DR ANTHONY MELVIN CRASTO Ph.D

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

A deeper shade of green: inspiring sustainable drug manufacturing

drugs Comments Off

Jan 062017

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

A deeper shade of green: inspiring sustainable drug manufacturing

Frank Roschangar,*^a Juan Colberg,^b Peter J. Dunn,^c Fabrice Gallou,^d John D. Hayler,^e Stefan G. Koenig,^f Michael E. Kopach,^g David K. Leahy,^h Ingrid Mergelsberg,ⁱ John L. Tucker,^j Roger A. Sheldon^k^l and Chris H. Senanayake^a

*Corresponding authors

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

^bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA

^cPfizer, Sandwich, UK

^dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland

^eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK

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

^gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA

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

ⁱProcess Chemistry, Merck, Rahway, New Jersey 07065, USA

^jProcess Development, Amgen, Thousand Oaks, USA

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

^lDelft University of Technology, 2628 BL Delft, Netherlands

Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim

Research and Development Sites

Ingelheim am Rhein, Germany

Research experience

Feb 2002–Sep 2015

Director

Boehringer Ingelheim

Germany · Nieder-Ingelheim
Aug 1996–Feb 1998

Postdoc

The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou

United States · La Jolla
Aug 1992–Aug 1996

PhD Candidate

Rice University · Department of Chemistry

United States · Houston

Supplementary References

1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.

2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.

3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.

4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.

5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.

6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.

7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.

8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.

9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.

10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.

11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.

12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.

13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.

14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.

15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.

16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.

17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

//////////green chemistry, drugs

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

Uncategorized Comments Off

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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Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

FLOW CHEMISTRY, flow synthesis Comments Off

Jan 022017

Abstract Image

Over the last 20 years organic carbamates have found numerous applications in pesticides, fungicides, herbicides, dyes, pharmaceuticals, cosmetics, and as protecting groups and intermediates for polyurethane synthesis. Recently, in order to avoid phosgene-based synthesis of carbamates, many environmentally benign and alternative pathways have been investigated. However, few examples of carbamoylation of aniline in continuous-flow apparatus have been reported. In this work, we report a high-yielding, dimethyl carbonate (DMC)-mediated carbamoylation of aniline in a fixed-bed continuously fed reactor employing basic zinc carbonate as catalyst. Several variables of the system have been investigated (i.e. molar ratio of reagents , flow rate, and reaction temperature) to optimize the operating conditions of the system.

Highly Selective Phosgene-Free Carbamoylation of Aniline by Dimethyl Carbonate under Continuous-Flow Conditions

Sandra Grego, Fabio Aricò, and Pietro Tundo*

Department of Environmental Sciences, Informatics and Statistics, Ca’ Foscari University of Venice, Dorsoduro 2137, 30123 Venezia, Italia

Org. Process Res. Dev., 2013, 17 (4), pp 679–683

DOI: 10.1021/op4000048, http://pubs.acs.org/doi/abs/10.1021/op4000048

*Tel.: (+39) 041 234 8642. Fax: (+39) 041 234 8620. E-mail: tundop@unive.it.

PIETRO TUNDO

Profile:

PIETRO R. TUNDO is Professor of Organic Chemistry at Ca’ Foscari University of Venice (Italy).
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).
He is Member of the Bureau of IUPAC.

P: Tundo is author of about 300 scientific publications, 40 patents and many books.
His scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry, heteropolyacids, and finally safe alternatives to harmful chemicals.
He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731). He founded and was Chairman (2004-2016) of the Working Party on “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

Founder of the IUPAC International Conferences Series on Green Chemistry, he was awarded by American Chemical Society on 1983 (Kendall Award, with Janos Fendler), and by Federchimica (Italian association of chemical industries) on 1997 (An Intelligent Future).

P. Tundo coordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia, Italy) sponsored by the EU, UNESCO and NATO.
He was guest researcher and teacher at College Station (Texas,1979-1981), Potsdam (New York, 1989-90) and Syracuse (New York, 1991-92), Chapel Hill, (North Carolina, 1995).

He is holder of the Unesco Chair on Green Chemistry (UNTWIN N.o 731) and author of about 260 scientific publications and 30 patents.

Scientific interests are in the field of organic synthesis in selective methylations with low environmental impact, continuous flow chemistry, chemical detoxification of contaminants, hydrodehalogenation under multiphase conditions, phase-transfer catalysis (gas-liquid phase-transfer catalysis, GL-PTC), synthesis of crown-ethers and functionalized cryptands, supramolecular chemistry and finally, heteropolyacids.

