CN107573360B - A kind of preparation method of multiple target point small molecule compound S63845 - Google Patents
A kind of preparation method of multiple target point small molecule compound S63845 Download PDFInfo
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Abstract
The invention discloses the preparation methods of multiple target point small molecule compound S63845 a kind of, are related to chemosynthesis technical field.The application is improved by the synthetic route to compound s 6 3845, is reduced to 16 steps by 18 original steps, is reduced protecting group (THP) and deprotection base (THP) two-step reaction, is reduced cost of material, improves product economy benefit；The total recovery of compound s 6 3845 is significantly improved simultaneously, can achieve 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 fields, more specifically, it relates to a kind of multiple target point small molecule compound
The preparation method of S63845.
Background technique
MCL1 real name " granulocytic leukemia rush survival molecule " belongs to and inhibits Apoptosis BCL-2 molecule families.Inhibition is withered
Dying can be with power-assisted tumour, it all exists in numerous tumours is overexpressed phenomenon.There are no people successfully to produce such medicine so far
MCL1 micromolecular inhibitor.Many members of BCL-2 molecule families, including MCL1 have one " BH3 combination ditch ", and 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, secret formula are that it has found " power knob " with MCL1, and perhaps it becomes one of 21 century at last
The broad-spectrum anti-tumor medicine having a bright future.The compound that following chemical structural formula 1 indicates is the small molecule to attract attention very much
It closes object S63845 (CAS :).
Chemical structural formula 1
In prior art Nature, 2016, vol.538, p.477-482 (separately have a Publication No. EP2886545A1's
European patent) in disclose a kind of preparation method of compound, which carries out:
However the reaction route step number is long, the synthesis cycle time is long, and the linear synthesis step number of especially S6-4 to S6 is long, always
Low yield is only 4.7%, causes synthesis cost height.Therefore it is necessary to the highly efficient synthetic route of exploitation obtain this have it is huge
The small molecule compound of big business potential value.
Summary of the invention
In view of the deficiencies of the prior art, the present invention intends to provide a kind of multiple target point small molecule compound
18 steps of former route are shorten to 16 steps by improving by the preparation method of S63845, to solve the above problems, tool
The advantages of being improved total recovery, reducing by-product and reduce cost of material.
To achieve the above object, the present invention provides the following technical scheme that
A kind of preparation method of multiple target point small molecule compound S63845, comprising the following steps:
Step 1: the preparation of compound s 6-2b
Raw material compound S6-2, tri isopropyl chlorosilane, imidazoles, methylene chloride are added in reaction flask, stirs at room temperature
Reaction is mixed, post-reaction treatment obtains compound s 6-2b；
Step 2: the preparation of compound s 6-2c
N,N-diisopropylethylamine, tetrahydrofuran are added in the reactor, is cooled to -30 DEG C of dropwise additions after the displacement of system nitrogen
N-BuLi, stirring is cooled to the tetrahydrofuran solution of-78 DEG C of dropwise addition compound s 6-2b, stirring, then iodomethane is added dropwise, natural
Temperature reaction, post-reaction treatment obtain compound s 6-2c；
Step 3: the preparation of compound s 6-2d
Compound s 6-2c, tetrabutyl ammonium fluoride are put into reaction flask, reaction are stirred at room temperature under nitrogen protection, after reaction
Processing, obtains compound s 6-2d；
Step 4: the preparation of compound s 6-2e
Compound s 6-2d, 1- ethoxy-4- methyl piperazine, triphenyl phosphorus, note is added into reaction flask under nitrogen protection
Tert-butyl azodicarboxylate, heating stirring reaction are added after entering toluene stirring and dissolving and becoming limpid, post-reaction treatment obtains
Compound s 6-2e；
Step 5: the preparation of compound s 6-2f
Compound s 6-2e, tetrahydrofuran are put into reaction flask, system nitrogen protection is cooled to-78 DEG C of dropwise addition normal-butyls
Lithium is added and is reacted 1 hour at -78 DEG C, and isopropanol pinacol borate is added dropwise at -78 DEG C, adds stirring half at -78 DEG C
Hour, natural temperature reaction 12-16 hours, post-reaction treatment obtained compound s 6-2f；
Step 6: the preparation of compound s 6-3b
Acetic acid, sulfuric acid, water, compound s 6-3 are separately added into reaction flask under nitrogen protection, periodic acid, iodine list is added
Matter is heated with stirring to 60 DEG C and is reacted to raw material disappearance, and post-reaction treatment obtains compound s 6-3b；
Step 7: the preparation of compound s 6-3c
