阅读说明：本技术 一种升压素v2受体拮抗剂的中间体的制备方法 (Preparation method of intermediate of vasopressin V2 receptor antagonist ) 是由 朱玉成 郑礼康 葛李薇 廖娟 周旭 王华萍 柴雨柱 徐丹 朱春霞 于 2020-05-25 设计创作，主要内容包括：本发明涉及一种升压素V2受体拮抗剂的中间体的制备方法,包括将2-甲基-4-氨基苯甲酸与邻甲基苯甲酰氯在N-甲基吡咯烷酮或2-吡咯烷酮中反应的步骤。本发明提供的方法能够高收率、高纯度地制备得到目标产物,而且反应不需要加入催化剂碱性物质,减少了试剂的使用,节约生产成本,适合工业化应用。(The invention relates to a preparation method of an intermediate of a vasopressin V2 receptor antagonist, which comprises the step of reacting 2-methyl-4-aminobenzoic acid with o-methylbenzoyl chloride in N-methylpyrrolidone or 2-pyrrolidone. The method provided by the invention can prepare the target product with high yield and high purity, and the reaction does not need to add a catalyst alkaline substance, so that the use of reagents is reduced, the production cost is saved, and the method is suitable for industrial application.)

1. A process for preparing a compound of formula II, the route is as follows:

reacting a compound of formula VI with a compound of formula V in an organic solvent to produce a compound of formula II, wherein the organic solvent is selected from N-methylpyrrolidone or 2-pyrrolidone, preferably N-methylpyrrolidone.

2. The method of claim 1, wherein the mass ratio of the compound of formula VI to the organic solvent is 1: 2-1: 8; preferably, the mass ratio of the compound of formula VI to the organic solvent is 1: 3-1: 6; more preferably, the mass ratio of the compound of formula VI to the organic solvent is 1: 3-1: 4.

3. the method of claim 1, wherein no catalyst is added to the reaction.

4. The method according to claim 1, wherein the reaction temperature of the reaction is 20-60 ℃; preferably 25 to 35 ℃.

5. The method of claim 1, wherein the post-processing of the reaction comprises: adjusting the pH of the reaction solution to be more than 10 by using an alkaline solution; adding dichloromethane or ethyl acetate for extraction; liquid separation; adjusting the pH of the water phase to below 7 by using an acid solution; stirring for crystallization, filtering and drying to obtain the product.

6. The method according to claim 5, wherein the alkaline solution in the post-treatment step is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution.

7. The method according to claim 5, wherein the acidic solution in the post-treatment step is selected from the group consisting of an aqueous hydrochloric acid solution, an aqueous hydrobromic acid solution, an aqueous phosphoric acid solution and an aqueous acetic acid solution; preferably aqueous hydrochloric acid or aqueous hydrobromic acid; more preferably an aqueous hydrochloric acid solution.

8. The process of claim 1, wherein the compound of formula V is prepared by: reacting o-methylbenzoic acid with thionyl chloride in an organic solvent or without a solvent, wherein the reaction temperature is 50-70 ℃, preferably 55-65 ℃, and after the reaction is finished, decompressing and evaporating to dryness to obtain the compound I; the organic solvent is selected from toluene or xylene.

9. The process of claim 8, wherein the compound of formula V is prepared by: reacting o-methylbenzoic acid with thionyl chloride under the condition of no addition of a solvent, wherein the reaction temperature is 50-70 ℃, preferably 55-65 ℃, and after the reaction is finished, decompressing and evaporating to dryness to obtain the methyl benzoate.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of an intermediate of a vasopressin V2 receptor antagonist.

Background

Tolvaptan is the first oral previtan drug in the world, and an oral dosage form selective vasopressin V2 receptor antagonist developed by Otsuka Pharm pharmaceutical company of Japan is approved by the United states FDA on 5/19 th 2009, and is the only drug approved for treating hyponatremia at present and the first and only V2 receptor antagonist in the Chinese market. Through the action of the antagonistic vasopressin, the water excretion in urine is increased, the clearance rate of free water is improved, and the osmotic pressure of urine is reduced, so that the blood sodium value is increased, but the urine sodium potassium secretion is not changed, and the blood potassium value is not influenced. Can be used for treating fluid retention, edema, hyponatremia, etc. caused by congestive heart failure, liver cirrhosis, etc. In addition, tolvaptan can reduce the occurrence and growth of renal polycythemia, so that the disease course of polycystic kidney is slowed down, and the tolvaptan is the first therapeutic drug aiming at the pathogenesis of polycystic kidney.

