CN117776951A

CN117776951A - Preparation method of Ukenafil intermediate

Info

Publication number: CN117776951A
Application number: CN202211144020.7A
Authority: CN
Inventors: 刘旭; 梁慧兴; 戴华山; 尹利献; 翟佳平; 吴雨蒙; 刘海华
Original assignee: Yangtze River Pharmaceutical Group Co Ltd
Current assignee: Yangtze River Pharmaceutical Group Co Ltd
Priority date: 2022-09-20
Filing date: 2022-09-20
Publication date: 2024-03-29

Abstract

The application relates to the technical field of medicine synthesis, and provides a preparation method of a compound of a formula (III), a eukenafil intermediate 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile and hydrochloride thereof (formula VI), wherein the preparation method of the compound of the formula (III) comprises the following steps: (1) Reacting ethyl haloacetate with n-propylamine to obtain a compound shown in a formula (I); (2) Reacting a compound of formula (I) in the presence of a first basic substance to obtain a compound of formula (II); (3) Subjecting the compound of formula (II) to a second baseReacting with acetic anhydride in the presence of the substance to obtain the compound of formula (III). The preparation method has the advantages of low cost and easy obtainment of raw materials, low production cost, no need of using toxic or explosive reagents with larger harm, safe and controllable production process and realization of industrial mass production.

Description

Preparation method of Ukenafil intermediate

Technical Field

The application relates to the technical field of drug synthesis, in particular to a preparation method of a Ukenafil intermediate.

Background

Yonkenafil (Yonkenafil) is the hydrochloride salt of Yonkenafil, its chemical name is: 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -5-methyl-7-propyl-3, 7-dihydro-pyrrolo [2,3-d ] pyrimidin-4-one monohydrochloride, wherein the eugenol hydrochloride has the structural formula:

ukenafil hydrochloride is a novel Phosphodiesterase (PDE) 5 inhibitor and can be used for treating erectile dysfunction (Erectile dysfunction, ED) by inhibiting PDE 5 activity and modulating cyclic guanylate (cGMP) levels. Earlier studies show that it has obvious advantages over the existing phosphodiesterase 5 inhibitor drugs.

2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile is a key intermediate for the synthesis of eukenafil, and has the following structural formula:

there are related literature reports on the synthetic route of the intermediate, for example, chinese patent application CN114085178A discloses a preparation method of the intermediate, which adopts malononitrile as a starting material and is obtained through condensation reactionThen the target product 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile is obtained after bromination reaction and condensation with propylamine. However, in the reaction, aluminum oxide is required to be used as a metal catalyst, the risk of residual aluminum is present in the product, the aluminum element is easy to cause senile dementia, the dust amount in the industrialized process is large, and the inhalation is easy to cause lung injury; in addition, in the reaction process, solvents with large harm such as benzoyl peroxide, chloroform and the like which are strong oxidants are needed, so that the method is not suitable for industrial production. Chinese patent application CN112266349a discloses a method for preparing 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile, which uses propylene oxide as a starting reagent, and is substituted with n-propylamine under the action of alkali, then amino protection is performed, alcohol is oxidized into aldehyde, then amino deprotection is performed, and finally ring closure reaction is performed with malononitrile to obtain the target product. However, the process route has certain defects, a large amount of hydrogen peroxide is needed in the reaction process, and the process belongs to explosive products and is not suitable for large-scale production; in addition, the reaction process adopts the steps of amino protection and deprotection, the reaction route is more complicated, and the industrial production cost is higher.

Therefore, a new preparation method of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile is needed to solve the industrial production problem of the Ubbelonafil intermediate.

Disclosure of Invention

The purpose of the application is to provide a preparation method of the Ug nafil intermediate to realize the economic, safe and industrialized mass production of the Ug nafil intermediate 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile.

In a first aspect the present application provides a process for the preparation of a compound of formula (III), comprising the steps of:

(1) Reacting ethyl haloacetate with n-propylamine to obtain a compound shown in a formula (I);

x is selected from Cl, br or I;

(2) Reacting the compound of formula (I) in the presence of a first basic substance to obtain a compound of formula (II);

(3) Reacting the compound of formula (II) with acetic anhydride in the presence of a second basic substance to obtain a compound of formula (III);

in some embodiments of the present application, in step (1), the molar ratio of the ethyl haloacetate to the n-propylamine is 1: (1-12), preferably 1: (1-10), more preferably 1: (2-4).

In some embodiments of the present application, in step (2), the mass ratio of the first basic substance to the ethyl haloacetate in step (1) is (0.5-2): 1, preferably (0.5-1): 1, more preferably (0.6-0.8): 1.

in some embodiments of the present application, the reaction temperature of step (2) is from 30 ℃ to 100 ℃, preferably from 40 ℃ to 60 ℃; preferably, the reaction time of step (2) is 0.5h-5h.

In some embodiments of the present application, in step (3), the second basic substance is selected from at least one of pyridine, 4-dimethylaminopyridine, triethylamine, N-diisopropylethylamine, methylimidazole, sodium acetate, sodium carbonate, potassium carbonate, and cesium carbonate.

In some embodiments of the present application, in step (3), the molar ratio of the second basic material to the acetic anhydride is 1: (1-6), preferably 1: (1-3).

