Synthesis method of clomastine intermediate

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and relates to a synthesis method of a clomastine intermediate. Comprising the following steps: taking N-methyl pyrrolidone and vinyl acetate as raw materials, and obtaining N-methyl-2-(2-ethoxyl) pyrrolidine according to the following reaction route; wherein the intermediate 1, sodium borohydride and boron trifluoride diethyl etherate are subjected to heating reflux in a solvent, and a reduction reaction is performed to obtain an intermediate 2. According to the synthesis method provided by the invention, the yield and the purity of carbonyl reduction products of amide can be improved at the same time, the dosage of a reducing agent can be reduced, and the cost of the clomastine intermediate can be reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and relates to a method for synthesizing an intermediate of clemastine. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Clemastine Fumarate is a representative second-generation H1 receptor antagonist, which is clinically used to treat various allergic diseases caused by histamine and is one of the best antihistamines recognized in the world. The intermediate usually involved in the synthesis of clemastine is N-methyl-2-(2-hydroxyethyl)pyrrolidine. Currently, there are few reports on the synthesis of this intermediate. The relatively feasible route is: using N-methylpyrrolidone and vinyl acetate as raw materials, and obtaining it through coupling, reduction, and hydrolysis. The key lies in the carbonyl reduction step of the amide. The reduction system reported currently is the sodium borohydride-phosphorus oxychloride system. The inventor found through experiments that when this reduction system is used for the carbonyl reduction of the amide, both the yield and purity are relatively low (yield 36%, purity 13%), the operation is complex, the dosage of sodium borohydride is large and the cost is high, and phosphorus oxychloride has strong corrosiveness, the reaction process is violent, and there are safety hazards. Moreover, the obtained reduction product has not undergone sufficient hydrolysis reaction, resulting in incomplete reaction and thus more impurities. Summary of the Invention

[0004] In order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing an intermediate of clemastine, which can simultaneously improve the yield and purity of the carbonyl reduction product of the amide, and at the same time reduce the dosage of the reducing agent, which is beneficial to reducing the cost of the intermediate of clemastine.

[0005] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0006] A method for synthesizing an intermediate of clemastine, comprising the step of obtaining N-methyl-2-(2-hydroxyethyl)pyrrolidine from N-methylpyrrolidone and vinyl acetate as raw materials according to the following reaction route;

[0007]

[0008] Among them, intermediate 1 is heated to reflux with sodium borohydride and boron trifluoride etherate in a solvent to carry out a reduction reaction, and intermediate 2 is obtained.

[0009] In the carbonyl reduction step of the amide of the present invention, a sodium borohydride-boron trifluoride reducing agent system is adopted. This reducing agent system has high efficiency and safety effects in the carbonyl reduction of this amide. At the same time, the present invention adds an alkali hydrolysis process step to make the reaction more complete, so that the yield and purity of the obtained N-methyl-2-(2-hydroxyethyl)pyrrolidine are higher.

[0010] In some embodiments, the mass ratio of intermediate 1, sodium borohydride, and boron trifluoride diethyl ether is 1:0.35 to 0.45:1.5 to 2.5, preferably 1:0.39 to 0.41:1.8 to 2.2.

[0011] In some embodiments, intermediate 1 and sodium borohydride are added to a solvent and mixed, then boron trifluoride diethyl ether is added dropwise, and then heated to react to obtain intermediate 2.

[0012] Specifically, during the addition of boron trifluoride diethyl ether, the temperature is controlled at 0 to 5 °C.

[0013] Specifically, the solvent is tetrahydrofuran.

[0014] Specifically, the temperature for the heating reflux reaction is 55 to 65 °C, and the reaction time is 1.5 to 2.5 h.

[0015] Specifically, an acid solution is added for quenching after the reaction.

[0016] In some embodiments, intermediate 1 is prepared by the coupling reaction of N-methylpyrrolidone and vinyl acetate.

[0017] Specifically, the mass ratio of N-methylpyrrolidone to vinyl acetate is 3 to 4:1.

[0018] Specifically, the initiator for the coupling reaction is di-tert-butyl peroxide. More specifically, the added mass of di-tert-butyl peroxide is 5.0 to 7.0% of the total mass of N-methylpyrrolidone and vinyl acetate.

