CN106866525A - For synthesizing (1R, 2S) shellfish up to the chiral induction agent of quinoline - Google Patents
For synthesizing (1R, 2S) shellfish up to the chiral induction agent of quinoline Download PDFInfo
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- CN106866525A CN106866525A CN201710180070.3A CN201710180070A CN106866525A CN 106866525 A CN106866525 A CN 106866525A CN 201710180070 A CN201710180070 A CN 201710180070A CN 106866525 A CN106866525 A CN 106866525A
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- quinoline
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- induction agent
- benzyl
- dried meat
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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
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- 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
- C07B2200/09—Geometrical isomers
Abstract
The present invention relates to synthesize (1R,2S) shellfish up to quinoline chiral induction agent.In the presence of chiral induction agent N benzyl L dried meat ammonia lithium alkoxides, two（Isopropyl）After lithium ammonium sloughs the benzyl position proton of the methoxy quinoline of 6 bromine, 3 benzyl 2 at low temperature, then with the acetone addition of 3 dimethylamino, 1 naphthyl 1, the adjacent ammonia lithium alkoxide of chirality significantly improve target enantiomter-（1R,2S）Up to the ratio of quinoline, it can be used to further prepare medicine shellfish（1R,2S）Shellfish reaches quinoline fumaric acid.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to synthesis (1R,2S)-Bei Da quinoline chiral induction agent.
Technical background
Multi-drug resistance tuberculosis（Multi-drug-resistant tuberculosis, MDR-TB）It is that one kind is drawn by bacterium
Rise, to isoniazid and rifampin-resistance, and any FQNS medicine and any two wires treating tuberculosis injection medicine（A meter Ka
Star, kanamycins or capreomycin）There is drug-fast tuberculosis.Treat the tuberculosis of these forms, 6 months lines of standard
Antituberculotic does not work, and may need up to 2 years or longer treatment time, and these medicine effects are small, toxicity
Greatly, it is about 20 dollars using the cost of a course for the treatment of standard tubercular drugs, and the cost of multi-drug resistance tuberculosis medicine can be with height
Up to 5000 dollars, even more high.In global range, receive in the middle of the patient for the treatment of, cure rate is up to 50%.Investigation is found to MDR-
100% is dead in the patient 3 years of TB therapies failure, and clinic is in the urgent need to the medicine of more preferable curative effect.
The U.S. FDA of in December, 2012 accelerates have approved Johson ＆ Johnson (Johnson Johnson) for treating drug resistance
Tuberculosis fumaric acid（1R,2S）- Bei Da quinoline, structural formula is：,
(1R,2S)-fumaric acid shellfish is up to quinoline by suppressing mycobacterium tuberculosis（M.tb）ATP synzyme kill tuberculosis point
Branch bacillus.The medicine turns into the first anti-TB medicines with brand-new mechanism of action over nearly more than 40 years, while being also first since the dawn of human civilization
It is specifically used for the anti-TB medicines of MDR-TB.The time of its 50% cure rate is 13 weeks（Former drug combination 2 years）, its 80% cure rate
Time is 6 months.With drug combination（2-4 kind medicines）Compare, the cure rate of the medicine is greatly improved, and treatment cycle significantly contracts
It is short.
Shellfish has four optical isomers, only (1 up to quinolineR,2S) configuration is effectively as medicinal.Original is ground（1R,2S）- Bei Da
The synthesis patent of quinoline（Authorization Notice No.：CN1286371C；CN101180302B）Disclose one-step synthesis, such as Fig. 1：By 6-
Bromo- 3- benzyls -2 methoxy quinoline is at low temperature（-72~-78℃）, by two（Isopropyl）Lithium ammonium（LDA）The proton of debenzylation
Afterwards, 4 optical isomer intermixtures of quinoline are reached with 3- dimethylamino -1- naphthyl -1- acetone addition generation shellfish（A is produced for target
Thing）, reaction mass concentration, then obtained dominating as A with Ethanol Treatment and A ' racemic product, wherein containing a small amount of B with
B ', then through with chiral resolving agent (RThe fractionation of)-dinaphthol phosphate, obtains（1R,2S）- Bei Da quinoline（A）, total recovery is very low,
Only 7 ~ 9%（In terms of the bromo- 3- benzyls -2 methoxy quinolines of 6-）.
In addition studies have reported that, such as Shibasaki（Saga Y et al. Catalytic Asymmetric Synthesis
of R207910. J. Am Chem. Soc.2010, 132: 7905-7907）And Chandrasekhar
（Chandrasekhar S et al. Practical Syntheses of (2S)-R207910 and (2R)-R207910. Eur. J. Org. Chem. 2011, 2057-2061）Report respectively and build first carbon hand in the method for asymmetry catalysis
Property, then second carbon chirality is built with asymmetric syntheses.This route has that reactions steps are more or yield is extremely low or using high
The various problems such as expensive reagent, chiral ligand, noble metal catalyst, its manufacturing cost is very high.
Also there are the related application for preparing patent, patent 1 in the country（Application number CN105175329A）：With -3- bromobenzyls -6-
Bromo- 2 methoxy quinoline is raw material, is first prepared into grignard reagent with magnesium, then with 1- naphthaldehyde additions etc., it is also the anti-of multi-step
Should, it is critical that the ratio of 4 isomers is not referred to yet in synthetic product；Patent 2（Application number CN105085396A）：To avoid
3- dimethylamino -1- naphthyl -1- acetone in the reaction enolization and cause the yield of addition compound product to decline, by 1- acetonaphthones and N,
Dinethylformamide dimethyl ketal reaction generation 3- dimethylaminos -2-（1- naphthyls）-propyl- 2- alkene -1- ketone, such as Fig. 2.
Although this naphthalenone intermediate 3- benzyls bromo- with 6--addition yield of the 2 methoxy quinoline in the presence of LDA has been carried
Height, but high-pressure hydrogenation step is increased, and the ratio of objective opticses isomers does not have improvement；Patent 3（Application number
CN105198808A）：It is then, by optical isomer scrap digestion after fractionation into 2 initial raw materials, to reuse.
More than various synthetic methods all each Shortcomings parts, 4 optical isomer intermixtures in original grinds patent
After total recovery is also close to 40%, but fractionation（1R,2S）The yield of-Bei Da quinoline is still very low.It is therefore desirable to develop more efficient side
Method synthesizes（1R,2S）- Bei Da quinoline.
In the presence of chiral vicinal amino alcohols lithium, induction deprotonation forms chiral carbanion to LDA, or with chiral induction agent
Chiral compound is formed, the anion participates in various reactions, can form some optical isomer and account for leading product
（Collum, D.B. et al.J. Am. Chem. Soc.2001,123: 9135–9143; M. Hasegawa et
al, Tetrahedron, 2000, 56:10153-10158；H. Pellissier, Tetrahedron, 2007, 63:
9267-9331）.Specific chirality vicinal amino alcohols lithium is added in the present invention, and succeed inductive formation target enantiomerism
Body-（1S,2R）- Bei Da quinoline makees leading product.
The content of the invention
The invention provides synthesis (1R,2S)-Bei Da quinoline chiral induction agent, the chiral induction is remarkably improved reaction
In product (1R,2S)-Bei Da quinoline optical isomers ratio.
To achieve the above object, the present invention is adopted the following technical scheme that：
Lithium alkoxide is prepared first, generally at low temperature -72 ~ -78 DEG C, positive fourth is added in the tetrahydrofuran solution of chiral vicinal amino alcohols
Base lithium obtains corresponding lithium alkoxide, adds two（Isopropyl）Lithium ammonium（LDA）, the bromo- 3- benzyls -2 methoxy quinolines of 6- are slowly added dropwise
Tetrahydrofuran solution, obtain corresponding benzyl lithium, finally at low temperature -72 ~ -78 DEG C addition 3-N, TMSDMA N dimethylamine base -1- naphthalenes
The tetrahydrofuran solution of base -1- acetone, generation product is 4 mixtures of optical isomer（A and A '；B and B '）, reaction equation is such as
Fig. 3.
To saturated ammonium chloride solution stopped reaction, fully precipitation is added in reaction mass, filtering removal is precipitated（Predominantly B with
B’）, after reaction mass concentration, it is beaten with ethanol and is heated, then cooled down and obtain（1R,2S）- Bei Da quinoline crude products, the crude product is in isopropyl
Recrystallized in alcohol optical purity and chemical purity are high（1R,2S）- Bei Da quinoline, it can be used to prepare fumaric acid shellfish up to quinoline
Quinoline.
Wherein, before the benzyl position proton of the LDA bromo- 3- benzyls -2 methoxy quinolines of de- 6-, chiral vicinal amino alcohols lithium is employed
Make chiral induction agent.The chiral vicinal amino alcohols lithium is prepared by n-BuLi in tetrahydrofuran solution, the consumption of n-BuLi with
Chiral vicinal amino alcohols equivalent, the tetrahydrofuran consumption of the chiral vicinal amino alcohols of dilution is 3ml/g.Other reaction conditions, operation
And reaction postprocessing method grinds patent with reference to original（CN101180302B）.
Wherein, the consumption of chiral vicinal amino alcohols is 1.0 to 2.0 equivalents of the bromo- 3- benzyls -2 methoxy quinolines of 6-, preferably
1.10 times of equivalents.
The present invention has filtered out the chiral induction agent of practicality and its preferred consumption.We investigated three it is common
, the chiral vicinal amino alcohols that price is relatively low：N- methyl-L- dried meat ammonia alcohol（Such as 1 structural formula in Fig. 4）, N- benzyl-L- dried meat ammonia alcohol
（Such as 2 structural formulas in Fig. 4）And（1R,2S）- 1- phenyl -2- (1- pyrrolidinyls) propane -1- alcohol（Such as 3 structural formulas in Fig. 4）
Chiral induction effect：
Document（Collum, D. B. et al.J. Am. Chem. Soc.2001,123: 9135–9143）Middle chiral induction
Agent consumption, most preferably 2.2 times equivalents, when substrate is the bromo- 3- benzyls -2 methoxy quinolines of 6- in the present invention, its 2 methoxyl groups
Oxygen lone pair electrons can be coordinated with lithium（1 structural formula in Fig. 5）Form 5 yuan of rings, it is thus possible to reduce the consumption of chiral ligands,
To 1.10 equivalents：
With reference to former patented method in present invention reaction（CN1286371C）, using high-efficient liquid phase technique（HPLC）Determine reaction mass
In ratio between each optical isomer.In the presence of no chiral induction agent, two couples of the amount A=A ', B=B ' of enantiomter；
And use chiral vicinal amino alcohols 3（3 structural formulas in Fig. 4）Result after induction is A/A '=92:8, than document case
（Collum, D.B.; et al.）Effect (50:1) it is poor, perhaps because bromo- 3- benzyls -2 methoxy quinolines of 6- in this case
Benzyl position lithium salts（1 structural formula in Fig. 5）, its steric hindrance is much larger than 2- cyclopropyl -1- propine lithium (2 structures in Fig. 5
Formula), therefore the decline of chiral induction effect；Using chiral vicinal amino alcohols 2（2 structural formulas in Fig. 4）Induction result is A/A '=82:
18；Induction result using chiral vicinal amino alcohols structure 2 is poor, is A/A '=64:36；Although the effect of chiral vicinal amino alcohols 3
It is optimal but more convenient in view of the source of chiral vicinal amino alcohols 2, therefore chiral vicinal amino alcohols 2 have more application value.
Technological merit of the invention：
In the presence of no chiral induction agent, two pairs of ratios of diastereomer（A+A’）/（B+B’）It is 4:1.And in the present case,（A
+A’）/（B+B’）Slightly improve, be 4.8-5:1.
Without chemical resolution agent in the present invention, direct crystallization is obtained from reaction mass after concentration（1R,2S）- Bei Da quinoline
Crude product, wherein only containing a small amount of enantiomer A '（Sometimes very small amount B and B ' can also be contained）.Hand is made using N- benzyl-L- dried meat ammonia alcohol
Property derivant,（1R,2S）Ee value reachable 90% of the shellfish up to quinoline crude product.What the crude product was obtained through recrystallisation from isopropanol（1R,2S）-
Shellfish reaches quinoline, optical purity ee values 99.2%, and chemical purity 99.6wt%,（1R,2S）- Bei Da quinoline reaches yield 15.6wt%
（In terms of the bromo- 3- benzyls -2 methoxy quinolines of 6-）, its quality standard reach further prepare medicine-（1R,2S）- Bei Da quinoline
The requirement of fumaric acid.The present invention has cut off the chemical resolution method of complexity and the resolving agent of costliness, and yield is also greatly improved（From 7% ~
9% brings up to 15.6%）.
