CN107501261B - The chiral resolution of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester - Google Patents

Abstract

The invention discloses one kind with (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid is chiral selectors, the method for carrying out chiral resolution to a kind of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's non-corresponding isomers containing two chiral centres.This method has the characteristics that resolution yield is high, chiral selectors are easy to get, chiral selectors easily recycle, splits and work well.

Description

The chiral resolution of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester

Technical field

The present invention relates to the chiral resolutions of 1H- pyridine [3,4-b] Benzazole compounds, especially a kind of containing in two chiralitys The chiral resolution of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's derivative species of the heart belongs to asymmetric syntheses neck Domain.

Background technique

Chirality is the essential characteristic of nature, if a molecule cannot be overlapped with its mirror image, which is known as chirality Molecule.Many bioactive molecules are all chiral molecules in nature.When the atom composition of two molecules is identical, but space structure Difference is the relationship in kind with mirror image between them, and when can also be compared to the relationship of right-hand man, mapping is different each other for the two molecules Structure body.The biomolecule to play a key effect in the generation of life and evolution process nearly all has chirality, such as naturally deposits Sugar be (D)-configuration, amino acid be (L)-configuration, and the helical conformation of protein and DNA are all dextrorotation.Therefore, work as hand When this asymmetric living nature, the bioactivity that two isomers show often is different property material effect, very To completely contradicting.For chiral drug, the drug effect of two kinds of isomers is usually differentiated, such as (S)-naproxen Antalgic and inflammation relieving activity be (R28 times of)-naproxen.The drug for treating hypertrophy of the prostate breathes out Lip river, (R)-enantiomer is on kidney Adrenoceptor antagonistic activity be (S320 times of)-enantiomer.For another example (SAnalgesia can be played after)-ibuprofen oral 15 minutes to make With, and racemic brufen needs 30 minutes.Sometimes the pharmacological action of two kinds of enantiomers of same drug is also different, such as chloramines Ketone (S)-enantiomer has an anesthetic effect, and (R)-enantiomer but has excitement and makes mental disorder effect, therefore its racemic Not only drug effect is low but also has side effect for body；Salbutamol (R)-enantiomer has the function of antihistamine treatment asthma, and (S)-mapping Body but has and makes airway constriction effect, so clinically can be very poor using its therapeutic effect of racemic modification.More importantly if The toxic side effect of two enantiomers of same drug is different, can bring danger using raceme, once has bitterness to this mankind Lesson.A kind of sedative neurosedyn for treating pregnancy reaction that a German drugmaker develops in last century the fifties (trade name: reaction stops), drug effect is fine, but has soon found that having taken the baby that the pregnant woman that reaction stops bears is much four limbs incompleteness Deformed child.Although various countries stopped the sale that reaction stops at once, oneself becomes shake through causing ten hundreds of children's deformities The drug accident of frightened world the world of medicine.Discovery later is only a pair of in the isomers for two kinds of various configurations that reaction stops including Physical efficiency is reflected to play the role of curing the disease, and another enantiomer has teratogenesis.For the potentially danger of racemic drugs, U.S.'s food Product promulgated new bill in 1992 with drug administration (FDA), the stringent use for limiting racemic modification drug.On the bill requires City's new drug will be sold as far as possible with the isomeric forms of single chiral, such as should strictly be studied in addition with what racemic form was sold A kind of pharmacological properties of isomers.Other western developed countries also propose similar bill in succession.These bills are to fining It learns industry and proposes new challenge.Drug manufacturer has to look for obtaining the effective way of single chiral isomers from this.Generally, The current method for obtaining optically active substance probably has Nature inorganic bone method, enzyme transforming process, racemoid Split Method, asymmetry Synthetic method etc..It says from the angle of research history, after nineteen nineties, dissymmetric synthesis, which achieves, advances by leaps and bounds Development.Chiral ligand accelerate catalytic asymmetric reaction be most challenging one of research field because it merged it is " organic Synthesis, Coordinative Chemistry, homogeneous catalysis, Kinet-ics and mechanism research and high spatial chemistry concept etc..Asymmetry catalysis with Chiral catalyst emerges in multitude, and is catalyzed the continuous expansion of reaction type, becomes research method with fastest developing speed.This method is only Need a small amount of chiral catalyst, so that it may synthesize a large amount of chiral drug chiral multiplication, and pollution is small, meets environmental requirement Green syt has become the research hotspot for the educational circles that organises so as to cause the very big concern of people in recent years.Asymmetry catalysis Synthesis is closely related with industry, it can be described as the high technology in organic synthesis.Pharmaceuticals usually compares concern and produced Inefficiency and the problem of cost control in the disposition of by-product and chemical production process in journey, therefore effective asymmetry is urged Being combined to method and technology has great attraction to them.In addition, the industries such as fragrance, food additives and pesticide are equally deposited In the requirement of " chirality ".Chiral liquid crystal, the polymer containing chiral backbone are because having unique physicochemical property to can be used as special device Part material and be increasingly valued by people.These have all promoted asymmetry catalysis to synthesize the fast development in recent two decades, Nobel chemistry Prize in 2001 is even more to have shifted this upsurge onto peak.Knowls, Noyori and Sharpless are exactly at this One field makes a great contribution, and the share chemical Nobel Prize in 2001.