In some embodiments of the present application, the reaction solvent of step (1) is selected from at least one of tetrahydrofuran, dioxane, and toluene;

preferably, the reaction temperature of step (1) is from-10 ℃ to 10 ℃, more preferably from-5 ℃ to 5 ℃;

preferably, the reaction time of the step (1) is 2-10 h.

In some embodiments of the present application, in step (1), n-propylamine is added first, followed by dropwise addition of ethyl haloacetate to effect the reaction.

In some embodiments of the present application, in step (2), the first alkaline substance is selected from at least one of an alkali metal hydroxide, an alkali metal carbonate, and an alkali metal phosphate; preferably, the alkali metal hydroxide is selected from at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the alkali metal carbonate is at least one selected from lithium carbonate, sodium carbonate and potassium carbonate; the alkali metal phosphate is at least one selected from lithium phosphate, sodium phosphate and potassium phosphate.

In some embodiments of the present application, in step (3), the molar ratio of the acetic anhydride to the ethyl haloacetate in step (1) is (8-12): 1.

in some embodiments of the present application, the reaction temperature of step (3) is from 100 ℃ to 140 ℃; preferably, the reaction time of step (3) is 2h-20h.

In some embodiments of the present application, the compound of formula (III) is prepared by a one-pot continuous reaction of step (1), step (2) and step (3).

In a second aspect, the present application provides a method for preparing a eukenafil intermediate, wherein the eukenafil intermediate is a compound of formula (V), the method comprising the steps of:

(4) Reacting a compound of formula (III) with hydrochloric acid to obtain a compound of formula (IV);

(5) Reacting the compound of formula (IV) with malononitrile in the presence of a third alkaline substance to obtain a compound of formula (V);

wherein the compound of formula (III) is prepared by the method described in the first aspect of the application.

In some embodiments of the present application, in step (4), the hydrochloric acid has a concentration of 5mol/L to 7mol/L;

preferably, the molar ratio of the hydrochloric acid to the compound of formula (iii) is (5-20): 1, a step of;

preferably, the reaction time of step (4) is 1h-8h.

In some embodiments of the present application, in step (5), the third alkaline substance is an inorganic base selected from at least one of sodium hydroxide and potassium hydroxide;

preferably, the reaction solvent in the step (5) is selected from at least one of methanol, ethanol and isopropanol;

preferably, the molar ratio of malononitrile to the compound of formula (iv) is (0.5-1.5): 1, a step of;

preferably, the reaction temperature of the step (5) is 0-30 ℃, and the reaction time is 0.2-2 h.

In a third aspect, the present application provides a method for preparing a midbody hydrochloride of eukenafil, wherein the midbody hydrochloride of eukenafil is a compound of formula (vi), and the method comprises the following steps:

(6) Reacting a compound of formula (V) with an organic solution of hydrogen chloride in the presence of acetone to form a salt, thereby obtaining a compound of formula (VI);

wherein the compound of formula (V) is prepared by a process as described in the second aspect of the present application.

In some embodiments of the present application, in step (6), the hydrogen chloride organic solution is selected from at least one of a hydrogen chloride/isopropanol solution and a hydrogen chloride/ethyl acetate solution;

preferably, the mass fraction of hydrogen chloride in the hydrogen chloride organic solution is 5% -15%;

preferably, the mass ratio of the compound of formula (v) to the organic solution of hydrogen chloride is 2: (4-6), preferably 2 (5-5.5);

preferably, the temperature of the salification reaction is-5 ℃ to 10 ℃;

preferably, the salt forming reaction is carried out for a period of time ranging from 1h to 10h.

The beneficial effects of this application lie in:

the application provides a preparation method of a compound of a formula (III), a eukenafil intermediate 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile and hydrochloride thereof (formula VI), and the method has the advantages of low-cost and easily obtained raw materials, low production cost, no need of using toxic or explosive reagents with larger harm and the like, safe and controllable production process and realization of industrialized amplified production.

Of course, not all of the above-described advantages need be achieved simultaneously in practicing any one of the products or methods of the present application.

Drawings

For a clearer description of the technical solutions of the present application or of the prior art, reference will be made below to the accompanying drawings used in the embodiments or in the description of the prior art, which are, obviously, only some embodiments of the present application, from which it is possible for a person skilled in the art to obtain other embodiments.

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound of formula (VI) in example 1;

FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound of formula (VI) in example 1.

Detailed Description

The following description of the embodiments of the present application will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all, of the embodiments of the present application. Based on the embodiments herein, a person of ordinary skill in the art would be able to obtain all other embodiments based on the disclosure herein, which are within the scope of the disclosure herein.

In a first aspect the present application provides a process for the preparation of a compound of formula (III), comprising:

in the step (1), ethyl haloacetate and n-propylamine are adopted to react to obtain a compound of the formula (I);

in some embodiments of the present application, halogen X in the ethyl haloacetate is selected from Cl, br or I, preferably ethyl bromoacetate is employed. By using inexpensive ethyl haloacetate as a starting material, industrial production costs can be reduced.

In some embodiments of the present application, the molar ratio of ethyl haloacetate to n-propylamine is 1: (1-12), for example, 1: 1. 1: 3. 1: 4. 1: 6. 1: 7. 1: 8. 1: 9. 1: 10. 1:11, etc., or any two of the above ratios as endpoints, preferably 1: (1-10), more preferably 1: (2-4).

