CN110885315A

CN110885315A - Preparation method of important intermediate of levosimendan

Info

Publication number: CN110885315A
Application number: CN201911283999.4A
Authority: CN
Inventors: 王亚军
Original assignee: Wuhan Garnor Kang Pharmaceutical Co Ltd
Current assignee: Wuhan Garnor Kang Pharmaceutical Co Ltd
Priority date: 2019-12-13
Filing date: 2019-12-13
Publication date: 2020-03-17

Abstract

The invention belongs to the field of synthesis of intermediates, and particularly relates to a preparation method of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one. The method takes N- (4-propionyl phenyl) acetamide as a starting material, obtains N- (4- (3- (dimethylamino) -2-methylpropionyl) phenyl) acetamide by Mannich reaction with formaldehyde and dimethylamine, and then obtains the (R) -N- (4- (3- (dimethylamino) -2-methylpropionyl) phenyl) acetamide with high chiral purity by chemical resolution and high yield; then (R) -N- (4- (3-cyano-2-methylpropanoyl) phenyl) acetamide is obtained through the quaternization of iodomethane and the substitution reaction of sodium cyanide; the product is hydrolyzed and cyclized with hydrazine hydrate to obtain an important target chiral intermediate. The method has the advantages of cheap and easily obtained starting materials, low resolution difficulty, high yield, no racemization in subsequent reactions after the intermediate is resolved, high quality of the obtained target product and suitability for industrial production.

Description

Preparation method of important intermediate of levosimendan

Technical Field

The invention relates to the technical field of synthesis of intermediates, and particularly relates to a preparation method of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one.

Background

(R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one is a medicinal intermediate, and has important application in the synthesis of various medicaments, such as levosimendan and other medicaments. Although various synthesis methods can be used for obtaining 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one at the present stage, the chiral compound R obtained by splitting the intermediate has the problems of complex operation, low yield and the like, and the specific reasons can be that the intermediate is weak in alkalinity and is not easy to be combined with a resolving agent, and the combination site is far away from the chiral center, so that the resolution efficiency is low, and the reasons greatly increase the production cost.

The original patent US6355269 discloses a method for resolving an intermediate 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one, which uses isopropanol and L-tartaric acid as resolving agents to resolve the intermediate, and the applicant reappears the experiments in the patent, and after multiple experiments, the method is found to have low resolving efficiency, the comprehensive resolving yield is only 20%, and multiple crystallization is required.

The document An Enantioselective Synthesis of SK & F93505, a Key Intermediate for preceding Carbotonic agents, synthesizes 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one by lactic acid. According to the literature, although chiral intermediates are obtained by chiral starting materials, the intermediates are racemized due to the subsequent SN2 reaction, so that the obtained 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one has not high chiral purity and cannot be used for drug production.

The document Toshimi SEKI (chem. pharm. bull.46(1)84-96(1998)) et al use a new concept for the preparation of 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one using well-established asymmetric reduction methods by constructing the double bond, but according to the document it is described that the construction of this intermediate requires a multi-step reaction and that for higher efficiency of chiral conversion a higher hydrogenation pressure is used. These limit the application of the process in production.

The above documents show that the prior art cannot obtain the target pharmaceutical intermediate in a simple and efficient manner. Therefore, an inexpensive process suitable for industrial production is urgently needed at the present stage to produce 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one, so that the production cost of levosimendan is reduced.

Disclosure of Invention

The invention provides a simple, convenient and efficient method for synthesizing (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one on the basis of synthesizing 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one by the prior art.

The route for the synthesis of 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one is as follows:

further, compound 1: the name is: n- (4-propionylphenyl) acetamide,

the structural formula is as follows:

further, compound 2: the name is: n- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide,

the structural formula is as follows:

further, compound 3: the name is: (R) -3- (4-acetamidophenyl) -N, N, N, 2-

Tetramethyl-3-oxopropane-1-ammonium iodide,

the structural formula is as follows:

further, compound 4: the name is: (R) -N- (4- (3-cyano-2-methylpropanoyl) phenyl) acetamide,

the structural formula is as follows:

further, compound 5: the name is: (R) -4- (4-aminophenyl) -3-methyl-4-oxobutanoic acid hydrochloride,

the structural formula is as follows:

further, compound 6: the name is: (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one,

the structural formula is as follows:

the invention synthesizes the target product (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one by a single structure substance compound 2A,

further, compound 2A: the name is: (R) -N- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide,

the structural formula is as follows:

the single configuration matter compound 2A is obtained by chiral resolution of a compound 2,

the resolution step requires the addition of a resolving agent and a resolving solvent,

the resolving agent is selected from at least one of the following resolving agents: d-tartaric acid, D-p-dimethoxybenzoyl tartaric acid and D-p-methoxybenzoyl tartaric acid;

the resolving solvent is at least one selected from isopropanol, methanol, ethyl acetate and toluene.