However, being wanted after the racemic modification obtained using common synthetic method (contrastingly with method of asymmetric synthesis) The compound for further obtaining optical voidness (or pure for optically-active), generally requires the method by fractionation.

There are many method of fractionation, wherein mainly have crystallisation, formation and separation diastereoisomer method, chromatography, Membrane separation process and enzyme Split Method, Extraction resolution method, capillary electrophoresis.

Crystallization Split Method is divided into two kinds again: crystal physical separation, seeded crystallization Split Method.Pair in racemic mixture It reflects body to be often spontaneously precipitated respectively with macroscopical crystal, come as these crystal can be seen difference, then being possible to amplifying With the help of mirror, they are separated with tweezers, here it is so-called crystal physical separations.L.Pasetur was prepared in 1848 The ammonium sodium salt of racemic tartaric acid, using the asymmetry of crystal, under the microscope by two kinds of material object-mirrors each other Crystal pick and separate, this is also the first report for obtaining optically pure compound in the world.Present in crystal physical separation Difficulty be that it is excessively cumbersome, and need to take a chance, because only that the enantiomer in only a few racemic mixture can Spontaneously it is precipitated respectively with macroscopical crystal.The crystal that obvious crystal physical separation is only used for two kinds of mappings can be seen area Those other raceme mixtures.If a kind of pure enantiomer conduct is added in the saturated solution of a racemic mixture Crystal seed, and it is suitably cooling, then the amount of the crystal will increase, considerable amount of enantiomer is precipitated, to reach separation mapping The requirement of body, here it is the seeded crystallization Split Methods often said.If the crystal of impure enantiomer can be used to be inoculated with, sometimes The crystal of other optically active compounds can also be used as crystal seed.Seeded crystallization Split Method simple process, cost is relatively low, and to certain A little racemic modification effects are preferable.Currently, the racemic modification that can be split with the method is not 300 lower in the case where continuous research, exploring, And if thering is dryed product largely to be split with such method.

