A process for the preparation of 3,3-tetramethylene glutarimide

Abstract

The application discloses a preparation method of 3,3-tetramethylene glutarimide, which comprises the following steps: (1) adding 1,1-cyclopentyldiacetic acid and a first part of ammonia water into a reaction kettle, adjusting the pH of a reaction system to 9-11 by controlling the amount of the first part of ammonia water, stirring and heating to 155-165 DEG C, then cooling to 115-125 DEG C, and adding a second part of ammonia water drop by drop to obtain a mixture containing 1,1-cyclopentyldiacetic acid ammonium salt; (2) when the temperature of the mixture prepared in the step (1) is reduced to 70-80 DEG C, the mixture is transferred into a water washing kettle to be subjected to water washing treatment, and 3,3-tetramethylene glutarimide is obtained through centrifugation. The preparation method is simple in operation, raw materials are easy to obtain, and no organic solvent is needed in the reaction process, so that the yield can be up to 90% or more, the purity is greater than 99%, and the method is suitable for industrial production of 3,3-tetramethylene glutarimide.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and specifically to a method for preparing 3,3-tetramethyleneglutamate. Background Technology

[0002] Buspirone belongs to the azaspirocyclodecanedione class of compounds and is a partial agonist of the 5-HT1A receptor. It activates the presynaptic 5-HT1A receptor, feedback-inhibiting 5-HT release, thereby reducing excessive activity in anxiety disorders and producing an anti-anxiety effect. It is currently used to treat various anxiety disorders, and is suitable for generalized anxiety disorder, especially chronic anxiety disorder, with phobic or depressive symptoms, and for those who cannot tolerate benzodiazepines. Patients with anxiety, such as those taking BDZ-like drugs or those who are particularly sensitive to BDZ.

[0003] 3,3-Tetramethyleneglutamate is an important intermediate in the synthesis of buspirone. Currently, it can be prepared from 1,1-cyclopentyldiacetic acid using 1,1-cyclopentyldiacetic acid as a starting material. Specifically, using 1,1-cyclopentyldiacetic acid and acetic anhydride as raw materials, 1,1-cyclopentyldiacetic anhydride is first prepared, followed by amination and acidification reactions to obtain 3,3-tetramethylenepentamidic acid. This is then heated under reflux with an organic solvent and acetic acid until completely dissolved, cooled, and filtered to obtain a filter cake. The filter cake is added to ammonia water and stirred to react, followed by filtration to obtain 3,3-tetramethyleneglutamate. However, the acetic anhydride used in this synthetic method is a precursor chemical and is unsuitable for industrial production of 3,3-tetramethyleneglutamate. Furthermore, this method has a complex synthetic route, requiring the use of organic solvents to dissolve the intermediate, increasing production costs, and the resulting product is prone to solvent residue.

[0004] Therefore, there is an urgent need for a preparation method that is free of solvent residue and has a high yield suitable for the industrial mass production of 3,3-tetramethyleneglutamate. Summary of the Invention

[0005] This invention provides a method for preparing 3,3-tetramethyleneglutamate, using 1,1-cyclopentyldiacetic acid as a raw material, preparing 1,1-cyclopentyldiacetic acid ammonium salt through an ammoniation reaction, and then dehydrating and deammonerating to obtain the target product 3,3-tetramethyleneglutamate. In the optimized synthetic route of this invention, no organic solvent is required, there is no problem of residual solvent, and the yield is as high as 90% or more, and the purity of the purified product is not less than 99%.

[0006] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0007] This invention provides a method for preparing 3,3-tetramethyleneglutamate, comprising the following steps:

[0008] (1) Add 1,1-cyclopentyl diacetic acid and the first part of ammonia water to the reaction vessel, adjust the pH of the reaction system to 9-11 by controlling the amount of the first part of ammonia water, stir and heat to 155-165℃, then cool down to 115-125℃, add the second part of ammonia water dropwise to obtain a mixture system;

[0009] (2) When the temperature of the mixture system in step (1) drops to 70-80℃, it is transferred to a water washing tank for water washing treatment, and the 3,3-tetramethyleneglutamate is obtained by centrifugation.