He is the sole author of the book “Continuous flow methods in organic synthesis” E. Horwood Pub., Chichester, UK, 1991 (378 pp.), and editor of about 15 books.

P. Tundo was President of Organic and Biomolecular Chemistry Division of IUPAC (biennium 2007-2009) and presently is Chairman of Working Party of “Green and Sustainable Chemistry” of Euchems (European Association for Chemical and Molecular Sciences).

P. Tundo co-ordinated many institutional and industrial research projects (EU, NATO, Dow, ICI, Roquette) and was Director of the 10 editions of the annual Summer School on Green Chemistry (Venezia), the latter sponsored by the EU, UNESCO and NATO.

Contact:

Professor of Organic Chemistry
Ca’ Foscari University of Venice
IUPAC Bureau Member
Tel. +39 041 2348642
Mob. +39 349 3486191
E-mail: tundop@unive.it

Phone	041 234 8642 / Lab .: 041 234 8669
E-mail	tundop@unive.it green.chemistry@unive.it – 6th IUPAC Conference on Green Chemistry unescochair@unive.it – TUNDO Pietro
Fax	041 234 8620
Web	www.unive.it/persone/tundop

Pietro Tundo

////////Carbamoylation of Aniline, Dimethyl Carbonate, Continuous-Flow Conditions, flow synthesis

“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

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

Uncategorized Comments Off

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.

Image result for International Consortium on Innovation and Quality in Pharmaceutical Development (IQ Consortium)

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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Reflections on Chirality in the Pharmaceutical Industry: Past, Present and Future Dr. Christopher J. Welch, Distinguished Scientist Process Research & Development Merck Research Laboratories, USA

Presentations Comments Off

Dec 262016

Image result for Christopher J. Welch

Christopher Welch

New Technologies, Postdoc Program, Science Lead, Analytical Chemistry at Merck

christopher_welch@merck.com

Reflections on Chirality in the Pharmaceutical Industry: Past, Present and Future
Dr. Christopher J. Welch, Distinguished Scientist
Process Research & Development Merck Research Laboratories, USA

A PRESENTATION
Image result for WAIT FOR PRESENTATION TO LOAD ANIMATION

Image result for loading gif

At Chiral India 2016, New horizons in Drug development, Harnessing the power of Chirality .Organised by chemical weekly at Holiday inn international, Mumbai, India, Nov 8 2016

Christopher J. Welch

Science Lead for Analytical Chemistry
Merck Research Laboratories

Christopher J. Welch is Science Lead for Analytical Chemistry within the Process and Analytical Chemistry area at Merck Research Laboratories in Rahway, NJ. Chris leads the New Technologies Review and Licensing Committee (NT-RLC), the organization that oversees identification, acquisition and evaluation of new technologies of potential value to Merck Research Laboratories. Chris also leads the MRL Postdoctoral Research Fellows Program. He received his BS degrees in Chemistry and Biochemistry from the University of Illinois at Urbana-Champaign in 1982 and a Ph.D. degree in Organic Chemistry (also U of I) in 1992. Dr. Welch has worked in a variety of fields within the chemical industry, including discovery synthesis of agrochemicals (Velsicol-Sandoz), development of reagents for improved immunodiagnostic assays (Abbott Laboratories), and development and commercialization of chromatographic stationary phases, reagents and enantioselective catalysts within a small chemical business environment (Regis Technologies). Since joining Merck in 1999, he has focused on developing and applying improved methods and equipment for purification, synthesis and analysis of pharmaceuticals and intermediates. Dr. Welch has authored more than 230 scientific publications and patents. He is co-founder of the journal, Enantiomer, a current or past member of the editorial advisory boards for the journals, Chirality, Organic & Biomolecular Chemistry, Journal of the Korean Chemical Society, Chemistry World, Chemical & Engineering News and ACS Central Science. Chris is past chair of the ACS Division of Organic Chemistry (ORGN), a member of the Executive Committee for the International Symposia on Chirality, a member of the ACS steering committee for Pacifichem and a member of the PittCon Program Resource Team. Honors and awards include the NJCG Award for Excellence in Chromatography (2004), the PACS Activated Carbon Hall of Fame award (2007), MRL Presidents Award for Environmental Achievement (2009), Microsoft Life Science Innovation Award (2010), Fellow of the American Chemical Society (2010), Fellow of the American Association for the Advancement of Science, AAAS (2013), the Chirality Medal (2015) and the University of Nebraska Industrial Advisory Board Award (2016).

