Process for the preparation of bilastine

Abstract

The application discloses a preparation process of bilastine, and belongs to the technical field of medicinal chemistry. The target compound is prepared through three-step chemical reactions by using a folding process, intermediate products do not need to be purified or only need to be simply extracted to remove impurities to meet production requirements; compound I is condensed with compound II in water to prepare compound III; then, a proton acid is added to deprotect to prepare a compound IV aqueous solution; after dichloromethane back extraction to remove impurities; the compound IV aqueous solution is subjected to a substitution reaction with compound V to prepare compound VI. The raw material adopted by the application is clear, cheap and easy to obtain, market supply is stable, the preparation process is simple, water is used as a solvent in the three-step reaction, and no special equipment is required, the production efficiency is improved, the production cycle is shortened, and the generation of three wastes is reduced, and the application is suitable for industrial production; the purity of each intermediate prepared is more than 99%, the purity of the final product can reach 99.88%, and the impurity spectrum is stable and clear.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and specifically relates to a preparation process of bilastin. Background Technology

[0002] Bilastine, a second-generation histamine H1 receptor antagonist developed by FAES Pharmaceuticals in Spain, was approved by the European Union in 2010 for the treatment of allergic rhinitis and chronic idiopathic urticaria. It has a good safety profile, without the sedative effects and cardiotoxicity commonly found in antihistamines.

[0003] Bilastin's chemical name is 2-[4-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)piperidin-1-yl)ethyl)phenyl]-2-methylpropionic acid, and its chemical structure is shown in Formula I.

[0004]

[0005] I

[0006] Currently, there are several main methods for synthesizing bilastine:

[0007] ① Patent CN104177331B reports a two-step process of methylation and hydrolysis to obtain birastin from 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)ethyl)phenyl)acetate esters (compounds of formula I). ​​Besides the high price and scarcity of the starting material (compounds of formula I) and the need for multiple reaction steps, the methylating reagents used in the methylation reaction are iodomethane or dimethyl sulfate, both highly toxic substances, which are not conducive to large-scale production. The reaction route is as follows:

[0008]

[0009] ② Patent CN104326909A reports a synthetic method for preparing bilastine. First, it provides a method for preparing α,α-dimethyl-4-(2-haloethyl)phenylacetic acid ester; then, it uses this compound to prepare bilastine. This method involves five steps, a long reaction route, and requires hydrolysis of the ester protecting group at the end, which is not conducive to industrial production. The reaction route is as follows:

[0010]

[0011] ③ Patent CN105017211A reports a method for obtaining bisurasine by using (compound of formula II) as a raw material, via catalytic coupling of manganese dioxide and biphenylpyridine nickel bromide, followed by methylation and hydrolysis. The metal catalyst used in this coupling process requires careful control and removal of residual metals; the methylation reaction uses NaH, which is relatively dangerous, and the methylating agent used is iodomethane, a highly toxic substance, which is unfavorable for large-scale production. The reaction route is as follows:

[0012]

[0013] ④ Patent CN106146459B reports a route using 2-nitroaniline (compound 1) as a starting material, followed by reductive cyclization, alkylation, organic acid hydrolysis, and coupling hydrolysis to obtain bilastine. This route involves the hydrolysis of intermediate 5 using organic acids, and the subsequent processing requires extraction and concentration, which is quite cumbersome. The preparation of compound 7 requires column chromatography purification, and its limited market supply restricts its industrial application prospects to some extent. The reaction route is as follows:

[0014] ⑤ Patent CN107365298A reports a two-step reaction in which compounds of formula 2 and formula 3 are substituted and hydrolyzed in water to obtain bilastine. The synthetic route is relatively short and shows promise for applications, but compound 3 is scarce in the market, and its preparation method is not further elaborated. The reaction route is as follows:

[0015]

[0016] ⑥ Patents CN107368294B and CN110950837 report the preparation of birastin mainly from compounds of formula 3 and formula 2 via reductive amination. Formula 2 is an aliphatic aldehyde compound with poor stability and requires oxidation to obtain it. The overall process involves relatively dangerous processes such as oxidation and reduction, and is not suitable for industrial production. The reaction route is as follows:

