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【结 构 式】 
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【分子编号】37279 【品名】2-benzylacrylic acid 【CA登记号】 |
【 分 子 式 】C10H10O2 【 分 子 量 】162.1882 【元素组成】C 74.06% H 6.21% O 19.73% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 2-benzylacrylic acid (I) with SOCl2 in hot toluene gives the acyl chloride (II), which is condensed with N-tosylglycine benzyl ester (III) by means of TEA in toluene to yield the corresponding amide (IV). Finally, this compound is condensed with thioacetic acid by heating at 80 C to afford the target acylthio compound.
| 【1】 Schwartz, J.-C.; Lecomte, J.-M.; Duhamel, P.; Duhamel, L.; Danvy, D.; Plaquevent, J.-C.; Monteil, T.; Piettre, S. (Societe Civile Bioprojet); Process for synthesizing N-(mercaptoacyl)amino acid derivs. from alpha-substd. acrylic acids. FR 2816309; US 2002055645 . |
| 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) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (II) | 55227 | 2-benzylacryloyl chloride | C10H9ClO | 详情 | 详情 | |
| (III) | 55228 | N-p-Tosylglycine benzyl ester | C16H17NO4S | 详情 | 详情 | |
| (IV) | 55229 | benzyl 2-[(2-benzylacryloyl)amino]acetate | C19H19NO3 | 详情 | 详情 | |
| (V) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)Alternatively, the condensation of dimethyl malonate (VI) with benzaldehyde (VII) by means of piperidine in refluxing toluene gives dimethyl benzylidenemalonate (VIII), which is reduced with H2 over Pd/C in toluene to yield the corresponding benzyl derivative (IX). The hydrolysis of (IX) with NaOH in water affords the benzylmalonic acid (X). Alternatively, intermediate (X) can also be obtained starting from diethyl malonate (XI), which is condensed with with benzaldehyde (VII) by means of piperidine in refluxing toluene to give diethyl benzylidenemalonate (XII). Reduction of (XII) with H2 over Pd/C in toluene yields the corresponding benzyl derivative (XIII), which is then hydrolized with NaOH in water. The monodecarboxylation of (X) and its condensation with paraformaldehyde and diethylamine in refluxing ethyl acetate provides 2-benzylacrylic acid (XIV), which is condensed with thioacetic acid (V) by heating at 70 C to afford 2-(acetylsulfanylmethyl)-3-phenylpropionic acid (XV). Finally, this compound is condensed with N-tosylglycine benzyl ester (XVI) by means of HOBt, DCC and TEA in THF.
| 【1】 Roques, B.; Schwartz, J.-C.; Lecomte, J.-M. (Societe Civile Bioprojet); Amino acid derivs. and their therapeutic application. EP 0038758 . |
| 【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 |
|---|---|---|---|---|---|---|
| (V) | 12893 | Ethanethioic S-acid | C2H4OS | 详情 | 详情 | |
| (VI) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 49460 | Dimethyl benzylidenemalonate | C12H12O4 | 详情 | 详情 | |
| (IX) | 49461 | dimethyl 2-benzylmalonate | C12H14O4 | 详情 | 详情 | |
| (X) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XI) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (XII) | 37482 | diethyl 2-benzylidenemalonate | 5292-53-5 | C14H16O4 | 详情 | 详情 |
| (XIII) | 20208 | diethyl 2-benzylmalonate | 607-81-8 | C14H18O4 | 详情 | 详情 |
| (XIV) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XV) | 55230 | 3-(acetylsulfanyl)-2-benzylpropanoic acid | C12H14O3S | 详情 | 详情 | |
| (XVI) | 55228 | N-p-Tosylglycine benzyl ester | C16H17NO4S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The reaction of N-Boc-L-serine (I) with 2-fluoronitrobenzene (II) by means of NaH in DMF gives N-Boc-O-(2-nitrophenyl)-L-serine (III), which is reduced with H2 over Pd/C in methanol yielding the 2-aminophenyl derivative (IV). The cyclization of (IV) by means of EDAC in DMF affords the benzoxazepinone (V), which is condensed with benzyl 2-bromoacetate (VI) by means of LHMDS in THF providing the benzoxazepinone acetic ester (VII). The deprotection of the carbamate group of (VII) with HCl in dioxane affords (VIII) with a free amino group that is condensed with 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) by means of EDAC in dichloromethane giving the corresponding amide (X). The deprotection of the benzyl groups of (X) with H2 over Pd/C in methanol yields the expected mixture of diastereomers that is resolved by preparative HPLC to afford the target compound. The intermediate 2-benzyl-3-[N-(benzyloxy)-N-formylamino]propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XI) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XII), which is condensed with O-benzylhydroxylamine (XIII) in refluxing ethanol yielding 2-benzyl-3-(benzyloxyamino)propionic acid (XIV). Finally, this compound is N-formylated with formic acid/acetic anhydride to afford the desired intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 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) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
| (II) | 13463 | o-Fluoronitrobenzene; 1-fluoro-2-nitrobenzene | 1493-27-2 | C6H4FNO2 | 详情 | 详情 |
| (III) | 37271 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-nitrophenoxy)propionic acid | C14H18N2O7 | 详情 | 详情 | |
| (IV) | 37272 | (2S)-3-(2-aminophenoxy)-2-[(tert-butoxycarbonyl)amino]propionic acid | C14H20N2O5 | 详情 | 详情 | |
| (V) | 37273 | tert-butyl (3S)-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-ylcarbamate | C14H18N2O4 | 详情 | 详情 | |
| (VI) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VII) | 37274 | benzyl 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C23H26N2O6 | 详情 | 详情 | |
| (VIII) | 37275 | benzyl 2-[(3S)-3-amino-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C18H18N2O4 | 详情 | 详情 | |
| (IX) | 37276 | 2-benzyl-N-(benzyloxy)-N-formyl-beta-alanine | C18H19NO4 | 详情 | 详情 | |
| (X) | 37278 | benzyl 2-[(3S)-3-([2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-4-oxo-3,4-dihydro-1,5-benzoxazepin-5(2H)-yl]acetate | C36H35N3O7 | 详情 | 详情 | |
| (XI) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XIV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XX)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XV) has been obtained as follows: The reaction of benzylmalonic acid (XIX) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XX), which is condensed with O-benzylhydroxylamine (XXI) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XXII). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (XV).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XIX) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XX) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XXI) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XXII) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XVI)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (XI) has been obtained as follows: The reaction of benzylmalonic acid (XV) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XVI), which is condensed with O-benzylhydroxylamine (XVII) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XVIII). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (XI).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XV) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XVI) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XVII) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XVIII) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(XIII)The intermediate 2(R)-benzyl-3-(benzyloxyamino)propionic acid (IX) has been obtained as follows: The reaction of benzylmalonic acid (XII) with aqueous formaldehyde and dimethylamine gives 2-benzyl-2-propenoic acid (XIII), which is condensed with O-benzylhydroxylamine (XIV) in refluxing ethanol yielding racemic 2-benzyl-3-(benzyloxyamino)propionic acid (XV). Finally, this compound is submitted to optical resolution with (1R,2S)(-)-ephedrine in acetonitrile to afford the chiral target intermediate (IX).
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XII) | 37280 | 2-benzylmalonic acid | 616-75-1 | C10H10O4 | 详情 | 详情 |
| (XIII) | 37279 | 2-benzylacrylic acid | C10H10O2 | 详情 | 详情 | |
| (XIV) | 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 |
| (XV) | 37277 | 2-benzyl-N-(benzyloxy)-beta-alanine | C17H19NO3 | 详情 | 详情 |