CN103044331A - Novel method for preparing Sildenafil intermediate 4-amino-1-methyl-3-n-propyl-pyrazole-5-formamide - Google Patents

Abstract

The invention discloses a new preparation method of sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide. The method uses ethyl 1-methyl-3-n-propylpyrazole-5-carboxylate as a raw material to prepare 4-amino-1-methyl-3-n-propylpyrazole-5 through bromination and amination - Formamide. The new method provided by the invention is safer, more efficient and more environmentally friendly, and is more suitable for industrial production.

Description

New method for preparing sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide

technical field

The invention relates to a new preparation method of sildenafil intermediate 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide, belonging to the technical field of pharmaceutical intermediate synthesis.

Background technique

Sildenafil, the chemical name is 1-methyl-3-n-propyl-5-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]- 1,6-dihydro-7H-pyrazolo[4,2-d]pyrimidin-7-one, its citrate salt is used clinically, the trade name is Viagra, developed by Pfizer, for the treatment of Erectile dysfunction in men. The chemical structure of sildenafil is shown below:

The main synthetic route of sildenafil is based on 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (formula I) and 2-ethoxybenzoic acid or 2-ethoxy Benzoyl chloride is used as the starting material, and sildenafil is obtained through condensation reaction, pyrimidinone ring closure reaction, chlorosulfonylation and condensation with methylpiperazine. The raw material of this route is easy to obtain, and the reaction is easy to operate, the yield is high, and it is suitable for industrial production. The reaction formula is as follows:

As mentioned above, 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide shown in formula I is a key intermediate for the synthesis of sildenafil. The synthetic route of this intermediate reported in the literature is to use 2-pentanone as a raw material. After condensation with diethyl oxalate, it is cyclized with hydrazine hydrate to obtain a pyrazole ring. After methylation, it is hydrolyzed and then nitrated with mixed acid to obtain 4-pentanone. Nitro-1-methyl-3-n-propylpyrazole-5-carboxylic acid; then use thionyl chloride to chlorinate to obtain acid chloride, then ammonolysis to obtain amide, and finally reduce nitro to obtain 4-amino-1-methyl Base-3-n-propylpyrazole-5-carboxamide. The reaction formula is as follows:

In this synthetic route, there are eight reactions in total, and the mixed acid nitration pyrazole ring reaction is adopted. The safety factor of this reaction is low, and it is very easy to cause an explosion. It needs careful operation and close monitoring of the reaction during industrialization, which is not conducive to large-scale industrial production. In addition, this route uses thionyl chloride to prepare acid chlorides, and then ammonolysis to obtain amides. However, thionyl chloride is very corrosive to equipment and produces a large amount of acid water, which puts a lot of pressure on environmental protection.

Contents of the invention

The object of the present invention is to provide a new method for preparing 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide, aiming to overcome the shortcomings in the above-mentioned preparation method. The new method is safer, more efficient and environmentally friendly.

The aromaticity of the pyrazole ring is relatively obvious, and substitution reactions such as halogenation, nitration, and sulfonation can occur. "Organic Heterocyclic Compounds" edited by Chen Minwei and Gan Lizhao mentioned when introducing the properties of pyrazoles that in aqueous sodium acetate solution, pyrazoles react with bromine to obtain 4-bromopyrazoles (1990, First Edition, p151).

Tu Meiling and others reported that 3-isobutyl-1-methyl-1H-pyrazole-5-carboxylic acid reacted with bromine in chloroform solution to obtain 4-bromo-3-isobutyl-1-methyl-1H-pyrazole Azole-5-carboxylic acid (Journal of Zhejiang University Science Edition, 2008, 35, 641~643.).

The Chinese patent applied by Bayer reported that 1-methyl-3-heptafluoropropyl-1H-pyrazole reacted with bromine in water to obtain 4-bromo-1-methyl-3-heptafluoropropyl-1H-pyrazole azole, yield 78% (CN200980143450.3).

Khan et al. reported the reaction of 1-methyl-3-n-propyl-1H-pyrazole-5-carboxylic acid with bromine in the presence of potassium carbonate in methylene chloride to give 4-bromo-1-methyl -3-n-propyl-1H-pyrazole-5-carboxylic acid, the yield was 88% (Molecular Diversity, 2005, 9, 15-26.).

