WO2014139410A1

WO2014139410A1 - Method for preparing intermediate of azelnidipine

Info

Publication number: WO2014139410A1
Application number: PCT/CN2014/073222
Authority: WO
Inventors: 徐�明
Original assignee: 沈阳中海药业有限公司
Priority date: 2013-03-14
Filing date: 2014-03-11
Publication date: 2014-09-18
Also published as: CN103130700B; CN103130700A

Abstract

Disclosed is a method for preparing 3-amino-3-iminopropanoic acid-1-(diphenylmethyl)-3-azetidinyl ester acetate used as intermediate of azelnidipine. In such method, 1-diphenylmethyl-3-azetidin-ol and cyano acetic acid used as raw materials, is subjected to the four steps of esterification, Pinner reaction, neutralization, and amidination to generate 3-amino-3-iminopropanoic acid-1-(diphenylmethyl)-3-azetidinyl ester acetate. By selecting suitable solvents and reaction conditions, the method has the advantages of mild reaction conditions, simple post-treatment and high reaction yield.

Description

Preparation method of adipinepine intermediate

The invention belongs to the technical field of medicine and provides an important intermediate of dihydropyridine calcium antagonist adipine, 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidine The synthesis process of ester acetate. Background technique

Azelnidipine is a new type of dihydropyridine calcium channel blocker developed by Sankyo and Ube Industries of Japan. It was approved for sale in Japan in late May 2003 under the trade name Calblock. Adipine has a selective blockade of calcium channels in arterial smooth muscle cells, it can dilate blood vessels, reduce peripheral vascular resistance and arterial pressure, and is widely used clinically for mild or moderate essential hypertension, renal disorders with hypertension And treatment of severe hypertension. Compared with nicardipine and nifedipine dihydropyridine calcium channel blockers, adipine is superior in selectivity, long-lasting and long-lasting, and has little effect on the heart.

A flat floor structure

At present, references to the preparation of agdipine include: European patents EP0266922; Chinese patent CN201010516967.7; Chinese Journal of Medicinal Chemistry, 2010, 20 (3): 192-194; Chinese Journal of Pharmaceutical Industry, 2008, 39 (3): 163-165; Chemical Industry and Engineering, 2009, 26 ( 1 ): 15-18; Qilu Pharmacy, 2005, 24 (6): 365-366. The preparation method of adipine in these literatures is based on the reaction of epichlorohydrin and diphenylamine with N-alkylation, cyclization, esterification, Pinner synthesis, neutralization, and oxime reaction. The intermediate 3-amino-3-iminopropionic acid-1-(diphenylfluorenyl)-3-azetidinyl acetate is prepared first, followed by 2-(3-nitrobenzylidene)acetyl Acepinedipine was obtained by the Hantzsch condensation of isopropyl acetate.

The control of the solvent and reaction conditions in the esterification, Pinner synthesis and neutralization three-step reaction in this route is critical. Using the preparation methods provided by these documents, we found that the operation was cumbersome and the yield and purity were not satisfactory.

In the esterification reaction, according to the method specifically reported in the above literature, the highest yield of the obtained product is only 85%, and the purity is poor, it is difficult to purify, and it is difficult to obtain a solid product.

We have found that 3-amino-3-iminopropionic acid-1- (3) is prepared by a three-step reaction from cyanoacetate-1-diphenylhydrazin-3-azetidinyl ester (3) according to the method specifically reported in the above literature. Diphenylhydrazino)-3-azetidinyl acetate (6), the reaction operation is cumbersome, and it is easy to produce by-products of hydrolysis of ester bonds and hydrolysis of imid bonds (7) and (8), three-step reaction. The total yield is only 20~30%, and the purification of the product is difficult, which seriously affects the quality of the final product and greatly increases the production cost.

