A method for recovering chiral phosphoric acid from bedaquiline waste liquor

Abstract

The application discloses a method for recovering chiral phosphoric acid from bedaquiline waste liquid, and belongs to the technical field of waste liquid recovery, and comprises the following steps: (1) separating enantiomers and chiral phosphoric acid salt: recovering bedaquiline split mother liquor under reduced pressure, and obtaining organic phase containing enantiomers and water phase containing chiral phosphoric acid salt after liquid separation; (2) recovering enantiomers: recovering the organic phase in step (1) under reduced pressure, crystallizing, filtering and drying to obtain enantiomers; (3) freeing chiral phosphoric acid: combining the water phase obtained in step (1) with the water phase generated in the bedaquiline freeing process, adjusting the pH to be acidic, adding diatomite for adsorption, filtering to obtain filter cake; (4) recovering chiral phosphoric acid: adding tetrahydrofuran and water into the filter cake, stirring and dispersing, crystallizing, filtering, drying and obtaining chiral phosphoric acid. The application can effectively recover chiral phosphoric acid contained in bedaquiline waste liquid, greatly reduces production cost, and has higher economic benefits.

Description

Technical Field

[0001] This application relates to a method for recovering chiral phosphoric acid from bedaquiline waste liquid, belonging to the field of waste liquid recovery technology. Background Technology

[0002] Bedaquinoline (CAS: 843663-66-1) has the following structural formula:

[0003]

[0004] Bedaquiline, developed by Johnson & Johnson, is a diarylquinoline antimycobacterial drug indicated as part of combination therapy for the treatment of multidrug-resistant tuberculosis in adults.

[0005] The synthesis methods of bedaquiline have been reported in the literature, and the mainstream synthetic routes are as follows:

[0006]

[0007] This synthetic route yields bedaquiline via condensation, resolution, and free fractionation. The condensation reaction produces three configurations besides the pharmaceutically acceptable (1R,2S) configuration. Therefore, in this route, the two diastereomer configurations (1R,2R) and (1S,2S) are removed by crystallization, the enantiomer (1S,2R) is removed by resolution, and then (1R,2S) bedaquiline is obtained by free fractionation. During the resolution process, the resolving agent R-binaphthol phosphate (i.e., chiral phosphate) used is 1.0 equivalent. Except for 0.5 equivalents that form phosphate with (1R,2S) bedaquiline, the remaining chiral phosphate and enantiomers remain in the resolution mother liquor. Furthermore, during the free fractionation process, potassium carbonate is used to extract the resolution product, enriching bedaquiline in the toluene layer, while the discarded aqueous layer also contains a large amount of chiral phosphate.

[0008] Therefore, the recovery of the large amount of chiral phosphoric acid contained in bedaquiline waste liquid is a problem that needs to be solved.

[0009] The bedaquiline waste liquid referred to in this invention refers to the mother liquor and aqueous phase in the bedaquiline resolution process.

[0010] The chiral phosphoric acid referred to in this invention is R-binaphthol phosphate. Summary of the Invention

[0011] In view of this, this application provides a method for recovering chiral phosphoric acid from bedaquiline waste liquid, which can recover enantiomers and more than 90% of chiral phosphoric acid from the mother liquor.

[0012] Specifically, this application is implemented through the following scheme:

[0013] A method for recovering chiral phosphoric acid from bedaquiline waste liquid, comprising the following steps:

[0014] (1) Separation of enantiomers and chiral phosphates

[0015] The mother liquor of bedaquiline was depressurized to recover acetone and obtain a concentrated solution. Toluene was added to the concentrated solution for dispersion, and then an alkaline solution was added. After mixing at high temperature, the mixture was separated to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0016] (2) Recovery of enantiomers

[0017] Toluene was recovered from the organic phase in step (1) under reduced pressure, then slurried with ethanol, cooled to crystallize, filtered, and dried to obtain the enantiomers.

[0018] (3) Free chiral phosphoric acid

[0019] The aqueous phase obtained in step (1) is combined with the aqueous phase generated during the bedaquiline release process, the pH is adjusted to acidic by adding acid, diatomaceous earth is added for adsorption, and the filter cake is obtained by filtration.

[0020] (4) Recovery of chiral phosphoric acid

[0021] Tetrahydrofuran and water were added to the aforementioned filter cake, stirred and dispersed, and then filtered to obtain a filtrate. The tetrahydrofuran was recovered from the filtrate under reduced pressure, and the filtrate was slurried with toluene, cooled to crystallize, filtered, and dried to obtain chiral phosphoric acid.