[0017]

[0018] ⑦ Patent CN109081827A reports a method for obtaining methyl bisurastin from compounds of formulas 1 and 2 via a substitution reaction, followed by hydrolysis of the ester protecting group to obtain bisurastin. The reaction route is as follows:

[0019]

[0020] ⑧ Patent CN109694367B reports a method for preparing an intermediate of formula 3 by substitution reactions of compounds of formula 1 and formula 2, followed by alkylation reaction with a compound of formula 4 to prepare an intermediate of formula 5, and finally hydrolysis of the dihydrooxazole ring protecting group to obtain bilastine. The overall route is slightly longer. The reaction route is as follows:

[0021]

[0022] ⑨ The synthetic process reported in patent CN112110893A is similar to that in CN109694367B, both employing a strategy of introducing a dihydrooxazole ring protecting group, followed by hydrolysis to obtain birastin. The reaction route is as follows:

[0023] Summary of the Invention

[0024] The technical problem to be solved by the present invention is to provide a process for preparing bilastine, which uses 4-(1H-benzo[D]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester, 2-ethoxychloroethane, 4-(2-chloroethyl)-α,α-dimethylphenylacetic acid and other starting materials as starting materials, and synthesizes high-purity and high-yield bilastine through alkylation, deprotection of Boc group and substitution reactions.

[0025] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0026] A process for preparing bilastin includes the following steps:

[0027] 1) Compound I undergoes a condensation reaction with compound II in water to prepare compound III, which can be directly proceeded to the next step of deprotection without purification;

[0028] 2) Compound III is deprotected by adding a protic acid, and after back-extraction with dichloromethane, an aqueous solution of compound IV is obtained, which is then directly used for the next reaction;

[0029] 3) Compound IV reacts with compound V in an aqueous solution via a substitution reaction to produce compound VI;

[0030] The reaction formula is as follows:

[0031] .

[0032] Further, in step 1), the molar ratio of compound I to compound II is 1:1.5, and the reaction temperature is 90~100℃.

[0033] Furthermore, in step 2), the protic acid is hydrochloric acid.

[0034] Furthermore, in step 2), the weight ratio of protic acid to compound I is 1.5:1; the reaction temperature is 20~30℃.

[0035] Furthermore, in step 3), the molar ratio of compound IV to compound V is 1:0.9.

[0036] Furthermore, in step 3), the base used is DBU.

[0037] Furthermore, in step 3), the pH range of the system is controlled to be 10.0~11.0.

[0038] Furthermore, in step 3), the reaction temperature is 90~100℃.

[0039] Furthermore, the purity of compound VI is 99.88%.

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] (1) The raw materials used in this invention are cheap and readily available, with stable market supply and controllable production costs; the preparation process is simple to operate, the reaction solvent is mainly water, the intermediate products do not need to be purified or only need simple extraction to remove impurities to meet production requirements, there are no special equipment requirements, which greatly shortens the production cycle and reduces the generation of waste, making it suitable for industrial production.

[0042] (2) The purity of each intermediate prepared by the present invention is above 99%, the purity of the final product can reach 99.88%, and the impurity spectrum is stable and clear. Attached Figure Description

[0043] Figure 1 Reaction route diagram for the preparation of bilastine in this application;

[0044] Figure 2 This is the HPLC chromatogram of compound III obtained in Example 1 of this application;

[0045] Figure 3 The HPLC chromatogram of compound IV obtained in Example 1 of this application;

[0046] Figure 4 This is the HPLC chromatogram of compound VI obtained in Example 1 of this application;

[0047] Figure 5 Compound VI obtained in Example 1 of this application 1 H-NMR spectrum;

[0048] Figure 6 This is an MS chromatogram of compound VI obtained in Example 1 of this application. Detailed Implementation

[0049] The present invention will be further illustrated below with reference to specific embodiments. These embodiments are implemented based on the technical solutions of the present invention, and it should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0050] The raw material information used in the following examples is shown in Table 1.