Byproducts (7) and (8) structural formula Summary of the invention

SUMMARY OF THE INVENTION It is an object of the present invention to provide a process for the preparation of the key intermediate of adipine, 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidinyl acetate. The adipine intermediate of the present invention 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidinyl acetate acetate has the following structural formula:

The preparation method of 3-amino-3-iminopropionic acid-1-(diphenylindenyl)-3-azetidinyl acetate of the present invention comprises the following steps: 1) Esterification: 1-diphenylhydrazin-3-azetidinol (2), cyanoacetic acid (1) and N,N-dicyclohexylcarbodiimide (DCC) in organic solvent at 0~ Reacting at 80 ° C, to obtain 7-diphenylindolyl-3-azetidinyl cyanoacetate (3);

2) Pinner reaction: Add intermediate (3), absolute ethanol to dichlorosilane, stir and cool

To -20~25 °C, dry hydrogen chloride gas is passed, and then the reaction solution is kept sealed at -20~25 °C to obtain 3-imino-3-ethoxypropionic acid-1-(diphenylfluorenyl) -3-azetidinyl ester hydrochloride (4);

3) Neutralization reaction: The intermediate (4) is dissolved in dichloromethane, and the base is added at -5 to 25 ° C to obtain 3-imino-3-ethoxypropionic acid-1-(diphenylhydrazine). Benzyl-3-azetidinyl ester (5);

4) Formation reaction: The intermediate (5) is dissolved in acetonitrile, ammonium acetate is added, and the temperature is raised to 40 to 60 ° C to obtain 3-amino-3-iminopropionic acid-1-(diphenylfluorenyl)-3. - azetidinium acetate compound (6). detailed description

On the basis of the above-mentioned contents, various modifications, alterations or changes can be made without departing from the basic technical scope of the invention.

As a preferred preparation method of the present invention, the following steps are included:

1) Esterification: 1-diphenylhydrazin-3-azetidinol (2), cyanoacetic acid (1) and N,N-dicyclohexane

The carbodiimide (DCC) is reacted in an organic solvent at 0 to 80 ° C for 0.5-11 hours. After cooling, suction filtration, the filtrate is washed with alkali, washed with water, dried and evaporated to dryness to give cyanoacetate-1-diphenylhydrazino-3-azetidinyl ester (3).

Wherein the organic solvent is selected from the group consisting of acetone, dichlorodecane, diethyl ether, chloroform, ethyl acetate, and acetic acid

One or a mixture of one or more of propyl ester, toluene, n-hexane, and acetonitrile. These organic solvents are good solvents for 1,3-dicyclohexylurea (DCU) and a good solvent for the product cyanoacetate-1-diphenylindol-3-azetidine, which is at 0°. The solubility of the solute at C is greater than 30 g/100 mL, and the poor solvent is such that the solubility of the solute is less than lg/100 mL at 0 °C.

A preferred organic solvent is one selected from the group consisting of dichlorosilane, chloroform, diethyl ether, ethyl acetate, toluene, acetonitrile or a mixed solvent of one or more.

The alkaline water is a saturated sodium bicarbonate solution.

To -20~25 °C, dry hydrogen chloride gas is passed for 0.5~10h, then the reaction solution is kept sealed at -20 25 °C for 1~48h, and the solvent is distilled off to obtain 3-imino-3-ethoxypropane. Acid-1-(diphenylindenyl)-3-azetidinium hydrochloride (4).

3) Neutralization reaction: The intermediate (4) is dissolved in dichloromethane, and the base is added at -5 to 25 ° C, stirred for 1.5 to 5 hours, suction filtered, and the solvent is distilled off to obtain 3-imino-3. - ethoxypropionic acid-1-(diphenylhydrazinyl)-3-azetidinyl ester (5).

Wherein the base is selected from one of an organic base and an inorganic base.

The organic base is

Wherein RR ² and R ³ are independently selected from the group consisting of hydrogen, dC ₄ alkyl, phenyl, phenyl dC ₄ alkyl, with the proviso that R ¹ R ² and R ^{3 are} not hydrogen at the same time.

Preferred organic bases are selected from the group consisting of decylamine, ethylamine, propylamine, decylamine, diethylamine, decylamine, triethylamine, aniline, N-mercaptoaniline, diisopropylethylamine, hydrazine, hydrazine-di Mercaptoaniline, ethylenediamine.

More preferred organic bases are selected from the group consisting of diamine, diethylamine, triethylamine, aniline, ethylenediamine. It refers to an organic base C _r C ₄ primary amines, aromatic primary amines, symmetric or asymmetric C _r C ₄ secondary amine, symmetrical or asymmetrical aromatic primary amine, symmetrical or asymmetrical tertiary C _r C _4, symmetric or asymmetric Aromatic tertiary amine, aliphatic diamine.

The inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide and potassium hydroxide.

The base is added so that the pH of the solution is from 7 to 10, preferably from 7 to 8.