Chiral reagent Split Method: in the solution of the enantiomer of a pair of of optical activity, being added optically pure compound, makes addition Optically pure compound reacts respectively with two structures in enantiomer, forms a pair of of non-corresponding isomers.It is some non-right The active natural bases of the tool of title, such as the salt of two kinds of tartaric acid of quinine alkali and brucine have quite different object Rationality matter, including solubility and optical activity.This is because the enantiomer of a pair of of optical activity is respectively anti-with another optically-active reagent It answers, obtained is the reason of two diastereoisomer derivatives.Their molecule is actually each other no longer each other Enantiomer, but the relationship of diastereoisomer.Because the variation of the stereochemical structure of molecule has crystal structure larger Influence, and make the dissolubility of diastereoisomer, apparent difference is presented in crystallinity, using the methods of crystallization by he Separate, refine.Then it recycles back reaction to remove resolving agent, obtains pure optically active compounds, achieve the purpose that fractionation.It is logical Often the optically pure alkaloid such as available strychnia, quinine and ephedrine splits acid racemic modification；With tartaric acid, camphorsulfonic acid Alkaline racemic modification is split etc. optically pure organic acid.Often to have the following conditions using chiral reagent Split Method: 1) split Compound between agent and the racemic modification being split must be easy to form, and is easy to be broken down into original component again.2) Being formed by two diastereoisomers at least alternative one must be able to the crystal to have been formed, and two diastereomeric solids Isomers has considerable difference in solubility.3) resolving agent must be cheap or easy recycling, and optically-active pure state is torn open Agent is divided to be easy preparation or obtain.

Chromatographic resolution method can be divided into gas chromatography and liquid chromatography.It is low and to heat that gas chromatography is only suitable for molecular weight The analysis of stable compound；The scope of application of liquid chromatography is slightly larger, and can be used for a small amount of preparative separations.Chromatographic resolution method sheet Matter is one kind of pillar layer separation method.

Select about method for splitting: various method for splitting respectively have superiority and inferiority, and crystallisation is more original, are chiefly used in certain specific objects The fractionation of matter；Chromatographic resolution method and film Split Method are often limited to production, experiment condition limitation is difficult to carry out；In contrast, chiral Reagent Split Method and Its Enzymatic Resolution method reaction mechanism understand that suitable species range is wide, be easier to carry out and be possible in laboratory into One step does industrial test.The difficult point of Its Enzymatic Resolution method is to find a kind of suitable enzyme to meet the needs for splitting experiment.

The Chinese invention patent CN201610804063.1(date of application: 2016.09.06；Inventor: Yang Weiqing, Li Hong Ocean, the town Wang Hui；Title: amidine compound synthesis and purposes of the one kind containing two chiral centres；Open notification number: CN106432237A it is that (its abbreviation of MIPO is by parent compound female ring English name 5- by MIPO that a kind of general formula is reported in) (methylimino) piperaz- in-2-one, which writes a Chinese character in simplified form, gets) the 1- methyl -5- methylene imine base-containing two chiral centres Piperazine -2- ketone derivatives class compound (formula 1) and its synthetic method.A kind ofization is as follows represented by invention formula M IPO It closes object structural formula (formula 1):

Contain 1 phenyl ring, 1 pyrrole ring, 1 piperidine ring, 1 piperazine azacyclo- in the structure of MIPO.In the mother of MIPO In body structure, R¹Indicate aryl, substituted aryl, heterocyclic aryl, substituted heterocycle aryl；R²Indicate hydrogen or alkyl, naphthenic base；R³ Indicate hydrogen or alkyl, naphthenic base；* chirality is represented.Containing there are two chiral centres (i.e. containing there are two chiral in the structure of MIPO Carbon), therefore in the MIPO structure of same molecular formula, so that it may can there are four kinds of chiral isomers (MIPO-1, MIPO-2, MIPO- 3, the structure of MIPO-4, as shown in Equation 2).

The compound synthesis that the invention general formula is MIPO is described as follows with following reaction skeleton symbol: general formula is the targeted of MIPO Close the compound H that object is A by general formula₂NR²(ammonia or monobasic ammonia) and general formula are the compound (1- piperazine -1,4- diketone of B Derivatives quasi-compound) it is reacted to obtain (formula 3).Wherein, the R in general formula A, B¹、R²、R³It refers to identical as formula M IPO.