[0022] This invention can effectively extract the waste enantiomers from the mother liquor of the resolution process and convert them into raw materials for the preparation of bedaquiline, thus reducing material loss. Simultaneously, it effectively recovers chiral phosphoric acid contained in the mother liquor and the aqueous phase during the resolution process. Since chiral phosphoric acid accounts for up to 50% of the overall material cost, recovering chiral phosphoric acid in actual production can significantly reduce production costs and has high economic benefits.

[0023] Furthermore, as a preferred option:

[0024] In step (1):

[0025] Acetone was recovered from the mother liquor of bedaquiline under reduced pressure to obtain a concentrated solution, which was then dispersed by adding toluene at a weight ratio of 1:0.3 to 1:0.8 of the mother liquor.

[0026] The alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, preferably an aqueous solution of sodium hydroxide, with the pH adjusted to 9-13, more preferably 11-12, and the temperature to 75-85°C.

[0027] In step (2):

[0028] The ethanol is pulped at a weight ratio of 1:0.2 to 1:0.5 between the organic phase and ethanol, at a temperature of 50 to 70°C. After pulping, the temperature is lowered to 0 to 20°C to induce crystallization, followed by filtration and drying to obtain the enantiomers.

[0029] In step (3):

[0030] The aqueous phase obtained in step (1) is combined with the aqueous phase generated during the bedaquiline release process, and the pH is adjusted to 1-5, preferably 2-3, by adding acid. The acid is any one of hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.

[0031] The adsorption process involves adding diatomaceous earth, with the weight ratio of the aqueous phase to the diatomaceous earth being 1:0.01 to 1:0.10. The resulting filter cake is a mixture of diatomaceous earth and chiral phosphoric acid.

[0032] Diatomaceous earth adsorption can shape the free chiral phosphoric acid, making it easier to separate and recover. Without diatomaceous earth adsorption, the free chiral phosphoric acid is viscous and easily clogs filter paper and filter cloth during filtration, making effective separation impossible.

[0033] In step (4):

[0034] A mixed solvent of tetrahydrofuran and water is added to the aforementioned filter cake. The weight ratio of the filter cake to the mixed solvent is 1:3 to 1:10, and the ratio of tetrahydrofuran to water in the mixed solvent is 1:0.05 to 1:1.

[0035] By adjusting the ratio of tetrahydrofuran to water as a solvent, chiral phosphoric acid in diatomaceous earth can be effectively dissolved, avoiding the use of DMSO as a solvent in the reaction and reducing the difficulty of solvent recovery in post-processing. Since subsequent purification is required, excessive moisture will worsen the crystallization state; therefore, a ratio of 1:0.05 to 1:0.10 is preferred.

[0036] The toluene is pulped, and toluene with a weight ratio of 1:1 to 1:5 of the filtrate is added. The temperature is 60 to 80°C. After pulping, the temperature is lowered to 0 to 20°C to induce crystallization. The mixture is then filtered and dried to obtain chiral phosphoric acid.

[0037] Impurities in the recovered crude chiral phosphoric acid can be effectively removed by pulping with toluene, resulting in a purity of over 99.8%.

[0038] The beneficial effects of this invention are as follows:

[0039] (1) This invention effectively extracts chiral phosphoric acid that would otherwise be discarded during the production process through simple operating steps, with a recovery rate of over 90%;

[0040] (2) This invention improves the problem of difficult separation of chiral phosphoric acid after it is free by adsorption with diatomaceous earth, and then dissolves the chiral phosphoric acid by a mixed solvent of tetrahydrofuran and water, thereby reducing the difficulty of post-processing.

[0041] (3) The present invention uses toluene pulping and refining, so that the recovered chiral phosphoric acid can be directly reused for the separation of bedaquiline, which has high economic benefits. Detailed Implementation

[0042] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0043] Unless otherwise specified, all percentages mentioned in the examples are mass percentages.

[0044] The "bedaquiline waste liquid" mentioned in this embodiment of the invention refers to the mother liquor obtained during the bedaquiline production process and the aqueous phase during the free process, as detailed below:

[0045] A method for synthesizing bedaquiline includes steps such as condensation reaction, resolution, and release:

[0046] (1) Condensation reaction: Under a nitrogen atmosphere, a solution of diisopropylaminolithium was added, and the temperature was lowered to -90 to -80°C. Then, a tetrahydrofuran solution of 3-benzyl6-bromo-2-methoxyquinoline was slowly added dropwise. After the addition was complete, the temperature was raised to -75°C. A tetrahydrofuran solution of 3-dimethylamino-1-naphthyl-1-propanone was slowly added dropwise. After the addition was complete, the reaction was carried out for 8 hours. The solution was quenched in a mixed solvent of tetrahydrofuran and acetic acid. Ethyl acetate and water were added and stirred to induce crystallization. The mixture was filtered to obtain the filtrate. Potassium carbonate was added to the filtrate and stirred. The organic phase was separated from the solvent and ethanol was added to induce crystallization. The mixture was filtered to obtain racemic bedaquiline.

