Large scale synthesis of chiral (3Z,5Z)-2,7-dihydro-1H-azepine-derived Hamari ligand for general asymmetric synthesis of tailor-made amino acids.

spectroscopy, SYNTHESIS Comments Off

Jan 292019

(R)-2,2′-bis(bromomethyl)-1,1′-binaphthalene ((R)-17) was prepared in the identical manner and had identical analytical properties to those given here.

¹H NMR (400 MHz, CDCl₃): δ 4.25 (4H, s, 2 × CH₂), 7.07 (2H, dd, J = 8.4, 0.8 Hz, ArH), 7.27 (2H, ddd, J = 8.4, 6.8, 1.2 Hz, ArH), 7.48 (2H, ddd, J = 8.2, 6.8, 1.2 Hz, ArH), 7.74 (2H, d, J = 8.6 Hz, ArH), 7.92 (2H, d, J = 8.2 Hz, ArH), 8.02 (2H, d, J = 8.6 Hz, ArH).

¹³C NMR (100.6 MHz, CDCl₃): δ 32.6 (CH₂), 126.80 (ArCH), 126.82 (ArCH), 126.84 (ArCH), 127.7 (ArCH), 128.0 (ArCH), 129.4 (ArCH), 132.5 (quaternary ArC), 133.3 (quaternary ArC), 134.1 (quaternary ArC), 134.2 (quaternary ArC).

[α]²⁰_D = +173.8° (c = 1.0, CHCl₃).

An advanced process for large scale (500 g) preparation of a (3Z,5Z)-2,7-dihydro-1H-azepine-derived chiral tridentate ligand (Hamari ligand), widely used for asymmetric synthesis of tailor-made α-amino acids via the corresponding glycine Schiff base Ni(II) complex, is disclosed. The process includes amidation, bis-alkylation, and precipitation/purification of the target compound by TFA as a counterion.

Large Scale Synthesis of Chiral (3Z,5Z)-2,7-Dihydro-1H-azepine-Derived Hamari Ligand for General Asymmetric Synthesis of Tailor-Made Amino Acids

Motohiro Takahashi*^†

, Hiroki Moriwaki^†, Toshio Miwa^†, Brittanie Hoang^‡, Peng Wang^‡, and Vadim A. Soloshonok*^§^∥

^† Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan

^‡ Hamari Chemicals USA, San Diego Research Center, 11494 Sorrento Valley Road, San Diego, California 92121, United States

^§ Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain

^∥ IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00406

Publication Date (Web): January 18, 2019

*E-mail: motohiro-takahashi@hamari.co.jp., *E-mail: vadym.soloshonok@ehu.es.

This article is part of the Japanese Society for Process Chemistry special issue.

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Combination of Enantioselective Preparative Chromatography and Racemization: Experimental Demonstration and Model-Based Process Optimization

PROCESS, SYNTHESIS Comments Off

Dec 122018

Conventional enantioselective preparative chromatographic separation using columns packed with chiral stationary phase is characterized by a 50% yield constraint. Racemization of the undesired enantiomer and recycling the formed mixture is an attractive option to tackle this limit. To implement this concept, potential is seen in particular in applying enzymes immobilized in a second fixed bed. However, the identification of suitable operating conditions and the direct connection of a chromatographic column and an enzymatic reactor is not trivial. The paper presents results of an experimental study applying jointly a batch-wise operated chiral Chirobiotic T column to resolve the two enantiomers of mandelic acid (MA) and a mandelate racemase immobilized on Eupergit CM. The general concept could be successfully demonstrated over several cycles focusing on the provision of (S)-MA. A mathematical model was developed in order to illustrate essential process features and to quantitatively describe the coupled separation and racemization processes. The key ingredients of this model, namely, the adsorption isotherms of the two enantiomers on the chiral column and the rate of racemization in the enzymatic reactor, were determined experimentally. The potential of applying the model for further process optimization and generalization is indicated.