[0051] Table 1. Information on Main Raw Materials

[0052]

[0053] Figure 1 The synthetic process flow diagram for preparing bilastine includes the following steps:

[0054] S1: 4-(1H-benzo[D]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (I) and 2-ethoxychloroethane (II) were condensed in the presence of crown ether 15-Crown-5 to prepare 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (III). After the reaction was completed and the temperature was lowered, the next step of deprotection was directly carried out.

[0055] S2: 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (III) was deprotected under hydrochloric acid conditions, and after the reaction was completed, dichloromethane was added for back-extraction to prepare 1-(2-ethoxyethyl)-2-(piperidine-4-yl)-1H-benzo[d]imidazol (IV), which was directly fed into the next step in the form of hydrochloric acid aqueous solution;

[0056] S3: The target compound bisurastin (VI) was prepared by a substitution reaction of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzis[d]imidazole (IV) with 4-(2-chloroethyl)-α,α-dimethylphenylacetic acid (V).

[0057] Example 1

[0058] A process for preparing bilastin includes the following steps:

[0059] 1) Synthesis of 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound III), the reaction formula is as follows:

[0060]

[0061] 20.00 g of compound I, 10.81 g of compound II, 7.96 g of sodium hydroxide, and 2.92 g of crown ether 15-Crown-5 were added to 250 mL of water. The mixture was heated to 90–100 °C and stirred for 8 h. After the reaction was complete, the temperature was lowered to 20–30 °C to obtain compound III. The molar yield was assumed to be 100%. Subsequent deprotection was performed directly, and the purity was 99.49%. The purity of compound III is as follows: Figure 2 As shown in Table 2.

[0062] Table 2 Purity results of compound III

[0063]

[0064] 2) Synthesis of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (compound IV), the reaction formula is as follows:

[0065]

[0066] Add 30.00 g of hydrochloric acid to the reaction solution from the previous step, maintain the temperature at 20-30℃ and stir for 2 hours. After the reaction is complete, add 60.00 g of dichloromethane for extraction. After separation, the aqueous phase is compound IV (hydrochloride aqueous solution). Assuming a molar yield of 100%, proceed directly to the next step. Purity as follows: Figure 3 As shown in Table 3.

[0067] Table 3 Purity results of compound IV

[0068]

[0069] 3) Preparation of bilastine (compound VI), the reaction formula is as follows:

[0070]

[0071] Add 40.75g of the aqueous solution of compound IV obtained in step 2). DBU was added to a system with a pH of 10.0–11.0. 13.54 g of compound V was added, and the mixture was heated to 90–100 °C and maintained at this temperature for 9 h. After the reaction was complete, the temperature was lowered to 20–30 °C, and 460 mL of water was added. The mixture was extracted three times with 180 mL of ethyl acetate each time. The pH of the aqueous phase was adjusted to 6.0–7.0 with hydrochloric acid. 148 mL of dichloromethane was added, and the mixture was stirred at 20–30 °C for 1 h. After filtration, the filter cake was added to 103 mL of acetonitrile and 23 mL of tetrahydrofuran. The mixture was heated to 60–70 °C and stirred for 1 h. After cooling to 20–30 °C, the mixture was filtered again. The filter cake was then added again to 29 mL of n-butanol and 29 mL of butyl acetate. The mixture was heated to 100–110 °C and stirred for 1 h. After cooling to 20–30 °C, the mixture was filtered and dried to obtain 15.01 g of bilastine, with a molar yield of 60.47% and a purity of 99.88%. 1H NMR (400MHZ, DMSO-d6): δ12.29 (brs, 1H) 7.55 (d, 1H, J=6.0Hz), 7.51 (d, 1H, J=6.0Hz), 7.26 (d, 2H, J=12 .0Hz), 7.20(d, 2H, J=12.0Hz), 7.16(m, 1H), 7.14(m, 1H), 4.39(t, 2H, J=6.0Hz), 3.65(t, 2H, J=6.0Hz), 3.35(q, 2H, J=6.0Hz), 3.06(d, 2H, J=12.0Hz), 3.01(m, 1H), 2.74(t, 2H, J=6.0Hz), 2.55(t, 2H, J=6.0Hz ), 2.13(t, 2H, J=12.0Hz), 1.92(m, 2H), 1.86(m, 2H), 1.46(s, 6H), 1.00(t, 3H, J=6.0Hz), MS: 463.62 (M+H + The prepared bilastin 1 H-NMR spectra and MS spectra, such as Figure 5 and Figure 6 As shown, the purity results are as follows: Figure 4 As shown in Table 4.

