CN111116591A

CN111116591A - Method for preparing sildenafil citrate

Info

Publication number: CN111116591A
Application number: CN201911001922.3A
Authority: CN
Inventors: 郝明春; 沈磊; 刘永贤; 王�琦; 王利春; 王晶翼
Original assignee: Tianjin Kelun Pharmaceutical Research Co ltd
Current assignee: Sichuan Kelun Pharmaceutical Research Institute Co Ltd
Priority date: 2018-10-30
Filing date: 2019-10-21
Publication date: 2020-05-08

Abstract

The application discloses a method for preparing sildenafil citrate. The preparation method comprises the following steps: (a) adding the compound II into chlorosulfonic acid for reaction to generate an intermediate III; (b) reacting the intermediate III with N-methylpiperazine to generate a sildenafil crude product; (c) recrystallizing the sildenafil crude product to obtain a sildenafil pure product; (d) and carrying out salt forming reaction on the pure sildenafil product to obtain sildenafil citrate. The method of the invention is beneficial to industrial production.

Description

Method for preparing sildenafil citrate

Technical Field

The invention relates to a preparation method of sildenafil citrate.

Background

The chemical name of sildenafil citrate is as follows: 5- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one citrate. The structural formula is as follows:

sildenafil citrate selectively inhibits cGMP PDE but not cAMP PDE, and is a raw material medicament for treating cardiovascular diseases at an early stage. Later researches show that the compound also has the effect of clinically treating male erectile dysfunction, and the medicinal preparation of the compound is called as hubokeketone or wanaike (Viagra).

Various processes for the preparation of sildenafil citrate have been disclosed, for example, patent applications CN 1168376a CN1437589A, CN1255497A, WO 2007/141805, EP 2168967a1, WO01/98303a1, and the like. However, these methods have a problem that they are not suitable for industrial production.

Chinese patent application CN 108117555 a also discloses a line for preparing sildenafil citrate. In the circuit shown below, compound SM2 was obtained by reducing compound SM1 as a starting material with Fe powder. And carrying out condensation reaction on the compound SM2 and acyl chloride generated by the reaction of 2-ethoxybenzoic acid and thionyl chloride to obtain a compound I. The compound I is then cyclized directly without purification to give compound II. In the reaction, in order to obtain 2-ethoxybenzoyl chloride by subjecting 2-ethoxybenzoic acid to acylchlorination, thionyl chloride is added, and is removed by distillation in the subsequent step. This increases the complexity and energy consumption of the process.

In this document, in particular, sulfonation reactions from compounds II are provided. Specifically, the compound II is added into chlorosulfonic acid, stirred at 25-30 ℃, added with thionyl chloride, and reacted under the reflux condition to obtain the compound III.

However, the present inventors have found that thionyl chloride in this reaction introduces a large amount of impurities, in which deethyl impurities and chloro-substituted impurities may be generated, and the generated impurities are difficult to remove in subsequent steps, affecting the subsequent reaction.

Chinese patent application CN1057464A discloses a process for preparing sildenafil citrate analogues. The reaction scheme is similar to the reaction scheme disclosed in CN 108117555A, and condensation, cyclization, sulfonation and other steps are also disclosed in the examples.

One difference is that the condensation step:

condensation step:

in the condensation step, 4- (2-ethoxybenzoylamino) -1-methyl-3-n-propylpyrazole-5-carboxamide is prepared by reacting 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide with 2-ethoxybenzoyl chloride, and DMAP (4-dimethylaminopyridine) is added as a catalyst. However, the substance has high toxicity and irritation, so that the method is not suitable for industrial production.

After the condensation reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in a mixed solution of dichloromethane and methanol (volume ratio: 19:1), washed with 1N hydrochloric acid, evaporated under reduced pressure, and separated by column chromatography. The process is complicated, takes a long time and has a low yield (40%).

