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【结 构 式】 
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【分子编号】14601 【品名】N-(2-oxo-2-phenylethyl)acetamide 【CA登记号】 |
【 分 子 式 】C10H11NO2 【 分 子 量 】177.20288 【元素组成】C 67.78% H 6.26% N 7.9% O 18.06% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of N-(2-oxo-2-phenylethyl)acetamide (I) with glyoxylic acid (II) by means of NaHCO3 in water gives threo-(2RS)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutanoic acid (III), which is reduced with H2 over Pd/C in acetic acid yielding threo-(2RS)-3-acetylamino-2-hydroxy-4-phenylbutanoic acid (IV). The treatment of (IV) with (S)-1-phenylethylamine followed by a fractionated crystallization affords (2S,3R)-3-acetyl-amino-2-hydroxy-4-phenylbutanoic acid (IV), which is hydrolyzed with HCl in refluxing water to afford (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (V). The protection of (V) with benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate (VI) by means of triethylamine in dioxane - water gives (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (VII), which is condensed whh benzyl (S)-leucinate (VIII) by means of di-cyclohexylcarbodiimide and p-toluenesulfonic acid yielding benzyl (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyl-(S)-leucinate (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in acetic acid.
| 【1】 Umezawa, H.; Aoyagi, T.; Shirai, T.; Nishizawa, R.; Suzuki, M.; Saino, T. (Nippon Kayaku Co., Ltd.); Process for producing threo-3-amino-2-hydroxybutanoyl-aminoacetic acids, as well as novel intermediated therefor and process for producing them. DE 2947140; ES 486572; FR 2442227; GB 2090595; US 4281180 . |
| 【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; Bestatin. Drugs Fut 1981, 6, 10, 604. |
| 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) | 14601 | N-(2-oxo-2-phenylethyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (II) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (III) | 32263 | (2S,3S)-3-(acetamido)-2-hydroxy-4-oxo-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-oxo-4-phenylbutyric acid | C12H13NO5 | 详情 | 详情 | |
| (IV) | 32264 | (2S,3R)-3-(acetamido)-2-hydroxy-4-phenylbutyric acid; threo-(2RS)-3-acetamido-2-hydroxy-4-phenylbutyric acid | C12H15NO4 | 详情 | 详情 | |
| (V) | 32265 | (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid | 62023-63-6 | C10H13NO3 | 详情 | 详情 |
| (VI) | 32266 | O-benzyl S-(4,6-dimethyl-2-pyrimidinyl) carbonothioate; benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate | C14H14N2O2S | 详情 | 详情 | |
| (VII) | 32267 | (2S,3R)-3-benzyIoxycarbonyIamino-2-hydroxy-4-phenylbutyric acid; (2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyric acid | C18H19NO5 | 详情 | 详情 | |
| (VIII) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
| (IX) | 32268 | benzyl (2S)-2-[((2S,3R)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutanoyl)amino]-4-methylpentanoate; benzyl (2S,3R)-3-Benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyI-(S)-Ieucinate | C31H36N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)2-Aminoacetophenone.HCl (IV) is prepared from acetophenone (I) via 2-bromoacetophenone (II) and the quaternary urotropine salt (III). Acetylation of (IV) with acetic anhydride in water in the presence of sodium hydrogen carbonate yields 2-acetamidoacetophenone (V), which is converted to 2-acetamido-3-hydroxypropiophenone.HCl (VI) with formaldehyde in water. After removing the acetyl group with hydrochloric acid in ethanol, 2-amino-3-hydroxypropiophenone.HCl (VII) is formed, which is reduced with hydrogen over Pd/C in methanol to rac-erythro-2-amino-1-phenyl-1,3-propanediol.HCl (VIII). Reductive condensation of the corresponding base (IX) with phenoxyacetone (X) and hydrogen over PtO2 affords a mixture of aminodiols epimeric at C-1' (XI). (XI) is finally converted to the corresponding hydrochloride salts, from which the salt of the less soluble [1R*,2S*(S*)]-stereoisomer, i.e., solpecainol is isolated by crystallization. Structure and purity of solpecainol have been confirmed by x-ray crystallography and HPLC-MS.
