CN107857727B - A kind of preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline - Google Patents

A kind of preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline Download PDF

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CN107857727B
CN107857727B CN201711015347.3A CN201711015347A CN107857727B CN 107857727 B CN107857727 B CN 107857727B CN 201711015347 A CN201711015347 A CN 201711015347A CN 107857727 B CN107857727 B CN 107857727B
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quinoline
bei
equivalents
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room temperature
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CN107857727A (en
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赵学清
赵云德
朱林飞
郑治尧
廖伟科
刘磊
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Sky Jiangsu And Pharmaceutical Co Ltd
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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
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a kind of preparation methods of (1R, 2S) and (1S, 2R)-Bei Da quinoline.The preparation method belongs to chemosynthesis technical field.(1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline are acted on through Lewis acid, form carbonium ion, then through the OH in alkaline solution‑Effect forms the new chiral tertiary alcohol, then (1R, 2S)-Bei Da quinoline is made through splitting.Reaction step of the present invention is few, and production efficiency is significantly promoted, and easily obtains the (1R of higher yields, 2S)-Bei Da quinoline is conducive to industrialized production, while impurity residual volume is few, target product purity is high, it is highly-safe there are no risk step, the entire production processes such as high-pressure hydrogenation must be increased.

Description

A kind of preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline
Technical field
The invention belongs to chemosynthesis technical fields, specifically, more particularly to a kind of (1R, 2S) and (1S, 2R)-shellfish Up to the preparation method of quinoline.
Background technique
Multi-drug resistance tuberculosis is one kind as caused by bacterium, to isoniazid and rifampin-resistance and any fluoquinolone Class medicine and any two wires treating tuberculosis injection drug (amikacin, kanamycins or capreomycin) have the tuberculosis of drug resistance. U.S. FDA in December, 2012 acceleration has approved Johson & Johnson (Johnson Johnson) for treating drug-resistant tuberculosis (1R, 2S)-Bei Da quinoline of drug fumaric acid, the ATP that fumaric acid (1R, 2S)-Bei Da quinoline passes through inhibition mycobacterium tuberculosis Synzyme kills mycobacterium tuberculosis, and 50% time cured was 13 weeks, and the time of 80% cure rate is 6 months, with connection It shares medicine (2-4 kind drug) to compare, the cure rate of the drug greatly improves, and treatment cycle substantially shortens.Fumaric acid (1R, 2S) the structural formula of-Bei Da quinoline are as follows:
Fumaric acid (1R, 2S)-Bei Da quinoline structure formula
Saga Y et al.Catalytic Asymmetric Synthesis of R207910.J.Am Chem.Soc.2010,132:7905-7907 and Chandrasekhar S et al.Practical Syntheses of (2S)-R207910and (2R)-R207910.Eur.J.Org.Chem.2011,2057-2061 is reported respectively with asymmetry The method of catalysis constructs first chiral carbon, then constructs second chiral carbon with asymmetric syntheses.
The synthesis patent (Authorization Notice No.: CN101180302B) that original grinds (1R, 2S)-Bei Da quinoline discloses one-step synthesis Method: at low temperature (- 72~-78 DEG C) by the bromo- 3- benzyl -2 methoxy quinoline of 6-, through two (isopropyl) lithium ammonium (LDA) debenzylations Proton after, with 3- dimethylamino -1- naphthalene -1- acetone addition generate shellfish reach quinoline 4 optical isomer intermixtures, through acid After neutralization, then A and A obtained with alcohol treatment ' it is leading racemic modification product, then through with chiral resolving agent (R)-dinaphthol phosphorus The fractionation of acid esters, obtains (1R, 2S)-Bei Da quinoline, and yield is only about 7~9% (with the bromo- 3- benzyl -2 methoxy quinoline of 6- Meter).Synthetic route is as follows:
Original grinds in patent the synthetic route of (1R, 2S)-Bei Da quinoline
Patent application CN105175329A is disclosed using the bromo- 2 methoxy quinoline of -3- bromobenzyl -6- as raw material, elder generation and magnesium Be prepared into grignard reagent, then with the multistep reactions such as 1- naphthaldehyde addition, obtain four isomers of synthetic product.