[0010] Further, in step (1), the molar ratio of the total amount of 1,1-cyclopentyl diacetic acid to ammonia is 1:2-3, and the total amount of ammonia is the sum of the first part of ammonia and the second part of ammonia.

[0011] Further, in step (1), the mass ratio of the first part of ammonia water to the second part of ammonia water is 3 to 4:1.

[0012] Further, in step (1), the mass percentage content of ammonia in the first part of ammonia water and the second part of ammonia water is 5%-20%.

[0013] Furthermore, in step (1), the heating rate during the stirring and heating process is 0.2-10℃ / min; the cooling rate during the cooling process is 0.1-4℃ / min.

[0014] Further, in step (1), the preparation method of the 1,1-cyclopentyldiacetic acid includes the following steps:

[0015] S1: Cyclopentanone, methyl cyanoacetate, and methanol were added to a reaction vessel, stirred and cooled to -5 to 0°C. Then liquid ammonia was introduced and the temperature was controlled at 0 to 5°C. The mixture was kept at this temperature for 20 to 30 hours and centrifuged to obtain the compound shown in formula (I).

[0016] S2: The sulfuric acid solution with a sulfuric acid content of 72% to 74% is heated. When the temperature reaches 140 to 145°C, the compound shown in formula (I) prepared by S1 is added and the temperature is controlled at 148 to 156°C. The temperature is maintained for 2 to 3 hours to obtain the 1,1-cyclopentyldiacetic acid.

[0017] The structure of equation (I) is as follows:

[0018]

[0019] Furthermore, the preparation method of 1,1-cyclopentyldiacetic acid also includes an alkaline dissolution and acid precipitation process for the 1,1-cyclopentyldiacetic acid prepared in step S2. Specifically, the 1,1-cyclopentyldiacetic acid prepared in step S2 is added to water, and liquid alkali is added dropwise until the pH is 9-10. Then activated carbon is added and stirred for filtration. Hydrochloric acid is added dropwise to the filtrate until the pH is 2-3. The filtrate is then centrifuged to obtain purified 1,1-cyclopentyldiacetic acid.

[0020] Furthermore, in step (2), the ratio of the amount of water used in the water washing process to the amount of 1,1-cyclopentyl diacetic acid fed in step (1) is preferably 1:2-3.

[0021] Furthermore, in step (2), the water washing process takes 0.5-2 hours.

[0022] Furthermore, the preparation method also includes a purification and decolorization process, specifically: heating and refluxing the 3,3-tetramethyleneglutamate prepared in step (2) with methanol until completely dissolved, then adding activated carbon and stirring for pressure filtration, cooling the filtrate to below 10°C, and centrifuging to obtain purified 3,3-tetramethyleneglutamate.

[0023] Furthermore, the purity of 3,3-tetramethyleneglutamate in the refined 3,3-tetramethyleneglutamate is not less than 99%.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0025] This invention provides a method for preparing 3,3-tetramethyleneglutamate, using 1,1-cyclopentyldiacetic acid and ammonia as raw materials. The method involves ammonium salt of 1,1-cyclopentyldiacetic acid via an ammoniation reaction, followed by dehydration and deammoniation to obtain the target product, 3,3-tetramethyleneglutamate. The synthetic route of this method is simple, and the reactants are readily available. No organic solvents are required during the preparation of the crude product, resulting in no residual organic solvents. Furthermore, the purification process uses low-boiling methanol for easy removal of these solvents, thus eliminating solvent residue issues in the product. In addition, the yield of 3,3-tetramethyleneglutamate prepared by this method can reach over 90%, and the purity of 3,3-tetramethyleneglutamate after purification can reach over 99.9%. Attached Figure Description

[0026] Figure 1 Synthetic route for preparing 3,3-tetramethyleneglutamate as shown in Example 1;

[0027] Figure 2 The 1H NMR spectrum of 3,3-tetramethyleneglutamate prepared in Example 1;

[0028] Figure 3 The HPLC chromatogram of 3,3-tetramethyleneglutamate prepared in Example 1 is shown below.

