1-chloroethyl cyclohexyl carbonate -Drug Synthesis Database

【结构式】

【分子编号】15573

【品名】1-chloroethyl cyclohexyl carbonate

【CA登记号】

【分子式】C₉H₁₅ClO₃

【分子量】206.669

【元素组成】C 52.31% H 7.32% Cl 17.15% O 23.22%

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：(III)

The reaction of 1-chloroethyl chloroformate (I) with cyclohexanol (II) by means of pyridine in dichloromethane gives 1-chloroethyl cyclohexyl carbonate (III), which is converted to the corresponding iodoethyl derivative (IV) with NaI in hot acetonitrile. Finaly this compound is condensed with potassium 7beta-[2-(2-aminothiazol-4-yl)acetamido]-3-[1-[2-(dimethylamino)ethyl]-1H-tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylate (V) in DMF.

参考文献中间体

合成目标

【1】 Yashiki, T.; Nishimura, T.; Numata, M.; Hirai, S.; Takanohashi, K.; Miyake, A.; Yoshimura, Y.; Hamaguchi, N.; Yamaoka, M.; Orally active 1-(cyclohexyloxycarbonyloxy)alkyl es. J Antibiot 1987, 40, 1, 81.
【2】 Hirai, S.; Koyama, H.; Makino, T. (Takeda Chemical Industries, Ltd.); Antibacterial solid compsn. for oral administratio. EP 0163433; JP 1985233012; JP 1987030713 .
【3】 Castaner, J.; Prous, J.; SCE-2174. Drugs Fut 1988, 13, 3, 231.

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)	22014	1-chloro-1-[(chlorocarbonyl)oxy]ethane	50893-53-3	C₃H₄Cl₂O₂	详情	详情
(II)	11306	Cyclohexanol	108-93-0	C₆H₁₂O	详情	详情
(III)	15573	1-chloroethyl cyclohexyl carbonate		C₉H₁₅ClO₃	详情	详情
(IV)	15339	cyclohexyl 1-iodoethyl carbonate	102672-57-1	C₉H₁₅IO₃	详情	详情
(V)	22018	potassium (7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)acetyl]amino]-3-[([1-[2-(dimethylamino)ethyl]-1H-1,2,3,4-tetraazol-5-yl]sulfanyl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate		C₁₈H₂₂KN₉O₄S₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XV)

1) The reaction of 2-methoxycyclohexanone (I) with dialkyl carbonate by means of NaH/KH in THF gives 3-methoxy-2-oxocyclohexanecarboxylic acid allyl ester (II), which is condensed with (3R,4R)-4-acetoxy-3-[1(R)-tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (III) by means of NaH in THF yielding the condensation product (IV) as a mixture of the alpha- and beta-stereoisomers at the methoxy group. The protection of the NH group of (IV) with tert-butyldimethylsilyl (TBS) trifluoromethanesulfonate affords the bis-TBS-protected compound (V), which is stereospecifically decarboxylated with palladium acetate, formic acid and triphenylphosphine to the protected azetidinone (VI) also as alpha- and beta-isomers. The selective desilylation of (VI) with tetrabutylammonium fluoride (TBAF) in acetic acid gives the O-protected azetidinone (VII) also as a mixture, which is epimerized by sequential treatments with lithium diisopropylamide (LDA), with ZnBr2 and finally with diethyl malonate to afford the alpha-(S)-epimer (VIII). The acylation of (VIII) with benzyloxalyl chloride and pyridine in dichloromethane gives the N-benzyloxazyl derivative (IX), which is cyclized by means of triethyl phosphite in refluxing xylene yielding (4S,8S,9R,10S)-10-[1(R)-(tert-butyldimethylsilyloxy)ethyl]-4-methoxy-11-oxo-1-azatricyclo[7.2.0.0(3,8)]undec-2-ene-2-carboxylic acid benzyl ester (X). The desilylation of (X) with TBAF in THF/acetic acid affords (XI) with a 1-hydroxyethyl group, which is hydrogenated with H2 over Pd/C in dioxane in the presence of 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene (XII) giving the addition salt (XIII). The treatment of (XIII) with potassium 2-ethylhexanoate yields the corresponding potassium salt (XIV) (1), which is finally esterified with 1-chloroethyl cyclohexyl carbonate (XV) by means of benzyltrimethylammonium chloride in DMF.

