【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% |
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 |