Combination of Enantioselective Preparative Chromatography and Racemization: Experimental Demonstration and Model-Based Process Optimization

Katarzyna Wrzosek*^†

, Isabel Harriehausen^†, and Andreas Seidel-Morgenstern^†^‡

^† Max-Planck Institute for Dynamics of Complex Technical System, Physical and Chemical Foundations of Process Engineering, 39106 Magdeburg, Germany

^‡ Otto von Guericke University, Chemical Process Engineering, 39106 Magdeburg, Germany

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00254

*E-mail: wrzosek@mpi-magdeburg.mpg.de. Tel.: +49 391 6110 321.

link https://pubs.acs.org/doi/10.1021/acs.oprd.8b00254

Image result for Magdeburg, Germany max planck

Dr. Katarzyna Wrzosek

Katarzyna Wrzosek

Dr. Katarzyna Wrzosek

Phone:+49 391 6110 321

Max-Planck Institute for Dynamics of Complex Technical System, Physical and Chemical Foundations of Process Engineering, 39106 Magdeburg, Germany

*E-mail: wrzosek@mpi-magdeburg.mpg.de.

M. Sc. Isabel Harriehausen

Isabel Harriehausen

M. Sc. Isabel Harriehausen

Phone:+49 391 6110 447 harriehausen@mpi-magdeburg.mpg.de

Prof. Dr.-Ing. Andreas Seidel-Morgenstern

Andreas Seidel-Morgenstern

Prof. Dr.-Ing. Andreas Seidel-Morgenstern

Phone:+49 391 6110 401

Email: seidel-morgenstern@mpi-magdeburg.mpg.de

Magdeburg, Germany

Image result for Magdeburg, Germany max planck

Image result for Magdeburg, Germany

Grüne Zitadelle Von Magdeburg

Image result for Magdeburg, Germany

Magdeburg Cathedral

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ANTHONY MELVIN CRASTO

https://newdrugapprovals.org/

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

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///////////////enantioselective chromatography, enzymatic reactor, equilibrium dispersion model, mandelate racemase, racemization

(1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene

spectroscopy, SYNTHESIS Comments Off

Dec 102018

(1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene (3a) Yellow liquid (25.2 mg, 95% yield):

1H NMR (300 MHz, CDCl3)   1.39 (s, 4H, alkyl), 3.77-3.80 (m, 1H, alkyl), 3.85 (s, 3H, OMe), 4.36 (d, J = 5.4 Hz, 1H, alkyl), 6.36 (dd, J = 6.0, 6.0 Hz, 1H, vinyl), 6.46 (dd, J = 6.0, 6.0 Hz, 1H, vinyl), 6.88-6.91 (m, 3H, vinyl + arom.), 7.67 (d, J = 8.3 Hz, 2H, arom.);

13C{1H} NMR (75 MHz, CDCl3)  = 24.7, 24.8, 37.1, 38.2, 55.4, 113.3, 130.8, 131.5, 133.2, 135.1, 146.5, 147.7, 162.6, 192.3;

HRMS (ESI-TOF) m/z calculated for C16H16NaO2 [M+Na]+ 263.1048, found 263.1036;

FT-IR (neat, cm-1 ) 1033, 1174, 1255, 1354, 1600, 1637, 1730, 2870, 2957, 3054.

Optical Rotation: []D 26 +39.9 (c 2.52, CHCl3) for an enantiomerically enriched sample of 94% ee.

HPLC analysis (column, CHIRALPAK AD-3, hexane/2-propanol = 98/2, flow rate 1.0 mL/min, 20 C, detection UV 250 nm light); tR of major-isomer 20.7

Org. Lett., 2018, 20 (23), pp 7353–7357

DOI: 10.1021/acs.orglett.8b02263

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(1S,4R)-2-(4-Methoxybenzoyl)bicyclo[2.2.2]octa-2,5-diene

Permalink spectroscopy, SYNTHESIS Comments Off

Nov 302018

Sodium aluminate is presented as a highly active heterogeneous catalyst that is able to convert a range of alcohols into the corresponding unsymmetrical carbonate esters by reaction with dimethyl carbonate. Preparing NaAlO₂ via spray drying boosts the basic properties and the activity of the catalyst.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00333

/////////////https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00333/suppl_file/op8b00333_si_001.pdf

carboxymethylation, dimethyl carbonate, mixed carbonate esters, sodium aluminate,

Use of Lipase Catalytic Resolution in the Preparation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate, a Key Intermediate of the β-Lactamase Inhibitor Avibactam

PROCESS, SYNTHESIS Comments Off

Nov 242018

Here we describe an efficient and cost-effective chemoenzymatic synthesis of the β-lactamase inhibitor avibactam starting from commercially available ethyl 5-hydroxypicolinate hydrochloride. Avibactam was synthesized in 10 steps with an overall yield of 23.9%. The synthetic route features a novel lipase-catalyzed resolution step during the preparation of (2S,5S)-ethyl 5-hydroxypiperidine-2-carboxylate, a valuable precursor of the key intermediate ethyl (2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxylate. Our synthetic route was used to produce 400 g of avibactam sodium salt.