Also, this patent application discloses that the use of 30% hydrogen peroxide and ethanol solution in the cyclization step (cyclization from 4- (2-ethoxybenzoylamino) -1-methyl-3-n-propylpyrazole-5-carboxamide to 5- (2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one) presents a risk of explosiveness. In addition, column chromatography separation is required for post-treatment of each step in the document, the operation is complicated, and the yield is relatively low, so that the method is not favorable for industrial production.

Therefore, there is still a need for a process for preparing sildenafil citrate suitable for industrial scale production with further improved yield and simplified operation.

Disclosure of Invention

In view of the above, the present invention aims to provide a preparation method of sildenafil citrate, which is more suitable for industrial scale production.

In order to achieve the above object, the present invention provides a sildenafil citrate preparation method, comprising:

(a) adding the compound II into chlorosulfonic acid for reaction to generate an intermediate III;

(b) reacting the intermediate III with N-methylpiperazine to generate a sildenafil crude product;

(c) recrystallizing the sildenafil crude product to obtain a sildenafil pure product; and

(d) and carrying out salt forming reaction on the pure sildenafil product to obtain sildenafil citrate.

According to one embodiment, no thionyl chloride is added in step (a).

According to one embodiment, the reaction temperature in step (a) is 0 to 40 ℃, preferably 25 to 30 ℃; the reaction time is 12-36 h, preferably 12-20 h. The molar ratio of the compound II to chlorosulfonic acid is 1: 3-15, preferably 1: 3-10, more preferably 1: 8-10, and most preferably 1: 9.5.

In addition, the step (a) further comprises extracting the compound III with an extraction solvent, and retaining the compound III in the extraction solvent for the reaction of the step (b).

Further, the extraction solvent is at least one selected from the group consisting of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, and benzene. Preferably dichloromethane.

According to one embodiment, the recrystallization solvent in the (c) step is selected from at least one of ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, acetone, butanone, toluene and benzene, preferably ethyl acetate; and the volume/weight ratio of the recrystallization solvent to the sildenafil crude product is 10-20: 1, preferably 14-17: 1.

According to one embodiment, in the step (d), the salt formation reaction is carried out in a solvent, the solvent is at least one selected from acetone, butanone, methanol and ethanol, preferably acetone, and the volume/weight ratio of the solvent to sildenafil is 1-2: 1, preferably 1.5-1.8: 1.

According to one embodiment, the method further comprises: the compound I is subjected to cyclization reaction in a solvent in the presence of alkali to obtain a compound II,

according to one embodiment, the base in the cyclization reaction is selected from at least one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and potassium carbonate, preferably sodium hydroxide.

The solvent in the cyclization reaction is selected from at least one of methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, 1, 4-dioxane and dimethylformamide, and is preferably tert-butyl alcohol.

The cyclization reaction temperature is 20-100 ℃, preferably 75-90 ℃, and more preferably 85-90 ℃; the reaction time is 0.5-24 h, preferably 3-5 h; the molar ratio of the compound I to the catalyst is 1: 1-5, preferably 1: 1-2, and more preferably 1: 1.2.

According to one embodiment, the method further comprises: in the absence of a catalyst, the compound SM2 reacts with o-ethoxybenzoyl chloride in the presence of an organic base to obtain a compound I,

the catalyst is in particular 4-dimethylaminopyridine.

The invention provides a method for controlling chlorinated impurities in sildenafil citrate, which comprises the following steps:

(d) the sildenafil pure product is subjected to salt forming reaction to obtain sildenafil citrate;

the structural formula of the chlorinated impurities is as follows:

according to one embodiment, no thionyl chloride is added in step (a).

the catalyst is in particular 4-dimethylaminopyridine.

The invention provides an improved preparation method of sildenafil citrate. The preparation method simplifies the process on the whole, thereby saving the cost and improving the whole efficiency; and the content of chlorinated impurities can be effectively controlled, and the purification difficulty is reduced, so that the method is beneficial to industrial production.

Detailed Description

Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. If there is a conflict, the present specification will control.

