Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

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Jan 062017

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Scheme 1. Pfizer’s Commercial Synthesis of sildenafil citrate (Viagra™)

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“Green chemistry” refers to the promotion of safe, sustainable, and waste-minimizing chemical processes. The proliferation of green chemistry metrics without any clear consensus on industry standards is a significant barrier to the adoption of green chemistry within the pharmaceutical industry. We propose the Green Aspiration Level™ (GAL) concept as a novel process performance metric that quantifies the environmental impact of producing a specific pharmaceutical agent while taking into account the complexity of the ideal synthetic process for producing the target molecule. Application of the GAL metric will make possible for the first time an assessment of relative greenness of a process, in terms of waste, versus industry standards for the production process of any pharmaceutical. Our recommendations also include a simple methodology for defining process starting points, which is an important aspect of standardizing measurement to ensure that Relative Process Greenness (RPG) comparisons are meaningful. We demonstrate our methodology using Pfizer’s Viagra™ process as an example, and outline aspiration level opportunities for industry and government to dismantle green chemistry barriers.

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

F. Roschangar,*^a R. A. Sheldon^b and C. H. Senanayake^a

*Corresponding authors

^aChemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^bDelft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands

Green Chem., 2015,17, 752-768

DOI: 10.1039/C4GC01563K, http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01563k#!divAbstract

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one

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Jan 022017

¹³C NMR (DMSO-d₆, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;

1H NMR

¹H NMR (DMSO-d₆, 400 MHz): δ = 2.64 (t, J = 6.8 Hz, 2H), 3.44 (s, 2H), 3.59 (q, J = 6.8 Hz, 2H), 4.62 (t, J = 5.2 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.2 Hz, 1H), 10.30 (s, 1H);

4-(2-Hydroxyethyl)-1,3-dihydro-2H-indol-2-one (13)

…………..as a white solid with 99% purity by HPLC (retention time: 19.0 min).

Mp: 145–147 °C (lit. mp 147–149).(Dagger, R. E.; Fortunak, J. M.; Mastrocola, A. J. Heterocycl. Chem. 1995, 32, 875)

¹³C NMR (DMSO-d₆, 100 MHz): δ = 35.2, 36.8, 61.5, 107.4, 122.5, 125.4, 127.8, 136.1, 143.8, 176.9;

ESI-MS (m/z) 178 [M + H]⁺. Anal. Calcd for C₁₀H₁₁NO₂: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.20; N, 7.82.

Abstract Image

A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.

Org. Process Res. Dev., 2013, 17 (4), pp 714–717

1H NMR PREDICT

DOI: 10.1021/op400024a

13C NMR PREDICT

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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GMP’s for Early Stage Development of new Drug substances and products

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Jan 022017

GMP’s for Early Stage Development of New Drug substances and products

The question of how Good Manufacturing Practice (GMP) guidelines should be applied during early stages of development continues to be discussed across the industry and is now the subject of a new initiative by the International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)—an association of pharmaceutical and biotechnology companies aiming to advance innovation and quality in the development of pharmaceuticals. They have assembled a multidisciplinary team (GMPs in Early Development Working Group) to explore and define common industry approaches and to come up with suggestions for a harmonized approach. Their initial thoughts and conclusions are summarized in Pharm. Technol. 2012, 36 (6), 54–58.

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From an industry perspective, it is common to consider the “early” phase of development as covering phases 1 and 2a clinical studies. During this phase, there is a high rate of product attrition and a high probability for intentionally introducing change into synthetic processes, dosage forms, analytical methods, and specifications. The quality system implemented during this early phase should take into account that these changes and adjustments are intrinsic to the work being performed prior to the determination of the final process and validation of the analytical methods during later stages of development.

FDA guidance is already available on GMP requirements for phase 1 materials. (See Org. Process. Res. Dev. 2008, 12, 817.) Because many aspects of phase 2a clinical studies are similar in their scope and expectations, the working group feels there is an opportunity to extend this guidance across all early phase studies. Because products and processes are less well understood in the early phases of development, activities should focus on accumulating the appropriate knowledge to adequately ensure patient safety. Focusing on this area should ensure that beneficial therapies reach the clinic in an optimum time scale with minimal safety concerns.

A follow-up article ( Pharm. Technol. 2012, 36 (7), 76−84) describes the working group’s approach to the subject of Analytical Method Validation. Their assessment has uncovered the need to differentiate the terms “validation” and “qualification”. Method qualification is based on the type, intended purpose, and scientific understanding of the type of method in use. Although not used for GMP release of clinical materials, qualified methods are reliable experimental methods that may be used for characterization work such as reference standards and the scientific prediction of shelf life. For example, in early development it would be sufficient for methods used for in-process testing to be qualified, whereas those methods used for release testing and for stability determination would be more fully validated.

In early development, a major purpose of analytical methods is to determine the potency of APIs and drug products to ensure that the correct dose is delivered in the clinic. Methods should also indicate stability, identify impurities and degradants, and allow characterization of key attributes. In the later stages, when processes are locked and need to be transferred to worldwide manufacturing facilities, methods need to be cost-effective, operationally viable, and suitably robust such that the methods will perform consistently. irrespective of where they are executed.

The authors advocate that the same amount of rigorous and extensive method-validation experiments, as described in ICH Q2, “Analytical Validation”, is not needed for methods used to support early stage drug development. For example, parameters involving interlaboratory studies (i.e., intermediate precision, reproducibility, and robustness) are not typically performed during early phase development, being replaced by appropriate method-transfer assessments and verified by system suitability requirements. Because of changes in synthetic routes and formulations, the impurities and degradation products formed may change during development.

Accordingly, related substances are often determined using area percentage by assuming that the relative response factors are similar to that of the API. As a result, extensive studies to demonstrate mass balance are typically not conducted during early development.

Detailed recommendations are provided for each aspect of method validation (specificity, accuracy, precision, limit of detection, limit of quantitation, linearity, range, robustness) according to the nature of the test (identification, assay, impurity, physical tests) for both early- and late phase development. These recommendations are also neatly summarized in a matrix form.

