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【结 构 式】 
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【分子编号】30424 【品名】2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride 【CA登记号】14337-43-0 |
【 分 子 式 】C4H6ClNO3 【 分 子 量 】151.54928 【元素组成】C 31.7% H 3.99% Cl 23.39% N 9.24% O 31.67% |
合成路线1
该中间体在本合成路线中的序号：(II)Condensation of ketoester (I) with ethyl chloro(hydroxymino)acetate (II) provided isoxazole (III), which was cyclized to isoxazolopyridazine (IV) using hydrazine. Alkylation of (II) with ethyl bromoacetate gave ester (V), which was finally hydrolyzed with NaOH to afford the title carboxylic acid.
| 【1】 Ciciani, G.; et al.; 5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: Synthesis and pharmacological evaluation. J Pharm Sci 1991, 80, 4, 341-348. |
| 【2】 Barlocco, D.; Vianello, P.; Dal Piaz, V.; Constantino, L.; Giovannoni, M.P.; Gamberini, C.; Rastelli, G.; Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors. J Med Chem 1999, 42, 11, 1894. |
| 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) | 30423 | ethyl 3-(4-chlorophenyl)-3-oxopropanoate | C11H11ClO3 | 详情 | 详情 | |
| (II) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (III) | 30425 | ethyl 4-(4-chlorobenzoyl)-5-methyl-3-isoxazolecarboxylate | C14H12ClNO4 | 详情 | 详情 | |
| (IV) | 30426 | 4-(4-chlorophenyl)-3-methylisoxazolo[3,4-d]pyridazin-7(6H)-one | C12H8ClN3O2 | 详情 | 详情 | |
| (V) | 30427 | ethyl 2-[4-(4-chlorophenyl)-3-methyl-7-oxoisoxazolo[3,4-d]pyridazin-6(7H)-yl]acetate | C16H14ClN3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Reduction of N-(benzyloxycarbonyl)-4-hydroxyproline (I) with boranedimethylsulfide complex in THF provided the corresponding diol, which was selectively protected at the primary hydroxyl group as the tert-butyldimethylsilyl ether (II). Swern oxidation of the remaining secondary alcohol of (II) afforded ketone (III). This was converted to alkene (IV) by Wittig olefination with methylene triphenylphosphorane. The 1,3-dipolar cycloaddition of (IV) with the nitrile oxide generated from chlorooxime (V) and Et3N furnished spirocycle (VI) as a diastereomeric mixture. Deprotection of the silyl ether of (VI) by treatment with tetrabutylammonium fluoride, followed by Swern oxidation of the resulting alcohol provided aldehyde (VII). Reductive amination of (VII) with 2-aminopyridine (VIII) gave amine (IX), which was protected as the tert-butyl carbamate (X) using Boc2O.
| 【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) | 36580 | benzyl (2S,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C19H31NO4Si | 详情 | 详情 | |
| (III) | 36581 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C19H29NO4Si | 详情 | 详情 | |
| (IV) | 36582 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C20H31NO3Si | 详情 | 详情 | |
| (V) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (VI) | 36583 | 7-benzyl 3-ethyl 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 | |
| (VII) | 36584 | 7-benzyl 3-ethyl 8-formyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C18H20N2O6 | 详情 | 详情 | |
| (VIII) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (IX) | 36585 | 7-benzyl 3-ethyl 8-[(2-pyridinylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C23H26N4O5 | 详情 | 详情 | |
| (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 |
合成路线3
该中间体在本合成路线中的序号：(II)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：(VIII)Treatment of trans-4-hydroxy-L-proline (I) with p-nitrobenzyl chloroformate gave the N-protected 4-hydroxyproline (II), which was esterified to afford the N-protected methyl ester (II). Protection of the hydroxyl group of (III) with t-butyl-dimethylsilyl chloride in the presence of imidazole, followed by reduction of the resulting ester (IV) with lithium borohydride, provided the alcohol (V). This was oxidized using pyridine-sulfur trioxide complex to give the formylpyrrolidine (VI). The vinylpyrrolidine (VII) was obtained by Wittig reaction of aldehyde (VI) with methylene triphenylphosphorane. Dipolar cycloaddition of the nitrile oxide resulting from ethyl chlorooximidoacetate (VIII) and Et3N to vinylpyrrolidine (VII) gave iso-oxazolidine (IX) as a mixture of diastereoisomers. After desilylation of (IX) with tetrabutylammonium fluoride, the resulting alcohol (X) was converted into the diastereomeric mixture of mesylates (XI). Chromatographic separation of the required isomer, followed by reduction with LiBH4, yielded alcohol (XII).