Use of Lipase Catalytic Resolution in the Preparation of Ethyl (2S,5R)-5-((Benzyloxy)amino)piperidine-2-carboxylate, a Key Intermediate of the β-Lactamase Inhibitor Avibactam

Tao Wang^†^§, Liang-Dong Du^‡, Ding-jian Wan^‡, Xiang Li^‡, Xin-Zhi Chen*^§

, and Guo-Feng Wu*^†

^† Research &Development Center, Zhejiang Medicine Co., Ltd, 59 East Huangcheng Road, Xinchang, Zhejiang 312500, P. R. China

^‡ Shanghai Laiyi Center for Biopharmaceuticals R&D, 5B, Building 8 200 Niudun Road Pudong District, Shanghai 201203, P. R. China

^§ Key Laboratory of Biomass Chemical Engineering of Ministry of Education, Zhejiang University, 38 Zhejiang University Road, Xihu District, Hangzhou 310007, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00173

Publication Date (Web): November 5, 2018

*E-mail: xcwuyuanzhang@163.com., *E-mail: xzchen@zju.edu.cn.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00173

///////////lipase, resolution, avibactam

Development of an SNAr Reaction: A Practical and Scalable Strategy To Sequester and Remove HF

organic chemistry, SYNTHESIS Comments Off

Sep 142018

Abstract Image

A simple and operationally practical method to sequester and remove fluoride generated through the S_NAr reaction between amines and aryl fluorides is reported. Calcium propionate acts as an inexpensive and environmentally benign in situ scrubber of the hydrofluoric acid byproduct, which is simply precipitated and filtered from the reaction mixture during standard aqueous workup. The method has been tested from 10 to 100 g scale of operation, showing >99.5% decrease in fluoride content in each case. Full mass recovery of calcium fluoride is demonstrated at both scales, proving this to be a general, efficient, and robust method of fluoride abstraction to help prevent corrosion of glass-lined reactors.

Development of an S_NAr Reaction: A Practical and Scalable Strategy To Sequester and Remove HF

A. John Blacker*^†

, Gabriel Moran-Malagon^†, Lyn Powell^‡, William Reynolds^†, Rebecca Stones^†, and Michael R. Chapman^†

^† Institute of Process Research and Development, School of Chemistry and School of Chemical and Process Engineering, University of Leeds, Leeds LS2 9JT, United Kingdom

^‡ Chemical Development, AstraZeneca, Macclesfield SK10 2NA, United Kingdom

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00090

*E-mail: j.blacker@leeds.ac.uk.

///////////////aryl amines, calcium fluoride, fluoride sequestration, scale-up, S_NAr reaction,

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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

Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C–H Arylation

MANUFACTURING, organic chemistry, spectroscopy, SYNTHESIS Comments Off

Sep 112018

There is significant interest in the development of process routes for active pharmaceutical ingredients using C–H arylation methodology. An efficient and practical synthetic route for febuxostat (1), which is the first non-purine-type xanthine oxidase inhibitor, was established via palladium- and copper-catalyzed C–H arylation of thiazole with aryl bromide. The catalyst loading was reduced to 0.1 mol % for the intermolecular C–H arylation, and a three-step synthesis produced febuxostat in 89% overall yield with excellent selectivity

Process Development of Febuxostat Using Palladium- and Copper-Catalyzed C–H Arylation

Masato Komiyama*

, Hideyoshi Tsuchiya, Mitsuru Teramoto, Naoki Yajima, Masayuki Kurokawa, Kunio Minamizono, Naoki Tsuchiya, Yoshiaki Kato, Yoshinori Sato, and Masahiko Dohi

Active Pharmaceutical Ingredient Technology Section, Pharmaceutical Preparation Department, Teijin Pharma Limited, 2-1 Hinode-cho, Iwakuni-shi, Yamaguchi 740-8511, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00164

*E-mail: m.komiyama@teijin.co.jp.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00164

1 (22.5 g, 98%) as a whitish solid. ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 3.91 (d, J = 6.6 Hz, 2H), 2.80 (s, 3H), 2.23–2.20 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H).

//////FEBUXOSTAT

Ethyl 4, 6-dichloro-1H-indole-2-carboxylate

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Aug 282018

Ethyl 4, 6-dichloro-1H-indole-2-carboxylate

ethyl 4,6-dichloro-1H-indole-2-carboxylate (1a) (2.70 kg, 99.5%).