Patent application CN105085396A, which is disclosed, reacts 1- acetonaphthone with n,N-Dimethylformamide dimethyl ketal Generate 3- dimethylamino -2- (1- naphthalene) -propyl- 2- alkene -1- ketone.This naphthalenone intermediate and the bromo- 3- benzyl -2 methoxy quinoline of 6- Addition yield is set to increase in the presence of LDA, synthetic route is as follows:
The synthesis of 3- dimethylamino -2- (1- naphthalene) -propyl- 2- alkene -1- ketone
In above-mentioned synthetic method, the various problems such as that there are reaction steps in method one is more, yield is extremely low, manufacturing cost is very Height, without practical application value；Two original of method grinds in patent that four optical isomer intermixtures are after splitting, (1R, 2S)-Bei Da Quinoline yield is still very low；Reaction step is more in method three, and the ratio of four optical isomers is without report；Increase in method four High-pressure hydrogenation step, there are the ratios of certain danger, and objective optics isomers improvement.
The tert-alcohols of benzyl position easily slough hydroxyl under strong Lewis acid environment at low temperature, are forming more stable carbon just Ionic structure ((a) G.A.Olah, R.H.Schlosberg, Chemistry in superacids.I.Hydrogen exchange and polycondensation of methane and alkanes in FSO3H-SbF5("magic acid")solution.Protonation of alkanes and the intermediacy of CH5 + and related hydrocarbon ions. The high chemical reactivity of"paraffins"in ionic solution reactions.[J] J.Am.Chem.Soc.1968,90,2726.(b)M.Thaning,L.G.Wistrand A Short Enantiodivergent Synthesis of the Geissman-Waiss Lactone[J]J. Org.Chem.1990, 55,1406.(c)D.A.W.Sharp,N.Sheppard Complex fluorides.Part VIII.The preparation and the properties of salts of triphenylmethyl cation:the infrared spectrum And configuration of ion. [J] J.Chem.Soc.1957,674.), this carbonium ion is SP2Almost plane knot Structure, if this tertiary alcohol is chiral alcohol, the chiral of prochirality carbon is eliminated at this time, adds alkaline aqueous solution, OH-It can be from carbon horizontal frontal plane Two-pronged attack, generate the compound of two chiral alcohols (one is prochirality configuration, another is opposite configuration).Base of the present invention In this principle, by (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline be converted into (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline obtains target product-(1R, 2S)-Bei Da quinoline according still further to existing method for splitting.
Summary of the invention
It is an object of that present invention to provide a kind of preparation methods of (1R, 2S) and (1S, 2R)-Bei Da quinoline.
In order to achieve the above technical purposes, the preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline of the invention uses Technical solution are as follows:
A kind of preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline, includes the following steps:
(1) (1R, the 2R)-Bei Da quinoline of identical mass ratio and (1S, 2S)-Bei Da quinoline are distributed in solvent, are stirred Be cooled to after certain temperature in being slowly added to appropriate Lewis acid in 10min, keep low-temp reaction for a period of time after, be added certain Diluted alkaline is measured, and temperature is warmed to room temperature, a period of time is stirred at room temperature, thick solution is made；
(2) water phase in thick solution is removed, organic phase is washed with saturated sodium-chloride, then through drying, concentration, oily is made Object；
(3) appropriate tetrahydrofuran is added into grease, is heated to reflux, is cooled to room temperature, be precipitated white solid and Mother liquor filters out white solid, continuously adds the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, With ethanol washing, (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline mixture are obtained；
(4) be added into (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline mixture (R)-dinaphthol phosphate into Row is split, and obtains (1R, 2S)-Bei Da quinoline.
Stirring is cooled to -90 DEG C~-70 DEG C in the step (1), and the low-temp reaction time is 15min, reacts at room temperature the time For 30min.
Solvent is methylene chloride in the step (1), and Lewis acid is boron trifluoride ether compound or titanium tetrachloride Dichloromethane solution, diluted alkaline are potassium hydroxide, sodium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus One or more of.
The boron trifluoride ether compound dosage is that (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mix 1.0~2.5 equivalents of object, the dichloromethane solution dosage of the titanium tetrachloride are (1R, 2R)-Bei Da quinoline and (1S, 2S)-shellfish Up to 1.0~2.5 equivalents of quinoline mixture.
The boron trifluoride ether compound dosage is that (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mix 1.2 equivalents of object.