Above text drew attention to a series of articles from the IQ Consortium (International Consortium on Innovation and Quality in Pharmaceutical Development) on appropriate good manufacturing practices (GMP) for the early development phases of new drug substances and products. The fifth article in this series(Coutant, M.; Ge, Z.; McElvain, J. S.; Miller, S. A.; O’Connor, D.; Swanek, F.; Szulc, M.; Trone, M. D.; Wong-Moon, K.; Yazdanian, M.; Yehl, P.; Zhang, S.Early Development GMPs for Small-Molecule Specifications: An Industry Perspective (Part V) Pharm. Technol. 2012, 36 ( 10) 86– 94) focuses on the setting of specifications during these early phases (I and IIa).

Due to the high attrition rate in early development, the focus should be on consistent specifications that ensure patient safety, supported by preclinical and early clinical safety studies. On the basis of the cumulative industry experience of the IQ working group members, the authors of this paper propose standardized early phase specification tests and acceptance criteria for both drug substance and drug product. In addition to release and stability tests, consideration is given to internal tests and acceptance criteria that are not normally part of formal specifications, but which may be performed to collect information for product and process understanding or to provide greater control.

Image result for preclinical animal studies

The drug substance used in preclinical animal studies (tox batch) is fundamental in defining the specifications for an early phase clinical drug substance (DS). Here, internal targets rather than formal specifications are routinely used while gathering knowledge about impurities and processing capabilities. At this stage the emphasis should be on ensuring the correct DS is administered, determining the correct potency value, and quantitating impurities for toxicology purposes. For DS intended for clinical studies, additional testing and controls may be required; the testing may be similar to that for the tox batch, but now with established acceptance criteria. For these stages the authors propose a standardized set of DS specifications, as follows.

Description	range of colour
identification	conforms to a reference spectrum
counterion	report results
assay	97–103% on a dry basis
impurities	NMT 3.0% total, NMT 1.0% each
unidentified	NMT 0.3%
unqualified	NMT 0.15%
mutagenic	follow EMA guidelines (pending ICH M7 guidance)
inorganic	follow EMA guidelines (pending ICH Q3D guidance)
residual solvents	use ICH Q3C limits or other justified limits for solvents used in final synthetic step
water content	report results
solid form	report results
particle size	report results
residue on ignition	NMT 1.0%

These may be altered in line with any specific knowledge of the compound in question. For example, if the DS is a hydrate or is known to be hygroscopic or sensitive to water, a specified water content may be appropriate. Of particular note is the use of impurity thresholds which are 3 times higher than those defined in ICH Q3 guidelines. Q3 was never intended to apply to clinical drugs, and higher thresholds can be justified by the limited exposure that patients experience during these early stages. Mutagenic impurities are the exception here, since in this area the existing official guidance does cover clinical drugs.

The fourth article in the series(Acken, B.; Alasandro, M.; Colgan, S.; Curry, P.; Diana, F.; Li, Q. C.; Li, Z. J.; Mazzeo, T.; Rignall, A.; Tan, Z. J.; Timpano, R.Early Development GMPs for Stability (Part IV) Pharm. Technol. 2012, 36 ( 9) 64– 70) considers appropriate approaches to stability testing during early clinical phases. Appropriate stability data at suitable storage conditions are required to support filing the clinical trial application (CTA/IND/IMPD) and use of the clinical material through the end of the clinical study. Several factors from business, regulatory, and scientific perspectives need to be taken into account when designing early stability studies, such as the risk tolerance of the sponsoring organization, the inherent stability of the drug substance and prior product, process and stability knowledge, the regulatory environment in the countries where the clinical trial will be conducted, and the projected future use of the product.

Often non-GMP DS batches are manufactured first and placed on stability to support a variety of product development activities.In many cases these batches will be representative of subsequent GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. In early development, it is common for the manufacturing process to be improved; therefore, as the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted.

The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability—otherwise not. Typical changes encountered at this stage include changes in synthetic pathway, batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps.

In most cases, these changes will not result in changes in DS stability. Changes to the impurity profile are unlikely to affect stability, since most organically related impurities will be inert. On the other hand, catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents may affect stability; thus, changes to these attributes would typically require the new batch to be placed in the stability program. Similarly, any changes to polymorphic form, particle size, or counterion would warrant extra testing. Packaging changes of the bulk material to a less protective package may require stability data to support the change.

Three approaches to stability data collection are commonly used. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH), and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). A second approach is to use high stress conditions such as a high temperature and high humidity with a short time. A third approach is the use of stress studies at several conditions coupled with modelling. The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

Ref

http://www.rcainc.com/wp-content/uploads/2014/06/RCA-GMPs-for-Early-Stage-Development-Projects.pdf

http://www.pharmtech.com/gmps-method-validation-early-development-industry-perspective-part-ii

http://www.pharmtech.com/gmps-small-molecule-drugs-early-development-part-i

https://iqconsortium.org/images/Publications/Presentations/GMPs_Workshop_-_Early_Development_Stability_(Industry_Perspective_-_Tony_Mazzeo,_BMS).pdf

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol , Furofuranol

Uncategorized Comments Off

Dec 232016

CAS :	156928-09-5
Molecular Formula:	C6H10O3
Molecular Weight:	130.144

Furo[2,3-b]furan-3-ol, hexahydro-, [3R-(3α,3aβ,6aβ)]-
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol
3R,3AS,6aR-hexahydrofuro[2,3-b]furan-3-ol
R,S,R-Bisfuran alcohol

WO2012075122 SP ROT= -13.2/1G/100ML, METHANOL

PATENT

http://www.google.com.ar/patents/WO2012070057A1?cl=en

The overall synthesis of the present invention is shown in the scheme 1:

Yet another aspect of present invention is to provide a process for the preparation of compound formula I as per below scheme 2.

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol

(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7) as clear oil (7.8 g, 96.8 A% purity by GC-MS, 55.7 mmol, 74% yield). C₆H₁₀O₃, GC-MS (EI): m/z 100 (M- H₂CO).

