A method for preparing pregabalin intermediate and recovering resolving agent
The quality deviations in the preparation of R)-3-isobutylglutarate monoamide and R)-phenyethylamine were solved by adopting specific pH adjustment and organic solvent extraction steps in the industrial production of pregabalin and The problem of low yields has achieved the acquisition of high-purity products and simplified wastewater treatment, reducing energy consumption and cost.
Patent Information
- Application Number
- CN201910132480.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2019-02-22
- Publication Date
- 2024-12-31
- Estimated Expiration
- 2039-02-22
AI Technical Summary
In the existing industrial production process of pregabalin, there are mass deviations, low yields, difficult wastewater treatment and energy consumption during the preparation of R)-3-isobutylglutarate monoamide and R)-phenyltamine. High problem.
The (R)-3-isobutylglutarate monoamide-(R)-phenyethylamine salt was dissolved in water at 15 to 45°C, and the ionic membrane liquid alkali was added to adjust the pH to 11.0 to 13.0, and then the addition of the Hydrochloric acid adjusts pH to 6.0-8.0, and performs organic solvent extraction. Finally, crystallization is performed under cooling conditions and distillation is performed under reduced pressure to obtain high purity R)-3-isobutylglutaric acid monoamide and recover R)-phenylethylene amine.
It improves the purity and recovery rate of the product, reduces the organic matter and nitrogen content in the wastewater, simplifies the treatment process, and reduces the wastewater treatment cost and energy consumption.
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Figure CN109761838B_ABST
Abstract
Description
Technical Field
[0001] The invention provides a method for preparing a pregabalin intermediate (R)-3-isobutylglutaric acid monoamide and recovering a resolving agent (R)-phenylethylamine, and belongs to the field of pharmaceutical chemical industry. Background of the Invention
[0002] Pregabalin (Compound 1) is a pharmacologically active (S)-isomer of 3-aminomethyl-5-methylhexanoic acid. It is mainly used in the treatment of peripheral neuropathy and adjuvant treatment of localized partial epileptic seizures. Pregabalin is a revolutionary drug for the treatment of neuropathic pain that was first successfully developed and registered by Pfizer in the United States. Pregabalin is an analog of the neurotransmitter GABA. It has an anti-epileptic effect by inhibiting the α2-σ subunit protein of the CNS voltage-dependent calcium channel. It also has good lipid solubility and can pass through the blood-brain barrier. It has shown good anti-epileptic therapeutic effects in clinical trials. Its binding force is 6 times higher than that of gabapentin (Compound 2), but it has a smaller dosage, longer duration, and fewer side effects. Pregabalin was launched in China in September 2010, solving the problem of the lack of truly effective and well-documented neuropathic pain treatment drugs in the Chinese market. As a new type of psychiatric treatment drug, pregabalin has a fast onset of action and few side effects, and has broad market development prospects.
[0003]
[0004] At present, there are two main industrial production processes for pregabalin: chemical synthesis and enzymatic method. The former is more widely used in industrialization. Among them, the chemical synthesis method mainly uses a splitting agent to split and then process to obtain S-pregabalin. The following two synthesis processes are widely used in industrial production.
[0005]
Technology 1
[0006]
[0007]
Technology 2
[0008]
[0009] Process 1 and process 2 use R-phenylethylamine (compound (1)) and S-mandelic acid (compound (2)) for separation, and then obtain S-pregabalin after treatment. The isomer (compound 6) obtained by separation in process 1 can be recovered by racemization to obtain its racemate (compound 5) and be recycled, which shows obvious cost advantage compared with process 2.
