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【结 构 式】 
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【分子编号】25095 【品名】methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate 【CA登记号】 |
【 分 子 式 】C9H18N2O4 【 分 子 量 】218.253 【元素组成】C 49.53% H 8.31% N 12.84% O 29.32% |
合成路线1
该中间体在本合成路线中的序号：(I)The sulfonation of 2(S)-amino-3-(tert-butoxycarbonylamino)propionic acid methyl ester (I) with 3,5-dimethylisoxazol-4-ylsulfonyl chloride (II) by means of triethylamine in dichloromethane gives the corresponding sulfonamide (III), which is deprotected with trifluoroacetic acid yielding the 3-aminopropionic acid derivative (IV). The condensation of (IV) with [3-(4-cyanophenyl)-4,5-dihydroisoxazol-5(R)-yl]acetic acid (V) by means of TBTU and triethylamine in DMF affords the carboxamide (VI). The cyano group of (VI) is treated first with dry HCl and then with NH3, NH4OAc, or CO3(NH4)2 to obtain the amidino group of (VII). Finally, compound (VII) is hydrolyzed with LiOH, 6N HCl, or rabbit liver esterase.
| 【1】 Sielecki, T.M.; Olson, R.E.; Wityak, J.; et al.; Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action. J Med Chem 1999, 42, 7, 1178. |
| 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) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 21618 | 3,5-dimethyl-4-isoxazolesulfonyl chloride | 80466-79-1 | C5H6ClNO3S | 详情 | 详情 |
| (III) | 25912 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C14H23N3O7S | 详情 | 详情 | |
| (IV) | 25913 | methyl (2S)-3-amino-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C9H15N3O5S | 详情 | 详情 | |
| (V) | 17555 | 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (VI) | 25910 | methyl (2S)-3-([2-[3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C21H23N5O7S | 详情 | 详情 | |
| (VII) | 25911 | methyl (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino]propanoate | C21H26N6O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Esterification of N2-benzyloxycarbonyl-(S)-2,3-diaminopropionic acid (I) by means of methanolic HCl, followed by protection of the resulting aminoester (II) with Boc2O provided methyl N2-Cbz-N3-Boc-L-2,3-diaminopropionate (III). Removal of the benzyloxycarbonyl group of (III) was effected by catalytic transfer hydrogenolysis with formic acid and Pd/C. The deprotected aminoester (IV) was then condensed with n-butyl chloroformate to give carbamate (V). Subsequent cleavage of the Boc protecting group of (V) using trifluoroacetic acid furnished the target intermediate (VI).
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Preparation of intermediate (IV) is illustrated in Scheme 25654801a: Methyl N3-Boc-(S)-2,3-diaminopropionate (I) was condensed with m-toluenesulfonyl chloride (II) to provide sulfonamide (III). The Boc group was then deprotected with HCl in dioxan to give amine (IV).
| 【1】 Wityak, J.; Xue, C.-B.; Sielecki-Dzurdz, T.M.; Olson, R.E.; Degrado, W.F.; Cain, G.A. (DuPont Pharmaceuticals Co.); Novel isoxazoline and isoxazole fibrinogen receptor antagonists. EP 0730590; EP 0832076; JP 1997505590; JP 1999504651; US 5849736; WO 9514683; WO 9638426 . |
| 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) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 23316 | 3-methylbenzenesulfonyl chloride | 1899-93-0 | C7H7ClO2S | 详情 | 详情 |
| (III) | 28132 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C16H24N2O6S | 详情 | 详情 | |
| (IV) | 28133 | methyl (2S)-3-amino-2-[[(3-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(4-cyanobenzyloxy)isoxazole-5-carboxylic acid (VII) by means of BOP or TBTU and triethylamine or DIEA in DMF giving the cyanobenzyl derivative (VIII). Finally, this compound treated first with HCl in methanol, and then with NH3 in the same solvent to provide the target compound.