| 【1】 Central Res. Inst. Chem. Hung. Acad. Sci. Report (27.10.1983) 1983. |
| 【2】 Levai, L.; Fazekas, G.; Petocz, L.; Grasser, K. (Egis Pharmaceuticals Ltd.); Novel N-alkyl derivs. of 1-phenyl-2-amino-1,3-propandiol and process for preparing same. DE 2810482; GB 1560470; JP 1978112827; US 4259257 . |
| 【3】 Vida, L.; Szepesy, L.; Lakszner, K.; Comparison and evaluation of derivatization methods for gas chromatographic determination of various propanediols. Chromatographia 1984, 19, 304. |
| 【4】 Berényi, E.; Petócz, L.; Blaskó, G.; Nógrádi, M.; Solpecainol Hydrochloride. Drugs Fut 1991, 16, 6, 514. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 | |
| (I) | 10317 | Acetophenone | 98-86-2 | C8H8O | 详情 | 详情 |
| (II) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (III) | 14599 | 2-(1-bromo-1lambda(5),3,5,7-tetraazatricyclo[3.3.1.1(3,7)]dec-1-yl)-1-phenyl-1-ethanone | C14H19BrN4O | 详情 | 详情 | |
| (IV) | 14600 | 2-(chloroamino)-1-phenylethanone | C8H8ClNO | 详情 | 详情 | |
| (V) | 14601 | N-(2-oxo-2-phenylethyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (VI) | 14602 | N-[1-(hydroxymethyl)-2-oxo-2-phenylethyl]acetamide | C11H13NO3 | 详情 | 详情 | |
| (VII) | 14603 | 2-(Cloroamino)-3-hydroxy-1-phenyl-1-propanone | C9H10ClNO2 | 详情 | 详情 | |
| (VIII) | 14604 | (1R,2S)-2-(Chloroamino)-1-phenylpropane-1,3-diol | C9H12ClNO2 | 详情 | 详情 | |
| (IX) | 14605 | (1R,2S)-2-amino-1-phenyl-1,3-propanediol | C9H13NO2 | 详情 | 详情 | |
| (X) | 10875 | 1-Phenoxyacetone; 1-Phenoxy-2-propanone | 621-87-4 | C9H10O2 | 详情 | 详情 |
| (XI) | 14607 | (1R,2S)-2-[(1-methyl-2-phenoxyethyl)amino]-1-phenyl-1,3-propanediol | C18H23NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The esterification of proline (I) with SOCl2 and ethanol gives ethyl prolinate (II), which by treatment with NH3 in methanol is converted into prolinamide (III). The acylation of (III) with cyclopropylcarbonyl chloride (IV) by means of K2CO3 in acetone yields 1-cyclopropylcarbonyl-2-carbamoylpyrrolidine (V), which is reduced with LiAlH4 in ether to afford 1-cyclopropylmethyl-2-aminomethylpyrrolidine (VI) (1,2). Finally this compound is condensed with ethyl 5-sulfamoyl-2-methoxybenzoate (VII) by heating at 120 C
| 【1】 Kaplan, J.P.; et al. (Synthelabo, S.A.); BE 857544; DE 2735036; FR 2360572; FR 2372157; FR 2395261; GB 1555890; JP 7825563; NL 7708571; ZA 7704743 . |
| 【2】 Kaplan, J.P.; et al. (Synthelabo, S.A.); BE 836752; CA 1039731; CH 612668; DE 2556457; FR 2294698; FR 2327771; FR 2331345; GB 1508880; JP 7748661; NL 7514620; US 4021567; US 4156060; US 4172143; US 4189495; ZA 7507828 . |
| 【3】 (Synthelabo, S.A.); BE 861866; FR 2394529; GB 1560019; JP 7905969; NL 7713631; ZA 7706950 . |
| 【4】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Hillier, K.; Cipropride. Drugs Fut 1981, 6, 4, 220. |
| 【5】 Obitz, D.C.L. (Synthelabo, S.A.); FR 2393794 . |
| 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) | 61051 | ethyl 2-pyrrolidinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (II) | 61052 | ethyl 2-pyrrolidinecarboxylate | C7H13NO2 | 详情 | 详情 | |
| (III) | 22654 | 2-pyrrolidinecarboxamide | 2812-47-7 | C5H10N2O | 详情 | 详情 |
| (IV) | 14601 | N-(2-oxo-2-phenylethyl)acetamide | C10H11NO2 | 详情 | 详情 | |
| (V) | 61053 | 1-(cyclopropylcarbonyl)-2-pyrrolidinecarboxamide | C9H14N2O2 | 详情 | 详情 | |
| (VI) | 61054 | [1-(cyclopropylmethyl)-2-pyrrolidinyl]methanamine; [1-(cyclopropylmethyl)-2-pyrrolidinyl]methylamine | C9H18N2 | 详情 | 详情 | |
| (VII) | 61055 | ethyl 5-(aminosulfonyl)-2-methoxybenzoate | C10H13NO5S | 详情 | 详情 |