[0010] Pregabalin is an S-isomer of 3-aminomethyl-5-methylhexanoic acid. In its chemical synthesis process, (R)-3-isobutylglutaric acid monoamide and R-phenylethylamine are very important intermediates and resolving agents. The synthesis of the intermediate and the resolving agent recovery route 1 reported in the literature can be described as follows (see Appendix Figure 1 ): In process 1, compound 7 ((R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt) is freed by acid adjustment, crystallized, and centrifuged to obtain compound 8 ((R)-3-isobutylglutaric acid monoamide), and the centrifuged mother liquor is freed by alkali adjustment to obtain R-phenylethylamine, which is extracted by an organic solvent to obtain an organic solution of R-phenylethylamine, and then the front boiling (extractant) and the middle boiling are removed by distillation, and finally R-phenylethylamine is obtained by distillation. However, the (R)-3-isobutylglutaric acid monoamide prepared by this process route contains residual R-phenylethylamine, resulting in the formation of R-phenylethylamine derivatives in the crude pregabalin prepared subsequently, resulting in its quality deviation, and the yield of the synthesized (R)-3-isobutylglutaric acid monoamide is low (about 85-93%) and the recovery rate of R-phenylethylamine is low (less than 97%). At the same time, wastewater 1 contains a high level of organic residues, which makes the treatment of high-concentration and high-salt wastewater difficult and requires high energy consumption. The total nitrogen and COD in the wastewater are at levels of 800-1000 mg / L and 50k-80k mg / L. Summary of the invention
[0011] The object of the present invention is to provide a method for preparing a pregabalin intermediate (R)-3-isobutylglutaric acid monoamide and recovering a resolving agent (R)-phenylethylamine, comprising the following steps:
[0012] 1) (R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt was dissolved in water;
[0013] 2) adding ion membrane liquid alkali at 15-45°C, adjusting the pH to 11.0-13.0, and keeping warm at this temperature;
[0014] 3) After the insulation is completed, add hydrochloric acid at 15-45°C to adjust the pH to 6.0-8.0;
[0015] 4) adding an organic solvent to extract and separate the layers;
[0016] 5) In step 4), hydrochloric acid is added to the aqueous layer at 15-45° C. to adjust the pH to 1.0-3.0, and the mixture is kept warm at this temperature;
[0017] 6) After the heat preservation is completed, the temperature is lowered to 0-15° C. to crystallize, filter and dry to obtain (R)-3-isobutylglutaric acid monoamide;
[0018] 7) In step 4), the organic layer is distilled off under reduced pressure to remove the front and middle boiling points, and the fractions at 90 to 130° C. are collected to obtain the recovered (R)-phenylethylamine.
[0019] The organic solvent in step 4) is selected from the group consisting of toluene, xylene, chloroform and dichloromethane; and the extraction times are 2 or more.
[0020] The volume amount of water used in step 1) is 3-6 ml per gram of compound 7.
[0021] The dissolving temperature in step 1) is 35-70°C.
[0022] The insulation time of step 2) is 0.5 to 1 h.
[0023] The total volume amount of the organic solvent in step 4) is 3 ml to 20 ml per gram of compound 7.
[0024] The insulation time of step 5) is 0.5 to 4 hours.
[0025] The vacuum degree of the reduced pressure distillation in step 7) is 0.08-0.10 MPa.
[0026] Route 2 of the present invention is shown in the attached Figure 2 .
[0027] The present invention is under the current safety and environmental protection, quality improvement and market fierce competition, and has obvious advantages: first, compound 7 is preferentially adjusted to be free, and organic solvent is used to extract free R-phenylethylamine from the aqueous phase, it is possible to avoid organic impurities such as R-phenylethylamine in route 1 from being accompanied by compound 8, and the phenomenon of bringing other impurities into the subsequent process to derive occurs, thereby improving compound 8 and subsequent step product quality, increasing the operation of adjusting pH to neutrality, reducing the decomposition of 3-isobutylglutaric acid monoamide to produce 3-isobutylglutaric acid impurities, and effectively improving product quality. Secondly, during the organic solvent extraction process, a large amount of organic impurities in the aqueous phase will be removed, so that the total nitrogen and COD in the filtrate (wastewater 2) of the compound 8 crystallization after the rejection filter are greatly reduced, meet the low-concentration wastewater treatment standard, and greatly reduce the three waste treatment efficiency and cost. Third, the compound 8 obtained by this route and the recovery R-phenylethylamine yield are significantly improved compared to route 1. Fourth, the purity of compound 8 obtained by this route can reach more than 99.7%, and the purity of recovered R-phenylethylamine can reach more than 99.5%. The operation is simple, and high-purity compound 8 and recovered R-phenylethylamine can be obtained without complex separation. In summary, the present invention provides a safe, environmentally friendly, simple and convenient method for preparing pregabalin intermediate (R)-3-isobutylglutaric acid monoamide and recovering the resolution agent (R)-phenylethylamine with high yield. BRIEF DESCRIPTION OF THE DRAWINGS
[0028] Figure 1 This is a schematic diagram of Route 1.
[0029] Figure 2 This is a schematic diagram of Route 2. DETAILED DESCRIPTION
[0030] The present invention is further described below with reference to examples, but these examples do not constitute any limitation to the present invention.
