CN109422679A - A kind of shellfish is up to the purifying of quinoline and the preparation method of stable crystal form - Google Patents
A kind of shellfish is up to the purifying of quinoline and the preparation method of stable crystal form Download PDFInfo
- Publication number
- CN109422679A CN109422679A CN201710761502.XA CN201710761502A CN109422679A CN 109422679 A CN109422679 A CN 109422679A CN 201710761502 A CN201710761502 A CN 201710761502A CN 109422679 A CN109422679 A CN 109422679A
- Authority
- CN
- China
- Prior art keywords
- quinoline
- shellfish
- added dropwise
- preparation
- ester salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The purifying of quinoline and the preparation method of stable crystal form are reached the present invention relates to a kind of shellfish.It will split after obtained shellfish dissociates to fall resolution reagent up to quinoline-dinaphthol phosphate ester salt buck, with grease is obtained after toluene extraction, concentration, ketone stirring and dissolving is added;Pure and mild purified water is added dropwise again, stirs evenly, the powdered crystal that shellfish reaches quinoline free alkali is precipitated.The method of the present invention by mixed solvent by shellfish reach quinoline free alkali polishing purification, significantly reduce impurity content, reached final product quality requirement, and obtain a kind of stable crystal form, convenient for storage and it is subsequent at salt process.Present invention process is easy to operate, and product yield is high, high-quality, is suitble to industrialized production.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of shellfish is up to the purifying of quinoline free alkali and the preparation side of stable crystal form
Method.
Background technique
It is successfully a kind of novel biaryl quinolin class that shellfish, which is researched and developed up to quinoline (bedaquiline) by Johnson Co.,
Anti- mycobacteria drug, is clinically used for tuberculotherapy.Entitled (1R, the 2S) -1- of its chemistry (the bromo- 2- methoxyl group -3- quinoline of 6-
Base) -4- dimethylamino -2- (1- naphthalene) -1- phenyl -2- butanol, structural formula is as follows:
It is the unique antituberculosis new drug for ratifying listing in the late four decades that shellfish, which reaches quinoline,.Its fumarate system of Johson & Johnson
At oral solid formulation, trade name Si Nairui (Sirturo) is a kind of novel anti-mycobacteria medicine of biaryl quinolin class
Object, by inhibiting mycobacterium tuberculosis ATP to synthesize the activity of enzyme proton pump, to influence the ATP synthesis of mycobacterium tuberculosis, thus
Antibacterial and bactericidal effect are played, for treating adult Drug resistant pulmonary tubeculosis (MDR-PTB), is suitable for treating adult (>=18 years old) resistance to
Multi-drug resistance pulmonary tuberculosis.
Shellfish has same bactericidal activity to common and drug resistant M. tuberculosis strains up to quinoline, with existing treating tuberculosis
Drug is and equally effective to suspend mode bacterium without crossing drug resistant.China is that global tuberculosis bears most heavy one of country, tuberculosis sufferer
Person's quantity is more than 5,000,000 people, is only second to India, occupies the whole world second.The medicine can cope with tuberculosis for China, and this serious public is defended
Raw problem provides new therapeutic choice, is expected to improve the therapeutic effect of Drug resistant pulmonary tubeculosis, meets Drug resistant pulmonary tubeculosis patient and face
Bed Treatment need, reduces China's tuberculosis Disease Spectrum.
Shellfish, which reaches in quinoline molecule, 2 chiral centres, and synthesis technology is more complex, and technical process can generate multiple process impurities
And chiral isomer.The shellfish that shellfish is obtained at salt up to quinoline and fumaric acid up to quinoline fumarate in multi-solvents dissolubility compared with
Difference, impurity are difficult to remove by purification.Though patent CN106316943 reports shellfish up to quinoline fumarate process for refining
Road, but attempted according to the method for this report, purification yield is not high (60~80%), and refines the rear impurity content range of decrease not
Greatly.Therefore there is an urgent need to grope a kind of method for effectively purifying shellfish and reaching quinoline, the shellfish before making into salt reaches the Control of Impurities of quinoline
Reach the level of finished product.
Since shellfish is difficult to refine up to the fumarate of quinoline, consider to purify shellfish up to quinoline, make after its impurity qualification again at
Salt.According to the description for reaching quinoline free alkali separation method in patent CN200680017475 to shellfish, many experiments are attempted, and use ethyl alcohol
Mashing handles the shellfish to dissociate and reaches quinoline grease, and solid is precipitated and is easy agglomerating, unobvious, the purity of impurity removing before and after solid is precipitated
It is only shown by 96.5% raising to 97.1%, HPLC and is difficult to remove there are two major impurity.
Summary of the invention
The defect of quinoline purification technique is reached in view of existing shellfish, technical problem to be solved by the invention is to provide a kind of shellfishes to reach
The preparation method of the purifying crystal form of quinoline.By the method for the invention, the powdered crystal that shellfish reaches quinoline free alkali, dispersed is precipitated
State is good, and impurity removing effect is obvious before and after crystallization, and purity is improved by 96.5% to 99.7%, and single maximum contaminant content is reduced
To 0.1% hereinafter, having reached the quality standard of finished product.
We devise the experimental program of system, are touched by the condition of screening and purification process to multiple dicyandiamide solutions
Rope, we have surprisingly found that, are dissolved free shellfish out up to quinoline using suitable ketone, then suitable pure and mild purified water is added dropwise,
The powdered crystal that shellfish reaches quinoline free alkali is precipitated, dispersity is good, and it is obvious to remove effect for impurity before and after crystallization.
Shellfish of the present invention is as follows up to quinoline purification process:
1) shellfish of mixed is reached into quinoline and resolution reagent dinaphthol phosphate in organic solvent into salt, shellfish is then demultiplex out
Up to quinoline-dinaphthol phosphate ester salt;
2) it will split after obtained shellfish dissociates to fall resolution reagent up to quinoline-dinaphthol phosphate ester salt buck, be extracted with toluene
Take, be concentrated after obtain grease, ketone stirring and dissolving is added;
3) alcohol is added dropwise into solution, stirs, then pure water is added dropwise;Or pure water is first added dropwise into solution, it stirs, then be added dropwise
Alcohol;
4) it stirs, the powdered crystal that shellfish reaches quinoline free alkali is precipitated.
The ketone of dissolution grease is acetone, butanone, pentanone, cyclohexanone etc. in step 2), and ketone and Bei Da quinoline (reach quinoline by shellfish
Quinoline-dinaphthol phosphate ester salt meter) volume mass ratio be (1.5~3) ml/1g, the temperature of stirring and dissolving is 30~60 DEG C, preferably
50~60 DEG C.
The alcohol being added dropwise in step 3) is methanol, ethyl alcohol, isopropanol etc., and alcohol and Bei Da quinoline (reach quinoline-dinaphthol phosphorus by shellfish
Acid esters salt meter) volume mass ratio be (1.5~3) ml/1g.
The volume mass of the purified water and Bei Da quinoline (by shellfish up to based on quinoline-dinaphthol phosphate ester salt) that are added dropwise in step 3)
Than for (1.5~3) ml/1g.
In step 3), it is added dropwise and the temperature of whipping process is 30~60 DEG C, preferably 50~60 DEG C.
According to the method for the present invention, the stable shellfish purified reaches the crystal form feature of quinoline are as follows: its X-ray powder diffraction
The principal character peak of map 2 θ values be 4.78 °, 7.99 °, 10.38 °, 10.64 °, 11.21 °, 11.58 °, 13.02 °,
13.69°、15.22°、15.89°、18.14°、18.49°、19.42°、19.84°、20.48°、20.94°、22.10°、22.76°、
23.03°、24.18°、25.48°、26.68°、28.70°。
The present invention is that anti-tubercular drug of new generation --- shellfish provides a kind of efficient and convenient purification process, yield up to quinoline
Height, it is quality controllable.The method of the present invention is easy to operate, technique, up to quinoline purity is high, can reach into convenient for amplification production, resulting shellfish
Qualified shellfish can be obtained up to quinoline fumarate finished product at salt with fumaric acid (pharmaceutical grade) in the medicinal standard of product.And the shellfish reaches
The crystal form of quinoline proves that its stability is good by stability experiment, convenient for storage, convenient for carrying out the conjunction that shellfish reaches other salt of quinoline
At and research.
Detailed description of the invention
Fig. 1, shellfish prepared by embodiment 9 save 0 day chromatogram up to quinoline.
Fig. 2, shellfish prepared by embodiment 9 reach quinoline and save the chromatogram after December.
Fig. 3, shellfish prepared by embodiment 11 save 0 day chromatogram up to quinoline.
Fig. 4, shellfish prepared by embodiment 11 reach quinoline and save the chromatogram after December.
Fig. 5, shellfish prepared by embodiment 9 save 0 day XRD diagram up to quinoline.
Fig. 6, shellfish prepared by embodiment 9 reach quinoline and save the XRD diagram after December.
Specific embodiment
Embodiment 1
1200g shellfish is reached into quinoline-dinaphthol phosphate ester salt, 12L toluene, wet chemical is (by 1.2kg Anhydrous potassium carbonate
Stirring and dissolving is in about 10.8kg purified water) it is added in 30L reaction kettle, it is warming up to 75~85 DEG C and stirs 1 hour, stand, divide while hot
Be transferred in another 30L reaction kettle from organic layer, be added 10% wet chemical (by 1.2kg Anhydrous potassium carbonate stirring and dissolving in
About 10.8kg purified water), it is warming up to 75~85 DEG C and stirs 15 minutes, stand 15 minutes, separate organic layer, it is anhydrous that 0.5kg is added
Sodium sulphate is 3 hours dry, filters, and filtrate is divided into 12 parts of concentration processing to be purified by volume.Sample detection HPLC purity is
96.1%.
Embodiment 2
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), is added third
Ketone 150ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, ethyl alcohol 150ml is added dropwise, drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition purified water 150ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 55.8g white solid is shellfish up to quinoline, yield: 90.7%, purity: 99.7%.
Embodiment 3
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), is added third
Ketone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, ethyl alcohol 250ml is added dropwise, drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition purified water 250ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 52.9g white solid is shellfish up to quinoline, yield: 86.0%, purity: 99.8%.
Embodiment 4
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), is added third
Ketone 150ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, methanol 150ml is added dropwise, drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition purified water 150ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 54.5g white solid is shellfish up to quinoline, yield: 88.6%, purity: 99.6%.
Embodiment 5
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), is added third
Ketone 200ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, isopropanol 200ml is added dropwise, after dripping off
Continue stirring 15 minutes, control 50~60 DEG C of dropwises addition purified water 200ml of temperature, be cooled to 30~40 DEG C, suction filtration, obtained solid in
50 ± 5 DEG C forced air drying 10 hours, obtaining 54.9g white solid is shellfish up to quinoline, yield: 89.3%, purity: 99.7%.
Embodiment 6
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), fourth is added
Ketone 300ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, methanol 300ml is added dropwise, drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition purified water 200ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 55.3g white solid is shellfish up to quinoline, yield: 89.9%, purity: 99.9%.
Embodiment 7
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), fourth is added
Ketone 300ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, ethyl alcohol 250ml is added dropwise, drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition purified water 200ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 53.2g white solid is shellfish up to quinoline, yield: 86.5%, purity: 99.8%.
Embodiment 8
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), 2- is added
Pentanone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, methanol 250ml is added dropwise, after dripping off
Continue stirring 15 minutes, control 50~60 DEG C of dropwises addition purified water 200ml of temperature, be cooled to 30~40 DEG C, suction filtration, obtained solid in
50 ± 5 DEG C forced air drying 10 hours, obtaining 52.5g white solid is shellfish up to quinoline, yield: 85.4%, purity: 99.7%.
Embodiment 9
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), 2- is added
Pentanone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, ethyl alcohol 250ml is added dropwise, after dripping off
Continue stirring 15 minutes, control 50~60 DEG C of dropwises addition purified water 200ml of temperature, be cooled to 30~40 DEG C, suction filtration, obtained solid in
50 ± 5 DEG C forced air drying 10 hours, obtaining 53.5g white solid is shellfish up to quinoline, yield: 87.0%, purity: 99.9%.Its
The 2 θ value of principal character peak of X-ray powder diffraction collection be 4.78 °, 7.99 °, 10.38 °, 10.64 °, 11.21 °, 11.58 °,
13.02°、13.69°、15.22°、15.89°、18.14°、18.49°、19.42°、19.84°、20.48°、20.94°、22.10°、
22.76°,23.03°,24.18°,25.48°,26.68°,28.70°.The XRD diagram that product saves 0 day and 12 months is shown in Fig. 5 and figure
6, the two has almost no change.
