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【结 构 式】

【分子编号】36588

【品名】tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate

【CA登记号】

【 分 子 式 】C16H26N2O4S

【 分 子 量 】342.45952

【元素组成】C 56.12% H 7.65% N 8.18% O 18.69% S 9.36%

与该中间体有关的原料药合成路线共 4 条

合成路线1

该中间体在本合成路线中的序号:(IX)

The cyclization of 4-amino-3-methylbenzoic acid ethyl ester (I) by reaction with NaNO2 and HCl catalyzed by NH4BF4 gives indazole-5-carboxylic acid ethyl ester (II), which is condensed with 2-(2-bromoethyl)-1,3-dioxolane (III) by means of sodium hexamethyldisylazane (NaHMDS) yielding the addition product (IV). The hydrolysis of the dioxolane ring of (IV) with AcOH affords the aldehyde (V), which is reductocondensed with 1-tritylimidazole-2-amine (VI) by means of NaBH(OAc)3 providing the intermediate (VII). The hydrolysis of (VII) with NaOH in ethanol/water gives the carboxylic acid (VIII), which is condensed with the 3-aminopropionic ester (IX) by means of DCC and HOBT yielding the amide (X). Finally, the tert-butyl ester of (X) is hydrolyzed with TFA in dichloromethane.

1 Petraitis, J.J.; Batt, D.G.; Houghton, G.C.; et al.; Disubstituted indazolines as potent antagonists of the integrin alphavbeta3. J Med Chem 2000, 43, 1, 41.
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) 38737 ethyl 4-amino-3-methylbenzoate 40800-65-5 C10H13NO2 详情 详情
(II) 38738 ethyl 1H-indazole-5-carboxylate C10H10N2O2 详情 详情
(III) 15724 2-(2-bromoethyl)-1,3-dioxolane 18742-02-4 C5H9BrO2 详情 详情
(IV) 38739 ethyl 1-[2-(1,3-dioxolan-2-yl)ethyl]-1H-indazole-5-carboxylate C15H18N2O4 详情 详情
(V) 38740 ethyl 1-(3-oxopropyl)-1H-indazole-5-carboxylate C13H14N2O3 详情 详情
(VI) 38741 1-trityl-1H-imidazol-2-amine; 1-trityl-1H-imidazol-2-ylamine C22H19N3 详情 详情
(VII) 38742 ethyl 1-[3-[(1-trityl-1H-imidazol-2-yl)amino]propyl]-1H-indazole-5-carboxylate C35H33N5O2 详情 详情
(VIII) 38743 1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazole-5-carboxylic acid C14H15N5O2 详情 详情
(IX) 36588 tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate C16H26N2O4S 详情 详情
(X) 38744 tert-butyl (2S)-3-[([1-[3-(1H-imidazol-2-ylamino)propyl]-1H-indazol-5-yl]carbonyl)amino]-2-[(mesitylsulfonyl)amino]propanoate C30H39N7O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

After ester (X) hydrolysis with LiOH, the free acid (XI) was coupled with tert-butyl (S)-3-amino-2-(2,4,6-trimethylphenylsulfonylamino)propionate (XII) to yield amide (XIII). Finally, the tert-butyl and Boc protecting groups of (XIII) were cleaved by treatment with trifluoroacetic acid.

1 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 36586 7-benzyl 3-ethyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate C28H34N4O7 详情 详情
(XI) 36587 7-[(benzyloxy)carbonyl]-8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid C26H30N4O7 详情 详情
(XII) 36588 tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate C16H26N2O4S 详情 详情
(XIII) 36589 benzyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate C42H54N6O10S 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IX)

Cycloaddition of 5-hexen-1-ol (I) with (II) in presence of NaHCO3 yields isoxazoline (III). Alternatively (III) can be obtained by treatment of (I) with diethyl nitromalonate (A) in mesitylene. Isoxazoline (III) is then oxidized by means of Jones reagent to provide acid (IV) which is coupled in presence of BOP with the imidazole derivative (V) and hydrolyzed with LiOH affording derivative (VI). Acid (VI) is coupled with derivative (IX) (obtained by reaction of diaminopropionate (VII) with (VIII) in presence of DIEA) by means of BOP, and finally hydrolyzed to afford the desired product.