¹H NMR (CDCl₃): 1.88 (m, 1H), 2.08 (bd, 1H, −OH), 2.31 (m, 1H), 2.87 (m, 1H), 3.64 (dd, J = 9.2, 7.0 Hz, 1H), 3.87–4.02 (abx system, 3H), 4.45 (m, 1H), 5.70 (d, J = 5.2 Hz, 1H).

¹³C NMR (CDCl₃): 109.54, 73.15, 71.00, 69.90, 46.58, 24.86.

Diastereomeric ratio of 7 to 12 = 98.2:1.8.

GC retention time of 7= 3.20 min; 12 = 3.09 min.

A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol—a key intermediate in the synthesis of darunavir—from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound’s ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.

Practical Synthesis of the Bicyclic Darunavir Side Chain: (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol from Monopotassium Isocitrate

Gary L. Moore, Rodger W. Stringham, David S. Teager, and Tai-Yuen Yue^*

Clinton Health Access Initiative, 800 North Five Points Road, West Chester, Pennsylvania 19380, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00377, http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00377

*E-mail address: tyue@clintonhealthaccess.org.

1H NMR PREDICT

13C NMR PREDICT

PATENT

WO2004033462

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I) . This synthesis is disclosed in detail in A.K. Ghosh et al . , Tetra- hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3- hydroxyhexahydrofuro [2, 3-b] pyran) .

Scheme 1 (prior art)

(91%)

Cobaloxime (catalytic) , NaBH₄, EtOH

Alternatively,

-OAc

0 Immobilized Lipase 30

0- pH 7 buffer 23°C, 24 h

⁽+⁾

R=Ac

MeLi, THF

^ R=H (Compound (I))

The present method of synthesizing bis-THF is summarized as follows:

(78-100%;

(70-90%)

(65-80%;

2. NaBH₄, EtOH (65-75%) -15°C, 1-3 h Compound (I) (bis-THF) Another aspect of the present invention is to provide a method of preparing a compound having a structure

then utilizing the benzyl-protected 5-hydroxymethyl- 5H-furan-2-one in the synthesis of compound (I) .

Another aspect of the present invention is to provide a method of preparing compounds related to bis-THF by using a starting material having a following structure:

R R

The synthesis of bis-THF (compound (I) ) is summarized below:

(1) (2)

(3)

15) (6)

(I)

(3R, 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3-b] uran (I)

(3R, 3aS, 6aR) -3-Hydroxyhexahydrofuxo [2, 3- b] furan (I) : To a solution containing 250 mg (1.95 mmol) (3aS, 6aR) -3-oxyhexahydrofuro [2, 3-b] furan (6) in EtOH (25 mL) was added ’89 mg (2.35 mmol) NaBH₄ at -18 °C. The reaction mixture was stirred at -18 °C for 2.5 hours, then the reaction was quenched with saturated NH₄C1 solution (5 mL) and warmed to room temperature. The resulting mixture was concentrated under reduced pressure, and then 10 mL water was added. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) and a solution of 70% CHC1₃, 20% MeOH, and 10% water (3 x 50 mL) . The combined organic extracts were dried over Na₂S0₄. Column chromatography (silica gel 80 g, MeOH in CHC1₃ 7%) gave compound (I) (178 mg. 70%) as a colorless solid, R_f=0.3, [α]²⁵ _D -12.4°, c 1.3, MeOH. IR (neat) 2951, 1641, 1211 cm^“1; ^XH-NMR (400 MHz CDC1₃) δ: 1.85 (m_c, IH) , 1.94 (bs, IH) , 2.27 (m_c, IH) , 2.84 (m_c, IH) , 3.63 (dd, IH, J=7.1 Hz, J=9.2 Hz), 3.89 (m_c, IH) , 3.97 (m_c, IH) , 4.43 (dd, IH, J=6.8 Hz, J=14.5 ” Hz), 5.68 (d, IH, J=5.2 Hz). ¹³C-NMR (125.8 MHz, CDC1₃, Dept) δ^‘: 25.27 (-) , 46.97 (+) , 70.31 (-) , . 71.26 (-), 73.50 (+) , 109.93. (+) . C₆H₁₀O₃; Exact Mass: 130.06; Mol. Wt . : 130.14; C, 55.37, H, 7.74, 0, 36.88.

Experimentals :

l-(Benzyloxy)-but-3-en-2-ol (±)-(8): To a solution of vinylmagnesium bromide (1 M in THF, 40 mL, 40 mmol) in THF (10 mL) at 0°C was added benz- yloxyacetaldehyde (7) (5 g, 33.3 mmol) dropwise. The mixture was stirred for 10 min at 0°C, and the reaction then was quenched with 20 L of saturated NaHC0₃ solution. The layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 20 mL) , and the combined organic extracts were dried over sodium sulfate. Evaporation of solvent under reduced pressure, followed by column chromatography on silica gel (20% EtOAc in hexanes as the eluent) yielded alcohol (±)-8 (5.22 g, 88%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes); ¹H-NMR (400 MHz, CDC1₃) δ: a 2.79 (bs, IH) , 3.39 (dd, IH, J=1.7, 7.85 Hz), 3.55 (dd, IH, J=3.35, 6.3 Hz), 4.35 (m, IH) , 4.58 (s, IH) , 5.21 (dt, IH, J=7.75, 1.4 Hz), 5.38 (dt, IH, J=14.18, 1.4 Hz), 5.84 (m, IH) , 7.30-7.38 (m, 5H) ; ¹³C-NMR (100.6 MHz, CDC1₃) δ: 71.52, 73.37, 74.02, 116.49, 127.85, 128.49, 136.58, 137.81. (S)-l-(Benzyloxy) -but-3-en-2-ol (9) and (R) -1- (benzyloxy) -but-3-en-2-oyl acetate (10):

