A process for the preparation of alpirotenan

Abstract

The application provides a preparation method of alpirozan, and belongs to the technical field of heterocyclic compounds. Alpirozan is prepared from masiprostan. Masiprostan is dissolved in a monosubstituted lower alcohol with C1-C4, and is hydrolyzed under the action of a solid acid at 50-110 DEG C to obtain an intermediate II. The intermediate II is reacted with aminosulfonyl chloride to obtain alpirozan. The application is used for the preparation of alpirozan, and has the advantages of a short reaction route, simple synthesis, high conversion rate, and convenience for industrial amplification.

Description

Technical Field

[0001] The present application relates to a method for preparing aprexitentan, and belongs to the technical field of heterocyclic compounds. Background Art

[0002] Aprocitentan, a novel oral small molecule drug jointly developed by Idorsia and Janssen, targets the dual endothelin receptors ETA / ETB. It is a metabolite (ACT-132577) of macitentan, a drug for the treatment of pulmonary arterial hypertension, and the first ETA / ETB inhibitor to be used in the treatment of hypertension. Clinical results have shown that aprocitentan significantly lowers both diastolic and systolic blood pressure in patients, is well tolerated, and has a low rate of adverse reactions with other medications, making it a promising treatment for patients with resistant hypertension.

[0003]

[0004] In 2017, Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, entered into a collaboration agreement with Idorsia to jointly develop aprocitentan and any derivative compounds or products thereof. Both parties have joint development rights to aprocitentan. On March 19, 2024, the drug was approved by the U.S. Food and Drug Administration (FDA) and is marketed by Idorsia Pharmaceuticals Ltd under the trade name

[0005] The compound structure of aprexitentan (Formula I) is as follows:

[0006]

[0007] Currently, the publicly reported synthesis routes of aprexitentan are mainly the following.

[0008] 1. The original patent CN105992762A discloses a method for synthesizing aprexitentan, which comprises nucleophilic substitution of 5-bromo-2-chloropyrimidine with ethylene glycol under strong alkaline conditions, followed by substitution with 5-(4-bromophenyl)-4,6-dichloropyrimidine to produce Formula 5, followed by fluorination with cesium fluoride, and finally substitution with sulfonamide to produce aprexitentan.

[0009]

[0010] This method for synthesizing aprexitentan is similar to the method previously described for the endocrine receptor antagonist macitentan. Using strong alkaline conditions, 5-bromo-2-chloropyrimidine, ethylene glycol, a 4,6-dichloropyrimidine derivative, and a sulfonamide are linked. The selectivity of the nucleophilic substitution reaction is a major challenge in this synthesis. Ethylene glycol and 5-(4-bromophenyl)-4,6-dichloropyrimidine both share two reactive substituents with similar reactivity, making them susceptible to double-linking side reactions. Furthermore, experiments have shown that direct reaction of Formula 5 with the sulfonamide does not effectively bridge the reaction under strong alkaline conditions. Therefore, a fluorination reaction is required to replace the chlorine substituent with a fluorine substituent. However, this fluorination reaction is highly corrosive to equipment and poses a health risk to operators. Furthermore, both amino groups of the sulfonamide can undergo nucleophilic substitution with the intermediate corresponding to Formula 6, generating dimeric impurities.

[0011] 2. CN101772494A discloses another method for synthesizing aprexitentan. To address the activity issues of the two amino groups on the sulfonamide and the inevitable disubstitution competition reaction, this route uses benzylamine to react with chlorosulfonic acid isocyanate to first prepare benzylaminosulfonamide, which is then substituted with 5-(4-bromophenyl)-4,6-dichloropyrimidine, ethylene glycol, and 5-bromo-2-chloropyrimidine in sequence. Debenzylation is then carried out in a BBr3 and chloroform system, and aprexitentan is obtained by column separation.

[0012] This route first performs benzyl protection on the sulfonamide and then performs nucleophilic substitution. The amino activity of the sulfonamide itself is weak, and the benzyl protection is performed to further reduce its basicity. Therefore, the conditions for synthesizing the intermediate of Formula 8 are harsh. In addition, the benzyl removal is performed under the conditions of BBr3 and chloroform, which takes a long reaction time and the debenzylation reaction under these conditions is very incomplete. The purity and yield of the solid obtained are low, and further column separation is required. The excessive amount of BBr3 causes severe corrosion to the equipment. Comprehensive analysis shows that this route is not conducive to industrialization and has low competitiveness.