In some embodiments of the present application, the reaction solvent in step (1) is selected from at least one of tetrahydrofuran, dioxane, and toluene. The amount of the reaction solvent to be added in the step (1) is not particularly limited as long as the object of the present application can be achieved, for example, the volume ratio of the reaction solvent to n-propylamine is (4-5): 1.

in some embodiments of the present application, the temperature of the reaction in step (1) is-10 ℃ -10 ℃, e.g., -10 ℃, -8 ℃, -5 ℃, -1 ℃,0 ℃,1 ℃,3 ℃,5 ℃, etc., or any two of the above values are used as endpoints to form a range, preferably-5 ℃ -5 ℃, and the time of the reaction is 2h-10h, e.g., 2h, 4h, 6h, 7h, 8h, 9h, 10h, etc., or any two of the above values are used as endpoints to form a range.

The inventor of the present application found that in step (1), n-propylamine was added first and then ethyl haloacetate was added dropwise, so that the reaction of ethyl haloacetate in excess to produce a by-product dimer was prevented.

The specific operation method of the step (1) is not limited, so long as the purpose of the application can be achieved, for example, after n-propylamine and the reaction solvent are mixed, the temperature is reduced to-10 ℃ to 10 ℃; and (3) dropwise adding ethyl haloacetate, and continuously stirring at room temperature after the completion of dropwise adding to obtain a product containing the compound of the formula (I).

In step (2), reacting the compound of formula (I) in the presence of a first basic substance to obtain a compound of formula (II);

in some embodiments of the present application, the mass ratio of the first basic substance to the ethyl haloacetate in step (1) is (0.5-2): 1, e.g., 0.5:1, 0.6:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 2:1, etc., or any two ratios thereof as defined above, are preferably (0.5-1): 1, more preferably (0.6-0.8): 1.

the form of adding the first alkaline substance used in the step (2) is not limited as long as the object of the present application can be achieved, and for example, an aqueous solution of the first alkaline substance may be used, and preferably the mass fraction of the aqueous solution of the first alkaline substance is 20% to 30%.

In some embodiments of the present application, the first alkaline substance is selected from at least one of an alkali metal hydroxide, an alkali metal carbonate, and an alkali metal phosphate. In a further embodiment, the alkali metal hydroxide is selected from at least one of lithium hydroxide, sodium hydroxide, and potassium hydroxide; the alkali metal carbonate is at least one selected from lithium carbonate, sodium carbonate and potassium carbonate; the alkali metal phosphate is at least one selected from lithium phosphate, sodium phosphate and potassium phosphate.

In some embodiments of the present application, the temperature of the reaction is in the range of 30 ℃ to 100 ℃, e.g., 30 ℃,40 ℃,45 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃,100 ℃, etc., or any two of the above values are formed as endpoints, preferably 40 ℃ to 60 ℃.

In some embodiments of the present application, in step (2), the reaction time is from 0.5h to 5h, such as 0.5h, 1h, 2h, 3h, 4h, 5h, etc., or any two of the above values are used as endpoints.

The specific operation method of the step (2) is not limited, so long as the purpose of the application can be achieved, for example, a first alkaline substance is added into the mixture obtained in the step (1), and the mixture is stirred for 0.5 to 5 hours at the temperature of 30 to 100 ℃; recovering the reaction solvent added in the step (1) under reduced pressure or concentrating, adjusting the pH of the residual liquid to 4-6 by hydrochloric acid, and optionally continuing concentrating under reduced pressure to obtain a product containing the compound of the formula (II).

In step (3), reacting the compound of formula (II) with acetic anhydride in the presence of a second basic material to obtain a compound of formula (III);

in some embodiments of the present application, the second basic substance is selected from at least one of pyridine, 4-dimethylaminopyridine, triethylamine, N-diisopropylethylamine, methylimidazole, sodium acetate, sodium carbonate, potassium carbonate, and cesium carbonate;

in some embodiments of the present application, the molar ratio of the second basic material to acetic anhydride is 1: (1-6), e.g., 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, etc., or any two ratios thereof as endpoints, preferably 1: (1-3).

In some embodiments of the present application, the molar ratio of acetic anhydride in step (3) to ethyl haloacetate in step (1) is (8-12): 1, e.g., 8:1, 9:1, 9.5:1, 10:1, 11:1, 11.3:1, 12:1, etc., or any two ratios thereof, as defined by the endpoints.

In some embodiments of the present application, the reaction temperature of step (3) is in the range of 100 ℃ to 140 ℃, e.g., 100 ℃, 105 ℃, 110 ℃, 120 ℃,130 ℃, 140 ℃, etc., or any two of the above values are used as endpoints.

In some embodiments of the present application, the reaction time of step (3) is from 2h to 20h, such as 2h, 4h, 6h, 8h, 12h, 16h, 20h, etc., or any two of the values recited above as the ranges formed by the endpoints.

The specific operation method of the step (3) is not limited, so long as the purpose of the application can be achieved, for example, a second alkaline substance and acetic anhydride are added into the mixture obtained in the step (2), and stirring is carried out for 2-20 h at 100-140 ℃; the obtained product is separated to obtain the compound of the formula (III). The reaction process is stable and does not need to be monitored.

