PG, Ross BS, Wang P, Zhang HR, Bansal S, Espiritu C, Keilman M, Lam AM, Steuer HM, Niu C, Otto MJ, Furman PA.

J Med Chem. 2010 Oct 14;53(19):7202-18. doi: 10.1021/jm100863x.

Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977.

Murakami E, Tolstykh T, Bao H, Niu C, Steuer HM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman PA.

J Biol Chem. 2010 Nov 5;285(45):34337-47. doi: 10.1074/jbc.M110.161802. Epub 2010 Aug 26.

 

Michael J. Sofia,Donghui Bao, Wonsuk Chang, Jinfa Du, Dhanapalan Nagarathnam, Suguna Rachakonda, P. Ganapati Reddy, Bruce S. Ross, Peiyuan Wang, Hai-Ren Zhang, Shalini Bansal, Christine Espiritu, Meg Keilman, Angela M. Lam, Holly M. Micolochick Steuer, Congrong Niu, Michael J. Otto, and Phillip A. Furman; Discovery of a β-D-2-Deoxy-2-a-fluoro-2-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus; J. Med. Chem. 2010, 53, 7202–7218; Pharmasset, Inc.

 

Bruce S. Ross, P. Ganapati Reddy , Hai-Ren Zhang , Suguna Rachakonda , and Michael J. Sofia; Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates; J. Org. Chem., 2011, 76 (20), pp 8311–8319; Pharmasset, Inc.

 

Peiyuan Wang, Byoung-Kwon Chun, Suguna Rachakonda, Jinfa Du, Noshena Khan, Junxing Shi, Wojciech Stec, Darryl Cleary, Bruce S. Ross and Michael J. Sofia; An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase; J. Org. Chem., 2009, 74 (17), pp 6819–6824;Pharmasset, Inc.

 

Jeremy L. Clark, Laurent Hollecker, J. Christian Mason, Lieven J. Stuyver, Phillip M. Tharnish, Stefania Lostia, Tamara R. McBrayer, Raymond F. Schinazi, Kyoichi A. Watanabe, Michael J. Otto, Phillip A. Furman, Wojciech J. Stec, Steven E. Patterson, and Krzysztof W. Pankiewicz; Design, Synthesis, and Antiviral Activity of 2‘-Deoxy-2‘-fluoro-2‘-C-methylcytidine, a Potent Inhibitor of Hepatitis C Virus Replication; J. Med. Chem., 2005, 48 (17), pp 5504–5508; Pharmasset, Inc

 

 

 

SOVALDI is the brand name for sofosbuvir, a nucleotide analog inhibitor of HCV NS5B polymerase.

The IUPAC name for sofosbuvir is (S)-Isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-(phenoxy)phosphorylamino)propanoate. It has a molecular formula of C22H29FN3O9P and a molecular weight of 529.45. It has the following structural formula:

 

 

SOVALDI™ (sofosbuvir) Structural Formula Illustration

 

Sofosbuvir is a white to off-white crystalline solid with a solubility of ≥ 2 mg/mL across the pH range of 2-7.7 at 37 oC and is slightly soluble in water.

SOVALDI tablets are for oral administration. Each tablet contains 400 mg of sofosbuvir. The tablets include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol, and microcrystalline cellulose. The tablets are film-coated with a coating material containing the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

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SEE………………….http://orgspectroscopyint.blogspot.in/2015/02/sofosbuvir-visited.html

J. Med. Chem. 2005, 48, 5504.
WO2008045419A1
CN201180017181

 

 

(WO2015139602) Sofosbuvir New Patent

(WO2015139602) 2′-SUBSTITUTED-2,2′-DEHYDRATED URIDINE OR 2′-SUBSTITUTED-2,2′-DEHYDRATED CYTIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF
ZHANG, Rongxia
A further object of the present invention to provide a method for preparing a compound of formula I.
The present invention provides a process for preparing a compound I 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-cytidine using the following formula or 2′-deoxy-2′-substituted 2′-2′-substituted nitrile or uridine 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound,
2′-deoxy-2′-fluoro-2′-methyl-uridine (IIIa) is the preparation of anti-hepatitis C drugs Sofosbuvir key intermediate.
Sofosbuvir developed by Gilead Science Company, FDA on December 6, 2013 Sofosbuvir formally approved for the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is first used to treat certain types of HCV infection without the use of interferon effective and safe drugs. Clinical trials have shown, sofosbuvir can achieve very high proportion of sustained virologic response (clinical cure). More revolutionary breakthrough that, sofosbuvir without joint peginterferon α situation is still very significant effect, such as sofosbuvir ribavirin genotype 2 and genotype 3 patients with previously untreated chronic hepatitis C continued virological response rate of 100%. Sofosbuvir is a prodrug is metabolized in vivo to 2′-deoxy-2′-fluoro-2′-methyl-uridine-5′-monophosphate.
Currently reported 2′-deoxy-2′-fluoro-2′-methyl uridine synthetic methods are as follows:

In the literature (Journal of Medicinal Chemistry, 2005,48,5504) in order cytidine as a raw material, first selectively protected 3 ‘, 5′-hydroxyl group, and then oxidizing the 2′-hydroxyl to a carbonyl group, and the reaction of methyllithium get the 2’-hydroxyl compound, and then removing the protective group, use benzoyl protected 3 ‘, 5’-hydroxyl group, and then reacted with DAST fluorinated compound, followed by hydrolysis and aminolysis reaction products, such as the following Reaction Scheme. The method of route length, the need to use expensive silicon ether protecting group molecule relatively poor economy; conducting methylation time will generate a non-methyl enantiomer beta bits.

In Patent (WO2005003147, WO2006031725A2, US20040158059) using 2′-fluoro-2′-methyl – ribose derivative with N- benzoyl cytosine for docking the reaction, then after the hydrolysis, aminolysis reaction to obtain the final product, As shown in the following reaction scheme. Raw material of the process is not readily available, synthetic steps cumbersome, expensive; the reaction product obtained contained docking base for the alpha position isomers, need purification removed to form waste.
SUMMARY OF THE INVENTION
The present inventors have designed and synthesized a compound of formula I as shown, the compound may be a fluorinated or nitrile reaction of 2′-deoxy-2′-fluoro-2′-get-substituted uridine or 2 under appropriate conditions’ – 2′-deoxy-2′-fluoro-2′-deoxy-2′-substituted cytidine or nitrile uridine or 2′-substituted-2′-deoxy-2′-substituted-2′-cytidine nitrile compound; or a compound of formula I or a nitrile group by fluoro reaction, followed by deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro–2 ‘- cytidine or 2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2′-cytidine compound nitrile group; or a compound of formula I through the opening cyclization reaction, and then through the group of fluoro or nitrile, and finally deprotection reaction to give 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2’-substituted Cellular glycoside or 2 ‘substituted-2′-deoxy-2′-carbonitrile 2′-deoxy-uridine or 2′-substituted-2’-cytidine compound nitrile group; or a compound of formula I through a ring-opening reaction, and then 2 ‘- hydroxyl forming a leaving group, and then after a nitrile group or a fluorinated reaction, the final deprotection reaction of 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′- cytidine or 2′-fluoro-2′-substituted-2′-deoxy-2′-nitrile-substituted uridine or 2′-deoxy-2′-substituted-2’-cytidine nitrile compound.
It is therefore an object of the present invention is to provide a compound of the general formula I prepared 2′-deoxy-2′-fluoro-2′-substituted uridine or 2′-deoxy-2′-fluoro-2′-substituted cytidine or 2′-substituted-2′-deoxy-2′-carbonitrile uridine or 2′-deoxy-2′-substituted-2′-carbonitrile The method of cytidine compound.
Example 1:
The 2′-C- methyl uridine (18.4g, 0.07mol), N, N’- carbonyldiimidazole (216.2g, 0.10mol), sodium bicarbonate (8.4g, 0.10mol) was suspended N, N- two dimethylformamide (50ml), the temperature was raised to 130 ℃, reaction for 4 hours, cooled and filtered to remove inorganic salts, the filtrate was added ethyl acetate (200ml), analyze the material at room temperature, suction filtered, washed with ethyl acetate cooled to, drying to give a yellow solid (19.9g, yield: 83%).
Ia: 1 H NMR (300 MHz, CD 3 OD): [delta] 7.80 (d, 1H, J = 7.5 Hz), 6.05 (d, 1H, J = 7.5 Hz), 5.91 (s, 1H), 4.34 (d, 1H, J = 4.8Hz), 4.07 (m, 1H), 3.56 (m, 2H), 1.63 (s, 3H); ESI-MS m / z (M + 1) 241.
Example 2:
The compound of Example 1 Ia (0.24g, 1mmol)) was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure, the residue was added acetone, beating, and filtered to give solid (0.18g, yield: 70%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 3:
Compound Ib (0.45g, 1mmol) was dissolved in a mixture of dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2), dried over anhydrous dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the residue was subjected to column chromatography to give the product (0.36g, yield: 78%).
IIa: 1 H NMR (400 MHz, CDCl 3 and DMSO-d 6 ): [delta] 7.99 (d, J = 7.6 Hz, 2H), 7.90 (d, J = 7.6 Hz, 2H), 7.34 ~ 7.61 (m, 7H ), 6.10 (brs, 1H), 5.64 (brs, 1H), 5.42 (d, J = 8.0Hz, 1H), 4.53-4.68 (m, 3H), 1.40 (d, J = 22.8Hz, 3H); ESI -MS m / z (M + 1) 469.
Example 4:
The compound of Example 3 IIa (0.47g, 1mmol) dissolved in 10% methanol solution of ammonia and stirred overnight, the solvent was removed under reduced pressure, and the residue was slurried in ethyl acetate, filtered to give a white solid (0.2g, yield : 77%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 5:
Compound IVa (0.57g, 1mmol) was dissolved in dichloroethane (20ml) was added trifluoromethanesulfonic acid trimethylsilyl ester (1ml), was heated for 12 hours, cooled, and the reaction solution was concentrated dryness, added two dichloromethane (100ml) was dissolved, washed successively with water (50ml) and saturated brine (50ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give an oil which was purified by column chromatography to give a white solid (0.3g, yield : 67%).
Ib: 1 H NMR (300 MHz, CDCl 3 ): δ7.96-8.10 (m, 6H), 7.41-7.65 (m, 9H), 7.32 (d, 1H, J = 5.4 Hz), 6.09 (d, 1H, J = 5.4Hz), 5.79 (m, 2H), 4.67 (m, 1H), 4.48 (m, 2H), 1.81 (s, 3H); ESI-MS m / z (M-1) 447.
Example 6:
N The compound of Example 1 Ia (1.3g, 5.4mmol) dissolved in dry, N- dimethylformamide (10ml) was added p-toluenesulfonic acid monohydrate (1.12g, 5.9mmol) and 3,4- dihydropyran (1.28ml, 14.04mmol), The reaction was stirred for 5 hours at room temperature, water was added and the methylene chloride solution was separated, the organic layer was concentrated and purified by silica gel chromatography to give the product 1.3g.
Ic: 1 H NMR (300 MHz, CDCl 3 ): [delta] 7.29 (m, 1H), 6.08 (m, 1H), 5.61 (m, 1H), 4.33-4.72 (m, 4H), 3.37-3.90 (m, 6H), 1.43-1.82 (m, 12H), 1.25 (s, 3H); ESI-MS m / z (M + 1) 427.
Example 7:
The solvent was removed, the residue was purified compound of Example 6 Ic (0.43g, 1mmol) was dissolved in 70% HF in pyridine was heated to 100 ~ 120 ℃, stirred for 5 hours, cooled, reduced pressure was purified through silica gel column to give a solid ( 0.18g, yield: 72%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 8:
The compound of Example 6 Ic (50mg, 0.122mmol) was dissolved in methanol (1ml) was added 1N sodium hydroxide solution (0.2ml), stirred at room temperature overnight, water was added and the methylene chloride solution was separated, the organic layer was concentrated after purified by column chromatography to give the product (45mg, yield: 87%).
VA: 1 H NMR (300 MHz, CDCl 3 ): [delta] 7.89 (d, 1H, J = 4.5Hz), 6.01 (s, 1H), 5.95 (d, 1H, J = 4.5Hz), 5.65 (m, 2H ), 4.73 (m, 3H), 4.59 (m, 1H), 3.52-4.30 (m, 4H), 1.56-1.80 (m, 12H), 1.32 (s, 3H); ESI-MS m / z (M + 35) 461.
Example 9:
The mixture of Example 8 Compound Va (0.43g, 1mmol) was dissolved in dichloromethane and pyridine, was added DAST (0.32g), stirred for 24 hours, added dichloromethane (20ml) was diluted with water (30ml × 2) and washed , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound IIb. Compound IIb is dissolved in methanol (10ml) was added p-toluenesulfonic acid (200mg), stirred for 6 hours at room temperature, the methanol was removed under reduced pressure, silica gel column chromatography to give the product IIIa (180mg, yield: 75%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.
Example 10:
The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added N, N’- carbonyldiimidazole (0.194g, 1.2mmol) and sodium bicarbonate (55mg, 0.66mmol), was heated to 130 ℃, stirred for 4 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled, The solvent was removed under reduced pressure, the residue was added to acetone and filtered to obtain a solid IIIa (0.12g, yield: 60%).
Example 11:
The 2′-C- methyl uridine (0.2g, 0.8mmol) was dissolved in N, N- dimethylformamide (4ml) was added diphenyl carbonate (0.256g, 1.2mmol) and sodium bicarbonate ( 55mg, 0.66mmol), was heated to 150 ℃, stirred for 6 hours, cooled and the solvent was removed under reduced pressure, and the residue was dissolved in 70% HF in pyridine was heated to 140 ~ 150 ℃, stirred for 3 hours, cooled and the solvent was removed under reduced pressure The residue was added to acetone and filtered to obtain a solid IIIa (0.13g, yield: 65%).
Example 12:
Under nitrogen, the compound of Example 9 Example Va (4.26g, 10mmol) was dissolved in dry tetrahydrofuran (100ml) was added triethylamine (6g, 60mmol), cooled to -78 ℃, was added trifluoromethanesulfonic anhydride (4.23g , 15mmol), stirred for 1 hour, the reaction system was added saturated ammonium chloride solution, extracted three times with methylene chloride, organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product Vb ( 4g, yield: 72%). ESI-MS m / z (M-1) 557.
Compound Vb (4g) was dissolved in dry tetrahydrofuran, was added tetrabutylammonium fluoride (1.87g, 7.1mmol), warmed to reflux, cooled to room temperature after heating for 1 hour, water was added to the reaction system, and extracted with methylene chloride three times, the combined organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography to give the product IIb (2.7g, yield: 88%). ESI-MS m / z (M-1) 427.
Compound IIb (2.7g) was dissolved in methanol (20ml) was added 3M hydrochloric acid (10ml), 50 ℃ stirred for 8 hours, and concentrated to give a solid, was added acetonitrile, beating, and filtered to give the product IIIa (1g, yield: 61%).
IIIa: 1 H NMR (300 MHz, DMSO-d 6 ): [delta] 11.48 (s, 1H), 7.82 (d, 1H, J = 6.0 Hz), 6.00 (d, 1H, J = 15.6 Hz), 5.67 (m , 2H), 5.30 (s, 1H), 3.85 (m, 3H), 3.62 (s, 1H), 1.25 (d, 3H, J = 16.8Hz), ESI-MS m / z (M-1) 259.








