A synthetic method for large-scale production of Zolpidem

Abstract

The invention belongs to the technical field of chemical synthesis, and specifically relates to a synthesis method for large-scale production of zolpidem. The method uses a composite catalyst composed of phosphorus tribromide and Lewis acid as a catalytic system for synthesizing zolpidem, further optimizes and controls the reaction conditions, and can commercially mass-produce zolpidem with a purity of more than 99.5%, and a high yield; the method has simple steps, simple operation, mild reaction conditions, short production cycle, low cost, safety and environmental protection, and is very suitable for large-scale industrial production of zolpidem.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and more specifically relates to a synthesis method for large-scale production of zolpidem. Background Art

[0002] Zolpidem is the first new generation of non-benzodiazepine sedative hypnotic drugs on the market, belonging to the imidazopyridine class of drugs. It produces pharmacological effects by selectively binding to the benzodiazepine receptors in the central nervous system, which are part of the GABAA receptors, to increase the transmission of GABA.

[0003] Prior art discloses multiple synthetic routes and methods of Zolpidem, such as U.S. patent application US4794185A discloses a method for synthesizing Zolpidem using 5-methyl-2-pyridinamine and p-methyl brominated phenylacetyl as starting materials, which is one of the main routes for commercial synthesis of Zolpidem at present; However, the route has many reaction steps, a long production cycle, and a low yield, and the sodium borohydride method is reduced and added to an acidic medium to produce hydrogen that is rapidly released, which has certain production risks. In order to increase the yield of intermediate 4, Chinese patent application CN113264932A optimizes and adjusts the reduction reaction step, and palladium carbon hydrogenation is used to reduce compound 4, thereby improving the yield of the intermediate product (compound 4), but the hydrogenation reaction in the method belongs to one of the eighteen dangerous control reactions of the country, and has certain dangers during production, and the price of palladium carbon catalyst is expensive, and the route reaction steps are still many, the production cycle is still very long, and the overall yield is low.

[0004]

[0005] In order to shorten the reaction route and reduce the reaction steps, Chinese patent application CN100408577C discloses a synthetic route and method of using N,N-dimethylglyoxylamide hemihydrate solid and compound 1 to condense to obtain compound 2, and then reducing and freeing it with phosphorus tribromide to obtain zolpidem. The reaction steps of this route are relatively short and dangerous reactions are avoided. However, the raw material N,N-dimethylglyoxylamide hemihydrate used in this reaction has almost no commercial sales channels and is difficult to obtain in large quantities. In addition, this method has only been carried out in a small-scale laboratory experiment with a very small feed amount. The data cannot support the commercial large-scale production of zolpidem, and the purity data of zolpidem obtained by this method is not disclosed. On the other hand, when only phosphorus tribromide is used for reduction, the conversion rate of the compound is not high, and it is easy to cause incomplete reaction of the raw material and difficulty in separating it from the product, and the post-processing purification operation is cumbersome.

[0006]

[0007] Therefore, there is an urgent need to provide a method for commercially synthesizing zolpidem with high conversion rate, high yield, economy and high efficiency. Summary of the invention

[0008] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing Zolpidem synthesis method, such as low yield, low purity, many impurities, complicated steps, etc., and to provide a Zolpidem synthesis method with high yield, high purity, economy and high efficiency.

[0009] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0010] A synthetic method for large-scale production of Zolpidem, the synthetic route is as follows:

[0011]

[0012] The specific steps include:

[0013] Dissolve compound 2 in an organic solvent, add a Lewis acid catalyst, cool to -40 to 0°C, drop phosphorus tribromide solution, and after the dropwise addition is complete, heat to reflux until the reaction is complete. Cool and add the reaction solution to a sodium carbonate solution to quench the reaction, and post-treat to obtain the product.

[0014] Furthermore, the Lewis acid catalyst is selected from one or more of aluminum chloride, ferric chloride, zinc chloride, boron trifluoride, sulfur trioxide, glacial acetic acid, phosphoric acid, and sulfuric acid.