The method for separating the product obtained in the step (3) is not particularly limited as long as the object of the present application can be achieved, for example, the product obtained in the step (3) can be filtered, the cake is washed with methylene chloride, the filtrate is distilled off under reduced pressure to remove methylene chloride, then the excess pyridine and acetic anhydride are recovered under reduced pressure, and the residue is subjected to fractional distillation under reduced pressure; or filtering the product obtained by the reaction in the step (3), washing a filter cake with dichloromethane, collecting the combined filtrate, concentrating under reduced pressure, and carrying out reduced pressure fractionation on the residue; the above-mentioned vacuum fractionation conditions: about 6mmHg to about 8mmHg; a thorn-shaped rectifying column, 30cm; fraction collection: collecting the front cut at 28-137 deg.c and yellow oily matter at 136-158 deg.c to obtain the compound of the formula (III).

According to the Dakin-West reaction mechanism, the inventor discovers that the acetic anhydride adopted in the step (3) can obtain a good effect by adopting the acetic anhydride as a reaction raw material, and the compound of the formula III can be obtained in one step, so that the complicated steps of firstly carrying out amino protection and then deprotection by adopting Boc anhydride in the prior art are avoided. In addition, because the method selects specific starting materials, a specific reaction route is obtained, and the oxidation of alcohol into aldehyde by using strong oxidants (such as hydrogen peroxide, concentrated sulfuric acid and the like) can be avoided.

In some embodiments of the present application, the compound of formula (III) is prepared by a one-pot continuous reaction of step (1), step (2) and step (3). The step (1), the step (2) and the step (3) are continuous reaction operation by a one-pot method, so that the production period can be effectively shortened while the product quality is ensured, and the production cost is reduced; the reaction process is stable and does not need to be monitored.

In a second aspect, the present application provides a process for the preparation of a eukenafil intermediate, said eukenafil intermediate being a compound of formula (v), comprising the steps of:

that is, the first three steps in the preparation method employ the aforementioned preparation method of the compound of formula (III).

In the step (4), the compound of the formula (III) reacts with hydrochloric acid to obtain a compound of the formula (IV);

in some embodiments of the present application, in step (4), the hydrochloric acid concentration is 5mol/L to 7mol/L, for example, 5mol/L, 5.5mol/L, 6mol/L, 7mol/L, etc., or any two values thereof are used as the end point forming range.

In some embodiments of the present application, in step (4), the molar ratio of the hydrochloric acid to the compound of formula (iii) is (5-20): 1, e.g., 5:1, 7:1, 9:1, 10:1, 15:1, 18:1, 20:1, etc., or any two of the foregoing values as endpoints.

In the research of the inventor, the compound of the formula (III) and hydrochloric acid are reacted in the step (4), so that the compound of the formula (III) forms hydrochloride while acetyl is removed, a solid sample is obtained, and the subsequent reaction and the post-treatment are facilitated; the effect of hydrochloric acid is difficult to achieve by other substances, and the effect is irreplaceable.

In some embodiments of the present application, in step (4), the reaction is a reflux reaction for a period of time ranging from 1h to 8h, such as 1h, 2h, 4h, 6h, 7h, 8h, etc., or any two of the foregoing values as endpoints.

The specific operation method of the step (4) is not limited, so long as the purpose of the application can be achieved, for example, hydrochloric acid is added into the compound of the formula (III), and the mixture is stirred and refluxed for 1h-8h; and separating the obtained product to obtain the compound of the formula (IV).

The method for separating the product obtained in the step (4) is not particularly limited as long as the object of the present application can be achieved, and for example, the product obtained in the step (4) may be concentrated under reduced pressure; adding acetone, and stirring at room temperature for 10-30 min; filtering, collecting pale yellow powdery solid, and vacuum drying at room temperature to obtain the compound of formula (IV).

The inventor of the application found in the study that after the feeding of the compound of the formula (III) and hydrochloric acid in the step (4) is amplified, the reaction yield is not reduced, which indicates that the process is stable and the method is applicable to industrial mass production.

In step (5), the compound of formula (IV) is reacted with malononitrile in the presence of a third basic substance to give a compound of formula (V).

In some embodiments of the present application, in step (5), the third alkaline substance is an inorganic base selected from at least one of sodium hydroxide and potassium hydroxide.

In some embodiments of the present application, the reaction solvent in step (5) is selected from at least one of methanol, ethanol, and isopropanol. The amount of the reaction solvent to be added in the step (5) is not particularly limited as long as the object of the present application can be achieved.

In some embodiments of the present application, in step (5), the molar ratio of the malononitrile to the compound of formula (iv) is (0.5-1.5): 1, e.g., 0.5:1, 0.7:1, 0.8:1, 1:1, 1.5:1, etc., or any two ratios thereof, as defined by the endpoints.

In some embodiments of the present application, the temperature of the reaction in step (5) is in the range of 0 ℃ to 30 ℃, e.g., 0 ℃,2 ℃,5 ℃, 8 ℃,10 ℃,12 ℃, 18 ℃, 20 ℃,30 ℃, etc., or any two of the above values are used as endpoints, and the time of the reaction is in the range of 0.2h to 2h, e.g., 0.2h, 0.5h, 1h, 1.2h, 1.8h, 2h, etc., or any two of the above values are used as endpoints.

