2,2-dimethylsuccinic acid -Drug Synthesis Database

【结构式】

【分子编号】46622

【品名】2,2-dimethylsuccinic acid

【CA登记号】

【分子式】C₆H₁₀O₄

【分子量】146.143

【元素组成】C 49.31% H 6.9% O 43.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VIII)

The selective monoesterification of 2,2-dimethylsuccinic acid (VIII) with methanol and sulfuric acid gives 2,2-dimethylsuccinic acid 4-methyl ester (IX), which is submitted to degradation with diphenylphosphoryl azide, TEA and benzyl alcohol in refluxing benzene, yielding 3-(benzyloxycarbonylamino)-3-methylbutyric acid methyl ester (X). The hydrolysis of (X) with NaOH in methanol affords the corresponding butyric acid (XI). The hydrogenation of 3-azido-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (XII) with H2 over Pt/C in methanol gives the racemic 3-amino derivative (XIII), which is submitted to optical resolution by crystallization of the L-tartrate salt, yielding the 3(R)-amino derivative (XIV). The condensation of amine (XIV) with acid (XI) by means of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BTPF) and DIEA in dichloromethane affords the corresponding amide (XV), which is condensed with the tetrazole derivative (VII) by means of NaH in DMF to provide the protected adduct (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol and a treatment with TFA.

参考文献中间体

合成目标

【1】 Watthey, J.W.; et al.; Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme. J Med Chem 1985, 28, 10, 1511.
【2】 Fisher, M.H.; Wyvratt, M.J.; Schoen, W.R.; DeVita, R.J. (Merck & Co., Inc.); Benzo-fused lactams promote release of growth hormone. EP 0513974; JP 1994172316; US 5206235; WO 9216524 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	15538	5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole	124750-51-2	C₃₃H₂₅BrN₄	详情	详情
(VIII)	46622	2,2-dimethylsuccinic acid		C₆H₁₀O₄	详情	详情
(IX)	46623	4-methoxy-2,2-dimethyl-4-oxobutyric acid		C₇H₁₂O₄	详情	详情
(X)	46624	methyl 3-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate		C₁₄H₁₉NO₄	详情	详情
(XI)	46625	3-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid		C₁₃H₁₇NO₄	详情	详情
(XII)	20891	3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₀N₄O	详情	详情
(XIII)	46628	3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₂N₂O	详情	详情
(XIV)	15929	(3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₂N₂O	详情	详情
(XV)	46626	benzyl 1,1-dimethyl-3-oxo-3-[[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]propylcarbamate		C₂₃H₂₇N₃O₄	详情	详情
(XVI)	46627	benzyl 1,1-dimethyl-3-oxo-3-[((3R)-2-oxo-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino]propylcarbamate		C₅₆H₅₁N₇O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Reaction of betulin (I) and 2,2-dimethylsuccinic acid (II) in refluxing pyridine, followed by HPLC separation of the two products obtained, affords derivative (III). Protection of the carboxylic group of (III) is then performed by formation of the corresponding allyl ester derivative (V) by reaction with allyl bromide (IV) and K2CO3 in acetone. Separately, 2,2-dimethylsuccinic acid (II) is treated with allyl alcohol (VI) in refluxing pyridine to give an isomeric mixture of compounds from which allyl succinate derivative (VII) is chromatographically isolated. Formation of the corresponding acid chloride (VIII) is finally performed by treatment of (VII) with (COCl)2 in refluxing benzene. Condensation between alcohol (V) and acid chloride (VIII) by means of DMAP in CH2Cl2 provides compound (IX), which is finally converted into the target product by removal of the allyl protecting groups by means of Pd(Ph3P)4 and morpholine.

参考文献中间体

合成目标

【1】 Chiyo, J.; Ikeshiro, Y.; Cosentino, L.M.; Kashiwada, Y.; Fowke, K.; Lee, K.H.; Okabe, H.; Nagao, T.; 3,28-Di-O-(dimethylsuccinyl)-betulin isomers as anti-HIV agents. Bioorg Med Chem Lett 2001, 11, 2, 183.

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)	50064	(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(hydroxymethyl)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysen-9-ol		C₃₀H₅₀O₂	详情	详情
(II)	46622	2,2-dimethylsuccinic acid		C₆H₁₀O₄	详情	详情
(III)	50065	4-[[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-3-yl]methoxy]-3,3-dimethyl-4-oxobutyric acid		C₃₆H₅₈O₅	详情	详情
(IV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(V)	50066	1-[[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-3-yl]methyl] 4-allyl 2,2-dimethylsuccinate		C₃₉H₆₂O₅	详情	详情
(VI)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(VII)	50067	4-(allyloxy)-3,3-dimethyl-4-oxobutyric acid		C₉H₁₄O₄	详情	详情
(VIII)	50068	allyl 4-chloro-2,2-dimethyl-4-oxobutanoate		C₉H₁₃ClO₃	详情	详情
(IX)	50069	4-[(1R,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-([[4-(allyloxy)-2,2-dimethyl-4-oxobutanoyl]oxy]methyl)-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysen-9-yl] 1-allyl 2,2-dimethylsuccinate		C₄₈H₇₄O₈	详情	详情

Extended Information