The compound that the compound (1- piperazine -1,4- diketone derivatives species compound) that 3 formula of of formula is B is C by general formula (tetrahydropyridine simultaneously [3,4-b] -2- chloracetyl indole -3-carboxylic acid methyl ester derivation) and general formula are the compound H of D₂NR³(ammonia or The monobasic ammonia of person) it synthesizes to obtain (formula 4) by condensation, Intra-molecular condensation.

Compound (tetrahydropyridine simultaneously [3,4-b] -2- chloracetyl indole -3-carboxylic acid derivation of methyl ester that 4 formula of of formula is C Object) by compound (tetrahydropyridine simultaneously [3,4-b] indole -3-carboxylic acid methyl ester derivation) and chloracetyl chloride that general formula is E by acyl Change reaction synthesis and obtains (formula 5).

The compound (tetrahydropyridine simultaneously [3,4-b] indole -3-carboxylic acid methyl ester derivation) that 5 formula of of formula is E is by compound F (tryptophan methyl ester) and aldehyde (R¹It CHO) is starting material, by condensation, then intramolecular cyclization obtains the compound that general formula is E (formula 6).From the point of view of from the reactions above, reaction equation 3,4,5 is not related to the generation of chiral centre.The generation of chiral centre is only anti- It answers in formula 6, i.e., in the synthesis step of compound E.

The aforementioned invention CN201610804063.1(date of application: 2016.09.06；Inventor: Yang Weiqing, Li Hong Ocean, the town Wang Hui；Title: amidine compound synthesis and purposes of the one kind containing two chiral centres), embodiment 9(application for a patent for invention 3 related data of table in specification page 17, the 0046th section ~ 0048 section and the description of the invention) in further illustrate: it is same Molecular formula four chiral isomers (such as: MIPO-6-1 ~ MIPO-6-4) sterilization/bacteriostatic activity has differences.Enantiomerism (MIPO-6-1 and MIPO-6-4 is a pair of of enantiomter to body；MIPO-6-2 and MIPO-6-3 is a pair of of enantiomter) between Sterilization/bacteriostatic activity it is essentially identical.But (MIPO-6-1 and MIPO-6-2 is a pair of of diastereo-isomerism to diastereoisomer Body；MIPO-6-1 and MIPO-6-3 is also a pair of of diastereoisomer；MIPO-6-4 and MIPO-6-2 is a pair of of diastereo-isomerism Body；MIPO-6-4 and MIPO-6-3 is also a pair of of diastereoisomer；) between sterilization/bacteriostatic activity there are notable differences.According to Raw experimental data (experimental method and initial data of embodiment 9), by taking bacterium of downy mildew of cucumber (V1) as an example, reactive compound MIPO-6-1 sterilizes it/bacteriostatic activity value is 98%, however, reactive compound MIPO-6-2 it is sterilized/bacteriostatic activity value only It is 16%, 6 times of activity difference between this pair of of diastereoisomer.Not only four kinds of chiral isomers of formula M IPO exist in this way Four kinds of chiral isomers of activity difference, other compounds equally exist such activity difference, aforementioned invention The table 3 of CN201610804063.1 specification has only lifted one of representative example.Aforementioned invention The CN201610804063.1(date of application: 2016.09.06；Inventor: the town Yang Weiqing, Li Hongyang, Wang Hui；Title: Yi Leihan The amidine compound synthesis of two chiral centres and purposes), embodiment 4(application for a patent for invention specification page 12, the 0030th Section) in further illustrate: by compound F(tryptophan methyl ester) hydrochloride reacted to obtain E- with 3,5- difluorobenzaldehyde 6-1 (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester), closely White solid 17.8g, yield 26.0%；It obtains simultaneously, another non-corresponding isomers E-6-2 (1 of E-6-1S, 3R)-1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester) near-white solid (E-6-2) 12.4g, yield 18.1%).As aforementioned invention CN201610804063.1(embodiment 9) described in, MIPO-6-1 with MIPO-6-2 is a pair of of non-corresponding isomers, and 6 times of activity difference.Embodiment also shows: in the synthesis process of this kind of compound E In, using chiralityRTryptophan methyl ester is predominant starting material, to generate two non-corresponding isomers, and the two are diastereomeric different Structure body content difference is little, and since structure is similar, polarity difference is small, and dissolubility, crystal property are also not significantly different, separation ten Divide difficult (it is usually necessary to use column chromatography means to be separated, and needs to separate repeatedly), separation costs are high, are unsatisfactory for advising greatly The requirement of mould production.

Summary of the invention

The present invention is precisely in order to overcome prior art defect, using the method for chiral reagent Split Method, low cost, high yield Obtain optically pure a kind of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's class derivatization for containing two chiral centres Close object.

The present invention is implemented as follows:

The chiral selectors (formula 7) of mixture and highly acid to be split that synthesis is obtained are in the molten middle carry out soda acid of solution Neutralization reaction, using dissolution sex differernce, at a certain temperature, the salt of chiral selectors and one of isomers is largely precipitated (R in formula 8¹=aryl, substituted aryl, heterocyclic aryl, substituted heterocycle aryl), suction filtration obtains the chiral selectors and wherein one The crystal of the salt of a isomers, then again by the dissolution of crystals in aqueous solution, with sodium hydrate aqueous solution, by the crystal solution From solvent extraction obtains the optical pure compound of the one of isomers of mixture to be split, and aqueous solution acidification recycling splits examination Agent:

In the method, crystallization temperature is 5-50 DEG C.

In the method, extractant is any one of methylene chloride, chloroform, toluene etc..

The present invention is initial, we have found according to theoretical calculation, is split object, the 1- aryl -1H- containing two chiral centres A pair of of non-corresponding isomers structure of pyridine [3,4-b] indole -3-carboxylic acid methyl ester is very special: containing two on a hexatomic ring A chiral centre, and two chiral centres are respectively at 1,3, and midfeather one NH, the NH have certain alkalinity；1 Chiral structure influences each other with 3 chiral structures.Since structure is special, the document that can not use for reference directly, in the present invention At the beginning of experiment, we have screened a large amount of chiral selectors and a large amount of method for splitting.

Palm of the hand resolution reagent of the present invention obtains by following reactive mode and (is detailed in the embodiment of the present invention 1): firstly, in alkalinity Under the conditions of, copper sulphate as catalyst, L-cysteine hydrochloride hydrate and carbon disulfide carry out ring closure reaction obtain (R)- 2- thioketones-tetrahydro-thiazoles-4-carboxylic acid's (formula 9)；Then, (R) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid is in catalyst benzyl triethyl ammonium In the presence of ammonium chloride, with chloracetyl chloride carry out nitrogen on acylation reaction obtain (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro thiophene Azoles -4- carboxylic acid (formula 10).

The present invention has a technical characterstic: chiral selectors are easy to get, and chiral from natural amino acid, optics Purity is high provides primary condition to split the high selectivity of acquisition；And after the completion of a resolution cycle process, examination is split Agent loss is few, can largely recycle, be further used for next resolution cycle process.

There are one technical characterstics by the present invention: the target chemical combination that the general formula according to the preparation of aforementioned present invention method for splitting is E Produce product are compared with documents (patent of invention CN2016108 04063.1), it is desirable to target compound content it is high, split effect Fruit is significant, has potential industrial application value.

Therefore, of the invention with good economic efficiency and social benefit in summary.

Specific embodiment by the following examples is again described in further detail above content of the invention.But The range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following instance.The above-mentioned technical idea feelings of the present invention are not being departed from Under condition, the various replacements or change made according to ordinary skill knowledge and customary means, should all include of the invention In range.

