CN103044331A - Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide - Google Patents
Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide Download PDFInfo
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Abstract
The invention discloses a novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide. According to the method, the 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide is prepared from 1-methyl-3-n-propyl-pyrazole-5-ethyl formate through bromation and ammoniation. The novel method disclosed by the invention is safe, efficient and environment-friendly and is suitable for industrial production.
Description
Technical field
The present invention relates to the new preparation method of Virga intermediate 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide, belong to the medicine intermediate synthesis technical field.
Background technology
Virga (Sildenafil); chemistry 1-methyl by name-3-n-propyl-5-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl) phenyl]-1; 6-dihydro-7H-pyrazolo [4; 2-d] pyrimidin-7-ones; use clinically its citrate; commodity are called viagra (Viagra), by Pfizer's research and development, are used for the treatment of male erectile dysfunction.The chemical structure of Virga is as follows:
The topmost synthetic route of Virga is take 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (formula I) and 2-ethoxybenzoic acid or 2-ethoxy benzoyl chloride as starting raw material, obtains Virga through condensation reaction, pyrimidone ring-closure reaction, chlorosulfonylation with the methylpiperazine condensation.This route raw material is easy to get, and reacts easy to operate, and yield is high, is fit to suitability for industrialized production.Reaction formula is as follows:
As mentioned above, the amino of the 4-shown in the formula I-1-methyl-3-n-propyl pyrazoles-5-methane amide is the key intermediate of synthetic Virga.The synthetic route of this intermediate of bibliographical information is take 2 pentanone as raw material, with the oxalic acid diethyl ester condensation after, obtain pyrazole ring with the hydrazine hydrate cyclization, after methylating again the hydrolysis after obtains 4-nitro-1-methyl-3-n-propyl pyrazoles-5-carboxylic acid with mixed acid nitrification; Re-use the sulfur oxychloride chlorination, obtain acyl chlorides after ammonia solve acid amides, the nitro that reduces at last obtains 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide.Reaction formula is as follows:
In this synthetic route, totally eight steps reaction, and adopted the reaction of mixed acid nitrification pyrazole ring.This reaction safety coefficient is lower, very easily sets off an explosion, and needs careful operation during industrialization, and need to carry out monitor closely to reaction, is unfavorable for large-scale commercial production.In addition, this route adopts sulfur oxychloride to prepare acyl chlorides, and then the ammonia solution obtains acid amides.And sulfur oxychloride is very serious to the corrosion of equipment, and produces a large amount of sour waters, causes very large pressure to environmental protection.
Summary of the invention
The object of the present invention is to provide the novel method of a kind of 4-of preparation amino-1-methyl-3-n-propyl pyrazoles-5-methane amide, be intended to overcome the shortcoming among the above-mentioned preparation method.Safer, the efficient and environmental protection of novel method.
The aromaticity of pyrazole ring is apparent in view, and the substitution reactions such as halo, nitrated, sulfonation can occur.Chen Minwei, sweet gift piebald horse chief editor " organic heterocyclic molecule " mentioned when having introduced the character of pyrazoles, and in sodium acetate aqueous solution, pyrazoles reacts with bromine, can obtain 4-bromine pyrazoles (nineteen ninety, first version, p151).
Tu Meiling etc. have reported that 3-isobutyl--1-methyl isophthalic acid H-pyrazoles-5-formic acid obtains 4-bromo-3-isobutyl--1-methyl isophthalic acid H-pyrazoles-5-formic acid (journal of Zhejiang university Edition, 2008,35,641～643.) with bromine reaction in chloroformic solution.
The Chinese patent of Beyer Co., Ltd's application has reported that 1-methyl-3-seven fluoropropyls-1H-pyrazoles obtains 4-bromo-1-methyl-3-seven fluoropropyls-1H-pyrazoles, yield 78% (CN200980143450.3) with the bromine reaction in water.
Khan etc. have reported in dichloromethane solution and in the presence of salt of wormwood, 1-methyl-3-n-propyl-1H-pyrazoles-5-carboxylic acid and bromine reaction obtain 4-bromo-1-methyl-3-n-propyl-1H-pyrazoles-5-carboxylic acid, yield 88% (Molecular Diversity, 2005,9,15～26.).
