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【结 构 式】 
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【药物名称】S-787 【化学名称】3(S)-(3,5-Dichloro-2-hydroxyphenyl)-3-[2-[3-hydroxy-5-(5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-ylamino)benzamido]acetamido]propionic acid 【CA登记号】243135-77-5, 243135-71-9 (monohydrochloride), 253866-56-7 (monotrifluoroacetate) 【 分 子 式 】C22H23Cl2N5O7 【 分 子 量 】540.36391 |
【开发单位】Pfizer (Originator) 【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, ONCOLYTIC DRUGS, Treatment of Osteoporosis, Angiogenesis Inhibitors, Apoptosis Inducers, Integrin alphavbeta3 (Vitronectin) Antagonists |
合成路线1
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
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 |