Experience

Distinguished Scientist, Process & Analytical Chemistry

Merck & Co., Inc.

May 1999 – Present (17 years 8 months)Rahway, NJ

Current responsibilities:
Scientific Lead, Analytical Chemistry
co-chair, New Technologies Review & Licensing Committee (NT-RLC)
co-chair, Merck Research Laboratories Postdoctoral Research Fellows Committee

Previous Positions at Merck:
Science Lead, Global Analytical Chemistry 8/10 – 8/12
Distinguished Senior Investigator, Process Research 7/07 – 8/10
Associate Director. Process Research 1/06 – 6/07
Senior Research Fellow, Process Research 6/03 – 12/05
Research Fellow, Process Research 5/99 – 6/03

Director of Research

Regis Technologies

May 1992 – March 1999 (6 years 11 months)Morton Grove, IL (Chicago area)

– New product development and commercialization (chromatography columns, reagents, enantioselective catalysts)
– Scientific evaluation of custom organic synthesis business
– Set up contract synthesis/preparative chromatographic separation business – first of kind

Honors & Awards

Fellow

American Association for the Advancement of Science (AAAS)

October 2012

Fellow

American Chemical Society (ACS)

August 2010

Chirality Medal 2015

January 2015

Presidential Green Chemistry Award

US Environmental Protection Agency

June 2014

– for precompetitive collaboration between Merck, Pfizer, Eli Lilly and University of Wisconsin on Aerobic Oxidation Methods for Pharmaceutical Synthesis – co-awardees: Shannon Stahl and Thatcher Root (U. Wisconsin), Joel Hawkins (Pfizer) and Joe Martinelli (Lilly)

Industrial Advisory Board (IAB) Award

University of Nebraska Department of Chemistry

March 2016

Inaugural IAB award from U. Nebraska recognizing excellence in scientific research in an industry setting

Organizations

American Chemical Society, Division of Organic Chemistry (ORGN)

Councilor and Chair

January 2006 – December 2015

Pacifichem

Member of Steering Committee for Pacifichem 2020

Starting August 2011

Chirality (Journal)

member, editorial board

Starting March 2002

Chemical & Engineering News

member, editorial advisory board

Starting February 2012

Chemistry Today (RSC)

member, editorial advisory board

Starting March 2011

Journal of the Korean Chemical Society

member, international advisory board

Starting February 2011

Pittcon

Member, Pittcon Program Committee Resource Team

Starting May 2012

ACS Central Science

Member of Editorial Advisory Board

Starting January 2015

American Chemical Society

Member, Committee on Science (ComSci

Starting January 2016

Publications

2014 publications, part 1

Use of a Miniature Mass Spectrometer to Support Pharmaceutical Process Research Investigations, Org. Proc. R&D 18, 103-108, 2014.

Chromatographic Separation and Assignment of Absolute Configuration of Hydroxywarfarin Isomers, Chirality 26, 95-101, 2014.

Chromatographic Resolution of Closely Related Species in Pharmaceutical Chemistry: Dehalogenation Impurities and Mixtures of Halogen…more

2014 publications – part 2

Precompetitive Collaboration on Enabling Technologies for the Pharmaceutical Industry, Org. Proc. R&D 18, 481–487, 2014.

Imine-based Chiroptical Sensing Approach for Analysis of Chiral Amines: From Method Design to Synthetic Application, Chem. Sci. 5, 2855-2861, 2014.

Advances in Achiral Stationary Phases for SFC, Amer. Pharm. Rev., April 2014, 36-41.

Liquid Chromatography Methods for…more

2013 Publications

Evaluation of core–shell particle columns for ion-pair reversed-phase liquid chromatography analysis of oligonucleotides, J. Pharm. Biomed. Anal. 72, 25–32, 2013.

Pharmaceutical Industry Practices on Genotoxic Impurities, in Pharmaceutical Industry Practices on Genotoxic Impurities, ed Heewoon Lee, Taylor & Francis, 2013.

Rapid Analysis of Residual Palladium in Pharmaceutical…more

2012 Publications
2012

A Simple Parallel Gas Chromatography Column Screening System, Wes Schafer, Simon E. Hamilton, Zainab Pirzada and Christopher J. Welch, Chirality, 24,1–4, 2012.

