CN109422679B - Purification of bedaquiline and preparation method of stable crystal form - Google Patents
Purification of bedaquiline and preparation method of stable crystal form Download PDFInfo
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- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 title claims abstract description 56
- 229960000508 bedaquiline Drugs 0.000 title claims abstract description 55
- 239000013078 crystal Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 11
- 238000000746 purification Methods 0.000 title description 9
- 238000003756 stirring Methods 0.000 claims abstract description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000002576 ketones Chemical class 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 229910019142 PO4 Inorganic materials 0.000 claims description 24
- 239000010452 phosphate Substances 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 8
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000008213 purified water Substances 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000012046 mixed solvent Substances 0.000 abstract 1
- 238000011112 process operation Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 26
- 238000007605 air drying Methods 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- 201000008827 tuberculosis Diseases 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- ZLVSPMRFRHMMOY-WWCCMVHESA-N bedaquiline fumarate Chemical group OC(=O)\C=C\C(O)=O.C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 ZLVSPMRFRHMMOY-WWCCMVHESA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 201000009671 multidrug-resistant tuberculosis Diseases 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229960001137 bedaquiline fumarate Drugs 0.000 description 3
- 229940072185 drug for treatment of tuberculosis Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000001355 anti-mycobacterial effect Effects 0.000 description 2
- 239000003926 antimycobacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000000814 tuberculostatic agent Substances 0.000 description 2
- 230000002407 ATP formation Effects 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000003960 Ligases Human genes 0.000 description 1
- 108090000364 Ligases Proteins 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- -1 diaryl quinoline Chemical compound 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229940048026 sirturo Drugs 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for purifying and preparing a stable crystal form of bedaquiline. Dissociating the resolving reagent from the bedaquiline-binaphthol phosphate salt obtained by resolving by using alkaline water, extracting by using toluene, concentrating to obtain an oily substance, adding ketone, and stirring for dissolving; and then dropwise adding alcohol and purified water, and uniformly stirring to separate out powdery crystals of the bedaquiline free alkali. The method of the invention refines and purifies the bedaquiline free alkali by the mixed solvent, obviously reduces the impurity content, meets the quality requirement of the finished product, obtains a stable crystal form, and is convenient for storage and the subsequent salt forming process. The invention has simple and convenient process operation, high product yield and good quality, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a purification method of bedaquiline free alkali and a preparation method of a stable crystal form.
Background
Bedaquine (bedaquiline) is successfully developed by Johnson corporation in America, is a novel diarylquinoline antimycobacterial drug and is clinically used for tuberculosis treatment. The chemical name of the compound is (1R,2S) -1- (6-bromo-2-methoxy-3-quinolyl) -4-dimethylamino-2- (1-naphthyl) -1-phenyl-2-butanol, and the structural formula is as follows:
bedaquiline is the only new anti-tuberculosis drug approved for the market in the last four decades. Qiangsheng company uses its fumarate salt to make oral solid preparation, its trade name is Sirturo, it is a new diaryl quinoline antimycobacterial drug, through inhibiting the activity of ATP synthetase proton pump of mycobacterium tuberculosis, influence ATP synthesis of mycobacterium tuberculosis, thus exert antibacterial and bactericidal action, used for treating adult multidrug-resistant tuberculosis (MDR-PTB), suitable for treating adult (more than or equal to 18 years old) multidrug-resistant tuberculosis.
The Bedaquinoline has the same bactericidal activity on common and drug-resistant mycobacterium tuberculosis strains, has no cross drug resistance with the existing antituberculosis drugs, and has the same effect on dormant bacteria. China is one of the countries with the most serious tuberculosis burden in the world, and tuberculosis patients are more than 500 million people, second only to India and second in the world. The medicine can provide new treatment selection for the serious public health problem of tuberculosis in China, is expected to improve the treatment effect of the multi-drug resistant tuberculosis, meets the clinical treatment requirement of the multi-drug resistant tuberculosis patients, and reduces the burden of tuberculosis diseases in China.
The Bedaquine molecule has 2 chiral centers, the synthesis process is complex, and a plurality of process impurities and chiral isomers are generated in the process. The solubility of the bedaquiline fumarate obtained by salifying bedaquiline and fumaric acid in various solvents is poor, and impurities are difficult to remove by refining. Although patent CN106316943 reports a purification process of bedaquiline fumarate, attempts according to the reported method have resulted in a low purification yield (60-80%) and a low reduction in impurity content after purification. Therefore, a method for effectively purifying the bedaquiline is urgently needed to be searched, so that the impurity control of the bedaquiline before salification reaches the level of a finished product.
