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【结 构 式】

【分子编号】47973

【品名】ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate

【CA登记号】

【 分 子 式 】C18H24Cl2N2O6

【 分 子 量 】435.30384

【元素组成】C 49.67% H 5.56% Cl 16.29% N 6.44% O 22.05%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

3,5-Dichlorosalicylaldehyde (I) was protected by treatment with methoxyethoxymethyl chloride (II) in the presence of K2CO3 in DMF. The protected aldehyde (III) was then condensed with (S)-phenylglycinol (IV) to give the chiral imine (V). Addition of the Reformatskii reagent (VI) to the imine function gave rise to aminoester (VII) as a single diastereoisomer. Dealkylation of (VII) with lead tetraacetate furnished the chiral primary amine (VIII). Subsequent acidic treatment of (VIII) cleaved the methoxyethoxy protecting group and the tert-butyl ester to afford (IX). Amine (IX) was then coupled with N-Boc-glycine N-hydroxysuccinimidyl ester (X), producing amide (XI). Acid cleavage of the N-Boc group of (XI) then yielded the intermediate (XII).

2 Ruminski, P.G.; Rogers, T.E. (Pharmacia Corp.); Meta-azacyclic amino benzoic acid cpds. and derivs. thereof being integrin antagonists. EP 1060164; WO 9944994 .
3 Gordon, G.B.; Ruminski, P.G.; Nickols, G.A.; Westlin, W.F.; Rogers, T.E.; Cunningham, J. (Pharmacia Corp.); Use of integrin antagonist and a chemotherapeutic agent in the treatment of neoplasia. WO 0051686 .
1 Ruminski, P.G.; Clare, M.; Collins, P.W.; Desai, B.N.; Lindmark, R.J.; Rico, J.G.; Rogers, T.E.; Russell, M.A. (Pharmacia Corp.); Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivs. as integrin antagonists. EP 0850221; JP 1999510814; US 6013651; WO 9708145 .
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) 21323 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde 90-60-8 C7H4Cl2O2 详情 详情
(II) 40670 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride 3970-21-6 C4H9ClO2 详情 详情
(III) 47968 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde C11H12Cl2O4 详情 详情
(IV) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(V) 47969 (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol C19H21Cl2NO4 详情 详情
(VI) 40586 bromo[2-(tert-butoxy)-2-oxoethyl]zinc C6H11BrO2Zn 详情 详情
(VII) 47970 tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate C25H33Cl2NO6 详情 详情
(VIII) 47971 tert-butyl (3S)-3-amino-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]propanoate C17H25Cl2NO5 详情 详情
(IX) 47972 ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C11H13Cl2NO3 详情 详情
(X) 16364 tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester 3392-07-2 C11H16N2O6 详情 详情
(XI) 47973 ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C18H24Cl2N2O6 详情 详情
(XII) 47974 ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C13H16Cl2N2O4 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

The hydroxyl group of 3,5-dichlorosalicylaldehyde (I) is protected as the methoxyethoxymethyl (MEM) ether (II) with MEM chloride in DMF. Condensation of the protected salicylaldehyde (II) with (S)-phenylglycinol (III) yields the chiral aldimine (IV). This is then reacted with the Reformatski reagent (VI), prepared from t-butyl bromoacetate (V), to provide adduct (VII). Oxidative removal of the chiral auxiliary group of (VII) with lead tetraacetate, followed by acidic cleavage of the t-butyl and MEM groups, leads to amino ester (VIII). Coupling of (VIII) with the succinimidyl ester of N-Boc-glycine (IX) furnishes amide (X). The N-Boc protecting group of (X) is then removed under acidic conditions to yield amine (XI) (1).

1 Miyashiro, J.M.; Gasiecki, A.F.; Khanna, I.K.; Chandrakumar, N.S.; Desai, B.N.; Russell, M.A.; Devadas, B.; Rico, J.G.; Rogers, T.E.; Rao, S.N.; Malecha, J.W.; Ruminski, P.G.; Yu, Y.; Huff, R. (Pfizer Inc.); Heterocyclic glycyl beta-alanine derivs. as vitronectin antagonists. EP 1070060; JP 2002511462; WO 9952896 .
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) 21323 3,5-dichloro-2-hydroxybenzaldehyde; 3,5-Dichlorosalicylaldehyde 90-60-8 C7H4Cl2O2 详情 详情
(II) 47968 3,5-dichloro-2-[(2-methoxyethoxy)methoxy]benzaldehyde C11H12Cl2O4 详情 详情
(III) 10973 (2S)-2-Amino-2-phenyl-1-ethanol; (S)-2-Hydroxy-1-phenylethylamine; (S)-(+)-2-Phenylglycinol; (S)-2-Amino-2-phenyl-1-ethanol 20989-17-7 C8H11NO 详情 详情
(IV) 47969 (2R)-2-[((E)-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]methylidene)amino]-2-phenyl-1-ethanol C19H21Cl2NO4 详情 详情
(V) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(VI) 40586 bromo[2-(tert-butoxy)-2-oxoethyl]zinc C6H11BrO2Zn 详情 详情
(VII) 47970 tert-butyl (3S)-3-[3,5-dichloro-2-[(2-methoxyethoxy)methoxy]phenyl]-3-[[(1R)-2-hydroxy-1-phenylethyl]amino]propanoate C25H33Cl2NO6 详情 详情
(VIII) 47972 ethyl (3S)-3-amino-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C11H13Cl2NO3 详情 详情
(IX) 16364 tert-butyl N-[2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-2-oxoethyl]carbamate; N-T-BOC-glycine N-hydroxysuccinimide ester 3392-07-2 C11H16N2O6 详情 详情
(X) 47973 ethyl (3S)-3-([2-[(tert-butoxycarbonyl)amino]acetyl]amino)-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C18H24Cl2N2O6 详情 详情
(XI) 47974 ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate C13H16Cl2N2O4 详情 详情
Extended Information