Cilostazol, OPC-21, OPC-13013, Pletaal, Pletal, -Drug Synthesis Database

【结构式】

【药物名称】Cilostazol, OPC-21, OPC-13013, Pletaal, Pletal

【化学名称】6-[4-(1-Cyclohexyltetrazol-5-yl)butoxy]-3,4-dihydrocarbostyril
　　　　　　6-[4-(1-Cyclohexyl-5-tetrazolyl)butoxy]-1,2,3,4-tetrahydro-2-oxoquinoline
　　　　　　6-[4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone

【CA登记号】73963-72-1

【分子式】C₂₀H₂₇N₅O₂

【分子量】369.47049

【开发单位】Otsuka (Originator), Pfizer (Licensee)

【药理作用】Antiplatelet Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Peripheral Vascular Disease, Treatment of, Stroke, Treatment of, Treatment of Intermittent Claudication, Phosphodiesterase III Inhibitors, Thromboxane Synthase Inhibitors

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

参考文献中间体

【1】 Nishi T,NakagawaI（．1981. Tetnuolylalkoxyc而otyril derivatives and pharmaceutical compositions containing them US 4277479
【2】 YamamotoA,FukuyamaN,et al.2004.Process for producing alostazoL W0 2004024716

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)	31946	N-[(4-chlorobutyl)carbonyl]cyclohexylamine; 5-chloro-N-cyclohexylpentanamide	15862-18-6	C₁₁H₂₀ClNO	详情	详情
(II)	66193	(Z)-5-chloro-N-cyclohexylpentanimidoyl chloride		C₁₁H₁₉Cl₂N	详情	详情
(III)	31947	1-Cyclohexyl-5-(4-chlorobutyl)tetrazole; 5-(4-Chlorobutyl)-1-cyclohexyl-1H-1,2,3,4-tetraazole	73963-42-5	C₁₁H₁₉ClN₄	详情	详情
(IV)	30226	6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril		C₉H₉NO₂	详情	详情

合成路线2

参考文献中间体

【1】 Beltnme A,CastaldiG. 2005.A process for the preparation of cilostazol and the intermediates theweof, WO 200501 9204

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)	31946	N-[(4-chlorobutyl)carbonyl]cyclohexylamine; 5-chloro-N-cyclohexylpentanamide	15862-18-6	C₁₁H₂₀ClNO	详情	详情
(II)	66193	(Z)-5-chloro-N-cyclohexylpentanimidoyl chloride		C₁₁H₁₉Cl₂N	详情	详情
(III)	31947	1-Cyclohexyl-5-(4-chlorobutyl)tetrazole; 5-(4-Chlorobutyl)-1-cyclohexyl-1H-1,2,3,4-tetraazole	73963-42-5	C₁₁H₁₉ClN₄	详情	详情

合成路线3

参考文献中间体

【1】 K.ankan RN, Rao DR, et aL 2005. Preparation of cilostazol. IN 2003MU00444

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)	17966	cyclohexanamine; cyclohexyl amine; cyclohexylamine	108-91-8	C₆H₁₃N	详情	详情
(II)	66194	delta-Valerolactone;Tetrahydro-2H-2-pyranone		C₅H₈O₂	详情	详情
(II)	66193	(Z)-5-chloro-N-cyclohexylpentanimidoyl chloride		C₁₁H₁₉Cl₂N	详情	详情
(III)	66195	5-Hydroxypentanoic acid cyclohexylamide	84996-93-0	C₁₀H₁₉NO₂	详情	详情

合成路线4

By reaction of N-[(4-chlorobutyl)carbonyl]cyclohexylamine (I) first with PCl5 and then with NH3 in benzene to give 1-cyclohexyl-5-(4-chlorobutyl)tetrazole (II), which is treated with 6-hydroxy-3,4-dihydrocarbostyril (III) and 1,5-diazabicyclo[5.4.0]undecene-5 (DBU) in ethanol. Alternatively, the condensation can be performed by means of either NaOH, KOH or KOH / K2CO3 in a great variety of solvents.

参考文献中间体

【1】 Nishi, T.; Nakagawa, K. (Otsuka Pharmaceutical Co., Ltd.); Tetrazolylalkoxycarbostyril derivatives and pharmaceutical compositions containing them. DE 2934747; FR 2434809; GB 2033893; JP 55035019; US 4277479 .
【2】 Finkelstein, N.; Mendelovichi, M.; Pilarksi, G. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for preparing cilostazol. WO 0214283 .
【3】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; OPC-13,013. Drugs Fut 1982, 7, 4, 264.

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)	31946	N-[(4-chlorobutyl)carbonyl]cyclohexylamine; 5-chloro-N-cyclohexylpentanamide	15862-18-6	C₁₁H₂₀ClNO	详情	详情
(II)	31947	1-Cyclohexyl-5-(4-chlorobutyl)tetrazole; 5-(4-Chlorobutyl)-1-cyclohexyl-1H-1,2,3,4-tetraazole	73963-42-5	C₁₁H₁₉ClN₄	详情	详情
(III)	30226	6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril		C₉H₉NO₂	详情	详情

合成路线5

The condensation of p-anisidine (IV) with 3-chloropropionyl chloride (V) by means of TEA in hot toluene, hot 2-butanone or DMF gives the corresponding amide (VI), which is then cyclized by means of AlCl3 in N,N-dimethylacetamide at 150-60 C and treated with NaBH4 in water to yield the desired 6-hydroxy-1,2,3,4-tetrahydroquinolin-2-one intermediate (III).

参考文献中间体

【1】 Mendelovici, M.; Nidam, T.; Pilarsky, G. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Processes for preparing 6-hydroxy-3,4-dihydroquinolinone, cilostazol and N-(4-methoxyphenyl)-3-chloropropionamide. WO 0170697 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	30226	6-Hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline; 6-Hydroxy-3,4-dihydro-2(1H)-quinolinone; 6-Hydroxy-3,4-dihydrocarbostyril		C₉H₉NO₂	详情	详情
(IV)	10478	p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine	104-94-9	C₇H₉NO	详情	详情
(V)	18936	3-chloropropanoyl chloride	625-36-5	C₃H₄Cl₂O	详情	详情
(VI)	55445	3-chloro-N-(4-methoxyphenyl)propanamide		C₁₀H₁₂ClNO₂	详情	详情

Extended Information