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Carotegrast methyl

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ChemSpider 2D Image | CAROTEGRAST METHYL | C28H26Cl2N4O5
Carotegrast methyl (JAN).png
2D chemical structure of 401905-67-7

Carotegrast methyl

FormulaC28H26Cl2N4O5
CAS401905-67-7
Mol weight569.4358

PMDA APROVED, CAROGRA, カロテグラストメチル

ON 2022/3/28

Antiasthmatic, Integrin alpha 4 inhibitor

  • An alpha4 integrin antagonist.

401905-67-7[RN]

L-Phenylalanine, N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1,4-dihydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-, methyl ester

methyl (2S)-2-[(2,6-dichlorophenyl)formamido]-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]phenyl}propanoate

Methyl N-(2,6-dichlorobenzoyl)-4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-L-phenylalaninate

Carotegrast Methyl

Methyl (2S)-2-(2,6-dichlorobenzamido)-3-{4-[6-(dimethylamino)-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}propanoate

C28H26Cl2N4O5 : 569.44
[401905-67-7]

PATENT

WO 2008062859

https://patents.google.com/patent/WO2008062859A1/en

Step 1

(Method 2): The title compound was prepared starting from 2-amino-5-dimethylamino- benzoic acid methyl ester dihydrochloride through the hydrolysis under basic condition To 5.0 g of 2-amino-5-dimethylamino-benzoic acid methyl ester di-hydrochloride, there were added 15 mL of water and 15.6 mL of a 6M aqueous solution of sodium hydroxide and the resulting mixture was heated to 40°C for 2 hours. After the confirmation of the progress of the reaction according to HPLC, the reaction system was cooled to room temperature, a 6M hydrochloric acid aqueous solution was dropwise added to the reaction system to thus neutralize the same and to separate out crystals (pH 4.9) and then the reaction system was stirred at 10°C for 2 hours. The solid thus obtained was isolated through the filtration under reduced pressure, washed with 30 mL of water and then dried under reduced pressure at 60°C for 14 hours. Title compound 3.14 g was obtained as gray-colored solid. The physical properties determined were almost identical to those observed for the same compound prepared in the above-mentioned synthesis example. H-NMR (400MHz, DMSO-d6): δ 8.21 (bs, 3H), 7.10 (d, 1H, J=2.8Hz), 6.97 (dd, 1H, J=9.1, 2.8Hz), 6.70 (d, 1H, J=9.1 Hz), 2.72 (s, 6H); 13C-NMR (100MHz, DMSO-d6): δ168.89, 144.55, 141.61, 123.29, 117.90, 114.78, 110.11,41.95; MS (ESI+): m/z 181.3 (MH+), (ESI-): m/z 179.2 (M-H).

Step 2

Step 1: Synthesis of Nα-(2,6-dichlorobenzoyl) -4-{2-ethoxycarbonylamino-5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester To 1.96 g of 2-amino-5-dimethylaminobenzoic acid, there were added 12 mL of acetonitrile and 5.29 mL of pyridine to form a suspension and then the resulting suspension was cooled to 4°C. To this suspension there was dropwise added 4.17 mL of ethyl chloroformate over 5 minutes and then the mixture was stirred at 25°C for one hour. After confirming the disappearance of the starting material by HPLC, 0.7 mL of ethanol was added to the mixture to thus decompose the excess ethyl chloroformate and the mixture was further stirred for additional one hour. To this reaction solution there were added 4.0 g of 4-amino-Nα-(2,6-dichlorobenzoyl)-L-phenylalanine methyl ester and 12 mL of N,Ndimethylformamide, and the resulting mixture was stirred overnight. Subsequently, 48 mL of methanol was drop-wise added, the resulting mixture was stirred at 10°C overnight and then the solid separated from the mixture was isolated through filtration under reduced pressure. The solid was then washed with 8 mL of methanol and dried at 70°C for 5 hours under reduced pressure. Title compound 5.50 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 10.29 (s, 1H), 9.42 (bs, 1H), 9.24 (d, 1H, J=7.9Hz), 7.73 (bs, 1H), 7.62 (d, 2H, J=8.4Hz), 7.48-7.44 (m, 2H), 7.41 (dd, 1H, J=9.5, 6.2Hz), 7.27 (d, 2H,J=8.4Hz), 7.01 (d, 1H, J=2.7Hz), 6.93 (dd, 1H, J=9.1, 2.9Hz), 4.71 (ddd, 1H, J=9.2, 8.1, 5.7Hz), 4.05 (q, 2H, J=7.0Hz), 3.66 (s, 3H), 3.10 (dd, 1H, J=14.0, 5.6Hz), 2.96 (dd, 1H, J=14.0, 9.2Hz), 2.93 (s, 6H), 1.18 (t, 3H, J=7.2Hz); MS (ESI+): m/z 601.2 (MH+) and 623.2 (M+Na), (ESI): m/z 599.1 (M-H).

Step 3

Step2: Synthesis of Na-(2,6-dichlorobenzoyl)-4-{6-dimethylamino-1-methylquinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine methyl ester To 2.0 g of Na-(2,6-dichlorobenzoyl)-4-{2-ethoxycarbonylamino -5-dimethyl- amino-benzoylamino}-L-phenylalanine methyl ester prepared in above-mentioned step 1, were added 16 mL of N,N-dimethylfbrmamide, 0.8 mL of methanol and 0.91 g of potassium carbonate, followed by the stirring of the resulting mixture at 25°C overnight. To this reaction solution, there was added 0.75 mL of methyl p-toluenesulfonate for subjecting the methyl ester to alkylation at 25~40°C. After confirming the disappearance of the starting material by HPLC, 0.75 mL of acetic acid was added to quench the reaction, 16 mL of water was dropped and the solid was separated. Further, 8 mLof N,N-dimethylformamide/water = 1/1 mixed liquid was added to the resulting mixture, followed by the stirring of the mixture at 25°C. Then the solid thus separated was isolated through filtration under reduced pressure and then washed with 8 mL of water. Thereafter, the isolated solid was dried at 70°C for 4 hours under reduced pressure. Desired compound 1.77 g was obtained as pale yellow solid. 1H-NMR (400MHz, DMSO-d6): δ 9.28 (d, 1H, J=8.1 Hz), 7.48-7.36 (m, 6H), 7.31 (dd, 1H, J=3.0, 9.0Hz), 7.24 (d, 1H, J=3.0Hz), 7.20-7.15 (m, 2H), 4.18 (ddd, 1H, J=10.2, 8.1,4.8Hz), 3.69 (s, 3H), 3.49 (s, 3H), 3.22 (dd, 1H, J=14.1, 4.8Hz), 3.02 (dd, 1H, J=14.2, 10.5Hz), 2.94 (s, 6H); MS (ESI+): m/z 569.2 (MH+) and 591.1 (M+Na), (ESI-): m/z 567.2 (M-H).

PATENT

https://patents.google.com/patent/WO2004074264A1/en

PATENT’ WO 2003070709

https://patents.google.com/patent/WO2003070709A1/en

PATENT

WO 2002016329

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/////////////Carotegrast methyl, CAROGRA, カロテグラストメチル , JAPAN 2022, APPROVALS 2022,

COC(=O)[C@H](Cc1ccc(cc1)N2C(=O)N(C)c3ccc(cc3C2=O)N(C)C)NC(=O)c4c(Cl)cccc4Cl

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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 AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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 Open superstar 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 32 PLUS year tenure till date Feb 2023, Around 35 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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