The preparation method has mild reaction conditions, high resolution efficiency, no chiral center racemization and high purity of the target product (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one.

The preparation method of the (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one of the invention has the following route:

specifically, the preparation method comprises the following steps:

the method comprises the following steps: reacting dimethylamine and formaldehyde with the compound 1 to prepare a compound 2 through a Mannich reaction;

step two: preparing a chirally pure compound 2A by splitting the compound 2;

step three: the prepared chiral pure compound 2A is methylated to prepare a compound 3;

further, the methylated reagent is methyl iodide and/or dimethyl sulfate;

step four: the compound 3 is substituted by cyano to prepare a compound 4;

further, the cyano group source is sodium cyanide, potassium cyanide and/or a cyano group-containing organic compound;

step five: hydrolyzing and deprotecting the compound 4 to obtain a compound 5;

step six: the compound 5 is subjected to cyclization to prepare a target intermediate (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one;

the cyclization reagent is hydrazine hydrate.

The method obtains the intermediate with high chiral purity by chiral resolution of the compound 2, and further obtains the 6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one with high chiral purity.

Compared with the prior art, the invention has the advantages and beneficial effects that:

1. the invention has low splitting difficulty. The existing resolution technology is based on the resolution of a target compound 6, has high resolution difficulty and low yield, basically maintains the resolution yield of about 20 percent, and is accompanied with operations such as thermal filtration and the like, or uses a more expensive resolving agent such as tartaric acid derivatives such as D-DBTA and the like for resolution. Because the resolution is carried out at the early stage (the compound 2 is resolved to obtain the compound 2A), the subsequent reaction is carried out by using a single-configuration substance, a large amount of resources are saved, and meanwhile, the reaction condition is mild, and the method is suitable for process amplification.

2. The invention has high splitting efficiency. Because the difference of the compound characteristics is large, the compound can obtain high chiral purity (more than 99%) only by salifying and crystallizing twice, and the chiral purity value of the obtained compound 6 can reach more than 99.5%. In the prior art, an expensive resolving agent is used, the chiral purity is still only about 93 percent after resolution and crystallization, and the chiral purity which can be achieved by the subsequent 1,4 dioxane crystallization process is more than 99 percent. The invention not only removes a large amount of complicated operations, but also is convenient for isomer control in the subsequent bulk drugs, and provides guarantee for safer medicine use.

3. The route of the invention does not generate racemization of chiral centers. As the chiral carbon atom does not relate to the subsequent reaction, the subsequent reaction does not generate the problem of racemization of the chiral carbon atom, and the target product 6 still has higher chiral purity which is more than 99 percent. However, in the existing similar method, chiral starting materials are used, and chiral carbon atoms participate in subsequent reactions, so that a large amount of racemate is generated in subsequent synthesis, and the obtained compound 6 has low chiral purity, and therefore, the method cannot be used for industrialization.

Drawings

FIG. 1 is a chromatogram of Compound 6 obtained after two resolution crystallizations according to the prior art.

FIG. 2 is a chromatogram of Compound 2A obtained by resolution of Compound 2 in example 1.

FIG. 3 is a chromatogram of Compound 2A obtained by resolution of Compound 2 in example 2.

FIG. 4 is a chromatogram of target compound 6 obtained by further synthesizing compound 2A in example 1.

FIG. 5 is a chromatogram of target compound 6 obtained by further synthesizing compound 2A in example 2.

Fig. 6 is an MS spectrum of the target intermediate compound 6 prepared in example 1.

Fig. 7 is a HNMR spectrum of the target intermediate compound 6 prepared in example 1.

Fig. 8 is an IR spectrum of the target intermediate compound 6 prepared in example 1.

Detailed Description

The applicants will now further describe the synthesis of the present invention in detail with reference to specific examples, but it should be understood that the following examples are only illustrative and not intended to limit the scope of the invention as claimed in the claims.

In the following examples, compound 1{ N- (4-propionylphenyl) acetamide } used was obtained from southern Sichuan scientific Co. Other raw materials are common commercial products.