[0047] (2) Resolution: Add 100g of racemic bedaquiline and 1260g of acetone, stir, and heat to 30℃. Prepare a solution of 57g of chiral phosphate and 110g of DMSO, and add the above solution dropwise. After the addition is complete, keep warm and stir for 30min until dissolved, heat to 60℃, stir for 3 hours, cool to room temperature, filter, and obtain bedaquiline chiral phosphate. The filtrate is the resolution mother liquor.

[0048] (3) Freeing: Add 60g of bedaquiline chiral phosphate and 312g of toluene, add 134g of potassium carbonate aqueous solution, heat to release, separate to obtain organic phase and aqueous phase, the aqueous phase is the aqueous phase in the freeing process. Recover the solvent from the organic phase, add ethanol to crystallize, filter to obtain bedaquiline.

[0049] Example 1:

[0050] (1) Take 300g of the mother liquor, recover acetone under reduced pressure, and obtain 41.7g of concentrated liquid. Add 210g of toluene for dispersion, add sodium hydroxide aqueous solution, adjust the pH to 11-12, heat to 80℃, and separate the liquid to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0051] (2) Toluene was recovered from the organic phase under reduced pressure. 100g of ethanol was added, and the mixture was stirred at 60°C. The temperature was then lowered to 10°C to allow crystallization. The mixture was filtered and dried to obtain 8.9g of enantiomers with a purity of 96.52% for related substances.

[0052] (3) Combine the aqueous phase from step (1) and the aqueous phase generated during the bedaquiline release process, with a total weight of 155g. The liquid phase external standard content detection system contains 12.3g of chiral phosphate. Adjust the pH to 2-3 with hydrochloric acid, add 15.5g of diatomaceous earth for adsorption, and filter to obtain 40.2g of filter cake.

[0053] (4) Add 120g of mixed solvent (tetrahydrofuran:water = 1:0.10) to the filter cake, stir to disperse, filter to obtain filtrate, recover tetrahydrofuran from the filtrate under reduced pressure, and obtain 15.5g of concentrate. Add 30g of toluene and slurry at 70℃, cool to 10℃ to crystallize, filter, and dry to obtain 11.8g of chiral phosphoric acid, with a purity of 99.93% for related substances and a recovery rate of 95.9%.

[0054] Example 2

[0055] (1) Take 300g of the mother liquor, recover acetone under reduced pressure, and obtain 42.5g of concentrated liquid. Add 210g of toluene for dispersion, add potassium carbonate aqueous solution, adjust the pH to 10-11, heat to 80℃, and separate the liquid to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0056] (2) Toluene was recovered from the organic phase under reduced pressure. 100g of ethanol was added, and the mixture was stirred at 60°C. The temperature was then lowered to 10°C to allow crystallization. The mixture was filtered and dried to obtain 9.3g of enantiomers with a purity of 95.27% for related substances.

[0057] (3) Combine the aqueous phase from step (1) and the aqueous phase generated during the bedaquiline release process, with a total weight of 169g. The liquid phase external standard content detection system contains 12.5g of chiral phosphate. Adjust the pH to 2-3 with hydrochloric acid, add 17.0g of diatomaceous earth for adsorption, and filter to obtain 42.3g of filter cake.

[0058] (4) Add 120g of mixed solvent (tetrahydrofuran:water = 1:1) to the filter cake, stir to disperse, filter to obtain filtrate, recover tetrahydrofuran from the filtrate under reduced pressure, and obtain 15.2g of concentrate. Add 30g of toluene and slurry at 70℃, cool to 10℃ to crystallize. During crystallization, the properties are poor, and it is viscous. The filtration speed is slow, and there is loss during the transfer process. After drying, 8.5g of chiral phosphoric acid is obtained, with a purity of 99.82% for related substances and a recovery rate of 68.0%.

[0059] analyze:

[0060] By comparing Example 1 and Example 2, it can be seen that if the water content in the mixed solvent is high, it will easily affect the crystallization process in the subsequent refining process, resulting in poor chiral phosphoric acid properties, slow filtration speed, and low yield.