Rapid catalyst identification for the synthesis of the pyrimidinone core of HIV integrase inhibitors, A. Bellomo, N. Celebi-Olcum, X. Bu, N. Rivera, R.T. Ruck, C.J. Welch, K.N. Houk, S.D. Dreher, Angew. Chem. Int. Ed., 51 (2012) 1-5
…more

2011 Publications

Application of Ion Mobility Spectrometry in Drug Substance Development, H. Gao, X. Jia, R. Xiang, X. Gong, C. Welch, Analytical Methods, 3, 1828-1837, 2011.

Analytical Method Volume Intensity Index:A Green Chemistry Metric for HPLC Methodology in the Pharmaceutical Industry, R. Hartman, R. Helmy, M. Al-Sayah, C. Welch, Green Chemistry 13, 934-939, 2011.

Does an Axial Propeller Shape on a…more

2010 Publications

High-throughput metal screening in pharmaceutical samples by ICP-MS with automated flow injection using a modified HPLC configuration, Tu, Wang, Welch, J. Pharm. Biomed. Anal., 51, 90-95, 2010.

Systematic Evaluation of New Chiral Stationary Phases for Supercritical Fluid Chromatography Using a Standard Racemate Library, Pirzada, Personick, Biba, Gong, Zhou, Schafer, Welch, J. Chromaogr.A,…more

Adsorbent Screening for Metal Impurity Removal in Pharmaceutical Process(Link)

Organic Process Research & Development

February 23, 2005

A microtube screening approach affords simple and convenient assessment of the selective adsorption of metal impurities by a variety of different process adsorbents. This approach is helpful in identifying rapid solutions to metal impurity problems in pharmaceutical process research. Several examples illustrating the utility of the approach are presented.

Online Analysis of Flowing Streams Using Microflow HPLC

Organic Process Research & Development

2009

Supercritical fluid chromatography for GMP analysis in support of pharmaceutical development and manufacturing activities(Link)

Journal of Pharmaceutical and Biomedical An

Response to Comment on “Cocktail Chromatography: Enabling the Migration of HPLC to Nonlaboratory Environments”(Link)

ACS Sustainable Chem. Eng. 2015, 3 (9), 1897.

Education

University of Illinois at Urbana-Champaign

Ph.D., Organic Chemistry

1996 – 1999

The University of Chicago

FUELING INNOVATION

Welch helped launch Merck’s new postdoctoral research fellowship program.

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.

/////////Reflections on Chirality in the Pharmaceutical Industry, Past, Present and Future
Dr. Christopher J. Welch, Distinguished Scientist, Process Research & Development, Merck Research Laboratories, USA, presentation

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

spectroscopy, SYNTHESIS Comments Off

Dec 252016

Graphical abstract: One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC03023H, Communication

P. Matzel, M. Gand, M. Hohne
Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines.

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

Imine reductases (IREDs) show great potential as catalysts for reductive amination of ketones to produce chiral secondary amines. In this work, we explored this potential and synthesized the pharmaceutically relevant (R)-rasagiline in high yields (up to 81%) and good enantiomeric excess (up to 90% ee) from the ketone precursor. This one-step approach in aqueous medium represents the shortest synthesis route from achiral starting materials. Furthermore, we demonstrate for the first time that tertiary amines also can be accessed by this route, which provides new opportunities for eco-friendly enzymatic asymmetric syntheses of these important molecules.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC03023H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

One-step asymmetric synthesis of (R)- and (S)-rasagiline by reductive amination applying imine reductases

P. Matzel,^a M. Gand^b and M. Höhne*^a

*Corresponding authors

^aInstitute of Biochemistry, Greifswald University, Felix-Hausdorff-Str. 4, 17487 Greifswald, Germany
E-mail: Matthias.Hoehne@uni-greifswald.de

^bBiocenter Klein Flottbek, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC03023H

////////////One-step, asymmetric synthesis, (R)- , (S)-rasagiline, reductive amination, imine reductases

(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

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

EMA issues new Guideline on “Chemistry of Active Substances”

EMA, regulatory Comments Off

Dec 222016

Image result for active substances

The new EMA “Guideline on the chemistry of active substances” represents the current state of the art in regulatory practice and fits into the context of the ICH Guidelines Q8-11. Find out what information regarding active substances European authorities expect in an authorization application.

http://www.gmp-compliance.org/enews_05704_EMA-issues-new-Guideline-on-%22Chemistry-of-Active-Substances%22_15982,15721,S-WKS_n.html

A medicinal product authorization application requires comprehensive information on origin and quality of an active substance. What information is required was defined in two Guidelines so far: the Guideline “Chemistry of Active Substances” (3AQ5a) from 1987 and the “Guideline on the Chemistry of New Active Substances” from 2004. Because both Guidelines’ content do not take into account the ICH Guidelines Q8-11 issued in the meantime and do thus not meet the current state of the art in sciences and in regulatory practice, the EMA Quality Working Party (QWP) developed an updated document entitled “Guideline on the chemistry of active substances” (EMA/454576/2016), which was issued on 21 November.

