Method for recovering chiral phosphoric acid from bedaquiline waste liquid

Abstract

The invention discloses a method for recovering chiral phosphoric acid from bedaquiline waste liquid, which belongs to the technical field of waste liquid recovery, and comprises the following steps: (1) separating enantiomers and chiral phosphate: recovering bedaquiline resolution mother liquid under reduced pressure, and separating the liquid to obtain an organic phase containing the enantiomers and a water phase containing the chiral phosphate; (2) enantiomer recovery: recovering the organic phase in the step (1) under reduced pressure, crystallizing, filtering and drying to obtain the enantiomer; (3) dissociating chiral phosphoric acid: combining the water phase obtained in the step (1) with a water phase generated in the dissociation process of bedaquiline, adjusting the pH value to be acidic, adding diatomite for adsorption, and filtering to obtain a filter cake; and (4) recovering the chiral phosphoric acid: adding tetrahydrofuran and water into the filter cake, stirring, dispersing, crystallizing, filtering and drying to obtain the chiral phosphoric acid. According to the method, chiral phosphoric acid contained in the bedaquiline waste liquid can be effectively recovered, the production cost is greatly reduced, and high economic benefits are achieved.

Description

TECHNICAL FIELD

[0001] The application relates to a method for recovering chiral phosphoric acid from bedaquiline waste liquid, and belongs to the technical field of waste liquid recovery. BACKGROUND

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

[0003]

[0004] Bedaquiline is a diarylquinoline anti-mycobacterial drug developed by Johnson & Johnson, and is suitable for treating adult multi-drug resistant pulmonary tuberculosis as part of combination therapy.

[0005] The synthesis method of bedaquiline has been reported in the literature, and the mainstream synthesis route is as follows:

[0006]

[0007] The synthesis route obtains bedaquiline through condensation reaction, resolution and free state. The condensation reaction produces three configurations except the medicinal configuration (1R, 2S), so in the route, two configurations (1R, 2R) and (1S, 2S) of the enantiomer are removed by crystallization, the enantiomer (1S, 2R) configuration is removed by resolution, and (1R, 2S) bedaquiline is obtained by free state. In the resolution process, the equivalent of the resolution agent R-binasphosphoric acid ester (i.e. chiral phosphoric acid) is 1.0, except for 0.5 equivalent of the phosphoric acid salt formed with (1R, 2S) bedaquiline, the remaining chiral phosphoric acid and the enantiomer are all left in the resolution mother liquor. In addition, in the free process, potassium carbonate is used to free the resolution product and extract, bedaquiline is enriched in the toluene layer, and the waste water layer also contains a large amount of chiral phosphoric acid salt.

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

[0009] The bedaquiline waste liquid referred to in the application is the mother liquor in the resolution process and the water phase in the free process of bedaquiline.

[0010] The chiral phosphoric acid referred to in the application is R-binasphosphoric acid ester. SUMMARY

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

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

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

[0014] (1) Separating enantiomers and chiral phosphoric acid salt

[0015] The bedaquiline split mother liquor is recovered under reduced pressure to obtain a concentrated solution, toluene is added to disperse the concentrated solution, a lye is added, and the mixture is mixed at high temperature and then separated to obtain an organic phase containing enantiomers and an aqueous phase containing chiral phosphoric acid salt.

[0016] (2) Recovering enantiomers

[0017] The organic phase obtained in step (1) is recovered under reduced pressure to recover toluene, and then ethanol is used for pulping, and the solution is cooled to precipitate crystals, filtered, and dried to obtain enantiomers.

[0018] (3) Free chiral phosphoric acid

[0019] The aqueous phase obtained in step (1) and the aqueous phase generated in the bedaquiline free process are combined, an acid is added to adjust the pH to be acidic, diatomite is added for adsorption, and the filter cake is obtained by filtration.

[0020] (4) Recovering chiral phosphoric acid

[0021] Tetrahydrofuran and water are added to the filter cake, the mixture is stirred and dispersed, and then filtered to obtain a filtrate, the filtrate is recovered under reduced pressure to recover tetrahydrofuran, toluene is used for pulping, and the solution is cooled to precipitate crystals, filtered, and dried to obtain chiral phosphoric acid.