| 【1】 Xue, C.-B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F.; Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg Med Chem Lett 1998, 8, 24, 3499. |
| 【2】 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 25098 | 3-[(4-cyanobenzyl)oxy]-5-isoxazolecarboxylic acid | C12H8N2O4 | 详情 | 详情 | |
| (VIII) | 25099 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-[([3-[(4-cyanobenzyl)oxy]-5-isoxazolyl]carbonyl)amino]propanoate | C21H24N4O7 | 详情 | 详情 | |
| (X) | 25100 | methyl (2S)-3-([[3-([4-[amino(imino)methyl]benzyl]oxy)-5-isoxazolyl]carbonyl]amino)-2-[(butoxycarbonyl)amino]propanoate | C21H27N5O7 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)The esterification of (S)-3-amino-2-(benzyloxycarbonylamino)propionic acid (I) with methanol/HCl gives the expected methyl ester (II), which is protected with di-tert-butyl dicarbonate and triethylamine in chloroform to the fully protected compound (III). The debenzylation of (III) by treatment with formic acid over Pd/C in methanol yields the 2-amino compound (IV), which is acylated with butyl chloroformate and NaHCO3 in THF affording 2(S)-(n-butoxycarbonylamino)-3-(tert-butoxycarbonylamino)propionic acid methyl ester (V).The selctive deacylation of (V) with trifluoroacetic acid in dichloromethane affords the 3-amino-2(S)-(n-butoxycarbonylamino)propionic ester (VI), which is acylated with 3-(chloromethyl)benzoyl chloride (VII) and triethylamine in dichloromethane giving the benzamido ester (VIII). The condensation of (VIII) with 4-hydroxybenzonitrile (IX) by means of NaH or K2CO3 yields the precursor (X), which is finally treated first with HCl in methanol, and then with NH3 in the same solvent to providde the target compound.
| 【1】 Degrado, W.F.; Xue, C.-B. (DuPont Pharmaceuticals Co.); Cpds. containing basic and acidic termini useful as fibrinogen receptor antagonists. US 5563158; WO 9518111 . |
| 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) | 18008 | (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propionic acid; N(alpha)-Z-L-2,3-diaminopropionic acid | 35761-26-3 | C11H14N2O4 | 详情 | 详情 |
| (II) | 25093 | methyl (2S)-3-amino-2-[[(benzyloxy)carbonyl]amino]propanoate | C12H16N2O4 | 详情 | 详情 | |
| (III) | 25094 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C17H24N2O6 | 详情 | 详情 | |
| (IV) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (V) | 25096 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[(butoxycarbonyl)amino]propanoate | C14H26N2O6 | 详情 | 详情 | |
| (VI) | 25097 | methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 25107 | 3-(chloromethyl)benzoyl chloride | 63024-77-1 | C8H6Cl2O | 详情 | 详情 |
| (VIII) | 25108 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-[[3-(chloromethyl)benzoyl]amino]propanoate | C17H23ClN2O5 | 详情 | 详情 | |
| (IX) | 25109 | 4-hydroxybenzonitrile | 767-00-0 | C7H5NO | 详情 | 详情 |
| (X) | 25110 | methyl (2S)-2-[(butoxycarbonyl)amino]-3-([3-[(4-cyanophenoxy)methyl]benzoyl]amino)propanoate | C24H27N3O6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of methyl N3-Boc-2,3-diaminopropionate (I) with o-tolylsulfonyl chloride (II) produced sulfonamide (III). Subsequent acid cleavage of the Boc protecting group of (III) gave amine (IV). Coupling of amine (IV) with the previously described (R)-oxazolidineacetic acid (V) using TBTU afforded amide (VI). Pinner reaction of (VI) with methanolic HCl converted nitrile (VI) into imidate (VII), which was further treated with ammonium acetate to furnish amidine (VIII). Finally, selective hydrolysis of the ester function of (VIII) was achieved with either LiOH or with an enzymatic method using rabbit liver esterase.