A: To a solution of alcohol (±)-(8) (5.21 g, 29.3 mmol) in acetic anhydride (14 mL, 147 mmol) and tert-butyl methyl ether (70 mL, 586 mmol) was added immobilized lipase PS-30 (5.3 g ) on Celite 521 (Aldrich) . The mixture was stirred at room temperature for 20 h, and then filtered through Celite. Removal of solvent under reduced pressure followed, by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate (10) (3.81 g, 54%) R_f=0.57 (30% EtOAc in hexanes) as a clear oil, [of]²⁵ _D -2° (c 1, CHC1₃) ; NMR (500 MHz, CDC1₃) δ: 2.10 (s, 3H) , 3.55-3.59 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.0 Hz), 5.24 (d, IH, J-10.6 Hz), 5.32 (d, IH, J=17.3 Hz), 5.50 (m, IH) , 5.84 (m, IH) , 7.25-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 21.62, 71.67, 73.57, 73.59, 118.39, 128.14, 128.84, 133.77, 138.32, 170.63; alcohol 9 (2.34 g, 45%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D– 8.3° (c 1.06, MeOH) .

B: To a solution of alcohol (±)-(8) (3.92 g, 22.0 mmol) in vinyl acetate (46 mL, 499 mmol) and ethylene glycol dimethyl ether (46 mL, 440 mmol) was added immobilized lipase PS-30 (4 g ) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 28 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10 and 15% EtOAc in hexanes as the eluents) yielded acetate

(10) (2.20 g, 45%) R_f=0.57 (30% EtOAc in hexanes) as a clear oil, [ ]²⁵ _D -2.7° (c 1.35, MeOH); alcohol (9) (2.00 g, 51%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D -11.4° (c 1.6, MeOH).

C: To a solution of alcohol (+)-(8) (30 mg, 0.168 mmol) in isopropenyl acetate (375 μL, 3.36 mmol) and ethylene glycol dimethyl ether (375 μL, 3.61mmol) was added immobilized lipase PS-30 (35 mg) on Celite-545 (Aldrich) . The mixture was stirred at room temperature for 23 h, and then filtered through celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (10) and 15% EtOAc in hexanes as the eluents) yielded acetate 10 (20.3 mg, 54%) as an oil, R_f=0.57 (30% EtOAc in hexanes), [α]²⁵ _D -1.4° (c 1.02, MeOH); alcohol (9) (13 mg, 43%) as a yellow oil, R_f=0.40

(30% EtOAc in hexanes), [ ]²⁵ _D -13.5° (c 1.3, MeOH). (R) -1- (Benzyloxy) -but-3-en-2-ol (11): To a solution of acetate (10) (3.7 g, 16.9 mmol) in methanol (20 mL) was added K₂C0₃ (7 g, 50.6 mmol). The mixture was stirred at room temperature for 35 min. Methanol then was removed under reduced pressure. The resulting solid residue was dissolved in ethyl acetate, washed with saturated NH₄C1 solution and brine, and dried over sodium sulfate. Removal of ethyl acetate under reduced pressure yielded the crude alcohol (11) (3 g, 100%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [α]²⁵ _D 8.3° (c 1.06, MeOH) .

(S)-l- (Benzyloxy) -but-3-en-2-ol (9) from (11): To a solution of crude alcohol (5) (2 g, 11.2 mmol), triphenylphosphine (5.88 g , 22.4 mmol), and 4-nitrobenzoic acid (2.81 g, 16.8 mmol) in benzene (35 mL) was added at room temperature diisopropyl azodicarboxylate (4.35 mL, 22.4 mmol) dropwise. The mixture was stirred for 40 min, followed by the re- moval of solvent under reduced pressure. All of the crude ester then was dissolved in a mixture of MeOH:Et₃N:H₂0 (20ml) in the ratio of 4:3:1 and reacted with LiOH (1.64 g, 39.3 mmol) at room temperature. The mixture was stirred for 2 h, followed by the removal of solvent. Column chromatography on silica gel (15% EtOAc in hexanes as the eluent) yielded alcohol (3) (1.64 g, 82%) as a yellow oil, R_f=0.40 (30% EtOAc in hexanes), [o;]²⁵ _D -7.3° (c 0.82, MeOH) . (S) -1- (Benzyloxy) -but-3-en-2-yl acrylate

(12): To a solution of alcohol (3) (1 g, 5.61 mmol) in CH₂C1₂ (20 L) was added acryloyl chloride (685 μL, 8.41 mmol) dropwise, followed by the addition of Et₃N (1.56 mL, 11.2 mmol). The resulting mixture was stirred for 10 min, and the solvent then was removed under reduced pressure. Filtration of the concentrated crude acrylate through a pad of silica gel using 15% EtOAc in hexanes, followed by the removal of solvent, yielded acrylate (12) (1.19 g, 92%) as a colorless oil, R_f=0.57 (30% EtOAc in hexanes), [α]²⁵ _D -5.7° (c 1.09, CHC1₃) ; ¹H-NMR (500 MHz, CDC1₃) δ: 3.59-3.65 (m, 2H) , 4.56 (q, 2H, J=12.2, 14.65 Hz), 5.25 (d, IH, J=10.6 Hz), 5.33 (d, IH, J=16.8 Hz), 5.57 (m, IH) , 5.84-5.91 (m, 2H) , 6.17 (dd, IH, J=6.9, 10.4 Hz), 6.44 (dd, IH, J=1.3, 16.2 Hz), 7.27-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 71 . 62 , 73 . 58 , 73 . 77 , 118 . 49 , 128 . 05 , 128 . 85 , 131 . 52 , 133 . 62 , 138 . 31 , 165 . 79 .

