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【结 构 式】 
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【分子编号】15728 【品名】(+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine 【CA登记号】312-84-5 |
【 分 子 式 】C3H7NO3 【 分 子 量 】105.09352 【元素组成】C 34.29% H 6.71% N 13.33% O 45.67% |
合成路线1
该中间体在本合成路线中的序号：(I)D-Serine (I) is nitrosated in the presence of bromide ion to give (R)-2-bromo-3-hydroxypropanoic acid (II), which is converted into (R)-2-hydroxy-3-(methylthio)propanoic acid (IV), via the epoxy acid (III), using sodium methoxide followed by sodium methanethiolate. This hydroxy acid (IV) is coupled to (S)-3-(acetylthio)-2-methylpropanoic acid using either the imidazolide or acid chloride. Final deprotection of 2(R)-[3-(acetylthio)-2(S)-methyl-1-oxopropoxy]-3-(methylthio)propanoic acid (V) is achieved using aqueous ammonia. FPL 66564 is conveniently isolated either as the 1-adamantanamine or L-lysine salt.
| 【1】 Baxter, A.J.G.; Meghani, P. (Celltech Medeva plc); Angiotensin converting enzyme inhibitors. EP 0535496; JP 1993507919; US 5348978; WO 9200276 . |
| 【2】 Fraser-Rae, L.; Eyley, S.C.; Baxter, A.J.G.; Hallam, C.; Harper, S.T.; King, S.J.; Carr, R.D.; Hurved, P.A.; Meghani, P.; (R)-2-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methylthio)propanoic acid (FPL 66564), the first ultra short-acting angiotensin converting enzyme inhibitor (USACEI). J Med Chem 1992, 35, 3718-20. |
| 【3】 Carr, R.D.; Baxter, A.J.G.; FPL 66564. Drugs Fut 1993, 18, 1, 12. |
| 【4】 Baxter, A.J.G.; Hallam, C.; Harper, S.T.; Meghani, P.; FPL 66564, the first ultra short-acting angiotensin converting enzyme inhibitor (USACEI). J Hypertension 1992, 10, Suppl. 4, S147. |
| 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) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (II) | 15729 | (2R)-2-bromo-3-hydroxypropionic acid | C3H5BrO3 | 详情 | 详情 | |
| (III) | 15730 | Oxirane-2(S)-carboxylic acid sodium salt | C3H3NaO3 | 详情 | 详情 | |
| (IV) | 15731 | (2R)-2-hydroxy-3-(methylsulfanyl)propionic acid | C4H8O3S | 详情 | 详情 | |
| (V) | 15732 | (2R)-2-[[(2S)-3-(acetylsulfanyl)-2-methylpropanoyl]oxy]-3-(methylsulfanyl)propionic acid | C10H16O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)D-Serine (I) was protected as the N-benzyloxycarbonyl derivative (II) by means of benzyl chloroformate in the presence of MgO. Methylation of the alcohol hydroxyl of (II) under Williamson conditions using iodomethane and Ag2O also produced esterification of the carboxyl group to give (III), which was further hydrolyzed to carboxylic acid (IV) with K2CO3 in MeOH-H2O. After activation of (IV) as the mixed anhydride with isobutyl chloroformate, coupling with benzyl amine furnished amide (V). This was alternatively obtained through a related procedure involving coupling of N-Cbz-serine (II) with benzylamine, followed by O-methylation of the resulting hydroxy amide (VI) with iodomethane and Ag2O. Finally, the N-carbobenzoxy protecting group of (V) was removed by catalytic hydrogenolysis in the presence of Pd/C.