Example 1: a preparation method of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one sequentially comprises the following steps:

the method comprises the following steps: preparation of N- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide

Dimethylamine hydrochloride (21g, 0.257mol) and 37% formaldehyde aqueous solution (16mL, 1.1mol) were added to the flask, stirred at room temperature, reacted for 30min, and then acetic anhydride (110mL) was added thereto, whereupon the reaction solution became an emulsion, and stirred until the reaction solution became clear. There is a significant exotherm. Compound 1(33g, 0.172mol) was added to the reaction mixture, and the mixture was reacted at 100 ℃ for 2 hours. The low boiling point substance was distilled off under reduced pressure at 60 to 65 ℃, the remaining gum was dissolved in 350mL of water, washed three times with 350mL of dichloromethane, extracted, 250mL of dichloromethane was added to the aqueous layer, neutralized to pH 10 with 2.5mol/L sodium hydroxide under cooling with cold water, the dichloromethane layer was separated, washed twice with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated by concentration to give 40g of an oily substance, that is, compound 2, in 92% yield.

Step two: preparation of (R) -N- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide

Adding 40g of compound 2 and 24.2g D-tartaric acid into a 2L mixed solvent of isopropanol/ethyl acetate (V: V ═ 1:1), heating to 70 ℃, stirring for dissolving, keeping the temperature for 30min, cooling for crystallization, and filtering after solid is precipitated. The crystallization was repeated twice to give the D-tartrate salt of Compound 2A, which was dissolved in 500mL of water and the pH was adjusted to 7.5 using aqueous ammonia. Ethyl acetate 500mL is added for extraction, and the mixture is concentrated to dryness to obtain 2A17.3g of compound with chiral purity of 99.22 percent by detection. The yield thereof was found to be 40%. The chromatogram of compound 2A is shown in FIG. 2.

Step three: preparation of (R) -3- (4-acetamidophenyl) -N, N, N, 2-tetramethyl-3-oxopropane-1-ammonium iodide

Methyl iodide (11mL, 0.16mol), oily 2A (17g), and acetone (200mL) were added to a reaction flask, stirred, allowed to react at room temperature for 5h to precipitate yellowish crystals, which were filtered and dried to give compound 3(18.7g) in a yield of 70.0% and a melting point of 206-.

Step four: preparation of (R) -N- (4- (3-cyano-2-methylpropanoyl) phenyl) acetamide

Compound 3(12.5g, 0.0321mol) was dissolved in water-methanol (water: methanol volume ratio 6:1) (150mL), sodium cyanide (4g, 0.076mol) dissolved in 100mL of water was added, nitrogen was introduced, the reaction solution became cloudy, an oil gradually precipitated, and the oil gradually formed a solid. After stirring at room temperature for 24 hours, the precipitated solid was filtered, washed with a large amount of water, dried, and recrystallized from 100mL of anhydrous ethanol to give 5.9g of Compound 4, with a yield of 80%.

Step five: preparation of (R) -4- (4-aminophenyl) -3-methyl-4-oxobutanoic acid hydrochloride

Compound 4(5g) was added to 230mL of 37 wt% concentrated hydrochloric acid and heated to 90 ℃ for reflux for 1h, a large amount of white solid was precipitated, cooled and filtered to give 5.2g of Compound 5, with a yield of 96.2%.

Step six: preparation of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one

Adding compound 5(5.2g) into 15mL of ethanol, adding hydrazine hydrate 3.5mL of 72 ℃, refluxing for 1h, generating white solid, cooling, and filtering to obtain 4.2g of white solid. The yield thereof was found to be 97%. The obtained white solid is detected by MS spectrogram, HNMR spectrogram and IR spectrogram, as shown in figure 6-8, and the chiral purity of the obtained white solid is 99.61% by detection, and the chromatogram is shown in figure 4, namely (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one.

Example 2: a preparation method of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one sequentially comprises the following steps:

Dimethylamine hydrochloride (21g, 0.257mol), 37% formaldehyde aqueous solution (21.8mL, 1.5mol) was added to the flask, stirred at room temperature, reacted for 1h, and then acetic anhydride (200mL) was added, at which time the reaction solution was in emulsion, and stirred until the reaction solution was clear. To the reaction mixture was added compound 1(33g, 0.172mol) and reacted at 120 ℃ for 2 hours. Evaporating low-boiling-point substances at 60-65 ℃ under reduced pressure, dissolving the residual jelly with 350mL of water, washing with 350mL of dichloromethane for three times, extracting, adding 250mL of dichloromethane into a water layer, neutralizing with 2.55mol/L of sodium hydroxide under the cooling of cold water until the pH value is 10, separating a dichloromethane layer, washing with saturated saline twice, drying with anhydrous magnesium sulfate, concentrating and evaporating the solvent to obtain 40g of oily substances, namely the compound 2; the yield thereof was found to be 92%.