The present invention will be specifically described below with reference to a production line for synthesizing sildenafil citrate from SM2 as a starting material according to an embodiment of the present invention. It should be understood that the scope of the invention is not limited to this specific embodiment.

In this embodiment, the entire synthetic route starting from SM2 is shown as follows:

in the procedure for the preparation of compound I according to the invention, starting material SM2 (4-amino-1-methyl-3-n-propyl-1H-pyrazole-5-carboxamide) was reacted with o-ethoxybenzoyl chloride to give compound I (4- (2-ethoxybenzylamido) -1-methyl-3-n-propylpyrazole-5-carboxamide). In this step, the present inventors have surprisingly found that, unlike what is taught in chinese patent application CN1057464A, the catalyst 4-Dimethylaminopyridine (DMAP) is not used, and yields of 89% to 99% can be obtained, thereby saving costs, and at the same time, the catalyst 4-Dimethylaminopyridine (DMAP) has high toxicity and irritation, making the method of adding the catalyst 4-Dimethylaminopyridine (DMAP) unfavorable for industrial production.

After the reaction is finished, the acid solution is directly added into the reaction solution, an organic phase is extracted and separated, the organic phase is decompressed, concentrated and evaporated to dryness to obtain the compound I, column chromatography separation is not needed, the operation is simple, and the purity of the compound I is ideal (the purity is more than 99 percent), so that the method is suitable for industrial scale production.

Specifically, in the process of synthesizing the compound I from SM2, the raw material SM2 is dissolved in a solvent and reacts with o-ethoxybenzoyl chloride under the action of an organic base.

The solvent used for the reaction is a conventional organic solvent, and there may be exemplified one or more of methylene chloride, chloroform, chlorobenzene, tetrahydrofuran, toluene, xylene, methyl t-butyl ether and the like, but not limited thereto.

The organic base is also not particularly limited, and for example, one or more of triethylamine, pyridine, N-ethyl-N, N-diisopropylamine, 2, 6-dimethylpyridine may be used, but is not limited thereto.

The reaction is usually carried out at 0 to 40 ℃ for 0.5 to 4.0 hours.

And after the reaction is finished, adding dilute hydrochloric acid to adjust the pH of the system to 6-7, separating liquid to obtain an organic phase, and drying under reduced pressure to obtain the compound I.

In the step of the present invention for producing compound II from compound I, cyclization reaction occurs from compound I in the presence of a base. Specifically, the reaction temperature is 20-100 ℃, preferably 75-90 ℃, and more preferably 85-90 ℃. The reaction time is 0.5-24 h, preferably 3-5 h.

The base for this step may be selected from at least one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and potassium carbonate, according to a preferred embodiment the base is sodium hydroxide.

The reaction is carried out in an organic solvent. The reaction solvent may be selected from at least one of methanol, ethanol, t-butanol, tetrahydrofuran, 1, 4-dioxane and dimethylformamide, and according to a preferred embodiment, the reaction solvent is preferably t-butanol.

The molar ratio of the compound I to the catalyst in the reaction is 1: 1-5, according to a preferred embodiment, the molar ratio of the compound I to the catalyst is 1: 1-2, and most preferably 1: 1.2.

After the reaction in the step is finished, adding a hydrochloric acid solution at 0-10 ℃ to adjust the pH value to about 7, directly stirring, crystallizing, filtering and drying to obtain a compound II without adopting a column chromatography separation method.

Compared with the condition that the reaction solvent is hydrogen peroxide, the method of the invention obtains ideal yield (89-99%), further improves the reaction safety and simplifies the post-treatment method.

In the step of preparing the compound III from the compound II, the present invention reacts the compound II directly with chlorosulfonic acid to obtain the compound III without thionyl chloride. And adjusting the reaction temperature and the post-treatment conditions, namely preferably, the reaction temperature is 25-30 ℃, and after the reaction is finished, quenching the reaction liquid by ice water to obtain a product with an ideal yield, avoiding unnecessary impurities and improving the efficiency of the whole reaction.