[0029] Figure 4 The HPLC chromatogram of the purchased product, 3,3-tetramethyleneglutamate;

[0030] Figure 5 The HPLC chromatogram of the standard 3,3-tetramethyleneglutaric acid is shown below.

[0031] Figure 6 The HPLC chromatogram is for the standard 3,3-cyclopentaneglutarimide. Detailed Implementation

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items. "Comprising" or "containing" as used herein means that it may include or contain other components in addition to the stated components. "Comprising" or "containing" as used herein may also be replaced with the closed form "is" or "consisting of".

[0033] Example 1

[0034] This embodiment provides a method for the industrial-scale preparation of 3,3-tetramethyleneglutamate, wherein the raw material 1,1-cyclopentyldiacetic acid is obtained in-house. The specific preparation process is as follows:

[0035] (1) Add 1200kg of methanol or recovered methanol, 570kg of cyclopentanone and 1425kg of methyl cyanoacetate to the reactor, start stirring and cool to -5 to 0℃; then introduce 320kg of liquid ammonia and control the temperature to 0 to 5℃. After the liquid ammonia is introduced, keep it at 0 to 5℃ for about 24 hours; after the temperature is maintained, centrifuge (pour the filtrate obtained by centrifugation into the methanol distillation vessel for distillation, slowly pass steam through the jacket and coil of the distillation column to heat it, and after reflux appears at the top of the column, reflux for half an hour to one hour and start collecting the fraction with a top temperature of 62 to 65℃, which is the recovered methanol). Pack the filter cake into bags, weigh it and attach a material label to it to obtain the condensed salt (wet product weight is about 1600kg, dry weight is 1300kg).

[0036] (2) Add 950 kg of tap water to a 5000 L hydrolysis reactor and start stirring. Slowly add 2640 kg of sulfuric acid (50% dilute sulfuric acid) and control its content between 72% and 74%. Then turn on the steam to heat up. When the temperature reaches 145°C, start adding salt and control the reaction temperature between 148°C and 156°C. After the salt is added, continue to keep warm for 2 hours. After the heat preservation is completed, cool to room temperature and then discharge the material for centrifugation to obtain crude product (about 840 kg of wet product).

[0037] (3) Put the crude product prepared in step (2) into a 5000L alkaline decolorizing kettle and add 940kg of tap water, and start stirring; slowly add liquid alkali from the high-level liquid alkali tank into the alkaline decolorizing kettle, and use pH test paper to track and control the pH to 9-10, then stop adding and continue stirring; when all the crude product in the alkaline decolorizing kettle is dissolved in the alkali solution and the pH is still controlled at 9-10, add 5kg of activated carbon and stir for 0.5 hours, then put the material into the suction filter bucket for suction filtration and pump the filtrate into the acid precipitation kettle; start stirring in the acid precipitation kettle and slowly add hydrochloric acid from the high-level hydrochloric acid tank into the acid precipitation kettle, and use pH test paper to track and control the pH to 2-3, then stop adding; put the liquid into a centrifuge for centrifugation and collect the filter cake, which is the wet product (the wet product is about 800kg, which is 650kg when dry, with a purity of ~95%).

[0038] (4) Add the wet product prepared in step (3) to the ammoniation kettle and add about 1375 kg of ammonia water (adjust the pH according to the actual content of ammonia water when adding the material, and control it at about 10), and start stirring and heating; when the material temperature rises to 160℃, cool it down to 120℃ and start adding ammonia water dropwise. After about 400 kg of ammonia water dropwise is added, while it is still hot (70-80℃), put the material into a water washing kettle with 1500 kg of water prepared, stir for 0.5 hours and then centrifuge; put the centrifuged filter cake into a bag, weigh it and hang the material label to obtain the crude product of 3,3-tetramethyleneglutamate (about 600 kg of wet product, 540 kg of dry product).