Product saved 0 day and after 12 month, and chromatography testing result is shown in Fig. 1 and Fig. 2 respectively, and the two has almost no change.
Embodiment 10
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), ring is added
Hexanone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, methanol 200ml is added dropwise, after dripping off
Continue stirring 15 minutes, control 50~60 DEG C of dropwises addition purified water 200ml of temperature, be cooled to 30~40 DEG C, suction filtration, obtained solid in
50 ± 5 DEG C forced air drying 10 hours, obtaining 54.0g white solid is shellfish up to quinoline, yield: 87.8%, purity: 99.7%.
Embodiment 11
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), ring is added
Hexanone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of temperature, isopropanol 250ml is added dropwise, drips off
After continue stirring 15 minutes, control 50~60 DEG C of dropwises addition purified water 200ml of temperature, be cooled to 30~40 DEG C, suction filtration, obtained solid
In 50 ± 5 DEG C forced air drying 10 hours, obtaining 54.5g white solid is shellfish up to quinoline, yield: 88.6%, purity: 99.9%.
Product saved 0 day and after 12 month, and chromatography testing result is shown in Fig. 3 and Fig. 4 respectively, and the two has almost no change.
Embodiment 12
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), fourth is added
Ketone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, and control 50~60 DEG C of temperature, dropwise addition purified water 200ml drips off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition methanol 200ml of temperature, 30~40 DEG C are cooled to, is filtered, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 52.1g white solid is shellfish up to quinoline, yield: 84.8%, purity: 99.8%.
Embodiment 13
Portion concentrate obtained in Example 1 (is equivalent to shellfish up to quinoline-dinaphthol phosphate ester salt 100g), is added third
Ketone 250ml, stirring are warming up to 50~60 DEG C to being completely dissolved, control 50~60 DEG C of dropwise addition purified water 200ml of temperature, drip off subsequent
Continuous stirring 15 minutes, controls 50~60 DEG C of dropwise addition isopropanol 250ml of temperature, is cooled to 30~40 DEG C, filters, obtained solid is in 50
± 5 DEG C forced air drying 10 hours, obtaining 56.5g white solid is shellfish up to quinoline, yield: 91.9%, purity: 99.9%.
Claims (7)
1. a kind of shellfish reaches the purifying of quinoline and the preparation method of stable crystal form, it is characterised in that the following steps are included:
1) shellfish of mixed is reached into quinoline and resolution reagent dinaphthol phosphate in organic solvent into salt, shellfish is then demultiplex out up to quinoline
Quinoline-dinaphthol phosphate ester salt;
2) it will split after obtained shellfish dissociates to fall resolution reagent up to quinoline-dinaphthol phosphate ester salt buck, with toluene extraction, dense
Grease is obtained after contracting, and ketone stirring and dissolving is added;
3) alcohol is added dropwise into solution, stirs, then pure water is added dropwise;Or pure water is first added dropwise into solution, it stirs, then alcohol is added dropwise;
4) it stirs, the powdered crystal that shellfish reaches quinoline free alkali is precipitated.
2. preparation method according to claim 1, which is characterized in that the ketone of dissolution grease is acetone, fourth in step 2)
The volume mass ratio of ketone, pentanone or cyclohexanone, ketone and Bei Da quinoline is 1.5~3ml/1g, and the shellfish reaches quinoline-by shellfish up to quinoline
Dinaphthol phosphate ester salt meter.
3. preparation method according to claim 1 or 2, which is characterized in that the temperature of step 2) stirring and dissolving is 30~60
℃。
4. preparation method according to claim 1, which is characterized in that the alcohol being added dropwise in step 3) is methanol, ethyl alcohol or different
The volume mass ratio of propyl alcohol, alcohol and Bei Da quinoline is 1.5~3ml/1g, and the shellfish reaches quinoline-dinaphthol phosphoric acid by shellfish up to quinoline
Ester salt meter.