Specifically, in the invention, the reaction temperature of the compound II and chlorosulfonic acid is 0-40 ℃, and according to a preferred embodiment, the reaction temperature is preferably 25-30 ℃; the reaction time is 12-36 h, preferably 12-20 h.

The molar ratio of the compound II to chlorosulfonic acid is 1: 3-15, and according to a preferred embodiment, the molar ratio of the compound II to chlorosulfonic acid is 1: 3-10, more preferably 1: 8-10, and most preferably 1: 9.5.

After the reaction is finished, the reaction solution is quenched by ice water, extracted by a solvent, and the organic phase is directly put into the reaction of the next step.

Wherein the extraction solvent is at least one selected from dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene and benzene; according to a preferred embodiment, the extraction solvent is preferably dichloromethane.

The present inventors have found that chlorosulfonated compound III is unstable in air and is easily decomposed. If the solvent is distilled off under reduced pressure by a conventional method, the compound III is extremely easily decomposed if not stored under special conditions, but the overall yield is reduced and unnecessary impurities are introduced. Therefore, in the invention, the compound III is kept in the extracted organic phase, so that enough stability is obtained, the compound III is directly used for the next reaction, the process is simplified, the yield and the efficiency are improved, and the method is beneficial to industrial production.

In the step of preparing sildenafil from the compound III, directly adding N-methylpiperazine into the organic phase containing the compound III extracted in the previous step for reaction to obtain a sildenafil crude product. Adding N-methylpiperazine into the compound III dissolved in the extraction organic solvent at room temperature, reacting for 1-2 h under the condition of heat preservation, separating to obtain an organic phase, and removing the solvent to obtain a sildenafil crude product.

Recrystallizing the crude sildenafil product to obtain a pure sildenafil product.

Wherein the solvent for recrystallization is at least one selected from the group consisting of ethyl acetate, methyl t-butyl ether, tetrahydrofuran, methanol, ethanol, acetone, butanone, toluene, and benzene. According to a preferred embodiment, the solvent of the recrystallization is preferably ethyl acetate.

Wherein, the recrystallization solvent (vol, ml) is crude sildenafil (wt, g) 10-20: 1; for example, it is preferably 14 to 20:1, preferably 14 to 17:1, for example, 16:1, 18:1, 20: 1.

After the pure sildenafil product is obtained, the pure sildenafil product is subjected to salt forming reaction to obtain the high-purity sildenafil citrate.

Specifically, the pure sildenafil and citric acid are refluxed in an organic solvent, then directly cooled to room temperature for crystallization, and the crystal is filtered and dried to directly obtain a product which can be used for a medicinal preparation.

Wherein the solvent for salt-forming reaction is selected from at least one of acetone, butanone, methanol and ethanol, and according to a preferred embodiment, the solvent for salt-forming reaction is preferably acetone.

Wherein, the salifying solvent (vol, ml) is sildenafil (wt, g) 1-2: 1, preferably 1.5-1.8: 1.

The processes of all the steps of the synthetic route from the raw material SM2 to sildenafil citrate are simplified, unnecessary auxiliary reaction reagents are saved, and the cost is saved. According to the method, each step obtains satisfactory high yield, so that the overall yield of the method is obviously improved, and the method is more suitable for industrial production.

The technical solutions of the present invention will be described more clearly and completely through the following embodiments, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

EXAMPLE 1 preparation of Compound I

1.1kg of methylene chloride, 30.0g of SM2 (4-amino-1-methyl-3-n-propyl-1-H-pyrazole-5-formamide) and 32.4g of triethylamine were sequentially added to a 2L reaction flask, and 30.4g of o-ethoxybenzoyl chloride was added to the system at room temperature, and after the addition, the reaction was carried out at room temperature for 1.5 hours.

And (3) after the reaction is finished, using a hydrochloric acid solution to adjust the pH value of the system to 6-7, separating the solution, and washing the organic phase once with purified water and separating the solution.

