CN107556308B - The asymmetric syntheses of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's derivative - Google Patents
The asymmetric syntheses of 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's derivative Download PDFInfo
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Abstract
The invention discloses one kind with (R)-tryptophan methyl ester and aldehyde are 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 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's class derivative compound containing two chiral centres of catalyst synthesis.Compared with existing public technology, reaction yield is not only improved, but also significantly improves reaction non-corresponding selectively.
Description
Technical field
The present invention relates to the synthesis of 1H- pyridine [3,4-b] Benzazole compounds, especially a kind of 1- for containing two chiral centres
The synthesis of aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's derivatives quasi-compound, belongs to the field of asymmetric synthesis.
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 method for currently preparing 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 is emerged in multitude with chiral catalyst, is catalyzed the continuous expansion of reaction type, becomes development most
Fast research method.This method only needs a small amount of chiral catalyst, so that it may synthesize a large amount of chiral drug chiral multiplication, and
It pollutes small, is the green syt for meeting environmental requirement, so as to cause the very big concern of people, has become organic chemistry in recent years
The research hotspot on boundary.Asymmetry catalysis synthesis is closely related with industry, it can be described as the high technology in organic synthesis.Medicine
Company usually compares inefficiency and cost control in the disposition of by-product in concern production process and chemical production process
Problem, therefore effective asymmetry catalysis synthetic method and technology have great attraction to them.In addition, fragrance, food
The industries such as additive and pesticide equally exist the requirement of " chirality ".Chiral liquid crystal, the polymer containing chiral backbone are because having uniqueness
Physicochemical property can be used as special device material and be increasingly valued by people.These have all promoted asymmetry catalysis conjunction
At 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 exactly makes a great contribution in this field, and share chemical Nobel in 2001
Prize.
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.
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 4(application for a patent for invention
Specification page 12, the 0030th section) in further illustrate: by compound F(tryptophan methyl ester) hydrochloride and 3,5- difluoro
Benzaldehyde is reacted to obtain E-6-1 (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b]
Indole -3-carboxylic acid methyl ester), near-white solid 17.8g, yield 26.0%；It obtains simultaneously, another non-corresponding isomery of E-6-1
Body E-6-2 (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%).Embodiment shows: in the synthesis process of this kind of compound E, using
It is chiralRTryptophan methyl ester is predominant starting material, to generate two non-corresponding isomers, and the two diastereoisomers contain
Amount difference is little, and since structure is similar, polarity difference is small, and separation is very difficult, and (it is usually necessary to use column chromatography means to be divided
From, and need to separate repeatedly), separation costs are high.Using E-6-1 as primary raw material, the successively reaction Jing Guo formula 5, formula 4, formula 3,
Obtain MIPO-6-1；Using E-6-2 as primary raw material, successively the reaction Jing Guo formula 5, formula 4, formula 3, obtains MIPO-6-2.As preceding
State patent of invention CN201610804063.1, described in embodiment 9, MIPO-6-1 and MIPO-6-2 are a pair of of non-corresponding isomers,
And 6 times of activity difference.If can be able to carry out enantioselectivity control during synthesizing E-6, as often as possible synthesize
To E-6-1, E-6-2 is not generated or generated less, is considerably improved sterilization/bacteriostatic activity of ideal product in this way.This hair
The bright this purpose that is based on: using catalysis method of asymmetric synthesis, highly selective obtains E-6-1 and the like, does not generate
Or E-6-2 and the like is generated less.
Summary of the invention
It is an object of the invention to report a kind of 1- aryl -1H- pyridine [3,4-b] indoles -3- for containing two chiral centres
Carboxylate methyl ester class derivative compound (compound E) method of asymmetric synthesis (formula 7):
The present invention tests in this way:
Magnetic stir bar, chiral tridentate ligand (compound L, structural formula such as 8 institute of formula are added into dry reaction tube
Show), vacuum drying, with nitrogen (nitrogen is High Purity Nitrogen, similarly hereinafter) displacement three times, sequentially added under nitrogen protection anhydrous solvent,
Ti(O- iPr)4Toluene solution, 4A molecular sieve, 30 DEG C are stirred to react 2 hours.Then, solvent and new is use up using vacuum pumping
The isopropanol of generation.Then add anhydrous THF, under nitrogen protection, reaction solution be cooled to 0 DEG C, and be added aldehyde andRTryptophan
Methyl esters, 0 DEG C is stirred to react 24 hours.At 0 DEG C, appropriate trifluoroacetic acid (TFA) is added, is stirred to react 2 hours, and allow its gradually
It is warmed to room temperature.Reaction body fluid is poured into appropriate saturated aqueous solution of sodium bicarbonate, makes it in alkalinity, several times with enough methylene chloride
Extraction, after the organic phase after merging uses anhydrous sodium sulfate dry, removed under reduced pressure methylene chloride obtains crude product, and gained is thick
Product pillar layer separation obtains target compound E.
