CN114920727B

CN114920727B - Preparation method of rupatadine

Info

Publication number: CN114920727B
Application number: CN202210587254.2A
Authority: CN
Inventors: 何志红; 何超
Original assignee: Chongqing Huapont Pharm Co Ltd
Current assignee: Chongqing Huapont Pharm Co Ltd
Priority date: 2022-05-26
Filing date: 2022-05-26
Publication date: 2023-07-25
Anticipated expiration: 2042-05-26
Also published as: CN114920727A

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of rupatadine. The method comprises the following steps: reducing a compound of the formula II in a solvent by sodium borohydride and boron trifluoride diethyl etherate, adding acid for hydrolysis, alkalizing, and adding an organic solvent for extraction; washing the extracted organic phase with sodium acetate buffer solution to remove impurities; refining with mixed solution of ethyl acetate and n-hexane to obtain crystalline solid rupatadine shown in formula I, wherein HPLC content is greater than 99.0%, and single impurity is less than 0.10%. The method has the advantages of simple operation, moderate reaction temperature, controllable conditions and convenient industrial production; the rupatadine prepared by the method is a crystal solid, has good stability, is convenient to store and transport, and is convenient to operate in production; the product has good quality and high yield, and is suitable for commercial production.

Description

Preparation method of rupatadine

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of rupatadine.

Background

Rupatadine fumarate (Rupatadine Fumarate), known as 8-chloro-11- [1- [ (5-methyl-3-pyridinyl) methyl ] -4-piperidino ] -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine fumarate, an antiallergic agent developed by Spanish Uriach, inc. having dual actions against histamine and Platelet Activating Factor (PAF), is indicated for seasonal and perennial allergic rhinitis. Rupatadine fumarate has the following chemical structural formula:

rupatadine is an important intermediate of rupatadine fumarate, and the method for preparing rupatadine by taking desloratadine as a raw material mainly comprises the following two steps:

the method comprises the following steps: 3, 5-lutidine is taken as a raw material to be subjected to chlorination or bromination to obtain 3-chloro (or bromo) methyl-5-methylpyridine, or 5-methylnicotinic acid is subjected to methyl esterification to obtain 3-methyl formate-5-methylpyridine, lithium aluminum hydride is used for reducing into alcohol, 3-chloro (or bromo) methyl-5-methylpyridine is obtained through halogenation, and rupatadine is obtained through reaction with desloratadine;

the method has the defects of more byproducts of preparing 3-chloro (or bromo) methyl-5-methylpyridine, difficult purification, low yield and high cost.

Reference document rupatadine synthesis (Xin Shuibo, journal of new Chinese medicine, 2005) uses 3, 5-lutidine to react with halogenated reagents such as NBS, NCS and the like under the action of equivalent initiator to prepare 3-chloro (or bromo) methyl-5-methylpyridine, the byproduct is more (through MS identification, mainly disubstituted product and halogenated product and pyridine nitrogen atom generate side reaction to generate quaternary ammonium salt), after multiple purification, HPLC purity is 60% -80%, and the highest yield is 8%. Reference Synthetic Communications,38 (1), 122-127;2008 is methyl esterified by 5-methylnicotinic acid to obtain 3-methyl formate-5-methylpyridine, lithium aluminum hydride is used for reducing the 3-methyl formate-5-methylpyridine into alcohol, and then the 3-chloromethyl-5-methylpyridine is obtained through chlorination, and the yield is lower than 10%.

The second method is as follows: generating amide by 5-methylnicotinic acid and desloratadine under the action of condensing agent (DCC, CDI, SOCl and the like), and reducing to obtain rupatadine;

in the second method, rupatadine is prepared by amide reduction, and the following documents and patents report that:

patent CN200510070952.1 discloses that rupatadine is prepared by reducing amide by sodium aluminate (Red-Al), the reagent sodium aluminate is expensive, and colloid byproducts are formed after the hydrolysis of the sodium aluminate, so that the separation and purification are not easy, and the production operation is not facilitated.

Patent CN200810005209.1 discloses that the preparation of rupatadine from acyloxy alkali metal borohydride reduction amide is costly in terms of acid water consumption for post-treatment, long reaction time and high production costs.

Patent CN201510437799.5 discloses that the preparation of rupatadine by reduction of amide with borane complex, the obtained rupatadine is oily, has low content, is unfavorable for storage and transportation, and is unfavorable for production operation.

Patent ES2087818 discloses the use of POCl ₃ The sodium borohydride reduces amide to prepare rupatadine, a large amount of colloid substances are generated in the reaction process, the impurities are more, and the product yield is low.

