4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione -Drug Synthesis Database

【结构式】

【分子编号】58982

【品名】4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione

【CA登记号】70-70-2

【分子式】C₉H₁₀O₂

【分子量】150.1772

【元素组成】C 71.98% H 6.71% O 21.31%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(IV)

Ursodeoxycholic acid (I) was activated as the mixed anhydride (II) with ethyl chloroformate and triethylamine, and subsequently coupled with the triethylamine salt of taurine (III) to produce the title conjugated bile acid. Optionally, the mixed anhydride (II) was previously converted to the active phenol ester (V) by treatment with p-hydroxypropiophenone (IV), and subsequently condensed with taurine (III). Alternatively, ursodeoxycholic acid (I) was directly coupled to taurine (III) employing as the coupling reagents 2-isobutyl-N-isobutyloxycarbonyl-1,2-dihydroquinoline (IIDQ), diethylphosphorocyanidate (DEPC), or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) under microwave irradiation.

参考文献中间体

合成目标

【1】 Momose, T.; et al.; An improved synthesis of taurine- and glycine-conjugated bile acids. Lipids 1997, 32, 7, 775.
【2】 Dayal, B.; et al.; Microwave-induced rapid synthesis of bile acid conjugates. Synlett 1997, 8, 861.
【3】 Bonadi, A.; Molinari, E.; Process for the preparation of taurine-conjugated bile acids. EP 0582891 .
【4】 Reiner, A. (SkyePharma AG); Process for preparing ursodeoxycholic acid derivates and their inorganic and organic salts having therapeutic activity. EP 0272462 .

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)	48093	(4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid	128-13-2	C₂₄H₄₀O₄	详情	详情
(II)	59137			C₂₇H₄₄O₆	详情	详情
(III)	34828	2-amino-1-ethanesulfonic acid	107-35-7	C₂H₇NO₃S	详情	详情
(IV)	58982	4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione	70-70-2	C₉H₁₀O₂	详情	详情
(V)	59138	4-propionylphenyl (4R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate		C₃₃H₄₈O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4 . The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the corresponding D-tartaric acid salts

参考文献中间体

合成目标

【1】 Chenard, B.L.; et al.; (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995, 38, 16, 3138.
【2】 Chenard, B.L. (Pfizer Inc.); 2-Piperidino-1-alkanol derivs. as antiischemic agents. US 5272160 .
【3】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. EP 1151995 .

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)	58982	4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione	70-70-2	C₉H₁₀O₂	详情	详情
(II)	62505	1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₁₈H₃₀O₂Si	详情	详情
(III)	62506	2-bromo-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₁₈H₂₉BrO₂Si	详情	详情
(IV)	28021	4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine	40807-61-2	C₁₁H₁₅NO	详情	详情
(V)	62507	2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₂₉H₄₃NO₃Si	详情	详情
(VI)	62508	1-((1S,2S)-2-hydroxy-1-methyl-2-{4-[(triisopropylsilyl)oxy]phenyl}ethyl)-4-phenyl-4-piperidinol		C₂₉H₄₅NO₃Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

4-Hydroxypropiophenone (I) was protected as the triisopropylsilyl ether (II) and subsequently brominated with elemental bromine in CCl4. The resultant bromo ketone (III) was subsequently coupled with 4-hydroxy-4-phenylpiperidine (IV) to afford the racemic amino ketone (V). This was stereoselectively reduced with NaBH4 in EtOH yielding the threo-amino alcohol (VI). Then, desilylation of (VI) with tetrabutylammonium fluoride furnished the racemic phenol compound. Resolution into the enantiomers has been reported by formation of the corresponding D-tartaric acid salts. Finally, the title product was obtained by dissolving D-(-)-tartaric salt (VII) in water in the presence of methanesulfonic acid

参考文献中间体

合成目标

【1】 Chenard, B.L.; et al.; (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: A potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem 1995, 38, 16, 3138.
【2】 Chenard, B.L. (Pfizer Inc.); 2-Piperidino-1-alkanol derivs. as antiischemic agents. US 5272160 .
【3】 Walinsky, S.W.; Rainville, J.P.; Sinay, T.G. Jr. (Pfizer Products Inc.); Process for the preparation of the mesylate salt trihydrate of 1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol. EP 1151995 .