The dichloromethane solution dosage of the titanium tetrachloride is that (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline are mixed Close 1.2 equivalents of object.
The dosage of the diluted alkaline is greater than 3.0 equivalents of boron trifluoride ether compound, and the dosage of the diluted alkaline is greater than four 4.0 equivalents of the dichloromethane solution of titanium chloride.
The dosage of the diluted alkaline is 3.2 equivalents of boron trifluoride ether compound.
The dosage of the diluted alkaline is 4.2 equivalents of the dichloromethane solution of titanium tetrachloride.
Compared with prior art, the beneficial effects of the present invention are:
The present invention is acted on by (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline through Lewis acid, formed carbon just from Son, then through the OH in alkaline solution-Effect forms the new chiral tertiary alcohol, then (1R, 2S)-Bei Da quinoline is made through splitting, more often Rule reaction, not only reaction step is few in entire reaction process, and production efficiency is significantly promoted, and uses this method, easily obtains (1R, 2S)-Bei Da quinoline of higher yields is obtained, yield is improved significantly, and is conducive to industrialized production, while impurity residual volume Few, target product purity is high is highly-safe there are no that must increase risk step, the entire production processes such as high-pressure hydrogenation.
Specific embodiment
With reference to embodiment, the present invention is furture elucidated, it should be understood that these embodiments are merely to illustrate this It invents rather than limits the scope of the invention, after the present invention has been read, those skilled in the art are to of the invention various The modification of equivalent form falls within the application range as defined in the appended claims.
Embodiment 1
Into 500mL three-necked flask be added 30mL anhydrous methylene chloride, 4.44g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, leads to nitrogen, and stirring is cooled to -70 DEG C~-78 DEG C, 1.36g boron trifluoride second is slowly added in 10min Ether compound keeps temperature-resistant, reacts the sodium hydroxide solution of addition 15mL2mol/L after 15min, temperature is risen to room Temperature, and solution is stirred into 30min at room temperature, water phase is removed, washs dichloromethane layer, dichloro with 60mL saturated sodium chloride solution Methane layer obtains oil product after drying, concentration again, carries out high performance liquid chromatography measurement to grease, measures (A+A ')/(B+ B ') ratio be 62/38；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 2.13g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 48% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 97/3.
Wherein, high performance liquid chromatography location parameter and chromatographic condition are as follows: chromatographic column: YMC Pro C18 column, 120A；150mm ×3.0mm；5.0μm；Flow velocity: 0.5ml/min；Detection wavelength: 230nm；Mobile phase:: A is that 10mM ammonium acetate solution contains 0.5% Acetic acid；Mobile phase: B is that acetonitrile/ethyl alcohol 60/40 (w/w) contains 0.25% acetic acid；Gradient elution: 70%A, 30%B are initiated with；Extremely 27 minutes are 10%A, 90%B, until the 35th minute.Synthetic route is as follows:
(1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline are converted to (1R, 2S)-Bei Da quinoline and (1S, 2R)-shellfish Up to the process of quinoline
(1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline are acted on through Lewis acid, form carbonium ion, alkaline solution In OH-From the two-pronged attack of carbonium ion plane, form the new chiral tertiary alcohol, obtain (1R, 2R)-Bei Da quinoline, (1S, 2S) four kinds of-Bei Da quinoline, (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline mixtures；
Due to (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline solubility very little in tetrahydrofuran solution；In benzene Solubility is very big in range of solvents, and freezing point is high；And solubility is big in methylene chloride, freezing point is low, meanwhile, methylene chloride with Strong Lewis acid has good compatibility, therefore makees solvent using methylene chloride；
Since carbonium ion will keep stable, need at low temperature, other many side reactions otherwise easily to occur, therefore low temperature selects Select -90 DEG C~-70 DEG C；
The carbonium ion formed at low temperature, although can be by the OH from carbonium ion plane two sides-Attack, but two The probability in face is different, OH-Preferentially from the attack of sterically hindered facet direction, obtain accounting for leading (1R, 2S)-Bei Da quinoline with (1S, 2R)-Bei Da quinoline, and the direction attack big from another side steric hindrance, obtain (1R, 2R)-Bei Da quinoline and (1S, 2S)-shellfish Be secondary product up to quinoline, that is, form two pairs of optical isomers: (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline and (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline；
Since (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline solubility in tetrahydrofuran solvent are big, and (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline solubility in tetrahydrofuran solvent are small, therefore feed the mixture into tetrahydro furan It mutters and carries out heating reflux reaction in solution, then cool down, make (1R, the 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline of the overwhelming majority Quinoline crystalline solid is precipitated, and filtrate is concentrated again, obtains (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline accounts for leading oily Object, then through dehydrated alcohol back flow reaction, be cooled to room temperature, white solid is precipitated, is (1R, 2S)-Bei Da quinoline and (1S, 2R)- Shellfish (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline up to quinoline product and on a small quantity；
Using (R)-dinaphthol phosphate carry out chemical resolution, pure (1R, 2S)-Bei Da quinoline is made, thus finally with richness Treating tuberculosis drug-fast bacteria drug-fumaric acid shellfish is made up to quinoline at salt in horse acid.