The specific operation method of step (5) is not limited as long as the object of the present application can be achieved, for example, the third alkaline substance and the reaction solvent are stirred and dispersed, and the ice water bath is cooled to below 10 ℃ to obtain a mixture; heating and dissolving a compound of the formula (IV) and malononitrile by using a reaction solvent, then dropwise adding the mixture, keeping the reaction temperature at 0-30 ℃, and stirring for 0.2-2 h; the obtained product is separated to obtain the compound of the formula (V).

The method for separating the product obtained in the step (5) is not particularly limited as long as the object of the present application can be achieved, and for example, the product obtained in the step (5) may be concentrated under reduced pressure; adding methylene dichloride into the concentrate for extraction, washing a methylene dichloride layer with water, and drying the methylene dichloride layer by anhydrous sodium sulfate; filtering and concentrating to obtain the compound (free base) of the formula (V).

wherein the compound of formula (V) is prepared by the method described in the second aspect of the application.

In some embodiments of the present application, in step (6), the hydrogen chloride organic solution is selected from at least one of a hydrogen chloride/isopropanol solution and a hydrogen chloride/ethyl acetate solution; wherein the mass fraction of hydrogen chloride in the hydrogen chloride organic solution is 5% -15%, such as 5%, 8%, 10%, 12%, 14%, 15%, etc., or any two of the above values are used as the end points to form a range.

In some embodiments of the present application, in step (6), the mass ratio of the compound of formula (v) and the hydrogen chloride organic solution is 2: (4-6), e.g., 2:4, 2:5, 2:6, etc., or any two of the above ratios as endpoints, preferably 2: (5-5.5).

In some embodiments of the present application, in step (6), the salt forming reaction is carried out at a temperature of from-5 ℃ to 10 ℃, such as from-5 ℃, -3 ℃, -1 ℃,0 ℃,1 ℃,2 ℃,4 ℃,5 ℃, 8 ℃,10 ℃, etc., or ranges formed by any two of the above values as endpoints.

In some embodiments of the present application, in step (6), the salt forming reaction is performed for a period of time ranging from 1h to 10h, such as 1h, 3h, 3.2h, 3.4h, 3.5h, 3.8h, 4h, 5h, 10h, etc., or any two of the foregoing values as endpoints.

The application has certain requirements on the reaction solvent in the step (6), wherein the reaction solvent is too small in polarity to dissolve the compound V, too large in polarity, and has an influence on solid precipitation after the solvent salifies, and a large number of experiments show that the reaction solvent is preferably acetone.

The specific operation method of the step (6) is not limited as long as the purpose of the application can be achieved, for example, the compound of the formula (V) obtained in the step (5) and acetone are mixed and stirred until being dissolved, the temperature is reduced to-5 ℃ to 5 ℃, hydrogen chloride organic solution is dropwise added, and the mixture is stirred for 3h to 4h under heat preservation; the obtained product is separated to obtain the compound of the formula (VI).

The method for separating the product obtained in the step (6) is not particularly limited as long as the purpose of the application can be achieved, for example, the product obtained in the reaction in the step (6) can be filtered, a filter cake is rinsed with precooled isopropyl alcohol and/or ethyl acetate, and the filter cake is collected; vacuum drying at 30-40 deg.c to obtain the compound of the formula (VI).

The present application is described in detail below with reference to specific examples.

Yield calculation: yield = actual synthetic product mass/theoretical synthetic product mass x 100%.

Example 1

1. Synthesis of N- (2-oxopropyl) -N-propylacetamide

(1) 400mL (4.866 mol) of n-propylamine and 2000mL of tetrahydrofuran are added into a 5L three-necked flask, and cooled to 0-10 ℃ in an ice-water bath; 183.4mL ethyl bromoacetate (1.254 mol,276.2 g) was added dropwise, and after completion of the addition, stirring was continued at room temperature for 4 hours to give a mixed product.

(2) To the mixed product obtained in the step (1), 730mL of 25wt% aqueous NaOH solution (182.5 g containing NaOH) was added under stirring, and the mixture was stirred at 55℃for 1 hour; recovering tetrahydrofuran under reduced pressure, regulating pH of the residue to 5 with hydrochloric acid, and concentrating under reduced pressure to obtain concentrated solution.

(3) 680mL (8.451 mol) of pyridine and 1560mL (16.610 mol) of acetic anhydride are added into the concentrated solution obtained in the step (2), and the mixture is stirred for 6 hours at 135 ℃; filtering, washing a filter cake with 1500mL of dichloromethane, evaporating the filtrate under reduced pressure to remove the dichloromethane, and then recovering excess pyridine and acetic anhydride under reduced pressure; the residue was subjected to fractional distillation under reduced pressure:

fractionation conditions: about 6mmHg to about 8mmHg; a thorn-shaped rectifying column, 30cm;

fraction collection: the front cut was collected at 28℃to 137℃and the product was collected at 136℃to 158℃as a yellow oil, i.e., the compound of formula (III) (192 g, overall yield of the first three steps: 73.7%).

