Preparation method of selepag intermediate

Abstract

The invention relates to a preparation method of a selepag intermediate, which comprises the following steps: reacting a compound 1 with 4-amino-1-butanol to obtain a compound 2, further reacting with acetic anhydride and bromoisopropane, and hydrolyzing to remove acetyl to obtain a target product 4-[(5, 6-diphenylpyrazine-2-yl) (isopropyl) amino]-1-butanol. The preparation yield of the compound 2 is higher than 95%, the compound 2 and a target product are subjected to three-step chemical reaction, the yield is still higher than 90%, the purity of the target product is higher than 99.8%, and the single impurity is smaller than 0.1%. And # imgabs0 #.

Description

Technical Field

[0001] The present invention relates to a method for preparing a selexipag intermediate, and belongs to the field of pharmaceutical chemistry. Background Art

[0002] Selexipag is an orally effective, highly selective, long-acting non-prostaglandin prostacyclin receptor (IP receptor) agonist. It was approved by the US FDA in 2015 and is the first prostacyclin drug that can be taken orally. It is easy to use and has high compliance. It avoids injection site reactions of intravenous administration and throat irritation and coughing of inhaled dosage forms.

[0003] On December 12, 2018, Selexipag tablets were approved by the China National Medical Products Administration for marketing for the treatment of pulmonary arterial hypertension, bringing new hope of survival to such patients.

[0004] Literature reports that there are two main synthetic routes for selexipag: Route 1 uses 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol as raw material, first reacts with tert-butyl bromoacetate, then hydrolyzes to carboxylic acid, and finally reacts with methanesulfonamide to obtain selexipag.

[0005] .

[0006] Route 2 directly prepares selexipag by reacting 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol with N-(2-chloroacetyl)methanesulfonamide.

[0007] .

[0008] It can be seen that 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol is a key intermediate for the synthesis of selexipag, and the difficulty of its preparation directly affects the production capacity of selexipag.

[0009] The main synthetic routes of [(5,6-diphenylpyrazine-2-yl)(isopropyl)amino]-1-butanol are: Route 1 (CN1301973C) is prepared by directly reacting 5-chloro-2,3-diphenylpyrazine with 4-(isopropylamino)-1-butanol. The reaction temperature of this route is above 170°C, which has high requirements for equipment and is not easy to industrialize. At the same time, due to the high reaction temperature, the chlorine in 5-chloro-2,3-diphenylpyrazine will be hydrolyzed into hydroxy impurities in large quantities, affecting the purity and yield of the product.

[0010] .

[0011] Route 2 (CN110437077A) uses 5-chloro-2,3-diphenylpyrazine as a raw material to first react with isopropylamine, then react with 4-bromobutyl acetate and hydrolyze to obtain the target product. Steps 1 and 2 of this route are both carried out under anhydrous and oxygen-free conditions and the action of a strong base, wherein step 1 needs to reach a low temperature of -30°C to -40°C and the product needs to be purified by column, which is not conducive to industrial scale-up production.

[0012] .

[0013] Route 3 (CN113214169B) uses 1,2-diphenylethylene oxide and 2-aminoacetamidine hydrobromide as starting materials to prepare 5,6-diphenylpyrazine-2-amine under the action of a catalyst, and further reacts with 4-bromo-1-butanol under the action of a base to obtain 4-[(5,6-diphenylpyrazine-2-yl)amino]-1-butanol, and finally reacts with isopropane bromide under the action of a base to obtain the target product. The starting material 1,2-diphenylethylene oxide in this preparation process is not easy to obtain, and 4-[(5,6-diphenylpyrazine-2-yl)amino]-1-butanol reacts directly with isopropane bromide, which is more likely to produce ether impurities after the reaction of alcohol and isopropane bromide in addition to the target product, affecting the product yield and quality.

[0014] . Summary of the invention

[0015] Due to the problems existing in the current process for preparing 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol, the inventors have developed a synthetic route with easily available raw materials, simple production process, and high product purity and yield through repeated experiments and investigations.