[0022] The present application can effectively extract the waste enantiomers in the split mother liquor, convert them into raw materials for preparing bedaquiline, and reduce material loss. At the same time, the chiral phosphoric acid contained in the mother liquor in the splitting process and the aqueous phase in the free process is effectively recovered. Since the chiral phosphoric acid accounts for as high as 50% in the overall material cost, the recovery of chiral phosphoric acid in actual production can greatly reduce the production cost and has high economic benefits.

[0023] Further, as a preferred scheme:

[0024] In step (1):

[0025] The bedaquiline split mother liquor is recovered under reduced pressure to obtain a concentrated solution, and toluene is added to disperse the concentrated solution at a weight ratio of 1:0.3 to 1:0.8.

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

[0027] In step (2):

[0028] The ethanol beating has a weight ratio of the organic phase to ethanol of 1:0.2-1:0.5 and a temperature of 50-70 DEG C, after beating, cooling to 0-20 DEG C, crystallization, filtration, drying to obtain the enantiomer.

[0029] In step (3):

[0030] The water phase obtained in step (1) and the water phase produced in the free process of bedaquiline are combined, and an acid is added to adjust the pH to 1-5, preferably 2-3, the acid being any one of hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.

[0031] The diatomite adsorption is added with a weight ratio of the water phase to diatomite of 1:0.01-1:0.10, and the filter cake is obtained by filtration, the filter cake being a mixture of diatomite and chiral phosphoric acid.

[0032] The diatomite adsorption can make the free chiral phosphoric acid form, which is convenient for separation and recovery. If the diatomite adsorption is not used, the free chiral phosphoric acid is in a sticky state, and the filter paper and filter cloth are easily blocked during filtration, and the separation cannot be effectively performed.

[0033] In step (4):

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

[0035] The ratio of the mixed solvent of tetrahydrofuran and water is adjusted, the chiral phosphoric acid in the diatomite can be effectively dissolved, and the DMSO used in the reaction is avoided as a solvent, and the difficulty of recovery of the solvent in the subsequent treatment is reduced. Since the subsequent refining is needed, the water content is too high, and the crystallization state is poor, and therefore the ratio is preferably 1:0.05-1:0.10.

[0036] The toluene beating is added with toluene in a weight ratio of 1:1-1:5, the temperature is 60-80 DEG C, after beating, cooling to 0-20 DEG C, crystallization, filtration, drying, and the chiral phosphoric acid is obtained.

[0037] The toluene beating refining can effectively remove the impurities in the recovered chiral phosphoric acid crude product, and the purity is above 99.8%.

[0038] The beneficial effects of the present application are as follows:

[0039] (1) The present application effectively extracts the chiral phosphoric acid which is usually discarded in the production process through simple operation steps, and the recovery rate is above 90%;

[0040] (2) The present application solves the separation difficulty of the free chiral phosphoric acid through diatomite adsorption, and the chiral phosphoric acid is dissolved by the mixed solvent of tetrahydrofuran and water, and the difficulty of the subsequent treatment is reduced.

[0041] (3) The application adopts toluene beating refining, so that the recovered chiral phosphoric acid can be directly used for resolving bedaquiline, and has high economic benefits. DETAILED DESCRIPTION

[0042] In order to make the technical problems, technical solutions and beneficial effects of the present application clearer, the technical solutions in the embodiments of the present application will be further described in detail below. It should be understood that the specific embodiments described herein are only used to explain the present application and not used to limit the technical solutions of the present application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of protection of the present application.

[0043] In the embodiments, the percentages appearing are all mass percentages unless otherwise specified.

[0044] The "bedaquiline waste liquid" referred to in the embodiments of the present application refers to the split mother liquor and the water phase in the free process obtained in the bedaquiline production process, and specifically as follows:

[0045] A synthesis method of bedaquiline includes steps of condensation reaction, resolution, and free process:

[0046] (1) Condensation reaction: under nitrogen atmosphere, lithium diisopropylamide solution is added, and then the temperature is lowered to -90 to -80℃, and then 3-benzyl 6-bromo-2-methoxy quinoline tetrahydrofuran solution is slowly added dropwise, and then the temperature is raised to -75℃ after the dropwise addition is completed. Slowly add dropwise 3-dimethylamino-1-naphthyl-1-propanone tetrahydrofuran solution, and then the dropwise addition is completed. After 8 hours of reaction, quenching is performed by pouring into a mixed solvent of tetrahydrofuran and acetic acid. Ethyl acetate and water are added for stirring and crystallization. Filtration is performed to obtain a filtrate. The filtrate is stirred with potassium carbonate, and then liquid-liquid separation is performed to obtain an organic phase. After the solvent is removed, ethanol is added for crystallization. Filtration is performed to obtain racemic bedaquiline.