The new Guideline describes the information on new or already existing active substances required in an authorization dossier. In the context of this Guideline “already existing” ingredients are those that are used in a product already authorized in the EU.

In detail the information and data regarding the substance have to be included in the following chapters of the CTD:

3.2.S.1: Nomenclature, information on the structural formula, pharmacological relevant physicochemical properties.

3.2.S.2: Information on the manufacturer(s), contractor(s), testing facilities etc.; description of the manufacturing processes (schematic representation with flow diagram as well as narrative); where appropriate detailed information on alternative manufacturing processes, for recovering of solvents and for routine reprocessing. Information with regard to re-working should not be included in the authorization dossier.

3.2.S.2.3: Information for controlling the material used during the manufacture and for its specification (incl. identity test). This paragraph is more comprehensive in the new Guideline compared with its predecessor and takes into account the requirements of the ICH Guideline Q11. This Guideline comprises requirements for the following materials: materials from biological sources, those used for the chemical synthesis of starting materials, materials from herbal origin, excipients like solvents (incl. water), reagents, catalysts etc.

3.2.S.2.4: Information on critical process steps (the Guideline comprises examples for these critical steps) as well as on quality and control of isolated intermediates within the synthesis steps. All information has to be provided with the appropriate justifications.

3.2.S.2.5: Information on Process Validation

3.2.S.2.6: Information on the development of the manufacturing process. Here all changes have to be described that were performed during the various phases (pre-clinical, clinical, scale-up, pilot and possibly production phase) of the process for new active substances. For already existing active substances available in production scale no information on process development is needed.

3.2.S.3: Information on Characterisation. Comprehensive information on the elucidation of the structure of the active substance, its physico-chemical properties and its impurities profile have to be provided. Further, the mutagenic potential of degradation products has to be considered. The analytical methods have to be described and their suitability has to be justified.

3.2.S.4: Information on the control of active substances. The analytical procedures and their validation have to be described. Data for the analytical method development should be provided if critical aspects of the analysis regarding the active substance’s specification need to be clarified. Analytical data are necessary for batches for pre-clinical and clinical studies as well as for pilot batches which are not less than 10% of the maximum production scale. The substance’s specification and its control strategy have to be justified on the basis of data from the pre-clinical and clinical phase and, if available, from the production phase.

3.2.S.5: Information on reference materials. If no Chemical Reference Substances (CRS) of the European Pharmacopoeia – counting as completely qualified reference standards – are used, comprehensive information on the analytical and physico-chemical characterization are required even for established primary standards.

3.2.S.6: Information on Container Closure System. Here a brief description is sufficient. However, if a Container-/Closure System is critical for the substance’s quality, its suitability has to be proven and justified. A reference to stability data can be used as supporting information.

3.2.S.7: Information on Stability. A detailed description of the stability studies carried out and the protocol used as well as a summary of the results are expected. Information on stress studies and conclusions on storage conditions and re-test dates or expiry dates are also to be made. This does not apply to substances monographed in the European Pharmacopoeia. If no re-test period or expiry date of batches on the production scale is available at the time of submission of the application, a stability commitment has to be attached with a post-approval stability protocol. The analytical methods have to be described.

The Guideline’s provisions also apply to an Active Substance Master File (ASMF) or to a Certificate of Suitability (CEP). They apply to active substances that have undergone development in a “traditional” way or according to the “enhanced” approach. The provisions of the ICH Guidelines Q8-11 have to be taken into account.

The Guideline is not applicable to active substances of herbal, biological and biotechnological origin as well as to radiolabelled products and radiopharmaceuticals.

The Guideline “Guideline on the chemistry of active substances” (EMA/454576/2016) becomes effective six months after issuing, which means in May 2017.

///////////////EMA, Guideline, chemistry of active substances

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.