1-cyclohexylpiperazine -Drug Synthesis Database

【结构式】

【分子编号】23174

【品名】1-cyclohexylpiperazine

【CA登记号】17766-28-8

【分子式】C₁₀H₂₀N₂

【分子量】168.28228

【元素组成】C 71.37% H 11.98% N 16.65%

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)

Oxidation of disulfide (I) with sulfuryl chloride in AcOH at -20 C afforded (4-methoxyphenyl)sulfinyl chloride (II), which was condensed with (1R,2S)-2-phenylcyclohexanol to provide sulfinate (IV) as a single diastereomer. Subsequent condensation with the Grignard reagent (V) produced the chiral sulfoxide (VI). The diethyl acetal of (VI) was then hydrolyzed to the corresponding benzaldehyde (VII) using p-TsOH in THF-H2O. Finally, condensation of (VII) with N-cyclohexylpiperazine (VIII) using titanium tetraisopropoxide, followed by addition of diethylaluminum cyanide, furnished the target piperazinylacetonitrile.

参考文献中间体

合成目标

【1】 Lowe, D.B.; Guzik, H.S.; Kozlowski, J.A.; et al.; Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor. Bioorg Med Chem Lett 2000, 10, 20, 2255.
【2】 Lowe, D.; Chang, W.; Kozlowski, J.; Berger, J.G.; McQuade, R.; Barnett, A.; Scherlock, M.; Tom, W.; Dugar, S.; Chen, L.-Y.; Clader, J.W.; Chackalamannil, S. (Schering Corp.); Benzylpiperidines and piperazines as muscarinic an. EP 0811002; JP 1999501014; US 5883096; WO 9626196 .

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)	23167	1-methoxy-4-[(4-methoxyphenyl)disulfanyl]benzene; bis(4-methoxyphenyl) disulfide	5335-87-5	C₁₄H₁₄O₂S₂	详情	详情
(II)	23168	4-methoxybenzenesulfinyl chloride		C₇H₇ClO₂S	详情	详情
(III)	23169	(1S,2R)-2-phenylcyclohexanol		C₁₂H₁₆O	详情	详情
(IV)	23170	(1S,2R)-2-phenylcyclohexyl 4-methoxybenzenesulfinate		C₁₉H₂₂O₃S	详情	详情
(V)	23171	bromo[4-(diethoxymethyl)phenyl]magnesium		C₁₁H₁₅BrMgO₂	详情	详情
(VI)	23172	[4-(diethoxymethyl)phenyl](4-methoxyphenyl)oxo-lambda(4)-sulfane; 4-(diethoxymethyl)phenyl 4-methoxyphenyl sulfoxide		C₁₈H₂₂O₄S	详情	详情
(VII)	23173	4-[(4-methoxyphenyl)sulfinyl]benzaldehyde		C₁₄H₁₂O₃S	详情	详情
(VIII)	23174	1-cyclohexylpiperazine	17766-28-8	C₁₀H₂₀N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Bromination of 1-(4-chloro-2-thienyl)ethanone (I) with Br2 in Et2O gives 2-bromo-1-(4-chloro-2-thienyl)ethanone (II), which by cyclocondensation with thiourea (III) in EtOH at 80 °C provides 2-amino-4-(4-chloro-2-thienyl)thiazole (IV). Treatment of thiazole (IV) with NBS in DMF and subsequent condensation with 1-cyclohexylpiperazine (V) by means of Et3N at 70 °C affords the 5-piperazinyl-thiazole derivative (VI). Coupling of the 2-aminothiazole (VI) with 5,6-dichloronicotinic acid (VII) in the presence of POCl3 in pyridine yields amide (VIII), which is then condensed with ethyl isonipecotate (IX) in THF at 50 °C to obtain the ethyl 1-(pyridyl)piperidine-4-carboxylate derivative (X). Finally, ethyl ester (X) is hydrolyzed by means of NaOH in MeOH .

参考文献中间体

合成目标

【1】 Watanuki, S., Nagata, H., Wakayama, R. et al. 2-Acylaminothiazole derivative or salt thereof. EP 1466912, EP 2314586, JP 2009111001, US 2005153977, US 7638536, US 2010222329, US 2010222361, WO 2003062233.

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)	68277	1-(4-chloro-2-thienyl)ethanone;4-Chloro-2-acetylthiophene	34730-20-6	C₆H₅ClOS	详情	详情
(II)	68278	2-bromo-1-(4-chloro-2-thienyl)ethanone		C₆H₄BrClOS	详情	详情
(III)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(IV)	68279	2-amino-4-(4-chloro-2-thienyl)thiazole		C₇H₅ClN₂S₂	详情	详情
(V)	23174	1-cyclohexylpiperazine	17766-28-8	C₁₀H₂₀N₂	详情	详情
(VI)	68280	4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-amine		C₁₇H₂₃ClN₄S₂	详情	详情
(VII)	68282	5,6-dichloronicotinic acid	41667-95-2	C₆H₃Cl₂NO₂	详情	详情
(VIII)	68281	5,6-dichloro-N-(4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)nicotinamide		C₂₃H₂₄Cl₃N₅OS₂	详情	详情
(IX)	17410	Ethyl isonipecotate; ethyl 4-piperidinecarboxylate	1126-09-6	C₈H₁₅NO₂	详情	详情
(X)	68283	ethyl 1-(3-chloro-5-((4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl)carbamoyl)pyridin-2-yl)piperidine-4-carboxylate		C₃₁H₃₈Cl₂N₆O₃S₂	详情	详情

Extended Information