Patent US5407941 discloses that the preparation of rupatadine by reducing amide with lithium aluminum hydride is expensive, sensitive and changeable, has hidden danger of explosion, has lower safety, has higher risk of hydrogenating lithium aluminum in production, and is not suitable for large-scale production.

Rupatadine reported in the current literature is a fat-like solid or oily substance, has a large amount of impurities and relatively low HPLC content, and has poor solubility after salifying rupatadine and fumaric acid, and no impurity removal effect after salifying and refining. Therefore, it is necessary to develop a high-yield, high-purity rupatadine.

Disclosure of Invention

In view of the above, the invention provides a pharmaceutical grade rupatadine preparation method which overcomes the defects of the prior art.

The invention aims at providing a preparation method of rupatadine, which provides a new idea for preparing rupatadine.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

the method specifically comprises the following steps:

s1: reacting the compound A with sodium borohydride and boron trifluoride diethyl etherate in tetrahydrofuran to extract an organic phase;

s2: washing the organic phase in the step S1 by using a buffer solution to remove impurities;

s3: refining the S2 product by using a mixed solution of ethyl acetate and normal hexane;

the structural formula of the compound A is shown as a formula II, the structural formula of rupatadine is shown as a formula I,

further, the molar ratio of the II compound, sodium borohydride and boron trifluoride diethyl etherate in S1 is 1:4.5-7.5:6-10.

Further, the solvent used for the extraction described in S1 is any one of toluene, ethyl acetate, and methylene chloride.

Further, as a preferable example, the solvent is toluene.

Further, the reaction control temperature in S1 is 20 to 50 ℃.

Further, the reaction pH in S1 is 9 to 11.

And the feeding sequence in the step S1 is to sequentially add the compound A, tetrahydrofuran and sodium borohydride into a reaction bottle, cool to 0-10 ℃, drop boron trifluoride diethyl ether, raise the temperature to 20-30 ℃ after the drop is finished, react for 1 hour, and then raise the temperature to 40-50 ℃ to react for 1 hour.

In the step S1, the temperature of the reaction solution is reduced to 0-10 ℃ after the reaction is finished, hydrochloric acid (preferably 1N hydrochloric acid) is added dropwise, and the temperature is increased to 85-95 ℃ after the dropwise addition is finished for reaction for 1 hour. Then cooling to 0-10 ℃, dripping sodium hydroxide solution to adjust the PH to 9-11, and then adding the solvent for extraction.

The buffer solution in S2 is any one of acetic acid, aqueous sodium acetate solution, aqueous potassium dihydrogen phosphate solution, aqueous acetic acid solution, and ammonium chloride solution.

Further, the pH was adjusted to 4 to 6 with the above-mentioned buffer.

Further, the number of washes described in S2 is at least 2.

Further, the organic phase in S1 is washed 2 times with the buffer solution and then 1 to 2 times with water, so that organic impurities and inorganic salts which can form salts with acids can be removed, and then the solvent is removed by concentrating under reduced pressure.

Further, the volume ratio of the ethyl acetate to the n-hexane mixed solution in the step S3 is 1:2-6.

And in step S3, adding the ethyl acetate into the residue after the concentration of the step S2, refluxing and dissolving, adding n-hexane, and gradually cooling to 0-10 ℃.

Further, S4 crystallization, filtration and drying are further included after S3.

The invention has the advantages that:

1) The rupatadine prepared by the method provided by the invention has the yield of 80-90%, the HPLC purity of more than 99.0%, and single unknown impurity of less than 0.10%, and can reach the medicinal grade.

2) The rupatadine prepared by the method is a crystal solid, has good stability and is convenient to store and transport.

3) The solvent or the reagent used in the invention is cheap and easy to obtain, the feeding is convenient, the operation is simple, and the method is suitable for commercial production.

Drawings

Fig. 1 is a high performance liquid chromatogram of rupatadine prepared in example 1.

Fig. 2 is a mass spectrum of rupatadine prepared in example 1.

Fig. 3 is a nuclear magnetic resonance hydrogen spectrum of rupatadine prepared in example 1.

Fig. 4 is a nuclear magnetic resonance chromatogram of rupatadine prepared in example 1.

Detailed Description

Hereinafter, preferred embodiments of the present invention will be described in detail. Experimental methods without specific conditions noted in the preferred embodiments, the present invention is better illustrated by the examples according to the conventional conditions, but the present invention is not limited to the examples. Those skilled in the art will appreciate that various modifications and adaptations of the embodiments described above are possible in light of the above teachings and are intended to be within the scope of the invention.

Example 1: preparation of rupatadine

The preparation method of the buffer solution comprises the following steps: after dissolving sodium hydroxide (10 g) in water (400 g), acetic acid (17 g) was added thereto, and the pH (5.47) was measured by pH meter.

