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【结 构 式】 
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【分子编号】10143 【品名】benzyl (2S)-2-aminopropanoate 【CA登记号】 |
【 分 子 式 】C10H13NO2 【 分 子 量 】179.21876 【元素组成】C 67.02% H 7.31% N 7.82% O 17.85% |
合成路线1
该中间体在本合成路线中的序号：(XIV)A new synthesis of FK-156 has been described: The esterification of meso-2,6-bis(benzyloxycarbonylamino)pimelic acid (I) with diazomethane gives the corresponding dimethyl ester (II), which is submitted to selective hydrolysis with a protease from Bacillus licheniformis, yielding the D-monoester (III). The reaction of (III) with PCl5 in dichloromethane affords the carboxyanhydride (IV), which is condensed with glycine 4-nitrobenzyl ester (V) by means of DIEA in dichloromethane to give the dipeptide (VI). The condensation of (VI) with tert-butoxycarbonyl-D-glutamic acid 1-benzyl ester (VII) by means of BOP and DIEA in dichloromethane-DMF affords the protected tripeptide (VIII), which is selectively deprotected with trifluoroacetic acid to the tripeptide (IX) with a free NH2 group. The condensation of (IX) with O-acetyl-D-lactyl-L-alanine (X) by means of BOP and DIEA as before yields the protected final peptide (XI), which is finally deprotected by hydrogenation with H2 over Pd/C in ethanol-formic acid and saponified with 1N NaOH. O-Acetyl-D-lactyl-L-alanine (X) is prepared as follows: The reaction of D-alanine (XII) with NaNO2 and acetic acid gives O-acetyl-D-lactic acid (XIII), which is condensed with L-alanine benzyl ester (XIV) with BOP and DIEA as before, yielding O-acetyl-D-lactyl-L-alanine benzyl ester (XV), which is finally debenzylated by hydrogenation with H2 over Pd/C in ethanol-formic acid to (X).
| 【1】 Kolodziejczyk, A.S.; Stoev, S.; Kolodziejczyk, A.M.; New convenient synthesis of immunostimulating peptides containing meso-diaminopimelic acid - Syntheses of FK-565 and. Int J Pept Protein Res 1992, 39, 4, 382. |
| 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) | 10130 | (2R,6S)-2,6-Bis[[(benzyloxy)carbonyl]amino]heptanedioic acid | C23H26N2O8 | 详情 | 详情 | |
| (II) | 10131 | dimethyl (2R,6S)-2,6-bis[[(benzyloxy)carbonyl]amino]heptanedioate | C25H30N2O8 | 详情 | 详情 | |
| (III) | 10132 | (2S,6R)-2,6-Bis[[(benzyloxy)carbonyl]amino]-7-methoxy-7-oxoheptanoic acid | C24H28N2O8 | 详情 | 详情 | |
| (IV) | 10133 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[(4S)-2,5-dioxo-1,3-oxazolan-4-yl]pentanoate | C17H20N2O7 | 详情 | 详情 | |
| (V) | 10134 | 4-Nitrobenzyl 2-aminoacetate | C9H10N2O4 | 详情 | 详情 | |
| (VI) | 10135 | methyl (2R,6S)-6-amino-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate | C25H30N4O9 | 详情 | 详情 | |
| (VII) | 10136 | (4R)-5-(Benzyloxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid; N-t-BOC-D-glutamic acid alpha-benzyl ester | 34404-30-3 | C17H23NO6 | 详情 | 详情 |
| (VIII) | 10137 | 14-benzyl 5-methyl (5R,9S,14R)-18,18-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16-trioxo-1-phenyl-2,17-dioxa-4,10,15-triazanonadecane-5,14-dicarboxylate | C42H51N5O14 | 详情 | 详情 | |
| (IX) | 10138 | methyl (2R,6S)-6-[[(4R)-4-amino-5-(benzyloxy)-5-oxopentanoyl]amino]-2-[[(benzyloxy)carbonyl]amino]-7-([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)-7-oxoheptanoate | C37H43N5O12 | 详情 | 详情 | |
| (X) | 10139 | (2S)-2-[[(2R)-2-(Acetoxy)propanoyl]amino]propionic acid | C8H13NO5 | 详情 | 详情 | |
| (XI) | 10140 | 14-benzyl 5-methyl (5R,9S,14R,17S,20R)-17,20-dimethyl-9-[([2-[(4-nitrobenzyl)oxy]-2-oxoethyl]amino)carbonyl]-3,11,16,19,22-pentaoxo-1-phenyl-2,21-dioxa-4,10,15,18-tetraazatricosane-5,14-dicarboxylate | C45H54N6O16 | 详情 | 详情 | |
| (XII) | 10141 | D-Alanine; D-2-Aminopropionic Acid | 338-69-2 | C3H7NO2 | 详情 | 详情 |
| (XIII) | 10142 | (2R)-2-(Acetoxy)propionic acid | 18668-00-3 | C5H8O4 | 详情 | 详情 |
| (XIV) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XV) | 10144 | benzyl (2S)-2-[[(2R)-2-(acetoxy)propanoyl]amino]propanoate | C15H19NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of (IX) with alanine benzyl ester (X) with sodium cyanoboohydride as before gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (XI), which is submitted to fractional crystallization with maleic acid yielding N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine benzyl ester (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol yielding the free acid (XIII). Finally, this compound is condensed with spirane (IV) through the N-hydroxysuccinimide ester, in the usual way.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
