CN114920727A

CN114920727A - Preparation method of rupatadine

Info

Publication number: CN114920727A
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: 2022-08-19
Anticipated expiration: 2042-05-26
Also published as: CN114920727B

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of rupatadine. The method specifically comprises the following steps: reducing a compound shown in a formula II in a solvent by using sodium borohydride and boron trifluoride diethyl etherate, adding acid for hydrolysis and alkalization, and adding an organic solvent for extraction; washing the extracted organic phase with sodium acetate buffer solution to remove impurities; the crystal solid rupatadine shown in the formula I is obtained by refining a mixed solution of ethyl acetate and normal hexane, the HPLC content of the crystal solid rupatadine is more than 99.0 percent, and the single impurity is less than 0.10 percent. The method has simple operation, moderate reaction temperature, controllable conditions and convenient industrial production; the rupatadine prepared by the method is a crystalline 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), with the chemical name of 8-chloro-11- [1- [ (5-methyl-3-pyridyl) methyl ] -4-piperidinylidene ] -6, 11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b ] pyridine Fumarate, an antiallergic drug developed by the company Uriach, Spain and having dual actions of antihistaminic and Platelet Activating Factor (PAF), and the indication is seasonal and perennial allergic rhinitis. The chemical structural formula of rupatadine fumarate is as follows:

the 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: the method comprises the following steps of (1) carrying out chlorination or bromination on 3, 5-dimethyl pyridine serving as a raw material to obtain 3-chloro (or bromo) methyl-5-methylpyridine, or carrying out methyl esterification on 5-methylnicotinic acid to obtain 3-methyl formate-5-methylpyridine, reducing the 3-methyl formate-5-methylpyridine into alcohol by lithium aluminum hydride, carrying out halogenation to obtain 3-chloro (or bromo) methyl-5-methylpyridine, and carrying out reaction on the 3-chloro (or bromo) methyl-5-methylpyridine and desloratadine to obtain rupatadine;

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

According to the reference document, 3, 5-dimethylpyridine reacts with halogenated reagents such as NBS, NCS and the like under the action of an equivalent initiator to prepare the 3-chloro (or bromo) methyl-5-methylpyridine in the synthesis of rupatadine (Xinshuibo, journal of New Chinese medicine, 2005), the byproducts are more (identified by MS, the byproducts are mainly disubstituted products, and the halogenated products and pyridine nitrogen atoms generate side reactions to generate quaternary ammonium salt), and the HPLC purity is 60-80% after multiple purifications, and the highest yield is 8%. References Synthetic Communications,38(1), 122-; 2008, methyl esterification is carried out on 5-methylnicotinic acid to obtain 3-methyl formate-5-methylpyridine, lithium aluminum hydride is used for reduction into alcohol, chlorination is carried out to obtain 3-chloromethyl-5-methylpyridine, and the yield is lower than 10%.

The second method comprises the following steps: the 5-methylnicotinic acid and the desloratadine generate amide under the action of a condensing agent (DCC, CDI, SOCl2 and the like), and the amide is reduced to obtain the rupatadine;

in the second method, rupatadine is prepared by amide reduction, and the following are reported in relevant documents and patents:

patent CN200510070952.1 discloses rupatadine prepared by reducing amide with sodium dihydroaluminate (Red-Al), wherein the used reagent sodium dihydroaluminate is expensive, and the sodium dihydroaluminate forms colloidal by-products after hydrolysis, so that the separation and purification are not easy, and the production operation is not facilitated.

Patent CN200810005209.1 discloses the preparation of rupatadine by reducing amide with acyloxy alkali metal borohydride, and the subsequent treatment of acid water is high in consumption, long in reaction time and high in production cost.

Patent CN201510437799.5 discloses the preparation of rupatadine by reducing amide with borane complex, and the obtained rupatadine is oily, low in content, not beneficial to storage and transportation, not beneficial to production operation.

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

Patent US5407941 discloses the preparation of rupatadine by reducing amide with lithium aluminum hydride, which is a reagent, expensive, sensitive and easy to change, has explosion hidden trouble and low safety, has high risk of lithium aluminum hydride in production and is not suitable for large-scale production.

Rupatadine reported in the literature at present is a greasy solid or oily substance, has a lot of impurities and relatively low HPLC content, but rupatadine and fumaric acid have poor solubility after salification, and has no impurity removal effect after salification and refining after salification. Therefore, it is necessary to develop rupatadine with high yield and high purity.

Disclosure of Invention

In view of this, the present invention provides a method for preparing rupatadine of pharmaceutical grade on overcoming the disadvantages of the prior art.

One of the purposes of the invention is to provide a preparation method of rupatadine, which provides a new idea for the preparation of rupatadine.

In order to achieve the purpose, the 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, and extracting an organic phase;

s2: washing the organic phase of S1 with buffer solution to remove impurities;

s3: refining the product obtained in the step S2 by using a mixed solution of ethyl acetate and n-hexane;

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

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

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

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

Further, the reaction temperature in S1 was controlled to 20 ℃ to 50 ℃.