4) Formation reaction: Intermediate (5) Dissolve in acetonitrile, add ammonium acetate, and heat up to 40~60 °C

After 0.5 to 10 hours, it is cooled, suction filtered, and dried to give 3-amino-3-iminopropionic acid-1-(diphenylhydrazinyl)-3-azetidinium acetate compound (6).

The present invention uses an organic base in the neutralization reaction, which reduces side reactions and improves product purity and yield. Preparation of an important intermediate of adipinepine using the method of the invention 3-amino-3-iminopropionic acid -1- (diphenylhydrazine)

Benzyl azetidine acetate, which can simplify the operation process and improve product yield and purity. The total yield of the three-step reaction is 73.1% based on the intermediate 3, and the product purity is 99.5%. The next step is to reduce production costs and shorten the reaction cycle, which is important in industrial production. Next, the above content of the present invention will be further described in detail by the following description of specific embodiments. It should be understood by those skilled in the art that the scope of the above-mentioned subject matter of the present invention is limited to the following description of the method; the technology implemented based on the above-mentioned contents of the present invention is within the scope of the present invention.

Example

1. Preparation of cyanoacetic acid-1-diphenylhydrazine-3-azetidine (esterification)

Method 1: Add 1-diphenylhydrazin-3-azetidinol (2, 235 g, 0.983 mol) and cyanoacetic acid (1, 100 g, 1.18 mol) to 1.5 mL of dichloromethane, and stir until fully dissolved. Ν, Ν-dicyclohexylcarbodiimide (DCC, 243 g, 1.18 mol) was added at 0-10 ° C and allowed to react at room temperature for 3 h. After the completion of the reaction, the reaction mixture was cooled to 0 to 5 ° C, and filtered, filtered, washed with a small portion of dichloromethane. The organic solvent was evaporated to dryness under reduced pressure and dried to give 275 g of white solid.

Method 2: chloroform was used as the reaction solvent, and the operation was the same as above, and the reaction was carried out at 55 ° C for 5 hours, the HPLC purity was 98.7%, and the product yield was 95.3%.

Method 3: Ethyl acetate was used as the reaction solvent, and the operation was the same as above, and the reaction was carried out at 55 ° C for 2 h, the HPLC purity was 98.9%, and the product yield was 96.1%.

Method 4: Using hydrazine as the reaction solvent, the operation was the same as above, and the reaction was carried out at 55 ° C for 7 h, the HPLC purity was 98.5%, and the product yield was 94.7%. 2. Preparation of 3-imino-3-ethoxypropionic acid-1-(diphenylfluorenyl)-3-azetidinyl ester hydrochloride (Pinner reaction)

Intermediate 3 (270 g, 0.882 mol), absolute ethanol (61.8 mL, 1.06 mol) was added to 1.5 L of dry dichloromethane, cooled to -5 to 0 ° C in a water salt bath, and dried. HC1 gas for 2.5 h, after the completion of the aeration, the reaction solution was kept under stirring at 0 ° C for 6 h.

Allow to stand overnight at 0-4 °C. After completion of the reaction, the solvent was evaporated under reduced pressure to give an oily viscous intermediate 4 .

3. Preparation of 3-imino-3-ethoxypropionic acid-1-(diphenylfluorenyl)-3-azetidinyl ester

Method 1: Add 1.4 L of dichloromethane to Intermediate 4, cool to 0-5 ° C, add dry diethylamine (182 mL, 1.76 mol) to the solution, adjust pH 7-8, continue to stir after the dropwise addition. 2h. The mixture was suction filtered, and the filtrate was evaporated to dryness vacuo.

Method 2: Diamine is used for neutralization, and the operation is the same as above.

Method 3: Triethylamine is used for neutralization, and the operation is the same as above.

Method 4: Ethylenediamine is used for neutralization, and the operation is the same as above.

Method 5: Add 1.4 L of dichloromethane to Intermediate 4, cool to 0-5 ° C, add potassium carbonate (242.88 g, 1.76 mol) to the solution in portions, adjust pH 7-8, continue stirring for 2 h. . The mixture was suction filtered, and the filtrate was evaporated to dryness vacuo. Method 6: Neutralize with sodium carbonate, and operate as above.

Method 7: Neutralize with sodium hydroxide, and operate as above.

