CN106866525B - For synthesizing the chiral induction agent of (1R, 2S)-Bei Da quinoline - Google Patents
For synthesizing the chiral induction agent of (1R, 2S)-Bei Da quinoline Download PDFInfo
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- CN106866525B CN106866525B CN201710180070.3A CN201710180070A CN106866525B CN 106866525 B CN106866525 B CN 106866525B CN 201710180070 A CN201710180070 A CN 201710180070A CN 106866525 B CN106866525 B CN 106866525B
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- quinoline
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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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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/09—Geometrical isomers
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Abstract
The present invention relates to synthesis (1R,2S)-Bei Da quinoline chiral induction agent.In the presence of chiral induction agent N- benzyl-L- prolinol lithium, after two (isopropyl) lithium ammoniums slough the benzyl position proton of the bromo- 3- benzyl -2 methoxy quinoline of 6- at low temperature, again with 3- dimethylamino -1- naphthalene -1- acetone addition, the chirality neighbour ammonia lithium alkoxide significantly improve target enantiomter-(1R,2S)-Bei Da quinoline ratio, can be used for further preparing drug (1R,2S)-Bei Da 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) is that one kind is drawn by bacterium
It rises, drug (A meter Ka is injected to isoniazid and rifampin-resistance and any fluoroquinolones medicine and any two wires treating tuberculosis
Star, kanamycins or capreomycin) there is the tuberculosis of drug resistance.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
It greatly, the use of the cost of a course for the treatment of standard tubercular drugs is about 20 dollars, and the cost of multi-drug resistance tuberculosis drug can be high
It is even higher up to 5000 dollars.In global range, in the patient that receives treatment, cure rate is up to 50%.Investigation discovery is to MDR-
100% is dead in patient 3 years of TB therapy failure, and clinical there is an urgent need to the drugs of more preferable curative effect.
U.S. FDA in December, 2012 acceleration has approved Johson & Johnson (Johnson Johnson) for treating drug resistance
(the 1 of tuberculosis fumaric acidR,2S)-Bei Da quinoline, structural formula are as follows:,
(1R,2S)-fumaric acid shellfish kills knot by inhibiting the ATP synzyme of mycobacterium tuberculosis (M.tb) up to quinoline
Core mycobacteria.The medicine becomes the first anti-TB drug with completely new mechanism of action over nearly more than 40 years, while being also since the dawn of human civilization
The first anti-TB drug for being specifically used for MDR-TB.The time of its 50% cure rate is 13 weeks (former drug combination 2 years), and 80% cures
The time of rate is 6 months.Compared with drug combination (2-4 kind drug), the cure rate of the drug is greatly improved, and treatment cycle is substantially
Shorten.
There are four optical isomers, only (1 up to quinoline for shellfishR,2S) configuration is effectively as medicinal.Original grinds (1R,2S)-Bei Da
Synthesis patent (the Authorization Notice No.: CN1286371C of quinoline；CN101180302B one-step synthesis, such as Fig. 1) are disclosed: by 6-
Bromo- 3- benzyl -2 methoxy quinoline at low temperature (- 72 ~ -78 DEG C), by the proton of two (isopropyl) lithium ammonium (LDA) debenzylations
Afterwards, with 3- dimethylamino -1- naphthalene -1- acetone addition generate shellfish up to quinoline 4 optical isomer intermixtures (A be target produce
Object), reaction mass concentration, then obtain dominating as A and A with alcohol treatment ' 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%(is in terms of the bromo- 3- benzyl -2 methoxy quinoline 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. Chem2011,2057-2061) it reports construct first carbon hand in the method for asymmetry catalysis respectively
Property, then second carbon chirality is constructed with asymmetric syntheses.This route is more there are reaction step or yield is extremely low or uses high
The various problems such as expensive reagent, chiral ligand, noble metal catalyst, manufacturing cost are very high.