(5S) -5- (Benzyloxymethyl) -5H-furan-2-one (13): To a solution of acrylate (12) (1.87 g, 8.05 mmol) in CH₂C1₂ (700 mL) was added second generation Grubbs’ catalyst (4 mol %, 170 mg, 0.322 mmol). The reaction mixture was refluxed for 5 hours, and the solvent then was removed under reduced pressure. Column chromatography on silica gel (30% EtOAc in hexanes as the eluent) yielded the furanone (13)

(1.62 g, 98%) as a brown oil, R_f=0.15 (30% EtOAc in hexanes), [α]²⁵ _D -81.3° (c 1.09, MeOH); ^αH-NMR (500 MHz, CDC1₃) δ: 3.66 (dd, IH, J=5.0, 5.5 Hz), 3.71 (dd, IH, J=5.0, 5.2 Hz), 4.57 (s, 2H) , 5.17 (m, IH) , 6.16 (dd, IH, J=1.9, 3.8 Hz), 7.29-7.37 (m, 5H) , 7.48 (dd, IH, J=1.4, 4.3 Hz); ¹³C-NMR (125.8 MHz, CDC1₃) δ: a 69.86, 74.18, 82.61, 123.03, 128.42, 128.95, 137.69, 154.32, 173.19.

(4S ,5S) -5- (Benzyloxymethyl) -4- [1 , 3] di- oxolan-2-yldihydrofuran-2-one (14) : A solution of furanone (13) (1.2 g, 5.88 mmols) and benzophenone

(108 mg, 0.588 mmols) in [1, 3] -dioxolane (108 mg) was degassed for 40 min in a stream of argon. The mixture then was irradiated using one 450 watt ACE glass medium pressure mercury lamp, from a distance of 15 cm, for 9 hours. Progress of this reaction was observed via ¹H-NMR. As the reaction mixture was degassed, and throughout all of the irradiation time, the reaction flask was held in a water cooled cooling mantel. The temperature of the cooling water was constantly maintained near 0°C. Upon completion of the reaction, solvent was removed under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent), yielding the title compound (1.34 g, 82%) as a clear oil, R_f=0.14 (30% EtOAc in hexanes), [α]²⁵ _D 16.5° (c 1.2, CHC1₃) ; ¹H-NMR (500 MHz, CDC1₃) δ: 2.50 (dd, IH, J=3.9, 12.9 Hz), 2.70-2.79 (m, 2H) , 3.58 (dd, IH, J=3.5, 7.2 Hz), 3.75 (dd, IH, J=2.8, 7.9 Hz), 3.87-3.92 (m, 2H) , 3.97-4.00 ( , 2H) , 4.51 (d, IH, J=11.9 Hz), 4.57-4.61 (m, 2H) , 4.88 (d, IH, J=3.6 Hz), 7.26-7.36 (m, 5H) ; ¹³C-NMR (125.8 MHz, CDC1₃) δ: 30.39, 40.53, 65.77, 71.74, 73.99, 79.52, 104.14, 128.00, 128.89, 138.07, 176.79.

(4S,5S) -4-[l,3]Dioxolan-2-yl-5-hydroxy- methyldihydrofuran-2-one (15) : To a solution of dihydrofuranone (14) (0.5 g, 1.79 mmol) in MeOH (30 mL) was added Pd/C (25 mg) . The mixture was stirred at room temperature under an H₂ balloon for 24 hours, and then filtered over Celite. Removal of solvent under reduced pressure, followed by column chromatography on silica gel (35% EtOAc in hexanes as the eluent) yielded the compound (15) (301 mg, 89%) as a white solid, R_f=0.28 (50% EtOAc in hexanes), [ ]²⁵ _D 22° (c 1.32, CHC1₃) ; ^XH-NMR (500 MHz, CDC1₃) δ: 2.54 (dd, IH, J=6.0, 11.4 Hz), 2.68-2.81 (m, 2H) , 3.66

(dd, IH, J=3.9-8.5 Hz), 3.88-3.95 (m, 3H) , 3.97-4.02 (m, 2H) , 4.53 (m, IH) , 4.91 (d, IH, J=3.9 Hz); ¹³C- NMR (125.8 MHz, CDC1₃) δ: 30.68, 40.12, 64.36, 65.77, 81.07, 103.94, 176.83. (3S , 3aS , 6aR) -3-Hydroxyhexahydrofuro [2 , 3- b] furan (5) : To a solution of lithium aluminum hydride (76 mg, 1.98 mmols) in THF (10 ml) at 0°C was added dihydrofuranone 15 (275 mg , 1.46 mmol) in THF (30 mL ) dropwise. Upon completion of the reduction after 4 hours, the reaction was quenched with a saturated aqueous sodium sulfate solution at 0°C. The solvent then was decanted and the remaining residue was washed with THF (3x) , EtOAc (3x) , and CHC1₃ (3x) . The organic extracts were combined and the solvent was removed under reduced pressure, yielding a crude (2S, 3S) -3- [1, 3] dioxolan-2- ylpentane-1, 2, 5-triol, which was immediately used in the next reaction.

The crude triol was dissolved in a mixture of THF:H₂0 (8ml) in the ratio of a 5:1. This solu- tion then was acidified at room temperature to pH 2- 3 with 1 N hydrochloric acid, and was stirred for 40 hours. Removal of solvent with the aid of benzene under reduced pressure, followed by column chromatography purification on silica gel (5% MeOH in CHCI₃ as the eluent) yielded the compound (5) (145 mg,

77%) as a white solid, R_f=0.40 (15% MeOH in CHC1₃) , [α]²⁵ _D -25.1° (c 1.05, CHC1₃) ; ^XH-NMR (500 MHz, CDCI3) δ: 1.67 ( , IH) , 2.13 (m, IH) , 2.31 (bs, IH) , 2.79 (m, IH) , 3.80-3.88 (m, 3H) , 3.95 (dd, IH, J=3.2, 7.1 Hz), 4.20 (d, IH, J=3.1 Hz), 5.86 (d, IH, J=4.9 Hz). Preparation of bis-THF derivative (I) (by Mitsunobu inversion of compound (5) ) : To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), tri- phenylphosphine (1.6 g, 61.4 mmol), and p-nitroben- zoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23 °C was added diisoproylazodicarboxylate (DIAD, 1.2 L, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et₃N:H₂0 (24 mL) , then treated with LiOH (450 mg, 10.7 mmol) . The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-

THF (I) (326 mg, 82%); [ ]²⁵ _D -12.4 (c 1.16 , MeOH)

In particular, the following synthetic scheme (1) illustrates the present commercial method of synthesizing compound (I). This synthesis is disclosed in detail in A.K. Ghosh et al., Tetra. hedron Letters, 36 (4) , pp. 505-508 (1995), incorporated herein by reference. Also see, A.K. Ghosh et al., J. Med. Chem . , 39, pp. 3278-3290 (1996) for the synthesis of compound (I) and a related compound of structural formula (II) (i.e., (3S, 3aR, 7aS) -3-hydroxyhexahydrofuro [2, 3-b] pyran).