The organic phase was concentrated to dryness under reduced pressure to give compound I (52.9g, 97.25% yield, 99.59% purity)

EXAMPLE 2 preparation of Compound II

A1L reaction flask was charged with 50.0g of Compound I, 300ml of t-butanol, and 7.2g of NaOH. Heating to 80-90 ℃.

And (3) after the system is subjected to heat preservation reaction at the temperature of 80-90 ℃ for 3-5 hours, cooling to 0-10 ℃, and adjusting the pH value of the system to 6-7 by using a hydrochloric acid solution. Precipitating a solid, and crystallizing for 1-2 h at 0-10 ℃. Filtration and washing of the filter cake with purified water. And (4) drying by blowing at 45 ℃ for 12-15 h. This gave compound II as a white solid powder (44.7g, yield 95.40%, purity 99.78%).

Examples 3 to 10

The yields of the work-up compound II after the reaction were shown in Table 1, varying the type and amount of base used according to the procedure described in example 2.

TABLE 1

Examples	Alkali	Batch charging ratio (Compound I: alkali)	Yield of
				3	Sodium hydroxide	1:1	90.23％
4	Sodium hydroxide	1:2	94.40％
				5	Sodium tert-butoxide	1:1	89.24％
6	Sodium tert-butoxide	1:1.25	91.35％
				7	Sodium tert-butoxide	1:2	92.46％
8	Sodium ethoxide	1:1	87.47％
				9	Sodium ethoxide	1:1.25	90.22％
10	Sodium ethoxide	1:2	92.26％

EXAMPLE 11 preparation of Compound III, sildenafil

To a 250mL four-necked flask was added 88mL of chlorosulfonic acid. 44.0g of the compound IIs obtained in example 4 was added to the system in portions, and after the addition, the reaction was stopped after the system was reacted at room temperature (20 to 30 ℃) for 12 hours.

The reaction solution was poured into 60.0g of ice water. The mixture was extracted with dichloromethane, and the organic phase was washed with saturated brine and purified water, and then separated, and the organic phase containing compound III was retained.

Without further separation, 14.1g of methylpiperazine is added into a dichloromethane solution of the compound III at room temperature, the mixture is kept warm and reacts for 1-2 hours, and then the reaction liquid is washed by saturated sodium bicarbonate solution and purified water to obtain an organic phase and separated.

The organic phase was distilled to dryness under reduced pressure, and the resulting solid was recrystallized from ethyl acetate (18Vol) to give sildenafil (58.8g, yield 88.00%, purity 99.98%) as a white solid.

Examples 12 to 13

According to the method described in example 11, thionyl chloride was added to chlorosulfonic acid in molar ratios of thionyl chloride to compound II of 0.5:1 and 1:1, respectively, to give sildenafil in yields and purities and chlorinated impurity contents as compared with the results of example 11, see Table 2.

TABLE 2

The structural formula of the chlorinated impurities is:

as can be seen from the above table, in the chlorosulfonation reaction process, thionyl chloride is not added, the yield and purity of the obtained product are both high, and the content of main impurities (chlorinated impurities) in the product is lower than that of the chlorinated impurities in the product obtained after thionyl chloride is added. And the generated chlorinated impurities are difficult to remove in the subsequent steps, so that the purification difficulty is increased, and the subsequent reaction is influenced.

Examples 14 to 15

The yield and purity of sildenafil obtained according to the method described in example 11 with varying amounts of chlorosulfonic acid are shown in table 3.

TABLE 3

When the molar ratio of chlorosulfonic acid to compound II is 6.0:1, most of compound II in the system cannot be dissolved, the system is difficult to stir, and the reaction is incomplete, so the reaction yield is low. When the molar ratio of the chlorosulfonic acid to the compound II is 9.5:1, the compound II can be completely dissolved, the reaction is completed, and the reaction yield is high; but the dosage of chlorosulfonic acid is further increased, and the reaction yield and purity are not improved.

Examples 16 to 17

The yield and purity of sildenafil obtained according to the method described in example 11 with varying reaction temperature are shown in table 4.

TABLE 4

Examples	Reaction temperature	Purity of the product	Product yield
				11	20～30℃	99.98％	88.02％
16	0～10℃	99.96％	87.80％
				17	35～45℃	99.92％	87.57％

When the reaction temperature is 0-45 ℃, the product purity is over 99.9 percent, and the product yield is over 87.5 percent.

Examples 18 to 28

The process of example 11 was followed, with the recrystallization solvent varied in type and amount, and the yields of sildenafil were as shown in Table 5.

TABLE 5

EXAMPLE 29 preparation of sildenafil citrate

900ml of acetone and 50.0g of sildenafil obtained in example 11 were sequentially added to a reaction flask, and the temperature was raised to reflux.

Adding 100ml of acetone solution of 22.0g of citric acid at 55-60 ℃; after the addition is finished, refluxing and stirring for 30min, cooling to 20-30 ℃, and crystallizing for 2 h; the solid was filtered and dried by air blow at 45 ℃ for 12 to 15 hours to obtain the title compound sildenafil citrate (67.8g, yield 96.52%, purity 99.99%).

The nuclear magnetic resonance hydrogen spectrum data of sildenafil citrate prepared by the invention is consistent with the nuclear magnetic resonance hydrogen spectrum data of sildenafil citrate reported in the literature, and the nuclear magnetic resonance hydrogen spectrum data of sildenafil citrate is proved to be a target product sildenafil citrate, and the specific data comparison is as follows:

the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention.

Claims

1. A process for preparing sildenafil citrate, the process comprising:

2. The process of claim 1, wherein no thionyl chloride is added in step (a).

3. The method according to claim 1, wherein the reaction temperature in the step (a) is 0-40 ℃, preferably 25-30 ℃; the reaction time is 12-36 h, preferably 12-20 h.

4. The method according to claim 1, wherein the molar ratio of the compound II to chlorosulfonic acid is 1:3 to 15, preferably 1:3 to 10, more preferably 1:8 to 10, and most preferably 1: 9.5.

5. The process of claim 1, wherein step (a) further comprises extracting compound III with an extraction solvent and retaining compound III in the extraction solvent for the reaction of step (b).

6. The method of claim 5, wherein the extraction solvent is selected from at least one of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, toluene, and benzene.

7. The method according to claim 1, wherein the recrystallization solvent in the step (c) is selected from at least one of ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, acetone, butanone, toluene, and benzene; and the volume/weight ratio of the recrystallization solvent to the sildenafil crude product is 10-20: 1, preferably 14-17: 1.

8. The method according to claim 1, wherein in the step (d), the salt formation reaction is carried out in a solvent, the solvent is at least one selected from acetone, butanone, methanol and ethanol, and the volume/weight ratio of the solvent to sildenafil is 1-2: 1, preferably 1.5-1.8: 1.

9. The method of claim 1, further comprising: the compound I is subjected to cyclization reaction in a solvent under the action of alkali to obtain a compound II,

10. the process of claim 9, wherein the base in the cyclization reaction is selected from at least one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide and potassium carbonate; the solvent in the cyclization reaction is selected from at least one of methanol, ethanol, tert-butyl alcohol, tetrahydrofuran, 1, 4-dioxane and dimethylformamide; the cyclization reaction temperature is 20-100 ℃, preferably 75-90 ℃, and more preferably 85-90 ℃; the reaction time is 0.5-24 h, preferably 3-5 h; the molar ratio of the compound I to the alkali is 1: 1-5, preferably 1: 1-2, and more preferably 1: 1.2.

11. The method of claim 9, further comprising: in the absence of a catalyst, the compound SM2 reacts with o-ethoxybenzoyl chloride in the presence of an organic base to obtain a compound I,

12. a method of controlling chlorinated impurities in sildenafil citrate, the method comprising:

the structural formula of the chlorinated impurities is as follows: