CN107573360A - A kind of Mutiple Targets micromolecular compound S63845 preparation method - Google Patents
A kind of Mutiple Targets micromolecular compound S63845 preparation method Download PDFInfo
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Abstract
The invention discloses a kind of Mutiple Targets micromolecular compound S63845 preparation method, it is related to chemosynthesis technical field.The application is reduced to 16 steps by being improved to the synthetic route of compound s 6 3845, by 18 original steps, reduces protection group（THP）With deprotection base (THP) two-step reaction, cost of material is reduced, improves product economy benefit；The total recovery of compound s 6 3845 is significantly improved simultaneously, can reach 5.7 6.7%, the total recovery higher than in the prior art 4.7%.
Description
Technical field
The present invention relates to chemosynthesis technical field, more specifically, it relates to a kind of Mutiple Targets micromolecular compound
S63845 preparation method.
Background technology
MCL1 real names " granulocytic leukemia rush survival molecule ", belong to and suppress Apoptosis BCL-2 molecule families.Suppression is withered
Dying can be with power-assisted tumour, and it all exists in numerous tumours is overexpressed phenomenon.Also nobody successfully makes such medicine so far
MCL1 micromolecular inhibitors.Many members of BCL-2 molecule families, including MCL1, there is one " BH3 combinations ditch ", MCL1 is just
It is the generation that modulating apoptosis is participated in by this bar ditch.Current study show that S63845 can successfully target MCL1, have excellent
Bioactivity, its secret formula are that it have found " power knob " with MCL1, and perhaps it is at last as one of 21 century
The broad-spectrum anti-tumor medicine having a bright future.The compound that following chemical structural formula 1 represents is the small molecule to attract attention very much
Compound S63845 (CAS:).
Chemical structural formula 1
In prior art Nature, 2016, vol.538, p.477-482 (separately there is Publication No. EP2886545A1 Europe
Patent) in disclose a kind of preparation method of the compound, the following reaction equation of the preparation method is carried out：
But the reaction scheme step number is grown, synthesis cycle time length, particularly S6-4 to S6 linear synthesis step number length, total recovery
Low is only 4.7%, causes to synthesize cost height.Therefore the highly efficient synthetic route of necessary exploitation, which obtains this, has huge business
The micromolecular compound of industry potentiality value.
The content of the invention
In view of the deficienciess of the prior art, it is an object of the invention to provide a kind of Mutiple Targets micromolecular compound
S63845 preparation method, 18 steps of former route are shorten to 16 steps by improving, to solve the above problems, it has
The advantages of being improved total recovery, reducing accessory substance and reduce cost of material.
To achieve the above object, the invention provides following technical scheme：
A kind of Mutiple Targets micromolecular compound S63845 preparation method, comprises the following steps：
Step 1：Compound s 6-2b preparation
Starting compound S6-2, tri isopropyl chlorosilane, imidazoles, dichloromethane are added in reaction bulb, is stirred at room temperature anti-
Should, post-reaction treatment, obtain compound s 6-2b；
Step 2：Compound s 6-2c preparation
DIPEA, tetrahydrofuran are added in the reactor, -30 DEG C are cooled to after system nitrogen displacement positive fourth is added dropwise
Base lithium, stirring is cooled to-78 DEG C of tetrahydrofuran solutions that compound s 6-2b is added dropwise, stirring, then iodomethane is added dropwise, and heats up naturally
Reaction, post-reaction treatment, obtains compound s 6-2c；
Step 3：Compound s 6-2d preparation
Compound s 6-2c, tetrabutyl ammonium fluoride, cyclopropyl magnesium bromide are put into reaction bulb, is stirred at room temperature under nitrogen protection anti-
Should, post-reaction treatment, obtain compound s 6-2d；
Step 4：Compound s 6-2e preparation
Compound s 6-2d, 1- ethoxy-4- methyl piperazines, triphenyl phosphorus are added into reaction bulb under nitrogen protection, injects first
Benzene stirring and dissolving adds tert-butyl azodicarboxylate after becoming limpid, heating stirring reaction, post-reaction treatment, obtain chemical combination
Thing S6-2e；
Step 5：Compound s 6-2f preparation
Compound s 6-2e, tetrahydrofuran are put into reaction bulb, the protection of system nitrogen is cooled to-78 DEG C of dropwise addition n-BuLis, added
It is complete to be reacted 1 hour at -78 DEG C, isopropanol pinacol borate is added dropwise at -78 DEG C, adds and stirs half an hour at -78 DEG C,
Natural temperature reaction 12-16 hours, post-reaction treatment, obtain compound s 6-2f；
Step 6：Compound s 6-3b preparation
Acetic acid, sulfuric acid, water, compound s 6-3 are separately added into reaction bulb under nitrogen protection, add periodic acid, elemental iodine,
It is heated with stirring to 60 DEG C and is reacted to raw material and disappeared, post-reaction treatment, obtains compound s 6-3b；
Step 7：Compound s 6-3c preparation
POCl3, triethanolamine are sequentially added in reaction bulb, compound s 6-3b, room temperature are added portionwise again after covering drying tube
Stirring, 12-16 hours are reacted at 105 DEG C, post-reaction treatment, obtain compound s 6-3c；
Step 8：Compound s 6-3d preparation
Compound s 6-3c, N-bromosuccinimide, acetonitrile, fluoboric acid ether are sequentially added in reaction bulb, system nitrogen is protected
Shield is reacted at room temperature, post-reaction treatment, obtains compound s 6-3d；
Step 9：The preparation of compound s 6-5
[2- (bromoethyl) phenyl] acetate, 2- methylphenyl acetic acids, N-bromosuccinimide and hexamethylene are added in flask,
Azodiisobutyronitrile is added with vigorous stirring and is stirred, and reaction is mixed at 80 DEG C, post-reaction treatment, obtains compound
S6-5；
Step 10：The preparation of compound s 6-6
Anhydrous Lithium chloride and anhydrous zinc chloride are added into reaction bulb, then dried 1 hour under 0.1mmHG pressure at 160 DEG C,
Room temperature is cooled under argon gas protection, magnesium chip is added into reaction bulb, is cooled to 0 DEG C of addition tetrahydrofuran in advance, by mixture in ice bath
Lower stirring 30 minutes, forms the inorganic matter of precooling, then compound s 6-5 is dissolved in tetrahydrofuran, add above-mentioned precooling
But inorganic matter, stirring, temperature are maintained at 0-5 DEG C, add the toluene solution of glyoxylic acid ethyl ester, be stirred for mixing, filter off and remove
Insoluble inorganic matter, filtrate methanol dilution, is stirred the mixture for, and then adds acetic acid and solvent is distilled off under reduced pressure, instead
It should post-process, fractionation obtains compound s 6-6；
Step 11：Compound s 6-6b preparation
Compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl phosphorus, first are added in reaction bulb
Benzene, tert-butyl azodicarboxylate, the protection reaction of system nitrogen, post-reaction treatment, obtain compound s 6-6b；
Step 12：Compound s 6-6c preparation
Compound s 6-6b, ethanol, caustic alcohol are added in reaction bulb, the protection of system nitrogen is lower to react at room temperature 12-16 hours, instead
It should post-process, obtain compound s 6-6c；
Step 13：Compound s 6-6d preparation
Compound s 6-6c, compound s 6-4d, cesium carbonate, the tert-butyl alcohol, system nitrogen protection reaction 12-16 are put into reaction bulb
Hour, post-reaction treatment, obtain compound s 6-6d；
Step 14：Compound s 6-6e preparation
Sequentially added in single port bottle compound s 6-6d, cesium carbonate, bi triphenyl phosphorus palladium chloride, DMF,
Water, compound s 6-3e, system nitrogen displacement, the heating response in oil bath, post-reaction treatment, obtain compound s 6-6e；
Step 15：Compound s 6-6f preparation
Put into reaction bulb compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, cesium carbonate, dichloro it is double [di-t-butyl-
(4- dimethylaminophenyls) phosphine] palladium (II), the protection isothermal reaction of system nitrogen, post-reaction treatment, obtain compound s 6-6f；
Step 16：Compound s 6-6g preparation
Compound s 6-6f, Isosorbide-5-Nitrae-dioxane, water, lithium hydroxide monohydrate room temperature reaction are sequentially added in reaction bulb, instead
It should post-process, compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC；
The following reaction equation of preparation method is carried out：
The method and condition of post-reaction treatment in the step 1-16 are the conventional method and condition of the such reaction in this area.
