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Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors

An alkyl and aryl technology, applied in the field of 2-aminothiazole-5-aromatic carboxamide, can solve problems such as low yield and generation of by-products

Active Publication Date: 2007-06-13
BRISTOL MYERS SQUIBB HLDG IRELAND UNLTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The disadvantages of the above method are the formation of by-products, the use of expensive coupling reagents, lower than desired yields, and the need for multiple reaction steps to obtain the 2-aminothiazole-5-carboxamide compound

Method used

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  • Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
  • Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
  • Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0360] Preparation of intermediates:

[0361] (S)-1-sec-butylthiourea

[0362]

[0363] To a solution of S-sec-butyl-amine (7.31 g, 0.1 mol) in chloroform (80 mL) was slowly added benzoylisothiocyanate (13.44 mL, 0.1 mol) at 0°C. The mixture was warmed to 10°C and stirred for 10 minutes. Then, the solvent was removed under reduced pressure, and the residue was dissolved in MeOH (80 mL). An aqueous solution (10 mL) of NaOH (4 g, 0.1 mol) was added to this solution, and the mixture was stirred at 60° C. for another 2 hours. Then, MeOH was removed under reduced pressure and the residue was stirred in water (50 mL). The precipitate was collected by vacuum filtration and dried to give S-1-sec-butyl-thiourea (12.2 g, 92% yield). mp133-134°C; 1 H NMR (500MHz, DMSO-D 6 )δ7.40(s, 1H), 7.20(br s, 1H), 6.76(s, 1H), 4.04(s, 1H), 1.41(m, 2H), 1.03(d, J=6.1Hz, 3H) , 0.81(d, J=7.7Hz, 3H); 13 CNMR (125 MHz, DMSO-D 6 )δ182.5, 50.8, 28.8, 19.9, 10.3; LRMS m / z133.2 (M+H); elemental a...

Embodiment 2

[0365] Preparation of intermediates:

[0366] (R)-1-sec-butylthiourea

[0367]

[0368] (R)-1-sec-butylthiourea was prepared according to the general method listed in Example 1, and the yield was 92%. mp133-134°C; 1 H NMR (500MHz, DMSO) δ0.80 (m, 3H, J = 7.7), 1.02 (d, 3H, J = 6.1), 1.41 (m, 2H), (3.40, 4.04) (s, 1H), 6.76 (s, 1H), 7.20 (s, br, 1H), 7.39 (d, 1H, J=7.2); 13C NMR (500MHz, DMSO) δ: 10.00, 19.56, 28.50, 50.20, 182.00; m / z 133.23 (M+H); elemental analysis C 5 h 12 N 2 Calculated for S: C, 45.41; H, 9.14.; N, 21.18; S, 24.25. Found: C, 45.32;

Embodiment 3

[0370] preparation:

[0371]

[0372] 3A.

[0373]

[0374] To a solution of 3-amino-N-methyl-4-methylbenzamide hydrochloride (1.0 g, 5 mmol) in acetone (10 mL) was added pyridine (1.2 mL, 15 mmol) dropwise via syringe at 0°C. ). 3-Methoxyacryloyl chloride (0.72 mL, 6.5 mmol) was added and the reaction was stirred at room temperature for 1 hour. The solution was cooled again to 0 °C, then 1 N HCl (1.5 mL) was added dropwise via pipette. The reaction mixture was stirred for 5 minutes, then water (8.5 mL) was added via addition funnel. Acetone was removed in vacuo and the resulting solution was stirred for 4 hours. Crystallization started within 15 minutes. After stirring for 4 hours, the vessel was cooled in an ice bath for 30 minutes, filtered, and rinsed with ice-cold water (2 x 3 mL) to afford compound 3A (0.99 g, 78% yield) as a white solid. 1 H NMR (400MHz, CDCl 3 )δ8.95(s, 1H), 8.12(br s, 1H), 7.76(s, 1H), 7.29(m, 2H), 7.05(d, J=7.9Hz, 1H), 5.47(d, J= 12.3Hz...

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Abstract

The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.

Description

field of invention [0001] The present invention relates to processes for the preparation of 2-aminothiazole-5-aromatic carboxamides, intermediates and crystalline forms thereof, as inhibitors of kinases such as protein tyrosine kinases and p38 kinases. Background of the invention [0002] The aminothiazole-aromatic amides of the formula I are useful as kinase inhibitors, in particular as inhibitors of protein tyrosine kinases and p38 kinases, [0003] [0004] where Ar is aryl or heteroaryl, L is an optional alkylene linker, and R 2 , R 3 , R 4 and R 5 as defined in this specification. They are expected to be useful in the treatment of diseases associated with protein tyrosine kinases such as immunological and oncological diseases [see, U.S. Patent No. 6,596,746 (the '746 patent), assigned to the present assignee and incorporated herein by reference], and p38 kinase-associated disorders such as inflammatory and immune disorders, as described in U.S. Patent Applicatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/56C07D417/12A61P31/04A61P31/12C07D241/00C07D277/00C07D239/00
Inventor 陈邦池罗伯托·德罗吉尼琼·莱朱尼斯约翰·D·迪马科迈克尔·盖尔拉拉马克里什南·奇丹巴拉姆
Owner BRISTOL MYERS SQUIBB HLDG IRELAND UNLTD
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