[0015] Furthermore, the molar ratio of the compound 2 to the Lewis acid catalyst is 1:(0.4-1.2).

[0016] Further, the molar ratio of the compound 2 to phosphorus tribromide is 1:(2-10). Preferably, the molar ratio of the phosphorus tribromide to the compound 2 is 1:(2-6.7).

[0017] Preferably, after adding the Lewis acid catalyst, the temperature is lowered to -20 to 0°C.

[0018] Furthermore, the organic solvent is selected from one or more of tetrahydrofuran, isopropyl acetate, 1,4-dioxane, 1,2-dichloroethane, acetonitrile and acetone. Preferably, the organic solvent is tetrahydrofuran, 1,4-dioxane or 1,2-dichloroethane.

[0019] Further, the mass ratio of the compound 2 to the organic solvent is 1:(10-14). Preferably, the mass ratio of the compound 2 to the organic solvent is 1:(10-12).

[0020] Furthermore, the reflux time is 0.5 to 4 hours. Preferably, the reflux time is 0.5 to 2 hours.

[0021] Furthermore, the phosphorus tribromide solution is prepared by dissolving phosphorus tribromide in an organic solvent.

[0022] Furthermore, the concentration of the sodium carbonate solution is 5-25% and the temperature is 0-5°C; preferably, the concentration of the sodium carbonate solution is 10-15%.

[0023] Furthermore, the post-processing specifically includes the following steps:

[0024] The reaction solution was concentrated under reduced pressure until no obvious droplets were seen from the system, ethyl acetate was added to remove the solvent or impurities, and the solution was concentrated under reduced pressure again until no obvious droplets were seen from the system; the temperature was lowered to 20-30°C, and the solution was extracted 1-3 times with ethyl acetate and water, and the solid-liquid separation was performed. The solid was washed with water and dried to obtain the product.

[0025] The present invention has the following beneficial effects:

[0026] The invention uses a composite catalyst composed of phosphorus tribromide and Lewis acid as a catalytic system for synthesizing zolpidem, further optimizes and controls reaction conditions, and can commercially mass-produce zolpidem with a purity of more than 99.5% and a high yield. The method has simple steps, easy operation, mild reaction conditions, a short production cycle, low cost, safety and environmental protection, and is very suitable for large-scale industrial production of zolpidem. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is the detection chromatogram of batch number 20201217X-2 in Example 3 of the present invention.

[0028] Figure 2 It is the detection chromatogram of batch number 20210105X-1 in Example 3 and Example 6 of the present invention.

[0029] Figure 3 This is the detection chromatogram of batch number 20210119X-2 in Example 3 of the present invention.

[0030] Figure 4 This is the chromatographic peak result of batch number 20210107X-1 in Example 4 of the present invention.

[0031] Figure 5 It is the detection chromatogram of batch number 20210122X-2 in Example 4 of the present invention. DETAILED DESCRIPTION

[0032] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

[0033] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0034] Among them, the reaction route of the synthesis method of Zolpidem in the present application is as follows:

[0035]

[0036] Wherein, compound 2 in the present invention is synthesized by referring to the method disclosed in the applicant's Chinese patent application CN113264932A.

[0037] Example 1 Large-scale industrial production of Zolpidem

[0038] The synthesis steps of Zolpidem are as follows:

[0039] S1. Weigh the materials, close the tank bottom valve, add drinking water (400 kg) and sodium carbonate (72 kg) into a 1000L reaction tank, start stirring, cool to 0-5°C, and obtain a sodium carbonate solution for standby use;

[0040] S2, weigh the materials, close the tank bottom valve, add compound 2 (20 kg) and tetrahydrofuran (160 kg) to the 500L reaction tank, start stirring, add aluminum chloride (3.3 kg), cool down, control the temperature below 0 ° C, and slowly add a tetrahydrofuran solution containing phosphorus tribromide (67 kg) dropwise;

