CN109776505B

CN109776505B - Preparation method of avanafil

Info

Publication number: CN109776505B
Application number: CN201910193398.8A
Authority: CN
Inventors: 汤俊; 徐园; 祝启迪
Original assignee: Yangzhou No3 Pharmaceutical Co ltd
Current assignee: Yangzhou No3 Pharmaceutical Co ltd
Priority date: 2019-03-14
Filing date: 2019-03-14
Publication date: 2021-07-27
Anticipated expiration: 2039-03-14
Also published as: CN109776505A

Abstract

The invention provides a preparation method of avanafil, which comprises the following steps: dissolving initial raw materials 4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethyl pyrrole-1-yl ] pyrimidine-5-carboxylic acid and 2-aminomethyl pyrimidine in a reaction solvent toluene, adding a boric acid porphyrin catalyst, heating and stirring to a reflux state, and catalyzing to obtain avanafil. The invention takes porphyrin borate as a catalyst to directly catalyze and synthesize avanafil. The catalyst has the advantages of small using amount, high reaction activity and relatively simple operation, the target product and the catalyst are easy to separate after the reaction is finished, the difficulty of separation and purification of the later-stage product is greatly reduced, the recovered catalyst can be recycled, the preparation cost can be obviously reduced, the whole catalytic reaction has the characteristics of simplicity, greenness, environmental protection and the like, the investment cost of manpower, raw materials and the like is obviously reduced, and the large-scale industrial production is facilitated.

Description

Preparation method of avanafil

Technical Field

The invention relates to the technical field of medicine production, in particular to a preparation method of avanafil.

Background

Avanafil CAS accession number: 330784-47-9, the structural formula of the compound is shown in figure 1. Is a drug developed by Vivus (Vivus) pharmaceutical company, granted by Mitsubishi pharmaceutical corporation, Ri Honda, for treating male erectile dysfunction. Was approved by the U.S. FDA for marketing in the united states at

month

4 and 27 of 2012 under the trade name Stendra.

As can be seen from fig. 2, the key step in the synthesis of avanafil is the fourth chemical reaction: namely amidation splicing of an intermediate 3, 4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid and a starting material, namely 3, 2-aminomethyl pyrimidine. Specifically, the amide is prepared by condensation of a carbodiimide condensation agent and an auxiliary acylation activating reagent. Commonly used carbodiimide condensing agents include Dicyclohexylcarbodiimide (DCC) and 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), and the acylation activating agent mainly comprises 1-hydroxybenzotriazole (HOBt) which needs to be added in an auxiliary way. Since the acid is not stable to the carbodiimide addition intermediate in the first stage of the reaction, it will itself rearrange to the corresponding stable urea by-product without conversion to the corresponding active ester by the acylation activating reagent. The domestic and foreign patents WO2015001567A1, EP1366760A1 and CN201310516008.9 have fully detailed reports on the problems.

The above amide synthesis methods have problems that: the activating reagent is used in the reaction in stoichiometric amount, sometimes even in large excess; after the acylation reaction is finished, the reaction product is converted into a useless byproduct, belongs to a consumable reagent and is contrary to the principle of atom economy; the separation of the amide from the by-products of the activation reagent is sometimes difficult and cumbersome; in addition, the activating reagents are often expensive and the cost becomes especially problematic in large scale production of amide products.

In view of the above, there is a need for an improved preparation method of avanafil in the prior art to solve the above problems.

Disclosure of Invention

The invention aims to disclose a preparation method of avanafil, which is used for overcoming the defects in the prior art, so as to improve the recovery rate of a catalyst and reduce the preparation cost.

