CN107556308A - The asymmetric syntheses of the carboxylate methyl ester derivative of 1 aryl 1H pyridines [3,4 b] indoles 3 - Google Patents
The asymmetric syntheses of the carboxylate methyl ester derivative of 1 aryl 1H pyridines [3,4 b] indoles 3 Download PDFInfo
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Abstract
The invention discloses one kind with (R) tryptophan methyl ester and aldehyde is predominant starting material, with chiral tridentate ligand compound L and Ti (O iPr)4Method of asymmetric synthesis of the chiral lewis acid of formation as a kind of carboxylate methyl ester class derivative compound of 1 aryl 1H pyridines [3,4 b] indoles 3 containing two chiral centres of catalyst synthesis.Compared with existing public technology, reaction yield is both improved, reaction non-corresponding is selectively significantly improved again.
Description
Technical field
The present invention relates to the synthesis of 1H- pyridines [3,4-b] Benzazole compounds, particularly a kind of 1- containing two chiral centres
Aryl -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester's derivatives quasi-compound synthesizes, and belongs to asymmetric syntheses field.
Background technology
Chirality is the essential characteristic of nature, if a molecule can not overlap with its mirror image, the molecule 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, it is the relation in kind with mirror image between them, when can also be compared to the relation of right-hand man, mapping is different each other for the two molecules
Structure body.The biomolecule to be played a key effect in the generation of life and evolution process nearly all has chirality, such as naturally deposits
Sugar for (D)-configuration, amino acid for (L)-configuration, and protein and DNA helical conformation are all dextrorotation.Therefore, hand is worked as
When property material acts on this asymmetric living nature, bioactivity that two isomers show be often it is different, very
To completely contradicting.For chiral drug, the drug effect of two kinds of isomers is typically differentiated, such as (S)-naproxen
Antalgic and inflammation relieving activity be (R28 times of)-naproxen.The medicine for treating hypertrophy of the prostate breathes out Lip river, its (R)-enantiomer is on kidney
Adrenoceptor antagonistic activity be (S320 times of)-enantiomer.And for example (S)-ibuprofen oral can play analgesia and make after 15 minutes
With, and racemic brufen needs 30 minutes.Sometimes the pharmacological action of two kinds of enantiomers of same medicine is also different, such as chloramines
Ketone (S)-enantiomer has an anesthetic effect, and (R)-enantiomer but has excited and acts on mental disorder, therefore its racemic
Not only drug effect is low but also has side effect for body；Salbutamol (R)-enantiomer has the function that antihistamine treatment asthma, and (S)-mapping
Body, which but has, acts on airway constriction, so clinically using racemic modification, its therapeutic effect can be very poor.More importantly if
The toxic side effect of same two enantiomers of medicine is different, and danger can be brought using raceme, once there is 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 it is much four limbs incompleteness to have taken the baby that the pregnant woman that reaction stops bears
Deformed child.Although various countries stopped the sale that reaction stops at once, oneself turns into shake through causing ten hundreds of children's deformities
Shy the medicine accident of international the world of medicine.Found later in the isomers for reacting two kinds of various configurations for stopping including, only a pair
Physical efficiency is reflected to play a part of curing the disease, and another enantiomer has teratogenesis.For the potentially danger of racemic drugs, U.S.'s food
Product and drug administration（FDA）New bill was promulgated in 1992, the strict use for limiting racemic modification medicine.In bill requirement
City's new drug will be sold with the isomeric forms of single chiral as far as possible, 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 becoming more meticulous
Learn industry and propose new challenge.The effective way that drug manufacturer has to look for obtaining single chiral isomers from this.Generally,
The current method for preparing optically active substance probably has Nature inorganic bone method, enzyme transforming process, racemoid Split Method, asymmetry
Synthetic method etc..Said from the angle of research history, after nineteen nineties, dissymmetric synthesis achieves what is advanced by leaps and bounds
Development.Chiral ligand accelerate catalytic asymmetric reaction be one of most challenging 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 emerge in multitude with chiral catalyst, the continuous expansion of catalytic reaction type, turn into development most
Fast research method.This method only needs a small amount of chiral catalyst, so that it may synthesize substantial amounts of chiral drug chiral multiplication, and
Pollute small, be the green syt for meeting environmental requirement, so as to arouse great concern, turn into organic chemistry in recent years
The study hotspot on boundary.Asymmetry catalysis synthesis is closely related with industry, and it can be described as the high technology in organic synthesis.Medicine
Company generally compares that efficiency in the disposal of accessory substance in concern production process and chemical process is low and cost control
Problem, therefore effective asymmetry catalysis synthetic method has great attraction to them with technology.In addition, spices, food
The industry such as additive and agricultural chemicals equally exists the requirement of " chirality ".Chiral liquid crystal, the polymer containing chiral backbone are because with uniqueness
Physicochemical property can be increasingly valued by people as special device material.These have all promoted asymmetry catalysis conjunction
Into 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 is exactly to make a great contribution in this field, and share chemical Nobel in 2001
Prize.