Specific embodiment

Embodiment 1: synthesis (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid's (compound English name Claim (R) -3- (2- chloro-acetyl) -2-thioxothiazolidine-4-carboxylic acid):

Be equipped with mechanical stirring, thermometer, dropping funel, reflux condensing tube four neck round-bottom flasks in, be added it is anhydrous 350 mL of toluene, (R) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid (40.81 g, 0.25 mol) ((R) -2- thioketones-tetrahydro-thiazoles - The synthesized reference document of 4- carboxylic acid: patent US3697516, October 10 1972 applying date, inventor Jack E. Reece Deng), 8.0 g catalyst benzyltriethylammoinium chlorides, chloracetyl chloride (33.88 g, 0.30 mol), gradient is to slowly warm up to back Stream generates a large amount of hydrogen chloride gas, and the hydrogen chloride gas of generation is absorbed using lye, is warming up to back flow reaction 8h.React liquid cooling But to after room temperature, reaction solution is poured into appropriate mixture of ice and water, is sufficiently stirred, stand branch vibration layer, upper organic layer is with full It is repeatedly washed with sodium-chloride water solution.Decompression rotation removing solvent toluene, obtains crude product, the crude product is mixed using second alcohol and water Bonding solvent (containing ethyl alcohol 25%) recrystallization, obtains near-white solid, 34.76 g, yield 58%, liquid chromatogram (chromatographic condition: Shimadzu Wondersal C18 alkyl column 250mm*4.6mm*5um；Mobile phase is chromatography methanol/deionized water=85:15,1 mL/ of flow velocity min；40 DEG C of column temperature；Ultraviolet detection wavelength 254nm) analysis relative amount 99.5%.High resolution mass spectrum [M+H]⁺= 239.9562。

Embodiment 2: synthesis (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] Yin Diindyl -3- carboxylate methyl ester (abbreviation E-6-1) and (1S, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4- B] indole -3-carboxylic acid methyl ester (abbreviation E-6-2) non-corresponding isomer mixture

(patent of invention CN201610804063.1, date of application are referred in being equipped with churned mechanically three-necked bottle 2016.09.06, inventor Yang Wei is clear etc.), it is added 250 mL of acetic acid, the hydrochloride of D-trp methyl esters (50.9 g, 200 Mmol), dissolution is stirred at room temperature, using ice salt bath, temperature of reaction system is dropped to 0 DEG C, sequentially adds 3,5- difluorobenzaldehyde (31.3 g, 220.5 mmol), benzoic acid (5.7 g, 46.7 mmol).It is stirred to react at 0 ~ 3 DEG C 19 hours, thin-layer chromatography prison Control stops reaction, removed under reduced pressure major part solvent acetic acid when the basic fully reacting of raw material D-trp methyl esters.To reaction system Middle 100 mL of addition methylene chloride, 10% aqueous sodium carbonate are appropriate, adjust pH=9 ~ 10, are extracted several times with enough methylene chloride It takes, after the organic phase after merging is using anhydrous sodium sulfate drying, removed under reduced pressure methylene chloride obtains solid, obtains crude product 66.50g, the crude product use liquid chromatogram (chromatographic condition: Shimadzu Wondersal C18 alkyl column 250mm*4.6mm*5um； Mobile phase is chromatography methanol/deionized water=80:20,1 mL/min of flow velocity；35 DEG C of column temperature；Ultraviolet detection wavelength 254nm) analysis Respectively content is respectively 58.82%, 41.18% (disregarding other impurities content) to E-6-1 and E-6-2.The crude product is directly used in down One step splits experiment.

Embodiment 3: experiment preparation E-6-1 is split

1) precipitate crystal: diastereoisomer (E-6-1 and E-6-2) mixture 6.65g(synthesized by embodiment 2), add Heat dissolves it in 60 mL methanol to 40 DEG C, at such a temperature, be slowly added dropwise into the solution containing (R) -3- (2- chlorine Acetyl group) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid (4.79 g, 20 mmol；Synthesized by embodiment 1) 20 mL of methanol solution, There is a small amount of solid to be precipitated during being added dropwise, be heated to flowing back, solid dissolution is cooled to 30 DEG C, and a large amount of crystal are precipitated, and quickly filter (saving filtrate, be labeled as filtrate A), filter cake (i.e. crystal) washed once with a small amount of methanol.