In the reaction, anhydrous solvent be anhydrous methylene chloride, anhydrous tetrahydro furan (THF), anhydrous ether, without water beetle
Benzene.
In the reaction, aldehyde is aromatic aldehyde, substituted aroma aldehyde, heteroaromatic aldehyde, substituted heterocycle aromatic aldehyde.
We analyze according to experimentation and theoretical calculation is found, reaction process of the present invention is very special: being catalyzed first
In the presence of agent, amino attack aldehyde carbonyl groups, dehydration forms imines (additive 4A molecular sieve facilitates dehydration progress)；Secondly exist
Chiral ligand and Ti (O-iPr)4Under the conditions of the chiral lewis acid catalyst of formation, imines carbonium ion (reversible mistake is formed
Journey)；Under the promotion of chiral lewis acid catalyst, imines carbonium ion and indoles cycloaddition one new five-membered ring of formation, five
Member ring passes through rearrangement immediately and obtains ideal compound.Since reaction process is special, the document that can not use for reference directly,
At the beginning of the present invention tests, we have screened a large amount of chiral ligand and a large amount of central metal.Since reaction process 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 ligand and Ti (O-iPr)4's
After toluene solution reacts generation catalyst in anhydrous solvent, in order to obtain better experiment effect, need chiral catalyst
The isopropanol generated in generating process is removed.
There are one technical characterstics by the present invention: due to starting materialRTryptophan methyl ester (also referred to as D-trp methyl esters) is certainly
Body has a chiral centre, asymmetric catalysis of the invention, it is also possible to exist simultaneously asymmetric induction effect inside.
The target compound product and documents (patent of invention that general formula according to the preparation of aforementioned present invention method is E
CN2016108 04063.1) compare, there is the target compound high income that non-corresponding is selectively good, desired potential industrialization to answer
With 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 compound F(reaction equation 9): (R)-tryptophan methyl ester (compound F English name: (R)-
Methyl-2-amino -3- (1H-indol-3-yl) propanoate)
In being equipped with churned mechanically three-necked bottle, addition 600 mL of anhydrous methanol, D-trp (102.1 g, 500
Mmol), be stirred at room temperature, using ice salt bath, temperature of reaction system dropped to 0 DEG C, be added dropwise thionyl chloride (71.4 g, 600
Mmol), after dripping, it is warming up to room temperature reaction about 12 hours.Thin-layer chromatography monitoring stops reaction when raw material fully reacting.Often
After pressure steams most of remaining thionyl chloride and methanol, decompression eliminates thionyl chloride and methanol, cooling, obtains solid tryptophan first
The hydrochloride of ester (isolation air, low temperature can save the long period).When using the tryptophan methyl ester of free state, before taking on a small quantity
The hydrochloride for stating tryptophan methyl ester, is dissolved using chloroform, and solution is washed using saturated solution of sodium bicarbonate to alkalescent, organic layer
It is dry, remove solvent chloroform, obtained solid (as tryptophan methyl ester) vacuum drying, it is generally the case that it does not need to be further purified,
It is used directly for next step asymmetric catalysis.If needing really, toluene and n-hexane mixed solvent can be used to color ammonia
Sour methyl esters recrystallization is used for next step asymmetric catalysis after gained recrystallizes after solid vacuum drying.
Embodiment 2: synthesis compound L (lR,2S)-2-(N- 2 '-hydroxyls -3 '-isopropyl -5 '-methoxy-benzyl) ammonia
Base -1,2- diphenyl ethyl alcohol
((l is added into round-bottomed flaskR,2S) -1,2 diphenyl amino ethyl alcohol, 853 mg (4 mmol) and magnetic stir bar,
It adds after 12 mL absolute ethyl alcohol are dissolved, 2- hydroxyl -3- isopropyl -5- methoxybenzaldehyde 777mg is then added
(4 mmol).It is stirred to react at 25 DEG C, is monitored and reacted using thin-layer chromatography (TLC), until raw material fully reacting.It is straight into system
It connects and NaBH is added4460mg (12 mmoL, 3eq.) is stirred to react 6 hours at 25 DEG C, and 25 mL water quenching reactions are added.With
The extraction of the methylene chloride of 25 mL × 3, saturated salt washing is primary, and anhydrous sodium sulfate is dry, filters, and decompression boils off methylene chloride,
White solid, 1.22 g, yield 78% are obtained through column chromatographic purifying.
