L-376062, -Drug Synthesis Database

【结构式】

【药物名称】L-376062

【化学名称】2-[3-(Benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]-N-[1-(N-tert-butylcarbamoylmethyl)-4-methyl-1H-imidazol-5-ylmethyl]acetamide

【CA登记号】214152-91-7

【分子式】C₂₆H₃₄N₆O₅S

【分子量】542.66208

【开发单位】Merck & Co. (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1 合成路线2

合成路线1

The condensation of 5-(hydroxymethyl)-4-methyl-1H-imidazole (I) with tert-butyl bromoacetate (II) by means of K2CO3 in DMF gives the imidazolylacetic ester (III), which is treated with diphenylphosphoryl azide and DBU in DMF yielding the azidomethyl compound (IV). The reduction of (IV) with H2 over Pd/C in ethyl acetate affords the aminomethyl compound (V), which is acylated with 2-[3-(benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid (VI) by means of EDC and HOBT in DMF providing the carboxamide (VII). Elimination of the tert-butyl group of (VII) with HCl in ethyl acetate gives the free carboxylic acid (VIII), which is finally amidated with tert-butylamine by means of EDC and HOBT in DMF.

参考文献中间体

【1】 Naylor-Olsen, A.M.; Newton, C.L.; Isaacs, R.C.A.; Dorsey, B.D. (Merck & Co., Inc.); Thrombin inhibitors. EP 0969840; US 5932606; WO 9842342 .

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)	26595	(4-methyl-1H-imidazol-5-yl)methanol	38585-62-5	C₅H₈N₂O	详情	详情
(II)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(III)	26596	tert-butyl 2-[5-(hydroxymethyl)-4-methyl-1H-imidazol-1-yl]acetate		C₁₁H₁₈N₂O₃	详情	详情
(IV)	26597	tert-butyl 2-[5-(azidomethyl)-4-methyl-1H-imidazol-1-yl]acetate		C₁₁H₁₇N₅O₂	详情	详情
(V)	26598	tert-butyl 2-[5-(aminomethyl)-4-methyl-1H-imidazol-1-yl]acetate		C₁₁H₁₉N₃O₂	详情	详情
(VI)	26599	2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid		C₁₅H₁₆N₂O₅S	详情	详情
(VII)	26600	tert-butyl 2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetate		C₂₆H₃₃N₅O₆S	详情	详情
(VIII)	26601	2-[5-[([2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetyl]amino)methyl]-4-methyl-1H-imidazol-1-yl]acetic acid		C₂₂H₂₅N₅O₆S	详情	详情

合成路线2

The intermediate 2-[3-(benzylsulfonamido)-6-methyl-2-oxo-1,2-dihydropyridin-1-yl]acetic acid (VI) has been obtained as follows: The reaction of 2-hydroxy-6-methylpyridine-3-carboxylic acid (IX) with diphenylphosphoryl azide (DPPA), triethylamine and benzyl alcohol in refluxing dioxane gives 3-(benzyloxycarbonylamino)-6-methylpyridin-2(1H)-one (X), which is condensed with tert-butyl bromoacetate (II) by means of NaH in THF yielding the expected condensation product (XI). The deprotection od the amino group of (XI) with H2 over Pd/C in ethanol/water gives the aminopyridone (XII), which is acylated with benzylsulfonylchloride (XIII) in pyridine yielding the sulfonamide (XIV). Finally, the tert-butyl ester group of (XIV) is hydrolyzed with HCl in ethyl acetate to afford the target intermediate (VI).

参考文献中间体

【1】 Naylor-Olsen, A.M.; Newton, C.L.; Isaacs, R.C.A.; Dorsey, B.D. (Merck & Co., Inc.); Thrombin inhibitors. EP 0969840; US 5932606; WO 9842342 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	26599	2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid		C₁₅H₁₆N₂O₅S	详情	详情
(IX)	26602	2-hydroxy-6-methylnicotinic acid	38116-61-9	C₇H₇NO₃	详情	详情
(X)	26603	benzyl 6-methyl-2-oxo-1,2-dihydro-3-pyridinylcarbamate		C₁₄H₁₄N₂O₃	详情	详情
(XI)	26604	tert-butyl 2-[3-[[(benzyloxy)carbonyl]amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₂₀H₂₄N₂O₅	详情	详情
(XII)	26605	tert-butyl 2-[3-amino-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₁₂H₁₈N₂O₃	详情	详情
(XIII)	25151	phenylmethanesulfonyl chloride	1939-99-7	C₇H₇ClO₂S	详情	详情
(XIV)	26606	tert-butyl 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetate		C₁₉H₂₄N₂O₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)