Chinese invention patent CN201610804063.1（Date of application：2016.09.06；Inventor：Yang Weiqing, Li Hong
Ocean, Wang Hui towns；Title：Amidine compound of the one kind containing two chiral centres synthesizes and purposes；Open notification number：
CN106432237A）In report a kind of formula (its abbreviation of MIPO be by parent compound female ring English name 5- for MIPO
(methylimino) piperaz- in-2-one, which write a Chinese character in simplified form, gets) the 1- methyl -5- methylene imines base containing two chiral centres -
Piperazine -2- ketone derivatives class compounds（Formula 1）And its synthetic method.A kind ofization is as follows represented by invention formula M IPO
Compound structural formula（Formula 1）：
Contain 1 phenyl ring, 1 pyrrole ring, 1 piperidine ring, 1 piperazine azacyclo- in MIPO structure.In MIPO parent knot
In structure, R1Represent aryl, substituted aryl, heterocyclic aryl, substituted heterocycle aryl；R2Represent hydrogen or alkyl, cycloalkyl；R3Represent
Hydrogen or alkyl, cycloalkyl；* chirality is represented.Contain two chiral centres (i.e. containing two chiral carbons) in MIPO structure, because
In the MIPO structures of this same molecular formula, so that it may can have four kinds of chiral isomers（MIPO-1、MIPO-2、MIPO-3、
MIPO-4 structure, as shown in Equation 2）.
The compound synthesis that the invention formula is MIPO is described as follows with following reaction skeleton symbol：Formula is MIPO target compound
By the compound H that formula is A2NR2（Ammonia or monobasic ammonia）With the compound that formula is B（1- piperazine -1,4- diketone derivatives
Species compound）Reacted to obtain（Formula 3）.Wherein, the R in formula A, B1、R2、R3Refer to identical with formula M IPO.
The formula of of formula 3 is B compound（1- piperazine -1,4- diketone derivatives species compounds）By the compound that formula is C（Tetrahydrochysene
Pyrido [3,4-b] -2- chloracetyl indole -3-carboxylic acid methyl ester derivations）With the compound H that formula is D2NR3（Ammonia or one
Substituted ammonia）Synthesize to obtain by condensation, Intra-molecular condensation（Formula 4）.
The formula of of formula 4 is C compound（Tetrahydropyridine simultaneously [3,4-b] -2- chloracetyl indole -3-carboxylic acid methyl ester derivations）By
Formula is E compound（Tetrahydropyridine simultaneously [3,4-b] indole -3-carboxylic acid methyl ester derivation）Pass through acylation reaction with chloracetyl chloride
Synthesis obtains（Formula 5）.
The formula of of formula 5 is E compound（Tetrahydropyridine simultaneously [3,4-b] indole -3-carboxylic acid methyl ester derivation）By compound F (colors
Propylhomoserin methyl esters) and aldehyde（R1CHO）For initiation material, by being condensed, then intramolecular cyclization obtains the compound that 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 simply being reacted
In formula 6, i.e., in compound E synthesis step.
Aforementioned invention CN201610804063.1（Date of application：2016.09.06；Inventor：Yang Weiqing, Li Hongyang, king
Can town；Title：Amidine compound of the one kind containing two chiral centres synthesizes and purposes）, embodiment 9（Application for a patent for invention explanation
Book page 17, the 0046th section ~ 0048 section, and the description of the invention in the related data of table 3）In further illustrate：Same molecule
Four chiral isomers of formula（Such as：MIPO-6-1~ MIPO-6-4）Sterilization/bacteriostatic activity has differences.Enantiomter
（MIPO-6-1 and MIPO-6-4 is a pair of enantiomters；MIPO-6-2 and MIPO-6-3 is a pair of enantiomters）Between
Sterilization/bacteriostatic activity is essentially identical.But diastereoisomer（MIPO-6-1 and MIPO-6-2 is a pair of diastereoisomers；
MIPO-6-1 and MIPO-6-3 is also a pair of diastereoisomers；MIPO-6-4 and MIPO-6-2 is a pair of diastereoisomers；
MIPO-6-4 and MIPO-6-3 is also a pair of diastereoisomers；）Between sterilization/bacteriostatic activity notable difference be present.According to original
Beginning experimental data（The experimental method and initial data of embodiment 9）, with bacterium of downy mildew of cucumber（V1）Exemplified by, reactive compound
MIPO-6-1 sterilizes to it/bacteriostatic activity value is 98%, however, reactive compound MIPO-6-2 it is sterilized/bacteriostatic activity value only
For 16%, 6 times of activity difference between this pair of diastereoisomers.Not only formula M IPO four kinds of chiral isomers are present so
Activity difference, four kinds of chiral isomers of other compounds equally exist such activity difference, aforementioned invention
The table 3 of CN201610804063.1 specifications has simply lifted one of representative example.
Aforementioned invention CN201610804063.1（Date of application：2016.09.06；Inventor：Yang Weiqing, Li Hong
Ocean, Wang Hui towns；Title：Amidine compound of the one kind containing two chiral centres synthesizes and purposes）, embodiment 4（Application for a patent for invention
Page 12, the 0030th section of specification）In further illustrate：By compound F（Tryptophan methyl ester）Hydrochloride and 3,5- difluoros
Benzaldehyde is reacted to obtain E-6-1 (1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b]
Indole -3-carboxylic acid methyl ester), near-white solid 17.8g, yield 26.0%；Obtain simultaneously, E-6-1 another non-corresponding isomery
Body E-6-2 (1S, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester)
Near-white solid (E-6-2) 12.4g, yield 18.1%）.Embodiment shows：In this kind of compound E building-up process, use
It is chiralR- tryptophan methyl ester is predominant starting material, to produce two non-corresponding isomers, and the two diastereoisomers contain
Amount difference is little, and because structure is similar, polarity difference is small, and separation is very difficult（It is generally necessary to divided using column chromatography means
From, and need to separate repeatedly）, separation costs height.Using E-6-1 as primary raw material, successively by the reaction of formula 5, formula 4, formula 3,
Obtain MIPO-6-1；Using E-6-2 as primary raw material, successively by the reaction of formula 5, formula 4, formula 3, MIPO-6-2 is obtained.As preceding
State patent of invention CN201610804063.1, described in embodiment 9, MIPO-6-1 and MIPO-6-2 is a pair of non-corresponding isomers,
And 6 times of activity difference.If it can carry out enantioselectivity control during E-6 is synthesized, as often as possible synthesize
To E-6-1, do not generate or generate E-6-2 less, be so considerably improved sterilization/bacteriostatic activity of ideal product.This hair
It is bright to be based on this purpose：Using catalysis method of asymmetric synthesis, high selectivity obtains E-6-1 and the like, not generated
Or E-6-2 and the like is generated less.
The content of the invention
It is an object of the invention to report a kind of 1- aryl -1H- pyridine [3,4-b] indoles -3- containing two chiral centres
Carboxylate methyl ester class derivative compound（Compound E）Method of asymmetric synthesis（Formula 7）：
The present invention so tests：
Magnetic stir bar, chiral tridentate part are added into dry reaction tube（Compound L, its structural formula are as shown in Equation 8）,
Drying is vacuumized, uses nitrogen（Nitrogen is High Purity Nitrogen, similarly hereinafter）Displacement three times, anhydrous solvent, Ti (O- is sequentially added under nitrogen protectioniPr)4Toluene solution, 4A molecular sieves, 30 DEG C of stirring reactions 2 hours.Then, using vacuum pumping solvent and newly-generated to the greatest extent
Isopropanol.Then add anhydrous THF, under nitrogen protection, reaction solution be cooled to 0 DEG C, and add aldehyde andR- tryptophan methyl ester, 0
DEG C stirring reaction 24 hours.At 0 DEG C, appropriate trifluoroacetic acid is added（TFA）, stirring reaction 2 hours, and allow it to be gradually increased to room
Temperature.Reaction body fluid is poured into appropriate saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it, is extracted several times with enough dichloromethane,
After organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure methylene chloride obtains crude product, gained crude product
With pillar layer separation, target compound E is obtained.