UPDATE DEC2015……….
File:Sofosbuvir structure.svg

SOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

Step (a):

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ8.25 & 7.94 (1: 1);

1 HNMR (CDCl 3 , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

13 C NMR (CDCl 3 , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

Step (b):

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ3.54ppm;

13 C NMR (CDCl 3 , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

MS (M + H): 530.1.

Preparation of compounds of formula 2 shown in Example 3-2

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

1 HNMR (CDCl 3 , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-18.16 / -18.26.

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

(4) nucleophile as NaN 3 , phase transfer catalyst is TBAB

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN 3 (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N 3 ).

1 HNMR (CDCl 3 , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

31 PNMR- (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ2.04 / 2.19.

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

1 HNMR (CDCl 3 , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-2.71 / -2.93.

Preparation Example 3 sofosbuvir implementation

(1) X is SCN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(2) X is N 3

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

(3) X is CN

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

File:Sofosbuvir structure.svg

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Portola gets FDA breakthrough therapy status for andexanet alfa

 breakthrough designation  Comments Off on Portola gets FDA breakthrough therapy status for andexanet alfa
Nov 282013
 

andexanet alfa

Portola gets FDA breakthrough therapy status for andexanet alfa
US-based biopharmaceutical firm Portola Pharmaceuticals has received breakthrough therapy designation from the US Food and Drug Administration (FDA) for its investigational Factor Xa inhibitor antidote, ‘andexanet alfa’.

read all at

http://www.pharmaceutical-technology.com/news/newsportola-gets-fda-breakthrough-therapy-status-for-andexanet-alfa?WT.mc_id=DN_News

Andexanet alfa (PRT4445*): FXa Inhibitor Antidote

Description

  • Recombinant Factor Xa inhibitor antidote
  • Portola has worldwide rights to develop and commercialize andexanet alfa.