1 Withyak, J.; Pitts, W.J.; Smallheer, J.M.; et al.; Isoxazolines as potent antagonists of the integrin alphavbeta3. J Med Chem 2000, 43, 1, 27.
2 Voss, M.E.; Jadhav, P.K.; Smallheer, J.M.; Batt, D.G.; Pitts, W.J.; Wityak, J. (DuPont Pharmaceuticals Co.); Isoxazoline and isoxazole derivs. as integrin receptor antagonists. EP 0828737; JP 1999506436; US 5710159; WO 9637492 .
3 Jadhav, P.; Repta, A.J.; Pitts, W.J.; Hussain, M.A.; Batt, D.G. (DuPont Pharmaceuticals Co.); Heterocyclic integrin inhibitor prodrugs. WO 9843962 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 41159 diethyl 2-nitromalonate C7H11NO6 详情 详情
(I) 41152 5-hexen-1-ol 821-41-0 C6H12O 详情 详情
(II) 30424 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride 14337-43-0 C4H6ClNO3 详情 详情
(III) 41153 ethyl 5-(4-hydroxybutyl)-4,5-dihydro-3-isoxazolecarboxylate C10H17NO4 详情 详情
(IV) 41154 4-[3-(ethoxycarbonyl)-4,5-dihydro-5-isoxazolyl]butyric acid C10H15NO5 详情 详情
(V) 41155 1H-imidazol-2-ylamine; 1H-imidazol-2-amine; 2-Aminoimidazole 7720-39-0 C3H5N3 详情 详情
(VI) 41156 5-[4-(1H-imidazol-2-ylamino)-4-oxobutyl]-4,5-dihydro-3-isoxazolecarboxylic acid C11H14N4O4 详情 详情
(VII) 41157 tert-butyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate C12H24N2O4 详情 详情
(VIII) 41158 2,4,6-trimethylbenzenesulfonyl chloride 773-64-8 C9H11ClO2S 详情 详情
(IX) 36588 tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate C16H26N2O4S 详情 详情

合成路线4

该中间体在本合成路线中的序号:(IX)

Reduction of protected hydroxyproline (I) by means of borane dimethylsulfide complex (BH3-Me2S) in THF affords protected hydroxy prolinol (II), which is then treated with tert-butyldimethylsilyl chloride and Et3N in CH2Cl2 to provide hydroxypyrrolidine derivative (III). Swern oxidation of (III) by means of oxalyl chloride in DMSO/CH2Cl2 yields pyrrolidinone (IV), which is then converted into methylenepyrrolidine (V) by reaction with methyltriphenylphosphonium bromide and KOtBu in ether. Treatment of (V) with ethyl chlorooximidoacetate (VI) and Et3N in CH2Cl2 gives spiro compound (VII), which is then subjected to saponification by treatment with LiOH in MeOH to afford carboxylic acid (VIII). Coupling of (VIII) with amine (IX) by means of BOPCl and N-methylmorpholine (NMM) in DMF furnishes amide (X), which is then converted into aldehyde (XI) by first TBDMS removal by treatment with tetrabutylammonium fluoride (TBAF) in THF and oxidation with Dess-Martin periodinane. Reductive amination of aldehyde (XI) with amine (XII) by means of Na(AcO)3BH in benzene/1,2-dichloroethane followed by treatment with Boc2O provides compound (XIII), whose Cbz is selectively removed by hydrogenation over Pd/Ba2SO4 to give secondary amine (XIV). Finally, acylation of (XIV) with chloroformate (XV) followed by Boc removal by means of TFA allows to obtain the desired product.

1 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 .
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) 36579 (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid 13504-85-3 C13H15NO5 详情 详情
(II) 48432 benzyl (2S,4S)-4-hydroxy-2-(hydroxymethyl)-1-pyrrolidinecarboxylate C13H17NO4 详情 详情
(III) 36580 benzyl (2S,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate C19H31NO4Si 详情 详情
(IV) 36581 benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate C19H29NO4Si 详情 详情
(V) 36582 benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate C20H31NO3Si 详情 详情
(VI) 30424 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride 14337-43-0 C4H6ClNO3 详情 详情
(VII) 48433 7-benzyl 3-ethyl (5R,8S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate C24H36N2O6Si 详情 详情
(VIII) 48434 (5R,8S)-7-[(benzyloxy)carbonyl]-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carboxylic acid C22H32N2O6Si 详情 详情
(IX) 36588 tert-butyl (2S)-3-amino-2-[(mesitylsulfonyl)amino]propanoate C16H26N2O4S 详情 详情
(X) 48435 benzyl (5R,8S)-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate C38H56N4O9SSi 详情 详情
(XI) 48436 benzyl (5R,8S)-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-8-formyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate C32H40N4O9S 详情 详情
(XII) 48437 2-Aminobenzimidazole; 2-Amino-1H-benzimidazol; 1H-Benzimidazol-2-amine; 2-Benzimidazolamine 934-32-7 C7H7N3 详情 详情
(XIII) 48438 benzyl (5R,8S)-8-[[1H-benzimidazol-2-yl(tert-butoxycarbonyl)amino]methyl]-3-[([(2S)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate C44H55N7O10S 详情 详情
(XIV) 48439 tert-butyl (2S)-3-[[((5R,8S)-8-[[1H-benzimidazol-2-yl(tert-butoxycarbonyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl)carbonyl]amino]-2-[(mesitylsulfonyl)amino]propanoate C36H49N7O8S 详情 详情
(XV) 48440 1-[(chlorocarbonyl)oxy]butane C5H9ClO2 详情 详情
Extended Information