[0047] (2) Resolution: 100g of racemic bedaquiline and 1260g of acetone are stirred, and then the temperature is raised to 30℃. A solution of 57g of chiral phosphoric acid and 110g of DMSO is prepared, and then the solution is added dropwise. After the dropwise addition is completed, the solution is stirred for 30 minutes. The temperature is raised to 60℃, and then the solution is stirred for 3 hours. The temperature is lowered to room temperature, and then filtration is performed to obtain bedaquiline chiral phosphoric acid salt. The filtrate is the split mother liquor.

[0048] (3) Free process: 60g of bedaquiline chiral phosphoric acid salt and 312g of toluene are added, and then 134g of potassium carbonate aqueous solution is added. The temperature is raised for free process, and then liquid-liquid separation is performed to obtain an organic phase and a water phase. The water phase is the water phase in the free process. The solvent of the organic phase is recovered, and then ethanol is added for crystallization. Filtration is performed to obtain bedaquiline.

[0049] Embodiment 1:

[0050] (1) Take 300 g of the resolution mother liquor, recover the acetone under reduced pressure to obtain 41.7 g of concentrated liquor, disperse with 210 g of toluene, add sodium hydroxide aqueous solution, adjust the pH to 11-12, and heat to 80°C to separate into an organic phase containing the enantiomer and an aqueous phase containing the chiral phosphate.

[0051] (2) Recover the toluene from the organic phase under reduced pressure, add 100 g of ethanol, pulp at 60°C, cool to 10°C, crystallize, filter, and dry to obtain 8.9 g of the enantiomer with a related substance purity of 96.52%.

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

[0053] (4) Add 120 g of mixed solvent (tetrahydrofuran: water = 1:0.10) to the filter cake, stir and disperse, filter to obtain a filtrate, recover the tetrahydrofuran from the filtrate under reduced pressure to obtain 15.5 g of concentrated liquor. Pulp with 30 g of toluene, pulp at 70°C, cool to 10°C, crystallize, filter, and dry to obtain 11.8 g of chiral phosphate with a related substance purity of 99.93% and a recovery rate of 95.9%.

[0054] Example 2

[0055] (1) Take 300 g of the resolution mother liquor, recover the acetone under reduced pressure to obtain 42.5 g of concentrated liquor, disperse with 210 g of toluene, add potassium carbonate aqueous solution, adjust the pH to 10-11, and heat to 80°C to separate into an organic phase containing the enantiomer and an aqueous phase containing the chiral phosphate.

[0056] (2) Recover the toluene from the organic phase under reduced pressure, add 100 g of ethanol, pulp at 60°C, cool to 10°C, crystallize, filter, and dry to obtain 9.3 g of the enantiomer with a related substance purity of 95.27%.

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

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

[0059] Analysis:

[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 properties of the chiral phosphoric acid, a slow filtration speed, and a low recovery rate.

[0061] Example 3

[0062] (1) Recover acetone from 300 g of the resolution mother liquor under reduced pressure to obtain 42.8 g of a concentrate, disperse 210 g of toluene, add an aqueous potassium hydroxide solution, adjust the pH to 12-13, and heat to 80°C to separate into an organic phase containing enantiomers and an aqueous phase containing chiral phosphoric acid salt.

[0063] (2) Recover toluene from the organic phase under reduced pressure, add 100 g of ethanol, disperse at 60°C, cool to 10°C to crystallize, filter, and dry to obtain 9.5 g of enantiomers, with a related substance purity of 94.58%.

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

[0065] (4) Add 120 g of mixed solvent (tetrahydrofuran: water = 1:0.10) to the filter cake, stir and disperse, filter to obtain a filtrate, and recover tetrahydrofuran from the filtrate under reduced pressure to obtain a concentrate 15.5 g. Add 30 g of toluene to the concentrate, and disperse at 70°C, then cool to 10°C to crystallize. During the crystallization process, the chiral phosphoric acid has poor properties, is sticky, and has a slow filtration speed. There is loss during the transfer process. After drying, 8.5 g of chiral phosphoric acid is obtained, with a related substance purity of 99.82% and a recovery rate of 68.0%.