40g of compound 2 and 49-p-dimethoxybenzoyl tartaric acid are added into a mixed solvent of 2.2L methanol/ethyl acetate (V: V ═ 1:1), the mixture is heated to 60 ℃ to be dissolved, and then cooled and crystallized, after solid is precipitated, the mixture is filtered. The crystallization was repeated twice to obtain D-p-dimethoxybenzoyl tartrate salt of compound 2A, which was dissolved in 500mL of water and the pH was adjusted to 8 using aqueous ammonia. Ethyl acetate 500mL is added for extraction, and the mixture is concentrated to dryness to obtain the compound 2A, 16g, which has chiral purity of 99.16% through detection. Detection method was carried out using a mobile phase (63% n-hexane: 36.9% ethanol: 0.1% diethylamine). A chromatographic column: xylonite OX-H250 x 4.6mm,5um. isocratic elution. The yield thereof was found to be 40%. The chromatogram of compound 2A is shown in FIG. 3.

Methyl iodide (8.8mL, 0.13mol), oily 2A (14g), and acetone (200mL) were added to a reaction flask, stirred, allowed to react at room temperature for 5h to precipitate yellowish crystals, which were filtered and dried to give compound 3(15g) in a yield of 72.0% and a melting point of 206-.

Compound 3(10g, 0.025mol) was dissolved in water-methanol (6:1) (150mL), sodium cyanide (3.2g, 0.06mol) dissolved in 100mL of water was added, and nitrogen was purged to the reaction solution to turn turbid and gradually separate out an oil which gradually became a solid. After stirring overnight at room temperature, the precipitated solid was filtered, washed with a large amount of water, dried, and recrystallized from 100ml of anhydrous ethanol to give Compound 4(4.7g) in 82% yield.

Compound 4(4.7g) was added to 180mL of 37 wt% concentrated hydrochloric acid and heated to 90 ℃ for reflux for 1h, whereupon a large amount of white solid precipitated, cooled and filtered to give 4.2g of Compound 5 with a yield of 95.7%.

Adding compound 5(4g) into 15mL of ethanol, adding hydrazine hydrate, 2.8mL of 72 ℃, refluxing for 1h, generating white solid, cooling, and filtering to obtain 3.3g of white solid. The yield thereof was found to be 94%. The obtained white solid is proved to be (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one by detection, the chiral purity is 99.54 percent by detection, and the chromatogram map is shown in figure 5.

Claims

1. A preparation method of (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one is characterized in that a target product (R) -6- (4-aminophenyl) -5-methyl-4, 5-dihydropyridazin-3 (2H) -one is synthesized by a single configurational substance compound 2A, and the name of the compound 2A is as follows: (R) -N- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide,

the structural formula is as follows:

the compound 2A is represented by compound 2: n- (4- (3- (dimethylamino) -2-methylpropanoyl) phenyl) acetamide is obtained by chiral resolution,

2. the method of claim 1, wherein the resolution step requires the addition of a resolving agent and a resolving solvent,

the resolving agent is selected from at least one of the following resolving agents: d-tartaric acid, D-p-dimethoxybenzoyl tartaric acid and D-p-dimethylbenzoyl tartaric acid;

3. The method for preparing according to claim 1 or 2, characterized in that it comprises the following steps:

the method comprises the following steps: reacting dimethylamine, formaldehyde and compound 1: reacting N- (4-propionyl phenyl) acetamide to obtain a compound 2 through a Mannich reaction;

step two: preparing a chirally pure compound 2A by splitting the compound 2;

step three: the prepared chiral pure compound 2A is methylated to prepare a compound 3: (R) -3- (4-acetamidophenyl) -N, 2-tetramethyl-3-oxopropane-1-ammonium iodide;

the methylation reagent is methyl iodide and/or dimethyl sulfate;

step four: and (3) preparing a compound 4 by cyano substitution: (R) -N- (4- (3-cyano-2-methylpropanoyl) phenyl) acetamide;

the cyano source is sodium cyanide, potassium cyanide and/or a cyano-containing organic compound;

step five: hydrolyzing and deprotecting the compound 4 to obtain a compound 5: (R) -4- (4-aminophenyl) -3-methyl-4-oxobutanoic acid hydrochloride;

the cyclization reagent is hydrazine hydrate.