Compound A (50 g,0.1165mol,1.0 eq) was added to a 3000ml reaction flask under nitrogen, tetrahydrofuran (750 ml) was added, sodium borohydride (26.4 g,0.699mol,6.0 eq) was added under stirring, the reaction solution was cooled to 0-10 ℃, nitrogen was turned off, and boron trifluoride diethyl ether (132.3 g,0.932mol,8.0 eq) was added dropwise. After the dripping is finished, the reaction solution is heated to 20-30 ℃ to react for 1 hour, and then heated to 40-50 ℃ to react for 1 hour.

The temperature of the reaction solution is reduced to 0-20 ℃, hydrochloric acid (1N, 480 ml) is added dropwise, and the temperature is raised to 85-95 ℃ after the completion of the dropwise addition for reaction for 1 hour.

The reaction solution was cooled to 30-50 ℃, toluene (400 ml) was added, and sodium hydroxide (10N, 220 g) solution was added dropwise to adjust the pH:9 to 11. The reaction solution was heated to 55-65 ℃ and stirred for dissolution, allowed to stand for delamination, washed twice with organic addition buffer (213.5 g/time), washed 1 time with water, concentrated under reduced pressure to remove the solvent, ethyl acetate (100 ml) was added to the residue, after dissolution under reflux, n-hexane (300 ml) was added, heating was turned off, cooling to 0-10 ℃ and stirred for crystallization for 90 minutes, filtration, washing with n-hexane, drying to obtain rupatadine (42.8 g), yield 88.3%, HPLC purity 99.83%, chromatogram as shown in fig. 1, and liquid chromatogram integration results as shown in table 1.MS-ESI (m/z): 416.4[ M+H ]] ⁺ As shown in fig. 2. ¹ H-NMR (nuclear magnetic resonance hydrogen spectrum), (400 MHz, DMSO): δ= 8.331 (dd, j= 1.6,1.6,1H); 8.287 (dd, j= 1.6,1.2,2H); 7.542 (dd, j= 1.2,1.2,1H); 7.51 (s, 1H); 7.285 (d, j= 3.2,1H); 7.209-7.165 (m, 2H); 7.059 (d, j= 8.4,1H); 3.45 (s, 2H); 3.293-3.282 (m, 2H); 2.839-2.787 (m, 2H); 2.601 (d, j= 4.4,2H); 2.347-2.312 (m, 2H); 2.282 (s, 3H); 2.200-2.148 (m, 4H), as shown in fig. 3. ¹³ C-NMR (nuclear magnetic resonance carbon spectrum) (600 MHz, CD3 OD): δ= 157.63;149.10;147.70;146.79;140.52;138.40;137.72;137.37;133.69;132.91;131.92;131.24;129.40;126.06;122.71;59.39;54.61;31.59;30.99;30.85;18.25 as shown in fig. 4.

TABLE 1

Example 2: preparation of rupatadine

Compound A (5 g, 0.011100 mol,1.0 eq) was added to a 250ml reaction flask under nitrogen, tetrahydrofuran (75 ml) was added, sodium borohydride (2.7 g,0.072mol,6.0 eq) was added under stirring, and boron trifluoride diethyl ether (13.6 g,0.096mol,8.0 eq) was added dropwise at 30-40℃to the reaction mixture. After the completion of the dropwise addition, the reaction was continued for 2 hours at a constant temperature.

The reaction solution was cooled to 0-20℃and hydrochloric acid (1N, 48 ml) was added dropwise, and after the completion of the addition, the temperature was raised to 85-95℃and the reaction was carried out for 1 hour, and HPLC showed that 5% of Compound A was not reacted.

Example 3: preparation of rupatadine

Under the protection of nitrogen, compound A (5 g, 0.011100 mol,1.0 eq) was added to a 250ml reaction flask, tetrahydrofuran (75 ml) was added, sodium borohydride (2.0 g,0.054mol,4.5 eq) was added under stirring, the reaction solution was cooled to 0-10 ℃, nitrogen was turned off, and boron trifluoride diethyl ether (10.2 g,0.072mol,6.0 eq) was added dropwise. After the dripping is finished, the temperature of the reaction solution is raised to 20-30 ℃ for reaction for 3 hours.

The reaction solution was cooled to 0-20℃and hydrochloric acid (2N, 11 ml) was added dropwise, and after the completion of the addition, the temperature was raised to 85-95℃for 1 hour, and HPLC showed 3.5% of Compound A was not reacted.