Phosphorus oxychloride, triethanolamine are sequentially added in reaction flask, and compound s 6-3b is added portionwise again after covering drying tube,
It is stirred at room temperature, is reacted 12-16 hours at 105 DEG C, post-reaction treatment obtains compound s 6-3c；
Step 8: the preparation of compound s 6-3d
Compound s 6-3c, N-bromosuccinimide, acetonitrile, fluoboric acid ether, system nitrogen are sequentially added in reaction flask
Gas shielded reacts at room temperature, post-reaction treatment, obtains compound s 6-3d；
Step 9: the preparation of compound s 6-5
By acetic acid -2- methylbenzene base ester, N-bromosuccinimide and hexamethylene be added beaker in, with vigorous stirring plus
Enter azodiisobutyronitrile and stir, reaction is mixed at 80 DEG C, post-reaction treatment obtains compound s 6-5；
Step 10: the preparation of compound s 6-6
Reaction flask is added in anhydrous lithium chloride and anhydrous zinc chloride, then drying 1 is small under 0.1mmHG pressure at 160 DEG C
When, it is cooled to room temperature under protection of argon gas, reaction flask is added in magnesium chip, is cooled to 0 DEG C of addition tetrahydrofuran in advance, mixture is existed
It is stirred 30 minutes under ice bath, forms the inorganic matter of precooling, then compound s 6-5 is dissolved in tetrahydrofuran, be added above-mentioned
The inorganic matter of precooling, stirring, temperature are maintained at 0-5 DEG C, add the toluene solution of glyoxylic acid ethyl ester, be stirred for mixing, and filter
Insoluble inorganic matter is removed, filtrate methanol dilution stirs the mixture for, and then addition acetic acid is distilled off molten under reduced pressure
Agent, post-reaction treatment, fractionation obtain compound s 6-6；
Step 11: the preparation of compound s 6-6b
Compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl are added in reaction flask
Phosphorus, toluene, tert-butyl azodicarboxylate, the reaction of system nitrogen protection, post-reaction treatment obtain compound s 6-6b；
Step 12: the preparation of compound s 6-6c
Compound s 6-6b, ethyl alcohol, sodium ethoxide are added in reaction flask, room temperature reaction 12-16 is small under system nitrogen protection
When, post-reaction treatment obtains compound s 6-6c；
Step 13: the preparation of compound s 6-6d
Compound s 6-6c, compound s 6-3d, cesium carbonate, the tert-butyl alcohol, the reaction of system nitrogen protection are put into reaction flask
12-16 hours, post-reaction treatment obtained compound s 6-6d；
Step 14: the preparation of compound s 6-6e
Compound s 6-6d, cesium carbonate, bi triphenyl phosphorus palladium chloride, N, N- dimethyl methyl are sequentially added in single port bottle
Amide, water, compound s 6-3e, the displacement of system nitrogen, heating reaction, post-reaction treatment obtain compound s 6-6e in oil bath；
Step 15: the preparation of compound s 6-6f
Compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, cesium carbonate, bis- [two uncles of dichloro are put into reaction flask
Butyl-(4- dimethylaminophenyl) phosphine] palladium (II), system nitrogen protection isothermal reaction, post-reaction treatment obtains compound
S6-6f；
Step 16: the preparation of compound s 6-6g
It is anti-that compound s 6-6f, 1,4- dioxane, water, lithium hydroxide monohydrate room temperature are sequentially added in reaction flask
It answers, post-reaction treatment, compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC；
The preparation method following reaction formula carries out:
Further preferably, the step 1 specifically includes the following steps: in reaction flask be added raw material compound S6-2,
Tri isopropyl chlorosilane, imidazoles, methylene chloride, the reaction system are stirred at room temperature 3 hours, thin-layer chromatography TLC, and petroleum ether/
Ethyl acetate=3/1 shows fully reacting, post-reaction treatment: saturated salt solution is first added, stands liquid separation, organic phase merges dense
Silica gel mixed sample is added in contracting, and column chromatography obtains colourless liquid, as compound s 6-2b；
The step 2 specifically includes the following steps: be added n,N-diisopropylethylamine, tetrahydrofuran, body in the reactor
It is to be cooled to -30 DEG C of dropwise addition n-BuLis after nitrogen is replaced, drips off and stir 45min under the conditions of -30-0 DEG C, be cooled to -78 DEG C
The tetrahydrofuran solution of compound s 6-2b is added dropwise, is stirred 1 hour under the conditions of-78 DEG C after dripping off, then under the conditions of-78 DEG C
Iodomethane is added dropwise again, natural temperature reaction 12-16 hours after adding, TLC shows fully reacting, post-reaction treatment: by reaction solution
It pours into ammonium chloride solution plus ethyl acetate liquid separation, water phase ethyl acetate is extracted twice, use saturated common salt again after merging organic phase
Washing is primary, and anhydrous sodium sulfate is dry, obtains yellow liquid, as compound s 6-2c after solvent evaporated.