In addition, ethyl 5-carboxylate on the pyrazole ring can be directly ammonolyzed to 5-carboxamide by ammonia water. Gong et al reported the reaction of ethyl 4-nitro-1-methyl-3-n-propylpyrazole-5-carboxylate with concentrated ammonia to obtain 4-nitro-1-methyl-3-n-propylpyrazole- 5-Formamide, yield 84.4% (Journal of Shenyang Pharmaceutical University, 2002, 19, 173-175.).

Inspired by the above methodology, the present invention has designed and implemented the following new method for the synthesis of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide: with 1-methyl-3-n- Propylpyrazole-5-ethyl carboxylate (formula II) is the starting material, in an organic solvent and at a certain temperature, reacts with bromine to obtain 4-bromo-1-methyl-3-n-propyl Ethyl pyrazole-5-carboxylate (formula III); ethyl 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylate and ammonia water or an alcoholic solution of ammonia, in the presence of a base, and React under certain temperature and pressure to obtain 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (Formula I). The reaction formula is as follows:

Specifically, the preparation method provided by the invention includes the following contents:

With 1-methyl-3-n-propylpyrazole-5-ethyl carboxylate (II) as the starting material, react with bromine in an organic solvent and at a certain temperature to obtain 4-bromo-1- Ethyl methyl-3-n-propylpyrazole-5-carboxylate (III). Wherein the organic solvent is selected from one or more mixtures of dichloromethane, chloroform, carbon tetrachloride, carbon disulfide, 1,2-dichloroethane, 1,2-dibromoethane, water; the reaction temperature is at -10°C to the reflux temperature of the solvent, preferably 10 to 50°C.

4-bromo-1-methyl-3-n-propylpyrazole-5-ethyl carboxylate (III) and ammonia water or ammonia alcohol solution, in the presence of a base, and react at a certain temperature and pressure to obtain 4-Amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I). Wherein the alcohol solution of ammonia is methanol solution of ammonia or ethanol solution of ammonia; alkali is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, 4-dimethylaminopyridine, DBU A mixture; the reaction temperature is 10-150°C, preferably 40-100°C.

The method provided by the invention not only eliminates the nitrification reaction with a low safety factor, avoids the use of strong corrosion and strong irritating sulfur oxychloride, but also shortens the two-step reaction, makes the operation process easier to control, and increases the total yield by 20%. above. In a word, the new method provided by the invention is safer, more efficient and environmentally friendly, and more suitable for industrial production.

Detailed ways

The following typical embodiments are used to illustrate the present invention. Simple replacements or improvements made by those skilled in the art are within the technical solutions protected by the present invention.

Example 1: Preparation of ethyl 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylate (III)

Add 2500ml of dichloromethane and 196.1g of ethyl 1-methyl-3-n-propylpyrazole-5-carboxylate (1.0mol) into a 5000ml three-necked flask equipped with mechanical stirring, and control the reaction temperature below 10°C 239.8g (1.5mol) of liquid bromine was slowly added dropwise under dark conditions, and the dropwise addition was completed in about 1 hour, and the temperature was raised to room temperature for reaction, followed by TLC until the raw material point disappeared. Then slowly add 1000ml of 15% sodium carbonate solution dropwise, stir for 1h after the dropwise addition, let the layers stand, discard the water layer, dry the organic phase with anhydrous sodium sulfate, filter, evaporate the solvent, and wash the residue with ethyl acetate 261.4 g of the product was obtained by recrystallization, with a yield of 95.4%.

Embodiment 2: the preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

Add 200g of ethyl 4-bromo-1-methyl-3-n-propylpyrazole-5-carboxylate (0.73mol) and 1800ml of concentrated ammonia water into a 3000ml autoclave, close it, start stirring, and heat up to 60°C The reaction was followed by TLC until the raw material spots disappeared. After cooling down to room temperature, it was concentrated to dryness under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 140.8 g of the product, with a yield of 91%.

Embodiment 3: the preparation of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide (I)

In a 3000ml autoclave, add 200g of 4-bromo-1-methyl-3-n-propylpyrazole-5-ethyl carboxylate (0.73mol), 1800ml of saturated ammonia ethanol solution and 57.7g of pyridine (0.73mol ), airtight, start stirring, heat up to 80°C for reaction, TLC tracking, until the raw material point disappears. After cooling down to room temperature, concentrate under reduced pressure to remove the solvent, dissolve the residue with 1500ml of dichloromethane, wash with 1N hydrochloric acid (600ml×3) and water (500ml×2) respectively, and recrystallize the residue with ethyl acetate to obtain the product 135.6g, 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 ℃.