Embodiment 2
Into 500mL three-necked flask be added 41mL anhydrous methylene chloride, 5.99g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mixture, leads to nitrogen, and stirring is cooled to -70 DEG C~-78 DEG C, 3.71g trifluoro is slowly added in 10min Change borate ether compound, keep temperature-resistant, the sodium hydroxide solution of addition 28mL2mol/L after 15min is reacted, by temperature Room temperature is risen to, and solution is stirred into 30min at room temperature, water phase is removed, washs dichloromethane with 80mL saturated sodium chloride solution Alkane layer, dichloromethane layer obtain oil product after drying, concentration again, carry out high performance liquid chromatography measurement to grease, measure (A+ A ')/ratio of (B+B ') is 63/37；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 3.08g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 52% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 96/4.
Embodiment 3
Into 500mL three-necked flask be added 36mL anhydrous methylene chloride, 5.33g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mixture, leads to nitrogen, and stirring is cooled to -70 DEG C~-78 DEG C, 1.63g trifluoro is slowly added in 10min Change borate ether compound, keep temperature-resistant, reacts the sodium carbonate liquor of addition 18mL2mol/L after 15min, it will be in temperature It is warmed to room temperature, and solution is stirred into 30min at room temperature, remove water phase, wash methylene chloride with 60mL saturated sodium chloride solution Layer, dichloromethane layer obtain oil product after drying, concentration again, carry out high performance liquid chromatography measurement to grease, measure (A+ A ')/ratio of (B+B ') is 62/38；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 2.67g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 50% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 96/4.
Embodiment 4
Into 500mL three-necked flask be added 35mL anhydrous methylene chloride, 5.60g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mixture, leads to nitrogen, and stirring is cooled to -80 DEG C~-90 DEG C, 1.72g trifluoro is slowly added in 10min Change borate ether compound, keep temperature-resistant, reacts the sodium hydroxide solution of addition 18.1mL2mol/L after 15min, it will be warm Degree rises to room temperature, and solution is stirred 30min at room temperature, removes water phase, washs dichloro with 50mL saturated sodium chloride solution Methane layer, dichloromethane layer obtain oil product after drying, concentration again, carry out high performance liquid chromatography measurement to grease, measure The ratio of (A+A ')/(B+B ') is 67/33；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 3.02g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 54% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 98/2.
Embodiment 5
Into 500mL three-necked flask be added 50mL anhydrous methylene chloride, 6.66g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mixture, leads to nitrogen, and stirring is cooled to -70 DEG C~-78 DEG C, 13.2mL tetrachloro is slowly added in 10min Change titanium dichloromethane solution (1.0mol, 13.2mmol), keep temperature-resistant, reacts the hydrogen of addition 27mL2mol/L after 15min Temperature is risen to room temperature, and solution is stirred 30min at room temperature by potassium oxide solution, removes water phase, is saturated chlorination with 80mL Sodium solution washs dichloromethane layer, and dichloromethane layer obtains oil product after drying, concentration again, carries out efficient liquid phase to grease Chromatographic determination, the ratio for measuring (A+A ')/(B+B ') is 63/35；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 3.19g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 48% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 99/1.