2) crystal dissociates: aforementioned filter cake (i.e. crystal) is dissolved in the mixed solvent of 30mL, 50 DEG C of first alcohol and water (containing first Alcohol 20%) in, at such a temperature, the solution that 0.8 gram of sodium hydroxide and 5 mL water are made into is slowly added dropwise, is added dropwise, stirs 5min, being cooled to room temperature (25 DEG C) has a large amount of solids to be precipitated, and is extracted with dichloromethane (20 mL*3), (water layer is labeled as liquid separation Aqueous solution B), combined dichloromethane layer is washed 1 time using saturated sodium-chloride water solution, is removed solvent, is obtained (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester (E-6-1) 2.67g(is from implementation Example 2, which is synthesized to, tears total recovery 40.0% in two steps open；Comparison: the reaction of patent of invention CN2016108 04063.1 is from being synthesized to column color Compose separation yield 26%), which analyzes E-6-1 and E-6-2 respectively content using liquid chromatogram (chromatographic condition is with embodiment 2) Respectively 99.17%, 0.83%.

3) recycle chiral selectors (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid:

By aforementioned obtained aqueous solution B, pH=3.0 are acidified to using l mol/L hydrochloric acid, using 30 mL*3 of chloroform more times Extraction, combined chloroform layer are washed 1 time using saturated sodium-chloride water solution, remove solvent chloroform, obtain (R) -3- (2- chloracetyl Base) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid 2.01g；

By aforementioned obtained filtrate A, about 50 mL are concentrated to, are heated to 50 DEG C, at such a temperature, is slowly added dropwise 1.2 grams The solution that sodium hydroxide and 6 mL water are made into has been cooled to room temperature a large amount of solids and has been precipitated, (20 mL*3) is extracted with dichloromethane, Organic layer is outwelled, and water layer (being labeled as aqueous solution C) retains.Aqueous solution C is acidified to pH=3.0 using l mol/L hydrochloric acid, using chlorine More extractions of imitative 30 mL*3, combined chloroform layer are washed 1 time using saturated sodium-chloride water solution, remove solvent chloroform, obtain (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid 2.54g；Chiral selectors (R) -3- (2- chloracetyl Base) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid recycling 4.55g, recycling yield is 95.0%, liquid chromatogram (the same embodiment of chromatographic condition 1) relative amount 95.8% is analyzed.

Embodiment 4: synthesis (1R, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid's first Ester (abbreviation E-1-1) and (1S, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester (letter Claim E-1-2) non-corresponding isomer mixture

(patent of invention CN201610804063.1, date of application are referred in being equipped with churned mechanically three-necked bottle 2016.09.06, inventor Yang Wei is clear etc.), it is added 250 mL of acetic acid, the hydrochloride of D-trp methyl esters (50.9 g, 200 Mmol), dissolution is stirred at room temperature, using ice salt bath, temperature of reaction system is dropped to 0 DEG C, sequentially add benzaldehyde (23.4 g, 220.5 mmol), benzoic acid (5.7 g, 46.7 mmol).It is stirred to react at 0 ~ 3 DEG C 18 hours, raw material is worked as in thin-layer chromatography monitoring The basic fully reacting of D-trp methyl esters stops reaction, removed under reduced pressure major part solvent acetic acid.Dichloro is added into reaction system 100 mL of methane, 10% aqueous sodium carbonate are appropriate, adjust pH=9 ~ 10, are extracted several times with enough methylene chloride, after merging After organic phase is using anhydrous sodium sulfate drying, removed under reduced pressure methylene chloride obtains solid, obtains crude product 57.87g, this is thick Product uses liquid chromatogram (chromatographic condition: Shimadzu Wondersal C18 alkyl column 250mm*4.6mm*5um；Mobile phase is color Compose methanol/deionized water=80:20,1 mL/min of flow velocity；35 DEG C of column temperature；Ultraviolet detection wavelength 254nm) analysis E-1-1 and E-1- 2 respective contents are respectively 55.29%, 44.71% (disregarding other impurities content).The crude product is directly used in be split in fact in next step It tests.