Also there are the application of related preparation patent, patent 1(application number CN105175329A in the country): with -3- bromobenzyl -6-
Bromo- 2 methoxy quinoline is raw material, is first prepared into grignard reagent with magnesium, then anti-with 1- naphthaldehyde addition etc. and multi-step
It answers, it is critical that the ratio of 4 isomers does not also refer in synthetic product；Patent 2(application number CN105085396A): to avoid
3- dimethylamino -1- naphthalene -1- acetone in the reaction enolization and cause the yield of addition product to decline, by 1- acetonaphthone and N,
The reaction of dinethylformamide dimethyl ketal generates 3- dimethylamino -2-(1- naphthalene) -propyl- 2- alkene -1- ketone, such as Fig. 2.
Although this naphthalenone intermediate is mentioned with addition yield of the bromo- 3- benzyl -2 methoxy quinoline of 6- in the presence of LDA
Height, but high-pressure hydrogenation step is increased, and the ratio of objective optics isomers does not have improvement；Patent 3(application number
CN105198808A): being then that optical isomer scrap digestion will be reused at 2 initial raw materials after splitting.
In place of above various synthetic methods all each Shortcomings, 4 optical isomer intermixtures are ground in patent in original
Total recovery is also close to 40%, but (1 after splittingR,2S)-Bei Da quinoline yield it is still very low.It is therefore desirable to develop more efficient side
Method synthesizes (1R,2S)-Bei Da quinoline.
For LDA in the presence of chiral vicinal amino alcohols lithium, induction deprotonation forms chiral carbanion, or with chiral induction agent
Chiral compound is formed, which 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).It joined specific chiral vicinal amino alcohols lithium in the present invention, succeed inductive formation target enantiomerism
Body-(1S,2R) the leading product of-Bei Da quinoline work.
Summary of the invention
The present invention provides synthesis (1R,2S)-Bei Da quinoline chiral induction agent, which is remarkably improved reaction
(1 in productR,2S)-Bei Da quinoline optical isomer ratio.
To achieve the above object, the present invention adopts the following technical scheme:
Lithium alkoxide is prepared first, usually at low temperature -72 ~ -78 DEG C, is added in the tetrahydrofuran solution of chiral vicinal amino alcohols
N-BuLi obtains corresponding lithium alkoxide, adds two (isopropyl) lithium ammoniums (LDA), and the bromo- 3- benzyl -2- methoxyl group of 6- is slowly added dropwise
The tetrahydrofuran solution of quinoline obtains corresponding benzyl lithium, finally -72 ~ -78 DEG C of addition 3-N at low temperature, TMSDMA N dimethylamine base -
The tetrahydrofuran solution of 1- naphthalene -1- acetone generates mixture (A and A ' that product is 4 optical isomers；B and B '), reaction
Formula such as Fig. 3.
Into reaction mass plus saturated ammonium chloride solution stopped reaction, sufficiently precipitate, filtering removal precipitating (predominantly B with
B '), it after reaction mass concentration, is beaten and is heated with ethyl alcohol, then cooling obtains (1R,2S)-Bei Da quinoline crude product, the crude product is in isopropyl
Recrystallized in alcohol optical purity and chemical purity it is high (1R,2S)-Bei Da quinoline, it can be used for preparing fumaric acid shellfish up to quinoline
Quinoline.
Wherein, before the benzyl position proton that LDA takes off the bromo- 3- benzyl -2 methoxy quinoline of 6-, chiral vicinal amino alcohols lithium is used
Make chiral induction agent.The chirality vicinal amino alcohols lithium is prepared in tetrahydrofuran solution by n-BuLi, the dosage of n-BuLi with
Chiral vicinal amino alcohols equivalent, the tetrahydrofuran dosage for diluting chiral vicinal amino alcohols is 3ml/g.Other reaction conditions, operation
And reaction postprocessing method grinds patent (CN101180302B) referring to original.
