Betrixaban；PRT-054021；MK-4448；PRT-021, -Drug Synthesis Database

【结构式】

【药物名称】Betrixaban；PRT-054021；MK-4448；PRT-021

【化学名称】N-(5-Chloropyridin-2-yl)-2-[4-(N,N-dimethylamidino)benzamido]-5-methoxybenzamide

【CA登记号】330942-05-7；936539-80-9 (maleate salt (1:1))

【分子式】C₂₃H₂₂ClN₅O₃

【分子量】451.905

【开发单位】Portola Pharmaceuticals, Inc. (U.S.)

【药理作用】Coagulation Factor FXa Inhibitor;Treatment of Venous Thromboembolism

合成路线1 合成路线2

合成路线1

Coupling of 5-methoxy-2-nitrobenzoic acid (I) with 2-amino-5-chloropyridine (II) by means of POCl3 and pyridine , optionally in acetonitrile solution , yields the corresponding amide (III) , which is then subjected to nitro group reduction to give amine (IV) by either treatment with SnCl2·H2O in refluxing EtOAc or catalytic hydrogenation over sulfided Pt/C in EtOAc or CH2Cl2 . Acylation of aniline (IV) with 4-cyanobenzoyl chloride (V) in the presence of pyridine in CH2Cl2 or THF affords diamide (VI). Finally, nitrile (VI) is converted to amidine by either Pinner reaction with MeOH and HCl in EtOAc and subsequent treatment of the intermediate imino ether with Me2NH in refluxing MeOH , or direct addition of lithium dimethylamide (generated from Me2NH and HexLi) to the cyano group in cold THF .
In an altenative procedure, betrixaban is obtained by coupling of aniline (IV) with the 4-amidinobenzoic acid (VII) in the presence of EDC and a catalytic amount of HCl in DMF or DMA .

参考文献中间体

【1】 Zhu, B.-Y., Wang, L., Goldman, E. et al. (Millennium Pharmaceuticals, Inc.). Benzamides and related inhibitors of factor Xa. EP 1259485, US 6376515, WO 200106442, WO 2001064643.
【2】 Zhang, P., Huang, W., Wang, L. et al. Discovery of betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl) benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett 2009, 19(8):2179-85.
【3】 Kanter, J.P., Sujino, K., Zuberi, S.S. (Millennium Pharmaceuticals, Inc.).WO 2008057972.
【4】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	68321	5-methoxy-2-nitrobenzoic acid;2-Nitro-5-methoxybenzoic acid		C₈H₇NO₅	详情	详情
(II)	18559	5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine	1072-98-6	C₅H₅ClN₂	详情	详情
(III)	68322	N-(5-chloropyridin-2-yl)-5-methoxy-2-nitrobenzamide		C₁₃H₁₀ClN₃O₄	详情	详情
(IV)	68323	2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide		C₁₃H₁₂ClN₃O₂	详情	详情
(V)	19280	4-cyanobenzoyl chloride	6068-72-0	C₈H₄ClNO	详情	详情
(VI)	68324	N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide		C₂₁H₁₅ClN₄O₃	详情	详情
(VII)	68325	4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride		C₁₀H₁₂N₂O₂.HCl	详情	详情

合成路线2

The 4-amidinobenzoic acid intermediate (VII) is prepared by esterification of 4-cyanobenzoic acid (VIII) with MeOH in the presence of H2SO4 at reflux to give methyl 4-cyanobenzoate (IXa), which is then subjected to Pinner reaction with EtOH in the presence of HCl to yield methyl 4-[ethoxy(imino)methyl]benzoate (X). Without isolation, imidate (X) reacts with dimethylamine hydrochloride in refluxing EtOH to provide methyl 4-[(dimethylamino)(imino)methyl]benzoate (XIa). The analogous ethyl ester (XIb) can be alternatively prepared by reaction of ethyl 4-cyanobenzoate (IXb) with Me2NLi (generated from Me2NH and HexLi) in THF. Finally, either methyl (XIa) or ethyl (XIb) esters are hydrolyzed with LiOH in H2O/THF, and then acidified with HCl .

参考文献中间体

【1】 Pandey, A., Leitao, E.P.T., Rato, J., Song, Z.J. (Millennium Pharmaceuticals, Inc.; Merck & Co., Inc.). Methods of synthesizing factor Xa inhibitors. EP 2513058, US 201131927, WO 201108419.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IXa)	10169	methyl 4-cyanobenzoate；4-Cyanobenzoic acid methyl ester	1129-35-7	C₉H₇NO₂	详情	详情
(IXb)	68326	ethyl 4-cyanobenzoate		C₁₀H₉NO₂	详情	详情
(XIa)	68328	methyl 4-[(dimethylamino)(imino)methyl]benzoate;methyl 4-(N,N-dimethylcarbamimidoyl)benzoate		C₁₁H₁₄N₂O₂	详情	详情
(XIb)	68329	ethyl 4-(N,N-dimethylcarbamimidoyl)benzoate		C₁₂H₁₆N₂O₂	详情	详情
(VII)	68325	4-(N,N-dimethylcarbamimidoyl)benzoic acid hydrochloride		C₁₀H₁₂N₂O₂.HCl	详情	详情
(VIII)	36897	4-cyanobenzoic acid；4-Carboxybenzonitrile;p-Carboxybenzonitrile	619-65-8	C₈H₅NO₂	详情	详情
(X)	68327	methyl 4-[ethoxy(imino)methyl]benzoate		C₁₁H₁₃NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)