| 【1】 Sielecki, T.M.; et al.; Synthesis and pharmacology of modified amidine isoxazoline glycoprotein IIb/IIIa receptor antagonists. Bioorg Med Chem Lett 2001, 11, 16, 2201. |
| 【2】 Sielecki, T.M.; Olson, R.E.; Wityak, J.; et al.; Orally active isoxazoline glycoprotein IIb/IIIa antagonists with extended duration of action. J Med Chem 1999, 42, 7, 1178. |
| 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) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (II) | 49841 | o-Toluenesulfonyl Chloride | 133-59-5 | C7H7ClO2S | 详情 | 详情 |
| (III) | 49842 | methyl (2S)-3-[(tert-butoxycarbonyl)amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C16H24N2O6S | 详情 | 详情 | |
| (IV) | 49843 | methyl (2S)-3-amino-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C11H16N2O4S | 详情 | 详情 | |
| (V) | 17555 | 2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid | C12H10N2O3 | 详情 | 详情 | |
| (VI) | 49844 | methyl (2S)-3-([2-[(5R)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C23H24N4O6S | 详情 | 详情 | |
| (VII) | 49845 | methyl (2S)-3-[[2-((5R)-3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C24H28N4O7S | 详情 | 详情 | |
| (VIII) | 49846 | methyl (2S)-3-[[2-((5R)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[[(2-methylphenyl)sulfonyl]amino]propanoate | C23H27N5O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VI)3,5-Dimethylphenol (I) was alkylated with ethyl 4-bromobutyrate (II) to provide the (dimethylphenoxy)butyrate ester (III), which was hydrolyzed under basic conditions to yield acid (IV). This was sulfonated with chlorosulfonic acid, and the resultant sulfonyl chloride (V) was condensed with Boc-diaminopropanoic acid (VI) to afford sulfonamide (VII). Coupling of (VII) with mono-benzyloxycarbonyl ethylenediamine (VIII) furnished amide (IX). Then, acid cleavage of the Boc protecting group of (IX) provided amine (X).
| 【1】 Cheesman, E.H.; et al.; Nonpeptide vitronectin antagonists labeles with in-111 for imaging tumors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 88. |
| 【2】 Rajopadhye, M.; Harris, T.D.; Cheesman, E.H. (DuPont Pharmaceuticals Co.); Vitronectin receptor antagonist pharmaceuticals. WO 0035488 . |
| 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) | 46786 | 3,5-dimethylphenol | 108-68-9 | C8H10O | 详情 | 详情 |
| (II) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (III) | 50998 | ethyl 4-(3,5-dimethylphenoxy)butanoate | C14H20O3 | 详情 | 详情 | |
| (IV) | 50999 | 4-(3,5-dimethylphenoxy)butyric acid | C12H16O3 | 详情 | 详情 | |
| (V) | 51000 | 4-[4-(chlorosulfonyl)-3,5-dimethylphenoxy]butyric acid | C12H15ClO5S | 详情 | 详情 | |
| (VI) | 25095 | methyl (2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoate | C9H18N2O4 | 详情 | 详情 | |
| (VII) | 51001 | 4-(4-[[((1S)-1-[[(tert-butoxycarbonyl)amino]methyl]-2-methoxy-2-oxoethyl)amino]sulfonyl]-3,5-dimethylphenoxy)butyric acid | C21H32N2O9S | 详情 | 详情 | |
| (VIII) | 51002 | benzyl 2-aminoethylcarbamate | C10H14N2O2 | 详情 | 详情 | |
| (IX) | 51003 | methyl (2S)-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]-3-[(tert-butoxycarbonyl)amino]propanoate | C31H44N4O10S | 详情 | 详情 | |
| (X) | 51004 | methyl (2S)-3-amino-2-[[(4-[4-[(2-[[(benzyloxy)carbonyl]amino]ethyl)amino]-4-oxobutoxy]-2,6-dimethylphenyl)sulfonyl]amino]propanoate | C26H36N4O8S | 详情 | 详情 |