[0061] Example 3

[0062] (1) Take 300g of the mother liquor, recover acetone under reduced pressure, and obtain 42.8g of concentrated liquid. Add 210g of toluene for dispersion, add potassium hydroxide aqueous solution, adjust the pH to 12-13, heat to 80℃, and separate the liquid to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0063] (2) Toluene was recovered from the organic phase under reduced pressure. 100g of ethanol was added, and the mixture was stirred at 60°C. The temperature was then lowered to 10°C to allow crystallization. The mixture was filtered and dried to obtain 9.5g of enantiomers with a purity of 94.58% for related substances.

[0064] (3) Combine the aqueous phase from step (1) and the aqueous phase generated during the bedaquiline release process, with a total weight of 163g. The liquid phase external standard content detection system contains 12.3g of chiral phosphate. Adjust the pH to 1-2 with sulfuric acid, add 15.5g of diatomaceous earth for adsorption, and filter to obtain 40.2g of filter cake.

[0065] (4) Add 120g of mixed solvent (tetrahydrofuran:water = 1:0.10) to the filter cake, stir to disperse, filter to obtain filtrate, recover tetrahydrofuran from the filtrate under reduced pressure, and obtain 15.5g of concentrate. Add 30g of toluene and slurry, slurry at 70℃, cool to 10℃, crystallize, filter, and dry to obtain 11.3g of chiral phosphoric acid, with a purity of 99.92% for related substances and a recovery rate of 91.9%.

[0066] Replacement example:

[0067] The preparation method is the same as in Example 3, except that the pH value is adjusted with sulfuric acid in step (3), and its effect on purity and recovery rate is tested.

[0068] Example 3 1～2 99.92 91.9 Example 3-2 2～3 99.93 94.2 Example 3-3 3～4 99.89 93.5 Examples 3-4 4～5 99.91 92.4 Examples 3-5 5～6 97.32 65.5 Examples 3-6 6～7 95.31 21.1

[0069] The analysis of the table above shows that adjusting the pH value has a significant impact on the purity and recovery rate of chiral phosphoric acid. The recovery rate is relatively high when the pH value is between 1 and 5, with pH value between 2 and 3 being more preferred.

[0070] Example 4

[0071] (1) Take 300g of the mother liquor, recover acetone under reduced pressure, and obtain 41.5g of concentrated liquid. Add 210g of toluene for dispersion, add sodium carbonate aqueous solution, adjust the pH to 9-10, heat to 80℃, and separate to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0072] (2) Toluene was recovered from the organic phase under reduced pressure. 100g of ethanol was added, and the mixture was stirred at 60°C. The temperature was then lowered to 10°C to allow crystallization. The mixture was filtered and dried to obtain 8.6g of enantiomers with a purity of 95.73% for related substances.

[0073] (3) Combine the aqueous phase from step (1) and the aqueous phase generated during the bedaquiline release process, with a total weight of 152g. The liquid phase external standard content detection system contains 11.9g of chiral phosphoric acid. Adjust the pH to 4-5 with phosphoric acid, add 15.2g of diatomaceous earth for adsorption, and filter to obtain 40.8g of filter cake.

[0074] (4) Add 120g of mixed solvent (tetrahydrofuran:water = 1:0.20) to the filter cake, stir to disperse, filter to obtain filtrate, recover tetrahydrofuran from the filtrate under reduced pressure, and obtain 14.9g of concentrate. Add 30g of toluene and slurry, slurry at 70℃, cool to 10℃, crystallize, filter, and dry to obtain 10.6g of chiral phosphoric acid, with a purity of 99.87% for related substances and a recovery rate of 93.8%.

[0075] Example 5

[0076] (1) Take 300g of the mother liquor, recover acetone under reduced pressure, and obtain 43.6g of concentrated liquid. Add 210g of toluene for dispersion, add sodium hydroxide aqueous solution, adjust the pH to 11-12, heat to 80℃, and separate the liquid to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates.

[0077] (2) Toluene was recovered from the organic phase under reduced pressure. 100g of ethanol was added, and the mixture was stirred at 60°C. The temperature was then lowered to 10°C to allow crystallization. The mixture was filtered and dried to obtain 8.5g of enantiomers with a purity of 95.82% for related substances.

[0078] (3) Combine the aqueous phase from step (1) and the aqueous phase generated during the bedaquiline release process, with a total weight of 159g. The liquid phase external standard content detection system contains 12.1g of chiral phosphate. Adjust the pH to 3-4 with hydrochloric acid, add 15.9g of diatomaceous earth for adsorption, and filter to obtain 42.9g of filter cake.