2. Synthesis of 1-propylamine-2-propanone hydrochloride

96g (0.611 mol) of the compound of formula (III) are introduced into a 2L reaction flask, 900mL of 6mol/L hydrochloric acid (containing 5.4mol of HCl) are added, and the mixture is stirred and refluxed for 4 hours; after the reaction is finished, concentrating under reduced pressure; adding 300mL of acetone into the concentrated solution, and stirring at room temperature for 20min; the pale yellow powdery solid was collected by filtration and dried under vacuum at room temperature to give the compound of formula (iv) (50.2 g, yield 53.9%).

3. Synthesis of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile (free base)

26g of sodium hydroxide is added into a 1L reaction bottle, 200mL of methanol is added, stirring and dispersion are carried out, and ice water bath is cooled to below 10 ℃ to obtain a mixture; 47g (0.310 mol) of the compound of formula (IV) and 20.5g (0.310 mol) of malononitrile are dissolved by heating with 250mL of methanol, and are added dropwise to the above mixture, the reaction temperature is kept at about 15 ℃, and stirring is continued for 20min; concentrating under reduced pressure to remove methanol, adding 150mL of dichloromethane to the concentrate for extraction, washing the dichloromethane layer with 90mL of water, and drying with anhydrous sodium sulfate; filtration and concentration gave a compound of formula (V) (43.8 g, 86.6% yield).

4. Synthesis of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile hydrochloride

Adding 20g of a compound of formula (V) and 100g of acetone into a 250mL flask, stirring until the compound and the acetone are dissolved, cooling to-5 ℃ and dropwise adding 50g of hydrogen chloride/isopropanol solution (4.5 g of hydrogen chloride is dissolved in 45.5g of isopropanol), keeping the temperature at 5 ℃ to 5 ℃ and stirring for 3 hours, filtering, leaching a filter cake with 5g of precooled isopropanol, and collecting the filter cake; vacuum drying at 30-40 ℃ gives the compound of formula (vi) (22.1 g, yield 90.0%). The obtained compound of formula (VI) has a nuclear magnetic resonance hydrogen spectrum shown in figure 1, a nuclear magnetic resonance carbon spectrum shown in figure 2, and the compound of formula (VI) is identified and confirmed to be 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile hydrochloride by the nuclear magnetic resonance hydrogen spectrum and the nuclear magnetic resonance carbon spectrum.

Example 2

1. Synthesis of N- (2-oxopropyl) -N-propylacetamide

(1) 80mL (0.973 mol) of n-propylamine and 400mL of dioxane are added into a 1L three-necked flask, and cooled to-5 ℃ to 5 ℃ in an ice-water bath; 38mL of ethyl bromoacetate (0.345 mol,57.2 g) was added dropwise, and stirring was continued at room temperature for 3 hours after completion of the addition to obtain a mixed product.

(2) To the mixed product obtained in the step (1), 160mL of 26wt% KOH aqueous solution (containing 41.6g of KOH) was added under stirring, and the mixture was stirred at 45℃for 2 hours; concentrating, adjusting pH of the residue to 5 with hydrochloric acid, and concentrating under reduced pressure to obtain concentrated solution.

(3) 160mL (1.187 mol) of 4-dimethylaminopyridine and 310mL (3.301 mol) of acetic anhydride were added to the concentrated solution obtained in the step (2), and the mixture was stirred at 130℃for 8 hours; the filter cake was washed with 300mL of dichloromethane, the combined filtrates were collected, concentrated to dryness under reduced pressure, and the residue was fractionated under reduced pressure:

fraction collection: the front cut was collected at 28℃to 137℃and the product was collected at 136℃to 158℃as a yellow oil, i.e., the compound of formula (III) (41.9 g, total yield of the first three steps 80.2%).

2. Synthesis of 1-propylamine-2-propanone hydrochloride

41.9g (0.267 mol) of the compound of the formula (III) are introduced into a 1L reaction flask, 380mL of 6mol/L hydrochloric acid (containing 2.28mol of HCl) are added, and the mixture is stirred and refluxed for 5 hours; after the reaction is finished, concentrating under reduced pressure; 130mL of acetone is added into the concentrated solution, and the mixture is stirred for 20min at room temperature; the pale yellow powdery solid was collected by filtration and dried under vacuum at room temperature to give the compound of formula (iv) (25.1 g, yield 62.0%).

3. Synthesis of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile (free base)

Adding 14g of sodium hydroxide into a 500mL reaction bottle, adding 105mL of ethanol, stirring and dispersing, and cooling the ice water bath to below 10 ℃ to obtain a mixture; 25.1g (0.166 mol) of the compound of formula (IV) and 12.0g (0.182 mol) of malononitrile are dissolved by heating with 130mL of ethanol, and added dropwise to the above mixture, the reaction temperature is kept at about 15 ℃, and stirring is continued for 20min; concentrating under reduced pressure to remove methanol, adding 80mL of dichloromethane to the concentrate for extraction, washing the dichloromethane layer with 48mL of water, and drying with anhydrous sodium sulfate; filtration and concentration gave the compound of formula (V) (23.7 g, yield 87.5%).

22g (0.135 mol) of the compound of formula (V) and 88g of acetone are added into a 250mL flask, stirred until the mixture is dissolved, cooled to-5 ℃ to 5 ℃,55 g of hydrogen chloride/ethyl acetate solution (5 g of hydrogen chloride is dissolved in 50g of ethyl acetate) is dropwise added, the mixture is stirred for 3 hours at the temperature of 5 ℃ to 5 ℃, filtered, and the filter cake is rinsed with 6g of precooled ethyl acetate, and the filter cake is collected; vacuum drying at 30-40 ℃ gives the compound of formula (vi) (24.6 g, 91.3% yield).