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

Further, the feeding sequence in the S1 is to sequentially add the compound A, tetrahydrofuran and sodium borohydride into a reaction bottle, cool the mixture to 0-10 ℃, dropwise add boron trifluoride diethyl etherate, heat the mixture to 20-30 ℃ after dropwise addition, react for 1 hour, and heat the mixture to 40-50 ℃ to react for 1 hour.

Further, in S1, after the reaction is completed, the reaction solution is cooled to 0 to 10 ℃, hydrochloric acid (preferably 1N hydrochloric acid) is added dropwise, and after the addition is completed, the temperature is raised to 85 to 95 ℃ to react for 1 hour. And cooling to 0-10 ℃, dropwise adding a sodium hydroxide solution to adjust the pH to 9-11, and then adding the solvent for extraction.

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

Further, the buffer solution is used for adjusting the pH value to be 4-6.

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

Further, washing the organic phase in S1 with the buffer solution for 2 times, then washing with water for 1-2 times, removing organic impurities and inorganic salts capable of forming salts with acid, and then carrying out reduced pressure concentration to remove the solvent.

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

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

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

The invention has the advantages that:

1) the yield of the rupatadine prepared by the method provided by the invention is as high as 80-90%, the HPLC purity is more than 99.0%, and the single unknown impurity is less than 0.10%, so that the rupatadine can reach the pharmaceutical grade.

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

3) The solvent or reagent used in the invention is cheap and easy to obtain, the material addition 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.

Figure 4 is the nmr spectrum of rupatadine prepared in example 1.

Detailed Description

Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art can make insubstantial modifications and adaptations to the embodiments described above without departing from the scope of the present invention.

Example 1: preparation of rupatadine

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

Under the protection of nitrogen, adding a compound A (50g, 0.1165mol, 1.0eq) into a 3000ml reaction flask, adding tetrahydrofuran (750ml), adding sodium borohydride (26.4g, 0.699mol, 6.0eq) under stirring, cooling the reaction liquid to 0-10 ℃, closing nitrogen, and dropwise adding boron trifluoride diethyl etherate (132.3g, 0.932mol, 8.0 eq). After the dropwise addition, heating the reaction solution to 20-30 ℃ for reaction for 1 hour, and then heating to 40-50 ℃ for reaction for 1 hour.

And cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (1N, 480ml), and heating to 85-95 ℃ after dropwise adding for reacting for 1 hour.

Cooling the reaction solution to 30-50 ℃, adding toluene (400ml), dropwise adding a sodium hydroxide (10N, 220g) solution to adjust the pH: 9 to 11. Heating the reaction solution to 55-65 ℃, stirring for dissolving, standing for layering, washing twice with organic phase buffer solution (213.5 g/time), washing for 1 time with water, concentrating under reduced pressure to remove the solvent, adding ethyl acetate (100ml) into the residue, refluxing for dissolving, adding n-hexane (300ml), closing the heating, cooling to 0-10 ℃, stirring for crystallization for 90 minutes, filtering, washing with n-hexane, and drying to obtain rupatadine (42.8g), wherein the yield is 88.3%, the HPLC purity is 99.83%, the chromatogram is shown in figure 1, and the integration results of liquid chromatography are shown in table 1. MS-ESI (m/z): 416.4[ M + H ]] ⁺ As shown in fig. 2. ¹ H-NMR (hydrogen nuclear magnetic resonance spectrum), (400MHz, DMSO): δ 8.331(dd, J1.6, 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) (600MHz, CD3 OD): 157.63; 149.10, respectively; 147.70, respectively; 146.79; 140.52; 138.40; 137.72, respectively; 137.37; 133.69; 132.91, respectively; 131.92; 131.24, respectively; 129.40, respectively; 126.06; 122.71; 59.39; 54.61, respectively; 31.59; 30.99; 30.85; 18.25 as shown in fig. 4.

TABLE 1

Example 2: preparation of rupatadine

Under the protection of nitrogen, adding compound A (5g, 0.01165mol, 1.0eq) into a 250ml reaction flask, adding tetrahydrofuran (75ml), adding sodium borohydride (2.7g, 0.072mol, 6.0eq) while stirring, controlling the reaction liquid at 30-40 ℃, and dropwise adding boron trifluoride diethyl etherate (13.6g, 0.096mol, 8.0 eq). After the dropwise addition, the reaction was incubated for 2 hours.

And cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (1N, 48ml), heating to 85-95 ℃ after dropwise adding, reacting for 1 hour, and performing HPLC (high performance liquid chromatography) to show that 5% of the compound A is not reacted completely.

Example 3: preparation of rupatadine

Adding a compound A (5g, 0.01165mol, 1.0eq) into a 250ml reaction flask under the protection of nitrogen, adding tetrahydrofuran (75ml), adding sodium borohydride (2.0g, 0.054mol, 4.5eq) under stirring, cooling the reaction liquid to 0-10 ℃, closing the nitrogen, and dropwise adding boron trifluoride diethyl etherate (10.2g, 0.072mol, 6.0 eq). After the dropwise addition, heating the reaction solution to 20-30 ℃ for reaction for 3 hours.