Embodiment 3: synthesis (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] Yin
Diindyl -3- carboxylate methyl ester (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate ligand (chemical combination are added into dry reaction tube
Object L, structural formula are as shown in Equation 8), vacuum drying three times with nitrogen displacement sequentially adds anhydrous 0.4 mL under nitrogen protection
Methylene chloride, 25 uL Ti (O-iPr)4The 1M toluene solution of (0.025 mmoL), 20 mg 4A molecular sieves, 30 DEG C of stirrings are anti-
It answers 2 hours.Then, solvent (methylene chloride, toluene) and newly-generated isopropanol are use up using vacuum pumping, it, will under nitrogen protection
Reaction system is cooled to 0 DEG C, spare.Then, magnetic stir bar, 35.6 mg is added in the dry reaction tube of another
(0.25 mmoL) 3,5- difluorobenzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuum drying are used
Nitrogen is replaced three times, and the anhydrous THF of 0.5 mL is added under nitrogen protection, and reaction solution is cooled to 0 DEG C, and by this THF solution needle
Cylinder is transferred in aforementioned catalytic agent test tube, and 0 DEG C is stirred to react 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acid (TFA) is added, stirs
Reaction 2 hours is mixed, and it is allowed to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, makes it
It in alkalinity, is extracted several times with methylene chloride (5 mL*3), after the organic phase after merging is using anhydrous sodium sulfate drying, decompression is removed
Fall methylene chloride and obtain crude product, gained crude product with pillar layer separation (eluant, eluent is methylene chloride: methanol=99:1),
Obtain target compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] Yin
Diindyl -3- carboxylate methyl ester), 69.9 mg of near-white solid, liquid phase normalizes content 99.3%, yield 81.7%.It obtains simultaneously, (E-
Another non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine of 6-1
[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%).It takes temperature from isolated product, which selectively reaches 90%(comparison: patent of invention CN2016108
18%) the 04063.1 reaction non-corresponding is selectively.Product E -6-1 fusing point and1HNMR data and document (patent of invention
CN2016108 04063.1) it is consistent.
4A molecular sieve is not used in the comparative experiments of embodiment 4(and embodiment 3, embodiment 4): synthesis (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)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate ligand (chemical combination are added into dry reaction tube
Object L, structural formula are as shown in Equation 8), vacuum drying three times with nitrogen displacement sequentially adds anhydrous 0.4 mL under nitrogen protection
Methylene chloride, 25 uL Ti (O-iPr)41M toluene solution, 0 mg of 4A molecular sieve of (0.025 mmoL), 30 DEG C are stirred to react 2
Hour.Then, solvent (methylene chloride, toluene) and newly-generated isopropanol are use up using vacuum pumping, under nitrogen protection, will reacted
System is cooled to 0 DEG C, spare.Then, magnetic stir bar, 35.6 mg (0.25 is added in the dry reaction tube of another
MmoL) 3,5- difluorobenzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuum drying are set with nitrogen
It changes three times, the anhydrous THF of 0.5 mL is added under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into aforementioned catalytic agent test tube, 0 DEG C is stirred to react 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acid (TFA) is added, is stirred to react 2
Hour, and it is allowed to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, making it is in alkalinity,
It is extracted several times with methylene chloride (5 mL*3), after the organic phase after merging is using anhydrous sodium sulfate drying, removed under reduced pressure solvent
Methylene chloride obtains crude product, and gained crude product obtains mesh with pillar layer separation (eluant, eluent is methylene chloride: methanol=99:1)
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indoles -3- carboxylic
Sour methyl esters), 59.3 mg of near-white solid, liquid phase normalizes content 98.8%, yield 69.3%.It obtains simultaneously, (E-6-1's is another
An outer non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b]
Indole -3-carboxylic acid methyl ester) 6.1 mg of near-white solid (E-6-2), liquid phase normalizes content 99.2%, yield 7.1%).From point
It takes temperature from obtained product, which is selectively 84%.
The comparative experiments of embodiment 5(and embodiment 3, embodiment 5 use equimolar Yb (OTf)3Ti in alternate embodiment 3
(O- iPr)4): synthesis (1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indoles -3- carboxylic
Sour methyl esters (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate ligand (chemical combination are added into dry reaction tube
Object L, structural formula are as shown in Equation 8), 15.5 mg (0.025 mmoL) metal salt Yb (OTf)3, vacuum drying vacuumizes dry
It is dry, three times with nitrogen displacement, anhydrous 0.4 mL methylene chloride, 20 mg of 4A molecular sieve, 30 DEG C of stirrings are sequentially added under nitrogen protection
Reaction 2 hours.Then, solvent (methylene chloride) and newly-generated isopropanol are use up using vacuum pumping, under nitrogen protection, will reacted
System is cooled to 0 DEG C, spare.Then, magnetic stir bar, 35.6 mg (0.25 is added in the dry reaction tube of another
MmoL) 3,5- difluorobenzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuum drying are set with nitrogen
It changes three times, the anhydrous THF of 0.5 mL is added under nitrogen protection, reaction solution is cooled to 0 DEG C, and this THF solution is shifted with syringe
Into aforementioned catalytic agent test tube, 0 DEG C is stirred to react 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acid (TFA) is added, is stirred to react 2
Hour, and it is allowed to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, making it is in alkalinity,
It is extracted several times with methylene chloride (5 mL*3), after the organic phase after merging is using anhydrous sodium sulfate drying, removed under reduced pressure solvent
Methylene chloride obtains crude product, and gained crude product obtains mesh with pillar layer separation (eluant, eluent is methylene chloride: methanol=99:1)
Mark compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indoles -3- carboxylic
Sour methyl esters), 4.5 mg of near-white solid, liquid phase normalizes content 99.4%, yield 5.3%.It obtains simultaneously, (E-6-1 is in addition
One non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] Yin
Diindyl -3- carboxylate methyl ester) 7.2 mg of near-white solid (E-6-2), liquid phase normalizes content 99.1%, yield 8.4%).From separation
Obtained product is taken temperature, which is selectively that -23%(and embodiment 3 compare).
The comparative experiments of embodiment 6(and embodiment 3,6 central metal Ti of embodiment and ligand (compound L) ratio use
Central metal Ti and ligand (compound L) ratio 1:1 in 2:1 alternate embodiment 3): synthesis (1R, 3R) -1- (3,5- difluorobenzene
Base) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester (E-6-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate ligand (chemical combination are added into dry reaction tube
Object L, structural formula are as shown in Equation 8), vacuum drying three times with nitrogen displacement sequentially adds anhydrous 0.4 mL under nitrogen protection
Methylene chloride, 50 uL Ti (O-iPr)4The 1M toluene solution of (0.050 mmoL), 20 mg 4A molecular sieves, 30 DEG C of stirrings are anti-
It answers 2 hours.Then, solvent (methylene chloride, toluene) and newly-generated isopropanol are use up using vacuum pumping, it, will under nitrogen protection
Reaction system is cooled to 0 DEG C, spare.Then, magnetic stir bar, 35.6 mg is added in the dry reaction tube of another
(0.25 mmoL) 3,5- difluorobenzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuum drying are used
Nitrogen is replaced three times, and the anhydrous THF of 0.5 mL is added under nitrogen protection, and reaction solution is cooled to 0 DEG C, and by this THF solution needle
Cylinder is transferred in aforementioned catalytic agent test tube, and 0 DEG C is stirred to react 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acid (TFA) is added, stirs
Reaction 2 hours is mixed, and it is allowed to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, makes it
It in alkalinity, is extracted several times with methylene chloride (5 mL*3), after the organic phase after merging is using anhydrous sodium sulfate drying, decompression is removed
Fall methylene chloride and obtain crude product, gained crude product with pillar layer separation (eluant, eluent is methylene chloride: methanol=99:1),
Obtain target compound E-6-1 ((1R, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] Yin
Diindyl -3- carboxylate methyl ester), 68.0 mg of near-white solid, liquid phase normalizes content 98.7%, yield 79.5%.It obtains simultaneously, (E-
Another non-corresponding isomers E-6-2 (1S, 3R) -1- (3,5- difluorophenyl) -2,3,4,9- tetrahydro -1H- pyridine of 6-1
[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%).It takes temperature from isolated product, the reaction non-corresponding selectivity 86%.
