Preparation method for removing formyl impurity from losartan potassium
By using the closed-loop reaction and condensation reaction of N-carboxymethylpentamidine and phosphorus oxychloride, a high-purity losartan potassium deformyl impurity was successfully prepared, which solved the lack of impurity preparation in the prior art, and improved the quality control and safe drug use of losartan potassium.
Patent Information
- Application Number
- CN202311653755.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-12-05
- Publication Date
- 2025-06-06
AI Technical Summary
The prior art has failed to effectively solve the problem of preparation of deformyl cyanomate during the synthesis of losartan potassium, which affects the quality control of losartan potassium.
N-carboxymethylpentamidine was used as the starting material to obtain deformylimidazole by closed-loop reaction with phosphorus oxychloride, and then condensation reaction with -cyano-4'-bromomethylbiphenyl to directly obtain the target product deformyl impurity.
It has achieved efficient preparation of losartan potassium deformyl impurities, with HPLC purity greater than 99%, suitable for industrial promotion, and provides guarantees for quality research on the raw materials for losartan potassium and safe use of drugs.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of pharmaceutical chemical synthesis, and in particular to a method for preparing losartan potassium deformyl impurities. Background Art
[0002] Losartan potassium is an angiotensin II receptor antagonist used to treat hypertension. It can be used alone or in combination with other antihypertensive drugs. The drug is well tolerated, with mild and short-lived adverse reactions. It is currently a commonly used drug for the treatment of hypertension. Losartan potassium is a synthetic, potent, orally active drug. With the rise of generic sartan drugs, the demand for losartan potassium API has also increased.
[0003] At present, 2-n-butyl-4-chloro-5-formyl imidazole (referred to as "imidazole aldehyde") is required in the synthesis route of preparing losartan potassium. The process route for synthesizing imidazole aldehyde in the prior art is as follows: During the experiment, it was found that in the process of preparing losartan potassium using imidazole aldehyde, a deoxycyanide may be produced, with the chemical name: 4'-[(2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile. Controlling the content of impurities in the synthesis process of losartan potassium is extremely important for the quality control of losartan potassium.
[0004] There is no literature report on the synthesis of deformyl cyanide using N-carboxymethylpentamidine as a starting material in the prior art. Summary of the invention
[0005] In order to solve the above problems, the present invention provides a method for preparing a Losartan potassium deformylated impurity. The method has readily available raw materials, a simple process, and is suitable for industrial promotion. The prepared deformylated impurity can be used as an impurity reference substance for quality research of Losartan potassium raw materials, thereby providing a guarantee for the safe use of Losartan potassium.
[0006] The invention provides a method for preparing a losartan potassium deformylated impurity. The deformylated impurity has a chemical name of 4'-[(2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile. N-carboxymethylpentamidine is used as a starting material and undergoes a ring-closing reaction with trichlorophosphine oxide to obtain deformylimidazole. Then, the deformylimidazole and -cyano-4'-bromomethylbiphenyl are subjected to a condensation reaction to directly obtain a target product deformylated impurity.
[0007] Furthermore, the reaction solvent in the ring-closing reaction is selected from one or more of toluene, n-heptane, and cyclohexane, preferably toluene.
[0008] Furthermore, when the temperature is controlled at -1 to 3°C, phosphorus oxychloride is slowly added to the system of N-carboxymethylpentamidine and toluene and then refluxed for reaction.
[0009] Furthermore, the molar ratio of N-carboxymethylpentamidine to phosphorus oxychloride is 1:(3-4).
[0010] Furthermore, the reaction solvent in the condensation reaction is selected from one or more of water, toluene, dichloromethane and chloroform, and a base and a phase transfer catalyst are also added in the condensation reaction.
[0011] Furthermore, the base is an inorganic base, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide and potassium carbonate, and the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate.
[0012] Furthermore, the molar ratio of the nor-formylimidazole, bromobiphenyl and base is (0.9-1.1):1:(2-3), and the added amount of the phase transfer catalyst is 4%-8% of the molar amount of the nor-formylimidazole.
[0013] Furthermore, the reaction temperature of the condensation reaction is room temperature.
[0014] The present invention provides a method for preparing losartan potassium deformyl impurities, and the method is as follows:
[0015] The invention provides a method for preparing losartan potassium norformyl impurities. After the closing reaction is completed, ice water is used to quench the reaction, and after adjusting the pH value with sodium hydroxide, toluene is used for extraction, and the crude norformyl imidazole is obtained by concentration, and the norformyl imidazole is obtained by refining with a silica gel column.
[0016] The invention provides a method for preparing a losartan potassium deformylated impurity. After a condensation reaction is completed, toluene is used for extraction, and the deformylated impurity is purified by a silica gel column after concentration to obtain the deformylated impurity.
[0017] Beneficial Effects No literature report on the synthesis of a deformylated cyanide using N-carboxymethylpentamidine as a starting material has been retrieved in the prior art. The present invention provides a method for preparing a deformylated impurity of losartan potassium. The method uses N-carboxymethylpentamidine as a starting material, has readily available raw materials, mild reaction conditions, simple post-treatment, and a simple process. The HPLC of the obtained deformylated impurity is greater than 99%, which is suitable for industrial promotion. The prepared deformylated impurity can be used as an impurity reference substance for the quality research of the bulk drug of losartan potassium, thereby providing a guarantee for the safe use of losartan potassium. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 LC-MS chart of the decarboxylated cyanide. DETAILED DESCRIPTION
[0019] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.