In order to achieve the above object, the present invention provides a method for preparing avanafil represented by formula (ii), comprising the steps of:

s1, dissolving a compound (I), namely 4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethyl pyrrole-1-yl ] pyrimidine-5-carboxylic acid and 2-aminomethyl pyrimidine in a reaction solvent, namely toluene, adding a boric acid porphyrin catalyst, heating and stirring to a reflux state, and catalyzing to obtain a compound (II), wherein the chemical reaction equation is shown as follows:

s2, after the reaction is completed, slowly cooling the reaction liquid, dropwise adding dilute hydrochloric acid, stirring to dissolve a product, filtering to recover a porphyrin borate catalyst, separating liquid to obtain a lower-layer water phase (an upper-layer toluene phase can be reserved, and the remaining porphyrin borate catalyst is recovered), adding dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH of the water phase to 7.0, stirring at room temperature to separate out a crude avanafil product, filtering, and washing a filter cake with purified water;

s3, adding the crude avanafil product washed in the step S2 into anhydrous methanol, heating to a reflux state, adding activated carbon, stirring, adsorbing and decoloring, filtering while hot, stirring and cooling the filtrate, crystallizing, filtering, washing the filter cake with ice methanol, and drying to obtain an avanafil finished product.

As a further improvement of the invention, the molar ratio of the compound (I) to the 2-aminomethyl pyrimidine is 1: 1.0 to 1.2.

As a further improvement of the invention, the molar ratio of the compound (I) to the boric porphyrin catalyst is 1: 0.01 to 0.1.

As a further improvement of the invention, the ratio of the reaction solvent toluene to the compound (I) is 3-5: 1L/mol.

As a further improvement of the invention, the reaction time for heating to the reflux state is 8-16 h.

As a further improvement of the invention, the concentration of the dilute hydrochloric acid is 2-8 wt%.

As a further improvement of the invention, the volume ratio of the dilute hydrochloric acid to the reaction solvent toluene is 1: 0.5 to 2.

As a further improvement of the invention, the volume ratio of the dichloromethane to the reaction solvent toluene is 1: 0.5 to 2.

As a further improvement of the invention, the ratio of the anhydrous methanol to the compound (I) is 8-10: 1L/mol.

As a further improvement of the invention, the ratio of the activated carbon to the compound (I) is 20-30: 1 g/mol.

Compared with the prior art, the invention has the beneficial effects that: according to the preparation method disclosed by the application, the porphyrinic acid is used as a catalyst to directly catalyze and synthesize the avanafil. The catalyst has small dosage, high reaction activity and relatively simple operation. After the reaction is finished, the target product and the catalyst are easy to separate, and the difficulty of separating and purifying the later-stage product is greatly reduced. The recovered catalyst can be recycled, and the preparation cost can be obviously reduced. The whole catalytic reaction has the characteristics of simplicity, greenness, environmental protection and the like, remarkably reduces the input cost of manpower, raw materials and the like, and is beneficial to large-scale industrial production.

In addition, compared with the amide prepared by condensing an activating reagent, the yield of the avanafil prepared by directly catalyzing with the porphyrin borate is obviously higher, and the purity is relatively better.

Drawings

FIG. 1 is a chemical structural formula of avanafil;

FIG. 2 is a diagram of a synthesis scheme for the synthesis of avanafil in the prior art;

FIG. 3 is a schematic diagram of the mechanism of the catalytic synthesis of amides with arylboronic acids according to the present invention;

FIG. 4 is a NMR spectrum of avanafil of the present invention;

FIG. 5 is a mass spectrum of avanafil of the present invention;

FIG. 6 is a liquid phase spectrum of avanafil of the present invention.

Detailed Description

The present invention is described in detail with reference to the embodiments shown in the drawings, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should understand that functional, methodological, or structural equivalents or substitutions made by these embodiments are within the scope of the present invention.

Before describing in detail the various embodiments of the present application, the reaction mechanism of organic synthesis involved in the present invention is briefly described.

The application relates to a preparation process of avanafil, which relates to a chemical reaction which is a direct catalytic synthesis amide reaction. Monoacyloxyboronic acid reactive intermediates (which can be considered mixed anhydrides of carboxylic acids and aryl boronic acids) can be formed by reacting an aryl boronic acid, which contains a certain amount of an aryl boronic anhydride, with a carboxylic acid. Intramolecular hydrogen bonds and electron-deficient boron in the active intermediate can activate carboxyl carbon, so that the characteristic of nucleophilic attack of amine is facilitated, and the active intermediate is innovatively applied to preparation and synthesis of avanafil. The catalytic mechanism is shown in figure 3.