Wherein, the dosage of chiral vicinal amino alcohols is 1.0 to 2.0 equivalents of the bromo- 3- benzyl -2 methoxy quinoline of 6-, preferably
1.10 equivalent again.
The present invention has filtered out a practical chiral induction agent and its preferred dosage.We investigated three it is common
, the lower chiral vicinal amino alcohols of price: N- methyl-L- prolinol (1 structural formula in such as Fig. 4), N- benzyl-L- prolinol
(2 structural formulas in such as Fig. 4) and (1R,2S) -1- phenyl -2- (1- pyrrolidinyl) propane -1- alcohol (3 structural formulas in such as Fig. 4)
Chiral induction effect:
Document (Collum, D. B. et al.J. Am. Chem. Soc.2001,123:9135-9143) in it is chiral
Inducer dosage, most preferably 2.2 times of equivalents, when substrate is the bromo- 3- benzyl -2 methoxy quinoline of 6- in the present invention, 2 first
The oxygen lone pair electrons of oxygroup can be coordinated (1 structural formula in Fig. 5) with lithium and form 5 member rings, it is thus possible to reduce chiral ligands
Dosage, until 1.10 equivalents:
Referring to former patented method (CN1286371C) in present invention reaction, reaction is determined using high-efficient liquid phase technique (HPLC)
Ratio in material between each optical isomer.In the presence of no chiral induction agent, the amount A=A ', B of two pairs of enantiomters=
B'；And use 3 structural formulas in chirality vicinal amino alcohols 3(Fig. 4) induction after result for A/A '=92:8, than document case
(Collum, D.B.;Et al.) effect (50:1) it is poor, be perhaps because this case in the bromo- 3- benzyl -2 methoxy quinoline of 6-
Benzyl position lithium salts (1 structural formula in Fig. 5), steric hindrance be much larger than 2- cyclopropyl -1- propine lithium (2 structures in Fig. 5
Formula), therefore chiral induction effect declines；Using 2 structural formulas in chiral vicinal amino alcohols 2(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 in view of the source of chiral vicinal amino alcohols 2 is more convenient, therefore chiral vicinal amino alcohols 2 have more application value.
Technological merit of the invention:
In the presence of no chiral induction agent, ratio (A+A ')/(B+B ') of two pairs of diastereomers is 4:1.And in this case
In, (A+A ')/(B+B ') is slightly improved, and is 4.8-5:1.
Chemical resolution agent is not necessarily in the present invention, from direct crystallization obtains (1 in reaction mass after concentrationR,2S)-Bei Da quinoline
Crude product, wherein containing only a small amount of enantiomer A ' (can also contain minute quantity B and B ' sometimes).Hand is made using N- benzyl-L- prolinol
Property inducer, (1R,2S) shellfish up to quinoline crude product ee value up to 90%.The crude product obtained through recrystallisation from isopropanol (1R,2S)-
Shellfish reaches quinoline, optical purity ee value 99.2% and chemical purity 99.6wt%, and (1R,2S)-Bei Da quinoline reaches yield 15.6wt%
(in terms of the bromo- 3- benzyl -2 methoxy quinoline of 6-), quality standard arrival further prepare drug-(1R,2S)-Bei Da quinoline
The requirement of fumaric acid.The present invention has cut off the resolving agent of complicated chemical resolution method and valuableness, yield also greatly improve (from 7% ~
15.6%) 9% is increased to.
It is ground patent (publication number 101547904A) referring to original, (1R,2S)-Bei Da quinoline and fumaric acid crystallize at salt, can make
The standby multi-drug resistant drug for the treatment of tuberculosis-fumaric acid shellfish reaches quinoline.
Detailed description of the invention
Fig. 1 is that original grinds in patent (1R,2S)-Bei Da quinoline synthetic reaction process figure；
Fig. 2 be 3- dimethylamino -2-(1- naphthalene) -propyl- 2- alkene -1- ketone synthetic reaction process figure；
Fig. 3 is (1R,2S)-Bei Da quinoline chiral induction response diagram；
Fig. 4 is the structural formula of three chiral vicinal amino alcohols；
Fig. 5 is lithium salts structural formula.