[0016] .

[0017] Step 1: The reaction is carried out at 70-130°C with a molar ratio of 4-amino-1-butanol to compound 1 (5-chloro-2,3-diphenylpyrazine) (1-3):1, and water is directly added for crystallization to obtain compound 2, which is easy to scale up for industrial production. Since 4-amino-1-butanol is used for the reaction, the reaction activity is improved during the preparation process, and the reaction temperature is reduced. The reaction selectivity is significantly improved, and basically no side reactions are produced. The yield can reach more than 95%. Compared with the formation of carbon-nitrogen bonds in routes 1, 2 and 3, it has the advantages of easy raw materials, simple reaction conditions, convenient post-treatment, few by-products and high yield.

[0018] Step 2: The molar ratio of acetic anhydride to compound 2 (1-2): 1 is reacted in pyridine at 50-90°C to obtain compound 3. After the reaction is completed, the excess pyridine and acetic anhydride are directly evaporated and the reaction of step 3 can be carried out without purification.

[0019] Step 3: Add DMF and sodium hydride to compound 3, wherein the molar ratio of sodium hydride to compound 2 is (2-5):1, react at 0-30°C for 30 minutes, add isopropyl bromide at a molar ratio of 1:1 to compound 2, and react at -10 to 10°C.

[0020] Step 4: After the reaction is completed, directly add water and heat to 20-50°C to remove the acetyl protection to obtain the target product.

[0021] Since the alcoholic hydroxyl group in compound 2 is protected by an acetyl group, a side reaction of compound 2 with isopropyl bromide to form an ether is prevented. At the same time, sodium hydride is used as a base, which can effectively promote the reaction and improve the reaction yield. After adding water, it is converted into sodium hydroxide to hydrolyze compound 4, reducing the addition of additional materials and shortening the operation process, thereby improving the reaction yield. From compound 2 to the target product, three steps of chemical reaction are performed, and the yield is still higher than 90%, the purity is greater than 99.8%, and a single impurity is less than 0.1%.

[0022] The synthetic process of the present invention is used to prepare 4-[(5,6-diphenylpyrazine-2-yl)(isopropyl)amino]-1-butanol. The materials used are easily available, the operation is simple, the reaction is mild, and the yield and purity are significantly higher than other processes currently reported in the literature. Specific embodiments

[0023] In Example 1: 66.8 g of 4-amino-1-butanol and 100 g of compound 1 (5-chloro-2,3-diphenylpyrazine) were added to a three-necked flask at a material molar ratio of 2:1. The temperature was raised to 95-105°C for reaction. After HPLC detection showed that the remaining amount of 5-chloro-2,3-diphenylpyrazine was less than 0.2%, 700 ml of water was added, stirred at 20-30°C for 1 hour, filtered, washed once with 200 ml of water, and the filter cake was dried at 60-65°C for 12 hours to obtain 117.1 g of compound 2 with a yield of 97.8%.

[0024] Example 2: 350 ml of pyridine, 117.1 g of compound 2, and finally 48.7 g of acetic anhydride were added to a three-necked flask, the molar ratio of acetic anhydride to compound 2 was 1.3:1, the temperature was raised to 65-75°C for reaction, and after HPLC detection of the residual amount of compound 2 being less than 0.1%, the reaction solution was distilled under reduced pressure at 70-80°C for standby use.

[0025] Example 3: DMF586ml was added to the evaporated product, cooled to below 10°C, 44g of sodium hydride with a content of 60% was added in 5 batches, the molar ratio of sodium hydride to compound 2 was 3:1, and the reaction was kept at 10-20°C for 30 minutes. 45.1g of isopropyl bromide was added and the reaction was kept at 0-5°C. After HPLC detected that the remaining amount of compound 3 was less than 0.5%, 937ml of water was added, the temperature was raised to 30-40°C for reaction, and HPLC detected that the remaining amount of compound 4 was less than 0.1%, 586ml of water was added, and dichloromethane was added for extraction 3 times, 300ml each time, the dichloromethane layers were combined, washed with water 2 times, 400ml each time, dried over anhydrous sodium sulfate, and distilled under reduced pressure at 35-45°C to obtain 121.1g of the product, the yield calculated from compound 2 was 91.4%, the purity was 99.83%, and the single maximum impurity was 0.07%.

