methyl (2S)-3-amino-2-[(butoxycarbonyl)amino]propanoate -Drug Synthesis Database

【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 合成路线2 合成路线3 合成路线4

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).

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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	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.

参考文献中间体

合成目标

【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.

参考文献中间体

合成目标

【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