[0031] Embodiment 1:
[0032] Add 100g of compound 7 to a four-necked flask, add 400mL of water, heat to 35-45℃, stir to dissolve, control the temperature at 15-30℃, add ion membrane liquid alkali, adjust pH=12-13, and stir for 30min. Add hydrochloric acid at 15-30℃ to adjust pH=6.0-7.0. Add toluene (200mL+100mL) and extract twice, combine the toluene layer for standby. Add hydrochloric acid to the water layer at 35-45℃, adjust pH=1.0, stir for 30min, cool to 5℃, and crystallize for 2h. Filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.9g, with a yield of 97.0% and a purity of 99.7%. After filtration, the COD of the wastewater is 6075mg / L and the total nitrogen is 220mg / L. The toluene layer was distilled under reduced pressure to remove the front and middle boiling points, and the fractions at 90-130° C. were collected to recover (R)-phenylethylamine, weighing 38.2 g, with a recovery rate of 97.2% (Compound 7 is (R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt, and the recovery rate of (R)-phenylethylamine is calculated based on 39.3 g of (R)-phenylethylamine in 100 g of compound 7, the same below), and a purity of 99.6%.
[0033] Embodiment 2:
[0034] Add 100g of compound 7 to a four-necked flask, add 600mL of water, heat to 45-60℃, stir to dissolve, control the temperature at 30-45℃, add ion membrane liquid alkali, adjust pH=12-13, and stir for 1h. Add hydrochloric acid at 30-45℃ to adjust pH=6.0-7.0. Extract twice with toluene (400mL+200mL), combine the toluene layers for standby. Add hydrochloric acid to the water layer at 15-35℃, adjust pH=2.0, stir for 30min, cool to 10℃, and crystallize for 1h. Filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.8g, with a yield of 96.9% and a purity of 99.8%. After filtration, the COD of the wastewater is 6926mg / L and the total nitrogen is 280mg / L. The toluene layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.4 g, with a recovery rate of 97.7% and a purity of 99.5%.
[0035] Embodiment 3:
[0036] Add 100g of compound 7 to a four-necked flask, add 300mL of water, heat to 60-70℃, stir and dissolve, control the temperature at 20-30℃, add ion membrane liquid alkali, adjust pH=11-12, and keep warm and stir for 0.5h. Add hydrochloric acid at 20-30℃ to adjust pH=7.0-8.0. Extract with xylene (300mL+200mL) twice, and combine the xylene layers for standby. Add hydrochloric acid to the water layer at 25-35℃, adjust pH=3.0, keep warm and stir for 30min, cool to 0℃ and keep warm for 0.5h, filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 59.4g, with a yield of 97.8% and a purity of 99.8%. After filtration, the COD of the wastewater is 6102mg / L and the total nitrogen is 214mg / L. The toluene layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.4 g, with a recovery rate of 97.7% and a purity of 99.7%.
[0037] Embodiment 4:
[0038] Add 100g of compound 7 to a four-necked flask, add 500mL of water, heat to 30-45℃, stir and dissolve, control the temperature at 20-30℃, add ion membrane liquid alkali, adjust pH=12-13, and keep warm and stir for 1h. Add hydrochloric acid at 20-30℃ to adjust pH=7.0-8.0. Extract with dichloromethane (300mL+100mL+100mL) 3 times, combine the dichloromethane layers for standby. Add hydrochloric acid to the water layer at 25-35℃, adjust pH=1.0, keep warm and stir for 3h, cool to 15℃ and keep warm for crystallization for 3h, filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.6g, yield 96.5%, purity 99.9%. After filtration, the wastewater COD is 7530mg / L and the total nitrogen is 240mg / L. The dichloromethane layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.5 g, with a recovery rate of 98.0% and a purity of 99.6%.
[0039] Embodiment 5:
[0040] Add 100g of compound 7 to a four-necked flask, add 400mL of water, heat to 30-45℃, stir to dissolve, control the temperature at 20-30℃, add ion membrane liquid alkali, adjust pH=12-13, and stir for 1h. Add hydrochloric acid at 20-30℃ to adjust pH=6.0-7.0. Extract twice with chloroform (300mL+200mL), combine the chloroform layers for standby. Add hydrochloric acid to the water layer at 20-30℃, adjust pH=1.0, stir for 1h, cool to 5℃, and crystallize for 1h. Filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.8g, with a yield of 96.9% and a purity of 99.8%. After filtration, the COD of the wastewater is 6018mg / L and the total nitrogen is 210mg / L. The chloroform layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.3 g, with a recovery rate of 97.5% and a purity of 99.8%.
[0041] Embodiment 6:
[0042] Add 100g of compound 7 to a four-necked flask, add 400mL of water, heat to 50-60℃, stir and dissolve, control the temperature at 25-35℃, add ion membrane liquid alkali, adjust pH=11-12, and stir for 0.5h. Add hydrochloric acid at 25-35℃ to adjust pH=7.0-8.0. Extract twice with dichloromethane (400mL+200mL), combine the dichloromethane layers for standby. Add hydrochloric acid to the water layer at 15-25℃, adjust pH=2.0, stir for 1h, cool to 5℃ and crystallize for 2h, filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.9g, with a yield of 97.1% and a purity of 99.8%. After filtration, the COD of the wastewater is 6328mg / L and the total nitrogen is 211mg / L. The dichloromethane layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.3 g, with a recovery rate of 97.5% and a purity of 99.6%.