More preferably, the step 1 specifically includes following steps：Added in reaction bulb starting compound S6-2,
Tri isopropyl chlorosilane, imidazoles, dichloromethane, the reaction system are stirred at room temperature 3 hours, thin-layer chromatography TLC (petroleum ether/
Ethyl acetate=3/1) show that reaction is complete, post-reaction treatment:Saturated aqueous common salt is first added, stands liquid separation, organic phase merges dense
Contracting adds silica gel mixed sample, and column chromatography obtains colourless liquid, as compound s 6-2b；
The step 2 specifically includes following steps：DIPEA, tetrahydrofuran, system nitrogen are added in the reactor
- 30 DEG C of dropwise addition n-BuLis are cooled to after gas displacement, drips off and 45min is stirred under the conditions of -30-0 DEG C, be cooled to -78 DEG C of dropwise additions
Compound s 6-2b tetrahydrofuran solution, stir 1 hour under the conditions of-78 DEG C after dripping off, then dripped again under the conditions of-78 DEG C
Add iodomethane, add rear natural temperature reaction 12-16 hours, TLC display reactions are complete, post-reaction treatment:Reaction solution is poured into
In ammonium chloride solution plus ethyl acetate liquid separation, aqueous phase ethyl acetate are extracted twice, and are washed again with saturated common salt after merging organic phase
Once, anhydrous sodium sulfate drying, yellow liquid, as compound s 6-2c are obtained after solvent evaporated.
More preferably, the step 3 specifically includes following steps：Compound s 6-2c, four fourths are put into reaction bulb
Base ammonium fluoride, tetrahydrofuran is reinjected, 12-16 hours are stirred at room temperature under nitrogen protection, TLC shows that compound s 6-2c disappears, instead
It should post-process：Saturated aqueous common salt is added into reaction solution and ethyl acetate liquid separation, aqueous phase are extracted with ethyl acetate twice, be associated with
Machine phase, then with saturated common salt washing once, anhydrous sodium sulfate drying, addition silica gel dry powder mixes sample, post after being filtered to remove drier
Chromatography (petrol ether/ethyl acetate=2/1) obtains yellow liquid, as compound s 6-2d；
The step 4 specifically includes following steps：Added under nitrogen protection into reaction bulb compound s 6-2d, 1- ethoxys-
4- methyl piperazines, triphenyl phosphorus, injection toluene stirring and dissolving add tert-butyl azodicarboxylate after becoming limpid, are heated to
45-55 DEG C of stirring reaction 1-3 hour, TLC show that compound s 6-2d reactions are complete, the product point S6-2e of generation polarity increase,
Post-reaction treatment：Add 30% methanol hydrochloride solution to be stirred at room temperature two hours, filter to get filtrate, filter cake is beaten with methyl tertiary butyl ether(MTBE)
Filtrate is starched to obtain, merging filtrate dry powder mixes sample, and column chromatography (methylene chloride/methanol=15/1) obtains yellow liquid, as compound
S6-2e。
More preferably, the step 5 specifically includes following steps：Compound s 6-2e, tetrahydrochysene are put into reaction bulb
Furans, the protection of system nitrogen are cooled to -78 DEG C of dropwise addition n-BuLis, add and reacted 1 hour at -78 DEG C, is added dropwise at -78 DEG C
Isopropanol pinacol borate, adds and is stirred half an hour at -78 DEG C, natural temperature reaction 12-16 hours, TLC display reactions
Completely, post-reaction treatment：Reaction solution is poured into ammonium chloride solution and is quenched, adds ethyl acetate, water to extract 3 merging organic phases,
Saturated common salt is washed once, anhydrous sodium sulfate drying, is spin-dried for, is obtained liquid, as compound s 6-2f；
The step 6 specifically includes following steps：Acetic acid, sulfuric acid, water, chemical combination are separately added into reaction bulb under nitrogen protection
Thing S6-3, periodic acid, elemental iodine are added, 60 DEG C is heated with stirring to and is reacted, LCMS monitorings display reaction raw materials after two hours
Disappear, post-reaction treatment：Room temperature is cooled to, is filtered, the elution of 15% acetic acid aqueous solution, petroleum ether elution, is spin-dried for obtaining yellow and consolidates
Body, as compound s 6-3b.
More preferably, the step 7 specifically includes following steps：POCl3, three are sequentially added in reaction bulb
Monoethanolamine, compound s 6-3b is added portionwise again after covering drying tube, after 10min is stirred at room temperature, 12-16 hours is reacted at 105 DEG C,
LCMS monitoring display reactions are complete, post-reaction treatment:Room temperature is filtered, and filter cake is poured into water, and cooling on the rocks, 5min is stirred at room temperature,
Filtering washing, petroleum ether elution, drains for 50 DEG C to obtain yellow solid, as compound s 6-3c；
The step 8 specifically includes following steps：Sequentially added in reaction bulb compound s 6-3c, N-bromosuccinimide,
Acetonitrile, fluoboric acid ether, system nitrogen protection room temperature reaction 8 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Room
Temperature filtering, filter cake are eluted with acetonitrile, drain for 50 DEG C to obtain yellow solid, as compound s 6-3d.
More preferably, the step 9 specifically includes following steps：By [2- (bromoethyl) phenyl] acetate, 2- first
Base phenylacetic acid, N-bromosuccinimide and hexamethylene are added in flask, then add azodiisobutyronitrile with vigorous stirring
And stir 30 minutes, mixed at 80 DEG C until not being further observed that conversion, post-reaction treatment:Then it is cooled to room
Temperature, it is filtered to remove sediment and washs filtrate with hexamethylene, obtain compound s 6-5.
More preferably, the step 11 specifically includes following steps：Compound s 6-6, (5- are added in reaction bulb
(1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl phosphorus, toluene, tert-butyl azodicarboxylate, system nitrogen protect
Shield reaction 12-16 hours, 45-55 DEG C of reaction temperature, LCMS monitoring reactions are complete, post-reaction treatment：Add silica gel dry powder and mix sample,
Column chromatography (petrol ether/ethyl acetate=20%) obtains weak yellow liquid, as compound s 6-6b；
The step 12 specifically includes following steps：Compound s 6-6b, ethanol, caustic alcohol, system nitrogen are added in reaction bulb
Protection lower room temperature reaction 12-16 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Add ammonium chloride solution, ethyl acetate
Extraction three times, merges organic phase, and saturated common salt is washed once, and anhydrous sodium sulfate drying, solvent evaporated, column chromatography obtains faint yellow
Liquid, as compound s 6-6c.
More preferably, the step 13 specifically includes following steps：Compound s 6-6c is put into reaction bulb, is changed
Compound S6-4d, cesium carbonate, the tert-butyl alcohol, system nitrogen protection reaction 12-16 hours, reaction temperature is 30-40 DEG C, LCMS monitorings
Display reaction is complete, post-reaction treatment：Add aqueous ammonium chloride solution, ethyl acetate is extracted three times, eaten after merging organic phase with saturation
Salt is washed once, anhydrous sodium sulfate drying, solvent evaporated, gained grease silica gel breading column chromatography (petrol ether/ethyl acetate=
10%-30%) obtain white solid, as compound s 6-6d；
The step 14 specifically includes following steps：Compound s 6-6d, cesium carbonate, bi triphenyl are sequentially added in single port bottle
Phosphorus palladium chloride, DMF, water, compound s 6-3e, system nitrogen displacement, are heated to 65-75 DEG C in oil bath
React 1-3 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Water quenching is added to go out reaction, ethyl acetate extraction three times,
Merge organic phase, saturated common salt is washed once, anhydrous sodium sulfate drying, silica gel breading, is spin-dried for column chromatography (petroleum ether/acetic acid second
Ester=0-20%), obtain yellow solid, as compound s 6-6e.
More preferably, the step 15 specifically includes following steps：Compound s 6-6e is put into reaction bulb, is changed
Double [di-t-butyl-(4- dimethylaminophenyls) phosphine] palladiums (II) of compound S6-2f, tetrahydrofuran, water, cesium carbonate, dichloro, system
Nitrogen protects isothermal reaction, and LCMS monitoring displays reaction is complete, post-reaction treatment：Saturated common salt water washing three times, anhydrous slufuric acid
Sodium is dried, and is spin-dried for, column chromatography (methylene chloride/methanol=0-5%), is obtained yellow, viscous liquid, as compound s 6-6f；
The step 16 specifically includes following steps：Sequentially added in reaction bulb compound s 6-6f, 1,4- dioxane, water,
Lithium hydroxide monohydrate reacts at room temperature 1 hour, and LCMS monitoring displays reaction is complete, post-reaction treatment:It is spin-dried for removing 1,4- bis-
The ring of oxygen six, methyl tertiary butyl ether(MTBE) is added, three times, it is 7 that aqueous phase is adjusted to pH value with hydrochloric acid, then is extracted with dichloromethane, is merged for extraction
Organic phase, anhydrous sodium sulfate drying are spin-dried for obtaining crude product, and compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC.
More preferably, 85-95 DEG C of constant temperature in the step 15, preferably 90 DEG C, the reaction time is 1-3 hours, excellent
Elect as 2 hours.
By using above-mentioned technical proposal, step 1-2 and former route are identical, step 6-8 and former route steps 5-7 phases
Together, the yield of former route steps 8 is low and former route needs 18 Walk, and synthetic route is 16 steps after improvement, reduces protection group
(THP) and base (THP) two-step reaction is deprotected, cost of material is relatively also more economical, and total recovery is significantly increased, and can reach
5.7-6.7%, purity 98%, product economy benefit are significantly improved.
The invention has the advantages that：
(1) the application is reduced to 16 steps by being improved to the synthetic route of compound s 6 3845 by 18 original steps, reduces
Upper protection group (THP) and deprotection base (THP) two-step reaction, reduce cost of material, improve product economy benefit；
(2) the application significantly improves the total recovery of compound s 6 3845, can reach 5.7-6.7%, higher than in the prior art
4.7% total recovery.
Brief description of the drawings
Fig. 1 is the synthetic route chart of compound s 6 3845 in the prior art；
Fig. 2 is the synthetic route chart of compound s 6 3845 in the present invention.
Embodiment
With reference to the accompanying drawings and examples, the present invention will be described in detail.Unless stated otherwise, institute in following examples
Reagent and instrument are commercially available product and laboratory conventional instrument.Medicine intermediate wherein in course of reaction is purchased from
Shanghai Bepharm Science ＆ Technology Co., Ltd. and Town in Shanghai Nai Ji Chemical Co., Ltd.s.
Embodiment 1：As shown in Fig. 2 a kind of Mutiple Targets micromolecular compound S63845 preparation method, including following step
Suddenly：
Step 1：Compound s 6-2b preparation
Raw material 143g compound s 6s -2,159.8g tri isopropyl chlorosilanes, 117.4g imidazoles, 1.2L dichloros are added in reaction bulb
Methane, the reaction system are stirred at room temperature 3 hours, and thin-layer chromatography TLC (petrol ether/ethyl acetate=3/1) displays have been reacted
Entirely, post-reaction treatment:Saturated aqueous common salt 500mL is first added, stands liquid separation, organic phase merges concentration and adds silica gel mixed sample, post layer
Analysis method obtains 240g colourless liquids, as compound s 6-2b, yield 96%.
Step 2：Compound s 6-2c preparation
Add 100mLN in the reactor, N- diisopropylethylamine, 1L tetrahydrofurans, be cooled to -30 DEG C after system nitrogen displacement
277mL n-BuLis are added dropwise, drips off and 45min is stirred under the conditions of-30-0 DEG C, is cooled to-78 DEG C and is added dropwise the four of compound s 6-2b
Hydrogen tetrahydrofuran solution 600mL, stirred 1 hour under the conditions of -78 DEG C after dripping off, 112g iodine first is then added dropwise again under the conditions of -78 DEG C
Alkane, rear natural temperature reaction 12-16 hours are added, TLC display reactions are complete, post-reaction treatment:Reaction solution is poured into 800mL chlorine
Change in ammonium salt solution plus ethyl acetate 500mL liquid separations, aqueous phase ethyl acetate 500mL are extracted twice, 700mL is used again after merging organic phase
Saturated common salt is washed once, anhydrous sodium sulfate drying, and 250g yellow liquids, as compound s 6-2c are obtained after solvent evaporated, is received
Rate 98%.
Step 3：S6-2d preparation
263g compound s 6s -2c, 191.1g tetrabutyl ammonium fluorides are put into reaction bulb, reinjects 1.32L tetrahydrofurans, nitrogen
12-16 hours are stirred at room temperature under protection, TLC shows that compound s 6-2c disappears, and generates the product S6-2d that a polarity becomes big, instead
It should post-process：Saturated aqueous common salt 1.0L and ethyl acetate 500mL liquid separations, aqueous phase ethyl acetate 300mL are added into reaction solution
It is extracted twice, merges organic phase, then washed once with saturated aqueous common salt 500mL, anhydrous sodium sulfate drying, after being filtered to remove drier
Add silica gel dry powder and mix sample, column chromatography (petrol ether/ethyl acetate=2/1) obtains 146g yellow liquids, as compound s 6-
2d, yield 95%.
Step 4：Compound s 6-2e preparation
Compound 31g S6-2d, 33g 1- ethoxy -4- methyl piperazines, 60g triphens are added into reaction bulb under nitrogen protection
Base phosphorus, injection 625mL toluene stirring and dissolvings add 52.7g tert-butyl azodicarboxylates after becoming limpid, are heated to 50 DEG C
Stirring reaction 2 hours, TLC show that compound s 6-2d reactions are complete, the product point S6-2e of generation polarity increase, locate after reaction
Reason：Add 30% methanol hydrochloride solution 300mL to be stirred at room temperature two hours, filter to get filtrate, filter cake is beaten with methyl tertiary butyl ether(MTBE)
Filtrate is obtained, merging filtrate dry powder mixes sample, and column chromatography (methylene chloride/methanol=15/1) obtains 22g yellow liquids, as compound
S6-2e, yield 57%.
Step 5：Compound s 6-2f preparation
22g compound s 6s -2e, 500mL tetrahydrofurans are put into reaction bulb, the protection of system nitrogen is cooled to -78 DEG C of dropwise additions
50.6mL n-BuLis, add and reacted 1 hour at -78 DEG C, 28.4g isopropanol pinacol borates are added dropwise at -78 DEG C, add
Complete to be stirred half an hour at -78 DEG C, natural temperature reaction 12-16 hours, TLC display reactions are complete, post-reaction treatment：Will reaction
Liquid is poured into 200mL ammonium chloride solutions and is quenched, and adds 250mL ethyl acetate, 100mL water to extract 3 merging organic phases, and 200mL satisfies
With salt washing once, anhydrous sodium sulfate drying, it is spin-dried for, obtains 20.8g liquid, as compound s 6-2f, yield 84%.
Step 6：Compound s 6-3b preparation
1.8L acetic acid, 53mL sulfuric acid, 356mL water, 284g compound s 6-3 are separately added into 5L reaction bulbs under nitrogen protection,
213g periodic acid, 427g elemental iodines are added, 60 DEG C is heated with stirring to and is reacted, LCMS monitorings display reaction raw materials after two hours
Disappear, post-reaction treatment：Room temperature is cooled to, is filtered, the elution of the acetic acid aqueous solutions of 300mL 15%, the elution of 200mL petroleum ethers, is spin-dried for
Obtain 459g yellow solids, as compound s 6-3b, yield 88%.
Step 7：Compound Compound S6-3c preparation
688mL POCl3s, 183g triethanolamines are sequentially added in 2L reaction bulbs, 459gization is added portionwise again after covering drying tube
Compound S6-3b, after 10min is stirred at room temperature, reacted at 105 DEG C 12-16 hours, LCMS monitoring display reactions are complete, locate after reaction
Reason:Room temperature is filtered, and filter cake is poured into 500mL water, cooling on the rocks, and 5min, filter 23 00mL washings, 300mL petroleum ethers is stirred at room temperature
Elution, drains for 50 DEG C to obtain 300g yellow solids, as compound s 6-3c, yield 61%.
Step 8：Compound s 6-3d preparation
338g compound s 6s -3c, 203g N-bromosuccinimides, 2.4L acetonitriles, 50mL fluorine boron are sequentially added in reaction bulb
Acid ether, LCMS monitors the complete 40g N-bromosuccinimides of adding of unreacted and stayed overnight after 5 hours, and LCMS is monitored not after 1 hour
React and added 40g N-bromosuccinimides, LC-MS monitoring unreacted is complete after 1 hour adds 50g N- bromos succinyl Asia
Amine, LC-MS monitoring unreacted is complete after 2 hours adds 50g N-bromosuccinimides, and LCMS monitoring display reactions are complete, react
Post processing：Room temperature is filtered, and filter cake is eluted with 400mL acetonitriles, drains for 50 DEG C to obtain 379g yellow solids, as compound s 6-3d,
Yield 88%.
Step 9：The preparation of compound s 6-5
60.07g [2- (bromoethyl) phenyl] acetate, 400mmol 2- methylphenyl acetic acids, 106.8g N- bromos succinyl is sub-
Amine and 500ml hexamethylenes are added in 1L flasks, then add 30 points of 3.284g azodiisobutyronitriles and stirring with vigorous stirring
Clock, mixed at 80 DEG C until not being further observed that conversion, post-reaction treatment:Then room temperature is cooled to, crosses and filters out
Remove sediment and wash filtrate with hexamethylene, obtain compound s 6-5, yield 90%.