Tolvaptan (Tolvaptan), trade name Samsca, chemical name N- [4- [ (5R) -7-chloro-5-hydroxy-2, 3,4, 5-tetrahydro-1-benzazepin-1-formyl ] -3-methylphenyl ] -2-methylbenzamide, having the structure shown below:

2-methyl-4- (2-methylbenzamido) benzoic acid is an intermediate for the synthesis of tolvaptan. Patent documents CN2013000368444.6 and cn201711349574.x disclose a synthesis method of the intermediate, which adopts the condensation reaction of 2-methyl-4-aminobenzoic acid and o-methylbenzoyl chloride in solvents such as tetrahydrofuran, 1, 4-dioxane, acetone, chloroform or diethyl ether under the catalysis of alkali.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of the prior art and provide the method for preparing the 2-methyl-4- (2-methylbenzamido) benzoic acid, the method can prepare the target product with high yield and high purity, and the reaction does not need to add a catalyst alkaline substance, so that the use of the reagent is reduced, the production cost is saved, and the method is suitable for industrial application.

The invention provides a preparation method of a compound shown as the following formula II, which comprises the following steps:

reacting a compound of formula VI with a compound of formula V in an organic solvent to produce a compound of formula II, wherein the organic solvent is selected from N-methylpyrrolidone or 2-pyrrolidone.

In some embodiments, the mass ratio of the compound of formula VI to the organic solvent is 1: 2-1: 8; in some typical embodiments, the mass ratio of the compound of formula VI to the organic solvent is 1: 3-1: 6; in some more typical embodiments, the mass ratio of the compound of formula VI to the organic solvent is 1: 3-1: 4.

in some embodiments, the organic solvent is N-methylpyrrolidone.

In some embodiments, no catalyst is added to the reaction.

In some embodiments, the reaction temperature of the reaction is 20 to 60 ℃; preferably 25 to 35 ℃.

In some embodiments, the post-treatment of the reaction comprises: adjusting the pH of the reaction solution to be more than 10 by using an alkaline solution; adding dichloromethane or ethyl acetate for extraction; liquid separation; adjusting the pH of the water phase to below 7 by using an acid solution; stirring for crystallization, filtering and drying to obtain the product.

In some embodiments, the alkaline solution in the post-treatment step is an aqueous sodium hydroxide solution or an aqueous potassium hydroxide solution. Any concentration of alkaline solution can be used in the present invention, preferably 5 to 30%, more preferably 21%.

In some embodiments, the acidic solution in the post-treatment step is selected from aqueous hydrochloric acid, aqueous hydrobromic acid, aqueous phosphoric acid, or aqueous acetic acid; preferably aqueous hydrochloric acid or aqueous hydrobromic acid; more preferably an aqueous hydrochloric acid solution. Any concentration of acidic solution can be used in the invention, and 1-10 mol/L is preferred; more preferably 2-8 mol/L; more preferably 4 mol/L.

In some embodiments, the compound of formula V is prepared by the following method: reacting o-methylbenzoic acid with thionyl chloride in an organic solvent or without a solvent, wherein the reaction temperature is 50-70 ℃, preferably 55-65 ℃, and after the reaction is finished, carrying out reduced pressure concentration to obtain the compound; the organic solvent is selected from toluene or xylene.

In some typical embodiments, the compound of formula V is prepared by: reacting o-methylbenzoic acid with thionyl chloride under the condition of no addition of a solvent, wherein the reaction temperature is 50-70 ℃, preferably 55-65 ℃, and after the reaction is finished, carrying out reduced pressure concentration to obtain the compound.

In some more typical embodiments, the present invention provides a method for preparing a compound of formula II, comprising: reacting o-methylbenzoic acid with thionyl chloride in an organic solvent or without a solvent to prepare a compound shown in the formula V, preferably without a solvent, wherein the reaction temperature is 50-70 ℃, preferably 55-65 ℃, and after the reaction is finished, carrying out reduced pressure concentration to obtain the compound; adding the compound of the formula V into an N-methyl pyrrolidone or 2-pyrrolidone solution of the compound of the formula VI, preferably N-methyl pyrrolidone, reacting at 20-60 ℃, preferably 25-35 ℃, and adjusting the pH of a reaction solution to be more than 10 by using an alkaline solution after the reaction is completed; adding dichloromethane or ethyl acetate for extraction; liquid separation; adjusting the pH of the water phase to below 7 by using an acid solution; stirring for crystallization, filtering and drying to obtain the product.

The preparation method of the compound shown in the formula II has the advantages that the target compound can be prepared with high yield and high purity, the reaction time is short, a catalyst is not required to be added into a reaction system, the use of reagents is reduced, and the preparation method is suitable for industrial application.

Description of the related Art

When the concentration is represented by "%", it means mass percent concentration.

