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【结 构 式】 
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【分子编号】47974 【品名】ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate 【CA登记号】 |
【 分 子 式 】C13H16Cl2N2O4 【 分 子 量 】335.18652 【元素组成】C 46.58% H 4.81% Cl 21.15% N 8.36% O 19.09% |
合成路线1
该中间体在本合成路线中的序号：(XII)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：(XII)The condensation of 1,3-diamino-2-propanol (XIII) with carbon disulfide produced 5-hydroxytetrahydropyrimidine-2-thione (XIV). Alkylation of thione (XIV) with iodomethane gave the cyclic S-methylisothiourea (XV), which was further protected as the N-Boc derivative (XVI). 3-Amino-5-hydroxybenzoic acid (XVIII) was prepared from 3,5-dihydroxybenzoic acid (XVII) by treatment with ammonia and ammonium chloride. Coupling of thioether (XVI) with amino acid (XVIII) in hot DMA furnished the guanidine adduct (XIX). This was then condensed with the intermediate (XII) via activation as the mixed anhydride with isobutyl chloroformate, producing amide (XX). Acid cleavage of the Boc group of (XX) gave (XXI). The ethyl ester of (XXI) was then hydrolyzed using NaOH in aqueous dioxan. The title compound was finally isolated as the hydrochloride salt after lyophilization from an HCl solution.
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 | |
| (XIII) | 47975 | 1,3-diamino-2-propanol | 616-29-5 | C3H10N2O | 详情 | 详情 |
| (XIV) | 47976 | 5-hydroxytetrahydro-2(1H)-pyrimidinethione | C4H8N2OS | 详情 | 详情 | |
| (XV) | 47977 | 2-(methylsulfanyl)-1,4,5,6-tetrahydro-5-pyrimidinol | C5H10N2OS | 详情 | 详情 | |
| (XVI) | 47978 | tert-butyl 5-hydroxy-2-(methylsulfanyl)-5,6-dihydro-1(4H)-pyrimidinecarboxylate | C10H18N2O3S | 详情 | 详情 | |
| (XVII) | 16230 | resorcylic acid; 3,5-dihydroxybenzoic acid | 99-10-5 | C7H6O4 | 详情 | 详情 |
| (XVIII) | 47979 | 3-amino-5-hydroxybenzoic acid | C7H7NO3 | 详情 | 详情 | |
| (XIX) | 47980 | 3-[[1-(tert-butoxycarbonyl)-5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl]amino]-5-hydroxybenzoic acid | C16H21N3O6 | 详情 | 详情 | |
| (XX) | 47981 | tert-butyl 2-(3-[[(2-[[(1S)-1-(3,5-dichloro-2-hydroxyphenyl)-3-ethoxy-3-oxopropyl]amino]-2-oxoethyl)amino]carbonyl]-5-hydroxyanilino)-5-hydroxy-5,6-dihydro-1(4H)-pyrimidinecarboxylate | C29H35Cl2N5O9 | 详情 | 详情 | |
| (XXI) | 47982 | ethyl (3S)-3-(3,5-dichloro-2-hydroxyphenyl)-3-[[2-([3-hydroxy-5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]benzoyl]amino)acetyl]amino]propanoate | C24H27Cl2N5O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)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 |
合成路线4
该中间体在本合成路线中的序号：(XI)5-Aminonicotinic acid (XII) is condensed with benzoyl isothiocyanate to form the benzoyl thiourea (XIII). Removal of the benzoyl group of (XIII) with NaOMe in MeOH, followed by alkylation with iodomethane, furnishes the S-methyl isothiourea (XIV). This is then condensed with 1,3-diamino-2-propanol (XV) in hot DMF, producing the tetrahydropyrimidine derivative (XVI). The carboxyl group of (XVI) is then activated as the mixed anhydride (XVII) employing isobutyl chloroformate and NMM. Coupling between anhydride (XVII) and amine (XI) in the presence of NMM leads to the diamide (XVIII). The ethyl ester group of (XVIII) is finally hydrolyzed by means of LiOH to the corresponding carboxylic acid.
| 【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 |
|---|---|---|---|---|---|---|
| (XI) | 47974 | ethyl (3S)-3-[(2-aminoacetyl)amino]-3-(3,5-dichloro-2-hydroxyphenyl)propanoate | C13H16Cl2N2O4 | 详情 | 详情 | |
| (XII) | 65053 | 5-aminonicotinic acid | C6H6N2O2 | 详情 | 详情 | |
| (XIII) | 65054 | 5-{[(benzoylamino)carbothioyl]amino}nicotinic acid | C14H11N3O3S | 详情 | 详情 | |
| (XIV) | 65055 | 5-{[imino(methylsulfanyl)methyl]amino}nicotinic acid | C8H9N3O2S | 详情 | 详情 | |
| (XV) | 47975 | 1,3-diamino-2-propanol | 616-29-5 | C3H10N2O | 详情 | 详情 |
| (XVI) | 65056 | 5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]nicotinic acid | C10H12N4O3 | 详情 | 详情 | |
| (XVII) | 65057 | C15H20N4O5 | 详情 | 详情 | ||
| (XVIII) | 65058 | ethyl (3S)-3-(3,5-dichloro-2-hydroxyphenyl)-3-({2-[({5-[(5-hydroxy-1,4,5,6-tetrahydro-2-pyrimidinyl)amino]-3-pyridinyl}carbonyl)amino]acetyl}amino)propanoate | C23H26Cl2N6O6 | 详情 | 详情 |