| 【1】 Park, S.W.; Yoo, K.H.; Shin, K.J.; Kang, Y.K.; Hong, C.Y.; Seo, K.J.; Park, S.Y.; Lee, C.-S.; Kim, D.J.; Synthesis and antibacterial activity of new carbapenems containing isoxazole moiety. Bioorg Med Chem Lett 2000, 10, 2, 95. |
| 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) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (II) | 22581 | (2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]-2-pyrrolidinecarboxylic acid | C13H14N2O7 | 详情 | 详情 | |
| (III) | 44922 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | C14H16N2O7 | 详情 | 详情 | |
| (IV) | 44923 | 2-methyl 1-(4-nitrobenzyl) (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,2-pyrrolidinedicarboxylate | C20H30N2O7Si | 详情 | 详情 | |
| (V) | 44924 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-(hydroxymethyl)-1-pyrrolidinecarboxylate | C19H30N2O6Si | 详情 | 详情 | |
| (VI) | 44925 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-formyl-1-pyrrolidinecarboxylate | C19H28N2O6Si | 详情 | 详情 | |
| (VII) | 44926 | 4-nitrobenzyl (2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-vinyl-1-pyrrolidinecarboxylate | C20H30N2O5Si | 详情 | 详情 | |
| (VIII) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (IX) | 44927 | ethyl (5R)-5-((2S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C24H35N3O8Si | 详情 | 详情 | |
| (X) | 44928 | ethyl (5R)-5-((2S,4R)-4-hydroxy-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C18H21N3O8 | 详情 | 详情 | |
| (XI) | 44929 | ethyl (5R)-5-((2S,4R)-4-[(methylsulfonyl)oxy]-1-[[(4-nitrobenzyl)oxy]carbonyl]pyrrolidinyl)-4,5-dihydro-3-isoxazolecarboxylate | C19H23N3O10S | 详情 | 详情 | |
| (XII) | 44930 | 4-nitrobenzyl (2S,4R)-2-[(5R)-3-(hydroxymethyl)-4,5-dihydro-5-isoxazolyl]-4-[(methylsulfonyl)oxy]-1-pyrrolidinecarboxylate | C17H21N3O9S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)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 |
合成路线6
该中间体在本合成路线中的序号：(III)The mono-Boc protected amino cyclopentenecarboxylate (I) is converted to the di-Boc derivative (II) by means of di-tert-butyl dicarbonate and DMAP. Dipolar cycloaddition of the nitrile oxide generated from ethyl 2-chloro-2-(hydroxyimino)acetate (III) to cyclopentene (II) gives the cis-fused cyclopentaisoxazole (IV) as a diastereomeric mixture. After cleavage of the acidic Boc groups, the desired isomer (V) can be isolated by column chromatography. Finally, alkaline hydrolysis of the ethyl ester functions of (V) affords the target dicarboxylic acid.
| 【1】 Conti, P.; De Amici, M.; Di Ventimiglia, S.J.; Stensbol, T.B.; Madsen, U.; Brauner-Osborne, H.; Russo, E.; De Sarro, G.; Bruno, G.; De Micheli, C.; Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids. J Med Chem 2003, 46, 14, 3102. |
| 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) | 64706 | ethyl 1-[(tert-butoxycarbonyl)amino]-3-cyclopentene-1-carboxylate | C13H21NO4 | 详情 | 详情 | |
| (II) | 64707 | ethyl 1-[bis(tert-butoxycarbonyl)amino]-3-cyclopentene-1-carboxylate | C18H29NO6 | 详情 | 详情 | |
| (III) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (IV) | 64708 | diethyl (3aS,6aS)-5-[bis(tert-butoxycarbonyl)amino]-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylate | C22H34N2O9 | 详情 | 详情 | |
| (V) | 64709 | diethyl (3aS,5R,6aS)-5-amino-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,5-dicarboxylate | C12H18N2O5 | 详情 | 详情 |