参考文献中间体

合成目标

【1】 Owen, M.R.; et al.; Efficiency by design: Optimisation in process research. Org Process Res Dev 2001, 5, 3, 308.
【2】 Ngo, J.; Castaner, J.; Sanfetrinem cilexetil. Drugs Fut 1996, 21, 12, 1238.
【3】 Hanessian, S.; Rozema, M.J.; A highly stereoselective and practical total synthesis of the tricyclic beta-lactam antibiotic GV104326 (4-methoxytrinem). J Am Chem Soc 1996, 118, 41, 9884-91.
【4】 Perboni, A.; Rossi, T.; Gaviraghi, G.; Ursini, A.; Tarzia, G. (Glaxo Wellcome plc); 10(1-Hydroxyethyl-11-oxo-1-azatricyclo[7.2.0.0.3.8]undec-2-ene-2-carboxylic acid esters and a process for preparing thereof. JP 1993502044; US 5587374; WO 9203437 .

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)	15559	2-methoxycyclohexanone	7429-44-9	C₇H₁₂O₂	详情	详情
(II)	15560	allyl 3-methoxy-2-oxocyclohexanecarboxylate		C₁₁H₁₆O₄	详情	详情
(III)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate		C₁₃H₂₅NO₄Si	详情	详情
(IV)	15562	allyl 1-[(2S,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl]-3-methoxy-2-oxocyclohexanecarboxylate		C₂₂H₃₇NO₆Si	详情	详情
(V)	15563	allyl 1-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]-3-methoxy-2-oxocyclohexanecarboxylate		C₂₈H₅₁NO₆Si₂	详情	详情
(VI)	15564	(3S,4R)-1-[tert-butyl(dimethyl)silyl]-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₂₄H₄₇NO₄Si₂	详情	详情
(VII)	15565	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₁₈H₃₃NO₄Si	详情	详情
(VIII)	15566	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-2-azetanone		C₁₈H₃₃NO₄Si	详情	详情
(IX)	15567	benzyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R,3S)-3-methoxy-2-oxocyclohexyl]-4-oxoazetidinyl]-2-oxoacetate		C₂₇H₃₉NO₇Si	详情	详情
(X)	15568	benzyl (1S,5S,8aS,8bR)-1-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₂₇H₃₉NO₅Si	详情	详情
(XI)	15569	benzyl (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₂₁H₂₅NO₅	详情	详情
(XII)	15570	2,2,4a,7,7-pentamethyl-1,2,3,4,4a,5,6,7-octahydro[1,8]naphthyridine; 3,3,6,9,9-pentamethyl-2,10-diazabicyclo[4.4.0]dec-1-ene	69340-58-5	C₁₃H₂₄N₂	详情	详情
(XIII)	15571	(1S,5S,8aS,8bR)-1-(1(R)-Hydroxyethyl)-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[3,1-a]isoindole-4-carboxylic acid 2,2,4a,7,7-pentamethyl-2,3,4,4a,5,6,7,8-octahydro-1,8-naphthyridine salt		C₂₇H₄₃N₃O₅	详情	详情
(XIV)	15572	potassium (1S,5S,8aS,8bR)-1-[(1R)-1-hydroxyethyl]-5-methoxy-2-oxo-1,2,5,6,7,8,8a,8b-octahydroazeto[2,1-a]isoindole-4-carboxylate		C₁₄H₁₈KNO₅	详情	详情
(XV)	15573	1-chloroethyl cyclohexyl carbonate		C₉H₁₅ClO₃	详情	详情

Extended Information