Embodiment 7: synthesis (1R, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid's first
Ester (E-1-1)
Magnetic stir bar, 9.8 mg (0.025 mmoL) chiral tridentate ligand (chemical combination are added into dry reaction tube
Object L, structural formula are as shown in Equation 8), vacuum drying three times with nitrogen displacement sequentially adds anhydrous 0.4 mL under nitrogen protection
Methylene chloride, 25 uL Ti (O-iPr)4The 1M toluene solution of (0.025 mmoL), 20 mg 4A molecular sieves, 30 DEG C of stirrings are anti-
It answers 2 hours.Then, solvent (methylene chloride, toluene) and newly-generated isopropanol are use up using vacuum pumping, it, will under nitrogen protection
Reaction system is cooled to 0 DEG C, spare.Then, magnetic stir bar, 26.5 mg is added in the dry reaction tube of another
(0.25 mmoL) benzaldehyde and 54.6 mg (0.25 mmoL) (R)-tryptophan methyl ester, vacuum drying, with nitrogen displacement three
It is secondary, the anhydrous THF of 0.5 mL is added under nitrogen protection, reaction solution is cooled to 0 DEG C, and before this THF solution is transferred to syringe
It states in catalyst test tube, 0 DEG C is stirred to react 24 hours.At 0 DEG C, 0.2 mL trifluoroacetic acid (TFA) is added, it is small to be stirred to react 2
When, and it is allowed to be gradually increased to room temperature.Reaction body fluid is poured slowly into 5 mL saturated aqueous solution of sodium bicarbonate, makes it in alkalinity, uses
Methylene chloride (5 mL*3) extracts several times, after the organic phase after merging is using anhydrous sodium sulfate drying, removed under reduced pressure solvent two
Chloromethanes obtains crude product, and gained crude product obtains target with pillar layer separation (eluant, eluent is methylene chloride: methanol=99:1)
Compound E-1-1 ((1R, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl esters), closely
63.4 mg of white solid, liquid phase normalize content 99.4%, yield 82.8%.It obtains simultaneously, (another non-corresponding of E-1-1
Isomers E-1-2 (1S, 3R) -1- phenyl -2,3,4,9- tetrahydro -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester) it is close white
Color solid (E-1-2) 3.2mg, liquid phase normalize content 99.2%, yield 4.1%).It takes temperature from isolated product, the reaction
Non-corresponding selectively reaches 91%.
Claims (2)
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 ligand chemical combination
Object L and Ti (O-iPr)4Synthetic method of the chiral lewis acid of formation as catalyst, main chemical reactions formula are as follows:
Method particularly includes: magnetic stir bar, chiral tridentate ligand compound L, structural formula are added into dry reaction tube
As shown in above formula, vacuum drying three times with high pure nitrogen displacement sequentially adds anhydrous solvent, Ti (O- under nitrogen protectioniPr)4Toluene solution, 4A molecular sieve, 30 DEG C are stirred to react 2 hours.Then, solvent and newly-generated is use up using vacuum pumping
Isopropanol.Then add anhydrous THF, under nitrogen protection, reaction solution be cooled to 0 DEG C, and be added aldehyde and (R)-tryptophan methyl ester,
0 DEG C is stirred to react 24 hours.At 0 DEG C, appropriate trifluoroacetic acid (TFA) is added, is stirred to react 2 hours, and it is allowed to be gradually increased to room
Temperature.Reaction body fluid is poured into appropriate saturated aqueous solution of sodium bicarbonate, makes it in alkalinity, is extracted several times with enough methylene chloride,
After organic phase after merging uses anhydrous sodium sulfate dry, removed under reduced pressure methylene chloride obtains crude product, gained crude product
With pillar layer separation, 1- aryl -1H- pyridine [3,4-b] indole -3-carboxylic acid methyl ester's class derivative goal compound E is obtained；It is chemical anti-
Ying Shizhong aldehyde R1CHO is one of benzaldehyde, 3,5- difluorobenzaldehyde.
2. in synthetic method described in claim 1, it is characterized in that anhydrous solvent is anhydrous methylene chloride, anhydrous tetrahydro furan, nothing
Any one of water ether, dry toluene.
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