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

Abstract

The invention discloses a method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid, wherein N-methylpyrrolidone shown in formula I is used as a starting material, and the compound shown in formula II is formed by alkali ring opening and hydrolysis, and the compound shown in formula II is reacted with nitrite to obtain a product shown in formula III. The method of the invention has a simple process route, is easy to operate, and has mild reaction conditions. The target product N-nitroso-N-methyl-4-aminobutyric acid is obtained by two-step organic synthesis, and HNMR shows no impurity peaks.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid. Background Art

[0002] Since NMBA is a known animal and potential human carcinogen, it is the third nitrosamine genotoxic impurity detected in marketed ARBs after N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).

[0003] In the FDA's published table of impurity limits for ARBs, the maximum daily allowable intake of NMBA is 0.96 ppm. The FDA evaluated exposure to 9.82 ppm NMBA compared to lifetime exposure to 0.96 ppm NMBA, indicating that 6 months of exposure would not pose a cancer risk.

[0004] Therefore, in order to ensure that patients can obtain losartan drugs during the buffer period, the FDA does not object to the continued sale of losartan containing NMBA below 9.82ppm. The FDA has set this transitional buffer period at 6 months until manufacturers provide losartan drugs that meet the requirements for nitrosamine impurities to fill the market. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing and purifying impurity NMBA. The method comprises adding N-methylpyrrolidone as a raw material to the reaction, performing a ring-opening reaction under alkaline conditions, filtering the hydrolyzate after acidification, and then performing a nitrosation reaction on the filtrate to obtain the target product NMBA, which can be used as an impurity reference substance.

[0006] The objective of the present invention is achieved through the following technical solutions:

[0007] A method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid comprises the following steps:

[0008]

[0009] N-methylpyrrolidone shown in formula I is used as a starting material, and the compound shown in formula II is formed by alkali ring opening and hydrolysis. The compound shown in formula II reacts with nitrite to obtain a product shown in formula III.

[0010] Preferably, the alkali is one or both of sodium hydroxide and potassium hydroxide.

[0011] Preferably, the nitrite is selected from one or both of sodium nitrite and potassium nitrite.

[0012] A method for synthesizing N-nitroso-N-methyl-4-aminobutyric acid comprises the following specific steps:

[0013] (1) Using N-methylpyrrolidone represented by formula I as the starting material, adding an organic solvent and a phase transfer catalyst, stirring to dissolve;

[0014] (2) Add a base to the solution obtained in step (1), and reflux at 50-110° C.; preferably, reflux for 24 h to 36 h, and more preferably, reflux for 28 h to 32 h.

[0015] (3) After the reaction in step (2) is completed (the progress of the reaction can be monitored by TLC), the reaction solution is cooled to room temperature, separated, the organic phase is discarded, and the aqueous phase is obtained. Acid is added to the aqueous phase to adjust the pH to 1.0-4.0, and the filtrate is obtained by filtration, and the filter cake is discarded;

[0016] (4) Add nitrite to the filtrate of step (3) and react at 0-20°C; preferably, stir the reaction for 1.0h-6.0h.

[0017] (5) Extraction and desolventization to obtain the product shown in formula III.

[0018] Preferably, the phase transfer catalyst in step (1) is selected from tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium hydrogen sulfate.

[0019] Preferably, the mass ratio of N-methylpyrrolidone to the organic solvent in step (1) is 1:10-15.

[0020] Preferably, the organic solvent in step (1) is dichloromethane or toluene.

[0021] Preferably, the molar ratio of the base to N-methylpyrrolidone in step (2) is 2 to 6:1.

[0022] Preferably, the acid in step (3) is one or both of hydrochloric acid and sulfuric acid.

[0023] Preferably, the extraction in step (5) is performed using an organic solvent, and the organic solvent is selected from ethyl acetate or dichloromethane.