[0013] 3. CN117843580A mentions a method for synthesizing aprexitentan. This route first involves acid protonation of sodium phenylsulfinate followed by substitution with 5-(4-bromophenyl)-4,6-dichloropyrimidine (Formula 4), followed by substitution with Formula 3 and sulfonamide to produce aprexitentan. The method provided in the patent suggests that the synthesis is relatively simple, but there are still many problems in the actual synthesis. First, it is difficult to protonate sodium phenylsulfinate with acetic acid. The acidity of acetic acid is weak, and sodium phenylsulfinate cannot be effectively dissolved and protonated to undergo substitution reaction. In addition, in the reaction from Formula C to Formula G, it is difficult to avoid the disproportionation reaction and substitution selectivity of sodium phenylsulfinate itself, resulting in a low actual conversion efficiency. In addition, the activity of the phenylsulfinic acid group and the chlorine substituent and the selectivity of the corresponding substitution cannot react sequentially as described in the patent. Under strong alkaline conditions, the phenylsulfonic acid group in Formula H is easily decomposed. Overall, this method still has many constraints and difficulties in actual reaction control, the reaction conversion is not complete, and the yield is low.

[0014] 4. CN117736152A provides a method for obtaining aprexitentan by aminolysis of a chlorine-substituted pyrimidine derivative, which is then reacted with an N-protected sulfonylation reagent and then deprotected. The method comprises the preparation of an aminopyrimidine, an N-protected sulfonylation reaction, and deprotection. This synthetic route has many steps. The sulfonamide protecting group is primarily an acyl group, and strong acid hydrolysis is generally used. This affects the stability of the sulfonamide bond and may lead to some degradation of the product. Another technical difficulty is the aminolysis of the chlorine-substituted pyrimidine group. The deprotection aminolysis is not very selective. In addition, the alkalinity of ammonia is much stronger than that of sulfonamide, which easily triggers the amination of the bromophenyl group and increases the potential for impurities.

[0015] 5. CN106478520A describes a method for preparing aminopyrimidine (crude intermediate II) by dissolving macitentan in ethanol and performing enhanced alkaline hydrolysis. This method is limited to the preparation of impurity reference substances. The reaction is as follows:

[0016]

[0017] This route involves dissolving macitentan in ethanol and then adding alkali for hydrolysis. Experiments conducted according to this protocol revealed that when macitentan is dissolved in ethanol and reacted with alkali at 70-80°C, the resulting intermediate II is not high in quality. The main impurity is the hydrolysis of the ether bond (Formula A), with the following structure:

[0018]

[0019] Obviously, this method is limited to the preparation of small amounts of impurity reference substances due to its low hydrolysis selectivity. If it is used for the large-scale preparation of intermediate II, its efficiency is low and it is difficult to achieve industrial scale-up.

[0020] 6. CN106279043A describes a method for preparing an aminopyrimidine derivative (Formula II) from macitentan, wherein macitentan is dissolved in 30 times more ethylene glycol, heated for 1 to 2 hours, and then quenched, extracted, concentrated, and crystallized to obtain impurity II.

[0021]

[0022] The example shows that after the reaction, intermediate II only accounts for 5-10% of the reaction liquid, and the conversion efficiency is low. Therefore, it can only be used for small-scale sample preparation, and it is difficult to achieve industrial mass production.

[0023] A comprehensive analysis of existing aprexitentan synthesis methods shows that the methods for preparing aprexitentan from halogen-substituted pyrimidine derivatives through sequential nucleophilic substitution reactions (Routes 1-3) face the following challenges: low selectivity of the nucleophilic substitution reaction, harsh reaction conditions, long routes, and difficulty in industrialization. The synthesis of aprexitentan from amino-substituted pyrimidine derivatives (Routes 4-6) is mainly limited by the low preparation efficiency of intermediate II and the high number of impurities, which makes it difficult to scale up industrially. Summary of the Invention

[0024] In view of this, the present application provides a method for preparing aprexitentan, which not only has a short reaction route with only two steps, but also improves the conversion rate of intermediate II, thereby achieving the preparation of high-purity aprexitentan.

[0025] Specifically, this application is implemented through the following solutions:

[0026] A method for preparing aprexitentan comprises using macitentan as a raw material, dissolving macitentan in a C1-C4 monosubstituted lower alcohol, and hydrolyzing the mixture at 50-110° C. under the action of a solid acid to obtain an intermediate II. The intermediate II is reacted with aminosulfonyl chloride to obtain aprexitentan, wherein the molar ratio of aminosulfonyl chloride to intermediate II is 1.1-2.0:1. The reaction process is as follows:

[0027]

[0028] Furthermore, as a preference:

[0029] The C1-C4 monosubstituted lower alcohol is methanol or ethanol.

[0030] The solid acid is iMoLbox-SAC03; the added amount is 2-50% by weight of macitentan, and preferably 10-20%.

[0031] The added amount of the C1-C4 monosubstituted lower alcohol is 12-40 times the mass of macitentan, and preferably 15-20 times.

[0032] The hydrolysis temperature is preferably 60-90° C., more preferably 70-90° C. More preferably, the hydrolysis is carried out in an autoclave to achieve reaction conditions higher than the boiling point of the C1-C4 monosubstituted lower alcohol.

