A preparation method of vonoprazan fumarate nitrosamine impurities

Abstract

The present invention relates to a method for preparing nitrosamine impurities in vonoprazan fumarate, belonging to the technical field of chemical synthesis. By mixing vonoprazan with an organic solvent and reacting the mixture with a nitrosating agent at room temperature, the nitrosamine impurities prepared by this method have a purity exceeding 85%. This method solves the problem of preparing nitrosamine impurities and also provides a reference substance for the study of impurities in vonoprazan fumarate.

Description

Technical Field

[0001] The invention relates to a preparation method of vonoprazan fumarate impurities and belongs to the technical field of medicines. Background Art

[0002] Vonoprazan fumarate is a novel gastric acid secretion inhibitor developed by Takeda Pharmaceuticals of Japan. It belongs to the next generation of potassium (K+) competitive acid blockers (P-CABs) and is a reversible proton pump inhibitor. It was first approved for marketing in Japan in December 2014 (under the trade name Takecab) for the treatment of gastric acid-related diseases (ARDs), including Helicobacter pylori infection, gastroesophageal reflux, peptic ulcer, duodenal ulcer, esophagitis, and gastric ulcer. In vitro activity studies have shown that this compound has a 400-fold greater proton pump inhibitory potency than lansoprazole and exhibits over 500-fold selectivity for Na,K-ATPase. In cultured rabbit gastric glandular tissue, TAK-438 exhibits a higher accumulation rate and slower clearance rate than lansoprazole, resulting in a more potent and sustained acid-suppressive effect in vivo.

[0003] On January 11, 2023, the FDA temporarily withheld approval of vonoprazan fumarate for a new indication for the treatment of erosive esophagitis, developed by Phathom, a company jointly founded by Takeda and Frazier. The reason was that in August 2022, Phathom discovered that trace amounts of the nitrosamine impurity N-nitroso-vonoprazan (NVP) were detected in its commercial batches of vonoprazan fumarate. Although the FDA has now set the acceptable daily intake limit for NVP at 96 ng / day, Phathom lacks additional stability data to demonstrate that its NVP levels remain below this limit throughout the product's proposed shelf life.

[0004] Summary of the Invention

[0005] The purpose of the present invention is to solve the problems existing in the prior art, to study the impurity NVP, and now it is necessary to provide a preparation method of the impurity NVP of vonoprazan fumarate and provide a qualified impurity NVP reference substance.

[0006] The technical solutions of the present invention are as follows:

[0007] The present invention relates to a method for preparing vonoprazan fumarate impurity NVP. Vonoprazan and sodium nitrite react in a solvent of dichloromethane to obtain the vonoprazan fumarate impurity NVP with high purity and high yield.

[0008] A method for preparing vonoprazan fumarate impurity NVP, characterized in that:

[0009]

[0010] Compound 4 can be obtained by various preparation methods in the prior art, for example:

[0011]

[0012] Effect of the Invention: The vonoprazan fumarate impurity NVP was detected in commercial batches of Phathom's products in August 2022. A literature review revealed no current preparation methods for this impurity. The present invention provides a simple, cost-effective, environmentally friendly, highly stable, and high-yield synthesis method for the vonoprazan fumarate impurity NVP, thereby filling the current synthesis gap for this impurity. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Impurity NVP mass spectrum

[0014] Figure 2 Impurity NVP H NMR spectrum

[0015] Figure 3 Infrared spectrum of impurity NVP DETAILED DESCRIPTION

[0016] The principles and features of the present invention are described below, and the examples are used to further explain the present invention but do not limit the scope of the present invention.