Example 1:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (10.9g,100mmol,1.0eq) and porphyrin borate (0.79g,1mmol,0.01eq) were added to 300mL of a toluene solution, and the mixture was heated under stirring to reflux and reacted for 8 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 300mL of 5 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. Separating the liquid and taking the water phase of the lower layer, adding 300mL of dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2h, filtering to obtain a crude avanafil product, and washing the filter cake with purified water for 2 times.

The crude avanafil product is added into 800mL of anhydrous methanol and heated to a reflux state, then 2.0g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and air blowing drying is carried out at 50 ℃ to obtain 40.4g of white needle-shaped solid (the yield is 83.5 percent, and the purity is 99.74 percent).

Example 2:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (10.9g,100mmol,1.0eq) and porphyrin borate (3.95g,5mmol,0.05eq) were added to 400mL of a toluene solution, heated under stirring to reflux, and reacted for 12 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 200mL of 8 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. Separating the liquid and taking the lower layer of water phase, adding 200mL of dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2h, filtering to obtain an avanafil crude product, and washing the filter cake with purified water for 2 times.

The crude avanafil product is added into 900mL of anhydrous methanol and heated to a reflux state, then 2.5g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and then air drying is carried out at 50 ℃ to obtain 42.6g of white needle-shaped solid (the yield is 88.1%, and the purity is 99.8%).

Example 3:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (12.0g,110mmol,1.1eq) and porphyrin borate (3.95g,5mmol,0.05eq) were added to 400mL of a toluene solution, heated under stirring to reflux, and reacted for 12 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 400mL of 5 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. Separating the liquid and taking the lower layer of water phase, adding 400mL of dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2h, filtering to obtain an avanafil crude product, and washing the filter cake with purified water for 2 times.

The crude avanafil product is added into 900mL of anhydrous methanol and heated to a reflux state, then 2.5g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and air drying is carried out at 50 ℃ to obtain 43.6g of white needle-shaped solid (the yield is 90.0%, and the purity is 99.92%).

Example 4:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (12.0g,110mmol,1.1eq) and porphyrin borate (7.9g,10mmol,0.1eq) were added to 500mL of a toluene solution, and the mixture was heated under stirring to reflux and reacted for 16 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 1000mL of 2 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. And (3) separating liquid, taking a lower-layer water phase, adding 500mL of dichloromethane, extracting and washing the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2 hours, filtering to obtain an avanafil crude product, and washing a filter cake with purified water for 2 times.

The crude avanafil product is added into 1000mL of anhydrous methanol and heated to a reflux state, then 3.0g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and then air drying is carried out at 50 ℃ to obtain 44.1g of white needle-shaped solid (the yield is 91.2%, and the purity is 99.63%).

Example 5:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (13.1g,120mmol,1.2eq) and porphyrin borate (0.79g,1mmol,0.01eq) were added to 300mL of a toluene solution, and the mixture was heated under stirring to reflux and reacted for 8 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 300mL of 8 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. And (3) separating and taking a lower-layer water phase, adding 600mL of dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2 hours, filtering to obtain an avanafil crude product, and washing a filter cake with purified water for 2 times.

The crude avanafil product is added into 800mL of anhydrous methanol and heated to a reflux state, then 2.0g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and air drying is carried out at 50 ℃ to obtain 43.6g of white needle-shaped solid (the yield is 84.2%, and the purity is 99.68%).

Example 6:

4- [ (3-chloro-4-methoxyphenyl) methylamino ] -2- [ (S) -2-hydroxymethylpyrrol-1-yl ] pyrimidine-5-carboxylic acid (39.3g,100mmol,1.0eq), 2-aminomethylpyrimidine (13.1g,120mmol,1.2eq) and porphyrin borate (7.9g,10mmol,0.1eq) were added to 500mL of a toluene solution, and the mixture was heated under stirring to reflux and reacted for 16 hours.

