4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】48735

【品名】4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile

【CA登记号】19812-93-2

【分子式】C₁₃H₉NO

【分子量】195.2206

【元素组成】C 79.98% H 4.65% N 7.17% O 8.2%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VIII)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol to afford the target acetic acid derivative.

参考文献中间体

合成目标

【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .

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)	48730	(S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone		C₂₄H₂₃NO₂	详情	详情
(II)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(III)	48731	benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₂H₂₉NO₄	详情	详情
(IV)	40664	tert-butyl 2-chloroacetate	107-59-5	C₆H₁₁ClO₂	详情	详情
(V)	48732	benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₈H₃₉NO₆	详情	详情
(VI)	48733	tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate		C₁₁H₁₉NO₄	详情	详情
(VII)	48734	tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₁₂H₂₁NO₆S	详情	详情
(VIII)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(IX)	48736	tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₂₄H₂₆N₂O₄	详情	详情
(X)	48737	methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate		C₂₁H₂₃N₃O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III), which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V). The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI), which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII). The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX), which by treatment with HCl in methanol, and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X). Finally, this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.

参考文献中间体

合成目标

【1】 Himmelsbach, F.; Austel, V.; Pieper, H.; Eisert, W.; Müller, T.; Weisenberger, J.; Linz, G.; Krüger, G. (Dr. Karl Thomae GmbH); Cyclic imino derivs., process for their preparation and drugs containing them. DE 4035961; EP 0483667; JP 1992264068; US 5591769 .
【2】 Himmelsbach, F.; Austel, V.; Pieper, H.; Linz, G.; Wisenberger, J.; Muller, T. (Dr. Karl Thomae GmbH); Cyclic imino derivs., medicaments containing these cpds. and processes for the production thereof. DE 4213919; EP 0567966; JP 1994073001 .

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)	48730	(S)-(+)-5-(Trityloxymethyl)-2-pyrrolidinone		C₂₄H₂₃NO₂	详情	详情
(II)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(III)	48731	benzyl (5S)-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₂H₂₉NO₄	详情	详情
(IV)	40664	tert-butyl 2-chloroacetate	107-59-5	C₆H₁₁ClO₂	详情	详情
(V)	48732	benzyl (3S,5S)-3-[2-(tert-butoxy)-2-oxoethyl]-2-oxo-5-[(trityloxy)methyl]-1-pyrrolidinecarboxylate		C₃₈H₃₉NO₆	详情	详情
(VI)	48733	tert-butyl 2-[(3S,5S)-5-(hydroxymethyl)-2-oxopyrrolidinyl]acetate		C₁₁H₁₉NO₄	详情	详情
(VII)	48734	tert-butyl 2-((3S,5S)-5-[[(methylsulfonyl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₁₂H₂₁NO₆S	详情	详情
(VIII)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(IX)	48736	tert-butyl 2-((3S,5S)-5-[[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]methyl]-2-oxopyrrolidinyl)acetate		C₂₄H₂₆N₂O₄	详情	详情
(X)	48737	methyl 2-[(3S,5S)-5-[([4'-[amino(imino)methyl][1,1'-biphenyl]-4-yl]oxy)methyl]-2-oxopyrrolidinyl]acetate		C₂₁H₂₃N₃O₄	详情	详情
(XI)	10257	methyl 2-chloroacetate; methyl chloroacetate	96-34-4	C₃H₅ClO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Alkylation of 4-cyano-4'-hydroxybiphenyl (I) with 1-bromo-3-chloropropane (II) yields the chloropropyl ether (III). This is then condensed with the mono-protected homopiperazine (IV) to furnish (V). Removal of the N-Boc group of (V) to afford amine (VI) is then accomplished by treatment with trifluoroacetic acid in CH2Cl2. Amine (VI) is subsequently coupled with N-Boc-D-thiazolylalanine (VII) in the presence of EDC/DMAP producing amide (VIII). (1,2)

参考文献中间体

合成目标

【1】 Curtis, M.P.; Dwight, W.; Fox, G.B.; Esbenshade, T.A.; Pan, J-B.; Bennani, Y.L.; Hancock, A.A.; Faghih, R.; A-320436: Potent human non-imidazole histamine H3 receptor antagonist. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 240.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .

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)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(II)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(III)	57817	4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carbonitrile		C₁₆H₁₄ClNO	详情	详情
(IV)	54079	tert-Butyl 1-homopiperazine carboxylate	n/a	C₁₀H₂₀N₂O₂	详情	详情
(V)	64053	1,1-dimethylethyl 4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepane-1-carboxylate		C₂₆H₃₃N₃O₃	详情	详情
(VI)	64054	4'-{[3-(1,4-diazepan-1-yl)propyl]oxy}[1,1'-biphenyl]-4-carbonitrile		C₂₁H₂₅N₃O	详情	详情
(VII)	12882	(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid		C₁₁H₁₆N₂O₄S	详情	详情
(VIII)	64055	1,1-dimethylethyl 2-(4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₃₂H₃₉N₅O₄S	详情	详情

Extended Information