[0079] 120g of a mixed solvent (tetrahydrofuran:water = 1:0.20) was added to the filter cake, stirred and dispersed, and filtered to obtain a filtrate. The tetrahydrofuran was recovered from the filtrate under reduced pressure to obtain 15.8g of concentrate. 30g of toluene was added and the mixture was stirred at 70℃. The mixture was then cooled to 10℃ to induce crystallization. After filtration and drying, 11.6g of chiral phosphoric acid was obtained. The purity of related substances was 99.93%, and the recovery rate was 95.9%.

[0080] Example 6: The recovered chiral phosphoric acid can be directly reused.

[0081] The chiral phosphoric acid recovered in Example 5 was directly applied to the resolution of racemic bedaquiline. The specific steps are as follows: 10 g of racemic bedaquiline and 126.4 g of acetone were added, stirred, and heated to 30°C. A solution of 5.70 g of recovered chiral phosphoric acid and 11 g of DMSO was prepared, and the above solution was added dropwise. After the addition was complete, the mixture was kept warm and stirred for 30 min until dissolved. The temperature was then raised to 60°C, stirred for 3 hours, cooled to room temperature, and filtered to obtain bedaquiline chiral phosphate with a chiral purity of 96.87% and a yield of 43.0%.

[0082] Analysis: The recovered chiral phosphoric acid can be directly used for the resolution of racemic bedaquiline, which can resolve the target isomer and obtain a product with chiral purity and yield within the normal process range.

[0083] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.

Claims

1. A method for recovering chiral phosphoric acid from bedaquiline waste liquid, characterized in that, Includes the following steps: (1) Separation of enantiomers and chiral phosphates The mother liquor of bedaquiline was depressurized to recover acetone and obtain a concentrated solution. Toluene was added to the concentrated solution for dispersion, and then an alkaline solution was added. After mixing at high temperature, the mixture was separated to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphates. (2) Recovery of enantiomers Toluene was recovered from the organic phase in step (1) under reduced pressure, then slurried with ethanol, cooled to crystallize, filtered, and dried to obtain the enantiomers. (3) Free chiral phosphoric acid The aqueous phase obtained in step (1) is combined with the aqueous phase generated during the bedaquiline release process, the pH is adjusted to acidic by adding acid, diatomaceous earth is added for adsorption, and the filter cake is obtained by filtration. (4) Recovery of chiral phosphoric acid In step (3), tetrahydrofuran and water are added to the filter cake, stirred and dispersed, and then filtered to obtain a filtrate. The tetrahydrofuran is recovered from the filtrate under reduced pressure, slurried with toluene, cooled and crystallized, filtered, and dried to obtain chiral phosphoric acid.

2. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (1): Acetone is recovered from the mother liquor of bedaquiline under reduced pressure to obtain a concentrate, which is then dispersed by adding toluene at a weight ratio of 1:0.3 to 1:0.8 of the mother liquor.

3. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (1): the alkaline solution is an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, with the pH adjusted to 9-13 and the temperature to 75-85℃.

4. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 3, characterized in that, In step (1): the alkaline solution is an aqueous solution of sodium hydroxide, and the pH is adjusted to 11-12.

5. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (2): the ethanol is pulped, the weight ratio of organic phase to ethanol is 1:0.2 to 1:0.5, the temperature is 50 to 70°C, after pulping, the temperature is lowered to 0 to 20°C, crystallization occurs, and the mixture is filtered and dried to obtain the enantiomer.

6. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (3): the aqueous phase obtained in step (1) is combined with the aqueous phase generated during the bedaquiline release process, and the pH is adjusted to 1-5 by adding acid, wherein the acid is any one of hydrochloric acid, sulfuric acid or phosphoric acid.

7. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 6, characterized in that, In step (3): add acid to adjust the pH to 2-3, and the acid is hydrochloric acid.

8. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (3): the addition of diatomaceous earth for adsorption, the weight ratio of aqueous phase to diatomaceous earth is 1:0.01 to 1:0.10, and the filter cake is obtained by filtration. The filter cake is a mixture of diatomaceous earth and chiral phosphoric acid.

9. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (4): a mixed solvent of tetrahydrofuran and water is added to the filter cake in step (3). The weight ratio of the filter cake to the mixed solvent is 1:3 to 1:10, and the ratio of tetrahydrofuran to water in the mixed solvent is 1:0.05 to 1:

1.

10. The method for recovering chiral phosphoric acid from bedaquiline waste liquid according to claim 1, characterized in that, In step (4): the toluene is pulped, and toluene with a weight ratio of 1:1 to 1:5 of the filtrate is added. The temperature is 60 to 80°C. After pulping, the temperature is lowered to 0 to 20°C to crystallize, filtered, and dried to obtain chiral phosphoric acid.

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