(2S)-2-[(Ethoxycarbonyl)amino]propionic acid -Drug Synthesis Database

【结构式】

【分子编号】13360

【品名】(2S)-2-[(Ethoxycarbonyl)amino]propionic acid

【CA登记号】

【分子式】C₆H₁₁NO₄

【分子量】161.15768

【元素组成】C 44.72% H 6.88% N 8.69% O 39.71%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

Synthesis of [14C]-labeled CI-980: The reaction of N-(ethoxycarbonyl)-L-alanine (VII) with N-methoxy-N-methylamine (VIII) by means of carbonyldiimidazole (CDI) in THF/dichloromethane gives the corresponding amide (IX), which is treated with phenylmagnesium bromide (1 mol) yielding the bromomagnesium salt (X). The bromination of [14C]-labeled benzene (XI) with Br2/HBr/H2O2 gives the labeled bromobenzene (XII), which is converted into the corresponding Grignard reagent (XIII) by reaction with Mg and dibromoethane in ether. The reaction of the previously obtained magnesium salt of alaninamide (X) with the labeled Grignard reagent (XIII) affords the labeled carbamate (XIV), which is reduced with NaBH4 in methanol and treated with KOH giving a mixture of the oxazolidinone (XV) and the aminoalcohol (XVI), separated by acidic extraction. The hydrolysis of the oxazolidinone (XV) with KOH yielded the desired aminoalcohol (XVI). The aminoalcohol (XVI) by means of triethylamine in refluxing ethanol gives (1S,2R)-N-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (XVII), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (XVIII). The reductocyclization of (XVIII) with H2 over RaNi in glacial acetic acid affords the free base of title compound (XIX), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.

参考文献中间体

合成目标

【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980.
【2】 Woo, P.W.K.; Lee, H.T.; Synthesis of [14C]CI-980, ethyl [5-amino-1,2-dihydro-2(S)-methyl-3-[14C]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. J Label Compd Radiopharm 1994, 34, 1, 1-10.

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)	13359	2-Hydroxy-1-ethanesulfonic acid	107-36-8	C₂H₆O₄S	详情	详情
(VII)	13360	(2S)-2-[(Ethoxycarbonyl)amino]propionic acid		C₆H₁₁NO₄	详情	详情
(VIII)	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(IX)	13358	ethyl (2S)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate		C₁₇H₁₉N₅O₂	详情	详情
(IX)	13362	ethyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate		C₈H₁₆N₂O₄	详情	详情
(X)	13363	N-(Ethoxycarbonyl)-N-[1(S)-(N-methoxy-N-methylcarbamoyl)ethyl]amide anion		C₈H₁₅N₂O₄	详情	详情
(XI)	13364	Benzene	71-43-2	C₆H₆	详情	详情
(XI)	44622			C₆H₆	详情	详情
(XII)	13365	Monobromobenzene; 1-Bromobenzene；Phenylbromide;bromobenzene	108-86-1	C₆H₅Br	详情	详情
(XII)	45166			C₆H₅Br	详情	详情
(XIII)	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(XIII)	45167			C₆H₅BrMg	详情	详情
(XIV)	13367	ethyl (1S)-1-methyl-2-oxo-2-phenylethylcarbamate		C₁₂H₁₅NO₃	详情	详情
(XIV)	45168			C₁₂H₁₅NO₃	详情	详情
(XV)	13368	(4S)-4-Methyl-5-phenyl-1,3-oxazolidin-2-one; (4S,5R)-(-)-4-Methyl-5-phenyl-2-oxazolidinone	16251-45-9	C₁₀H₁₁NO₂	详情	详情
(XV)	45169			C₉H₁₃NO	详情	详情
(XVI)	13355	2-Amino-1-phenyl-1-propanol; (1S,2R)-(+)-Norephedrine	37577-28-9	C₉H₁₃NO	详情	详情
(XVI)	45170			C₁₀H₁₁NO₂	详情	详情
(XVII)	13356	ethyl 6-amino-4-[[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate		C₁₇H₂₁N₅O₅	详情	详情
(XVII)	63746			C₁₇H₂₁N₅O₅	详情	详情
(XVIII)	13357	ethyl 6-amino-4-[[(1S)-1-methyl-2-oxo-2-phenylethyl]amino]-5-nitro-2-pyridinylcarbamate		C₁₇H₁₉N₅O₅	详情	详情
(XVIII)	63747			C₁₇H₁₉N₅O₅	详情	详情
(XIX)	63748			C₁₇H₁₉N₅O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