Specific embodiment
Further to disclose rather than the present invention is limited, the present invention is described in further detail below in conjunction with example.
(1R,2S)-Bei Da quinoline preparation
Embodiment 1
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 45ml and N- benzyl-L- dried meat is added
Ammonia alcohol 15.4g(80.5mmol, 1.10eq), reaction flask is placed in cold-trap (- 72 ~ -78 DEG C), adds 2.5M n-BuLi
Hexane solution 32ml(80.5mmol), be subsequently added into 2.0M LDA (heptane-ethylbenzene-tetrahydrofuran mixed solvent)
44.0 ml(88.0mmol), 21 ml of THF.By the bromo- 3- benzyl of 6- -2 methoxy quinoline 24.0 g(73.2mmol, 1.0eq)
Be dissolved in 30 ml of THF, be slowly dropped into above-mentioned four-hole bottle, be added dropwise in 70 min, charging process keep in temperature for-
It 72 ~ -78 DEG C, finishes and continues to stir 3 h.In 160 subsequent min, it is slowly added dropwise into 3-N, TMSDMA N dimethylamine base -1- naphthalene -1-
17.4 g(76.9mmol of acetone) solution that is made into 50 ml of THF, process is added dropwise and is kept for Nei Wen -72 ~ -78 DEG C, finishes, continues
React 3h.The HPLC testing result 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, ratio (A+A ')/(B+B ') of two pairs of diastereomers is 4:1.
It is slowly added to 30 mL of saturated aqueous ammonium chloride in above-mentioned reactant, is kept stirring after being slowly increased to room temperature, puts
It sets 12 h, precipitating is precipitated, filter, pour filter wash cake with 25 mL of ethyl acetate, the overwhelming majority is diastereomer (B, B ') in filter cake.
Filtrate isolates organic layer, after anhydrous sodium sulfate drying is added, solvent is removed under reduced pressure, ethyl alcohol 120mL, heating are added in residue
It is beaten to 80 DEG C and stirs 2 h.Stop cooled to room temperature after heating, continues to stir 2 h.It filters, is poured with 25 mL of ethyl alcohol
Filter wash cake.It is dried in vacuo 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%), (B+B ') containing 2.3wt%.
Above-mentioned (1R,2S)-Bei Da quinoline crude product 9.8g, add isopropanol 250ml, dissolves by heating, be cooled to 0 DEG C of crystallization, mistake
Filter, a small amount of cold isopropanol washing, vacuum drying obtain white crystals: (1R,2S)-Bei Da quinoline 6.40g, yield 15.6wt%(with
The bromo- 3- benzyl -2 methoxy quinoline meter of 6-), optical purity ee:99.2%, chemical purity 99.6%(are free of B and B ').
Embodiment 2
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 67ml and N- benzyl-L- dried meat is added
Ammonia alcohol 22.4g(117mmol, 1.50eq), reaction flask is placed in cold-trap (- 72 ~ -78 DEG C), adds 2.5M n-BuLi
Hexane solution 46.5ml(117mmol), other step operations and material amounts are the same as embodiment 1, resulting reaction mass
HPLC testing result: enantiomer A/A '=81:19；Diastereomer (A+A ')/(B+B ')=5:1.
Embodiment 3
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 90ml and N- benzyl-L- dried meat is added
Ammonia alcohol 30.8g(161mmol, 2.0eq), reaction flask is placed in cold-trap (- 72 ~ -78 DEG C), adds 2.5M n-BuLi
Hexane solution 64ml(161mmol), other steps and material amounts are the same as embodiment 1, resulting reaction mass HPLC detection knot
Fruit: enantiomer A/A '=82:18；Diastereomer (A+A ')/(B+B ')=5.1:1.