N：mol/L

Drawings

FIG. 1 is an HPLC chromatogram of the product obtained in example 2

FIG. 2 is an HPLC chromatogram of the product obtained in comparative example 1

Detailed Description

The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.

HPLC detection method:

chromatographic conditions

A chromatographic column: a chromatographic column: kromasil C18(4.6 mm. times.250 mm, 5 μm);

column temperature: 30 ℃;

flow rate: 1.0 ml/min;

detection wavelength: 254 mn;

mobile phase: phase A-0.1% phosphoric acid solution

Phase B-acetonitrile

The gradient elution was as follows:

time (min)	Mobile phase A (%)	Mobile phase B (%)
			0	80	20
25	30	70
			33	30	70
33.1	80	20
			40	80	20

Example 1

466g of o-methylbenzoic acid and 816g of thionyl chloride are added into a reaction bottle, the reaction is carried out at 55-65 ℃ until the end point, the reaction product is concentrated under reduced pressure, and then the concentrated product is added into 466g of N-methylpyrrolidone (1.92Kg) suspension of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, the pH value is adjusted to be more than 10 by using 21% sodium hydroxide aqueous solution, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain compound of formula II with yield of 95.8% and HPLC purity of 99.3%.

Example 2

Adding 7.50kg of o-methylbenzoic acid and 13.10kg of thionyl chloride into a reaction bottle, reacting at 55-65 ℃ until the end point, concentrating under reduced pressure, and adding the concentrated solution into 7.50kg of N-methylpyrrolidone (27.80kg) suspension of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, the pH value is adjusted to be more than 10 by using 21% sodium hydroxide aqueous solution, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring, crystallizing, centrifuging, filtering, and drying to obtain compound of formula II with yield of 98.0% and HPLC purity of 99.53%, and the HPLC figure is shown in FIG. 1.

Comparative example 1

440g of o-methylbenzoic acid and 760g of thionyl chloride are added into a reaction bottle, the reaction is carried out at 55-65 ℃ until the end point, the reaction is carried out under reduced pressure and concentrated, and then the reaction product is added into a suspension of 4-amino-2-methylbenzoic acid (440g) and sodium hydroxide (190g) in N-methylpyrrolidone (1.8 kg). After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, 21% sodium hydroxide solution is used for adjusting the pH value to be more than 10, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain compound of formula II with yield of 53.7% and HPLC purity of 86.5%, shown in figure 2 of HPLC.

Comparative example 2

2.5g of o-methylbenzoic acid and 4.3g of thionyl chloride are added into a reaction bottle, the reaction is carried out at 55-65 ℃ until the end point, the reaction solution is concentrated under reduced pressure, and then the concentrated solution is added into a suspension of 2.78g of 1,4 dioxane (20ml) of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, 21% sodium hydroxide solution is used for adjusting the pH value to be more than 10, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain the compound of formula II with yield of 79% and HPLC purity of 95.3%.

Comparative example 3

2.5g of o-methylbenzoic acid and 4.3g of thionyl chloride are added into a reaction bottle, the reaction is carried out at 55-65 ℃ until the end point, the reaction product is concentrated under reduced pressure, and then the reaction product is added into a suspension of 2.78g of 1,4 dioxane/ethyl acetate (6ml/14ml) of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, 21% sodium hydroxide solution is used for adjusting the pH value to be more than 10, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain the compound of formula II with yield of 79% and HPLC purity of 93.6%.

Comparative example 4

2.5g of o-methylbenzoic acid and 4.3g of thionyl chloride are added into a reaction bottle, the reaction is carried out at 55-65 ℃ until the end point, the reaction product is concentrated under reduced pressure, and then the reaction product is added into a suspension of 2.78g of N-methylpyrrolidone/dichloromethane (6ml/14ml) of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, 21% sodium hydroxide solution is used for adjusting the pH value to be more than 10, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain the compound of formula II with yield of 78% and HPLC purity of 92.8%.

Comparative example 5

2.5g of o-methylbenzoic acid and 4.3g of thionyl chloride are added into a reaction flask, the reaction is carried out at 55-65 ℃ until the end point, the reaction solution is concentrated under reduced pressure, and then the reaction solution is added into a suspension of 2.78g of tetrahydrofuran (20ml) of 4-amino-2-methylbenzoic acid. After the addition, the temperature is kept at 25-35 ℃ for reaction, after the reaction is carried out for 1h, 21% sodium hydroxide solution is used for adjusting the pH value to be more than 10, and dichloromethane is added for extraction. Separating, adjusting pH of the water phase to below 7 with 4N hydrochloric acid solution, stirring for crystallization, centrifuging, filtering, and drying to obtain the compound of formula II with yield of 73% and HPLC purity of 87.9%.