In the reaction, anhydrous solvent is anhydrous methylene chloride, anhydrous tetrahydro furan（THF）, absolute ether, without water beetle
Benzene.
In the reaction, aldehyde is aromatic aldehyde, substituted aroma aldehyde, heteroaromatic aldehyde, substituted heterocycle aromatic aldehyde.
We are analyzed according to experimentation and theoretical calculation is found, course of reaction of the present invention is very special：It is being catalyzed first
In the presence of agent, amino attack aldehyde carbonyl groups, dehydration forms imines（Additive 4A molecular sieves contribute to dehydration to carry out）；Secondly exist
Chiral ligand and Ti (O-iPr)4Under the conditions of the chiral lewis acid catalyst of formation, imines carbonium ion is formed（Reversible mistake
Journey）；Under the promotion of chiral lewis acid catalyst, imines carbonium ion and indoles cycloaddition one new five-membered ring of formation, five
Yuan of rings obtain ideal compound by rearrangement immediately.Because course of reaction is special, without the document that can directly use for reference,
At the beginning of present invention experiment, we have screened substantial amounts of chiral ligand and substantial amounts of central metal.Because course of reaction is special, in detail
Thin catalytic cycle process, we are also among further research.
The present invention has a technical characterstic：In the preparation process of catalyst, chiral tridentate part and Ti (O-iPr)4's
After toluene solution reacts generation catalyst in anhydrous solvent, in order to obtain more preferable experiment effect, it is necessary to by chiral catalyst
Caused isopropanol is removed in generating process.
The present invention also has a technical characterstic：Due to initiation materialR- tryptophan methyl ester（Also referred to as D-trp methyl esters）From
Body has individual chiral centre, asymmetric catalysis of the invention, it is also possible to while asymmetric induction effect be present inside.
The target compound product and documents that the formula prepared according to the invention described above method is E（Patent of invention
CN2016108 04063.1）Compare, the target compound high income that non-corresponding is selectively good, desired, have potential industrialization should
With value.
Therefore, the present invention has good economic benefit and social benefit in summary.
Embodiment by the following examples is described in further detail to the above of the present invention again.But
The scope 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 technological thought 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, it all should be included in the present invention's
In the range of.
Embodiment
Embodiment 1：Synthesize compound F（Reaction equation 9）：（R）- tryptophan methyl ester（Compound F English names: (R)-
methyl-2-amino -3-(1H-indol-3-yl) propanoate）
In churned mechanically three-necked bottle is equipped with, the mL of absolute methanol 600, D-trp are added（102.1 g, 500 mmol）,
It is stirred at room temperature, using ice salt bath, temperature of reaction system is dropped to 0 DEG C, thionyl chloride is added dropwise（71.4 g, 600 mmol）, it is added dropwise
After complete, room temperature reaction about 12 hours is warming up to.Thin-layer chromatography is monitored, and when raw material reaction is complete, stopping is reacted.Normal pressure steams big portion
After dividing remaining thionyl chloride and methanol, decompression eliminates thionyl chloride and methanol, cools down, obtains the hydrochloride of solid tryptophan methyl esters
（Completely cut off air, low temperature can preserve the long period）.When using the tryptophan methyl ester of free state, a small amount of foregoing tryptophan first is taken
The hydrochloride of ester, is dissolved using chloroform, and solution is washed to alkalescent, organic layer using saturated solution of sodium bicarbonate and dried, removing
Solvent chloroform, gained solid（As tryptophan methyl ester）Vacuum drying, it is generally the case that do not need to be further purified, can be direct
For next step asymmetric catalysis.If needing really, toluene and n-hexane mixed solvent tryptophan methyl esters weight can be used
Crystallization, after gained recrystallizes after solid vacuum drying, for next step asymmetric catalysis.