[0039] (5) Add 1200 kg of methanol and crude 3,3-tetramethylene glutarimide prepared in step (4) to a refining and decolorizing kettle, start stirring and heat to reflux until completely dissolved; add 2 kg of activated carbon to the kettle and stir for 0.5 hours, then discharge and filter the material into a 2000 L refining and cooling kettle; cool the material to below 10 °C in the refining and cooling kettle, centrifuge to obtain the filter cake, which is the refined 3,3-tetramethylene glutarimide (approximately 600 kg of wet product).

[0040] (6) The wet product of the 3,3-tetramethyleneglutamate concentrate prepared in step (5) was dried at 50-60°C to obtain 510 kg. The yield of the refined product prepared from the product in step (3) was about 92%.

[0041] The product was characterized by NMR and high-performance liquid chromatography. The 1H NMR spectrum of the product prepared in this embodiment is as follows: Figure 2 As shown in the figure, the product is 3,3-tetramethyleneglutamate. Figure 3 The HPLC results for the product show that the peak at retention time of 5.3333 min corresponds to the product 3,3-tetramethyleneglutimide. Figure 4 The peak position of the commercially available product 3,3-tetramethyleneglutarimide is consistent with that of the product. The chromatographic peak at a retention time of 4.922 min corresponds to the impurity 3,3-tetramethyleneglutaric acid. Figure 5 The peak position of the standard 3,3-tetramethyleneglutaric acid was consistent with that of the standard, and the chromatographic peak at retention time 6.603 corresponded to the impurity 3,3-cyclopentaneglutarimide. Figure 6 The elution positions of the standard 3,3-cyclopentaneglutarimide were consistent.

[0042] HPLC test results show that the purity of 3,3-tetramethyleneglutamate in the product can reach over 99.9%.

[0043] Example 2

[0044] This embodiment provides an industrial-scale method for preparing 3,3-tetramethyleneglutamate, using commercially available 1,1-cyclopentyldiacetic acid as a raw material. The specific preparation process is as follows:

[0045] (1) Add 6.50g of 1,1-cyclopentyl diacetic acid and about 13.75g of ammonia water to the reactor (adjust the pH according to the actual content of ammonia water when adding the material, and control it at about 10), and start stirring and heating; when the material temperature reaches 160℃, cool it down to 120℃ and start adding ammonia water dropwise. After about 4g of ammonia water has been added, while it is still hot (70~80℃), put the material into the reactor with 15mL of water prepared, stir for 0.5 hours, and centrifuge to obtain crude 3,3-tetramethylene glutarimide;

[0046] (2) Add 12g of methanol and crude 3,3-tetramethylene glutarimide prepared in step (2) to the reaction vessel, start stirring and heat to reflux until completely dissolved; add 2g of activated carbon to the vessel and stir for 0.5 hours, then discharge and filter, cool the filtrate to below 10°C, centrifuge to obtain filter cake, which is the refined 3,3-tetramethylene glutarimide.

[0047] (3) The wet product of the 3,3-tetramethyleneglutamate concentrate prepared in step (2) was dried at 50-60°C to obtain 5.26 g of dry product, with a yield of ~90.02%.

[0048] Comparative Example 1

[0049] This comparative example relates to the preparation of 3,3-tetramethyleneglutamate, and differs from Example 2 in that the operation of step (1) is as follows:

[0050] Add 6.50 g of 1,1-cyclopentyl diacetic acid and 18 g of ammonia water to the reaction vessel, start stirring and heat to 120 °C, then transfer to another reaction vessel with 15 mL of water, stir for 0.5 hours and centrifuge to obtain crude 3,3-tetramethyleneglutamate.

[0051] The remaining operations were the same as in Example 2, and 4.25 g of dried product was obtained, with a yield of ~72.7%.