Example 3

1. Synthesis of N- (2-oxopropyl) -N-propylacetamide

(1) Adding 1L (12.164 mol) n-propylamine and 4L tetrahydrofuran into a 10L double-layer glass reaction kettle, and cooling to-5 ℃; 370mL ethyl bromoacetate (3.336 mol,557.2 g) was added dropwise, and stirring was continued at room temperature for 5 hours after completion of the addition to give a mixed product.

(2) Adding 1.5L of 25wt% NaOH aqueous solution (containing 375g of NaOH) into the mixed product obtained in the step (1) under stirring, and stirring at 40 ℃ for 3 hours; concentrating under reduced pressure, transferring the residue to a reaction kettle, and adjusting pH to 5 with hydrochloric acid.

(3) 1.6L (19.883 mol) pyridine and 3.2L (34.072 mol) acetic anhydride are added into the residual liquid after the pH adjustment in the step (2), and the mixture is stirred for 12 hours at 125 ℃; the filter cake was washed with 3L of dichloromethane, the combined filtrates were collected, concentrated under reduced pressure and the residue was fractionated under reduced pressure:

fraction collection: the front cut was collected at 28℃to 137℃and the product was collected at 136℃to 158℃as a yellow oil, i.e., the compound of formula (III) (428 g, overall yield of the first three steps was 81.9%).

2. Synthesis of 1-propylamine-2-propanone hydrochloride

428g (2.722 mol) of the compound of formula (III) are added into a 10L double-layer glass reaction kettle, 4L of 6mol/L hydrochloric acid (containing 24mol of HCl) are added, and stirring reflux is carried out for 8h; after the reaction is finished, concentrating under reduced pressure; adding 1.4L of acetone into the concentrated solution, and stirring at room temperature for 20min; the pale yellow powdery solid was collected by filtration and dried under vacuum at room temperature to give the compound of formula (iv) (273.9 g, yield 66.4%).

3. Synthesis of 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile (free base)

Adding 145g of sodium hydroxide into a 5L double-layer glass reaction kettle, adding 1L of methanol, stirring and dispersing, and cooling to-5-10 ℃ to obtain a mixture; 273.9g (1.806 mol) of a compound of formula (IV) and 100g (1.514 mol) of malononitrile are dissolved by heating with 1.3L of methanol, added dropwise to the above mixture, the reaction temperature is kept at 15-25℃and stirring is continued for 2h; concentrating under reduced pressure to remove methanol, adding 1L of dichloromethane into the concentrate for extraction, washing a dichloromethane layer with 500mL of water, and drying with anhydrous sodium sulfate; filtration and concentration gave the compound of formula (V) (262.3 g, 88.9% yield).

240g (1.470 mol) of the compound of formula (V) and 1.2kg of acetone are added into a 3L flask, stirred until the mixture is dissolved, cooled to-5 ℃ to 5 ℃, 600g of hydrogen chloride/isopropanol solution (70 g of hydrogen chloride is dissolved in 530g of isopropanol) is added dropwise, the mixture is stirred for 4 hours at 5 ℃ to 5 ℃, filtered, and the filter cake is rinsed with 80g of pre-cooled ethyl acetate, and the filter cake is collected; vacuum drying at 30-40 ℃ gives the compound of formula (vi) (263.8 g, 89.9% yield).

Examples 4 to 7 and comparative examples 1 to 3

The procedure of example 1 was repeated except that the parameters were adjusted as shown in Table 1.

The parameters related to examples 1 to 7 and comparative examples 1 to 3 and the yields of the compounds of formula (III) and formula (VI) are shown in Table 1 below.

TABLE 1 parameters related to examples 1-7 and comparative examples 1-3 and product yields

Note that: "-" means absent

According to the results, the preparation process can obtain the compound of the formula (III) with high yield, so that the yield and purity of the Ukenafil intermediate and the hydrochloride thereof can be further improved, the overall reaction yield is further improved, and the preparation process has important significance for industrial scale-up production.

Comparative example 4

Referring to the process disclosed in patent CN112266349a, compound iii is prepared by omitting the protection of the secondary amine in step (2) and directly oxidizing compound I.

Preparation of compound I: 30g of propylene oxide and 160mL of methylene dichloride are added into a 500mL three-port bottle, the mixture is stirred for 10min, the temperature is reduced to 0-10 ℃, 0.5g of triethylamine is added dropwise, the mixture is stirred for 30min under the condition of heat preservation, 32g of n-propylamine is added dropwise at the temperature of 0-10 ℃, and the reaction is carried out for 3h under the condition of heat preservation. Concentrated to dryness and distilled under reduced pressure to give the target compound (compound I) (54.6 g, yield 90.2%).

Preparation of compound III: to a 500mL three-necked flask, 2.93g (0.025 mol) of Compound I and 50mL of methylene chloride were added, and 11.3g (0.1 mol) of 30wt% hydrogen peroxide was added dropwise under reflux. After the dripping is finished, reflux reaction is carried out for 8 hours, and the temperature is reduced to 0-10 ℃; dropwise adding 10wt% sodium sulfite solution, layering, extracting, washing, and combining organic phases; the organic phase was concentrated under reduced pressure and the concentrate was a black oil, and no solid was obtained.

