CH4630808

CH4630808
syn   https://newdrugapprovals.org/2018/07/02/ch4630808/

Paper

Development of a Kilogram-Scale Synthesis of a Novel Anti-HCV Agent, CH4930808

CH4630808 corrected

Tsuyoshi Haneishi*† , Yoshiaki Kato‡, Hiroshi Fukuda†, Tomoyuki Shimamura‡, Takemi Tanokura‡, Akira Hiraide‡, Kaichiro Koyama‡, Masato Fudesaka‡, Kenji Maeda‡, Nobuyuki Nakata‡, Masahiro Nagase‡, Takahiko Yabuzaki‡, Hiroaki Takao‡, Masaharu Kigawa‡, Hitoshi Shimizu‡, and Makoto Shimizu§

† Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

‡ Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan

§ Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan

Org. Process Res. Dev., 2018, 22 (2), pp 236–240

DOI: 10.1021/acs.oprd.7b00383

*E-mail: haneishitys@chugai-pharm.co.jp. Tel.: +81-550-87-9102. Fax: +81-550-87-5326.

Abstract

Herein, we report the kilogram-scale synthesis of CH4930808 (1) CH 4630808 CORRECTED, a novel anti-hepatitis C virus agent. While pursuing improved productivity using many through-process strategies, we conducted scrupulous impurity control. Finally, we successfully developed a practical and scalable process for the synthesis of (1·1.5Na·2.5H2O), by which we prepared 3.28 kg of the active pharmaceutical ingredient for clinical studies

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00383/suppl_file/op7b00383_si_001.pdf

1H-NMR and 13C-NMR spectra of compound 5·HCl S 3– S 4

1H-NMR spectra of compound 1·1.5 Na·2.5 H2O S 5

13C-NMR spectra compound 1·1.5 Na·2.5 H2O S 6

1H-COSY spectra of compound 1·1.5 Na·2.5 H2O S 7 – S 8

DEPT spectra of compound 1·1.5 Na·2.5 H2O S 9 – S 10

HMBC spectra of compound 1·1.5 Na·2.5 H2O S 11 – S 17

MASS

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Abiraterone Acetate

Abiraterone Acetate (1)
syn https://newdrugapprovals.org/2018/07/01/bms-986169/

1 in 81% yield (1.8 kg). HPLC Purity: 99.72%, Assay: 98.8% (HPLC, w/w). MS: m/z = 392.7 [M + H]+. IR (KBr) (cm–1): 3047, 2936, 1735, 1244, 1035, 801, 714. 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1 H), 8.43–8.42 (d, 1 H), 7.76–7.74 (d, 1 H), 7.34–7.31 (dd, 1 H), 6.11 (s, 1 H), 5.38 (s, 1 H), 4.44 (m, 1H), 2.19–2.50 (m, 3H), 1.98–2.08 (m, 6H), 1.39–1.85 (m, 9H), 1.03–1.11 (m, 8H). 13C NMR (CDCl3): δ 170.4, 151.6, 147.9, 147.8, 140.0, 133.6, 132.9, 129.1, 122.9, 122.2, 73.8, 57.4, 50.2, 47.3, 38.1, 36.9, 36.7, 35.1, 31.7, 31.4, 30.3, 27.7, 21.4, 20.8, 19.2, 16.5.

https://pubs.acs.org/doi/suppl/10.1021/op500044p/suppl_file/op500044p_si_001.pdf

Abiraterone (2)

2 (2.88 kg, 72%) as a white solid. HPLC Purity: 99.87%. MS: m/z = 350.3 [M + H]+. IR (KBr) (cm–1): 3236, 3062, 3031, 2931,1596, 1065, 803. 1H NMR (400 MHz, CDCI3): δ 8.61 (s, 1 H), 8.44–8.46 (d, 1 H), 7.63–7.65 (d, 1 H), 7.20–7.23 (dd, 1 H), 5.993–5.996 (d, 1 H), 5.38–5.99 (d, 1 H), 3.48–3.54 (m, 1 H), 2.24–2.32 (m, 3H), 1.97–2.10 (m, 3H), 1.47–1.86 (m, 10H), 1.04–1.10 (s, 8H). 13C NMR (CDCl3): δ 16.58, 19.34, 20.88, 30.45, 31.52, 31.63, 31.81, 35.27, 36.71, 37.20, 42.32, 47.34, 50.37, 57.56, 71.62, 121.28, 123.03, 129.24, 132.99, 133.70, 141.21, 147.79, 147.88, 151.68

see supp info

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PAPER

https://pubs.acs.org/doi/abs/10.1021/op500044p

Improved Procedure for Preparation of Abiraterone Acetate

Mukesh Kumar Madhra*, Hari Mohan Sriram, Murad Inamdar, Mukesh Kumar Sharma, Mohan Prasad, and Sony Joseph

Chemical Research Division, Ranbaxy Research Laboratory, Gurgaon, Haryana 122001, India

Org. Process Res. Dev., 2014, 18 (4), pp 555–558

DOI: 10.1021/op500044p

*E-mail: Mukesh.madhra@ranbaxy.com. Tel: (91-124)4011832.