[0017] Preparation of Vonoprazan Fumarate Impurity NVP

[0018]

[0019] Example 1: 30 ml of dichloromethane, 3.45 g of compound 4 (0.01 mol), and 1.03 g of sodium sulfite (0.015 mol) were added to a 100 ml four-necked flask in sequence. The mixture was stirred at room temperature at 25°C for 2 hours, filtered, and the filter cake was dried under forced air at 60°C to obtain 3.36 g of vonoprazan fumarate impurity NVP as a white solid. The yield was 89.7%, the HPLC purity was 99.7%, and the structural confirmation data were as follows: MS (M / Z): 375.0926 ([M+H]+). See attached. Figure 1 ;

[0020] 1H NMR (deuterated MeOH, 500MHZ): δ2.988 (3H,s), δ4.611 (2H,s), δ6.103-6.200 (1H), δ6.995-7.017 (1H,m), δ7.116-7.260 (2H,m), δ7.330-7.369 (1H,m), δ7.388-7.409 (1H,m), δ 7.421-7.482 (1H,m), δ7.659-7.669 (1H,m), δ8.563-8.592 (1H,m), δ8.765-8.786 (1H,m), see attachment Figure 2 ;

[0021] The infrared absorption spectrum obtained by measuring potassium bromide tablets was at 3447.50 cm -1 ,3039.23 cm -1 ,1522.59cm -1 ,1621.20 cm -1 ,1262.35 cm -1 ,1125.87 cm -1 ,1306.29 cm -1 ,702.77 cm -1 ,756.55 cm -1 ,819.08 cm -1 With characteristic peaks, see attached Figure 3 ;

[0022] Example 2: In a 100 ml four-necked flask, 30 ml of dichloromethane, 3.45 g of compound 4 (0.01 mol), and 4.33 g of 4-butylammonium nitrite (0.015 mol) were added in sequence. The mixture was stirred at room temperature (25°C) for 2 hours. The mixture was filtered and the filter cake was dried under forced air at 60°C to obtain 2.56 g of vonoprazan fumarate impurity NVP as a white solid with a yield of 68.4% and an HPLC purity of 87.6%.

[0023] Example 3: In a 100 ml four-necked flask, 30 ml of dichloromethane, 3.45 g of compound 4 (0.01 mol), and 1.74 g of N-nitrosomorpholine (0.015 mol) were added in sequence. The mixture was stirred at room temperature (25°C) for 2 hours, filtered, and the filter cake was air-dried at 60°C to obtain 3.06 g of vonoprazan fumarate impurity NVP as a white solid. The yield was 81.8%, and the HPLC purity was 91.6%.

[0024] Example 4: In a 100 ml four-necked flask, 30 ml of ethyl acetate, 3.45 g of compound 4 (0.01 mol), and 1.38 g of sodium sulfite (0.02 mol) were added in sequence. The mixture was stirred at room temperature (25°C) for 2 hours. The mixture was filtered and the filter cake was dried under forced air at 60°C to obtain 3.20 g of vonoprazan fumarate impurity NVP as a white solid with a yield of 85.6% and an HPLC purity of 98.6%.

[0025] Example 5: Into a 100 ml four-necked flask were added 30 ml of anhydrous ethanol, 3.45 g of compound 4 (0.01 mol), and 0.69 g of sodium sulfite (0.01 mol). The mixture was stirred at room temperature (25°C) for 2 hours, filtered, and the filter cake was air-dried at 60°C to obtain 2.89 g of vonoprazan fumarate impurity NVP as a white solid in a yield of 77.3% and an HPLC purity of 99.2%.

Claims

1. A method for preparing nitrosamine impurities of vonoprazan fumarate, characterized in that After mixing vonoprazan with an organic solvent, the mixture is reacted with a nitrosating agent at room temperature to obtain an impurity. 。 2. The preparation method according to claim 1, wherein The molar feed ratio of vonoprazan to the nitrosating agent is 1:1-2.

3. The preparation method according to claim 1, wherein The organic solvent is one of ethyl acetate, dichloromethane and anhydrous ethanol.

4. The preparation method according to claim 1, characterized in that The nitrosating agent is one of 4-butylammonium nitrite, N-nitrosomorpholine and sodium nitrite.

5. The preparation method according to claim 2, characterized in that The molar ratio of vonoprazan to the nitrosating agent is 1:1.

5.

6. The preparation method according to claim 3, characterized in that The organic solvent is dichloromethane.

7. The preparation method according to claim 4, characterized in that The nitrosating agent is sodium nitrite.

8. The preparation method according to claim 1, characterized in that The room temperature was 25°C and the reaction time was 2 h.

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