4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol -Drug Synthesis Database

【结构式】

【分子编号】46836

【品名】4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol

【CA登记号】

【分子式】C₉H₁₃NO₂

【分子量】167.20776

【元素组成】C 64.65% H 7.84% N 8.38% O 19.14%

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：(IV)

The condensation of 4-(2-bromoethyl)phenol (I) with ethyl bromoacetate (II) in the presence of K2CO3 produced the phenoxyacetate (III). This was then condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-propan-1-ol (IV) to give adduct (V). the ethyl ester group of (V) was finally hydrolyzed with NaOH to yield the title carboxylic acid.

参考文献中间体

合成目标

【1】 Tamai, T.; Akahane, M.; Mukaiyama, H.; Muranaka, H.; Tanaka, N.; Sato, M.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Aminoethylphenoxyacetic acid derivs. and drugs for pain remission and calculi removal promotion in urinary lithiasis. EP 1002791; WO 9905090 .

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)	46834	4-(2-bromoethyl)phenol		C₈H₉BrO	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	46835	ethyl 2-[4-(2-bromoethyl)phenoxy]acetate		C₁₂H₁₅BrO₃	详情	详情
(IV)	46836	4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol		C₉H₁₃NO₂	详情	详情
(V)	46837	ethyl 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]acetate		C₂₁H₂₇NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of 2-(4-aminophenyl)ethanol (I) with ethyl 2-bromoacetate (II) by means of K2CO3 in DMF gives 2-[4-(2-hydroxyethyl)phenylamino]acetic acid ethyl ester (III), which is chlorinated with t-butyl hypochlorite in dichloromethane to yield the 2,6-dichlorophenyl derivative (IV). The bromination of (IV) by means of PPh3 and CBr4 in dichloromethane affords the 2-bromoethyl derivative (V), which is condensed with (1R,2S)-2-amino-1-(4-hydroxyphenyl)-1-propanol (VI) by means of DIEA in hot DMF to provide the ethyl ester precursor (VII). Finally, this compound is hydrolyzed with aq. 1N NaOH to give the target N-phenylglycine derivative.

参考文献中间体

合成目标

【1】 Tanaka, N.; Mukaiyama, H.; Akahane, M.; Miyata, H.; Akahane, S.; Muranaka, H.; Hirabayashi, A.; Tamai, T.; Discovery of novel N-phenylglycine derivatives as potent and selective beta3-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence. J Med Chem 2001, 44, 9, 1436.
【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hirabayashi, A. (Kissei Pharmaceutical Co., Ltd.); Phenylaminoalkylcarboxylic acid derivs. and medicinal compsns. containing the same. EP 1043308; WO 9931045 .

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)	14019	p-Aminophenylethanol; 2-(4-Aminophenyl)-1-ethanol	104-10-9	C₈H₁₁NO	详情	详情
(II)	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
(III)	55795	ethyl 2-[4-(2-hydroxyethyl)anilino]acetate		C₁₂H₁₇NO₃	详情	详情
(IV)	55796	ethyl 2-[2,6-dichloro-4-(2-hydroxyethyl)anilino]acetate		C₁₂H₁₅Cl₂NO₃	详情	详情
(V)	55797	ethyl 2-[4-(2-bromoethyl)-2,6-dichloroanilino]acetate		C₁₂H₁₄BrCl₂NO₂	详情	详情
(VI)	46836	4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol		C₉H₁₃NO₂	详情	详情
(VII)	55798	ethyl 2-[2,6-dichloro-4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)anilino]acetate		C₂₁H₂₆Cl₂N₂O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(X)

2-(4-Hydroxyphenyl)ethanol (I) was protected at the aliphatic hydroxyl group by the following sequence. Reaction of (I) with methoxymethyl chloride and NaH blocked the phenolic hydroxyl as the methoxymethyl ether (II), which was subsequently treated with benzyl bromide to produce the fully protected compound (III). Further hydrolysis of the methoxymethyl ether using trifluoroacetic acid gave rise to 4-(2-benzyloxyethyl)phenol (IV). Condensation of phenol (IV) with 1,1,1-trichloro-2-methyl-2-propanol (V) under basic conditions generated the 2-(aryloxy)isobutyric acid (VI). After esterification of (VI) with SOCl2 in EtOH to give (VII), its O-benzyl protecting group was removed by catalytic hydrogenation to produce (VIII). Alcohol (VIII) was then converted into alkyl bromide (IX) by using CBr4 and PPh3. Alkylation of (-)-4'-hydroxynorephedrine (X) with bromide (IX) in hot DMF afforded the secondary amine (XI). The ethyl ester group of (XI) was finally hydrolyzed with NaOH to the title carboxylic acid.

参考文献中间体

合成目标

【1】 Hirabayashi, A.; Tamai, T.; Muranaka, H.; Tanaka, N.; Ishikawa, T.; Mukaiyama, H.; Akahane, M.; Akahane, S.; beta(3)- Adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[1S,2R)-2- hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001, 9, 12, 3265.
【2】 Sato, M.; Tanaka, N.; Akahane, M.; Tamai, T.; Muranaka, H.; Mukaiyama, H.; Hiribayashi, A. (Kissei Pharmaceutical Co., Ltd.); 2-Methylpropionic acid derivs. and medicinal compsns. containing the same. EP 1072583; WO 9952856 .

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)	47355	4-(2-hydroxyethyl)phenol	501-94-0	C₈H₁₀O₂	详情	详情
(II)	56061	sodium 2-[4-(methoxymethoxy)phenyl]-1-ethanolate		C₁₀H₁₃NaO₃	详情	详情
(III)	56062	benzyl 4-(methoxymethoxy)phenethyl ether; 1-[2-(benzyloxy)ethyl]-4-(methoxymethoxy)benzene		C₁₇H₂₀O₃	详情	详情
(IV)	56063	4-[2-(benzyloxy)ethyl]phenol		C₁₅H₁₆O₂	详情	详情
(V)	25975	1,1,1-trichloro-2-methyl-2-propanol	57-15-8	C₄H₇Cl₃O	详情	详情
(VI)	56064	2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoic acid		C₁₉H₂₂O₄	详情	详情
(VII)	56065	ethyl 2-{4-[2-(benzyloxy)ethyl]phenoxy}-2-methylpropanoate		C₂₁H₂₆O₄	详情	详情
(VIII)	56066	ethyl 2-[4-(2-hydroxyethyl)phenoxy]-2-methylpropanoate		C₁₄H₂₀O₄	详情	详情
(IX)	56067	ethyl 2-[4-(2-bromoethyl)phenoxy]-2-methylpropanoate		C₁₄H₁₉BrO₃	详情	详情
(X)	46836	4-[(1R,2S)-2-amino-1-hydroxypropyl]phenol		C₉H₁₃NO₂	详情	详情
(XI)	56068	ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropanoate		C₂₃H₃₁NO₅	详情	详情

Extended Information