Embodiment 2：Synthesize compound L (lR,2S)-2-(N- 2 '-hydroxyl -3 '-isopropyl -5 '-methoxy-benzyl) amino -1,
2- diphenyl ethanol
((l is added into round-bottomed flaskR,2S) -1, the mg of 2 diphenyl amino ethanol 853 (4 mmol) and magnetic stir bar, then add
Enter after 12 mL absolute ethanol are dissolved, then add 2- hydroxyl -3- isopropyl -5- methoxybenzaldehydes 777mg (4
mmol).Stirring reaction at 25 DEG C, using thin-layer chromatography（TLC）Monitoring reaction, until raw material reaction is complete.Into system directly
Add NaBH4460mg (12 mmoL, 3eq.), stirring reaction 6 hours at 25 DEG C, add 25 mL water quenchings and go out reaction.With 25
The extraction of the dichloromethane of mL × 3, saturated salt are washed once, anhydrous sodium sulfate drying, are filtered, and decompression boils off methylene chloride, are passed through
Column chromatography purifies to obtain white solid, 1.22 g, yield 78%.
Embodiment 3：Synthesize (1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] Yin
Diindyl -3- carboxylate methyl esters (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate part are added into dry reaction tube（Compound L,
Its structural formula is as shown in Equation 8）, drying is vacuumized, with nitrogen displacement three times, anhydrous 0.4 mL dichloros are sequentially added under nitrogen protection
Methane, 25 uL Ti (O-iPr)4（0.025 mmoL）1M toluene solutions, 20 mg 4A molecular sieves, 30 DEG C of stirring reactions 2 are small
When.Then, using vacuum pumping solvent to the greatest extent（Dichloromethane, toluene）With newly-generated isopropanol, nitrogen protection under, by reactant
System is cooled to 0 DEG C, standby.Then, magnetic stir bar, 35.6 mg (0.25 are added in the reaction tube that another is dried
MmoL) 3,5- difluorobenzaldehydes and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuumizes drying, is put with nitrogen
Change three times, add the anhydrous THF of 0.5 mL under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into Above-mentioned catalytic agent test tube, 0 DEG C of stirring reaction 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acids are added（TFA）, stirring reaction 2
Hour, and allow it to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it,
Use dichloromethane（5 mL*3）Extract several times, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure solvent
Dichloromethane obtains crude product, gained crude product pillar layer separation（Eluant, eluent is dichloromethane：Methanol=99:1）, obtain mesh
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -3- carboxylics
Sour methyl esters), the mg of near-white solid 69.9, liquid phase normalization content 99.3%, yield 81.7%.Obtain simultaneously, (E-6-1's is another
An outer non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b]
Indole -3-carboxylic acid methyl ester) near-white solid (E-6-2) 3.7mg, liquid phase normalization content 98.9%, yield 4.3%）.From separation
Obtained product is taken temperature, and the reaction non-corresponding selectively reaches 90%（Contrast：The reactions of patent of invention CN2016108 04063.1
Non-corresponding is selectively 18%）.Product E -6-1 fusing points and1HNMR data and document（Patent of invention CN2016108 04063.1）
Unanimously.
Embodiment 4（With the contrast experiment of embodiment 3,4A molecular sieves are not used in embodiment 4）：Synthesis (1R, 3R) -1- (3,
5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate part are added into dry reaction tube（Compound L,
Its structural formula is as shown in Equation 8）, drying is vacuumized, with nitrogen displacement three times, anhydrous 0.4 mL dichloros are sequentially added under nitrogen protection
Methane, 25 uL Ti (O-iPr)4（0.025 mmoL）1M toluene solutions, the mg of 4A molecular sieves 0,30 DEG C of stirring reactions 2 are small
When.Then, using vacuum pumping solvent to the greatest extent（Dichloromethane, toluene）With newly-generated isopropanol, nitrogen protection under, by reactant
System is cooled to 0 DEG C, standby.Then, magnetic stir bar, 35.6 mg (0.25 are added in the reaction tube that another is dried
MmoL) 3,5- difluorobenzaldehydes and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuumizes drying, is put with nitrogen
Change three times, add the anhydrous THF of 0.5 mL under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into Above-mentioned catalytic agent test tube, 0 DEG C of stirring reaction 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acids are added（TFA）, stirring reaction 2
Hour, and allow it to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it,
Use dichloromethane（5 mL*3）Extract several times, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure solvent
Dichloromethane obtains crude product, gained crude product pillar layer separation（Eluant, eluent is dichloromethane：Methanol=99:1）, obtain mesh
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -3- carboxylics
Sour methyl esters), the mg of near-white solid 59.3, liquid phase normalization content 98.8%, yield 69.3%.Obtain simultaneously, (E-6-1's is another
An outer non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b]
Indole -3-carboxylic acid methyl ester) 6.1 mg of near-white solid (E-6-2), liquid phase normalization content 99.2%, yield 7.1%）.From point
Taken temperature from obtained product, the reaction non-corresponding is selectively 84%.