[0020] Example 1 Preparation of Norformyl Imidazole 25 g (0.1592 mol, 1.0 equivalent) of N-carboxymethylpentamidine and 125 g of toluene were added to the reaction flask and the temperature was lowered to 0° C. The temperature was controlled at about 0° C. and 77.8 g (0.5277 mol, 3.3 equivalent) of phosphorus oxychloride was added dropwise. After the addition, the temperature was raised to reflux for 12 hours.
[0021] After the reaction was completed, the reaction was quenched with ice water, and 200 g of water was added, and the pH was neutralized to weak alkalinity with sodium hydroxide aqueous solution, and the layers were separated, and the aqueous layer was extracted with toluene twice. The toluene layers were combined and concentrated to obtain the crude product of norformyl imidazole.
[0022] The crude product was separated by silica gel column to obtain 13 g. HPLC: 99%.
[0023] Example 2 Preparation of Noryl Cyanide 11.5 g (0.0725 mol, 1.0 equivalent) of norformylimidazole obtained in Example 1, 19.7 g (0.0724 mol, 1.0 equivalent) of bromobiphenyl, 1.0 g of TBAB and 80 ml of toluene were added into a reaction flask, 30% sodium hydroxide (5.8 g, 0.145 mol, 2.0 equivalent) was added dropwise at 20-30° C., and the reaction was carried out at room temperature.
[0024] After the reaction was completed, the layers were separated. The aqueous layer was extracted twice with toluene, and the toluene layers were combined. The toluene was concentrated to obtain 21 g of crude deoxycyanide.
[0025] The crude product was separated by silica gel column to obtain 8 g of yellow oil. HPLC>99%, LC-MS Figure 1 As shown, it can solidify into a yellow solid if placed in the refrigerator for a long time.
[0026] Example 3 Preparation of Norformyl Imidazole 25 g (0.1592 mol, 1.0 equivalent) of N-carboxymethylpentamidine and 130 g of toluene were added to the reaction flask and the temperature was lowered to -1°C. At about -1°C, 97.4 g (0.6368 mol, 4 equivalents) of phosphorus oxychloride was added dropwise, and the temperature was raised to reflux for 12 hours after the addition was completed.
[0027] After the reaction was completed, the reaction was quenched with ice water, and 200 g of water was added, and the pH was neutralized to weak alkalinity with sodium hydroxide aqueous solution, and the layers were separated, and the aqueous layer was extracted with toluene twice. The toluene layers were combined and concentrated to obtain the crude product of norformyl imidazole.
[0028] The crude product was separated by silica gel column to obtain 13.8 g. HPLC: 99%.
[0029] Example 4 Preparation of Noryl Cyanide 11.5 g (0.0725 mol, 1.0 equivalent) of norformylimidazole obtained in Example 3, 21.7 g (0.0796 mol, 1.0 equivalent) of bromobiphenyl, 2.0 g of tetrabutylammonium bromide and 80 ml of toluene were added into a reaction flask, 30% sodium hydroxide (5.8 g, 0.145 mol, 2.0 equivalent) was added dropwise at 20-30° C., and the reaction was carried out at room temperature.
[0030] After the reaction was completed, the layers were separated. The aqueous layer was extracted twice with toluene, and the toluene layers were combined. The toluene was concentrated to obtain 22.5 g of crude deoxycyanide.
[0031] The crude product was passed through a silica gel column to separate 9 g of yellow oil. HPLC>99%, and it solidified into a yellow solid after being placed in a refrigerator for a long time.
Claims
1. A method for preparing losartan potassium deformyl impurity, It is characterized in that The chemical name of the deformylated impurity is 4'-[(2-butyl-4-chloro-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile. N-carboxymethylpentamidine is used as a starting material and undergoes a ring-closing reaction with trichlorophosphine to obtain deformylated imidazole. Then, deformylated imidazole and -cyano-4'-bromomethylbiphenyl undergo a condensation reaction to directly obtain the target product deformylated impurity.
2. The preparation method according to claim 1, It is characterized in that The reaction solvent in the ring-closing reaction is selected from one or more of toluene, n-heptane, and cyclohexane, preferably toluene.
3. The preparation method according to claim 1, It is characterized in that When the temperature is controlled at -1 to 3°C, phosphorus oxychloride is slowly added into the system of N-carboxymethylpentamidine and toluene, and then refluxed for reaction.
4. The preparation method according to claim 1, It is characterized in that The molar ratio of the N-carboxymethylpentamidine to phosphorus oxychloride is 1:(3-4).
5. The preparation method according to any one of claims 1 to 4, It is characterized in that The reaction solvent in the condensation reaction is selected from one or more of water, toluene, dichloromethane and chloroform, and a base and a phase transfer catalyst are also added in the condensation reaction.
6. The preparation method according to claim 5, It is characterized in that The base is an inorganic base, which is selected from one or more of sodium hydroxide, potassium hydroxide and potassium carbonate, and the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulfate.
7. The preparation method according to claim 6, It is characterized in that The molar ratio of the nor-formylimidazole, bromobiphenyl and base is (0.9-1.1):1:(2-3), and the added amount of the phase transfer catalyst is 4%-8% of the molar amount of the nor-formylimidazole.
8. The preparation method according to claim 7, It is characterized in that The reaction temperature of the condensation reaction is room temperature.
9. The preparation method according to claim 8, It is characterized in that The method is as follows: 。