[0033] An acid binding agent is added during the reaction of the intermediate II with aminosulfonyl chloride, and the molar ratio of the acid binding agent to the intermediate II is 1.2 to 2.0: 1. More preferably, the acid binding agent is pyridine.

[0034] The specific steps of the above process are as follows:

[0035] Step 1: adding macitentan to a C1-C4 monosubstituted lower alcohol and heating to dissolve the mixture; then adding a solid acid and maintaining the temperature for reaction.

[0036] Step 2: filter out the solid acid, recover part of the C1-C4 monosubstituted lower alcohol, cool and crystallize to obtain a crude intermediate II, add acetone and heat to slurry to obtain intermediate II.

[0037] Step 3: Dissolve intermediate II in THF, add an acid-binding agent, and dropwise add aminosulfonyl chloride to obtain aprexitentan. In this process, preferably, aminosulfonyl chloride is dissolved in THF and added dropwise as a THF solution of the obtained aminosulfonyl chloride.

[0038] Intermediate II is primarily derived from the degradation of macitentan. In this case, macitentan is added to a C1-C4 monosubstituted lower alcohol (such as methanol or ethanol). Upon prolonged heating and dissolution, a significant amount of degradation impurities, approximately 5-10%, is generated. These impurities primarily consist of the cleavage of the sulfonamide bond connecting the aminopyrimidine, resulting in Intermediate II. This method significantly improves the conversion rate of macitentan while maintaining high selectivity in the degradation reaction. Specifically, by dissolving macitentan in methanol or ethanol, adding a solid acid catalyst, and heating and maintaining the reaction for a period of time, the conversion rate of macitentan reaches over 85%. DETAILED DESCRIPTION

[0039] The following examples merely represent several feasible implementation methods of the present invention. Although the descriptions thereof are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. The examples are also not intended to limit the scope of protection in the claims of the present invention. It will be apparent to those skilled in the art that various modifications and improvements may be made without departing from the scope of the present invention. Any equivalent implementation or modification that does not depart from the scope of the present invention should be included in the technology of the present invention.

[0040] Example 1

[0041] This example is used to prepare intermediate II, and the reaction process is expressed as follows:

[0042]

[0043] The reaction process is as follows:

[0044] 20 g of macitentan and 250 ml of methanol were added to the autoclave, along with 2 g of iMoLbox-SAC03 solid acid. After nitrogen replacement, the autoclave was sealed and heated to 85°C for 12 hours. The remaining macitentan was detected to be <5%, and the solid acid was removed by hot filtration. The methanol solution was concentrated until approximately 80 ml of solution remained, with a large amount of precipitation. The solution was cooled to 0°C and filtered. The solid was added to 50 ml of acetone, stirred at room temperature for approximately 1 hour, cooled to 5°C, filtered, and dried under reduced pressure to obtain Intermediate II. The powder yield was 13.78 g, 99.05% of related substances, and a yield of 86.8%.

[0045] Example 1-1

[0046] The configuration of this embodiment is the same as that of embodiment 1, except that:

[0047] Add 20g of macitentan and 500ml of methanol to the reaction flask, heat to 65°C to dissolve, add 4g of iMoLbox-SAC03 solid acid, reflux for 48h, detect the remaining macitentan <5%, and remove the solid acid by hot filtration. Concentrate the methanol solution until the solution remains approximately 100ml, and a large amount of precipitation occurs. Cool to 5°C and filter. Add the solid to 40ml of acetone, heat to 40°C, stir for approximately 1h, cool to 5°C, filter, and dry under reduced pressure to obtain Intermediate II. The powder is 13.26g, 98.66% of related substances, and the yield is 83.5%.

[0048] In Example 1-1, the reaction vessel was replaced with a reaction flask. Compared with the autoclave in Example 1, the reaction temperature was lowered, the amount of methanol and solid acid used was significantly increased, the reaction time was greatly increased, and the yield and product purity were lower than those in Example 1. It can be seen that in the preparation process of Intermediate II in this case, the introduction of the autoclave is conducive to achieving a reaction above the boiling point of methanol and obtaining the preparation of Intermediate II with higher purity.

[0049] Example 1-2

[0050] The preparation process of intermediate II in this example is as follows:

[0051] Add 20g of macitentan and 800ml of ethanol to a reaction flask, heat to 78°C to dissolve, add 3g of iMoLbox-SAC03 solid acid, and reflux for 30h. Detect the remaining macitentan to <5%, then remove the solid acid by hot filtration. Concentrate the ethanol solution until approximately 200ml of solution remains, cool to 0°C, and filter. Add the resulting wet solid to 60ml of acetone, stir at 30°C for approximately 1h, cool to 5°C, filter, and dry under reduced pressure to obtain Intermediate II. A powder of 13.12g is obtained, containing 98.4% of related substances, for a yield of 82.6%.