Because the fumarate of the bedaquiline is difficult to purify, the bedaquiline is purified, and the impurities are qualified and then salified. According to the description of a method for separating out the bedaquiline free base in the patent CN200680017475, a plurality of experimental attempts are carried out, the free bedaquiline oily substance is treated by using ethanol pulping, the separated solid is easy to agglomerate, impurities are not obviously removed before and after the solid is separated out, the purity is only improved to 97.1% from 96.5%, and HPLC (high performance liquid chromatography) shows that two main impurities are difficult to remove.
Disclosure of Invention
In view of the defects of the existing bedaquiline purification technology, the invention aims to provide a preparation method of a purified crystal form of bedaquiline. By the method, the powdery crystals of the bedaquiline free alkali are separated out, the dispersion state is good, the impurity removal effect before and after crystallization is obvious, the purity is improved to 99.7% from 96.5%, the single maximum impurity content is reduced to below 0.1%, and the quality standard of a finished product is achieved.
We design a systematic experimental scheme, and by groping the conditions of a screening and purifying method of a plurality of solvent systems, we surprisingly find that the free bedaquiline is dissolved by using proper ketone, proper alcohol and purified water are dripped to separate out powdery crystals of bedaquiline free alkali, the dispersion state is good, and the impurity removal effect before and after crystallization is obvious.
The method for purifying the bedaquiline comprises the following steps:
1) salifying the racemic bedaquiline and a resolving agent binaphthol phosphate in an organic solvent, and separating the bedaquiline-binaphthol phosphate;
2) dissociating the resolving reagent from the bedaquiline-binaphthol phosphate salt obtained by resolving by using alkaline water, extracting by using toluene, concentrating to obtain an oily substance, adding ketone, and stirring for dissolving;
3) dropwise adding alcohol into the solution, stirring, and dropwise adding pure water; or firstly dripping pure water into the solution, stirring, and then dripping alcohol;
4) stirring to separate out powdery crystals of the bedaquiline free alkali.
The ketone for dissolving the oily matter in the step 2) is acetone, butanone, pentanone, cyclohexanone and the like, the volume-mass ratio of the ketone to the bedaquiline (calculated by the bedaquiline-binaphthol phosphate salt) is (1.5-3) ml/1g, and the stirring and dissolving temperature is 30-60 ℃, preferably 50-60 ℃.
The alcohol dripped in the step 3) is methanol, ethanol, isopropanol and the like, and the volume mass ratio of the alcohol to the bedaquiline (calculated by bedaquiline-binaphthol phosphate ester salt) is (1.5-3) ml/1 g.
The volume-mass ratio of the purified water dripped in the step 3) to the bedaquiline (calculated by bedaquiline-binaphthol phosphate salt) is (1.5-3) ml/1 g.
In the step 3), the temperature in the processes of dripping and stirring is 30-60 ℃, and preferably 50-60 ℃.
According to the method, the stable beraquiline crystal form obtained by purification has the characteristics that: the main characteristic peaks of the X-ray powder diffraction pattern are 4.78 degrees, 7.99 degrees, 10.38 degrees, 10.64 degrees, 11.21 degrees, 11.58 degrees, 13.02 degrees, 13.69 degrees, 15.22 degrees, 15.89 degrees, 18.14 degrees, 18.49 degrees, 19.42 degrees, 19.84 degrees, 20.48 degrees, 20.94 degrees, 22.10 degrees, 22.76 degrees, 23.03 degrees, 24.18 degrees, 25.48 degrees, 26.68 degrees and 28.70 degrees at the 2 theta value.
The invention provides a high-efficiency and convenient purification method for a new generation antituberculosis drug, namely the bedaquiline, and the method has the advantages of high yield and controllable quality. The method has simple and convenient operation and convenient process for enlarged production, the prepared bedaquiline has high purity and can reach the medicinal standard of finished products, and the qualified bedaquiline fumarate finished products can be obtained by salifying the bedaquiline with fumaric acid (medicinal grade). And stability experiments prove that the crystal form of the bedaquiline has good stability, is convenient to store and is convenient for the synthesis and research of other salts of the bedaquiline.
Drawings
FIG. 1, chromatogram of Bedaquin prepared in example 9 stored for 0 day.
FIG. 2, chromatogram of Bedaquine prepared in example 9 after 12 months storage.
FIG. 3, chromatogram of Bedaquin prepared in example 11 stored for 0 day.