[0041] S3, after the addition is completed, the temperature is raised to reflux, reacted for 1 hour, then cooled to below 20°C, and the reaction solution is slowly added to the sodium carbonate solution obtained in step S1 to quench the reaction. After the quenching is completed, the pH is measured to be 7-9;

[0042] S4, concentrating under reduced pressure until no obvious droplets flow out of the system, adding ethyl acetate, concentrating under reduced pressure until no obvious droplets flow out of the system; cooling to 25±5°C, adding ethyl acetate (35kg) and drinking water (100kg), stirring, transferring the material to a centrifuge for centrifugation, washing the solid with drinking water and centrifuging, and transferring to a vacuum drying oven for drying to obtain 15.988kg of Zolpidem, with a yield of 84.1% and a purity of 100.00% of Zolpidem.

[0043] [M+H]308.17438; 1 H NMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.49 (t, J = 9.0Hz, 3H), 7.21 (d, J = 7.7Hz, 2H), 6.99 (d d,J=9.2,1.7Hz,1H),4.02(s,2H),2.90(s,3H),2.84(s,3H),2.35(s,3H),2.29(s,3H).

[0044] Example 2 Large-scale industrial production of Zolpidem

[0045] The synthesis steps of Zolpidem are as follows:

[0046] S1. Weigh the materials, close the bottom valve of the tank, add drinking water (300 kg) and sodium carbonate (54 kg) into a 1000L reaction tank, start stirring, cool to 0-5°C, and obtain a sodium carbonate solution for standby use;

[0047] S2, weigh the materials, close the tank bottom valve, add compound 2 (15 kg) and tetrahydrofuran (120 kg) into the 500L reaction tank, start stirring, add zinc chloride (3.2 kg), cool down, control the temperature below 0°C, and slowly drop a tetrahydrofuran solution containing phosphorus tribromide (50.25 kg);

[0048] S3, after the addition is completed, the temperature is raised to reflux, reacted for 1 hour, then cooled to below 20°C, and the reaction solution is slowly added to the sodium carbonate solution obtained in step S1 to quench the reaction. After the quenching is completed, the pH is measured to be 7-9;

[0049] S4, concentrating under reduced pressure until no obvious liquid drips out of the system, adding ethyl acetate to redissolve, and concentrating under reduced pressure until no obvious liquid drips out of the system; cooling to 25±5°C, adding ethyl acetate (26kg) and drinking water (75kg), stirring, transferring the material to a centrifuge for centrifugation, washing the solid with drinking water and centrifuging, and then transferring to a vacuum drying oven for drying to obtain 11.863kg of Zolpidem, with a yield of 83.2% and a purity of 99.91%.

[0050] Example 3 Effect of different catalysts on the reaction

[0051] Referring to the production parameters of Example 1, Zolpidem was prepared using different catalytic systems shown in Table 1. The results are shown in Table 1, wherein the chromatograms of batch numbers 20201217X-2, 20210105X-1, and 20210119X-2 are shown in Table 1. Figures 1 to 3 , the purity is above 99.5%.

[0052] Table 1 Effect of different catalysts on the reaction

[0053]

[0054] Note: Impurities 1 to 4 are unknown impurities found during testing.

[0055] As can be seen from the table, when PBr3 is used alone as a catalyst, the yield and purity of Zolpidem are very low, and the total impurity content is very high, and subsequent separation and purification are still required; when PBr3 and Lewis acid are combined as a catalytic system to jointly carry out a reduction reaction, the yield and purity of Zolpidem are significantly improved.

[0056] Example 4 Effect of different phosphorus tribromide addition amounts on the reaction

[0057] Referring to the production parameters of Example 1, Zolpidem was prepared by adding different amounts of phosphorus bromide as shown in Table 2. The results are shown in Table 2, wherein the chromatographic peak results of batch number 20210107X-1 are shown in Table 2. Figure 4 .

[0058] Table 2 Effect of different phosphorus tribromide addition amounts on the reaction

[0059]

[0060] Note: Impurities 1 and 2 are unknown impurities found during testing.

