CN109956886B

CN109956886B - Preparation method of ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate

Info

Publication number: CN109956886B
Application number: CN201711339196.7A
Authority: CN
Inventors: 朱强; 李云飞; 徐丹丹; 单文俊
Original assignee: Lianyungang Hengyun Pharmaceutical Co ltd
Current assignee: Lianyungang Hengyun Pharmaceutical Co ltd
Priority date: 2017-12-14
Filing date: 2017-12-14
Publication date: 2023-03-07
Anticipated expiration: 2037-12-14
Also published as: CN109956886A

Abstract

The invention discloses a preparation method of Apixaban intermediate (Z) - [ (4-methoxyphenyl) hydrazono ] ethyl chloroacetate. The product prepared by the synthesis method has the advantages of high purity, stable quality, high yield, simple synthesis process, mild reaction conditions, simple and convenient reaction operation, environmental protection and capability of meeting the requirement of industrial production of the product.

Description

Preparation method of ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate

Technical Field

The invention relates to the field of drug synthesis, in particular to a preparation method of (Z) - [ (4-methoxyphenyl) hydrazono ] ethyl chloroacetate.

Background

Apixaban, chemical name: 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6,7-tetrahydro-1H-pyrazole [3,4-c ] -pyridine-3-carboxamide, CAS:503612-47-3, structure:

apixaban is an anticoagulant agent commonly reported by the pharmaceutical company of Peui and the company of Baishimei Guibao, directly acts on coagulation factor Xa, and is used for treating venous thrombosis diseases including Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE), and the bleeding adverse reaction is lower than that of the old medicine warfarin. In 5 months 2011, the european union approved the oral factor Xa direct inhibitor apixaban (trade name Eliquis) for marketing to adult patients in elective hip or knee replacement surgery to prevent Venous Thrombosis (VTE). EMA approval was obtained at 11 months 2012, FDA and PMDA approval was obtained at 12 months 2012, respectively, for the prevention of stroke in patients with atrial fibrillation.

The ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate is an important intermediate for synthesizing apixaban, and a plurality of documents report preparation methods of the intermediate. The most reported method is to take p-methoxyaniline as a raw material to react with sodium nitrite solution in acidic solution to generate diazonium salt, and then react with ethyl 2-chloroacetoacetate under alkaline condition to generate a key intermediate (I). In document WO2003049681, the solvent used is ethyl acetate, which is a two-phase reaction due to its non-miscibility with water, with a reaction time of more than 12h producing more impurities with a yield of only 74%. The solvent adopted in the document CN101967145 is methanol, although the reaction is a homogeneous reaction, the product (Z) - [ (4-methoxyphenyl) hydrazono ] ethyl chloroacetate is insoluble in the reaction solution, a black sticky solid is obtained after the reaction, which contains many impurities, and the product purity is low, in the post-treatment process, the methanol in the reaction solution is firstly distilled off by rotation, then the ethyl acetate is used for extraction, and then the crude product is obtained after washing and drying, the post-treatment process is complicated, and the yield is only 76%. And the preparation method can generate one molar equivalent of acetaldehyde, can be further oxidized into acetic acid in water, can generate a large amount of waste liquid, and is not beneficial to environmental protection. Therefore, the preparation process of ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate, which has high yield, simple reaction and environmental protection, is urgently needed in the field.

Disclosure of Invention

The invention aims to solve the problems and provides a novel preparation process of ethyl (Z) - [ (4-methoxyphenyl) hydrazono ] chloroacetate, which comprises the following steps:

(1) Adding acid into the compound shown in the formula (II), and then adding sodium nitrite aqueous solution;

(2) Filtering to obtain filtrate;

(3) Then adding an organic solvent, sodium acetate and the compound of the formula (III) into the filtrate to prepare the compound of the formula (I);

according to the preparation method of the invention, the molar weight ratio of the compound of formula (II) to sodium nitrite is 1.2 to 2, preferably 1.

According to the preparation method, the mass fraction of the sodium nitrite is 30-40%.

According to the preparation method of the invention, the molar weight ratio of the compound of the formula (II) to the acid is 1.5-6, preferably 1:3-4.

According to the preparation method of the invention, sodium bromide is added into the step (1) before adding sodium nitrite, and the molar weight ratio of the compound shown in the formula (II) to the sodium bromide is 1:0.01 to 0.1. The sodium nitrite is added in batches, and the total amount of the sodium nitrite is one tenth of the total amount of the sodium nitrite.

According to the preparation process of the present invention, the acid is selected from hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably dilute sulfuric acid.

According to the preparation method, the concentration of the sulfuric acid is 2-6mol/L.

According to the production method of the present invention, the reaction temperature in the step (1) and the step (3) is-10 to 20 ℃, preferably 0 to 20 ℃.

According to the preparation method, the reaction solvent in the step (1) is water, the reaction solvent in the step (3) is a mixed solvent of ethanol and diethyl ether, and the volume ratio of the ethanol to the diethyl ether is 1:1 to 3.

According to the preparation method of the invention, the weight-to-volume ratio of the compound of the formula (II) to the mixed solvent of ethanol and diethyl ether is 1:5-15, preferably 1:7-12, and the unit is g/mL.

According to the preparation method of the invention, the molar weight ratio of the sodium acetate to the compound of the formula (II) is 2-5: 1.

according to the preparation method of the invention, the molar weight ratio of the compound of the formula (II) to the compound of the formula (III) is 1:1 to 1.5.

In order to reduce the generation of waste materials, ethyl chloroacetate is selected as a reactant instead of ethyl chloroacetoacetate. Meanwhile, the preparation process is optimized, conditions such as reaction reagents, solvents, temperature and the like are screened, and the prepared target compound is high in yield and good in purity and meets pharmaceutical requirements.

Detailed Description

Example 1

P-methoxyaniline (0.1mol, 12.3 g), sulfuric acid (75mL, 2mol/L) are added and stirred until dissolved, sodium bromide (1mmol, 1mg) is added at the temperature of 20 ℃, sodium nitrite solution (0.12mol, 13mL) with the concentration of 40% is added in portions at the temperature of below 5 ℃, after stirring for 20 minutes under heat preservation, filtration is carried out, the temperature is raised to 20 ℃, chloroacetoacetic acid (0.1mol, 12.2g), sodium acetate (0.25mol, 20.5 g) and 100mL of ethanol/ether mixed solution (1:1) are added into the filtrate, stirring reaction is continued for 2 hours, the filtrate is poured into 200mL of ice water to precipitate solid, and the solid is filtered, washed by water and dried to obtain 23.1g of solid with the yield of 90% and the HPLC purity of 98.3%.

MS(ESI)：256.9[M+H] ⁺ .

¹ H NMR(CDCl ₃ )δ：8.28(s，1H)，7.23(d，2H)，6.96(d，2H)，4.38(q，2H)，3.83(s，3H)，1.37(t，3H)。

Example 2

P-methoxyaniline (0.1mol, 12.3g), sulfuric acid (40mL, 4 mol/L) are added, stirring is carried out until dissolution is achieved, the temperature is controlled at 10 ℃, sodium bromide (1mmol, 2mg) is added, the temperature is controlled below 5 ℃, 40% sodium nitrite solution (0.12mol, 13mL) is added in portions, stirring is carried out for 20 minutes under heat preservation, filtration is carried out, the temperature is raised to 10 ℃, chloroacetoacetic acid (0.11mol, 15.2mL), sodium acetate (0.25mol, 20.5g), 150mL of ethanol/ether mixed solution (1:2) are added to the filtrate, stirring and reaction is carried out for 3 hours, the mixture is poured into 400mL of ice water, solid is precipitated, filtered, washed with water and dried, 23.7g of solid is obtained, the yield is 92.3%, the purity HPLC is 98.1%, and the mass spectrum and the hydrogen spectrum are consistent with example 1.

Example 3

P-methoxyaniline (0.1mol, 12.3g), hydrochloric acid (40mL, 4 mol/L) were added, the mixture was stirred until dissolved, the temperature was controlled at 5 ℃ or lower, 40% sodium nitrite solution (0.12mol, 13mL) was added in portions, the mixture was stirred at constant temperature for 1 hour, then the temperature was raised to 10 ℃ and chloroacetoacetic acid (0.111mol, 15.2mL), sodium acetate (0.25mol, 20.5g) and 100mL of a mixed solution of ethanol and water (1:2) were added, the reaction was continued for 4 hours, the mixture was poured into 200mL of ice water to precipitate a solid, and the solid was filtered, washed with water and dried to obtain 17.9g of a solid, a yield of 69.7%, an HPLC purity of 82.6%, and a mass spectrum and a hydrogen spectrum were identical to those of example 1.

Claims

1. A process for the preparation of a compound of formula (I) comprising the steps of,

(2) Filtering to obtain filtrate;

(3) Then adding an organic solvent, sodium acetate and a compound shown in a formula (III) into the filtrate to prepare a compound shown in a formula (I);

the preparation method also comprises the following step of adding sodium bromide into the step (1) before adding the sodium nitrite, wherein the molar weight ratio of the compound shown in the formula (II) to the sodium bromide is 1:0.01 to 0.1.

2. The preparation process according to claim 1, characterized in that the molar weight ratio of the compound of formula (II) to sodium nitrite is 1.2 to 2.

3. The production method according to claim 2, characterized in that the molar weight ratio of the compound of formula (II) to sodium nitrite is 1.2 to 1.5.

4. The production method according to claim 1, characterized in that the mass fraction of the sodium nitrite is 30 to 40%.

5. The process according to claim 1, wherein the molar weight ratio of the compound of formula (II) to the acid is 1.

6. The process according to claim 5, wherein the molar weight ratio of the compound of formula (II) to the acid is 1:3 to 4.

7. The process according to claim 1, wherein the acid is hydrochloric acid, sulfuric acid or trifluoroacetic acid.

8. The method of claim 7, wherein the acid is sulfuric acid.

9. The production method according to claim 8, wherein the concentration of the sulfuric acid is 2 to 6mol/L.

10. The production method according to claim 1, wherein the reaction temperature in the step (3) is-10 to 20 ℃.

11. The production method according to claim 10, characterized in that the reaction temperature in the step (3) is 10 to 20 ℃.

12. The production method according to claim 1, characterized in that the organic solvent in the step (3) is a mixed solvent of ethanol and diethyl ether.

13. The process according to claim 12, wherein the volume ratio of ethanol to diethyl ether is 1:1 to 3.

14. The process according to claim 1, wherein the molar weight ratio of sodium acetate to the compound of formula (II) in step (3) is from 2 to 5:1.