Patent is ground with reference to original（Publication number 101547904A）,（1R,2S）- Bei Da quinoline is crystallized with fumaric acid into salt, can be made
The multi-drug resistant medicine of standby treating tuberculosis-fumaric acid shellfish reaches quinoline.
Brief description of the drawings
Fig. 1 grinds in patent for original（1R,2S）The synthetic reaction process figure of-Bei Da quinoline；
Fig. 2 is 3- dimethylaminos -2-（1- naphthyls）The synthetic reaction process figure of -propyl- 2- alkene -1- ketone；
Fig. 3 is（1R,2S）The chiral induction response diagram of-Bei Da quinoline；
Fig. 4 is three structural formulas of chiral vicinal amino alcohols；
Fig. 5 is lithium salts structural formula.
Specific embodiment
For further disclosure is of the invention rather than limitation, below in conjunction with example, the present invention is described in further detail.
（1R,2S）The preparation of-Bei Da quinoline
Embodiment 1
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, THF 45ml and N- benzyl-L- dried meat ammonia alcohol is added
15.4g（80.5mmol, 1.10eq）, reaction bulb is placed in cold-trap（-72~ -78℃）, adding 2.5M n-BuLis just
Hexane solution 32ml（80.5mmol）, it is subsequently added into 2.0M LDA (mixed solvent of heptane-ethylbenzene-tetrahydrofuran) 44.0
ml（88.0mmol）、THF 21 ml.By the bromo- 3- benzyls of 6--g of 2 methoxy quinoline 24.0（73.2mmol, 1.0eq）It is dissolved in
In the ml of THF 30, be slowly dropped into above-mentioned four-hole bottle, the completion of dropping in 70 min, charging process keep in temperature for -72 ~ -
78 DEG C, finish continuation and stir 3 h.In 160 subsequent min, it is slowly added dropwise into 3-N, TMSDMA N dimethylamine base -1- naphthyl -1- acetone
17.4 g（76.9mmol）The solution being made into the ml of THF 50, is added dropwise process and keeps Nei Wen -72 ~ -78 DEG C, finishes, and continues to react
3h.The HPLC testing results of reaction mass：Enantiomer A/A '=82:18（ee：64%）；Diastereomer (A+A ')/(B+B ')=
4.8.In the presence of no chiral induction agent, two pairs of ratios of diastereomer（A+A’）/（B+B’）It is 4:1.
The mL of saturated aqueous ammonium chloride 30 is slowly added in above-mentioned reactant, after being kept stirring for being slowly increased to room temperature, is put
Put 12 h, separate out precipitation, suction filtration pours filter wash cake with the mL of ethyl acetate 25, the overwhelming majority is diastereomer (B, B ') in filter cake.
Filtrate isolates organic layer, and after adding anhydrous sodium sulfate drying, removal of solvent under reduced pressure adds ethanol 120mL, heating in residue
2 h are beaten and stirred to 80 DEG C.Room temperature is naturally cooled to after stopping heating, continues to stir 2 h.Suction filtration, is poured with the mL of ethanol 25
Filter wash cake.It is vacuum dried at room temperature, get Bei Da quinoline（1R,2S）Crude product：Off-white powder, 10.4g, HPLC testing result：
A/A’=95:5（ee：90%）, containing 2.3wt%'s（B+B’）.
It is above-mentioned（1R,2S）- Bei Da quinoline crude product 9.8g, plus isopropanol 250ml, heating for dissolving, are cooled to 0 DEG C of crystallization, mistake
Filter, a small amount of cold isopropanol washing, vacuum drying obtains white crystals：（1R,2S）- Bei Da quinoline 6.40g, yield 15.6wt%（With
The bromo- 3- benzyls -2 methoxy quinoline meters of 6-）, optical purity ee：99.2%, chemical purity 99.6%（Without B and B '）.
Embodiment 2
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, THF 67ml and N- benzyl-L- dried meat ammonia alcohol is added
22.4g（117mmol, 1.50eq）, reaction bulb is placed in cold-trap（-72~ -78℃）, adding 2.5M n-BuLis just
Hexane solution 46.5ml（117mmol）, with embodiment 1, the reaction mass HPLC of gained is examined for other step operations and material amounts
Survey result：Enantiomer A/A '=81:19；Diastereomer (A+A ')/(B+B ')=5:1.
Embodiment 3
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, THF 90ml and N- benzyl-L- dried meat ammonia alcohol is added
30.8g（161mmol, 2.0eq）, reaction bulb is placed in cold-trap（-72~ -78℃）, add 2.5M n-BuLis just oneself
Alkane solution 64ml（161mmol）, other steps and material amounts are with embodiment 1, the reaction mass HPLC testing results of gained：
Enantiomer A/A '=82:18；Diastereomer (A+A ')/(B+B ')=5.1:1.
Embodiment 4
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, THF 28ml and N- methyl-L- dried meat ammonia alcohol is added
9.26g（80.5mmol, 1.10eq）, reaction bulb is placed in cold-trap（-72~ -78℃）, adding 2.5M n-BuLis just
Hexane solution 32ml（80.5mmol）, other steps and material amounts are with embodiment 1, the reaction mass HPLC detection knots of gained
Really：Enantiomer A/A '=64:36；Diastereomer (A+A ')/(B+B ')=5:1.
Embodiment 5
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, add THF 49ml and（1R,2S）- 1- phenyl-
2- (1- pyrrolidinyls) propane -1- alcohol 16.5g（80.5mmol, 1.10eq）, reaction bulb is placed in cold-trap（-72~ -78℃）,
Add the hexane solution 32ml of 2.5M n-BuLis（80.5mmol）, other steps and material amounts are with embodiment 1, institute
The reaction mass HPLC testing results for obtaining：Enantiomer A/A '=92:8;Diastereomer (A+A ')/(B+B ')=5:1.
Last handling process is obtained with embodiment 1（1R,2S）- Bei Da quinoline 6.81g, yield 18.1%（With the bromo- 3- benzyls of 6-
Base -2 methoxy quinoline meter）, optical purity ee：99.5%, chemical purity 99.7%（Without B and B '）.
Embodiment 6
Under nitrogen protection, in tetra- mouthfuls of glass reaction bottles of dry 500mL, add THF 49ml and（1R,2S）- 1- phenyl-
2- (1- pyrrolidinyls) propane -1- alcohol 33.0g（161mmol, 2.0eq）, reaction bulb is placed in cold-trap（-72~ -78℃）, then
Add the hexane solution 32ml of 2.5M n-BuLis（80.5mmol）, other steps and material amounts are with embodiment 1, gained
Reaction mass HPLC testing results：Enantiomer A/A '=92:8；Diastereomer (A+A ')/(B+B ')=4.9:1.
The foregoing is only presently preferred embodiments of the present invention, all impartial changes done according to scope of the present invention patent with
Modification, should all belong to covering scope of the invention.
Claims (6)
1. it is used to synthesize（1R,2S）The chiral induction agent of-Bei Da quinoline, it is characterised in that：Described chiral shift reagent is N-
Benzyl-L- dried meat ammonia alcohol, N- methyl-L- dried meat ammonia alcohol,（1R,2S）One kind in -1- phenyl -2- (1- pyrrolidinyls) propane -1- alcohol.
2. chiral induction agent according to claim 1, it is characterised in that：Described chiral shift reagent is N- benzyls-L-
Dried meat ammonia alcohol.
3. a kind of purposes of chiral induction agent as claimed in claim 2, it is characterised in that：With the bromo- 3- benzyls -2- methoxies of 6-
Base quinoline and 3-N, TMSDMA N dimethylamine base -1- naphthyl -1- acetone are raw material, add the induction of chiral induction agent N- benzyl-L- dried meat lithium alkoxide
Synthesis（1R,2S）- Bei Da quinoline.
4. the purposes of chiral induction agent according to claim 3, it is characterised in that：Comprise the following steps：
At low temperature -72 ~ -78 DEG C in the tetrahydrofuran solution of N- benzyl-L- dried meat lithium alkoxides, two are added（Isopropyl）Lithium ammonium LDA,
The tetrahydrofuran solution of the bromo- 3- benzyls -2 methoxy quinolines of 6- is slowly added dropwise, is further continued for adding 3-N, TMSDMA N dimethylamine base -1- naphthalenes
The tetrahydrofuran solution of base -1- acetone, the resulting separated purification of product obtains (1R,2S）- Bei Da quinoline.
