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Nonsteroidal antiandrogens, (S)-N-(2-bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide

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 str1
C12 H17 Br N2 O3, 317.18
Butanamide, N-(2-bromo-6-methoxy-4-pyridinyl)-2-hydroxy-2,3-dimethyl-, (2S)-

(S)-N-(2-bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide

(S)-N-(2-Bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide

CAS 1433905-44-2

Figure

Nonsteroidal antiandrogens

HPLC (Daicel Chiralpak IC 250 × 4.6 mm, 5 μm, n-heptane/IPA/TFA 930:70:1, 1 mL·min–1, 25 °C, UV 210 nm): tr (minor) = 5.1 min, tr (major) = 5.9 min.

NMR 1H (400 MHz, DMSO-d6): 10.0 (sl, 1H); 7.73 (s, 1H); 7.33 (s, 1H); 5.70 (sl, 1H); 3.80 (s, 3H); 1.79–1.67 (m, 2H); 1.49 (dd, J = 13.6 and 5.2 Hz, 1H); 1.32 (s, 3H); 0.89 (d, J = 6.4 Hz, 3H); 0.78 (d, J = 6.4 Hz, 3H).

NMR 13C (100 MHz, DMSO-d6): 176.7, 164.0, 149.5, 138.1, 111.1, 74.9, 53.9, 48.6, 27.5, 24.3, 23.6, 23.2.

ESI-HRMS(m/z) calcd for C13H20BrN2O3+ [M+H]+ 331.0652 found 331.0654.

PATENT

WO 2013064681

str1

Synthesis 71

(R)-2-Hydroxy-2,4-dimethyl-pentanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide

(Compound 71A)

(S)-2-Hydroxy-2,4-dimethyl-pentanoic acid (2-bromo-6-methoxy-pyridin-4-yl)-amide

(Compound 71 B)

The two enantiomers of the racemic mixture prepared in Synthesis 41 were separated by HPLC (high pressure liquid chromatography) on a chiral stationary phase Chiralpak type la, Chiral Technologies, diameter 2 cm, length 25 cm, eluting with 93/7 (v/v) heptane / isopropanol containing 0.1 % (v/v) trifluoroacetic acid. The flow rate was 18 mL/minute. The injection volume was 1 mL of a solution of 20 mg of the racemic mixture dissolved in a 1 /1 (v/v) mixture of heptane / isopropanol. The retention times of the two enantiomers were 8.38 minutes and 9.70 minutes. After 6 injections, 40 mg of the two enantiomers were obtained as oils after solvent evaporation.

Analysis 71

Further analysis was performed using chiral HPLC (Chiralpak type la, Chiral

Technologies, 250 x 4, 6 mm, eluent 93/7 (v/v) heptane / isopropanol containing 0.1 % (v/v) trifluoroacetic acid with a flow rate of 1 mL/minute for 20 minutes. Compound 71 A had a retention time of 6.77 minutes, and Compound 71 B had a retention time of 8.71 minutes.

The absolute configuration of Compound 71 B was determined using X-ray diffraction (XRD), and found to be the (S) configuration. Accordingly, Compound 71 A was determined to be in the (R) configuration.

Figure

a(a) H2O2, TFA, 80%. (b) H2SO4, HNO3, 73%. (c) Fe, NH4Cl, EtOH, 51%. (d) MeOH, NaOH, MW 120 °C, 7 bar, 84%. (e) DCC, pyruvic acid, NMP, 29%. (f) i-BuMgCl, THF, 34%. (g) Chiral HPLC separation, 45%.

PAPER

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00392

Process Development and Crystallization in Oiling-Out System of a Novel Topical Antiandrogen

Nestlé Skin Health R&D Les Templiers, 2400 Route des colles BP 87, 06902 Sophia-Antipolis CEDEX, France
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00392
*Telephone: +33 4 92 95 29 48; E-mail: Jean-Guy.Boiteau@galderma.com.

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

Abstract Image

An efficient route to (S)-N-(2-bromo-6-methoxypyridin-4-yl)-2-hydroxy-2,4-dimethylpentanamide 1, a new topical antiandrogen, is described. The target compound has been manufactured on kilogram scale with an overall yield of 25% (HPLC purity 98.8% and >99% ee) from citrazinic acid. The key amide coupling between aminopyridine 4 and α-hydroxy-acid 6 was performed using a temporary protecting group to facilitate the acyl chloride formation. Aminopyridine 4 was manufactured from commercially available citrazinic acid via dibromide formation using phosphorus(V) oxybromide followed by mono SNAr reaction with sodium methoxide and a final Hofmann rearrangement. Enantiopure α-hydroxy-acid 6 was obtained using an enantioselective cyanosilylation followed by salt resolution with (S)-α-methyl benzylamine. The absolute configuration of compound 1 was determined with anomalous scattering and the final crystallization of API was performed after seeding a liquid–liquid mixture below the monotectic temperature and afforded a crystalline powder presenting a “desert rose” shape clusters.

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///////Nonsteroidal antiandrogens,

Brc1cc(NC(=O)[C@@](C)(O)C(C)C)cc(OC)n1

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc 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 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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