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【结 构 式】 
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【药物名称】Dazopride succinate, AHR-5531C(fumarate), AHR-5531D 【化学名称】4-Amino-5-chloro-N-(1,2-diethyl-4-pyrazolidinyl)-2-methoxybenzamide succinate 【CA登记号】70181-03-2 (free base), 81957-25-7 (fumarate (1:1)) 【 分 子 式 】C19H29ClN4O6 【 分 子 量 】444.91918 |
【开发单位】Wyeth Consumer Healthcare (Originator) 【药理作用】Gastric Emptying Disorders,Treatment of of, GASTROINTESTINAL DRUGS, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, Prokinetic Agents, 5-HT3 Antagonists |
合成路线1
The dialkylation of aqueous N,N'-diacetyl-hydrazine by simultaneous addition of diethyl sulfate and potassium hydroxide so as to maintain a pH of 10.5-11.5 affords N,N'-diacetyl-N,N'-diethylhydrazine, which is hydrolyzed to diethylhydrazine (II) by hydrochloric acid. The pH of the acid solution is adjusted to 10, where it is maintained during the addition of epichlorohydrin to give 1,2-diethyl-4-pyrazolidinol (III). The pyrazolidinol is converted to 1,2-diethyl 4-aminopyrazolidine (VIII) by either amination of the corresponding chloro compound (IV) or displacement of the mesyloxy group in compound (V) by the azide ion, followed by reduction.
| 【1】 Munson, H.R. Jr.; Cale, A.D. Jr, Lo, Y.S.; Lunsford, C.D.; Synthetic and pharmacological properties of N-(1,2-dialkyl-4-pyrazolidinyl)benzamides - Selective gastric prokinetic agents. 187th ACS Natl Meet (April 8-13, St. Louis) 1984, 7, 9, 650. |
| 【2】 Cale, A.D.Jr.; Jenkins, H. (A.H. Robins Co. Inc.); Process for the preparation of 4-Pyrazolidinols. DE 2031489; ES 380355; FR 2053022; GB 1309018; US 3660426 . |
| 【3】 Cale, A. Jr.; Dazopride succinate. Drugs Fut 1985, 10, 7, 553. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10416 | (3aS,12bS)-2-Methyl-5-nitro-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole | C17H16N2O3 | 详情 | 详情 | |
| (A) | 27379 | N'-acetylacetohydrazide | 3148-73-0 | C4H8N2O2 | 详情 | 详情 |
| (I) | 27380 | N'-acetyl-N,N'-diethylacetohydrazide | C8H16N2O2 | 详情 | 详情 | |
| (II) | 27381 | 1,2-diethylhydrazine | C4H12N2 | 详情 | 详情 | |
| (III) | 27382 | 1,2-diethyl-4-pyrazolidinol | C7H16N2O | 详情 | 详情 | |
| (IV) | 27383 | 4-chloro-1,2-diethylpyrazolidine | C7H15ClN2 | 详情 | 详情 | |
| (V) | 27384 | 1,2-diethyl-4-(methylsulfonyl)pyrazolidine | C8H18N2O2S | 详情 | 详情 | |
| (VIII) | 27385 | 1,2-diethyl-4-pyrazolidinamine | 70180-92-6 | C7H17N3 | 详情 | 详情 |
合成路线2
An alternative method of producing the 1,2-diethyl-4aminopyrazolidine (VIII) is by reduction of the corresponding nitro compound (VII), which is derived from 1,3-dimorpholino-2-nitropropane (VI) and 1,2-diethylhydrazine (II).
| 【1】 Lo, Y.S.; Munson, H.R.Jr. (A.H. Robins Co. Inc.); Synthesis of 4-nitro-1,2-hydrocarbyl pyrazolidines and process for preparation thereof. DE 3130833; FR 2490639; FR 2491065; GB 2081713; JP 3204859; JP 57059868; US 4309552; US 4358599 . |
| 【2】 Cale, A. Jr.; Dazopride succinate. Drugs Fut 1985, 10, 7, 553. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 27381 | 1,2-diethylhydrazine | C4H12N2 | 详情 | 详情 | |
| (VI) | 27386 | 4-[3-(4-morpholinyl)-2-nitropropyl]morpholine | C11H21N3O4 | 详情 | 详情 | |
| (VII) | 27387 | 1,2-diethyl-4-nitropyrazolidine | C7H15N3O2 | 详情 | 详情 | |
| (VIII) | 27385 | 1,2-diethyl-4-pyrazolidinamine | 70180-92-6 | C7H17N3 | 详情 | 详情 |
| (C) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线3
Dazopride can be prepared by the condensation of the 1,2-diethyl-4-aminopyrazolidine (VIII) with either 4-amino-5-chloro-2-methoxybenzoic acid in the presence of phosphorus trichloride-pyridine or the corresponding mixed anhydride (IX).
| 【1】 Munson, H.R. Jr.; Cale, A.D. Jr, Lo, Y.S.; Lunsford, C.D.; Synthetic and pharmacological properties of N-(1,2-dialkyl-4-pyrazolidinyl)benzamides - Selective gastric prokinetic agents. 187th ACS Natl Meet (April 8-13, St. Louis) 1984, 7, 9, 650. |
| 【2】 Cale, A.D.Jr.; Lunsfod, C.D. (A.H. Robins Co. Inc.); N-(4-Pyrazolidinyl)benzamides and their amino precursors. US 4207327 . |
| 【3】 Cale, A. Jr.; Dazopride succinate. Drugs Fut 1985, 10, 7, 553. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (E) | 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 |
| (D) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VIII) | 27385 | 1,2-diethyl-4-pyrazolidinamine | 70180-92-6 | C7H17N3 | 详情 | 详情 |
| (IX) | 27388 | 4-Amino-5-chloro-2-methoxybenzoic acid ethoxycarbonyl anhydride | C11H12ClNO5 | 详情 | 详情 |