According to detection, various impurities exist in the black oily matter, and almost no target compound, namely a compound III exists, and the main impurity structure is as follows:

the results show that the method disclosed by CN112266349A is adopted to prepare 2-amino-4-methyl-1-propyl-1H-pyrrole-3-carbonitrile, wherein Boc anhydride is adopted to carry out amino protection and deprotection is required as an indispensable step, the reaction route is complex, the production cost is high, and the method is not suitable for industrial mass production.

In contrast, the preparation methods provided in examples 1-3 of the present application use ethyl haloacetate, such as ethyl bromoacetate, as starting material, and in step (3) the Dakin-West reaction is carried out in one step directly using the specific acetic anhydride to obtainThe method does not need to adopt a strong oxidant, and can realize safe mass production; the step (1), the step (2) and the step (3) are continuous reaction operation by a one-pot method, so that the production period is greatly shortened while the quality is ensured, and the production cost is low; in addition, the initial raw material is halogenated ethyl acetate such as ethyl bromoacetate, which is economical and cheap, and can effectively control the raw material cost, thereby greatly reducing the industrial production cost.

In this specification, each embodiment is described in a related manner, and identical and similar parts of each embodiment are all referred to each other, and each embodiment mainly describes differences from other embodiments.

The foregoing description is only of the preferred embodiments of the present application and is not intended to limit the scope of the present application. Any modifications, equivalent substitutions, improvements, etc. that are within the spirit and principles of the present application are intended to be included within the scope of the present application.

Claims

1. A process for the preparation of a compound of formula (III) comprising the steps of:

x is selected from Cl, br or I;

2. the method according to claim 1, wherein in the step (1), the molar ratio of the ethyl haloacetate to the n-propylamine is 1: (1-12), preferably 1: (1-10), more preferably 1: (2-4).

3. The production method according to claim 1, wherein in the step (2), the mass ratio of the first basic substance to the ethyl haloacetate in the step (1) is (0.5-2): 1, preferably (0.5-1): 1, more preferably (0.6-0.8): 1.

4. the process according to claim 1, wherein the reaction temperature of step (2) is 30-100 ℃, preferably 40-60 ℃; preferably, the reaction time of step (2) is 0.5h-5h.

5. The production method according to claim 1, wherein in the step (3), the second basic substance is selected from at least one of pyridine, 4-dimethylaminopyridine, triethylamine, N-diisopropylethylamine, methylimidazole, sodium acetate, sodium carbonate, potassium carbonate and cesium carbonate.

6. The method according to claim 1, wherein in the step (3), the molar ratio of the second basic substance to the acetic anhydride is 1: (1-6), preferably 1: (1-3).

7. The method according to claim 1, wherein the reaction solvent in the step (1) is at least one selected from the group consisting of tetrahydrofuran, dioxane and toluene;

preferably, the reaction time of the step (1) is 2-10 h.

8. The method according to claim 1, wherein in the step (1), the reaction is performed by adding the n-propylamine and then adding the ethyl haloacetate dropwise.

9. The production method according to claim 1, wherein in the step (2), the first alkaline substance is selected from at least one of an alkali metal hydroxide, an alkali metal carbonate, and an alkali metal phosphate; preferably, the alkali metal hydroxide is selected from at least one of lithium hydroxide, sodium hydroxide and potassium hydroxide; the alkali metal carbonate is at least one selected from lithium carbonate, sodium carbonate and potassium carbonate; the alkali metal phosphate is at least one selected from lithium phosphate, sodium phosphate and potassium phosphate.

10. The process according to claim 1, wherein in step (3), the molar ratio of acetic anhydride to ethyl haloacetate in step (1) is (8-12): 1.

11. the method of claim 1, wherein the reaction temperature in step (3) is 100 ℃ to 140 ℃; preferably, the reaction time of step (3) is 2h-20h.

12. The preparation method according to claim 1, wherein the compound of formula (III) is prepared by a one-pot continuous reaction of step (1), step (2) and step (3).

13. A process for the preparation of a eukenafil intermediate, wherein said eukenafil intermediate is a compound of formula (V), comprising the steps of:

wherein the compound of formula (iii) is prepared by the method of any one of claims 1 to 12.

14. The method according to claim 13, wherein in the step (4), the concentration of the hydrochloric acid is 5mol/L to 7mol/L;

preferably, the reaction time of step (4) is 1h-8h.

15. The production method according to claim 13, wherein in the step (5), the third alkaline substance is an inorganic base selected from at least one of sodium hydroxide and potassium hydroxide;

16. A process for the preparation of a midbody hydrochloride salt of eukenafil, which is a compound of formula (vi), comprising the steps of:

wherein the compound of formula (V) is prepared by the method of any one of claims 13 to 15.

17. The method according to claim 16, wherein in the step (6), the hydrogen chloride organic solution is selected from at least one of a hydrogen chloride/isopropyl alcohol solution and a hydrogen chloride/ethyl acetate solution;

preferably, the temperature of the salification reaction is-5 ℃ to 10 ℃;