Mp 187–188 °C; HRMS (ESI) m/z [M – H]⁻ calcd for C₁₁H₈NO₂Cl₂ 255.9927, found 255.9930;

¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 7.10 (s, 1H), 4.43–4.30 (q, 2H), 1.34 (d, 3H);

¹³C NMR (151 MHz, CDCl₃) δ 161.69, 137.08, 131.00, 128.45, 128.37, 125.31, 121.26, 110.52, 107.07, 61.56, 14.32;

IR (cm^–1) 3314.3, 2987.6, 1700.2, 1615.8, 1566.2, 1523.7, 1487.2, 1323.3, 1247.2, 1072.4, 840.1, 770.2.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00144

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00144

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00144/suppl_file/op8b00144_si_001.pdf

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A versatile biosynthetic approach to amide bond formation

organic chemistry, SYNTHESIS Comments Off

Aug 022018

Graphical abstract: A versatile biosynthetic approach to amide bond formation

A versatile biosynthetic approach to amide bond formation

Helena K. Philpott,^a Pamela J. Thomas,^b David Tew,^a Doug E. Fuerst^c and Sarah L. Lovelock*^a

Author affiliations

*Corresponding authors

^aAdvanced Manufacturing Technologies, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK
E-mail: sarah.lovelock@manchester.ac.uk

^bMolecular Design, Computational and Modelling Sciences, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, UK

^cAdvanced Manufacturing Technologies, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, USA

Abstract

The development of versatile and sustainable catalytic strategies for amide bond formation is a major objective for the pharmaceutical sector and the wider chemical industry. Herein, we report a biocatalytic approach to amide synthesis which exploits the diversity of Nature’s amide bond forming enzymes, N-acyltransferases (NATs) and CoA ligases (CLs). By selecting combinations of NATs and CLs with desired substrate profiles, non-natural biocatalytic pathways can be built in a predictable fashion to allow access to structurally diverse secondary and tertiary amides in high yield using stoichiometric ratios of carboxylic acid and amine coupling partners. Transformations can be performed in vitro using isolated enzymes, or in vivo where reactions rely solely on cofactors generated by the cell. The utility of these whole cell systems is showcased through the preparative scale synthesis of a key intermediate of Losmapimod (GW856553X), a selective p38-mitogen activated protein kinase inhibitor.

http://pubs.rsc.org/en/Content/ArticleLanding/2018/GC/C8GC01697F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

////////////biosynthetic, amide bond

Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

organic chemistry, spectroscopy, SYNTHESIS Comments Off

Jul 262018

Copper-catalyzed pyrrole synthesis from 3,6-dihydro-1,2-oxazines

Naoki Yasukawa,^a Marina Kuwata,^a Takuya Imai,^a Yasunari Monguchi,^a Hironao Sajiki*^a and Yoshinari Sawama*^a

Author affiliations

*Corresponding authors

^aLaboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
E-mail: sajiki@gifu-pu.ac.jp, sawama@gifu-pu.ac.jp
Fax: +81-58-230-8109

Abstract

Highly-functionalized pyrroles could be effectively synthesized from 3,6-dihydro-1,2-oxazines using a heterogeneous copper on carbon (Cu/C) under neat heating conditions. Furthermore, the in situ formation of 3,6-dihydro-1,2-oxazines via the hetero Diels–Alder reaction between nitroso dienophiles and 1,3-dienes and the following Cu/C-catalyzed pyrrole synthesis also provided the corresponding pyrrole derivatives in a one-pot manner.

Brown solid; M. p. 107–108 o C;

IR (ATR) cm-1 : 3064, 2923, 2851, 1687, 1596, 1562, 1541, 1498, 1488, 1459, 1451, 1422, 1390, 1343, 1319, 1256, 1187, 1098, 1073, 1053, 1037, 1009;

1 H NMR (500 MHz, CDCl3): δ 7.37–7.28 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.95 (dd, J = 2.0, 3.0 Hz, 1H), 6.45 (dd, J = 2.0, 3.0 Hz, 1H), 6.37 (dd, J = 3.0, 3.0 Hz, 1H);

13C NMR (125 MHz, CDCl3): δ 140.19, 132.52, 131.85, 131.19, 129.65, 129.14, 126.84, 125.69, 124.83, 120.24, 110.97, 109.38;

ESI-HRMS m/z: 298.0231([M+H+ ]); Calcd for C16H13NBr: 298.0226.