And (3) cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (2N, 11ml), heating to 85-95 ℃ after dropwise adding, reacting for 1 hour, and performing HPLC (high performance liquid chromatography) to show that 3.5% of the compound A is not reacted completely.

Example 4: preparation of rupatadine

Under the protection of nitrogen, adding compound A (5g, 0.01165mol, 1.0eq) into a 250ml reaction flask, adding tetrahydrofuran (75ml), adding sodium borohydride (2.7g, 0.072mol, 6.0eq) under stirring, cooling the reaction solution to 0-10 ℃, closing nitrogen, and dropwise adding boron trifluoride diethyl etherate (13.6g, 0.096mol, 8.0 eq). After the dropwise addition, heating the reaction solution to 20-30 ℃ for reaction for 3 hours.

And (3) cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (2N, 11ml), heating to 85-95 ℃ after dropwise adding, reacting for 1 hour, and displaying that the compound A is completely reacted by HPLC.

Example 5: preparation of rupatadine

Adding a compound A (5g, 0.01165mol, 1.0eq) into a 250ml reaction flask under the protection of nitrogen, adding tetrahydrofuran (75ml), adding sodium borohydride (3.4g, 0.09mol, 7.5eq) under stirring, cooling the reaction liquid to 0-10 ℃, closing the nitrogen, and adding boron trifluoride diethyl etherate (17.0g, 0.12mol, 10.0eq) dropwise. After the dropwise addition, heating the reaction solution to 20-30 ℃ for reaction for 3 hours.

And cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (2N, 11ml), heating to 85-95 ℃ after dropwise adding, reacting for 1 hour, and displaying that the compound A is completely reacted by HPLC.

Example 6: preparation of rupatadine

Under the protection of nitrogen, adding a compound A (100g, 0.233mol, 1.0eq) into a 3000ml reaction flask, adding tetrahydrofuran (1500ml), adding sodium borohydride (52.8g, 1.396mol, 6.0eq) while stirring, cooling the reaction liquid to 0-10 ℃, closing nitrogen, and dropwise adding boron trifluoride diethyl etherate (264.6g, 1.864mol, 8.0 eq). After the dripping is finished, the temperature of the reaction solution is raised to 20-30 ℃ for reaction for 1 hour, and then raised to 40-50 ℃ for reaction for 1 hour.

And cooling the reaction liquid to 0-20 ℃, dropwise adding hydrochloric acid (1N, 960ml), and heating to 85-95 ℃ after dropwise adding for reacting for 1 hour.

Cooling the reaction solution to 30-50 ℃, adding toluene (800ml), dropwise adding a sodium hydroxide (10N, 440g) solution to adjust the pH: 9 to 11. Heating the reaction solution to 50-60 ℃, stirring and dissolving, standing and layering, separating a water phase, and dividing an organic phase into 10 parts. 20% aqueous potassium dihydrogen phosphate (pH: 4.55), aqueous acetic acid and sodium acetate (pH: 4.65, 5.20, 5.24, 5.53, 5.94, 6.15), aqueous ammonium chloride (pH: 6), and aqueous acetic acid (pH: 4.26) were each prepared. And respectively taking the same volume of buffer solution to wash the organic phase, wherein the washing mode and the washing times are the same, and sending the organic phase before and after washing to HPLC (high performance liquid chromatography) for detection. As a result, it was found that the washing with 20% aqueous potassium dihydrogen phosphate (pH: 4.55) had a good impurity removing effect, and the lower the pH of the aqueous solution of acetic acid and sodium acetate, the better the impurity removing effect, and the impurity removing effect was better in two washes than in one wash. 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 solution of acetic acid and sodium acetate, the lower the yield. Therefore, the organic phase is washed twice by using acetic acid with the pH value of 5-6 and sodium acetate aqueous solution. The washing impurities of the different buffer solutions are shown in Table 2 below.

TABLE 2

Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, 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 or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.

Claims

1. The method for preparing rupatadine is characterized by comprising the following steps:

s2: washing the organic phase of S1 with buffer solution to remove impurities;

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

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

4. The method of claim 1, wherein the reaction temperature in S1 is controlled to be 20-50 ℃.

5. The method of claim 1, wherein the reaction pH in S1 is 9-11.

6. The method according to claim 1, wherein the buffer solution in S2 is any one of acetic acid and sodium acetate aqueous solution, potassium dihydrogen phosphate aqueous solution, acetic acid aqueous solution, and ammonium chloride solution.

7. The method of claim 6, wherein the buffer is used to adjust the pH to 4-6.

8. The method of claim 1, wherein the number of washing in S2 is at least 2.

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

10. The method of claim 1, further comprising S4 crystallization, filtration and drying after S3.