[0019] Specifically, the temperature of the coupling reaction is 125 to 135 °C. The time of the coupling reaction is 1.5 to 2.5 h.

[0020] In some embodiments, a part of N-methylpyrrolidone is mixed evenly with vinyl acetate and the initiator to obtain a mixed solution. Under the reaction temperature condition, the mixed solution is added dropwise to the remaining part of N-methylpyrrolidone for the coupling reaction. More specifically, after the addition is completed, keep warm and continue the reaction for 1.5 to 2.5 h. Research shows that this reaction operation is more conducive to the reaction.

[0021] In some embodiments, an aqueous solution of a hydroxide of an alkali metal is added to the reaction solution containing Intermediate 2 after acid quenching, and a hydrolysis reaction is carried out to obtain N-methyl-2-(2-hydroxyethyl)pyrrolidine.

[0022] Specifically, the temperature of the hydrolysis reaction is 65 to 75 °C.

[0023] Specifically, the time of the hydrolysis reaction is 2.5 to 3.5 h.

[0024] In some embodiments, the refining method of N-methyl-2-(2-hydroxyethyl)pyrrolidine is vacuum distillation.

[0025] The beneficial effects of the present invention are as follows:

[0026] In the process of preparing the clemastine intermediate of the present invention, in the carbonyl reduction step of the amide, a sodium borohydride-boron trifluoride reducing agent system is adopted, so that both the product yield and purity are improved, and the reaction efficiency is increased. At the same time, the amount of sodium borohydride used is reduced, and the production cost is reduced.

[0027] The present invention adopts a sodium borohydride-boron trifluoride reducing agent system, which has high safety, low corrosivity, and mild and easy-to-control reactions.

[0028] The present invention decomposes the original reduction hydrolysis step into two steps and operates in one pot, adding a hydrolysis step of the ester under strong base conditions, and the hydrolysis to remove the acetyl group is more complete, further improving the yield of N-methyl-2-(2-hydroxyethyl)pyrrolidine. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The accompanying drawings forming a part of this specification are used to provide a further understanding of the present invention, and the schematic embodiments and descriptions thereof of the present invention are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0030] Figure 1 1H NMR spectrum of N-methyl-2-(2-hydroxyethyl)pyrrolidine prepared in Example 1 of the present invention;

[0031] Figure 2 13C NMR spectrum of N-methyl-2-(2-hydroxyethyl)pyrrolidine prepared in Example 1 of the present invention;

[0032] Figure 3 Mass spectrum of N-methyl-2-(2-hydroxyethyl)pyrrolidine prepared in Example 1 of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] In order to enable those skilled in the art to more clearly understand the technical solutions of the present invention, the technical solutions of the present invention will be described in detail below with specific examples and comparative examples.

[0034] Example 1

[0035] Add 400 g of N-methylpyrrolidone into the reaction flask, heat and stir to raise the temperature to 130 °C, and slowly drip a mixed solution containing 100 g of N-methylpyrrolidone, 150 g of vinyl acetate, and 40 g of di-tert-butyl peroxide into the reaction flask through a constant-pressure dropping funnel. After the dropping is completed, keep the temperature at 130 °C and stir for reaction for 2 h until the reaction is completed. Cool down to 100 °C, first recover N-methylpyrrolidone by vacuum concentration, and then subject the residue to vacuum distillation. Cut the fraction at 1.3 KPa / 190 - 210 °C to obtain 92.5 g of yellow oily liquid N-methyl-5-(2-acetoxy)ethyl-2-pyrrolidone (Intermediate 1).

[0036] Add 22.2 g of Intermediate 1 prepared in Example 1, 60 ml of THF, and 9.08 g of sodium borohydride into the reaction flask, cool and stir in an ice-water bath, control the temperature at 0 - 5 °C, and drip 45.6 g of boron trifluoride diethyl etherate. After the dropping is completed, raise the temperature to 60 °C and stir for reaction for 2 h, then cool down. Add 100 ml of 10% hydrochloric acid aqueous solution dropwise into the reaction flask to quench the reaction.

[0037] Then add 100 ml of 20% sodium hydroxide aqueous solution into the reaction flask, raise the temperature to 70 °C and stir for reflux for 3 h, cool down, extract the reaction solution with 100 ml × 3 of ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 13.8 g of light yellow oily liquid. GC: 72.2%, yield 62.1%.