Absolute Quantification of Lipophilic Shellfish Toxins by Quantitative Nuclear Magnetic Resonance Using Removable Internal Reference Substance with SI Traceability

Absolute Quantification of Lipophilic Shellfish Toxins by Quantitative Nuclear Magnetic Resonance Using Removable Internal Reference Substance with SI Traceability

Tsuyoshi KATO, Maki SAITO, Mika NAGAE, Kazuhiro FUJITA, Masatoshi WATAI, Tomoji IGARASHI, Takeshi YASUMOTO, and Minoru INAGAKI

Keywords: Lipophilic shellfish toxin, okadaic acid, dinophysistoxin-1, polyethers, qNMR, AQARI

Analytical Sciences, 2016, 32(7), 729.

DOI: 10.2116/analsci.32.729

• Read abstract
• View this article in J-STAGE
• Okadaic acid (OA), a lipophilic shellfish toxin, was accurately quantified using quantitative nuclear magnetic resonance with internal standards for the development of an authentic reference standard. Pyridine and the residual proton in methanol-d₄ were used as removable internal standards to limit any contamination. They were calibrated based on a maleic acid certified reference material. Thus, the concentration of OA was traceable to the SI units through accurate quantitative NMR with an internal reference substance. Signals from the protons on the oxygenated and unsaturated carbons of OA were used for quantification. A reasonable accuracy was obtained by integrating between the lower and upper ¹³C satellite signal range when more than 4 mg of OA was used. The best-determined purity was 97.4% (0.16% RSD) when 20 mg of OA was used. Dinophysistoxin-1, a methylated analog of OA having an almost identical spectrum, was also quantified by using the same methodology.

 

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TIPIFARNIB, типифарниб , تيبيفارنيب , 替匹法尼 ,

TIPIFARNIB
R-115777, NSC-702818
Categories

• Antineoplastic Agents
• P-glycoprotein/ABCB1 Inhibitors
• Quinolines

UNIIMAT637500A
CAS number 192185-72-1 +form
192185-68-5 (racemate)
192185-69-6 (racemic; fumarate)
192185-70-9 (racemic; diHCl)
(+)-(R)-6-[1-Amino-1-(4-chlorophenyl)-1-(1-methylimidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one

2(1H)-Quinolinone, 6-[(R)-amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-

Weight Average: 489.396
Chemical Formula C₂₇H₂₂Cl₂N₄O

типифарниб [Russian] [INN]

تيبيفارنيب [Arabic] [INN]

替匹法尼 [Chinese] [INN]

(R)-(+)-R115777

(R)-6-(Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone

(R)-6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1-methylquinolin-2(1H)-one

2 (1H))-Quinolinone,6-(amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl)-4-(3-chlorophenyl)-1-methyl-, 2(1H )-quinolinone

 

Title: Tipifarnib

CAS Registry Number: 192185-72-1; 192185-68-5 (unspecified stereo)

CAS Name: 6-[(R)-Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone

Manufacturers' Codes: R-115777

Trademarks: Zarnestra (Janssen)

Molecular Formula: C27H22Cl2N4O

Molecular Weight: 489.40

Percent Composition: C 66.26%, H 4.53%, Cl 14.49%, N 11.45%, O 3.27%

Literature References: Farnesyl transferase inhibitor. Prepn: M. G. Venet et al., WO 9721701; eidem, US 6037350 (1997, 2000 both to Janssen). Review of syntheses: P. R. Angibaud et al., Eur. J. Org. Chem. 2004, 479-486. Inhibition of farnesyl protein transferase and antitumor effects in vivo: D. W. End et al., Cancer Res. 61, 131 (2001). Clinical pharmacology and pharmacokinetics: J. Zujewski et al., J. Clin. Oncol. 18, 927 (2000). Accelerator mass spec determn in biological samples: R. C. Garner et al., Drug Metab. Dispos. 30, 823 (2002). Clinical evaluation in hematologic malignancies: J. Cortes et al., Blood 101, 1692 (2003). Review of clinical experience: P. Norman, Curr. Opin. Invest. Drugs 3, 313-319 (2002).

Properties: Crystals from 2-propanol, mp 234°. [a]D20 +22.86° (c = 0.98 in methanol).