FIG. 4, chromatogram of Bedaquin prepared in example 11 after 12 months storage.
Figure 5, XRD pattern of bedaquiline prepared in example 9 was preserved for 0 days.
Figure 6, XRD pattern after 12 months storage of bedaquiline prepared in example 9.
Detailed Description
Example 1
1200g of benaquiline-binaphthol phosphate, 12L of toluene and a potassium carbonate aqueous solution (1.2 kg of anhydrous potassium carbonate is dissolved in about 10.8kg of purified water) are added into a 30L reaction kettle, the temperature is increased to 75-85 ℃, the mixture is stirred for 1 hour, the mixture is kept stand, an organic layer is separated while the mixture is hot and transferred into another 30L reaction kettle, a 10% potassium carbonate aqueous solution (1.2 kg of anhydrous potassium carbonate is dissolved in about 10.8kg of purified water) is added, the temperature is increased to 75-85 ℃, the mixture is stirred for 15 minutes, the mixture is kept stand for 15 minutes, the organic layer is separated, 0.5kg of anhydrous sodium sulfate is added, the mixture is dried for 3 hours, the filtration is carried out, and the filtrate is concentrated to be purified according to. The HPLC purity was 96.1% by sampling.
Example 2
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 150ml of acetone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 150ml of ethanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 150ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 55.8g of white solid, namely the bedaquiline, wherein the yield is as follows: 90.7%, purity: 99.7 percent.
Example 3
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of acetone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 250ml of ethanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 250ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 52.9g of white solid, namely the bedaquiline, wherein the yield is as follows: 86.0%, purity: 99.8 percent.
Example 4
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 150ml of acetone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 150ml of methanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 150ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 54.5g of white solid, namely the bedaquiline, wherein the yield is as follows: 88.6%, purity: 99.6 percent.
Example 5
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 200ml of acetone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 200ml of isopropanol, continuing stirring for 15 minutes after dropwise adding, controlling the temperature to be 50-60 ℃, dropwise adding 200ml of purified water, cooling to be 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 54.9g of white solid, namely the bedaquiline, wherein the yield is as follows: 89.3%, purity: 99.7 percent.
Example 6
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 300ml of butanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 300ml of methanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 55.3g of white solid, namely the bedaquiline, wherein the yield is as follows: 89.9%, purity: 99.9 percent.
Example 7
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 300ml of butanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 250ml of ethanol, continuing stirring for 15 minutes after the dropwise adding is finished, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 53.2g of white solid, namely the bedaquiline, wherein the yield is as follows: 86.5%, purity: 99.8 percent.
Example 8
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of 2-pentanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 250ml of methanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 52.5g of white solid, namely the bedaquiline, wherein the yield is as follows: 85.4%, purity: 99.7 percent.
Example 9
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of 2-pentanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 250ml of ethanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 53.5g of white solid, namely the bedaquiline, wherein the yield is as follows: 87.0%, purity: 99.9 percent. The main characteristic peak 2 theta values of the X-ray powder diffraction pattern are 4.78 degrees, 7.99 degrees, 10.38 degrees, 10.64 degrees, 11.21 degrees, 11.58 degrees, 13.02 degrees, 13.69 degrees, 15.22 degrees, 15.89 degrees, 18.14 degrees, 18.49 degrees, 19.42 degrees, 19.84 degrees, 20.48 degrees, 20.94 degrees, 22.10 degrees, 22.76 degrees, 23.03 degrees, 24.18 degrees, 25.48 degrees, 26.68 degrees and 28.70 degrees. The XRD patterns of the product stored for 0 day and 12 months are shown in fig. 5 and 6, and both are hardly changed.
After the product is stored for 0 day and 12 months, the chromatographic detection results are respectively shown in figure 1 and figure 2, and the two results have almost no change.
Example 10
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of cyclohexanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 200ml of methanol, continuing stirring for 15 minutes after the dropwise adding is finished, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 54.0g of white solid, namely the bedaquiline, wherein the yield is as follows: 87.8%, purity: 99.7 percent.
Example 11
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of cyclohexanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, dropwise adding 250ml of isopropanol, continuing stirring for 15 minutes after dropwise adding, dropwise adding 200ml of purified water at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 54.5g of white solid, namely the bedaquiline, wherein the yield is as follows: 88.6%, purity: 99.9 percent. After the product is stored for 0 day and 12 months, the chromatographic detection results are respectively shown in fig. 3 and fig. 4, and the two results have almost no change.