[0038] When preparing the refined product, subject the crude product to vacuum distillation, cut the fraction at 1.8 KPa / 110 - 120 °C, and 10.2 g of refined product can be obtained. GC: 95.1%. The chemical structure is characterized as Figures 1 - 3 shown.

[0039] Example 2

[0040] Add 22.2 g of Intermediate 1 prepared in Example 1, 60 ml of THF, and 9.08 g of sodium borohydride into the reaction flask, cool and stir in an ice-water bath, control the temperature at 0 - 5 °C, and drip 45.6 g of boron trifluoride diethyl etherate. After the dropping is completed, raise the temperature to 60 °C and stir for reaction for 2.5 h, then cool down. Add 100 ml of 10% hydrochloric acid aqueous solution dropwise into the reaction flask to quench the reaction.

[0041] Then add 100 ml of 20% sodium hydroxide aqueous solution into the reaction flask, raise the temperature to 70 °C and stir for reflux for 3.5 h, cool down, extract the reaction solution with 100 ml × 3 of ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain 15.7 g of light yellow oily liquid. GC: 66.1%, yield 70.8%.

[0042] Example 3

[0043] Add 22.2 g of Intermediate 1 prepared in Example 1, 60 ml of THF, and 9.08 g of sodium borohydride to the reaction flask. Cool and stir in an ice-water bath, control the temperature at 0 - 5°C, and dropwise add 45.6 g of boron trifluoride diethyl ether complex. After the addition is complete, raise the temperature to 60°C and stir for 2.5 h, then cool down. Dropwise add 100 ml of 10% hydrochloric acid aqueous solution to quench the reaction.

[0044] Then add 100 ml of 20% sodium hydroxide aqueous solution to the reaction flask, raise the temperature to 70°C and stir under reflux for 3 h, then cool down. Extract the reaction solution with 100 ml × 3 of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness to obtain 14.4 g of a light yellow oily liquid. GC: 66.5%, yield 65.0%.

[0045] Example 4

[0046] Add 22.2 g of Intermediate 1 prepared in Example 1, 60 ml of THF, and 9.08 g of sodium borohydride to the reaction flask. Cool and stir in an ice-water bath, control the temperature at 0 - 5°C, and dropwise add 45.6 g of boron trifluoride diethyl ether complex. After the addition is complete, raise the temperature to 60°C and stir for 2 h, then cool down. Dropwise add 100 ml of 10% hydrochloric acid aqueous solution to quench the reaction.

[0047] Then add 100 ml of 20% sodium hydroxide aqueous solution to the reaction flask, raise the temperature to 70°C and stir under reflux for 3.5 h, then cool down. Extract the reaction solution with 100 ml × 3 of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness to obtain 13.8 g of a light yellow oily liquid. GC: 67.8%, yield 62.2%.

[0048] Example 5

[0049] Add 22.2 g of Intermediate 1 prepared in Example 1, 60 ml of THF, and 9.08 g of sodium borohydride to the reaction flask. Cool and stir in an ice-water bath, control the temperature at 0 - 5°C, and dropwise add 45.6 g of boron trifluoride diethyl ether complex. After the addition is complete, raise the temperature to 60°C and stir for 2 h, then cool down. Dropwise add 100 ml of 10% hydrochloric acid aqueous solution to quench the reaction.

[0050] Then add 100 ml of 20% sodium hydroxide aqueous solution to the reaction flask, raise the temperature to 70°C and stir under reflux for 3 h, then cool down. Extract the reaction solution with 100 ml × 3 of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness to obtain 14.9 g of a light yellow oily liquid. GC: 70.4%, yield 67.1%.

[0051] Comparative Example 1

[0052] Add 22.2 g of Intermediate 1 prepared in Example 1 and 18.4 g of phosphorus oxychloride into the reaction flask, heat up to 60 °C and stir for 15 min, then concentrate under reduced pressure to dryness at 60 °C to obtain a brownish-black viscous liquid. Add 60 ml of ethanol, place the reaction flask in an ice bath for cooling, and slowly add 13.6 g of sodium borohydride in portions with stirring while controlling the temperature at 0 - 5 °C (the reaction is highly exothermic, maintain good cooling). After addition, stir at 0 - 5 °C for 0.5 h, dropwise add 30 ml of 17% dilute hydrochloric acid, stir for 5 min, then distill off ethanol under reduced pressure. Add 60 ml of water and 60 ml of ethyl acetate to the residue, stir and let it stand for liquid separation, and discard the ethyl acetate layer. Adjust the pH of the aqueous phase to 11 with saturated sodium carbonate solution, then extract with 100 ml of ethyl acetate for 3 times. Combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 8.1 g of a pale yellow oily liquid. GC: 13.3%, yield: 36.4%.