Melting point: mp 234°

Optical Rotation: [a]D20 +22.86° (c = 0.98 in methanol)

Therap-Cat: Antineoplastic.

Keywords: Antineoplastic; Farnesyl Transferase Inhibitors.

NMR SIMULATION

PREDICTED VALUES

1H NMR: δ 3.42 (3H, s), 3.63 (3H, s), 6.57 (1H, s), 6.67 (1H, d, J = 1.7 Hz), 7.27 (1H, dd, J = 8.3, 1.5 Hz), 7.36-7.59 (8H, 7.46 (ddd, J = 8.3, 1.5, 0.5 Hz), 7.41 (ddd, J = 8.1, 8.1, 0.5 Hz), 7.39 (ddd, J = 8.1, 1.6, 1.5 Hz), 7.49 (ddd, J = 8.1, 1.7, 1.5 Hz), 7.55 (ddd, J = 8.3, 1.6, 0.5 Hz), 7.58 (d, J = 1.7 Hz)), 7.66 (1H, dd, J = 8.3, 0.5 Hz), 7.71 (1H, dd, J = 1.5, 0.5 Hz), 7.84 (1H, ddd, J = 1.7, 1.6, 0.5 Hz).

13C NMR PREDICT

COSY PREDICT

HSQC PREDICT

See SYNTHESIS

 https://newdrugapprovals.org/2018/06/21/tipifarnib-%D1%82%D0%B8%D0%BF%D0%B8%D1%84%D0%B0%D1%80%D0%BD%D0%B8%D0%B1-%D8%AA%D9%8A%D8%A8%D9%8A%D9%81%D8%A7%D8%B1%D9%86%D9%8A%D8%A8-%E6%9B%BF%E5%8C%B9%E6%B3%95%E5%B0%BC/

Catalyst-free three-component synthesis of highly functionalized 2,3-dihydropyrroles

Catalyst-free three-component synthesis of highly functionalized 2,3-dihydropyrroles

Dong Wang,a  Linna Li,a  Hairong Feng,a  Hua Sun,a  Fabrice Almeida-Veloso,b  Marine Charavin,b Peng Yua  and  Laurent Désaubry*abc 

 Author affiliations

*Corresponding authors

aSino-French Joint Lab of Food Nutrition/Safety and Medicinal Chemistry, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
E-mail: desaubry@unistra.fr

bLaboratory of Therapeutic Innovation (UMR 7200), University of Strasbourg-CNRS, Faculty of Pharmacy, 67400 Illkirch, France

cLaboratory of Biomolecules (UMR7203), Sorbonne University – CNRS, 4 place Jussieu, 75005 Paris, France

Abstract

An efficient synthesis of fully substituted 2,3-dihydropyrroles has been achieved in one step through the three-component reaction of amines, aromatic aldehydes and α-ketoamides. This atom-economical and catalyst-free reaction is highly stereoselective and generates underexplored heterocycles in a single step. These compounds were examined in an enzymatic assay that led to the identification of potent α-glucosidase inhibitors, thereby demonstrating the utility of this novel methodology in medicinal chemistry.

http://pubs.rsc.org/en/Content/ArticleLanding/2018/GC/C8GC00987B?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

N-(4-Chlorophenyl)-2-oxopropanamide (3a) Cl H N O O 3a Using 4-chloroaniline (1.0 g, 7.8 mmol), in accordance with General Procedure A, the title compound 3a was obtained (810 mg, 52% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.1, 157.6, 135.0, 130.6, 129.5, 121.1, 24.2. HRMS (ESI-TOF) m/z calcd. for C9H7NO2Cl- [M-H]- : 196.0171, found 196.0170

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Tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

tert-butyl (N-[3-[(3S,4R)-3-amino-4-fluoro-4-(hydroxymethyl)tetrahydrofuran-3-yl]-4-fluorophenyl]acetamide)

1H-NMR (500 MHz, DMSO-d6): 1.31 (s, 9H), 2.02 (s, 3H), 3.21 (m, 1H), 3.88 (m, 1H), 3.94 (m, 1H), 4.03 (m, 1H), 4.13 (m, 1H), 4.74 (m, 1H), 5.07 (m, 1H), 7.08 (m, 1H), 7.43 (bs, 1H), 7.63 (m, 1H), 7.67 (m, 1H), 10.03 (s, 1H) .

13C-NMR (125 MHz, DMSO-d6): 24.3, 28.5, 60.8, 65.1, 72.6, 78.1, 78.9, 105.8, 116.4, 119.7, 120.8, 127.2, 136.2, 155.2, 156.4, 168.7.

19F-NMR (470.6 MHz, DMSO-d6): -164.77, -117.26.

 

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Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00069