Further preferably, the step 3 in reaction flask specifically includes the following steps: put into compound s 6-2c, four fourths
Base ammonium fluoride reinjects tetrahydrofuran, is stirred at room temperature under nitrogen protection 12-16 hours, and TLC shows that compound s 6-2c disappears, instead
It should post-process: saturated salt solution is added into reaction solution and ethyl acetate liquid separation, water phase are extracted with ethyl acetate twice, are associated with
Machine phase, then washed once with saturated common salt, addition silica gel dry powder mixes sample, column after anhydrous sodium sulfate dries, filters removing desiccant
Chromatography, petrol ether/ethyl acetate=2/1 obtains yellow liquid, as compound s 6-2d；
The step 4 into reaction flask specifically includes the following steps: be added compound s 6-2d, 1- hydroxyl under nitrogen protection
Ethyl -4- methyl piperazine, triphenyl phosphorus, injection toluene stirring and dissolving add tert-butyl azodicarboxylate after becoming limpid,
It is heated to 45-55 DEG C to be stirred to react 1-3 hours, TLC shows compound s 6-2d fully reacting, generates the product point that polarity increases
S6-2e, post-reaction treatment: being added 30% methanol hydrochloride solution and be stirred at room temperature two hours, filter to get filtrate, filter cake methyl- tert fourth
Base ether is beaten to obtain filtrate, and merging filtrate dry powder mixes sample, and column chromatography, methylene chloride/methanol=15/1 obtains yellow liquid, as
Compound s 6-2e.
Further preferably, the step 5 in reaction flask specifically includes the following steps: put into compound s 6-2e, tetrahydro
Furans, system nitrogen protection are cooled to -78 DEG C of dropwise addition n-BuLis, add and react 1 hour at -78 DEG C, are added dropwise at -78 DEG C
Isopropanol pinacol borate, adds and stirs half an hour at -78 DEG C, and natural temperature reaction 12-16 hours, TLC display reaction
Completely, post-reaction treatment: reaction solution being poured into ammonium chloride solution and is quenched, and ethyl acetate, water is added to extract 3 merging organic phases,
Saturated common salt washing is primary, and anhydrous sodium sulfate is dry, is spin-dried for, obtains liquid, as compound s 6-2f；
The step 6 specifically includes the following steps: be separately added under nitrogen protection into reaction flask acetic acid, sulfuric acid, water,
Compound s 6-3 is added periodic acid, elemental iodine, is heated with stirring to 60 DEG C and is reacted, LCMS monitoring display reaction after two hours
Raw material disappears, and post-reaction treatment: being cooled to room temperature, filtering, the elution of 15% acetic acid aqueous solution, and petroleum ether elution is spin-dried for obtaining Huang
Color solid, as compound s 6-3b.
Further preferably, the step 7 in reaction flask specifically includes the following steps: sequentially add phosphorus oxychloride, three
Ethanol amine is added portionwise compound s 6-3b after covering drying tube again, after 10min is stirred at room temperature, reacts 12-16 hours at 105 DEG C,
LCMS monitoring display fully reacting, post-reaction treatment: room temperature filtering, filter cake are poured into water, and 5min is stirred at room temperature in cooling on the rocks,
Filtering washing, petroleum ether elution, drains for 50 DEG C to obtain yellow solid, as compound s 6-3c；
The step 8 in reaction flask specifically includes the following steps: sequentially add compound s 6-3c, N- bromo succinyl
Imines, acetonitrile, fluoboric acid ether, system nitrogen protection react at room temperature 8 hours, LCMS monitoring display fully reacting, after reaction
Reason: room temperature filtering, filter cake are eluted with acetonitrile, drain for 50 DEG C to obtain yellow solid, as compound s 6-3d.
Further preferably, the step 9 is specifically includes the following steps: by acetic acid -2- methylbenzene base ester, N- bromo amber
Acid imide and hexamethylene are added in beaker, and azodiisobutyronitrile is then added with vigorous stirring and stirs 30 minutes, at 80 DEG C
Until not being further observed that conversion, post-reaction treatment: being then cooled to room temperature, and is filtered to remove sediment simultaneously for lower mixing
Filtrate is washed with hexamethylene, obtains compound s 6-5.