Key Characteristics

  • Acts as a Factor Xa decoy that binds and sequesters direct Factor Xa inhibitors in the blood. Once bound to andexanet alfa, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa. The native Factor Xa is then available to participate in the coagulation process and restore hemostasis (normal clotting).
  • Preclinical and Phase 1 studies suggest that andexanet alfa has the potential to be a universal reversal agent for all Factor Xa inhibitors.

Potential Indications

  • Reverse Factor Xa inhibitor anticoagulant activity in patients treated with a Factor Xa inhibitor who suffer an uncontrolled bleeding episode or need to undergo emergency surgery

Clinical Development

Phase 2 proof-of-concept studies are underway or planned. These randomized, double-blind, placebo-controlled studies are designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of andexanet alfa after dosing of a direct/indirect Factor Xa inhibitor in healthy volunteers.

  • Positive pharmacodynamic and safety data from a Phase 2 study evaluating andexanet alfa with Eliquis® (apixaban) were presented in an oral session at the XXIV Congress of the International Society on Thrombosis and Haemostasis in Amsterdam in July 2013. This study is ongoing to evaluate the administration of andexanet alfa bolus plus extended-duration infusion.
  • A Phase 2 study evaluating andexanet alfa and XARELTO® (rivaroxaban) is ongoing.
  • Separate studies evaluating andexanet alfa with Lovenox® (enoxaparin), Lixiana® (edoxaban) and betrixaban are planned.

 

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Roche Gets Breakthrough Status for Lung Cancer Drug

 breakthrough designation, Uncategorized  Comments Off on Roche Gets Breakthrough Status for Lung Cancer Drug
Sep 242013
 

 

ALECTINIB

http://www.who.int/medicines/publications/druginformation/issues/PL_108.pdf

9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-
6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
tyrosine kinase inhibitor, antineoplastic

C30H34N4O2, CAS 1256580-46-7

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation for Roche’s alectinib – a promising investigational 2nd generation ALK inhibitor – based on data that will be presented at European Cancer Congress (ECC). Read more…http://www.dddmag.com/news/2013/09/roche-gets-breakthrough-status-lung-cancer-drug?et_cid=3497158&et_rid=523035093&type=cta

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FDA Grants ‘Breakthrough’ Designation to Synageva Drug

 breakthrough designation  Comments Off on FDA Grants ‘Breakthrough’ Designation to Synageva Drug
May 222013
 

 

SEBELIPASE ALFA

STRUCTURAL FORMULA
SGGKLTAVDP ETNMNVSEII SYWGFPSEEY LVETEDGYIL CLNRIPHGRK 50
NHSDKGPKPV VFLQHGLLAD SSNWVTNLAN SSLGFILADA GFDVWMGNSR 100
GNTWSRKHKT LSVSQDEFWA FSYDEMAKYD LPASINFILN KTGQEQVYYV 150
GHSQGTTIGF IAFSQIPELA KRIKMFFALG PVASVAFCTS PMAKLGRLPD 200
HLIKDLFGDK EFLPQSAFLK WLGTHVCTHV ILKELCGNLC FLLCGFNERN 250
LNMSRVDVYT THSPAGTSVQ NMLHWSQAVK FQKFQAFDWG SSAKNYFHYN 300
QSYPPTYNVK DMLVPTAVWS GGHDWLADVY DVNILLTQIT NLVFHESIPE 350
WEHLDFIWGL DAPWRLYNKI INLMRKYQ 378
Glycosylation sites (N)
Asn-15 Asn-80 Asn-140 Asn-252 Asn-300

http://www.ama-assn.org/resources/doc/usan/sebelipase-alfa.pdf  see cas  no , codes etc

FDA grants ‘breakthrough’ designation to Synageva drug

BOSTON, May 20, 2013 (BOSTON HERALD)–Synageva BioPharma Corp., a Lexington-based biopharmaceutical company that develops drugs for rare diseases, said today that the U.S. Food and Drug Administration has granted breakthrough therapy designation to a drug calledsebelipase alfa to treat early onset lysosomal acid lipase deficiency, also known as Wolman disease.

The designation was based on data generated from clinical trials with sebelipase alfa in patients with early onset LAL Deficiency, officials said.

LAL Deficiency is a rare autosomal recessive lysosomal storage disorder caused by a marked decrease in LAL enzyme activity. Early onset LAL Deficiency is the most rapidly progressive form of LAL Deficiency and is usually fatal within the first six months of life, the company said, adding that affected infants develop severe malabsorption, growth failure and liver failure.

According to the FDA, breakthrough therapy designation is intended to speed up the development and review of drugs for serious or life-threatening conditions.

 

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