| (X) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XI) | 27321 | ethyl 2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XIII) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)Condensation of piperonyl chloride (I) with diethyl malonate (II) by means of Na in anhydrous refluxing EtOH (NaOEt) provides 2-[3,4-(methylenedioxy)benzyl]malonic acid diethyl ester (III), which is converted into the monoethyl ester (IV) by saponification with KOH in EtOH. Treatment of (IV) with diethylamine in paraformaldehyde/H2O affords acrylic ester (V), which is then subjected to saponification with NaOH in acetone/H2O to provide [3,4-(methylenedioxy)benzyl]-2-propenoic acid (VI). Alternatively, derivative (VI) can also be obtained by following this route: treatment of piperonal (VII) with diethyl malonate (II) in refluxing toluene in the presence of piperidine and acetic acid provides diethyl piperonylidene malonate (VIII), which is then hydrogenated over Pd/C to furnish diethyl piperonylmalonate (IX). Saponification of the ethyl ester moiety of (IX) by refluxing with NaOH in H2O affords piperonylmalonic acid (X), which is finally converted into intermediate (VI) by decarboxylation by treatment with diethylamine in refluxing paraformaldehyde. Reaction of (VI) with thioacetic acid at 70 C affords a racemic mixture of propionic acid derivatives (XI), which is resolved by first formation of a chiral salt (either by reaction with (R)-alpha-methylbenzylamine or by reaction with (+)-ephedrine in ether), recrystallization of the corresponding diastereomer and finally liberation of the 2-(S)-(acetylthiomethyl)-3-[3,4-(methylenedioxy)benzyl]propionic acid [(S)-(XII)] by hydrolysis with HCl in H2O/CH2Cl2. Finally, fasidotril is obtained by condensation of (S)-(XII) with benzyl alaninate (XIII) by means of HOBt and DCC in THF/CHCl3 in the presence of Et3N.
| 【1】 Plaquevent, J.-C.; Danvy, D.; Monteil, T.; Greciet, H.; Duhamel, L.; Duhamel, P.; Gros, C.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs., method for their preparation and their therapeutic application. EP 0419327; FR 2652087; WO 9104246 . |
| 【2】 Lecomte, J.-M.; Duhamel, P.; Danvy, D.; Schwartz, J.-C.; Duhamel, L.; Monteil, T. (Societe Civile Bioprojet); Process for the synthesis of alpha-substd. acrylic acids and their application. EP 0729936 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III),(IX) | 49496 | diethyl 2-(1,3-benzodioxol-5-ylmethyl)malonate | C15H18O6 | 详情 | 详情 | |
| (S)-(XII) | 49501 | (2S)-3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid | C13H14O5S | 详情 | 详情 | |
| (I) | 28617 | 5-(chloromethyl)-1,3-benzodioxole | C8H7ClO2 | 详情 | 详情 | |
| (II) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (IV) | 49497 | 2-(1,3-benzodioxol-5-ylmethyl)-3-ethoxy-3-oxopropionic acid | C13H14O6 | 详情 | 详情 | |
| (V) | 38469 | ethyl (E)-3-(1,3-benzodioxol-5-yl)-2-propenoate | C12H12O4 | 详情 | 详情 | |
| (VI) | 11634 | (E)-3-(1,3-Benzodioxol-5-yl)-2-propenoic acid; 3,4-(Methylenedioxy)cinnamic acid | 2373-80-0 | C10H8O4 | 详情 | 详情 |
| (VII) | 10127 | 1,3-Benzodioxole-5-carbaldehyde; Heliotropine | 120-57-0 | C8H6O3 | 详情 | 详情 |
| (VIII) | 49499 | diethyl 2-(1,3-benzodioxol-5-ylmethylene)malonate | C15H16O6 | 详情 | 详情 | |
| (X) | 49500 | 2-(1,3-benzodioxol-5-ylmethyl)malonic acid | C11H10O6 | 详情 | 详情 | |
| (XI) | 49498 | 3-(acetylsulfanyl)-2-(1,3-benzodioxol-5-ylmethyl)propionic acid | C13H14O5S | 详情 | 详情 | |
| (XIII) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The monoacylation of disulfide (I) with 2-furylcarbonyl chloride (II) by means of 48% HBr in ethanol/water at 80 C gives the monoamide (III), which is then condensed with 2-chloro-6,7-dimethoxyquinazoline-4-amine (IV) in refluxing isoamyl alcohol.
| 【1】 Minarini, A.; Budriesi, R.; Chiarini, A.; Leonardi, A.; Melchiorre, C.; Search for alpha1-adrenoceptor subtypes selective antagonists: Design, synthesis and biological activity of cystazosin, an alpha1D-adrenoceptor antagonist. Bioorg Med Chem Lett 1998, 8, 11, 1353. |
| 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) | 26092 | N-methyl-2-[[2-(methylamino)ethyl]disulfanyl]-1-ethanamine; N-methyl-N-(2-[[2-(methylamino)ethyl]disulfanyl]ethyl)amine | C6H16N2S2 | 详情 | 详情 | |
| (II) | 26093 | 2-Furoyl chloride | 527-69-5 | C5H3ClO2 | 详情 | 详情 |
| (III) | 26094 | N-methyl-N-(2-[[2-(methylamino)ethyl]disulfanyl]ethyl)-2-furamide | C11H18N2O2S2 | 详情 | 详情 | |
| (IV) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 |