Further preferably, the step 11 in reaction flask specifically includes the following steps: be added compound s 6-6, (5-
(1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl phosphorus, toluene, tert-butyl azodicarboxylate, system nitrogen guarantor
Shield reaction 12-16 hours, 45-55 DEG C of reaction temperature, LCMS monitors fully reacting, post-reaction treatment: silica gel dry powder is added and mixes sample,
Column chromatography, petrol ether/ethyl acetate=20% obtain weak yellow liquid, as compound s 6-6b；
The step 12 in reaction flask specifically includes the following steps: be added compound s 6-6b, ethyl alcohol, sodium ethoxide, system
It is reacted at room temperature 12-16 hours under nitrogen protection, post-reaction treatment: LCMS monitoring display fully reacting adds ammonium chloride solution, acetic acid
Ethyl ester extracts three times, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry, and solvent evaporated, column chromatographs to obtain light
Yellow liquid, as compound s 6-6c.
Further preferably, the step 13 in reaction flask specifically includes the following steps: putting into compound s 6-6c, changing
Object S6-3d, cesium carbonate, the tert-butyl alcohol are closed, system nitrogen protection is reacted 12-16 hours, and reaction temperature is 30-40 DEG C, LCMS monitoring
It shows fully reacting, post-reaction treatment: adding aqueous ammonium chloride solution, ethyl acetate extracts three times, uses saturation food after merging organic phase
Salt washing is primary, and anhydrous sodium sulfate is dry, solvent evaporated, gained grease silica gel breading column chromatography, and petrol ether/ethyl acetate=
10%-30% obtains white solid, as compound s 6-6d；
The step 14 in single port bottle specifically includes the following steps: sequentially add compound s 6-6d, cesium carbonate, double three
Phenyl phosphorus palladium chloride, n,N-Dimethylformamide, water, compound s 6-3e, the displacement of system nitrogen, are heated to 65- in oil bath
75 DEG C reaction 1-3 hours, LCMS monitoring display fully reacting, post-reaction treatment: be added water quenching reaction, ethyl acetate extraction three
It is secondary, merge organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry, silica gel breading, revolves dry chromatography, petroleum ether/acetic acid
Ethyl ester=0-20% obtains yellow solid, as compound s 6-6e.
Further preferably, the step 15 in reaction flask specifically includes the following steps: putting into compound s 6-6e, changing
Close object S6-2f, tetrahydrofuran, water, cesium carbonate, bis- [di-t-butyl-(4- dimethylaminophenyl) phosphine] palladiums (II) of dichloro, system
Nitrogen protection isothermal reaction, LCMS monitoring display fully reacting, post-reaction treatment: saturated common salt water washing three times, anhydrous slufuric acid
Sodium is dry, is spin-dried for, and column chromatography, methylene chloride/methanol=0-5% obtains yellow, viscous liquid, as compound s 6-6f；
The step 16 in reaction flask specifically includes the following steps: sequentially add compound s 6-6f, 1,4- dioxy six
Ring, water, lithium hydroxide monohydrate react at room temperature 1 hour, post-reaction treatment: LCMS monitoring display fully reacting is spin-dried for removing
Methyl tertiary butyl ether(MTBE) is added in Isosorbide-5-Nitrae-dioxane, and three times, it is 7 that water phase, which is adjusted to pH value with hydrochloric acid, then is extracted with methylene chloride for extraction
It takes, merges organic phase, anhydrous sodium sulfate is dry, is spin-dried for obtaining crude product, compound s 6-6g, i.e. product is prepared in chiral HPLC
S63845。
Further preferably, 85-95 DEG C of constant temperature in the step 15, preferably 90 DEG C, the reaction time is 1-3 hours, excellent
It is selected as 2 hours.
By using above-mentioned technical proposal, step 1-2 is identical, step 6-8 and former route steps 5-7 phase with former route
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 protecting 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 achieve
5.7-6.7%, purity 98%, product economy benefit are significantly improved.
The invention has the following advantages:
(1) the application is improved by the synthetic route to compound s 6 3845, is reduced to 16 steps by 18 original steps,
Reduce protecting group (THP) and deprotection base (THP) two-step reaction, reduce cost of material, improves product economy benefit；
(2) the application significantly improves the total recovery of compound s 6 3845, can achieve 5.7-6.7%, is higher than existing skill
4.7% total recovery in art.
Detailed description of the invention
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.
Specific embodiment
With reference to the accompanying drawings and examples, the present invention will be described in detail.Unless stated otherwise, institute in following embodiment
Reagent and instrument are commercially available product and laboratory conventional instrument.Wherein the medicine intermediate in reaction process is purchased from
Shanghai Bepharm Science & Technology Co., Ltd. and Town in Shanghai Nai Ji Chemical Co., Ltd..
