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【结 构 式】

【分子编号】25097

【品名】methyl (2S)-3-amino-2-[(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%

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:(VI)

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2

该中间体在本合成路线中的序号:(VI)

Coupling of (R)-acid (XI) with (S)-aminoester (VI) employing either BOP or TBTU gave rise to amide (XIV). Conversion of the nitrile group of (XIV) to imidate (XV), followed by reaction with ammonium carbonate in MeOH afforded amidine (XVI). Finally, the methyl ester group of (XVI) was hydrolyzed by means of LiOH in aqueous methanol.

1 Wityak, J.; Sielecki, T.M.; Xue, C.-B.; et al.; Discovery of an orally active series of isoxazoline glycoprotein IIb/IIIa antagonists. J Med Chem 1997, 40, 13, 2064-84.
2 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
(VI) 25097 methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate C9H18N2O4 详情 详情
(XI) 33754 2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetic acid C12H10N2O3 详情 详情
(XIV) 33757 methyl (2S)-2-[(butoxycarbonyl)amino]-3-([2-[(5S)-3-(4-cyanophenyl)-4,5-dihydro-5-isoxazolyl]acetyl]amino)propanoate C21H26N4O6 详情 详情
(XV) 33758 methyl (2S)-2-[(butoxycarbonyl)amino]-3-[[2-((5S)-3-[4-[imino(methoxy)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]propanoate C22H30N4O7 详情 详情
(XVI) 33759 methyl (2S)-3-[[2-((5S)-3-[4-[amino(imino)methyl]phenyl]-4,5-dihydro-5-isoxazolyl)acetyl]amino]-2-[(butoxycarbonyl)amino]propanoate C21H29N5O6 详情 详情

合成路线3

该中间体在本合成路线中的序号:(VI)

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4

该中间体在本合成路线中的序号:(VI)

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
Extended Information