| 【1】 Andurkar, S.V.; et al.; Synthesis and anticonvulsant activities of (R)-(O)-methylserine derivatives. Tetrahedron Asymmetry 1998, 9, 21, 3841. |
| 【2】 Kohn, H.; Andurkar, S.V. (Research Corporation Technologies, Inc.); Anticonvulsant enantiomeric amino acid derivs.. US 6048899; WO 0000463 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (II) | 32794 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxypropionic acid | C11H13NO5 | 详情 | 详情 | |
| (III) | 38794 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropanoate | C13H17NO5 | 详情 | 详情 | |
| (IV) | 38795 | (2R)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropionic acid | C12H15NO5 | 详情 | 详情 | |
| (V) | 38796 | benzyl (1R)-2-(benzylamino)-1-(methoxymethyl)-2-oxoethylcarbamate | C19H22N2O4 | 详情 | 详情 | |
| (VI) | 38797 | benzyl (1R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethylcarbamate | C18H20N2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Coupling of decanoylchloride (I) with D-serine (II) under Schotten-Baumann conditions (with Na2CO3 in H2O/THF) provides N-decanoyl-D-serine (III). Separately, aldehyde (IV) is reduced by means of NaBH4 in EtOH to yield alcohol (V), whose nitro group is reduced by means of In and NH4Cl in EtOH to afford substituted aniline (VI). Coupling of 5-amino-2-hydroxybenzyl alcohol (VI) with serine (III) by means of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) in DMF furnishes compound (VII), which is finally oxidized with NaIO4 in MeOH/H2O to yield the desired spiroepoxide.
| 【1】 Giannis, A.; Arenz, C.; Synthesis of the first selective irreversible inhibitor of neutral sphingomyelinase. Angew Chem. Int Ed Engl 2000, 39, 8, 1440. |
| 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) | 28271 | decanoyl chloride | 112-13-0 | C10H19ClO | 详情 | 详情 |
| (II) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (III) | 47198 | (2R)-2-(decanoylamino)-3-hydroxypropionic acid | C13H25NO4 | 详情 | 详情 | |
| (IV) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (V) | 47199 | 2-(hydroxymethyl)-4-nitrophenol | C7H7NO4 | 详情 | 详情 | |
| (VI) | 47200 | 4-amino-2-(hydroxymethyl)phenol | C7H9NO2 | 详情 | 详情 | |
| (VII) | 47201 | N-[(1R)-2-[4-hydroxy-3-(hydroxymethyl)anilino]-1-(hydroxymethyl)-2-oxoethyl]decanamide | C20H32N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)Ketal exchange between the chiral acetonide (I) and 2-(benzoyloxy)acetaldehyde (II) under acidic conditions affords the 2-(benzoyloxymethyl) dioxolane (III) as a diastereomeric mixture. Alternatively, diazotization of D-serine (IV) in the presence of NaNO2 and H2SO4 produces D-glyceric acid (V), which is further esterified with methanol to afford the methyl ester (VI). Condensation of dihydroxy ester (VI) with 2-(benzoyloxy)acetaldehyde dimethyl acetal (VII) then gives dioxolane (III).
| 【1】 Nguyen-Ba, N. (Shire BioChem Inc.); Antiviral nucleoside analogues. EP 1140937; JP 2002533470; US 6358963; WO 0039143 . |
| 【2】 Cimpoia, A.; Janes, L.; Kazlauskas, R. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0047759 . |
| 【3】 Cimpoia, A.; Wang, Y.-F. (Shire BioChem Inc.); Stereoselective synthesis of nucleoside analogues. WO 0158894 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 57514 | methyl (2S,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (IIIb) | 57515 | methyl (2R,4R)-2-[(benzoyloxy)methyl]-1,3-dioxolane-4-carboxylate | C13H14O6 | 详情 | 详情 | |
| (I) | 20917 | methyl (4R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate | 52373-72-5 | C7H12O4 | 详情 | 详情 |
| (II) | 15605 | 2-oxoethyl benzoate | C9H8O3 | 详情 | 详情 | |
| (IV) | 15728 | (+)-2-Amino-3-hydroxypropionic acid; D-(+)-Serine; D-serine | 312-84-5 | C3H7NO3 | 详情 | 详情 |
| (V) | 57516 | (2R)-2,3-dihydroxypropanoic acid | C3H6O4 | 详情 | 详情 | |
| (VI) | 20916 | methyl (2R)-2,3-dihydroxypropanoate | C4H8O4 | 详情 | 详情 | |
| (VII) | 57517 | 2,2-dimethoxyethyl benzoate | C11H14O4 | 详情 | 详情 |