Example 4: preparation of rupatadine

Under the protection of nitrogen, compound A (5 g, 0.011100 mol,1.0 eq) was added to a 250ml reaction flask, tetrahydrofuran (75 ml) was added, sodium borohydride (2.7 g,0.072mol,6.0 eq) was added under stirring, the reaction solution was cooled to 0-10 ℃, nitrogen was turned off, and boron trifluoride diethyl ether (13.6 g,0.096mol,8.0 eq) was added dropwise. After the dripping is finished, the temperature of the reaction solution is raised to 20-30 ℃ for reaction for 3 hours.

The temperature of the reaction solution is reduced to 0-20 ℃, hydrochloric acid (2N, 11 ml) is added dropwise, the temperature is raised to 85-95 ℃ after the dropwise addition, the reaction is carried out for 1 hour, and HPLC shows that the reaction of the compound A is finished.

Example 5: preparation of rupatadine

Under the protection of nitrogen, compound A (5 g, 0.011100 mol,1.0 eq) was added to a 250ml reaction flask, tetrahydrofuran (75 ml) was added, sodium borohydride (3.4 g,0.09mol,7.5 eq) was added under stirring, the reaction solution was cooled to 0-10 ℃, nitrogen was turned off, and boron trifluoride diethyl ether (17.0 g,0.12mol,10.0 eq) was added dropwise. After the dripping is finished, the temperature of the reaction solution is raised to 20-30 ℃ for reaction for 3 hours.

Example 6: preparation of rupatadine

Compound A (100 g,0.233mol,1.0 eq) was added to a 3000ml reaction flask under nitrogen, tetrahydrofuran (1500 ml) was added, sodium borohydride (52.8 g,1.396mol,6.0 eq) was added under stirring, the reaction mixture was cooled to 0-10℃and nitrogen was turned off, boron trifluoride diethyl ether (264.6 g,1.864mol,8.0 eq) was added dropwise. After the dripping is finished, the reaction solution is heated to 20-30 ℃ to react for 1 hour, and then heated to 40-50 ℃ to react for 1 hour.

The temperature of the reaction solution is reduced to 0-20 ℃, hydrochloric acid (1N, 960 ml) is added dropwise, and the temperature is raised to 85-95 ℃ for reaction for 1 hour after the completion of the dropwise addition.

The reaction solution was cooled to 30-50 ℃, toluene (800 ml) was added, and sodium hydroxide (10N, 440 g) solution was added dropwise to adjust the pH:9 to 11. The reaction solution is heated to 50-60 ℃ and stirred for dissolution, and is kept stand for layering, the water phase is separated, and the organic phase is divided into 10 parts. Respectively preparing 20% potassium dihydrogen phosphate aqueous solution (PH: 4.55), acetic acid aqueous solution (PH: 4.65, 5.20, 5.24, 5.53, 5.94, 6.15), ammonium chloride aqueous solution (PH: 6), acetic acid aqueous solution (PH: 4.26). The organic phase was washed with the same volume of buffer, the same washing pattern and washing times, and the organic phase before and after washing was subjected to HPLC detection. As a result, it was found that the washing with a 20% aqueous solution of potassium dihydrogen phosphate (pH: 4.55) was excellent in the effect of removing impurities, the lower the pH value of the aqueous solution of acetic acid and sodium acetate was, the better the effect of removing impurities by washing, and the effect of removing impurities by washing twice was excellent than that by washing once. The washing with an aqueous ammonium chloride solution (pH: 6) and an aqueous acetic acid solution (pH: 4.26) was poor in the effect of removing impurities. Because the monopotassium phosphate contains phosphorus, the environment is polluted, and the scale-up production is not facilitated. The lower the pH of the aqueous acetic acid and sodium acetate solution, the lower the yield. Therefore we chose to wash the organic phase twice with aqueous acetic acid and sodium acetate at pH 5-6. The washing and impurity removal conditions of the different buffer solutions are shown in Table 2 below.

TABLE 2

Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.

Claims

1. A process for the preparation of rupatadine, characterized in that it comprises in particular the following steps:

s2: washing the organic phase in the step S1 by using a buffer solution to remove impurities; the buffer solution is acetic acid and sodium acetate water solution, the pH is adjusted to 5-6 by the buffer solution, and the washing times are at least 2 times;

2. the process according to claim 1, wherein the molar ratio of the compound of formula II, sodium borohydride and boron trifluoride etherate in S1 is 1:4.5-7.5:6-10.

3. The method according to claim 1, wherein the solvent used for the extraction in S1 is any one of toluene, ethyl acetate, and methylene chloride.

4. The process of claim 1 wherein the reaction control temperature in S1 is 20 ℃ to 50 ℃.

5. The method according to claim 1, wherein the volume ratio of ethyl acetate to n-hexane in S3 is 1:2-6.

6. The method of claim 1, wherein S3 further comprises S4 crystallization, filtration, and drying.