CN112094198B

CN112094198B - A method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid

Info

Publication number: CN112094198B
Application number: CN202010542760.0A
Authority: CN
Inventors: 李维思; 史凌云; 高倩; 孙春霞; 许林菊; 柳贞; 袁涛
Original assignee: Jiangsu Zhongbang Pharmaceutical Co ltd; Nanjing Red Sun Pharmaceutical Research Institute Co ltd
Current assignee: Jiangsu Zhongbang Pharmaceutical Co ltd; Nanjing Red Sun Pharmaceutical Research Institute Co ltd
Priority date: 2020-06-15
Filing date: 2020-06-15
Publication date: 2025-02-11
Anticipated expiration: 2040-06-15
Also published as: CN112094198A

Abstract

The invention discloses a synthesis method of N-nitroso-N-methyl-4-aminobutyric acid, which takes N-methylpyrrolidone shown in a formula I as a starting material, and forms a compound shown in a formula II through alkali ring opening and hydrolysis, wherein the compound shown in the formula II reacts with nitrite to obtain a product shown in a formula III. The method has the advantages of simple process route, simple and convenient operation and mild reaction conditions, and the target product N-nitroso-N-methyl-4-aminobutyric acid is obtained through two-step organic synthesis, and HNMR shows no impurity peak.

Description

Synthesis method of N-nitroso-N-methyl-4-aminobutyric acid

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of N-nitroso-N-methyl-4-aminobutyric acid.

Background

Since NMBA is a known animal and potentially human carcinogenic chemical substance, it is the third nitrosamine genotoxic impurity detected in ARBs drugs marketed following N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA).

In the ARBs drug nitrosamine impurity limits published by the FDA, the daily allowable intake of NMBA is a maximum of 0.96ppm. FDA assessed the level of NMBA exposure to 9.82ppm compared to the level of dosing of 0.96ppmNMBA for lifetime, indicating that 6 months of exposure would not present a risk of cancer.

Thus, to ensure that patients are available with losartan medoxomil during the buffer period, the FDA does not hold sales against losartan containing less than 9.82ppm NMBA. The transition buffer period FDA is set to be 6 months until a production enterprise provides losartan medicament with nitrosamine impurities meeting requirements to fill the market.

Disclosure of Invention

The invention aims to provide a method for preparing and purifying impurity NMBA, which comprises the steps of adding N-methyl pyrrolidone serving as a raw material into a reaction, performing ring-opening reaction under alkaline conditions, acidifying hydrolysis liquid, filtering, and performing nitrosation reaction on filtrate to obtain a target product NMBA which can be used as an impurity reference substance.

The invention aims at realizing the following technical scheme:

A synthesis method of N-nitroso-N-methyl-4-aminobutyric acid comprises the following steps:

N-methyl pyrrolidone shown in a formula I is used as a starting material, and is subjected to alkali ring opening and hydrolysis to form a compound shown in a formula II, and the compound shown in the formula II reacts with nitrite to obtain a product shown in a formula III.

Preferably, the alkali is one or two of sodium hydroxide and potassium hydroxide.

Preferably, the nitrite is selected from one or two of sodium nitrite and potassium nitrite.

The synthesis method of the N-nitroso-N-methyl-4-aminobutyric acid comprises the following specific steps:

(1) Taking N-methyl pyrrolidone shown in a formula I as a starting material, adding an organic solvent and a phase transfer catalyst, and stirring to dissolve;

(2) Adding alkali into the solution obtained in the step (1), and refluxing at 50-110 ℃, wherein the preferable refluxing is carried out for 24-36 hours, and the more preferable refluxing is carried out for 28-32 hours.

(3) After the reaction in the step (2) is finished (the reaction progress can be detected by TLC), the obtained reaction liquid is cooled to room temperature, then the liquid is separated, an organic phase is discarded to obtain a water phase, the pH value of the water phase is adjusted to 1.0-4.0 by adding acid, the filtrate is obtained by filtering, and a filter cake is discarded;

(4) And (3) adding nitrite into the filtrate in the step (3) to react at the temperature of 0-20 ℃, and preferably stirring to react for 1.0-6.0 h.

(5) Extracting and desolventizing to obtain a product shown in a formula III.

Preferably, the phase transfer catalyst in step (1) is selected from tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium bisulfate.

Preferably, the mass ratio of the N-methyl pyrrolidone to the organic solvent in the step (1) is 1:10-15.

Preferably, the organic solvent in the step (1) is dichloromethane or toluene.

Preferably, the molar ratio of the alkali to the N-methylpyrrolidone in the step (2) is 2-6:1.

Preferably, the acid in the step (3) is one or two of hydrochloric acid and sulfuric acid.

Preferably, the extraction in step (5) is performed with an organic solvent selected from ethyl acetate or methylene chloride.

Advantageous effects

The preparation method is simple, N-methyl pyrrolidone is adopted as the initial raw material, the process route is simple and convenient, the operation is simple and convenient, the reaction condition is mild, and the target product N-nitroso-N-methyl-4-aminobutyric acid is obtained through two-step organic synthesis, wherein HNMR shows no impurity peak.

Drawings

FIG. 1 example 1 product hydrogen spectrum

Detailed Description

The invention will be further illustrated by the following examples, which are intended to illustrate, but not to limit, the invention. It will be understood by those of ordinary skill in the art that these examples are not limiting of the invention in any way and that appropriate modifications and data changes may be made thereto without departing from the spirit and scope of the invention.