The present method of synthesizing bis-THF is summarized as follows:

The synthesis of bis-THF (compound (I) ) is summarized below:

previously.

REF

Ghosh, Arun K.; Journal of Organic Chemistry 2004, 69(23), pg 7822-7829
Kulkarni, Mukund G.; Tetrahedron: Asymmetry 2010, 21(19), pg 2394-2398
Quaedflieg, Peter J. L. M.; Organic Letters 2005, 7(26), pg 5917-5920
Black, David M.; Tetrahedron: Asymmetry 2008, 19(17), pg 2015-2019
Ghosh, Arun K.; Synthesis 2006, (18),pg 3015-3018
Canoy, Will L.; Organic Letters 2008, 10(6), pg 1103-1106
Ghosh, Arun K.; ACS Medicinal Chemistry Letters 2011, 2(4), pg 298-302
Kesteleyn, Bart Rudolf Romanie; WO 2003022853 A1 2003
Yu, Richard H.; Organic Process Research & Development 2007, 11(6), pg 972-980
Khmelnitsky, Yuri L.; Organic Process Research & Development 2011, 15(1), pg 279-283

//////////(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, furofuranol, DARUNAVIR

O[C@H]1CO[C@H]2OCC[C@@H]12

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Uncategorized Comments Off

Dec 222016

Abstract Image

The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Joseph D’Attoma^†, Titi Camara^‡, Pierre Louis Brun^‡, Yves Robin^‡, Stéphane Bostyn^*^§, Frédéric Buron^*^†

, and Sylvain Routier^*^†

^† Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 CEDEX 2 Orléans, France

^‡ ISOCHEM, 4 Rue Marc Sangnier, BP 16729, 45300 Pithiviers, France

^§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, Avenue de la Recherche Scientifique, 45071 CEDEX 2 Orléans, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00318, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00318

*E-mail: frederic.buron@univ-orleans.fr., *E-mail: sylvain.routier@univ-orleans.fr., *E-mail: stephane.bostyn@univ-orleans.fr.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

2,5-Dichloro-1,3-benzoxazole (33)

The reaction was carried out as described in general procedure B using 2-Amino-5-chlorobenzoxazole (221 mg, 1.31 mmol). After purification with silica flash chromatography (EP 100%), the product was isolated as a yellow oil (62 mg, 25%).

CAS number 3621-81-6.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

¹³C NMR (101 MHz, Chloroform-d) δ 152.27 (C), 150.12 (C), 142.06 (C), 130.79 (C), 125.85 (CH), 119.78 (CH), 111.16 (CH).

HRMS [M + H]+ (EI) calcd for C₇H₄Cl₂NO: 187.9664, found: 187.9663.

1H NMR PREDICT

13 C NMR PREDICT

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

5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

Uncategorized Comments Off

Dec 212016

COSY PREDICT

1H NMR PREDICT

¹H NMR (DMSO-d₆, 400 MHz): δ_H 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).

13C NMR PREDICT

¹³C NMR (DMSO-d₆, 100 MHz): δ_C 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);

Houben-Weyl methods of organic chemistry, 4th ed.; Vol. E 9c Hetarenes III part 3; p 279.

5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one (Impurity A)

M.p.: 252.09 °C.

¹H NMR (DMSO-d₆, 400 MHz): δ_H 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).

¹³C NMR (DMSO-d₆, 100 MHz): δ_C 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);

HRMS (ESI) calcd for C₁₃H₁₇O₃N₆: 305. 13338 ([M + H]⁺), found; 305.13566([M + H]⁺).

IR (KBr, cm^–1): 3248.13 (NH), 2970.38 and 2931.80 (CH), 1705.07 and 1689.64 (C═O), 1564.27 (NH bending), 1512.19 (C═N).

Study on the Isolation and Chemical Investigation of Potential Impurities in Dexrazoxane Using 2D-NMR and LC-PDA-MS

Vinodh Guvvala^§^†, Venkatesan Chidambaram Subramanian^*^†, Jayashree Anireddy^§, and Mahesh Konda^*^†

^§ Centre for Chemical Science & Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University, Hyderabad 500085, Telangana, India

^†Gland Pharma Ltd, Research and Development, D.P.Pally, Hyderabad 500043, Telangana, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00219

Publication Date (Web): December 7, 2016

*E-mail: venkatesan@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800., *E-mail: maheshk@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00219

Vinodh Guvvala

A chemical investigation of process related impurities associated with the synthesis of dexrazoxane was performed. The degradation product of dexrazoxane is known in the literature; however, the information related to process impurities is not available. For the first time, two process related impurities were isolated, characterized, and confirmed by their individual chemical synthesis. The present study describes the isolation methods of the impurities and their structural elucidation using IR, ¹H, ¹³C, 2D NMR, and mass spectrometry. The identification of these impurities would be highly valuable for the quality control during the production of the dexrazoxane drug substance

The U.S. Food and Drug Administration (FDA)(5) and the European Medicine Agency (EMA)(6) require analytical characterization not only for the active pharmaceutical ingredient (API), but also for its key starting materials and advanced intermediates. The determination of a drug substance impurity profile, including especially known pharmacopeial impurities, as well as other unknown impurities, could have a significant impact on the quality and the safety of the drug products. The health implications of the impurities could be significant because of their potential mutagenic or carcinogenic effects. Therefore, the International Conference on Harmonization (ICH) has set a high standard for the purity of drug substances.(7) If the dose is less than 2 g/day, then impurities over 0.10% are expected to be identified, qualified, and controlled. If the dose exceeds 2 g/day, then the qualification threshold is lowered to 0.05%. It is therefore essential to monitor and control the impurities in both the drug substance (API) and the drug products.