Embodiment 6
Into 500mL three-necked flask be added 24mL anhydrous methylene chloride, 3.55g (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline mixture, leads to nitrogen, and stirring is cooled to -70 DEG C~-78 DEG C, 7.7mL tetrachloro is slowly added in 10min Change titanium dichloromethane solution (1.0mol, 7.68mmol), keep temperature-resistant, reacts the hydrogen of addition 12mL2mol/L after 15min Temperature is risen to room temperature, and solution is stirred 30min at room temperature by potassium oxide solution, removes water phase, is saturated chlorination with 40mL Sodium solution washs dichloromethane layer, and dichloromethane layer obtains oil product after drying, concentration again, carries out efficient liquid phase to grease Chromatographic determination, the ratio for measuring (A+A ')/(B+B ') is 67/33；
The tetrahydrofuran of 25mL is added into this grease again, is heated to reflux, is cooled to room temperature, be precipitated white solid with And mother liquor, white solid is filtered out, filtering out solid is (1R, 2R)-Bei Da quinoline and (1S, 2S)-Bei Da quinoline, mother liquor concentrations Grease is obtained afterwards, is continuously added the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, ethanol washing, The mixture of 1.78g (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline is obtained, yield 50% is surveyed through high performance liquid chromatography Fixed, the ratio for obtaining (A+A ')/(B+B ') is 97/3.

Claims (9)

1. the method that one kind prepares (1R, 2S) and (1S, 2R)-Bei Da quinoline by (1R, 2R) and (1S, 2S)-Bei Da quinoline, special Sign is: including the following steps:
(1R, the 2R)-Bei Da quinoline of identical mass ratio and (1S, 2S)-Bei Da quinoline are distributed in solvent by step (1), are stirred In being slowly added to appropriate Lewis acid in 10min after being cooled to -90 DEG C~-70 DEG C, keep low-temp reaction for a period of time after, be added A certain amount of diluted alkaline, and temperature is warmed to room temperature, a period of time is stirred at room temperature, thick solution is made；The solvent is dichloromethane Alkane, the Lewis acid are the dichloromethane solution of boron trifluoride ether compound or titanium tetrachloride；
Step (2) removes the water phase in thick solution, washs organic phase with saturated sodium-chloride, then through drying, concentration, oily is made Object；
Appropriate tetrahydrofuran is added into grease for step (3), is heated to reflux, and is cooled to room temperature, be precipitated white solid and Mother liquor filters out white solid, continuously adds the reaction of 20mL alcohol reflux, is cooled to room temperature, white solid is precipitated, filters, With ethanol washing, (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline mixture are obtained；
Step (4) be added into (1R, 2S)-Bei Da quinoline and (1S, 2R)-Bei Da quinoline mixture (R)-dinaphthol phosphate into Row is split, and obtains (1R, 2S)-Bei Da quinoline.
2. according to claim 1 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the low-temp reaction time is 15min in the step (1), and the room temperature reaction time is 30min.
3. according to claim 1 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: diluted alkaline is potassium hydroxide, sodium hydroxide, cesium hydroxide, sodium carbonate, carbon in the step (1) One or more of sour hydrogen sodium, potassium carbonate, saleratus.
4. according to claim 3 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the boron trifluoride ether compound dosage be (1R, 2R)-Bei Da quinoline and (1S, 2S) 1.0~2.5 equivalents of-Bei Da quinoline mixture, the dichloromethane solution dosage of the titanium tetrachloride are (1R, 2R)-Bei Da 1.0~2.5 equivalents of quinoline and (1S, 2S)-Bei Da quinoline mixture.
5. according to claim 4 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the boron trifluoride ether compound dosage be (1R, 2R)-Bei Da quinoline and (1S, 2S) 1.2 equivalents of-Bei Da quinoline mixture.
6. according to claim 4 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the dichloromethane solution dosage of the titanium tetrachloride be (1R, 2R)-Bei Da quinoline and (1S, 2S) 1.2 equivalents of-Bei Da quinoline mixture.
7. according to claim 3 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the dosage of the diluted alkaline is greater than 3.0 equivalents of boron trifluoride ether compound, described dilute The dosage of alkali is greater than 4.0 equivalents of the dichloromethane solution of titanium tetrachloride.
8. according to claim 7 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the dosage of the diluted alkaline is 3.2 equivalents of boron trifluoride ether compound.
9. according to claim 7 prepare (1R, 2S) and (1S, 2R)-Bei Da by (1R, 2R) and (1S, 2S)-Bei Da quinoline The method of quinoline, it is characterised in that: the dosage of the diluted alkaline is 4.2 equivalents of the dichloromethane solution of titanium tetrachloride.
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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
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