[0066] Alternative:

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

[0068] Serial No. pH in Step 3 Purity / % Recovery / % 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 Example 3-4 4～5 99.91 92.4 Example 3-5 5～6 97.32 65.5 Example 3-6 6～7 95.31 21.1

[0069] From the above table analysis can be seen, the adjustment of pH, the purity of chiral phosphoric acid, the recovery rate is larger, among which in pH 1-5, the recovery rate is at a higher level, among which pH 2-3 is more preferred.

[0070] Example 4

[0071] (1) Take 300g resolution mother liquor, recovery of acetone under reduced pressure, get 41.5g concentrated liquid, add 210g toluene dispersion, add sodium carbonate aqueous solution, adjust pH to 9-10, heating to 80℃, liquid separation to get the organic phase containing enantiomer and the water phase containing chiral phosphate.

[0072] (2) The organic phase is recovered under reduced pressure, 100g ethanol is added, 60℃ beating, cooling to 10℃, crystallization, filtration, drying to get enantiomer 8.6g, related substance purity 95.73%.

[0073] (3) The water phase of step (1) and the water phase produced in the process of bedaquiline free are combined, the total weight is 152g, the liquid phase external standard content detection system contains 11.9g chiral phosphoric acid, the pH is adjusted to 4-5 with phosphoric acid, 15.2g diatomite is added for adsorption, and the filter cake 40.8g is obtained by filtration.

[0074] (4) The filter cake is added with 120g mixed solvent (tetrahydrofuran: water = 1:0.20), stirring and dispersing, and the filtrate is obtained by filtration. The filtrate is recovered under reduced pressure to get the concentrate 14.9g. 30g toluene is added for beating, 70℃ beating, cooling to 10℃, crystallization, filtration, drying to get chiral phosphoric acid 10.6g, related substance purity 99.87%, recovery rate 93.8%.

[0075] Example 5

[0076] (1) Take 300g resolution mother liquor, recovery of acetone under reduced pressure, get 43.6g concentrated liquid, add 210g toluene dispersion, add sodium carbonate aqueous solution, adjust pH to 9-10, heating to 80℃, liquid separation to get the organic phase containing enantiomer and the water phase containing chiral phosphate.

[0077] (2) The organic phase is recovered under reduced pressure, 100g ethanol is added, 60℃ beating, cooling to 10℃, crystallization, filtration, drying to get enantiomer 8.6g, related substance purity 95.73%.

[0078] (3) The water phase of step (1) and the water phase produced in the process of bedaquiline free are combined, the total weight is 152g, the liquid phase external standard content detection system contains 11.9g chiral phosphoric acid, the pH is adjusted to 4-5 with phosphoric acid, 15.2g diatomite is added for adsorption, and the filter cake 40.8g is obtained by filtration.

[0079] The filter cake was added with 120 g of mixed solvent (tetrahydrofuran: water = 1:0.20), stirred and dispersed, filtered to obtain a filtrate, and the tetrahydrofuran in the filtrate was recovered under reduced pressure to obtain a concentrate 15.8 g. The concentrate was added with 30 g of toluene and slurried at 70 °C, and then cooled to 10 °C to crystallize, filtered, and dried to obtain 11.6 g of chiral phosphoric acid with a purity of 99.93% and a recovery rate of 95.9%.

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

[0081] The recovered chiral phosphoric acid of Example 5 was directly reused for the resolution of racemic bedaquiline, and the specific steps were as follows: 10 g of racemic bedaquiline and 126.4 g of acetone were added and stirred, and the temperature was raised to 30 °C. A solution of 5.70 g of recovered chiral phosphoric acid and 11 g of DMSO was prepared, and the solution was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 min, and then the temperature was raised to 60 °C and stirred for 3 h. The mixture was then cooled to room temperature, filtered, and bedaquiline chiral phosphate salt was obtained with a chiral purity of 96.87% and a yield of 43.0%.

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

[0083] The above examples only express several feasible embodiments of the present application, and the description is relatively specific and detailed, but it should not be understood as a limitation on the scope of the present application. The examples are not intended to limit the protection scope of the claims of the present application. For those skilled in the art, without departing from the concept of the present application, several modifications and improvements can be made, and any equivalent implementation or change made without departing from the present application shall be included in the present application.

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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