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)	58982	4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione	70-70-2	C₉H₁₀O₂	详情	详情
(II)	62505	1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₁₈H₃₀O₂Si	详情	详情
(III)	62506	2-bromo-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₁₈H₂₉BrO₂Si	详情	详情
(IV)	28021	4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine	40807-61-2	C₁₁H₁₅NO	详情	详情
(V)	62507	2-(4-hydroxy-4-phenyl-1-piperidinyl)-1-{4-[(triisopropylsilyl)oxy]phenyl}-1-propanone		C₂₉H₄₃NO₃Si	详情	详情
(VI)	62508	1-((1S,2S)-2-hydroxy-1-methyl-2-{4-[(triisopropylsilyl)oxy]phenyl}ethyl)-4-phenyl-4-piperidinol		C₂₉H₄₅NO₃Si	详情	详情
(VII)	62509	1-[(1S,2S)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]-4-phenyl-4-piperidinol		C₂₀H₂₅NO₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

Condensation of 2,6-diaminopyrimidin-4-one (I) with 1,3-dichloroacetone (II) affords the furopyrimidine (III). Subsequent reaction of (III) with tributylphosphine provides the phosphonium salt (IV). Treatment of 4-hydroxypropiophenone (V) with trifluoromethanesulfonic anhydride leads to the aryl triflate (VI). This is then subjected to palladium-catalyzed carbonylation under modified Gerlach's conditions to furnish ethyl 4-propionylbenzoate (VII). Wittig condensation between the phosphorane derived from (IV) and keto ester (VII) produces olefin (VIIIa-b) as a mixture of Z/E isomers. Subsequent hydrogenation of (VIIIa-b) over Pd/C gives (IX). The methyl ester group of (IX) is hydrolyzed under alkaline conditions to afford acid (X), which is then activated as the mixed anhydride (XI) with isobutyl chloroformate and triethylamine.

参考文献中间体

合成目标

【1】 Mcguire, J.J.; Zeng, Y.; Gangjee, A.; Kisliuk, R.L.; Synthesis of N-[4-[ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate. J Med Chem 2002, 45, 9, 1942.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	58984	methyl 4-[(Z)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate		C₁₈H₁₈N₄O₃	详情	详情
(VIIIb)	58985	methyl 4-[(E)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate		C₁₈H₁₈N₄O₃	详情	详情
(I)	14277	2,6-Diamino-4(3H)-pyrimidinone		C₄H₆N₄O	详情	详情
(II)	63907	1,3-dichloroacetone		C₃H₄Cl₂O	详情	详情
(III)	18884	5-(chloromethyl)furo[2,3-d]pyrimidine-2,4-diamine; 2-amino-5-(chloromethyl)furo[2,3-d]pyrimidin-4-ylamine		C₇H₇ClN₄O	详情	详情
(IV)	58981	tributyl[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]phosphonium chloride		C₁₉H₃₄ClN₄OP	详情	详情
(V)	58982	4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione	70-70-2	C₉H₁₀O₂	详情	详情
(VI)	58983	4-propionylphenyl trifluoromethanesulfonate		C₁₀H₉F₃O₄S	详情	详情
(VII)	11008	methyl 4-propionylbenzoate		C₁₁H₁₂O₃	详情	详情
(IX)	58988	methyl 4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoate		C₁₈H₂₀N₄O₃	详情	详情
(X)	58986	4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoic acid		C₁₇H₁₈N₄O₃	详情	详情
(XI)	58987			C₂₂H₂₆N₄O₅	详情	详情

Extended Information