5 Guidance for Industry on Abbreviated New Drug Applications: Impurities in Drug Substances; Availability;Fed. Regist. 2009, 74, 34359– 34360.
6.The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Impurities in New Drug Substances Q3A (R2); IGH: Geneva, Switzerland, 2006.
7.International Conference on Harmonization; revised guidance on Q3A impurities in new drug Substances; Availability; Fed. Regist. 2003, 68, 6924– 6925.

//////////5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

O=C1Nc3ncncc3N(C1)[C@@H](C)CN2CC(=O)NC(=O)C2

Synthesis of (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Dec 212016

Cas 1204588-48-6

MF C₂₁ H₂₀ N₄ O₄

_{MW 392.41}

Benzenamine, 2,4-dinitro-N-[(2E,4E)-4-phenyl-5-(1-pyrrolidinyl)-2,4-pentadien-1-ylidene]-, [N(E)]-

(E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

Molbank 2009, 2009(3), M604; doi:10.3390/M604

http://www.mdpi.com/1422-8599/2009/3/M604/htm

Synthesis of (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

Nosratollah Mahmoodi ¹^,*, Manuchehr Mamaghani ¹, Ali Ghanadzadeh ², Majid Arvand ³ and Mostafa Fesanghari ¹

¹Laboratory of Organic Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran,

²Departments of Physical Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran

³Departments of Analytical Chemistry, Faculty of Science, University of Guilan, P.O.Box 1914, Rasht, Iran

*Author to whom correspondence should be addressed

mahmoodi@guilan.ac.ir, m-chem41@guilan.ac.ir, aggilani@guilan.ac.ir, arvand@guilan.ac.ir, nosmahmoodi@gmail.com

Abstract:

(E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene) aniline dye was prepared in one pot by reaction of premade N-2,4-dinitrophenyl-3-phenylpyridinium chloride (DNPPC) and pyrrolidine in absolute MeOH.

Keywords:

N-2,4-dinitrophenyl-3-phenylpyridinium chloride (DNPPC); photochromic; pyridinium salt

N-2,4-Dinitrophenyl-3-phenylpyridinium chloride (DNPPC) 1 was prepared according to the literature method [1,2,3,4,5,6,7]. Recently, we became interested in the synthesis of photochromic compounds [8,9,10]. The UV-Vis spectra under irradiation of UV light of dye 2 indicate photochromic properties for this molecule. The salt 1 was premade and typically isolated and purified by recrystallization and characterized. To a solution of 1-chloro-2,4-dinitrobenzene (1.42 g, 7.01 mmol) in acetone (10 mL) was added 3-phenylpyridine (1.0 mL, 6.97 mmol). The reaction was heated at reflux for 48 h. The solvent was removed under reduced pressure and the red residue was stirred in hexanes. The precipitated product was collected by vacuum filtration to afford pure pyridinium salt 1 as a reddish brown solid (2.23 g, 6.25 mmol, 90%). ¹H NMR (CDCl₃, 500 MHz): δ (ppm) 9.9 (s, 1H), 9.4 (d, J = 6.0 Hz, 1H), 9.3 (d, J = 8.3 Hz, 1H), 9.2 (d, J = 2.2 Hz, 1H), 9.0 (dd, J = 8.7, 2.4 Hz, 1H), 8.5-8.6 (m, 2H), 8.0 (d, J = 7.3 Hz, 2H), 7.6- 7.7 (m, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 149.2, 145.6, 144.3, 144.2, 143.0, 139.2, 138.7, 132.5, 132.3, 130.6, 130.2, 129.6, 128.0, 127.6, 121.3; IR (KBr pellet) 3202, 3129, 2994, 2901, 1609 cm^-1; m. p. = 182-183 °C; HRMS m/z Calcd for C₁₇H₁₂N₃O₄⁺ (M)⁺ 322.0828, found 322.0836.

Reaction of pyrrolidine with salt (1) leads to the opening of the pyridinium ring and formation of dye 2. This dye was prepared from reaction of salt 1 (0.5 g, 1.4 mmol) in 5 mL absolute MeOH after cooling a reaction mixture to -10^oC and keeping at this temperature for 15 min. To this was added pyrrolidine (0.1 g, 1.4 mmol) in 3 mL absolute MeOH over a period of 10 min. The prepared solid was filtered, washed with CH₂Cl₂, dried and recrystallized from n-hexane to yield 68% (0.37 g, 0.95 mmol) of pure metallic greenish-brown 2,

m.p. = 146 ^oC.

IR (KBr): 3040, 2950, 1616, 1514, 1492, 1469, 1321, 1215, 1170, 1105, 956, 904, 862, 727 cm^-1.

¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.7 (d, J = 2.4 Hz, 1H) 8.3 (dd, J = 2.4, 8.84 Hz, 1H), 8.0 (s, 1H), 7.5 (d, J = 7.4 Hz, 2H), 7.4-7.5 (t, J = 7.5 Hz, 2H), 7.3-7.4 (m, 1H), 7.2 (d, J = 12.5 Hz, 1H), 7.1 (d, J = 8.9 Hz, 1H), 7.0 (d, J = 12.1 Hz, 1H), 5.4 (t, J = 12.2 Hz, 1H), 3.3 (br, 4H), 2.0 (br, 4H);

¹³C NMR (125 MHz, CDCl₃): δ (ppm) 22.0, 55.6, 114.7, 117.4, 120.0, 124.1, 126.4, 128.7, 128,8, 129.0, 132.7, 137.1, 137.3, 142.9, 147.8, 150.2, 163.8.

Anal. Calcd for C₂₁H₂₀N₄O₄: %C = 64.28, %H = 5.14, %N = 14.28. Found: %C = 64.08, %H = 5.11, %N = 14.07.

1H NMR PREDICT

ACTUAL….