[0024] Beneficial Effects

[0025] The preparation method of the invention is simple, uses N-methylpyrrolidone as a starting raw material, has a simple process route, is easy to operate, and has mild reaction conditions. The target product N-nitroso-N-methyl-4-aminobutyric acid is obtained through two-step organic synthesis, and HNMR shows no impurity peaks. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Example 1 Product Hydrogen Spectrum DETAILED DESCRIPTION

[0027] The present invention can be further described by the following examples, which are intended to illustrate but not to limit the present invention. Any person skilled in the art will appreciate that these examples do not limit the present invention in any way and that appropriate modifications and data conversions may be made thereto without violating the spirit of the present invention and departing from the scope of the present invention.

[0028] The hydrogen nuclear magnetic resonance spectra involved in the examples were measured using a Bruker Ascend TM-400 hydrogen nuclear magnetic resonance spectrometer produced by Bruker.

[0029] Example 1

[0030] In a 250mL four-necked flask, add 5.0g (0.05mol) of N-methylpyrrolidone and 50g of toluene, stir to dissolve, add 0.5g of tetrabutylammonium bromide, add aqueous sodium hydroxide solution (sodium hydroxide: 4g (0.1mol); water: 40g), heat to 50°C, stir to react for 28h, separate the liquids, discard the organic phase, adjust the pH of the aqueous phase to 1.0 with hydrochloric acid, filter, collect the filtrate, and discard the filter cake.

[0031] Add 6.9 g (0.1 mol) of sodium nitrite to the filtrate, cool to 0°C, stir and react for 1.0 h, heat to 25°C, extract twice with 50 g of dichloromethane, combine the dichloromethane phases, desolventize, and obtain a light yellow oily substance as the target product, N-nitroso-N-methyl-4-aminobutyric acid. 1 H-NMR spectrum Figure 1 shown. 1 HNMR(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).

[0032] Example 2

[0033] In a 250mL four-necked flask, add 5.0g (0.05mol) of N-methylpyrrolidone and 75g of toluene, heat to 70°C, stir to dissolve, add 0.5g of tetrabutylammonium bromide, add aqueous sodium hydroxide solution (sodium hydroxide: 12g (0.3mol); water: 120g), heat to 110°C, stir to react for 32h, separate the liquids, discard the organic phase, adjust the pH of the aqueous phase to 4.0 with hydrochloric acid, filter, collect the filtrate, and discard the filter cake.

[0034] Add 13.8 g (0.2 mol) of sodium nitrite to the filtrate, cool to 20°C, keep stirring and react for 6.0 h, heat to 25°C, extract twice with 50 g of dichloromethane, combine the dichloromethane phases, desolventize, and obtain a light yellow oil as the target product, N-nitroso-N-methyl-4-aminobutyric acid.

[0035] Example 3

[0036] In a 250mL four-necked flask, add 5.0g (0.05mol) of N-methylpyrrolidone and 75g of toluene, stir to dissolve, add 0.5g of tetrabutylammonium bromide, add aqueous sodium hydroxide solution (sodium hydroxide: 6g (0.15mol); water: 60g), heat to 80°C, stir to react for 32h, separate the liquids, discard the organic phase, adjust the pH of the aqueous phase to 4.0 with hydrochloric acid, filter, collect the filtrate, and discard the filter cake.

[0037] Add 10.4 g (0.15 mol) of sodium nitrite to the filtrate, cool to 10°C, keep stirring and react for 3.0 h, heat to 25°C, extract twice with 50 g of dichloromethane, combine the dichloromethane phases, desolventize, and obtain a light yellow oil as the 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: Using N-methylpyrrolidone of formula I as the starting material, the compound of formula II is formed by alkaline hydrolysis and ring opening, and the compound of formula II is reacted with nitrite to obtain the product of 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, characterized in that The alkali is one or both of sodium hydroxide and potassium hydroxide.

3. The synthesis method according to claim 1, characterized in that 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 the 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 the 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 using an organic solvent, and the organic solvent is selected from ethyl acetate or dichloromethane.

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