[0052] Comparative Example 2

[0053] This comparative example relates to the preparation of 3,3-tetramethyleneglutamate, and differs from Example 2 in that the operation of step (1) is as follows:

[0054] 6.50 g of 1,1-cyclopentyl diacetic acid and 18 g of ammonia were added to the reaction vessel and stirred for 24 h. The mixture was then transferred to another reaction vessel with 15 mL of water. The mixture was then heated to 150 °C and stirred for 0.5 h. After cooling, the mixture was centrifuged to obtain only a very small amount of crude 3,3-tetramethyleneglutamate (yield <30%).

[0055] The embodiments described above are merely preferred examples to fully illustrate the present invention, and the scope of protection of the present invention is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention. The scope of protection of the present invention is defined by the claims.

Claims

1. A method for preparing 3,3-tetramethyleneglutamate, characterized in that, Includes the following steps: (1) Add 1,1-cyclopentyl diacetic acid and the first part of ammonia water to the reaction vessel, adjust the pH of the reaction system to 9~11 by controlling the amount of the first part of ammonia water, stir and heat to 155~165 ℃, then cool to 115~125 ℃, and add the second part of ammonia water dropwise to obtain a mixture system; the mass ratio of the first part of ammonia water to the second part of ammonia water is 3-4:1; (2) When the temperature of the mixture system in step (1) drops to 70~80 ℃, it is transferred to a water washing tank for water washing treatment, and the 3,3-tetramethyleneglutamate is obtained by centrifugation; (3) The 3,3-tetramethyleneglutamate prepared in step (2) is heated and refluxed with methanol until completely dissolved. Then activated carbon is added and stirred for pressure filtration. The filtrate is cooled to below 10 °C and centrifuged to obtain purified 3,3-tetramethyleneglutamate. The mass purity of 3,3-tetramethyleneglutamate in the purified 3,3-tetramethyleneglutamate is not less than 99%.

2. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of 1,1-cyclopentyl diacetic acid to the total amount of ammonia is 1:2-3, and the total amount of ammonia is the sum of the first part of ammonia and the second part of ammonia.

3. The preparation method according to claim 1, characterized in that, In step (1), the mass percentage content of ammonia in the first part of ammonia water and the second part of ammonia water is 5%-20%.

4. The preparation method according to claim 1, characterized in that, In step (1), the heating rate during the stirring and heating process is 0.2-10 ℃ / min; the cooling rate during the cooling process is 0.1-4 ℃ / min.

5. The preparation method according to claim 1, characterized in that, In step (1), the preparation method of 1,1-cyclopentyldiacetic acid includes the following steps: S1: Cyclopentanone, methyl cyanoacetate, and methanol were added to a reaction vessel, stirred and cooled to -5 to 0 °C, then liquid ammonia was introduced and the temperature was controlled at 0 to 5 °C. The mixture was kept at this temperature for 20 to 30 h and centrifuged to obtain the compound shown in formula (I). S2: The sulfuric acid solution with a sulfuric acid content of 72%~74% is heated. When the temperature reaches 140~145 ℃, the compound of formula (I) prepared in step (1) is added and the temperature is controlled at 148~156 ℃. The temperature is kept for 2~3 h to obtain the 1,1-cyclopentyl diacetic acid. The structure of equation (I) is as follows: （I）。 6. The preparation method according to claim 5, characterized in that, The method for preparing 1,1-cyclopentyldiacetic acid further includes an alkaline dissolution and acid precipitation process for the 1,1-cyclopentyldiacetic acid obtained in step S2. Specifically, the 1,1-cyclopentyldiacetic acid obtained in step S2 is added to water, and liquid alkali is added dropwise until the pH is 9-10. Then activated carbon is added and stirred for filtration. Hydrochloric acid is added dropwise to the filtrate until the pH is 2-3. The filtrate is then centrifuged to obtain purified 1,1-cyclopentyldiacetic acid.

7. The preparation method according to claim 1, characterized in that, In step (2), the ratio of the amount of water used in the water washing process to the amount of 1,1-cyclopentyl diacetic acid fed in step (1) is 1:2-3; the water washing time is 0.5-2 h.

Images