[0052] In Example 1-2, ethanol was used as the solvent, and the amount of solvent for dissolving macitentan was significantly increased. At the same temperature, the reaction rate of sulfonamide bond cleavage was lower than that of methanol, and ultimately, intermediate II could be efficiently prepared from macitentan.

[0053] Example 2

[0054] In this example, aprexitentan was prepared from intermediate II by the following process:

[0055] Under nitrogen, 12 g of Intermediate II and 60 ml of THF were added to a reaction flask, stirred until dissolved, and 3.05 g of pyridine was added. The temperature was lowered to 10°C, and a solution of aminosulfonyl chloride (4.4 g of aminosulfonyl chloride + 15 ml of THF) was added dropwise to the reaction solution. After the addition was complete, the reaction was incubated at 20°C for 4 h. HPLC analysis showed that the residual amount of Intermediate II in the reaction solution was <2%. 120 ml of dichloromethane and 80 ml of a 2% aqueous sodium bicarbonate solution were added to the reaction solution, stirred, and separated. The aqueous layer was extracted once with 50 ml of dichloromethane. The organic layers were combined and concentrated under reduced pressure to a solid. 60 ml of methanol was added, and the temperature was lowered to 5°C and incubated for 1 h. The mixture was filtered, washed, and the filter cake was dried under reduced pressure to obtain 11.72 g of crude aprexitentan, 99.68% of related substances, and a yield of 83.5%.

[0056] Example 3

[0057] In this example, aprexitentan was prepared as follows:

[0058] Under nitrogen, 20 g of Intermediate II and 80 ml of THF were added to a reaction flask, stirred until clear, and 4.8 g of pyridine was added. The temperature was lowered to 10°C, and a solution of 6 g of aminosulfonyl chloride in 30 ml of THF was added dropwise to the reaction solution. After the addition was complete, the reaction was incubated at 30°C for 4 h. HPLC analysis showed that the residual Intermediate II in the reaction solution was <2%. 80 ml of deionized water was added to the reaction solution, stirred until clear, and the pH was adjusted to 6.0 with 20% potassium carbonate solution. The solution was concentrated under reduced pressure at 40°C to remove almost no THF, filtered, and dried. The filter cake was added to 80 ml of methanol, stirred and slurried at 40°C for 2 h, cooled to 10°C, filtered, and dried under reduced pressure to obtain 20.2 g of crude aprexitentan, 99.60% of related substances, and a yield of 86.4%.

Claims

1. A method for preparing aprexitentan, characterized in that: Using macitentan as a raw material, macitentan is dissolved in a C1-C4 monosubstituted lower alcohol, and hydrolyzed at 50-110°C under the action of a solid acid to obtain an intermediate II. Intermediate II reacts with aminosulfonyl chloride to obtain aprexitentan. The molar ratio of aminosulfonyl chloride to intermediate II is 1.1-2.0:

1. The solid acid is iMoLbox-SAC03 solid acid, and the amount of solid acid added is 2-50% by weight of macitentan. The reaction formula of the above reaction process is as follows: .

2. The method for preparing aprexitentan according to claim 1, wherein: The C1-C4 monosubstituted lower alcohol is methanol or ethanol.

3. The method for preparing aprexitentan according to claim 1, wherein: The added amount of the C1-C4 monosubstituted lower alcohol is 12-40 times the mass of macitentan.

4. The method for preparing aprexitentan according to claim 1, wherein: The added amount of the solid acid is 10-20% of the weight of macitentan.

5. The method for preparing aprexitentan according to claim 1, wherein: The hydrolysis temperature is 60-90°C.

6. The method for preparing aprexitentan according to claim 1, wherein: The hydrolysis was carried out in an autoclave.

7. The method for preparing aprexitentan according to claim 1, wherein: An acid binding agent is added during the reaction of the intermediate II with aminosulfonyl chloride, and the molar ratio of the acid binding agent to the intermediate II is 1.2-2.0:

1.

8. The method for preparing aprexitentan according to claim 7, wherein: The acid binding agent is pyridine.

9. The method for preparing aprexitentan according to any one of claims 1 to 8, wherein: Step 1: adding macitentan to a C1-C4 monosubstituted lower alcohol and heating to dissolve the mixture, followed by adding a solid acid and maintaining the temperature for reaction; Step 2: filter out the solid acid, recover part of the C1-C4 monosubstituted lower alcohol, cool and crystallize to obtain a crude intermediate II, add acetone and heat to slurry to obtain intermediate II; Step 3: Dissolve intermediate II in THF, add an acid-binding agent, and dropwise add aminosulfonyl chloride to react to obtain aprexitentan.

Images