Embodiment 4
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 28ml and N- methyl-L- dried meat is added
Ammonia alcohol 9.26g(80.5mmol, 1.10eq), reaction flask is placed in cold-trap (- 72 ~ -78 DEG C), adds 2.5M n-BuLi
Hexane solution 32ml(80.5mmol), other steps and material amounts are the same as embodiment 1, resulting reaction mass HPLC inspection
Survey result: enantiomer A/A '=64:36；Diastereomer (A+A ')/(B+B ')=5:1.
Embodiment 5
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 49ml and (1 is addedR,2S) -1- benzene
Base -2- (1- pyrrolidinyl) propane -1- alcohol 16.5g(80.5mmol, 1.10eq), reaction flask is placed in cold-trap (- 72 ~ -78
DEG C), add the hexane solution 32ml(80.5mmol of 2.5M n-BuLi), other steps and the same embodiment of material amounts
1, resulting reaction mass HPLC testing result: enantiomer A/A '=92:8;Diastereomer (A+A ')/(B+B ')=5:1.
Last handling process obtains (1 with embodiment 1R,2S)-Bei Da quinoline 6.81g, yield 18.1%(be with the bromo- 3- benzyl of 6-
Base -2 methoxy quinoline meter), optical purity ee:99.5%, chemical purity 99.7%(are free of B and B ').
Embodiment 6
Under nitrogen protection, in dry tetra- mouthfuls of glass reaction bottles of 500mL, THF 49ml and (1 is addedR,2S) -1- benzene
Base -2- (1- pyrrolidinyl) propane -1- alcohol 33.0g(161mmol, 2.0eq), reaction flask is placed in cold-trap (- 72 ~ -78
DEG C), add the hexane solution 32ml(80.5mmol of 2.5M n-BuLi), other steps and the same embodiment of material amounts
1, resulting reaction mass HPLC testing result: enantiomer A/A '=92:8；Diastereomer (A+A ')/(B+B ')=4.9:1.
The foregoing is merely presently preferred embodiments of the present invention, all equivalent changes done according to scope of the present invention patent with
Modification, is all covered by the present invention.
Claims (3)
1. a kind of purposes of chiral induction agent, it is characterised in that: with the bromo- 3- benzyl -2 methoxy quinoline of 6- and 3-N, N- bis-
Methylamino -1- naphthalene -1- acetone is raw material, and chiral induction agent N- benzyl-L- prolinol induction synthesis (1 is addedR,2S)-Bei Da
Quinoline；Specifically includes the following steps:
At low temperature -72 ~ -78 DEG C in the tetrahydrofuran solution of N- benzyl-L- prolinol, two (isopropyl) lithium ammonium LDA are added,
The tetrahydrofuran solution of the bromo- 3- benzyl -2 methoxy quinoline of 6- is slowly added dropwise, is further continued for that 3-N, TMSDMA N dimethylamine base -1- naphthalene is added
The tetrahydrofuran solution of base -1- acetone, acquired product obtain (1 through separating-purifyingR,2S)-Bei Da quinoline.
2. the purposes of chiral induction agent according to claim 1, it is characterised in that: the dosage of N- benzyl-L- prolinol is
1.0 to 2.0 equivalent of the bromo- 3- benzyl -2 methoxy quinoline of 6-
3. the purposes of chiral induction agent according to claim 2, it is characterised in that: the dosage of N- benzyl-L- prolinol is
1.10 equivalents of the bromo- 3- benzyl -2 methoxy quinoline of 6-.
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| 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 |
| CN117399070A (en) * | 2022-07-07 | 2024-01-16 | 上海交通大学 | Chiral metal synergistic catalytic system containing chelating ligand and application of chiral metal synergistic catalytic system in asymmetric synthesis of bedaquiline |
| US12116345B2 (en) | 2023-08-01 | 2024-10-15 | Shanghai Jiaotong University | Low-temperature continuous-flow preparation method of bedaquiline |
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| 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 |
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