The nuclear magnetic resonance hydrogen spectra referred to in the examples were measured by Bruker Assetnd TM-400 nuclear magnetic resonance hydrogen spectrometer (Bruker).

Example 1

Into a 250mL four-necked flask, 5.0g (0.05 mol) of N-methylpyrrolidone was added, 50g of toluene was added, the mixture was stirred and dissolved, 0.5g of tetrabutylammonium bromide was added, an aqueous sodium hydroxide solution (sodium hydroxide: 4g (0.1 mol); water: 40 g) was added, the temperature was raised to 50 ℃, the mixture was stirred and reacted for 28 hours, the liquid was separated, the organic phase was discarded, the aqueous phase was adjusted to pH=1.0 with hydrochloric acid, the mixture was filtered, the filtrate was collected, and the cake was discarded.

6.9G (0.1 mol) of sodium nitrite is added into the filtrate, the temperature is reduced to 0 ℃, the temperature is kept and the stirring reaction is carried out for 1.0h, the temperature is raised to 25 ℃, 50 g/time of dichloromethane is used for 2 times of extraction, the dichloromethane phases are combined and desolventized, and a light yellow oily substance is obtained as a target product N-nitrosyl-N-methyl-4-aminobutyric acid. The ¹ H-NMR spectrum of the product is shown in FIG. 1 .¹HNMR(400MHz,DMSO-d6)d: 10.53(s,1H,COOH),4.13(t,J＝14Hz,2H,CH₂-N),2.97(s,3H,CH₃-N),2.24(t,J＝14.4Hz,2H, CH₂-COOH),1.91(m,J＝28Hz,2H,CH₂-CH₂-CH₂).

Example 2

Into a 250mL four-necked flask, 5.0g (0.05 mol) of N-methylpyrrolidone was added, 75g of toluene was added, the temperature was raised to 70℃and the mixture was stirred to dissolve, 0.5g of tetrabutylammonium bromide was added, an aqueous sodium hydroxide solution (sodium hydroxide: 12g (0.3 mol); water: 120 g) was added, the temperature was raised to 110℃and the mixture was stirred for 32 hours, the liquid was separated, the organic phase was discarded, the aqueous phase was adjusted to pH=4.0 with hydrochloric acid, the mixture was filtered, the filtrate was collected, and the cake was discarded.

13.8G (0.2 mol) of sodium nitrite is added into the filtrate, the temperature is reduced to 20 ℃, the temperature is kept, the stirring reaction is carried out for 6.0h, the temperature is raised to 25 ℃, 50 g/time of dichloromethane is used for 2 times of extraction, the dichloromethane phases are combined, and the light yellow oily substance is obtained as the target product N-nitroso-N-methyl-4-aminobutyric acid through desolventizing.

Example 3

Into a 250mL four-necked flask, 5.0g (0.05 mol) of N-methylpyrrolidone was added, 75g of toluene was added, the mixture was stirred and dissolved, 0.5g of tetrabutylammonium bromide was added, an aqueous sodium hydroxide solution (sodium hydroxide: 6g (0.15 mol); water: 60 g) was added, the temperature was raised to 80 ℃, the mixture was stirred and reacted for 32 hours, the liquid was separated, the organic phase was discarded, the aqueous phase was adjusted to pH=4.0 with hydrochloric acid, and the filtrate was collected and the cake was discarded.

10.4G (0.15 mol) of sodium nitrite is added into the filtrate, the temperature is reduced to 10 ℃, the temperature is kept, the stirring reaction is carried out for 3.0h, the temperature is raised to 25 ℃, 50 g/time of dichloromethane is used for 2 times of extraction, methylene dichloride phases are combined, and desolventizing is carried out, thus obtaining a light yellow oily substance which is a target product N-nitroso-N-methyl-4-aminobutyric acid.

Claims

1. A method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid, characterized in that N-methylpyrrolidone shown in formula I is used as a starting material, and the compound shown in formula II is formed by alkaline hydrolysis and ring opening, and the compound shown in formula II reacts with nitrite to obtain a product shown in formula III:

The specific steps include:

(1) Using N-methylpyrrolidone represented by formula I as the starting material, adding an organic solvent and a phase transfer catalyst, stirring to dissolve;

(2) adding a base to the obtained solution and refluxing at 50-110°C;

(3) separating the obtained reaction solution to obtain an aqueous phase, adding acid to the aqueous phase to adjust the pH to 1.0 to 4.0, and filtering to obtain a filtrate;

(4) adding nitrite to the filtrate and reacting at 0-20°C;

(5) extracting and desolventizing to obtain the product represented by formula III;

The phase transfer catalyst in step (1) is selected from tetrabutylammonium bromide.

2. The synthesis method according to claim 1, wherein the alkali is one or both of sodium hydroxide and potassium hydroxide.

3. The synthesis method according to claim 1, wherein the nitrite is selected from one or both of sodium nitrite and potassium nitrite.

4. The synthesis method according to claim 1, characterized in that the mass ratio of N-methylpyrrolidone to the organic solvent in step (1) is 1:10-15.

5. The synthesis method according to claim 1, characterized in that the organic solvent in step (1) is dichloromethane or toluene.

6. The synthesis method according to claim 1, characterized in that the molar ratio of the base to N-methylpyrrolidone in step (2) is 2 to 6:1.

7. The synthesis method according to claim 1, characterized in that the acid in step (3) is one or both of hydrochloric acid and sulfuric acid.

8. The synthesis method according to claim 1, characterized in that the extraction in step (5) is performed by an organic solvent extraction, and the organic solvent is selected from ethyl acetate or dichloromethane.