Embodiment 5（With the contrast experiment of embodiment 3, embodiment 5 is using equimolar Yb (OTf)3Ti in alternate embodiment 3
(O- iPr)4）：Synthesize (1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -3- carboxylics
Sour methyl esters (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate part are added into dry reaction tube（Compound L,
Its structural formula is as shown in Equation 8）, 15.5 mg (0.025 mmoL) metal salt Yb (OTf)3, vacuumize drying and vacuumize drying,
With nitrogen displacement three times, anhydrous 0.4 mL dichloromethane, the mg of 4A molecular sieves 20 are sequentially added under nitrogen protection, 30 DEG C of stirrings are anti-
Answer 2 hours.Then, using vacuum pumping solvent to the greatest extent（Dichloromethane）With newly-generated isopropanol, nitrogen protection under, by reactant
System is cooled to 0 DEG C, standby.Then, magnetic stir bar, 35.6 mg (0.25 are added in the reaction tube that another is dried
MmoL) 3,5- difluorobenzaldehydes and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuumizes drying, is put with nitrogen
Change three times, add the anhydrous THF of 0.5 mL under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into Above-mentioned catalytic agent test tube, 0 DEG C of stirring reaction 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acids are added（TFA）, stirring reaction 2
Hour, and allow it to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it,
Use dichloromethane（5 mL*3）Extract several times, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure solvent
Dichloromethane obtains crude product, gained crude product pillar layer separation（Eluant, eluent is dichloromethane：Methanol=99:1）, obtain mesh
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -3- carboxylics
Sour methyl esters), the mg of near-white solid 4.5, liquid phase normalization content 99.4%, yield 5.3%.Obtain simultaneously, (E-6-1 is in addition
One non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] Yin
Diindyl -3- carboxylate methyl esters) 7.2 mg of near-white solid (E-6-2), liquid phase normalization content 99.1%, yield 8.4%）.From separation
Obtained product is taken temperature, and the reaction non-corresponding is selectively -23%（Contrasted with embodiment 3）.
Embodiment 6（With the contrast experiment of embodiment 3, the central metal Ti of embodiment 6 and part（Compound L）Ratio uses
2:Central metal Ti and part in 1 alternate embodiment 3（Compound L）Ratio 1:1）：Synthesize (1R, 3R) -1- (3,5- difluorobenzenes
Base) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate part are added into dry reaction tube（Compound L,
Its structural formula is as shown in Equation 8）, drying is vacuumized, with nitrogen displacement three times, anhydrous 0.4 mL dichloros are sequentially added under nitrogen protection
Methane, 50 uL Ti (O-iPr)4（0.050 mmoL）1M toluene solutions, 20 mg 4A molecular sieves, 30 DEG C of stirring reactions 2 are small
When.Then, using vacuum pumping solvent to the greatest extent（Dichloromethane, toluene）With newly-generated isopropanol, nitrogen protection under, by reactant
System is cooled to 0 DEG C, standby.Then, magnetic stir bar, 35.6 mg (0.25 are added in the reaction tube that another is dried
MmoL) 3,5- difluorobenzaldehydes and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuumizes drying, is put with nitrogen
Change three times, add the anhydrous THF of 0.5 mL under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into Above-mentioned catalytic agent test tube, 0 DEG C of stirring reaction 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acids are added（TFA）, stirring reaction 2
Hour, and allow it to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it,
Use dichloromethane（5 mL*3）Extract several times, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure solvent
Dichloromethane obtains crude product, gained crude product pillar layer separation（Eluant, eluent is dichloromethane：Methanol=99:1）, obtain mesh
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indoles -3- carboxylics
Sour methyl esters), the mg of near-white solid 68.0, liquid phase normalization content 98.7%, yield 79.5%.Obtain simultaneously, (E-6-1's is another
An outer non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyls) -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b]
Indole -3-carboxylic acid methyl ester) near-white solid (E-6-2) 5.1mg, liquid phase normalization content 99.0%, yield 6.0%）.From separation
Obtained product is taken temperature, reaction non-corresponding selectivity 86%.