3) Synthesis of [3H]-labeled CI-980: The reaction of butyllithium with m-dibromobenene (XVII) in ether gives the monolithium derivative (XVIII), which is condensed with N-(ethoxycarbonyl)-L-alanine (VII) yielding the carbamate (XIX). The reduction of (XIX) with NaBH4 in methanol affords the hydroxylated carbamate (XX), which is treated with NaOH in methanol to give the aminoalcohol (XXI). The condensation of N-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (I) with 2(S)-amino-1-(3-bromophenyl)-1-propanol (XXI) by means of triethylamine in refluxing ethanol gives N-[2-amino-4-[2-(3-bromophenyl)-2-hydroxy-1(S)-methylethylamino]-3-nitropyridin-6-yl]carbamic acid ethyl ester (XXII), which is oxidized with CrO3-pyridine in dichloromethane yielding the corresponding ketone (XXIII). The reductocyclization of (XXIII) with Fe and acetic acid affords the 3-bromo analogue of CI-980 (XXIV), which is finally hydrogenated with 3H2 over Pd/C in THF, and treated with 2-hydroxyethanesulfonic acid in methanol.

参考文献中间体

合成目标

【1】 Graul, A.; Martell, A.M.; Castaner, J.; Mivobulin Isethionate. Drugs Fut 1997, 22, 9, 980.
【2】 Lee, H.T.; Woo, P.W.K.; Synthesis of [3H]CI-980, ethyl[5-amino-1,2-dihydro-2(S)-methyl-3(3-[3H]phenyl)pyrido[3,4-b] pyrazin-7-yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. J Label Compd Radiopharm 1994, 34, 1, 11-16.

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)	13354	ethyl 6-amino-4-chloro-5-nitro-2-pyridinylcarbamate		C₈H₉ClN₄O₄	详情	详情
(VI)	13359	2-Hydroxy-1-ethanesulfonic acid	107-36-8	C₂H₆O₄S	详情	详情
(VII)	13360	(2S)-2-[(Ethoxycarbonyl)amino]propionic acid		C₆H₁₁NO₄	详情	详情
(XVII)	13370	1,3-Dibromobenzene	108-36-1	C₆H₄Br₂	详情	详情
(XVIII)	13371	(3-Bromophenyl)lithium		C₆H₄BrLi	详情	详情
(XIX)	13372	ethyl (1S)-2-(3-bromophenyl)-1-methyl-2-oxoethylcarbamate		C₁₂H₁₄BrNO₃	详情	详情
(XX)	13373	ethyl (1S)-2-(3-bromophenyl)-2-hydroxy-1-methylethylcarbamate		C₁₂H₁₆BrNO₃	详情	详情
(XXI)	13374	(2S)-2-Amino-1-(3-bromophenyl)-1-propanol		C₉H₁₂BrNO	详情	详情
(XXII)	13375	ethyl 6-amino-4-[[(1S)-2-(3-bromophenyl)-2-hydroxy-1-methylethyl]amino]-5-nitro-2-pyridinylcarbamate		C₁₇H₂₀BrN₅O₅	详情	详情
(XXIII)	13376	ethyl 6-amino-4-[[(1S)-2-(3-bromophenyl)-1-methyl-2-oxoethyl]amino]-5-nitro-2-pyridinylcarbamate		C₁₇H₁₈BrN₅O₅	详情	详情
(XXIV)	13377	ethyl (2S)-5-amino-3-(3-bromophenyl)-2-methyl-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate		C₁₇H₁₈BrN₅O₂	详情	详情

Extended Information