Step 10：The preparation of compound s 6-6
23.10g anhydrous Lithium chlorides and 65.36g anhydrous zinc chlorides are added into 2L reaction bulbs, then the 0.1mmHG pressure at 160 DEG C
Lower drying 1 hour, under argon gas protection are cooled to room temperature, and the chip of 26.49g magnesium is added into reaction bulb, are cooled to 0 DEG C of addition tetrahydrochysene in advance
Furans, mixture is stirred 30 minutes under ice bath, forms the inorganic matter of precooling；Then by 100g [2- (three bromomethyl) second
Acetoacetic ester (S6-5) is dissolved in 120mL tetrahydrofurans, and the inorganic matter of above-mentioned precooling, caused mixing were added in 15 minutes
Thing is stirred 45 minutes, and temperature is maintained between 0-5 DEG C, and the toluene solution of 64.82mL glyoxylic acid ethyl esters was added in 5 minutes, then
It is stirred 15 minutes, then removes insoluble inorganic matter by filtering off, filtrate is stirred mixture with 500mL methanol dilution
Mix, then add 30mL acetic acid fugitive constituents and solvent is distilled off under reduced pressure, then add 350mL water, mixture acetic acid second
Ester extracts, then washes organic phase with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfate drying, filters, filtrate decompression concentration, then
100mL n-hexanes are added, are stirred 30 minutes at 0 DEG C, using filtering and WATER-WASHING METHOD, fractionation obtains white crystal, as chemical combination
Thing S6-6, yield 40%.
Step 11：Compound s 6-6b preparation
10.0g compound s 6s -6,14.3g (5- (1- (2,2,2,-trifluoroethyl) pyrazoles) base) first are added in 500mL reaction bulbs
Alcohol, 20.8g triphenyl phosphorus, 200mL toluene, 18.3g tert-butyl azodicarboxylates, system nitrogen protection reaction 12 hours, instead
Temperature 50 C is answered, LCMS monitoring reactions are complete, post-reaction treatment：Add 50g silica gel dry powder and mix sample, column chromatography (petroleum ether/acetic acid
Ethyl ester=20%) obtain 10.0g weak yellow liquids, as compound s 6-6b, yield：60%.
Step 12：Compound s 6-6c preparation
10g compound s 6s -6b, 50mL ethanol, 0.08g caustic alcohols are added in reaction bulb, the protection of system nitrogen is lower to be reacted at room temperature
12-16 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Adding 100mL ammonium chloride solutions, ethyl acetate extracts three times,
Merge organic phase, 60mL saturated common salts are washed once, and anhydrous sodium sulfate drying, solvent evaporated, it is faint yellow that column chromatography obtains 8.8g
Liquid, as compound s 6-6c, yield 98%.
Step 13：Compound s 6-6d preparation (because step 13 and step 14 merge, being not drawn into S6-6d structural formula)
16.6g compound s 6s -6c, 15.2g compound s 6s -4d, 18.5g cesium carbonates, uncle 300mL are put into 500mL reaction bulbs
Butanol, system nitrogen protection reaction 12-16 hours, reaction temperature is 35 DEG C, and LCMS monitoring display reactions are complete, locate after reaction
Reason：Add 1.5L aqueous ammonium chloride solutions, 300mL ethyl acetate is extracted three times, and 300mL saturated common salts washing one is used after merging organic phase
It is secondary, anhydrous sodium sulfate drying, solvent evaporated, gained grease silica gel breading column chromatography (petrol ether/ethyl acetate=10%-
30%) 24.5g white solids, as compound s 6-6d, yield 85% are obtained.
Step 14：Compound s 6-6e preparation
Sequentially added in 500mL single port bottles 12g compound s 6s -6d, 8.3g cesium carbonates, 1.2g bi triphenyl phosphorus palladium chloride,
200mLN, dinethylformamide, 40mL water, 8g compound s 6-3e, system nitrogen displacement, 70 DEG C are heated in oil bath instead
Answer 2 hours, room temperature is placed 12-16 hours, and LCMS monitoring display reactions are complete, post-reaction treatment：1L water quenchings are added to go out reaction,
300mL ethyl acetate is extracted three times, merges organic phase, and 300mL saturated common salts are washed once, and anhydrous sodium sulfate drying, silica gel is mixed
Powder, column chromatography (petrol ether/ethyl acetate=0-20%) is spin-dried for, obtains 20.8g yellow solids, as compound s 6-6e, yield
92%.
Step 15：Compound s 6-6f preparation
18g compound s 6s -6e, 18g compound s 6s -2f, 360mL tetrahydrofurans, 120mL water, 14.9g are put into 1L reaction bulbs
Double [di-t-butyl-(4- dimethylaminophenyls) phosphine] palladiums (II) of cesium carbonate, 0.76g dichloros, system nitrogen 90 DEG C of constant temperature of protection
Reaction 2 hours, LCMS monitoring displays reaction is complete, post-reaction treatment：Saturated common salt water washing three times (400mL × 3), anhydrous sulphur
Sour sodium is dried, and is spin-dried for, column chromatography (methylene chloride/methanol=0-5%), is obtained 20.5g yellow, viscous liquid, as compound
S6-6f, yield 89%.
Step 16：Compound s 6-6g preparation
22g compound s 6s -6f, 220mL 1,4- dioxane, 220mL water, 7.54g hydroxides are sequentially added in 1L reaction bulbs
Lithium monohydrate reacts at room temperature 1 hour, and LCMS monitoring displays reaction is complete, post-reaction treatment:It is spin-dried for removing Isosorbide-5-Nitrae-dioxane,
100mL methyl tertiary butyl ether(MTBE)s are added, three times, it is 7 that aqueous phase is adjusted to pH value with 1mol hydrochloric acid, then is extracted with 150mL dichloromethane for extraction
Take, merge organic phase, anhydrous sodium sulfate drying, be spin-dried for obtaining 15g crude products, 10g compound s 6-6g are prepared in chiral HPLC, i.e.,
Product S63845, yield：46%.
1H NMR(400MHz,DMSO-d6) δ 8.55 (s, 1H), 7.57 (d, J=1.8Hz, 1H), 7.28-7.14 (m, 3H),
7.06 (d, J=7.9Hz, 1H), 6.78 (t, J=7.4Hz, 1H), 6.60-6.53 (m, 1H), 6.25 (dd, J=7.2,0.8Hz,
1H), 5.86 (dd, J=6.8,3.6Hz, 1H), 5.67 (t, J=3.5Hz, 1H), 5.38 (dd, J=10.1,3.0Hz, 1H),
5.26 (d, J=13.2Hz, 1H), 5.20 (d, J=13.2Hz, 1H), 5.18 (q, J=2Hz), 4.32-4.21 (m, 2H), 3.16
(dd, J=13.6,2.4Hz, 1H), 2.84-2.72 (m, 2H), 2.63-2.39 (m, 8H), 2.30 (dd, J=13.6,2.4Hz,
13.9,10.4Hz,1H),2.23(s,3H),1.92(s,3H).
Embodiment 2：A kind of Mutiple Targets micromolecular compound S63845 preparation method, is with the difference of embodiment 1, step
45 DEG C are heated in rapid 4.
Embodiment 3：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In being heated to 55 DEG C in step 4.
Embodiment 4：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 1 hour in step 4.
Embodiment 5：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 3 hours in step 4.
Embodiment 6：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 14 hours in step 11.
Embodiment 7：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 16 hours in step 11.
Embodiment 8：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 45 DEG C in step 11.
Embodiment 9：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 55 DEG C in step 11.
Embodiment 10：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 30 DEG C in step 13.
Embodiment 11：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 40 DEG C in step 13.
Embodiment 12：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In oil bath heating is to 65 DEG C in step 14.
Embodiment 13：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In oil bath heating is to 75 DEG C in step 14.
Embodiment 14：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 1 hour in step 14.
Embodiment 15：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 3 hours in step 14.
Embodiment 16：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In 85 DEG C of constant temperature in step 15.
Embodiment 17：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In 95 DEG C of constant temperature in step 15.
Embodiment 18：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 1 hour in step 15.
Embodiment 19：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In the reaction time is 3 hours in step 15.
Comparative example 1：Using the method prepare compound S63845 disclosed in European patent EP 2886545A1, preparation method
Reaction equation as shown in Figure 1 is carried out.
Comparative example 2：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In being heated to 40 DEG C in step 4.
Comparative example 3：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 40 DEG C in step 11.
Comparative example 4：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In reaction temperature is 25 DEG C in step 13.
Comparative example 5：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In oil bath heating is to 55 DEG C in step 14.
Comparative example 6：A kind of Mutiple Targets micromolecular compound S63845 preparation method, exists with the difference of embodiment 1
In 75 DEG C of constant temperature in step 15.
Test a total recovery and purity testing
Test method：Test specimen 1-19 is used as using the compound s 6 3845 obtained in embodiment 1-19, using comparative example 1-6
The compound s 6 3845 of middle acquisition is used as control sample 1-6, calculates test specimen 1-19 and control sample 1-6 total recovery respectively
And its purity is determined, total recovery is that the product of yield is often walked in step 9-16.
Result of the test：Test specimen 1-19 and control sample 1-6 measurement result are as shown in table 1.As seen from table, control sample
Product 1-6 total recovery is 4.7-5.3%, and purity is 96.5 or so；Test specimen 1-19 total recovery is 5.7-6.7%, is higher than
Control sample 1, purity is 98% or so, higher than control sample 1-6.Illustrate that the application passes through the synthesis road to compound s 6 3845
Line is improved, and significantly improves the total recovery of compound s 6 3845, while preparation method is reduced to 16 steps by 18 original steps,
Reduce protection group (THP) and deprotection base (THP) two-step reaction, reduce cost of material, improve product economy benefit.
The test specimen 1-19 of table 1 and control sample 1-6 measurement result
Described above is only the preferred embodiment of the present invention, and protection scope of the present invention is not limited merely to above-described embodiment,
All technical schemes belonged under thinking of the present invention belong to protection scope of the present invention.It should be pointed out that for the art
For those of ordinary skill, some improvements and modifications without departing from the principles of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of Mutiple Targets micromolecular compound S63845 preparation method, it is characterised in that comprise the following steps：
Step 1：Compound s 6-2b preparation
Starting compound S6-2, tri isopropyl chlorosilane, imidazoles, dichloromethane are added in reaction bulb, is stirred at room temperature anti-
Should, post-reaction treatment, obtain compound s 6-2b；
Step 2：Compound s 6-2c preparation
DIPEA, tetrahydrofuran are added in the reactor, -30 DEG C are cooled to after system nitrogen displacement positive fourth is added dropwise
Base lithium, stirring is cooled to-78 DEG C of tetrahydrofuran solutions that compound s 6-2b is added dropwise, stirring, then iodomethane is added dropwise, and heats up naturally
Reaction, post-reaction treatment, obtains compound s 6-2c；
Step 3：Compound s 6-2d preparation
Compound s 6-2c, tetrabutyl ammonium fluoride, cyclopropyl magnesium bromide are put into reaction bulb, is stirred at room temperature under nitrogen protection anti-
Should, post-reaction treatment, obtain compound s 6-2d；
Step 4：Compound s 6-2e preparation
Compound s 6-2d, 1- ethoxy-4- methyl piperazines, triphenyl phosphorus are added into reaction bulb under nitrogen protection, injects first
Benzene stirring and dissolving adds tert-butyl azodicarboxylate after becoming limpid, heating stirring reaction, post-reaction treatment, obtain chemical combination
Thing S6-2e；
Step 5：Compound s 6-2f preparation
Compound s 6-2e, tetrahydrofuran are put into reaction bulb, the protection of system nitrogen is cooled to-78 DEG C of dropwise addition n-BuLis, added
It is complete to be reacted 1 hour at -78 DEG C, isopropanol pinacol borate is added dropwise at -78 DEG C, adds and stirs half an hour at -78 DEG C,
Natural temperature reaction 12-16 hours, post-reaction treatment, obtain compound s 6-2f；
Step 6：Compound s 6-3b preparation
Acetic acid, sulfuric acid, water, compound s 6-3 are separately added into reaction bulb under nitrogen protection, add periodic acid, elemental iodine,
It is heated with stirring to 60 DEG C and is reacted to raw material and disappeared, post-reaction treatment, obtains compound s 6-3b；
Step 7：Compound s 6-3c preparation
POCl3, triethanolamine are sequentially added in reaction bulb, compound s 6-3b, room temperature are added portionwise again after covering drying tube
Stirring, 12-16 hours are reacted at 105 DEG C, post-reaction treatment, obtain compound s 6-3c；
Step 8：Compound s 6-3d preparation
Compound s 6-3c, N-bromosuccinimide, acetonitrile, fluoboric acid ether are sequentially added in reaction bulb, system nitrogen is protected
Shield is reacted at room temperature, post-reaction treatment, obtains compound s 6-3d；
Step 9：The preparation of compound s 6-5
[2- (bromoethyl) phenyl] acetate, 2- methylphenyl acetic acids, N-bromosuccinimide and hexamethylene are added in flask,
Azodiisobutyronitrile is added with vigorous stirring and is stirred, and reaction is mixed at 80 DEG C, post-reaction treatment, obtains compound
S6-5；
Step 10：The preparation of compound s 6-6
Anhydrous Lithium chloride and anhydrous zinc chloride are added into reaction bulb, then dried 1 hour under 0.1mmHG pressure at 160 DEG C,
Room temperature is cooled under argon gas protection, magnesium chip is added into reaction bulb, is cooled to 0 DEG C of addition tetrahydrofuran in advance, by mixture in ice bath
Lower stirring 30 minutes, forms the inorganic matter of precooling, then compound s 6-5 is dissolved in tetrahydrofuran, add above-mentioned precooling
But inorganic matter, stirring, temperature are maintained at 0-5 DEG C, add the toluene solution of glyoxylic acid ethyl ester, be stirred for mixing, filter off and remove
Insoluble inorganic matter, filtrate methanol dilution, is stirred the mixture for, and then adds acetic acid and solvent is distilled off under reduced pressure, instead
It should post-process, fractionation obtains compound s 6-6；
Step 11：Compound s 6-6b preparation
Compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl phosphorus, first are added in reaction bulb
Benzene, tert-butyl azodicarboxylate, the protection reaction of system nitrogen, post-reaction treatment, obtain compound s 6-6b；
Step 12：Compound s 6-6c preparation
Compound s 6-6b, ethanol, caustic alcohol are added in reaction bulb, the protection of system nitrogen is lower to react at room temperature 12-16 hours, instead
It should post-process, obtain compound s 6-6c；
Step 13：Compound s 6-6d preparation
Compound s 6-6c, compound s 6-4d, cesium carbonate, the tert-butyl alcohol, system nitrogen protection reaction 12-16 are put into reaction bulb
Hour, post-reaction treatment, obtain compound s 6-6d；
Step 14：Compound s 6-6e preparation
Sequentially added in single port bottle compound s 6-6d, cesium carbonate, bi triphenyl phosphorus palladium chloride, DMF,
Water, compound s 6-3e, system nitrogen displacement, the heating response in oil bath, post-reaction treatment, obtain compound s 6-6e；
Step 15：Compound s 6-6f preparation
Put into reaction bulb compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, cesium carbonate, dichloro it is double [di-t-butyl-
(4- dimethylaminophenyls) phosphine] palladium (II), the protection isothermal reaction of system nitrogen, post-reaction treatment, obtain compound s 6-6f；
Step 16：Compound s 6-6g preparation
Compound s 6-6f, Isosorbide-5-Nitrae-dioxane, water, lithium hydroxide monohydrate room temperature reaction are sequentially added in reaction bulb, instead
It should post-process, compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC；
The following reaction equation of preparation method is carried out：
The method and condition of post-reaction treatment in the step 1-16 are the conventional method and condition of the such reaction in this area.
2. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 1 specifically includes following steps：Starting compound S6-2, tri isopropyl chlorosilane, imidazoles, dichloromethane are added in reaction bulb
Alkane, the reaction system are stirred at room temperature 3 hours, and thin-layer chromatography TLC (petrol ether/ethyl acetate=3/1) display reactions are complete,
Post-reaction treatment:Saturated aqueous common salt is first added, stands liquid separation, organic phase merges concentration and adds silica gel mixed sample, and column chromatography obtains
Colourless liquid, as compound s 6-2b；
The step 2 specifically includes following steps：DIPEA, tetrahydrofuran, system nitrogen are added in the reactor
- 30 DEG C of dropwise addition n-BuLis are cooled to after gas displacement, drips off and 45min is stirred under the conditions of -30-0 DEG C, be cooled to -78 DEG C of dropwise additions
Compound s 6-2b tetrahydrofuran solution, stir 1 hour under the conditions of-78 DEG C after dripping off, then dripped again under the conditions of-78 DEG C
Add iodomethane, add rear natural temperature reaction 12-16 hours, TLC display reactions are complete, post-reaction treatment:Reaction solution is poured into
In ammonium chloride solution plus ethyl acetate liquid separation, aqueous phase ethyl acetate are extracted twice, and are washed again with saturated common salt after merging organic phase
Once, anhydrous sodium sulfate drying, yellow liquid, as compound s 6-2c are obtained after solvent evaporated.
3. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 3 specifically include following steps：Compound s 6-2c, tetrabutyl ammonium fluoride are put into reaction bulb, reinjects tetrahydrofuran, nitrogen
12-16 hours are stirred at room temperature under gas shielded, TLC shows that compound s 6-2c disappears, post-reaction treatment：Added into reaction solution full
With saline solution and ethyl acetate liquid separation, aqueous phase is extracted with ethyl acetate twice, merges organic phase, then wash one with saturated common salt
Secondary, anhydrous sodium sulfate drying, addition silica gel dry powder mixes sample, column chromatography (petrol ether/ethyl acetate=2/ after being filtered to remove drier
1) yellow liquid, as compound s 6-2d are obtained；
The step 4 specifically includes following steps：Added under nitrogen protection into reaction bulb compound s 6-2d, 1- ethoxys-
4- methyl piperazines, triphenyl phosphorus, injection toluene stirring and dissolving add tert-butyl azodicarboxylate after becoming limpid, are heated to
45-55 DEG C of stirring reaction 1-3 hour, TLC show that compound s 6-2d reactions are complete, the product point S6-2e of generation polarity increase,
Post-reaction treatment：Add 30% methanol hydrochloride solution to be stirred at room temperature two hours, filter to get filtrate, filter cake is beaten with methyl tertiary butyl ether(MTBE)
Filtrate is starched to obtain, merging filtrate dry powder mixes sample, and column chromatography (methylene chloride/methanol=15/1) obtains yellow liquid, as compound
S6-2e。
4. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 5 specifically include following steps：Compound s 6-2e, tetrahydrofuran are put into reaction bulb, the protection of system nitrogen is cooled to-78
DEG C be added dropwise n-BuLi, add and react 1 hour at -78 DEG C, at -78 DEG C dropwise addition isopropanol pinacol borate, add -
Stirred half an hour at 78 DEG C, natural temperature reaction 12-16 hours, TLC display reactions are complete, post-reaction treatment：Reaction solution is fallen
Enter in ammonium chloride solution and be quenched, add ethyl acetate, water to extract 3 merging organic phases, saturated common salt is washed once, anhydrous sodium sulfate
Dry, be spin-dried for, obtain liquid, as compound s 6-2f；
The step 6 specifically includes following steps：Acetic acid, sulfuric acid, water, chemical combination are separately added into reaction bulb under nitrogen protection
Thing S6-3, periodic acid, elemental iodine are added, 60 DEG C is heated with stirring to and is reacted, LCMS monitorings display reaction raw materials after two hours
Disappear, post-reaction treatment：Room temperature is cooled to, is filtered, the elution of 15% acetic acid aqueous solution, petroleum ether elution, is spin-dried for obtaining yellow and consolidates
Body, as compound s 6-3b.
5. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 7 specifically include following steps：POCl3, triethanolamine are sequentially added in reaction bulb, is added portionwise again after covering drying tube
Compound s 6-3b, after 10min is stirred at room temperature, reacted at 105 DEG C 12-16 hours, LCMS monitoring display reactions are complete, after reaction
Processing:Room temperature is filtered, and filter cake is poured into water, cooling on the rocks, 5min is stirred at room temperature, filtering washing, petroleum ether elution, 50 DEG C are drained
Obtain yellow solid, as compound s 6-3c；
The step 8 specifically includes following steps：Sequentially added in reaction bulb compound s 6-3c, N-bromosuccinimide,
Acetonitrile, fluoboric acid ether, system nitrogen protection room temperature reaction 8 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Room
Temperature filtering, filter cake are eluted with acetonitrile, drain for 50 DEG C to obtain yellow solid, as compound s 6-3d.
6. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 9 specifically include following steps：By [2- (bromoethyl) phenyl] acetate, 2- methylphenyl acetic acids, N-bromosuccinimide and
Hexamethylene is added in flask, is then added azodiisobutyronitrile with vigorous stirring and is stirred 30 minutes, mixes and stir at 80 DEG C
Mix until not being further observed that conversion, post-reaction treatment:Then room temperature is cooled to, sediment is filtered to remove and uses hexamethylene
Filtrate is washed, obtains compound s 6-5.
7. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 11 specifically include following steps：Compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) are added in reaction bulb
Methanol, triphenyl phosphorus, toluene, tert-butyl azodicarboxylate, system nitrogen protection reaction 12-16 hours, reaction temperature 45-55
DEG C, LCMS monitoring reactions are complete, post-reaction treatment：Add silica gel dry powder and mix sample, column chromatography (petrol ether/ethyl acetate=20%)
Obtain weak yellow liquid, as compound s 6-6b；
The step 12 specifically includes following steps：Compound s 6-6b, ethanol, caustic alcohol, system nitrogen are added in reaction bulb
Protection lower room temperature reaction 12-16 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Add ammonium chloride solution, ethyl acetate
Extraction three times, merges organic phase, and saturated common salt is washed once, and anhydrous sodium sulfate drying, solvent evaporated, column chromatography obtains faint yellow
Liquid, as compound s 6-6c.
8. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 13 specifically include following steps：Compound s 6-6c, compound s 6-4d, cesium carbonate, the tert-butyl alcohol, system are put into reaction bulb
Nitrogen protection reaction 12-16 hours, reaction temperature are 30-40 DEG C, and LCMS monitoring display reactions are complete, post-reaction treatment：Chlorination
Change aqueous ammonium, ethyl acetate extracts three times, is washed once, anhydrous sodium sulfate drying, is steamed with saturated common salt after merging organic phase
Dry solvent, gained grease silica gel breading column chromatography (petrol ether/ethyl acetate=10%-30%) obtain white solid, are
Compound s 6-6d；
The step 14 specifically includes following steps：Compound s 6-6d, cesium carbonate, bi triphenyl are sequentially added in single port bottle
Phosphorus palladium chloride, DMF, water, compound s 6-3e, system nitrogen displacement, are heated to 65-75 DEG C in oil bath
React 1-3 hours, LCMS monitoring display reactions are complete, post-reaction treatment：Water quenching is added to go out reaction, ethyl acetate extraction three times,
Merge organic phase, saturated common salt is washed once, anhydrous sodium sulfate drying, silica gel breading, is spin-dried for column chromatography (petroleum ether/acetic acid second
Ester=0-20%), obtain yellow solid, as compound s 6-6e.
9. Mutiple Targets micromolecular compound S63845 according to claim 1 preparation method, it is characterised in that the step
Rapid 15 specifically include following steps：Compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, carbonic acid are put into reaction bulb
Double [di-t-butyl-(4- dimethylaminophenyls) phosphine] palladiums (II) of caesium, dichloro, the protection isothermal reaction of system nitrogen, LCMS monitoring
Display reaction is complete, post-reaction treatment：Saturated common salt water washing three times, anhydrous sodium sulfate drying, is spin-dried for, column chromatography (dichloromethane
Alkane/methanol=0-5%), obtain yellow, viscous liquid, as compound s 6-6f；
The step 16 specifically includes following steps：Sequentially added in reaction bulb compound s 6-6f, 1,4- dioxane, water,
Lithium hydroxide monohydrate reacts at room temperature 1 hour, and LCMS monitoring displays reaction is complete, post-reaction treatment:It is spin-dried for removing 1,4- bis-
The ring of oxygen six, methyl tertiary butyl ether(MTBE) is added, three times, it is 7 that aqueous phase is adjusted to pH value with hydrochloric acid, then is extracted with dichloromethane, is merged for extraction
Organic phase, anhydrous sodium sulfate drying are spin-dried for obtaining crude product, and compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC.
10. Mutiple Targets micromolecular compound S63845 according to claim 9 preparation method, it is characterised in that described
85-95 DEG C of constant temperature in step 15, preferably 90 DEG C, reaction time are 1-3 hours, preferably 2 hours.
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| CN115813929A (en) * | 2022-11-15 | 2023-03-21 | 暨南大学附属第一医院（广州华侨医院） | Application of S63845 in preparation of anti-influenza virus infection medicines |
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| US10676485B2 (en) | 2017-08-15 | 2020-06-09 | Abbvie Inc. | Macrocyclic MCL-1 inhibitors and methods of use |
| WO2020078875A1 (en) | 2018-10-15 | 2020-04-23 | Les Laboratoires Servier | New process for the synthesis of piperazinyl-ethoxy-bromophenyl derivates and their application in the production of compounds containing them |
| CN112930340A (en) * | 2018-10-15 | 2021-06-08 | 法国施维雅药厂 | Process for the synthesis of piperazinyl-ethoxy-bromophenyl derivatives and their use in the production of compounds containing them |
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| JP7448532B2 (en) | 2018-10-15 | 2024-03-12 | レ ラボラトワール セルヴィエ | New synthetic methods for piperazinyl-ethoxy-bromophenyl derivatives and their application in the production of compounds containing them |
| CN115804775A (en) * | 2022-11-15 | 2023-03-17 | 暨南大学附属第一医院（广州华侨医院） | Application of S63845 in preparation of anti-neocoronavirus infection medicine |
| CN115813929A (en) * | 2022-11-15 | 2023-03-21 | 暨南大学附属第一医院（广州华侨医院） | Application of S63845 in preparation of anti-influenza virus infection medicines |
| CN115804775B (en) * | 2022-11-15 | 2023-05-16 | 暨南大学附属第一医院（广州华侨医院） | Application of S63845 in preparation of medicines for resisting new coronavirus infection |
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| CN107573360B (en) | 2019-08-09 |
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