Embodiment 5: experiment preparation E-1-1 is split

1) it precipitates crystal: by non-enantiomer mixture 5.80g (E-1-1 and E-1-2；Synthesized by embodiment 4), add Heat dissolves it in 55 mL methanol to 40 DEG C, at such a temperature, be slowly added dropwise into the solution containing (R) -3- (2- chlorine Acetyl group) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid (4.79 g, 20 mmol；Synthesized by embodiment 1) 20 mL of methanol solution, There is a small amount of solid to be precipitated during being added dropwise, be heated to flowing back, solid dissolution is cooled to 30 DEG C, and a large amount of crystal are precipitated, quickly Filtering (saves filtrate, be labeled as filtrate A), and filter cake (i.e. crystal) washed once with a small amount of methanol.

2) crystal dissociates: aforementioned filter cake (i.e. crystal) being heated to 50 DEG C, is made it dissolve in the mixing of 30mL first alcohol and water In solvent (containing methanol 20%), at such a temperature, the solution that 0.8 gram of sodium hydroxide and 5 mL water are made into is slowly added dropwise, drips Finish, stirs 5min, being cooled to room temperature (25 DEG C) has a large amount of solids to be precipitated, it is extracted with dichloromethane (20 mL*3), liquid separation (water layer, Labeled as aqueous solution B), combined dichloromethane layer is washed 1 time using saturated sodium-chloride water solution, removes solvent, obtain (1R, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester (E-1-1) 2.02g(is closed from embodiment 4 At to tearing total recovery 36.3% in two steps open), which analyzes E-1-1 and E-1- using liquid chromatogram (chromatographic condition is with embodiment 2) 2 respective contents are respectively 99.26%, 0.74%.

3) recycle chiral selectors (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid, it operates with real Apply example 3:

Recycling chiral selectors (R) -3- (2- chloracetyl) -2- thioketones-tetrahydro-thiazoles-4-carboxylic acid 4.50g, recycling is always Yield is 93.8%, and liquid chromatogram (chromatographic condition is with embodiment 1) analyzes relative amount 96.2%.

Claims (4)

1. 1- aryl -1H- pyridine [3,4-b] the indole -3-carboxylic acid methyl ester's diastereoisomer of one kind containing two chiral centres Method for splitting is characterized in that using the specific structure that is shown below as chiral selectors, wherein 1- aryl -1H- pyridine [3,4- B] indole -3-carboxylic acid methyl ester's diastereoisomer and chiral selectors structural formula it is as follows, R in formula¹=aryl:

Specific method for splitting are as follows: the chiral selectors of mixture and highly acid to be split for obtaining synthesis in solution is molten into Row acid-base neutralization reaction is crystallized at a certain temperature using dissolution sex differernce, chiral selectors and one of isomers Salt is largely precipitated, and filters and obtains the crystal of the salt of the chiral selectors and one of isomers；Then again that the crystal is molten In aqueous solution, with alkaline aqueous solution, which is dissociated for solution, and solvent extraction obtains the one of isomery of mixture to be split Body, aqueous solution acidification recycling resolution reagent.

2. in method for splitting described in claim 1, it is characterized in that crystallization temperature is 5-50 DEG C.

3. in method for splitting described in claim 1, it is characterized in that extractant is methylene chloride, appointing in chloroform, toluene It is a kind of.

4. in method for splitting described in claim 1, it is characterized in that alkaline aqueous solution is sodium hydrate aqueous solution, potassium hydroxide is water-soluble Any one of liquid, wet chemical.