5. the purposes of chiral induction agent according to claim 3, it is characterised in that：The consumption of N- benzyl-L- dried meat ammonia alcohol is
1.0 to 2.0 equivalents of the bromo- 3- benzyls -2 methoxy quinolines of 6-.
6. the purposes of chiral induction agent according to claim 5, it is characterised in that：The consumption of N- benzyl-L- dried meat ammonia alcohol is
1.10 equivalents of the bromo- 3- benzyls -2 methoxy quinolines of 6-.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109387594A (en) * | 2017-08-08 | 2019-02-26 | 武汉武药科技有限公司 | The method that a kind of point of analysis of variance shellfish reaches quinoline optical isomer |
| WO2020161743A1 (en) * | 2019-02-08 | 2020-08-13 | Mylan Laboratories Limited | Process for the preparation of bedaquiline fumarate |
| WO2023151700A1 (en) * | 2022-02-08 | 2023-08-17 | 上海交通大学 | Double-chiral metal cooperative catalysis system and use thereof in asymmetric synthesis of bedaquiline |
| WO2024007621A1 (en) * | 2022-07-07 | 2024-01-11 | 上海交通大学 | Bi-chiral metallic synergic catalysis system comprising chelating ligand and use thereof in asymmetric synthesis of bedaquiline |
Citations (4)
| 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 |
| CN105085396A (en) * | 2014-05-07 | 2015-11-25 | 国药集团国瑞药业有限公司 | Intermediate for preparing bedaquiline, preparation method therefor and application thereof |
| CN105175329A (en) * | 2014-06-10 | 2015-12-23 | 重庆圣华曦药业股份有限公司 | New synthesis route and method of bedaquiline racemate |
| CN105198808A (en) * | 2014-05-27 | 2015-12-30 | 北京万生药业有限责任公司 | Method for high efficiency production of Bedaquiline |
-
2017
- 2017-03-24 CN CN201710180070.3A patent/CN106866525B/en not_active Expired - Fee Related
Patent Citations (4)
| 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 |
| CN105085396A (en) * | 2014-05-07 | 2015-11-25 | 国药集团国瑞药业有限公司 | Intermediate for preparing bedaquiline, preparation method therefor and application thereof |
| CN105198808A (en) * | 2014-05-27 | 2015-12-30 | 北京万生药业有限责任公司 | Method for high efficiency production of Bedaquiline |
| CN105175329A (en) * | 2014-06-10 | 2015-12-23 | 重庆圣华曦药业股份有限公司 | New synthesis route and method of bedaquiline racemate |
Non-Patent Citations (2)
| Title |
|---|
| -: "RN 34381-71-0，RN 53912-80-4，RN 127641-25-2", 《STN REGISTRY》 * |
| RODNEY L. PARSONS, JR. ET AL.: "NMR Spectroscopic Investigations of Mixed Aggregates Underlying Highly Enantioselective 1,2-Additions of Lithium Cyclopropylacetylide to Quinazolinones", 《J. AM. CHEM. SOC.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109387594A (en) * | 2017-08-08 | 2019-02-26 | 武汉武药科技有限公司 | The method that a kind of point of analysis of variance shellfish reaches quinoline optical isomer |
| CN109387594B (en) * | 2017-08-08 | 2021-01-19 | 武汉武药科技有限公司 | Method for separating and analyzing Bedaquinoline optical isomer |
| WO2020161743A1 (en) * | 2019-02-08 | 2020-08-13 | Mylan Laboratories Limited | Process for the preparation of bedaquiline fumarate |
| WO2023151700A1 (en) * | 2022-02-08 | 2023-08-17 | 上海交通大学 | Double-chiral metal cooperative catalysis system and use thereof in asymmetric synthesis of bedaquiline |
| WO2024007621A1 (en) * | 2022-07-07 | 2024-01-11 | 上海交通大学 | Bi-chiral metallic synergic catalysis system comprising chelating ligand and use thereof in asymmetric synthesis of bedaquiline |
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