After the reaction is finished, slowly cooling the reaction solution to 10-20 ℃, and dropwise adding 1000mL of 5 wt% hydrochloric acid aqueous solution. Controlling the temperature of the system to be not more than 20 ℃, stirring for 30min, and filtering and recovering the porphyrin borate catalyst. Separating the liquid and taking the lower layer of water phase, adding 1000mL of dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH value of the water phase to 7.0, stirring and crystallizing at room temperature for 2h, filtering to obtain an avanafil crude product, and washing the filter cake with purified water for 2 times.

The crude avanafil product is added into 1000mL of anhydrous methanol and heated to a reflux state, then 3.0g of activated carbon is added, stirring, adsorption and decoloration are carried out for 30min, the mixture is filtered while the mixture is hot, the filtrate is stirred and cooled to 30 ℃, crystallization is carried out for about 3 hours, the filtration is carried out, the mixture is washed for 2 times by using ice methanol, and then air drying is carried out at 50 ℃ to obtain 43.7g of white needle-shaped solid (the yield is 90.3%, and the purity is 99.59%).

The purity of the obtained avanafil finished product is higher than 99.5 percent and the single impurity content is less than 0.1 percent by HPLC detection.

The detection conditions of HPLC are as follows: octadecylsilane chemically bonded silica was used as a filler (250X 4.6mm, 5 μm); taking 0.02mol/L sodium dihydrogen phosphate solution as a mobile phase A and acetonitrile as a mobile phase B; the detection wavelength is 240 nm; the flow rate is 1.0 ml/min; the column temperature was 30 ℃. Gradient elution was performed as follows:

time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	62	38
10	62	38
			17	25	75
40	25	75
			45	62	38
55	62	38

Through detection, the nuclear magnetic resonance hydrogen spectrum of the avanafil finished product is shown in figure 4, the mass spectrum is shown in figure 5, and the liquid phase spectrum is shown in figure 6.

Compared with the amide prepared by condensing an activating reagent, the yield of the avanafil prepared by directly catalyzing with the porphyrin borate is obviously higher, and the purity is relatively better.

The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims

1. A preparation method of avanafil shown in a formula (II) is characterized by comprising the following steps:

s2, after the reaction is completed, slowly cooling the reaction liquid, dropwise adding dilute hydrochloric acid, stirring to dissolve the product, filtering to recover the porphyrin borate catalyst, separating the liquid to obtain a lower-layer water phase, adding dichloromethane to extract and wash the water phase, slowly adding solid NaOH to adjust the pH of the water phase to 7.0, stirring at room temperature to separate out an avanafil crude product, filtering, and washing a filter cake with purified water;

2. The process according to claim 1, wherein the molar ratio of compound (i) to 2-aminomethylpyrimidine is 1: 1.0 to 1.2.

3. The process according to claim 1, wherein the molar ratio of compound (i) to porphyrin borate catalyst is 1: 0.01 to 0.1.

4. The preparation method according to claim 1, wherein the ratio of the reaction solvent toluene to the compound (I) is 3-5: 1L/mol.

5. The method according to claim 1, wherein the heating to the reflux state is carried out for a reaction time of 8 to 16 hours.

6. The method according to claim 1, wherein the dilute hydrochloric acid has a concentration of 2 to 8 wt%.

7. The preparation method according to claim 1, wherein the volume ratio of the dilute hydrochloric acid to the reaction solvent toluene is 1: 0.5 to 2.

8. The method according to claim 1, wherein the volume ratio of the dichloromethane to the reaction solvent toluene is 1: 0.5 to 2.

9. The method according to claim 1, wherein the ratio of the absolute methanol to the compound (I) is 8 to 10: 1L/mol.

10. The preparation method according to claim 1, wherein the ratio of the activated carbon to the compound (I) is 20-30: 1 g/mol.