In addition, the 5-ethyl formate on the pyrazole ring can be the 5-methane amide by the direct ammonia solution of ammoniacal liquor.Palace equality has reported that 4-nitro-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester and strong aqua reaction obtain 4-nitro-1-methyl-3-n-propyl pyrazoles-5-methane amide, yield 84.4% (Shenyang Pharmaceutical University's journal, 2002,19,173～175.).
Under above methodological inspiration, the present invention's design has also been implemented following novel method of synthesizing 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide: take 1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (formula II) as starting raw material, in organic solvent and at a certain temperature, with the bromine reaction, obtain 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (formula III); The alcoholic solution of 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester and ammoniacal liquor or ammonia in the presence of alkali, and reacts under certain temperature and pressure, obtains 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (formula I).Reaction formula is as follows:
Specifically, preparation method provided by the invention comprises following content:
Take 1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (II) as starting raw material, in organic solvent, also at a certain temperature, with the bromine reaction, obtain 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (III).Wherein organic solvent is selected from methylene dichloride, trichloromethane, tetracol phenixin, dithiocarbonic anhydride, 1, one or more mixtures in 2-ethylene dichloride, glycol dibromide, the water; Temperature of reaction is at-10 ℃ of reflux temperatures to solvent, preferred 10～50 ℃.
The alcoholic solution of 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (III) and ammoniacal liquor or ammonia in the presence of alkali, and reacts under certain temperature and pressure, obtains 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (I).Wherein the alcoholic solution of ammonia is the methanol solution of ammonia or the ethanolic soln of ammonia; Alkali is selected from one or more mixtures among yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, pyridine, 4-dimethylamino pyridine, the DBU; Temperature of reaction is 10～150 ℃, preferred 40～100 ℃.
Method provided by the invention has not only been got rid of the low nitration reaction of safety coefficient, avoids using the sulfur oxychloride of deep-etching, strong and stimulating, and has shortened the reaction of 2 steps, so that operating procedure is more easy to control, and total recovery has improved more than 20%.In a word, safer, the efficient and environmental protection of novel method provided by the invention is more suitable for suitability for industrialized production.
Embodiment
Following exemplary embodiments is used for illustrating the present invention, all belongs within the technical scheme that the present invention protects in simple replacement that those skilled in the art do the present invention or improvement etc.
The preparation (III) of embodiment 1:4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester
The 1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (1.0mol) that in the there-necked flask of churned mechanically 5000ml is housed, adds 2500ml methylene dichloride and 196.1g, control reaction temperature control is below 10 ℃, slowly drip bromine 239.8g (1.5mol) under the lucifuge condition, about 1h dropwises, be warming up to room temperature reaction, TLC follows the tracks of, until raw material point disappears.Slowly be added dropwise to subsequently 15% sodium carbonate solution of 1000ml, dropwise rear stirring 1h, standing demix discards water layer, and the organic phase anhydrous sodium sulfate drying filters, and boils off solvent, and resistates obtains product 261.4g with re-crystallizing in ethyl acetate, yield 95.4%.
The preparation (I) of embodiment 2:4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide
In the autoclave of 3000ml, add the 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (0.73mol) of 200g and the strong aqua of 1800ml, airtight, open and stir, be warming up to 60 ℃ of reactions, TLC follows the tracks of, until raw material point disappears.After being cooled to room temperature, be evaporated to driedly, resistates gets product 140.8g with re-crystallizing in ethyl acetate, yield 91%.
The preparation (I) of embodiment 3:4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide
Ethanolic soln and the 57.7g pyridine (0.73mol) of the saturated ammonia of the 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (0.73mol) of adding 200g, 1800ml in the autoclave of 3000ml, airtight, open and stir, be warming up to 80 ℃ of reactions, TLC follows the tracks of, until raw material point disappears.After being cooled to room temperature, concentrating under reduced pressure steams and desolventizes, and resistates is used respectively hydrochloric acid (600ml * 3) and water (500ml * 2) washing of 1N with the dissolving of 1500ml methylene dichloride, and resistates gets product 135.6g with re-crystallizing in ethyl acetate, yield 87.6%.
Claims (6)
1. the novel method of the 4-amino shown in the preparation formula I-1-methyl-3-n-propyl pyrazoles-5-methane amide is characterized in that described preparation method may further comprise the steps:
(a) take the 1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester shown in the formula II as starting raw material, in organic solvent, also at a certain temperature, with the bromine reaction, obtain the 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester shown in the formula III;
(b) alcoholic solution of 4-bromo-1-methyl-3-n-propylpyrazole 5-carboxylic acid ethyl ester (III) and ammoniacal liquor or ammonia in the presence of alkali, and reacts under certain temperature and pressure, obtains 4-amino-1-methyl-3-n-propyl pyrazoles-5-methane amide (I).
2. method according to claim 1 is characterized in that organic solvent is selected from methylene dichloride, trichloromethane, tetracol phenixin, dithiocarbonic anhydride, 1, one or more mixtures in 2-ethylene dichloride, glycol dibromide, the water in the step (a).
3. method according to claim 1 is characterized in that the middle temperature of reaction of step (a) at-10 ℃ of reflux temperatures to solvent, preferred 10～50 ℃.
4. method according to claim 1, the alcoholic solution that it is characterized in that the ammonia described in the step (b) is the methanol solution of ammonia or the ethanolic soln of ammonia.
5. method according to claim 1 is characterized in that the alkali described in the step (b) is selected from one or more mixtures among yellow soda ash, salt of wormwood, sodium bicarbonate, triethylamine, pyridine, 4-dimethylamino pyridine, the DBU.
6. method according to claim 1 is characterized in that the temperature of reaction described in the step (b) is 10～150 ℃, preferred 40～100 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0253776A (en) * | 1988-08-17 | 1990-02-22 | Mitsubishi Kasei Corp | 4-halogeno-5-pyrazolecarboxylic acid derivative |
| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
| WO2002016364A1 (en) * | 2000-08-23 | 2002-02-28 | Lg Life Sciences Ltd. | Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence |
| CN1358722A (en) * | 2001-08-21 | 2002-07-17 | 常州市天普生物化学制药厂 | Process for preparing citrat |
| CN102267986A (en) * | 2011-09-01 | 2011-12-07 | 中国农业大学 | Pyrazole bisamide compounds as well as synthesis method and application thereof |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0253776A (en) * | 1988-08-17 | 1990-02-22 | Mitsubishi Kasei Corp | 4-halogeno-5-pyrazolecarboxylic acid derivative |
| US6200980B1 (en) * | 1995-06-07 | 2001-03-13 | Cell Pathways, Inc. | Method of treating a patient having precancerous lesions with phenyl purinone derivatives |
| WO2002016364A1 (en) * | 2000-08-23 | 2002-02-28 | Lg Life Sciences Ltd. | Polyethoxylated pyrazolo pyrimidinone derivatives, process for preparation thereof and pharmaceutical compositions comprising the same for the treatment of impotence |
| CN1358722A (en) * | 2001-08-21 | 2002-07-17 | 常州市天普生物化学制药厂 | Process for preparing citrat |
| CN102267986A (en) * | 2011-09-01 | 2011-12-07 | 中国农业大学 | Pyrazole bisamide compounds as well as synthesis method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| 沈之芹: "《合成化学》", 《3-正丙基-4-氨基-5-酰胺基-1-甲基吡唑的合成》 * |
| 秦绍清: "《4-氨基-1-甲基-3-丙基吡唑-5-甲酰胺的合成新路线》", 《精细与专用化学品》 * |
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Effective date of registration: 20170921 Address after: 213200, No. 6, Chang Dong Dong Road, Jintan District, Jiangsu, Changzhou Patentee after: Changzhou Yabang Pharmaceutical Co., Ltd. Address before: 213163 No. 105 Renmin West Road, Wujin District, Jiangsu, Changzhou Co-patentee before: Changzhou Yabang Pharmaceutical Co., Ltd. Patentee before: Changzhou Yabang Pharmaceutical & Chemical Co., Ltd. Co-patentee before: Yabang Pharmaceutical Co., Ltd. |