[0053] The purities and yields of the crude products prepared in each example and comparative example are shown in Table 1.

[0054] Table 1 Purities and yields of the crude products prepared in each example and comparative example

[0055] Purity (%) Yield (%) Example 1 72.2 62.1 Example 2 66.1 70.8 Example 3 66.5 65.0 Example 4 67.8 62.2 Example 5 70.4 67.1 Comparative Example 1 13.3 36.4

[0056] From the comparison of the purities and yields of each example and comparative example, it can be seen that by using the sodium borohydride-boron trifluoride reducing agent system of the present invention and adding the strong base hydrolysis step, the yield and purity of the clemastine intermediate (N-methyl-2-(2-hydroxyethyl)pyrrolidine) can be greatly improved.

[0057] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, various modifications and changes can be made to the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a clemastine intermediate, characterized in that: The method comprises the steps of using N-methylpyrrolidone and vinyl acetate as raw materials to obtain N-methyl-2-(2-hydroxyethyl)pyrrolidine according to the following reaction route; Among them, intermediate 1 is heated to reflux with sodium borohydride and boron trifluoride ether in a solvent to carry out a reduction reaction to obtain intermediate 2.

2. The synthesis method according to claim 1, characterized in that the intermediate 1. The mass ratio of sodium borohydride to boron trifluoride ether is 1:0.35-0.45:1.5-2.5, preferably 1:0.39-0.41:1.8-2.

2.

3. The synthesis method according to claim 1, characterized in that: Intermediate 1 and sodium borohydride are added to a solvent and mixed, and then boron trifluoride ether is added dropwise, and then heated to react to obtain intermediate 2.

4. The synthesis method according to claim 3, characterized in that: During the dropwise addition of boron trifluoride etherate, the temperature was controlled at 0-5°C. Specifically, the solvent is tetrahydrofuran. Specifically, the temperature of the heating reflux reaction is 55-65° C., and the reaction time is 1.5-2.5 h. Specifically, an acid solution is added after the reaction for quenching.

5. The synthesis method according to claim 1, characterized in that: Intermediate 1 was prepared by coupling reaction of N-methylpyrrolidone and vinyl acetate.

6. The synthesis method according to claim 5, characterized in that: The mass ratio of N-methylpyrrolidone to vinyl acetate is 3 to 4:1; Or, the initiator of the coupling reaction is di-tert-butyl peroxide; preferably, the added mass of di-tert-butyl peroxide is 5.0-7.0% of the total mass of N-methylpyrrolidone and vinyl acetate; Alternatively, the coupling reaction temperature is 125-135° C.; preferably, the coupling reaction time is 1.5-2.5 h.

7. The synthesis method according to claim 1, characterized in that: A portion of N-methylpyrrolidone is uniformly mixed with vinyl acetate and an initiator to obtain a mixed solution, and the mixed solution is dropwise added to the remaining portion of N-methylpyrrolidone under reaction temperature conditions to perform a coupling reaction to obtain intermediate 1; preferably, after the dropwise addition is completed, the reaction is continued for 1.5 to 2.5 hours while maintaining the temperature.

8. The synthesis method according to claim 1, characterized in that: An alkali metal hydroxide solution is added to the reaction solution containing the intermediate 2 after acid quenching to carry out a hydrolysis reaction to obtain N-methyl-2-(2-hydroxyethyl)pyrrolidine.

9. The synthesis method according to claim 8, characterized in that: The temperature of the hydrolysis reaction is 65-75°C; Alternatively, the hydrolysis reaction time is 2.5 to 3.5 hours.

10. The synthesis method according to claim 1, characterized in that: The purification method of N-methyl-2-(2-hydroxyethyl)pyrrolidine is vacuum distillation.

Images