Embodiment 7：Synthesize (1R, 3R) -1- phenyl -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid's first
Ester (E-1-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate part are added into dry reaction tube（Compound L,
Its structural formula is as shown in Equation 8）, drying is vacuumized, with nitrogen displacement three times, anhydrous 0.4 mL dichloros are sequentially added under nitrogen protection
Methane, 25 uL Ti (O-iPr)4（0.025 mmoL）1M toluene solutions, 20 mg 4A molecular sieves, 30 DEG C of stirring reactions 2 are small
When.Then, using vacuum pumping solvent to the greatest extent（Dichloromethane, toluene）With newly-generated isopropanol, nitrogen protection under, by reactant
System is cooled to 0 DEG C, standby.Then, magnetic stir bar, 26.5 mg (0.25 are added in the reaction tube that another is dried
MmoL) benzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuumizes drying, with nitrogen displacement three times, nitrogen
The anhydrous THF of 0.5 mL are added under gas shielded, reaction solution are cooled to 0 DEG C, and this THF solution is transferred to Above-mentioned catalytic with syringe
In agent test tube, 0 DEG C of stirring reaction 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acids are added（TFA）, stirring reaction 2 hours, and allow
It is gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, it is used dichloromethane in alkalescence
（5 mL*3）Extract several times, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure methylene chloride obtains
To crude product, gained crude product pillar layer separation（Eluant, eluent is dichloromethane：Methanol=99:1）, obtain target compound E-
1-1 ((1R, 3R) -1- phenyl -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl esters), near-white solid
63.4 mg, liquid phase normalization content 99.4%, yield 82.8%.Obtain simultaneously, (E-1-1 another non-corresponding isomers E-
1-2 (1S, 3R) -1- phenyl -2,3,4,9- tetrahydrochysene -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester) near-white solid (E-
1-2) 3.2mg, liquid phase normalization content 99.2%, yield 4.1%）.Taken temperature from isolated product, reaction non-corresponding choosing
Selecting property reaches 91%.
Claims (3)
1. 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester class derivative compound E of the one kind containing two chiral centres is not
Symmetrical synthetic method, it is characterised in that with (R)-tryptophan methyl ester and aldehyde are predominant starting material, with chiral tridentate part chemical combination
Thing L and Ti (O-iPr)4Synthetic method of the chiral lewis acid of formation as catalyst, main chemical reactions formula are as follows：
Specifically synthetic method is：Magnetic stir bar, chiral tridentate ligand compound L are added into dry reaction tube, it is tied
Structure formula is as shown in above formula）, drying is vacuumized, with high pure nitrogen displacement three times, anhydrous solvent, Ti are sequentially added under nitrogen protection
(O- iPr)4Toluene solution, 4A molecular sieves, 30 DEG C of stirring reactions 2 hours；Then, using vacuum pumping solvent and new life to the greatest extent
Into isopropanol；Then add anhydrous THF, under nitrogen protection, reaction solution be cooled to 0 DEG C, and add aldehyde and (R)-tryptophan
Methyl esters, 0 DEG C of stirring reaction 24 hours；At 0 DEG C, appropriate trifluoroacetic acid is added（TFA）, stirring reaction 2 hours, and make its gradual
It is warmed to room temperature；Reaction body fluid is poured into appropriate saturated aqueous solution of sodium bicarbonate, it is in alkalescence to make it, with enough dichloromethane several times
Extraction, after the organic phase after merging uses anhydrous sodium sulfate drying, removed under reduced pressure methylene chloride obtains crude product, and gained is thick
Product pillar layer separation, obtain 1- aryl -1H- pyridines [3,4-b] indole -3-carboxylic acid methyl ester's class derivative goal compound E.
2. in synthetic method described in claim 1, it is characterized in that anhydrous solvent is anhydrous methylene chloride, anhydrous tetrahydro furan
（THF）, absolute ether, any of dry toluene etc..
3. in synthetic method described in claim 1, it is characterized in that aldehyde is that aromatic aldehyde, substituted aroma aldehyde, heteroaromatic aldehyde, substitution are miscellaneous
Any of ring aromatic aldehyde etc..
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