[0043] Embodiment 7:
[0044] Add 100g of compound 7 to a four-necked flask, add 500mL of water, heat to 50-60℃, stir to dissolve, control the temperature at 25-35℃, add ion membrane liquid alkali, adjust pH=12-13, and keep warm and stir for 0.5h. Add hydrochloric acid at 25-35℃ to adjust pH=7.0-8.0. Extract with toluene (300mL+100mL+100mL) 3 times, combine the toluene layers for standby. Add hydrochloric acid to the water layer at 25-35℃, adjust pH=1.0, keep warm and stir for 1h, cool to 0℃ and keep warm for crystallization for 1h, filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.4g, with a yield of 96.2% and a purity of 99.8%. After filtration, the COD of the wastewater is 6283mg / L and the total nitrogen is 208mg / L. The toluene layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.4 g, with a recovery rate of 97.7% and a purity of 99.7%.
[0045] Embodiment 8:
[0046] Add 100g of compound 7 to a four-necked flask, add 400mL of water, heat to 45-60℃, stir to dissolve, control the temperature at 30-45℃, add ion membrane liquid alkali, adjust pH=11-12, and stir for 1h. Add hydrochloric acid at 30-45℃ to adjust pH=6.0-7.0. Extract twice with toluene (300mL+200mL), combine the toluene layers for standby. Add hydrochloric acid to the water layer at 15-25℃, adjust pH=3.0, stir for 30min, cool to 5℃, and crystallize for 3h. Filter and dry to obtain (R)-3-isobutylglutaric acid monoamide, weighing 58.7g, with a yield of 96.7% and a purity of 99.9%. After filtration, the COD of the wastewater is 6018mg / L and the total nitrogen is 255mg / L. The toluene layer was distilled under reduced pressure to remove the front boiling and middle boiling, and the fraction at 90-130° C. was collected to obtain the recovered (R)-phenylethylamine, weighing 38.7 g, with a recovery rate of 98.5% and a purity of 99.6%.
Claims
1. A method for preparing pregabalin intermediate (R)-3-isobutylglutaric acid monoamide and recovering the resolving agent (R)-phenylethylamine, characterized in that The following steps are involved: (1) (R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt was dissolved in water; (2) adding ion membrane liquid alkali at 15-45° C., adjusting the pH to 11.0-13.0, and keeping the temperature at that temperature; (3) After the heat preservation reaction in step (2) is completed, hydrochloric acid is added at 15 to 45° C. to adjust the pH to 6.0 to 8.0; (4) adding an organic solvent for extraction to separate an organic layer and an aqueous layer, wherein the organic solvent is selected from one or more of toluene, xylene, chloroform and dichloromethane; (5) adding hydrochloric acid to the aqueous layer in step (4) at 15 to 45° C. to adjust the pH to 1.0 to 3.0, and then keeping the temperature at that temperature; (6) After the heat preservation is completed, the temperature is lowered to 0-15° C., crystallization is performed, filtration is performed, and drying is performed to obtain (R)-3-isobutylglutaric acid monoamide; (7) In step (4), the organic layer is distilled under reduced pressure to remove the front boiling point and the middle boiling point, and the fraction at 90 to 130° C. is collected to obtain the recovered (R)-phenylethylamine.
2. The method according to claim 1, characterized in that The volume amount of water in step (1) is 3 mL to 6 mL per gram of (R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt.
3. The method according to claim 1, characterized in that The dissolving temperature in step (1) is 35-70°C.
4. The method according to claim 1, characterized in that The insulation time in step (2) is 0.5 to 1 h.
5. The method according to claim 1, characterized in that The insulation time in step (5) is 0.5 to 4 hours.
6. The method according to claim 1, characterized in that The number of extractions in step (4) is 2 or more.
7. The method according to claim 1, characterized in that The volume amount of the organic solvent in step (4) is 3 mL to 20 mL per gram of (R)-3-isobutylglutaric acid monoamide-(R)-phenylethylamine salt.
8. The method according to claim 1, characterized in that The crystallization time of step (6) is 1.0 to 6.0 hours.
9. The method according to claim 1, characterized in that The vacuum degree of the reduced pressure distillation in step (7) is 0.08-0.10 MPa.