13 C NMR PREDICT

ACTUAL…….¹³C NMR (125 MHz, CDCl₃): δ (ppm) 22.0, 55.6, 114.7, 117.4, 120.0, 124.1, 126.4, 128.7, 128,8, 129.0, 132.7, 137.1, 137.3, 142.9, 147.8, 150.2, 163.8.

////////////Synthesis, (E)-2,4-Dinitro-N-((2E,4E)-4-phenyl-5-(pyrrolidin-1-yl)penta-2,4-dienylidene)aniline

[O-][N+](=O)c3ccc(\N=C\C=C\C(=C/N1CCCC1)c2ccccc2)c([N+]([O-])=O)c3

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Dec 202016

2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester

2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d‘éthyle

Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate

Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat

1206769-44-9

2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)

AGN-PC-0JIRMK

AKOS016034964

ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate

MWt310.819

MFC16H23ClN2O2

NMR IS EASY

1H NMR PREDICT

ACTUAL VALUES……..¹H NMR (400 MHz, CDCl₃): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH₂-CH₃), 1.35 (s, 6H, 2 x CH₃), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 4.20 (q, 2H, J = 7.2 Hz, -CH₂-CH₃), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).

13C NMR PREDICT

ACTUAL VALUES……..¹³C NMR (100 MHz, CDCl₃): δ ppm 14.3 (CH₃), 22.7 ((CH₃)₂), 46.6 (-CH₂-N-CH₂-), 49.7 (-CH₂-N-CH₂-), 60.5 (O-CH₂), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).

Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30^oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

Melting Point: 56^oC.

EI-MS m/z (rel. int. %): 311 (100) [M+1]⁺, 236(40), 197(60), 154(45).

IR ν _max (KBr) cm^-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH₂-CH₃), 1.35 (s, 6H, 2 x CH₃), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 4.20 (q, 2H, J = 7.2 Hz, -CH₂-CH₃), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).

¹³C NMR (100 MHz, CDCl₃): δ ppm 14.3 (CH₃), 22.7 ((CH₃)₂), 46.6 (-CH₂-N-CH₂-), 49.7 (-CH₂-N-CH₂-), 60.5 (O-CH₂), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).

Elemental analysis: Calculated for C₁₆H₂₃ClN₂O₂: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.

Molbank 2009, 2009(3), M607; doi:10.3390/M607

http://www.mdpi.com/1422-8599/2009/3/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

Hari N. Pati^1,* ,Bijay K. Mishra¹ andVijay S. Satam²

¹Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India

²Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India

^*Author to whom correspondence should be addressed.

Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, ¹H NMR, ¹³C NMR and Mass spectroscopic data are reported.

Keywords: 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropionic acid; N-alkylation; 4-(4-Chlorophenyl)piperazine

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CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C

Prof. K.V. Thomas Endowment International Symposium on New Trends in Applied Chemistry (NTAC -2017) 9-11 February, 2017, Department of Chemistry, Sacred Heart College (Autonomous), Thevara, Kochi, India

CONFERENCE, Uncategorized Comments Off

Nov 052016

Hearty Welcome to International Symposium, NTAC – 2017

The organizing committee of NTAC – 2017 and The Post Graduate and Research Department of Chemistry, Sacred Heart College (Autonomous),Thevara, Kochi , India are pleased to announce and invite you to attend the Prof. K.V. Thomas Endowment International symposium on New Trends in Applied Chemistry-2017 (NTAC-2017).

Prof. K.V. Thomas Endowment International Symposium on New Trends in Applied Chemistry (NTAC -2017)9-11 February, 2017, Department of Chemistry, Sacred Heart College (Autonomous), Thevara, Kochi, India link ishttp://www.ntac.shcollege.in/ please click

Symposium Dates: 9-11 February, 2017

Last Date for Abstract Submission: 9th December 2016

Last Date for Submission of Full Paper: 9th January 2017

Early Bird Registration: 9th December 2016

SH Symposium

Hearty Welcome to International Symposium, NTAC – 2017

The organizing committee of NTAC – 2017 and The Post Graduate and Research Department of Chemistry, Sacred Heart College (Autonomous),Thevara, Kochi are pleased to announce and invite you to attend the Prof. K.V. Thomas Endowment International symposium on New Trends in Applied Chemistry-2017 (NTAC-2017).
VENUE

Inaugural Session: Sacred Heart College,Thevara

Technical Sessions: Crowne Plaza, Kochi

Eminent scholars and young investigators, covering different parts of the globe are expected to participate in the symposium.
The theme of the three day symposium cover the following areas:

Medicinal and Pharmaceutical chemistry
Flow chemistry
Synthesis of natural and unnatural materials
Enzymes and biochemistry
Organometallic/Catalysis
Material science
Polymer chemistry
Computational chemistry

We cordially invite you to present your most recent research accomplishments, share your knowledge, and actively engage in scientific discourse with other experts in NTAC-2017.

http://www.ntac.shcollege.in/

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Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

PROCESS, SYNTHESIS, Uncategorized Comments Off

Oct 202016

Evacetrapib

The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, “in control” versus “at steady state”, lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crystallization, and isolation.

Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

Scott A. May^*, Martin D. Johnson^*, Jonas Y. Buser, Alison N. Campbell, Scott A. Frank, Brian D. Haeberle‡, Philip C. Hoffman, Gordon R. Lambertus, Adam D. McFarland, Eric D. Moher, and Timothy D. White ,

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States

D. Declan Hurley^*, Aoife P. Corrigan, Olivia Gowran, Niall G. Kerrigan, Marie G. Kissane, Regina R. Lynch, Paul Sheehan, and Richard D. Spencer ,

Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland

Shon R. Pulley§ and James R. Stout

D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00148

Publication Date (Web): October 19, 2016

*E-mail (Scott A. May): may_scott_a@lilly.com., *E-mail: (Martin D. Johnson): johnson_martin_d@lilly.com., *E-mail: (Declan D. Hurley):hurley_declan_d@lilly.com.

link http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00148

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.