[0061] As can be seen from the table, when the Lewis acid / PBr3 catalyst system is used for the reduction reaction, the purity of Zolpidem is very high and the yield is significantly increased; when different amounts of phosphorus tribromide are added, the yield varies.

[0062] Example 5 Effect of Different Phosphorus Tribromide Addition Temperatures on the Reaction

[0063] Referring to the production parameters of Example 1, Zolpidem was prepared by using different phosphorus tribromide addition temperatures shown in Table 3. The results are shown in Table 3.

[0064] Table 3 Effect of different phosphorus tribromide addition temperatures on the reaction

[0065]

[0066]

[0067] As can be seen from the table, different dropping temperatures of PBr3 will affect the yield and purity of Zolpidem, and the dropping temperature should be kept at ≤0°C.

[0068] Example 6 Effect of different Lewis acid catalyst addition amounts on the reaction

[0069] Referring to the production parameters of Example 1, Zolpidem was prepared by using different Lewis acid catalysts shown in Table 4 and further limiting their addition amounts. The results are shown in Table 4, wherein the chromatogram of batch number 20210105X-1 is shown in Figure 2 .

[0070] Table 4 Effect of different Lewis acid catalyst addition amounts on the reaction

[0071]

[0072] As can be seen from the table, different addition amounts of Lewis acid (phosphoric acid) have a certain influence on the yield and purity of the reaction. Preferably, the addition amount of Lewis acid is 0.4 to 1.2 eq.

[0073] Example 7 Effect of different solvent addition amounts on the reaction

[0074] Referring to the production parameters of Example 1, Zolpidem was prepared by adding different solvents as shown in Table 5. The results are shown in Table 5, wherein the chromatogram of batch number 20210122X-2 is shown in Figure 5 .

[0075] Table 5 Effect of different solvent addition amounts on the reaction

[0076]

[0077] As can be seen from the table, the amount of solvent used has a certain influence on the progress of the reaction and the purity and yield of the product. Preferably, the amount of solvent added is 10 to 14 times.

[0078] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A synthetic method for large-scale production of zolpidem, characterized in that: The synthetic route is as follows: The specific steps include: Dissolve compound 2 in an organic solvent, add a Lewis acid catalyst, cool to -40 to 0°C, drop phosphorus tribromide solution, and after the dropwise addition is complete, heat to reflux until the reaction is complete. Cool and add the reaction solution to a sodium carbonate solution to quench the reaction, and post-treat to obtain the product; The Lewis acid catalyst is selected from one or more of aluminum chloride, ferric chloride, zinc chloride and phosphoric acid.

2. The method for synthesizing Zolpidem according to claim 1, wherein The molar ratio of the compound 2 to the Lewis acid catalyst is 1:(0.4-1.2).

3. The method for synthesizing Zolpidem according to claim 1, characterized in that: The molar ratio of the compound 2 to phosphorus tribromide is 1:(2-10).

4. The method for synthesizing Zolpidem according to claim 1, characterized in that: After the Lewis acid catalyst is added, the temperature is lowered to -20 to 0°C.

5. The method for synthesizing Zolpidem according to claim 1, characterized in that: The organic solvent is selected from one or more of tetrahydrofuran, isopropyl acetate, 1,4-dioxane, 1,2-dichloroethane, acetonitrile and acetone.

6. The method for synthesizing Zolpidem according to claim 1, characterized in that: The mass ratio of the compound 2 to the organic solvent is 1:(10-14).

7. The method for synthesizing Zolpidem according to claim 1, characterized in that: The reflux time is 0.5 to 4 hours.

8. The method for synthesizing Zolpidem according to claim 1, characterized in that: The phosphorus tribromide solution is prepared by dissolving phosphorus tribromide in an organic solvent.

9. The method for synthesizing Zolpidem according to claim 1, characterized in that: The concentration of the sodium carbonate solution is 5-25%, and the temperature is 0-5°C.

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