NK-3201, -Drug Synthesis Database

【结构式】

【药物名称】NK-3201

【化学名称】N-[1-Benzyl-2,3-dioxo-6-(2-pyridyloxy)hexyl]-2-[5-(formylamino)-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl]acetamide

【CA登记号】204460-24-2

【分子式】C₃₁H₂₉N₅O₆

【分子量】567.60668

【开发单位】Nippon Kayaku (Originator)

【药理作用】Acute Myocardial Infarction, Treatment of, Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Chymase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Hydroxy amino ester (I) was protected as the oxazolidine (III) upon heating with 2,2-dimethoxypropane (II) in the presence of p-toluenesulfonic acid. Conversion of the ester group of (III) into aldehyde (V) was accomplished by reduction to alcohol (IV) with LiAlH4, followed by NaOCl oxidation catalyzed by 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) and NaBr. Addition of 3-(benzyloxy)propylmagnesium bromide (VI) to aldehyde (V) furnished carbinol (VII), which was further protected as the silyl ether (VIII) by treatment with tert-butyldimethylsilyl chloride and imidazole. After hydrogenolysis of the O-benzyl protecting group of (VIII), the resultant primary alcohol (IX) was converted to bromide (X) employing the N-bromosuccinimide/triphenylphosphine reagent.

参考文献中间体

【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323.
【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 .

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)	52327	methyl 3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-hydroxy-4-phenylbutanoate		C₁₆H₂₃NO₅	详情	详情
(II)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(III)	52319	3-(1,1-dimethylethyl) 5-methyl 2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3,5-dicarboxylate		C₁₉H₂₇NO₅	详情	详情
(IV)	52320	1,1-dimethylethyl 5-(hydroxymethyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₁₈H₂₇NO₄	详情	详情
(V)	52321	1,1-dimethylethyl 5-formyl-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₁₈H₂₅NO₄	详情	详情
(VI)	52322	bromo{3-[(phenylmethyl)oxy]propyl}magnesium		C₁₀H₁₃BrMgO	详情	详情
(VII)	52323	1,1-dimethylethyl 5-{1-hydroxy-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₂₈H₃₉NO₅	详情	详情
(VIII)	52324	1,1-dimethylethyl 5-{1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-[(phenylmethyl)oxy]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₃₄H₅₃NO₅Si	详情	详情
(IX)	52325	1,1-dimethylethyl 5-(1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-hydroxybutyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₂₇H₄₇NO₅Si	详情	详情
(X)	52326	1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate		C₂₇H₄₆BrNO₄Si	详情	详情

合成路线2

Alkylation of 2-hydroxypyridine (XI) with bromide (X) produced a mixture of the N-alkylated pyridone (XII) and the pyridyl ether (XIII), which were separated by column chromatography. The required minor regioisomer (XIII) was desilylated with tetrabutylammonium fluoride, and the resultant alcohol (XIV) was oxidized under Swern conditions to the ketone (XV). Acidic hydrolysis of the cyclic aminal function of (XV) furnished amino alcohol (XVI). This was then coupled with the pyrimidinylacetic acid (XVII) to yield amide (XVIII). The free hydroxyl group of (XVIII) was subsequently esterified with acetic anhydride giving ester (XIX).

参考文献中间体

【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323.
【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	52326	1,1-dimethylethyl 5-(4-bromo-1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}butyl)-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate	C₂₇H₄₆BrNO₄Si	详情	详情
(XI)	52328	2-pyridinol	C₅H₅NO	详情	详情
(XII)	52329	1,1-dimethylethyl 5-{1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-[2-oxo-1(2H)-pyridinyl]butyl}-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate	C₃₂H₅₀N₂O₅Si	详情	详情
(XIII)	52330	1,1-dimethylethyl 5-[1-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-4-(2-pyridinyloxy)butyl]-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate	C₃₂H₅₀N₂O₅Si	详情	详情
(XIV)	52331	1,1-dimethylethyl 5-[1-hydroxy-4-(2-pyridinyloxy)butyl]-2,2-dimethyl-4-(phenylmethyl)-1,3-oxazolidine-3-carboxylate	C₂₆H₃₆N₂O₅	详情	详情
(XV)	52332	1,1-dimethylethyl 2,2-dimethyl-4-(phenylmethyl)-5-[4-(2-pyridinyloxy)butanoyl]-1,3-oxazolidine-3-carboxylate	C₂₆H₃₄N₂O₅	详情	详情
(XVI)	52333	2-amino-3-hydroxy-1-phenyl-7-(2-pyridinyloxy)-4-heptanone	C₁₈H₂₂N₂O₃	详情	详情
(XVII)	52334	2-[5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetic acid	C₁₇H₁₉N₃O₅	详情	详情
(XVIII)	52335	1,1-dimethylethyl 1-(2-{[2-hydroxy-3-oxo-1-(phenylmethyl)-6-(2-pyridinyloxy)hexyl]amino}-2-oxoethyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinylcarbamate	C₃₅H₃₉N₅O₇	详情	详情
(XIX)	52336	1-[1-({2-[5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetyl}amino)-2-phenylethyl]-2-oxo-5-(2-pyridinyloxy)pentyl acetate	C₃₇H₄₁N₅O₈	详情	详情

合成路线3

Acidic Boc group cleavage from (XIX) produced amine (XX). This was converted to formamide (XXI) upon treatment with in situ-generated formic acetic anhydride. Selective hydrolysis of the acetate ester of (XXI) was then achieved by treatment with K2CO3 in MeOH. The resultant keto alcohol (XXII) was finally oxidized to the title diketone employing DMSO in the presence of EDC and pyridinium trifluoroacetate

参考文献中间体

【1】 Doggrell, S.A.; Castaner, J.; NK-3201. Drugs Fut 2003, 28, 4, 323.
【2】 Suzuki, Y.; Ishida, K. (Nippon Kayaku Co., Ltd.); Novel acetamide derivs. and protease inhibitors. EP 0936216; US 6271238; WO 9809949 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	52336	1-[1-({2-[5-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetyl}amino)-2-phenylethyl]-2-oxo-5-(2-pyridinyloxy)pentyl acetate	C₃₇H₄₁N₅O₈	详情	详情
(XX)	52337	1-[1-({2-[5-amino-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetyl}amino)-2-phenylethyl]-2-oxo-5-(2-pyridinyloxy)pentyl acetate	C₃₂H₃₃N₅O₆	详情	详情
(XXI)	52338	1-[1-({2-[5-(formylamino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]acetyl}amino)-2-phenylethyl]-2-oxo-5-(2-pyridinyloxy)pentyl acetate	C₃₃H₃₃N₅O₇	详情	详情
(XXII)	52339	2-[5-(formylamino)-6-oxo-2-phenyl-1(6H)-pyrimidinyl]-N-[2-hydroxy-3-oxo-1-(phenylmethyl)-6-(2-pyridinyloxy)hexyl]acetamide	C₃₁H₃₁N₅O₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)