4. Preparation of 3-amino-3-iminopropionic acid-1-(diphenylindenyl)-3-azetidinyl acetate (formed into 脒)

To the intermediate 5, 1.2 L of acetonitrile was added, and after dissolution, ammonium acetate (68.0 g, 0.882 mol) was added, and the mixture was heated to 55 ° C for 6 h. After the reaction, it was naturally cooled, crystallization, suction filtration, acetonitrile washing cake, and dried to give 236 g of a white solid. The total yield of the three-step reaction was 69.9 73.1%.

Claims

claims

1. A method for preparing 3-amino-3-iminopropionic acid-1-(diphenylmethyl)-3-azetidinyl acetate, which is characterized in that it includes the following steps:

1) Esterification reaction: 1-diphenylmethyl-3-azetidinol (2), cyanoacetic acid (1) and N, N-dicyclohexylcarbodiimide (DCC) in an organic solvent at 0~ React at 80°C to obtain cyanoacetic acid-7-diphenylmethyl-3-azetidine ester (3);

2) Pinner reaction: Add intermediate (3) and absolute ethanol to dichloromethane, stir and cool.

to -20~25°C, pass dry hydrogen chloride gas, and then continue to seal and stir the reaction solution at -20~25°C to obtain 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl) ) -3-Azetidinyl hydrochloride (4);

3) Neutralization reaction: Dissolve intermediate (4) in dichloromethane, add alkali at -5~25°C to obtain 3-imino-3-ethoxypropionic acid-1-(diphenylmethane) base) -3-azetidinyl ester (5);

4) Reaction to form amidine: Intermediate (5) is dissolved in acetonitrile, ammonium acetate is added, and the temperature is raised to 40~60°C for reaction to obtain 3-amino-3-iminopropionic acid-1-(diphenylmethyl)-3 -Azetidine acetate compound (6).

2. A method for preparing 3-amino-3-iminopropionic acid-1-(diphenylmethyl)-3-azetidinyl acetate, which is characterized in that it includes the following steps:

1) Esterification reaction: 1-diphenylmethyl-3-azetidinol (2), cyanoacetic acid (1) and N, N-dicyclohexylcarbodiimide (DCC) in an organic solvent at 0~ React at 80°C for 0.5-11 hours. After the reaction is completed, cool down, filter with suction, wash the filtrate with alkaline water, wash with water, dry and evaporate the solvent to obtain ethyl cyanide. Acid-1-diphenylmethyl-3-azetidine (3);

to -20~25°C, pass dry hydrogen chloride gas for 0.5~10h, and then continue to seal and stir the reaction solution at -20~25°C for 1~48h, evaporate the solvent to obtain 3-imino-3-ethoxypropane Acid-1-(diphenylmethyl)-3-azetidine hydrochloride (4);

3) Neutralization reaction: Dissolve intermediate (4) in dichloromethane, add alkali at -5~25°C, stir for 1~5h, filter with suction, and evaporate the solvent from the filtrate to obtain 3-imino-3 -Ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine ester (5);

4) Reaction to form amidine: Intermediate (5) is dissolved in acetonitrile, ammonium acetate is added, and the temperature is raised to 40~60°C for reaction.

0.5~10 hours, cool, filter and dry to obtain 3-amino-3-iminopropionic acid-1-(diphenylmethyl)-3-azetidinyl acetate acetate compound (6).

3. The preparation method according to claim 1, characterized in that: in the esterification reaction, the organic solvent is selected from the group consisting of acetone, dichloromethane, diethyl ether, chloroform, ethyl acetate, isopropyl acetate, One or more mixed solvents from toluene, n-hexane, and acetonitrile.

4. The preparation method according to claim 1, characterized in that: in the esterification reaction, the organic solvent is selected from dichloromethane, chloroform, diethyl ether, ethyl acetate, toluene, and acetonitrile. one or more mixed solvents.

5. The preparation method according to claim 1, characterized in that: in the neutralization reaction, the base is selected from one of organic bases and inorganic bases;

6. The preparation method according to claim 1, characterized in that: wherein, in The organic base described in the reaction is NR^I^R ³ ;

in,

RR ² and R ³ are independently selected from hydrogen, dC ₄ alkyl, phenyl, phenyl Ci-C ₄ alkyl, provided that R ¹ R ² and R ³ are not hydrogen at the same time.

7. The preparation method according to claim 1, characterized in that: wherein the organic base in the neutralization reaction is selected from the group consisting of methylamine, ethylamine, propylamine, dimethylamine, diethylamine, methylethylamine, and triethylamine. Ethylamine, aniline, N-methylaniline, diisopropylethylamine, N,N-dimethylaniline, ethylenediamine.

8. The preparation method according to claim 1, characterized in that: in the neutralization reaction, the organic base is selected from the group consisting of dimethylamine, diethylamine, triethylamine, aniline, and ethylenediamine.

9. The preparation method according to claim 1, wherein: in the neutralization reaction, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide. .

10. The preparation method according to claim 1, characterized in that: the alkali added in the neutralization reaction causes the pH of the solution to be 7-10.

11. The preparation method according to claim 1, characterized in that: the alkali added in the neutralization reaction causes the pH of the solution to be 7-8.

12. The preparation method according to claim 1, characterized in that: comprising the following steps:

Add 0.983mol 1-diphenylmethyl-3-azetidinol and 1.18mol cyanoacetic acid to 1.5L of dichloromethane, and add 1.18mol N,N-dicyclohexylcarbodiimide while maintaining 0-10°C. Reaction, after the reaction is completed, cool the reaction solution to 0-5°C, filter with suction, and rinse the filter cake with a small amount of dichloromethane. Wash, the filtrate is washed with saturated sodium bicarbonate solution, and then washed with water. The organic layer is separated and dried with anhydrous sodium sulfate. The organic solvent is evaporated to dryness under reduced pressure. After drying, a white solid cyanoacetic acid-1-diphenylmethyl-3-nitrogen is obtained. heterocyclobutyl ester;

Add 0.882 mol of 1-diphenylmethyl-3-azetidine cyanoacetate and 1.06 mol of absolute ethanol to 1.5 L of dry dichloromethane, and cool to -5~0°C in a water-salt bath. , add dry HC1 gas. After the ventilation is completed, keep the reaction solution below 0°C and stir the reaction to obtain an oily viscous substance 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3 -Azetidinyl hydrochloride, add 1.4L dichloromethane to 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidinyl hydrochloride alkane, cool to 0-5°C, add dry 1.76 mol diethylamine dropwise to the solution, adjust the pH to 7-8, and continue stirring after the dropwise addition, to obtain a white solid 3-imino-3-ethoxypropionic acid-1 - (Diphenylmethyl)-3-azetidine ester,

Add 1.2L acetonitrile to 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine, add 0.882mol ammonium acetate, heat to 55°C to react, react After completion, a white solid was obtained.

13. The preparation method according to claim 1, characterized in that: comprising the following steps:

Add 0.983 mol 1-diphenylmethyl-3-azetidinol and 1.18 mol cyanoacetic acid to 1.5 L of dichloromethane, stir until fully dissolved, and add 1.18 mol N, N-bicyclo while maintaining 0-10°C. Hexylcarbodiimide, react at room temperature for 3 hours. After the reaction is completed, cool the reaction solution to 0-5°C, filter with suction, rinse the filter cake with a small amount of dichloromethane, wash the filtrate with saturated sodium bicarbonate solution, and then wash with water. The organic layer was separated and dried over anhydrous sodium sulfate, and the organic solvent was evaporated to dryness under reduced pressure. After drying, white solid 1-diphenylmethyl-3-azetidinyl cyanoacetate was obtained; Add 0.882 mol of 1-diphenylmethyl-3-azetidine cyanoacetate and 1.06 mol of absolute ethanol to 1.5 L of dry dichloromethane, and cool to -5~0°C in a water-salt bath. , vent dry HC1 gas for 2.5h. After the aeration is complete, keep the reaction solution below 0°C and stir for 6h. Let it stand at 0-4°C overnight. After the reaction is completed, the solvent is evaporated under reduced pressure to obtain an oily viscous substance 3- Imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine hydrochloride,

Add 1.4L dichloromethane to 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine hydrochloride and cool to 0-5°C. Add 1.76 mol of dry diethylamine dropwise to the solution, adjust the pH to 7-8, and continue stirring for 2 hours after the dropwise addition. Suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain white solid 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine ester.

Add 1.2L acetonitrile to 3-imino-3-ethoxypropionic acid-1-(diphenylmethyl)-3-azetidine. After dissolving, add 0.882mol ammonium acetate and heat to 55°C for reaction. After 6 hours, the reaction was completed, cooled naturally, crystallized, filtered with suction, washed the filter cake with acetonitrile, and dried to obtain a white solid.