-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-(3,5-Dimethylisothiazol-4-ylmethyl)-3-[2(S)-hydroxy-4(R)-[N-[3(S)-hydroxy-3,4-dihydro-2H-1-benzopyran-4(S)-yl]carbamoyl]-5-phenylpentanoyl]-5,5-dimethylthiazolidine-4(R)-carboxamide

【CA登记号】

【分子式】C₃₃H₄₀N₄O₆S₂

【分子量】652.83795

【开发单位】Merck & Co. (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, HIV Protease Inhibitors

合成路线1 合成路线2

合成路线1

5,5-Dimethylthiazolidine-4-carboxylic acid (I) is protected as the N-Boc derivative (II), and subsequently treated with allyl bromide (III) and triethylamine to form the allyl ester (IV). Acidic Boc group cleavage in (IV) provides amino ester (V), which is further coupled to the lactone acid (VI) to furnish amide (VII). The allyl ester group of (VII) is then removed by treatment with morpholine and Pd(PPh3)4, yielding acid (VIII). This is then coupled to (3,5-dimethylisothiazol-4-yl)methyl amine (IX) employing EDC/HOAt to afford the corresponding amide (X). Lactone ring opening in (X) by hydrolysis with LiOH gives rise to the hydroxy acid (XI), which is further protected as the silyl ether (XII) employing t-butyldimethylsilyl triflate.

参考文献中间体

【1】 Bohn, J.; Lu, Z.; Raghavan, S.; Charest, M.; Stahlhut, M.; Rutkowski, C.A.; Himmelberger, A.L.; Olsen, D.B.; Scheleif, W.A.; Carella, A.; Gabryelski, L.; Jin, L.; Lin, J.H.; Tata, J.R.; Chapman, K.; Synthesis of highly potent HIV protease inhibitors with activity against protease resistant virus. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 205.

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)	34776	(4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid	72778-00-8	C₆H₁₁NO₂S	详情	详情
(II)	34777	(4R)-3-(tert-butoxycarbonyl)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid		C₁₁H₁₉NO₄S	详情	详情
(III)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(IV)	65046	4-allyl 3-(tert-butyl) (4R)-5,5-dimethyl-1,3-thiazolidine-3,4-dicarboxylate		C₁₄H₂₃NO₄S	详情	详情
(V)	65047	allyl (4R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylate		C₉H₁₅NO₂S	详情	详情
(VI)	65048	(2S,4R)-4-benzyl-5-oxotetrahydro-2-furancarboxylic acid		C₁₂H₁₂O₄	详情	详情
(VII)	65049	allyl (4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylate		C₂₁H₂₅NO₅S	详情	详情
(VIII)	65050	(4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid		C₁₈H₂₁NO₅S	详情	详情
(IX)	65059	(3,5-dimethyl-4-isothiazolyl)methanamine; (3,5-dimethyl-4-isothiazolyl)methylamine		C₆H₁₀N₂S	详情	详情
(X)	65060	(4R)-3-{[(2S,4R)-4-benzyl-5-oxotetrahydro-2-furanyl]carbonyl}-N-[(3,5-dimethyl-4-isothiazolyl)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide		C₂₄H₂₉N₃O₄S₂	详情	详情
(XI)	65061	(2R,4S)-2-benzyl-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-4-hydroxy-5-oxopentanoic acid		C₂₄H₃₁N₃O₅S₂	详情	详情
(XII)	65062	(2R,4S)-2-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-5-oxopentanoic acid		C₃₀H₄₅N₃O₅S₂Si	详情	详情

合成路线2

Coupling of acid (XII) with (S,S)-4-aminochroman-3-ol (XIII) in the presence of HBTU provides amide (XIV). Finally, desilylation of (XIV) with tetrabutylammonium fluoride gives rise to the target compound.

参考文献中间体

【1】 Bohn, J.; Lu, Z.; Raghavan, S.; Charest, M.; Stahlhut, M.; Rutkowski, C.A.; Himmelberger, A.L.; Olsen, D.B.; Scheleif, W.A.; Carella, A.; Gabryelski, L.; Jin, L.; Lin, J.H.; Tata, J.R.; Chapman, K.; Synthesis of highly potent HIV protease inhibitors with activity against protease resistant virus. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 205.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	65062	(2R,4S)-2-benzyl-4-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4R)-4-({[(3,5-dimethyl-4-isothiazolyl)methyl]amino}carbonyl)-5,5-dimethyl-1,3-thiazolidin-3-yl]-5-oxopentanoic acid	C₃₀H₄₅N₃O₅S₂Si	详情	详情
(XIII)	56265	(3S,4S)-4-amino-3,4-dihydro-2H-chromen-3-ol	C₉H₁₁NO₂	详情	详情
(XIV)	65092	(4R)-3-((2S,4R)-4-benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}-5-{[(3S,4S)-3-hydroxy-3,4-dihydro-2H-chromen-4-yl]amino}-5-oxopentanoyl)-N-[(3,5-dimethyl-4-isothiazolyl)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide	C₃₉H₅₄N₄O₆S₂Si	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)