[0072] Table 4. Purity results of bilastine (compound VI)

[0073]

[0074] Example 2

[0075] A process for preparing bilastin includes the following steps:

[0076] 1) Synthesis of 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (compound III):

[0077] 180.00 g of compound I, 97.29 g of compound II, 71.64 g of sodium hydroxide and 26.28 g of crown ether 15-Crown-5 were added to 2250 mL of water, heated to 90-100 °C and stirred for 8 h. After the reaction was completed, the temperature was lowered to 20-30 °C to obtain compound III. The molar yield was assumed to be 100%, and the subsequent deprotection operation was carried out directly.

[0078] 2) Synthesis of 1-(2-ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (compound IV):

[0079] Add 270.00g of hydrochloric acid to the reaction solution from the previous step, and stir at 20~30℃ for 2 hours. After the reaction is complete, add 540.00g of dichloromethane for extraction. The aqueous phase after separation is compound IV (hydrochloride aqueous solution). The molar yield is 100%, and the next step of feeding is carried out directly.

[0080] 3) Preparation of bilastine (compound VI):

[0081] Add 366.75g of the aqueous solution of compound IV obtained in step 2). DBU was added to a system with a pH of 10.0–11.0. 121.86 g of compound V was added, and the mixture was heated to 90–100 °C and maintained at this temperature for 9 h. After the reaction was complete, the temperature was lowered to 20–30 °C, and 4140 mL of water was added. The mixture was extracted three times with 1620 mL of ethyl acetate each time. The pH of the aqueous phase was adjusted to 6.0–7.0 with hydrochloric acid. 1332 mL of dichloromethane was added, and the mixture was stirred at 20–30 °C for 1 h. After filtration, the filter cake was added to 927 mL of acetonitrile and 207 mL of tetrahydrofuran. The mixture was heated to 60–70 °C and stirred for 1 h. After cooling to 20–30 °C, the mixture was filtered again. The filter cake was then added to 261 mL of n-butanol and 261 mL of butyl acetate. The mixture was heated to 100–110 °C and stirred for 1 h. After cooling to 20–30 °C, the mixture was filtered and dried to obtain 138.87 g of bilastine, with a molar yield of 62.16% and a purity of 99.87%.

[0082] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for preparing bilastine, characterized in that: Includes the following steps: 1) Compound I undergoes a condensation reaction with compound II in water to prepare compound III, which can be directly proceeded to the next step of deprotection without purification; 2) Compound III is deprotected by adding a protic acid, and after back-extraction with dichloromethane, an aqueous solution of compound IV is obtained, which is then directly used for the next reaction; 3) Compound IV reacts with compound V in an aqueous solution via a substitution reaction to produce compound VI; The reaction formula is as follows: 。 2. The preparation process of bilastine according to claim 1, characterized in that: In step 1), the molar ratio of compound I to compound II is 1:1.5, and the reaction temperature is 90~100℃.

3. The preparation process of bilastine according to claim 1, characterized in that: In step 2), the protic acid is hydrochloric acid.

4. The preparation process of bilastine according to claim 1, characterized in that: In step 2), the weight ratio of protic acid to compound I is 1.5:1; the reaction temperature is 20~30℃.

5. The preparation process of bilastine according to claim 1, characterized in that: In step 3), the molar ratio of compound IV to compound V is 1:0.

9.

6. The preparation process of bilastine according to claim 1, characterized in that: In step 3), the base used is DBU.

7. The preparation process of bilastine according to claim 1, characterized in that: In step 3), the pH range of the system is controlled to be 10.0~11.

0.

8. The preparation process of bilastine according to claim 1, characterized in that: In step 3), the reaction temperature is 90~100℃.

9. The preparation process of bilastine according to claim 1, characterized in that: The purity of compound VI is 99.88%.

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