5. preparation method according to claim 1, which is characterized in that the purified water being added dropwise in step 3) and Bei Da quinoline
Volume mass ratio is 1.5~3ml/1g, and the shellfish is up to quinoline by shellfish up to based on quinoline-dinaphthol phosphate ester salt.
6. according to claim 1, preparation method described in 4 or 5, which is characterized in that step 3) is added dropwise and the temperature of whipping process
It is 30~60 DEG C.
7. preparation method according to claim 1, which is characterized in that obtained shellfish reaches the crystal form feature of quinoline are as follows: its X-
The principal character peak of ray powder diffraction 2 θ values be 4.78 °, 7.99 °, 10.38 °, 10.64 °, 11.21 °, 11.58 °,
13.02°、13.69°、15.22°、15.89°、18.14°、18.49°、19.42°、19.84°、20.48°、20.94°、22.10°、
22.76°、23.03°、24.18°、25.48°、26.68°、28.70°。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710761502.XA CN109422679B (en) | 2017-08-30 | 2017-08-30 | Purification of bedaquiline and preparation method of stable crystal form |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710761502.XA CN109422679B (en) | 2017-08-30 | 2017-08-30 | Purification of bedaquiline and preparation method of stable crystal form |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109422679A true CN109422679A (en) | 2019-03-05 |
CN109422679B CN109422679B (en) | 2021-06-25 |
Family
ID=65504013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710761502.XA Active CN109422679B (en) | 2017-08-30 | 2017-08-30 | Purification of bedaquiline and preparation method of stable crystal form |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109422679B (en) |
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 |
-
2017
- 2017-08-30 CN CN201710761502.XA patent/CN109422679B/en active Active
Patent 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 |
Non-Patent Citations (3)
Title |
---|
侯玲等: "新型抗结核药物贝达喹啉的合成", 《广西大学学报》 * |
刘卫等: "《综合化学实验》", 31 December 2016 * |
赵临襄等: "《化学制药工艺学》", 31 December 2015 * |
Also Published As
Publication number | Publication date |
---|---|
CN109422679B (en) | 2021-06-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102050774B (en) | Oxiracetam compound and new method thereof | |
CN101643466A (en) | Epigallo-catechin gallate (EGCG) with high purity and preparation method thereof | |
US20210002200A1 (en) | Method for purification of 4-hydroxyacetophenone | |
CN102010454B (en) | Citicoline sodium compound and new method thereof | |
CN104478877B (en) | The method preparing Lei Dipawei intermediate | |
JP6159480B2 (en) | Preparation of (-)-Huperzine A | |
CN105481952B (en) | Composition containing nitrogen heterocyclic hexapeptide precursor and preparation method and application thereof | |
CN109912645A (en) | The preparation method of egg yolk lecithin | |
CN101941983B (en) | Preparation method of high-purity cefoxitin sodium | |
CN106496295A (en) | The preparation method of Suo Feibuwei crystal formations 6 | |
WO2023170048A1 (en) | Crystallization of 4-hydroxyacetophenone from ethanol and ethyl acetate | |
CN109422679A (en) | A kind of shellfish is up to the purifying of quinoline and the preparation method of stable crystal form | |
CN1374310A (en) | Prepn process of sodium cantharidinate | |
CN102746121B (en) | Refining method of high purity borneol | |
CN102492020A (en) | Pidotimod compound and new preparation method thereof | |
JP6764998B2 (en) | How to make hydronidon | |
JP6764999B2 (en) | How to make hydronidon | |
CN104402815A (en) | Control method of piperaquine phosphate impurity | |
CN104557655A (en) | Oxiracetam purifying method | |
CN108409735A (en) | A kind of purification process of moxifloxacin hydrochloride and the preparation method of moxifloxacin hydrochloride | |
CN104402798B (en) | A kind of 3-amino-1, the method for splitting of 2,3,4-tetrahydro carbazoles | |
JP2009533432A (en) | Narcotine purification method | |
CN107759505A (en) | A kind of purification process of high purity atorvastatin calcium | |
CN113402444A (en) | Carbazole compound and application thereof in preparation of medicines for treating metabolic related diseases such as fatty liver and type 2 diabetes | |
CN102372623A (en) | Croceic acid diammonium salt |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |