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Wednesday 4 July 2018

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

Graphical abstract: A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

A borrowing hydrogen methodology: palladium-catalyzed dehydrative N-benzylation of 2-aminopyridines in water

 
 Author affiliations

Isao Azumaya

Abstract

We demonstrate a greener borrowing hydrogen methodology using the π-benzylpalladium system, which offers an efficient and environmentally friendly dehydrative N-monobenzylation of 2-aminopyridines with benzylic alcohols in the absence of base. The crossover experiment using benzyl-α,α-d2 alcohol and 3-methylbenzyl alcohol afforded H/D scrambled products, suggesting that the dehydrative N-benzylation in our catalytic system involves a borrowing hydrogen pathway. KIE experiments show that C–H bond cleavage at the benzylic position of benzyl alcohol is involved in the rate-determining step (KIE = 2.9). This simple base-free protocol can be achieved under mild conditions in an atom-economic process, affording the desired products in moderate to excellent yields.
N-Benzylpyridin-2-amine 3a 1 Yield 165 mg (90%) as a white solid; mp 90-91 C; IR (KBr) (cm-1) 3226, 3029, 1600, 1575; 1H NMR (400 MHz, CDCl3):  4.50 (d, J=5.7 Hz, 2H), 4.95 (brs, 1H), 6.36 (dt, J=8.5, 0.9 Hz, 1H), 6.58 (ddd, J=7.1, 5.0, 0.9 Hz, 1H), 7.23-7.36 (m, 4H), 7.39 (dd, J=8.7, 7.1, 1.8 Hz, 1H), 8.09 (ddd, J=5.0, 1.8, 0.9 Hz, 2H); 13C-NMR (100 MHz, CDCl3): 46.3, 106.8, 113.1, 127.2, 127.4, 128.6, 137.5, 139.2, 148.2, 158.6; MS (FAB): m/z 185 [M+H]+ .
STR2STR1
/////////////borrowing hydrogen methodology, palladium-catalyzed,  dehydrative N-benzylation, 2-aminopyridines,

Tuesday 3 July 2018

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
 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.201822 (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

Abstract Image
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
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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Saturday 30 June 2018

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.
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
Improved Procedure for Preparation of Abiraterone Acetate
Chemical Research Division, Ranbaxy Research Laboratory, Gurgaon, Haryana 122001, India
Org. Process Res. Dev.201418 (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 Sciences2016, 32(7), 729.
DOI: 10.2116/analsci.32.729
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Thursday 21 June 2018

TIPIFARNIB, типифарниб , تيبيفارنيب , 替匹法尼 ,

Tipifarnib.svgDB04960.pngChemSpider 2D Image | tipifarnib | C27H22Cl2N4O

str1
TIPIFARNIB
R-115777, NSC-702818
Categories
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 9721701eidemUS 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

str1

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/