[0026] Example 4: 100.2 g of 4-amino-1-butanol and 100 g of compound 1 (5-chloro-2,3-diphenylpyrazine) were added to a three-necked flask at a material molar ratio of 3:1. The temperature was raised to 85-95°C for reaction. After HPLC detection showed that the remaining amount of 5-chloro-2,3-diphenylpyrazine was less than 0.2%, 700 ml of water was added, stirred at 20-30°C for 1 hour, filtered, washed once with 200 ml of water, and the filter cake was dried at 60-65°C for 12 hours to obtain 117.8 g of compound 2 with a yield of 98.4%.

[0027] Example 5: To a three-necked flask, 350 ml of pyridine, 117.8 g of compound 2, and finally 60.2 g of acetic anhydride were added, with a molar ratio of acetic anhydride to compound 2 of 1.6:1. The temperature was raised to 55-65°C for reaction. After HPLC detection showed that the residual amount of compound 2 was less than 0.1%, the reaction solution was distilled under reduced pressure at 70-80°C for later use.

[0028] Example 6: DMF590ml was added to the evaporated product, cooled to below 10°C, 66.4g of sodium hydride with a content of 60% was added in 5 batches, the molar ratio of sodium hydride to compound 2 was 4.5:1, and the reaction was kept at 10-20°C for 30 minutes. 45.4g of isopropyl bromide was added and the reaction was kept at 5-10°C. After HPLC detected that the remaining amount of compound 3 was less than 0.5%, 942ml of water was added, the temperature was raised to 40-50°C for reaction, HPLC detected that the remaining amount of compound 4 was less than 0.1%, 590ml of water was added, and dichloromethane was added for extraction 3 times, 300ml each time, the dichloromethane layers were combined, washed with water 2 times, 400ml each time, dried over anhydrous sodium sulfate, and distilled under reduced pressure at 35-45°C to obtain 123.5g of the product, the yield was 92.6% based on compound 2, the purity was 99.87%, and the single maximum impurity was 0.06%.

Claims

1. A method for preparing a selexipag intermediate, characterized in that: The steps include: (1) Compound 1 reacts with 4-amino-1-butanol to obtain compound 2; (2) Compound 2 reacts with acetic anhydride to obtain compound 3; (3) Compound 3 reacts with isopropyl bromide to obtain compound 4; (4) Compound 4 was hydrolyzed to obtain the target product 4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]-1-butanol.

2. The method for preparing compound 2 according to claim 1, characterized in that: The molar ratio of 4-amino-1-butanol to compound 1 is 1-3:

1.

3. The method for preparing compound 2 according to claim 1, characterized in that: The reaction temperature is 70-130°C.

4. The method for preparing compound 3 according to claim 1, characterized in that: The molar ratio of acetic anhydride to compound 2 is 1-2:

1.

5. The method for preparing compound 3 according to claim 1, characterized in that: The reaction temperature is 50-90°C.

6. The method for preparing compound 4 according to claim 1, characterized in that: The molar ratio of sodium hydride to compound 2 is 2-5:

1.

7. The method for preparing compound 4 according to claim 1, characterized in that: The reaction temperature after adding sodium hydride is 0-30°C.

8. The method for preparing compound 4 according to claim 1, characterized in that: The molar ratio of isopropyl bromide to compound 2 is 1:

1.

9. The method for preparing compound 4 according to claim 1, characterized in that: The reaction temperature after adding isopropyl bromide is -10°C to 10°C.

10. The method for preparing 4-[(5,6-diphenylpyrazine-2-yl)(isopropyl)amino]-1-butanol according to claim 1, characterized in that: The hydrolysis temperature is 20-50°C.

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