Example 12
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of butanone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, controlling the temperature to be 50-60 ℃, continuously stirring for 15 minutes after 200ml of purified water is dripped, dropwise adding 200ml of methanol at the temperature of 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 52.1g of white solid, namely the bedaquiline, wherein the yield is as follows: 84.8%, purity: 99.8 percent.
Example 13
Taking one part of the concentrated solution (equivalent to 100g of the bedaquiline-binaphthol phosphate salt) obtained in the example 1, adding 250ml of acetone, stirring and heating to 50-60 ℃ until the solution is completely dissolved, dropwise adding 200ml of purified water at 50-60 ℃, continuing stirring for 15 minutes after dropwise adding, dropwise adding 250ml of isopropanol at 50-60 ℃, cooling to 30-40 ℃, performing suction filtration, and performing forced air drying on the obtained solid at 50 +/-5 ℃ for 10 hours to obtain 56.5g of white solid, namely the bedaquiline, wherein the yield is as follows: 91.9%, purity: 99.9 percent.
Claims (7)
1. A method for purifying and preparing a stable crystal form of bedaquiline is characterized by comprising the following steps:
1) salifying the racemic bedaquiline and a resolving agent binaphthol phosphate in an organic solvent, and separating the bedaquiline-binaphthol phosphate;
2) dissociating the resolving reagent from the bedaquiline-binaphthol phosphate obtained by resolving with alkaline water, extracting with toluene, concentrating to obtain an oily substance, adding ketone, stirring and dissolving, wherein the ketone for dissolving the oily substance is acetone, butanone, 2-pentanone or cyclohexanone;
3) dropwise adding alcohol into the solution, stirring, and dropwise adding pure water; or firstly dripping pure water into the solution, stirring, and then dripping alcohol; the dropwise added alcohol is methanol, ethanol or isopropanol;
4) stirring to separate out powdery crystals of the bedaquiline free alkali.
2. The preparation method according to claim 1, wherein the volume-to-mass ratio of the ketone to the bedaquiline in step 2) is 1.5 to 3ml/1g, and the bedaquiline is calculated according to bedaquiline-binaphthol phosphate.
3. The preparation method according to claim 1 or 2, wherein the temperature for stirring and dissolving in the step 2) is 30 to 60 ℃.
4. The preparation method according to claim 1, wherein the volume-to-mass ratio of the alcohol to the bedaquiline in step 3) is 1.5 to 3ml/1g, and the bedaquiline is calculated by bedaquiline-binaphthol phosphate.
5. The preparation method according to claim 1, wherein the volume-to-mass ratio of the pure water added dropwise in the step 3) to the bedaquiline is 1.5-3 ml/1g, and the bedaquiline is calculated by bedaquiline-binaphthol phosphate.
6. The preparation method according to claim 1, 4 or 5, wherein the temperature during the dropping and stirring in step 3) is 30 to 60 ℃.
7. The preparation method according to claim 1, wherein the crystal form of the bedaquiline obtained is characterized by: the main characteristic peaks of the X-ray powder diffraction are 4.78 degrees, 7.99 degrees, 10.38 degrees, 10.64 degrees, 11.21 degrees, 11.58 degrees, 13.02 degrees, 13.69 degrees, 15.22 degrees, 15.89 degrees, 18.14 degrees, 18.49 degrees, 19.42 degrees, 19.84 degrees, 20.48 degrees, 20.94 degrees, 22.10 degrees, 22.76 degrees, 23.03 degrees, 24.18 degrees, 25.48 degrees, 26.68 degrees and 28.70 degrees at the 2 theta value.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180302A (en) * | 2005-05-25 | 2008-05-14 | 詹森药业有限公司 | Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
| CN105085395A (en) * | 2014-05-07 | 2015-11-25 | 国药集团国瑞药业有限公司 | Preparation method for bedaquiline |
| WO2017015793A1 (en) * | 2015-07-24 | 2017-02-02 | 浙江海正药业股份有限公司 | Method for separating diastereoisomer a of bedaquiline |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180302A (en) * | 2005-05-25 | 2008-05-14 | 詹森药业有限公司 | Process for preparing (alpha s, beta r)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
| CN105085395A (en) * | 2014-05-07 | 2015-11-25 | 国药集团国瑞药业有限公司 | Preparation method for bedaquiline |
| WO2017015793A1 (en) * | 2015-07-24 | 2017-02-02 | 浙江海正药业股份有限公司 | Method for separating diastereoisomer a of bedaquiline |
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