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【结 构 式】

【分子编号】25315

【品名】methyl 2-aminopropanoate; Alanine, methyl ester

【CA登记号】7625-53-8

【 分 子 式 】C4H9NO2

【 分 子 量 】103.121

【元素组成】C 46.59% H 8.8% N 13.58% O 31.03%
与该中间体有关的原料药合成路线共 6 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5合成路线6

合成路线1

该中间体在本合成路线中的序号：(III)

Treatment of 4-bromophenol (I) with phosphoryl chloride gave p-bromophenyl phosphoro- dichloridate (II), which was condensed with alanine methyl ester (III) to furnish alaninyl phosphorochloridate (IV). Further coupling of (IV) with 3'-azidothimidine (V) in the presence of N-methylimidazole afforded phosphate (VI). Then, addition of methyl hypobromite, (prepared from bromine and MeOH) provided the title compound as a diastereomeric mixture.

参考文献 中间体
合成目标
【1】 D'Cruz, O.; Jan, S.-T.; Shih, M.-J.; Chen, C.-L.; Uckun, F.M.; Venkatachalam, T.K.; Synthesis of dual function (5R,6R)- and (5S,6S)-5-bromo-6-methoxy-5,6-dihydro-AZT-5'-(para-bromophenyl methoxyalaninyl phosphate) as novel spermicidal and anti-HIV agents. Antivir Chem Chemother 1999, 10, 1, 39.
【2】 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 .
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) 25313 4-bromophenol 106-41-2 C6H5BrO 详情 详情
(II) 25314 Dichlorophoephoric acid 4-bromophenyl ester C6H4BrCl2O2P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 25316 methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate C10H12BrClNO4P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VI) 25318 methyl 2-[[[((2S,3S,5R)-3-azido-5-[[(propionylamino)carbonyl]amino]tetrahydro-2-furanyl)methoxy](4-bromophenoxy)phosphoryl]amino]propanoate C20H24BrN6O8P 详情 详情

合成路线2

该中间体在本合成路线中的序号：(III)

The reaction of 4-methoxyphenol (I) with POCl3 and triethylamine in ethyl ether gives the dichlorophosphate (II), which is condensed with alanine methyl ester (III) by means of triethylamine in dichloromethane yielding the amide (IV). The condensation of (IV) with azidothymidine (V) by means of N-methylimidazole (NMI) in THF affords the 5'-phosphate derivative (VI), which is finally treated with methyl hypobromite (Br2 in methanol).

参考文献 中间体
合成目标
【1】 Uckun, F.M.; Venkatachalam, T.; D'Cruz, O. (Parker Hughes Institute); AZT derivs. exhibiting spermicidal and anti-viral activity. WO 9948902 .
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) 32744 4-methoxyphenol 150-76-5 C7H8O2 详情 详情
(II) 32741 Dichlorophosphoric acid 4-methoxyphenyl ester C7H7Cl2O3P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 32742 methyl 2-[[chloro(4-methoxyphenoxy)phosphoryl]amino]propanoate C11H15ClNO5P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 详情 详情
(VI) 32743 methyl 2-[[([(2S,3S,5R)-3-azido-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methoxy)(4-methoxyphenoxy)phosphoryl]amino]propanoate C21H27N6O9P 详情 详情

合成路线3

该中间体在本合成路线中的序号：(II)

The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(R)-amino-3-methy-piperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(I) 31032 alanine 302-72-7 C3H7NO2 详情 详情
(II) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(III) 31022 methyl 2-[[(E)-benzylidene]amino]propanoate C11H13NO2 详情 详情
(IV) 31023 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione C11H10INO2 详情 详情
(V) 31024 methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate C22H22N2O4 详情 详情
(VI) 31025 methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate C15H18N2O4 详情 详情
(VII) 31026 3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(VIII) 31027 (3R)-3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(IX) 31028 5-nitro-2-benzofuran-1,3-dione 5466-84-2 C8H3NO5 详情 详情
(X) 31029 2-([[(3R)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid C14H15N3O6 详情 详情
(XI) 31030 2-[(3R)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H13N3O5 详情 详情
(XII) 31031 2-[(3R)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H11N3O6 详情 详情

合成路线4

该中间体在本合成路线中的序号：(II)

The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(S)-amino-3-methylpiperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.

参考文献 中间体
合成目标
【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10498 Benzaldehyde;Benzoic aldehyde;Phenylmethanal 100-52-7 C7H6O 详情 详情
(I) 31032 alanine 302-72-7 C3H7NO2 详情 详情
(II) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(III) 31022 methyl 2-[[(E)-benzylidene]amino]propanoate C11H13NO2 详情 详情
(IV) 31023 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione C11H10INO2 详情 详情
(V) 31024 methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate C22H22N2O4 详情 详情
(VI) 31025 methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate C15H18N2O4 详情 详情
(VII) 31026 3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(VIII) 31033 (3S)-3-amino-3-methyl-2-piperidinone C6H12N2O 详情 详情
(IX) 31028 5-nitro-2-benzofuran-1,3-dione 5466-84-2 C8H3NO5 详情 详情
(X) 31034 2-([[(3S)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid C14H15N3O6 详情 详情
(XI) 31035 2-[(3S)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H13N3O5 详情 详情
(XII) 31036 2-[(3S)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione C14H11N3O6 详情 详情

合成路线5

该中间体在本合成路线中的序号：(III)

Treatment of p-bromophenol (I) with phosphoryl chloride and triethylamine furnished p-bromophenyl phosphorodichloridate (II), which was condensed with alanine methyl ester (III) to give the intermediate phosphorochloridate (IV). Then, coupling of chloridate (IV) with azidothimidine (V) in the presence of N-methylimidazole yielded the title compound.

参考文献 中间体
合成目标
【1】 Venkatachalam, T.K.; Zhu, Z.; Shih, M.-J.; Tai, H.-L.; Uckun, F.M.; Jan, S.-T.; AZT-5'-(p-bromophenyl methoxyalaninyl phosphate) as a potent and non-toxic anti-human immunodeficiency virus agent. Antivir Chem Chemother 1999, 10, 1, 47.
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) 25313 4-bromophenol 106-41-2 C6H5BrO 详情 详情
(II) 25314 Dichlorophoephoric acid 4-bromophenyl ester C6H4BrCl2O2P 详情 详情
(III) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(IV) 25316 methyl 2-[[(4-bromophenoxy)(chloro)phosphoryl]amino]propanoate C10H12BrClNO4P 详情 详情
(V) 25317 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione 101703-35-9 C10H13N5O4 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 alanine methyl ester (I) with benzyl isothiocyanate (II) in the presence of Et3N produced the thiohydantoin (III). This was further acetylated by means of acetic anhydride and DMAP to yield the title compound.

参考文献 中间体
合成目标
【1】 Le Tiran, A.; et al.; Functionalized amino acid anticonvulsants: Synthesis and pharmacological evaluation of conformationally restricted analogues. Bioorg Med Chem 2001, 9, 10, 2693.
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) 25315 methyl 2-aminopropanoate; Alanine, methyl ester 7625-53-8 C4H9NO2 详情 详情
(II) 53401 1-(isothiocyanatomethyl)benzene; benzyl isothiocyanate 622-78-6 C8H7NS 详情 详情
(III) 53402 3-benzyl-5-methyl-2-thioxo-4-imidazolidinone n/a C11H12N2OS 详情 详情
Extended Information