Embodiment 1: as shown in Fig. 2, a kind of preparation method of multiple target point small molecule compound S63845, including following step
It is rapid:
Step 1: the preparation of compound s 6-2b
Raw material 143g compound s 6-2,159.8g tri isopropyl chlorosilane, 117.4g imidazoles, 1.2L are added in reaction flask
Methylene chloride, the reaction system are stirred at room temperature 3 hours, and thin-layer chromatography TLC (petrol ether/ethyl acetate=3/1) display is anti-
Should completely, post-reaction treatment: being first added saturated salt solution 500mL, stands liquid separation, and organic phase merges concentration and silica gel mixed sample is added,
Column chromatography obtains 240g colourless liquid, as compound s 6-2b, yield 96%.
Step 2: the preparation of compound s 6-2c
100mL n,N-diisopropylethylamine, 1L tetrahydrofuran are added in the reactor, be cooled to after the displacement of system nitrogen-
30 DEG C of dropwise addition 277mL n-BuLis, drip off and stir 45min under the conditions of-30-0 DEG C, are cooled to-78 DEG C of dropwise addition compound s 6-2b
Tetrahydrofuran solution 600mL, stirred 1 hour under the conditions of -78 DEG C after dripping off, 112g be then added dropwise again under the conditions of -78 DEG C
Iodomethane, natural temperature reaction 12-16 hours after adding, TLC shows fully reacting, and post-reaction treatment: reaction solution is poured into
In 800mL ammonium chloride solution plus ethyl acetate 500mL liquid separation, water phase ethyl acetate 500mL are extracted twice, after merging organic phase again
Primary with the washing of 700mL saturated common salt, anhydrous sodium sulfate is dry, obtains 250g yellow liquid, as compound after solvent evaporated
S6-2c, yield 98%.
The preparation of step 3:S6-2d
263g compound s 6-2c, 191.1g tetrabutyl ammonium fluoride are put into reaction flask, reinject 1.32L tetrahydrofuran,
It is stirred at room temperature under nitrogen protection 12-16 hours, TLC shows that compound s 6-2c disappears, and generates the product S6- that a polarity becomes larger
Post-reaction treatment: 2d saturated salt solution 1.0L and ethyl acetate 500mL liquid separation, water phase ethyl acetate is added into reaction solution
300mL is extracted twice, and merges organic phase, then washed once with saturated salt solution 500mL, and it is dry that anhydrous sodium sulfate dries, filters removing
Silica gel dry powder is added after drying prescription and mixes sample, column chromatography (petrol ether/ethyl acetate=2/1) obtains 146g yellow liquid, as chemical combination
Object S6-2d, yield 95%.
Step 4: the preparation of compound s 6-2e
Compound 31gS6-2d, 33g1- ethoxy -4- methyl piperazine, 60g tri- is added into reaction flask under nitrogen protection
Phenyl phosphorus, injection 625mL toluene stirring and dissolving add 52.7g tert-butyl azodicarboxylate after becoming limpid, are heated to 50
It DEG C is stirred to react 2 hours, TLC shows compound s 6-2d fully reacting, the product point S6-2e that polarity increases is generated, after reaction
Reason: 30% methanol hydrochloride solution 300mL is added and is stirred at room temperature two hours, filters 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 liquid, as compound
S6-2e, yield 57%.
Step 5: the preparation of compound s 6-2f
22g compound s 6-2e, 500mL tetrahydrofuran are put into reaction flask, system nitrogen protection is cooled to-78 DEG C of drops
Add 50.6mL n-BuLi, add and reacted 1 hour at -78 DEG C, 28.4g isopropanol pinacol borate is added dropwise at -78 DEG C,
It adds and is stirred half an hour at -78 DEG C, natural temperature reaction 12-16 hours, TLC showed fully reacting, post-reaction treatment: will be anti-
It answers liquid to pour into 200mL ammonium chloride solution to be quenched, 250mL ethyl acetate, 100mL water is added to extract 3 merging organic phases, 200mL
Saturated common salt washing is primary, and anhydrous sodium sulfate is dry, is spin-dried for, obtains 20.8g liquid, as compound s 6-2f, yield 84%.
Step 6: the preparation of compound s 6-3b
1.8L acetic acid, 53mL sulfuric acid, 356mL water, 284g compound are separately added into 5L reaction flask under nitrogen protection
S6-3 is added 213g periodic acid, 427g elemental iodine, is heated with stirring to 60 DEG C and is reacted, and LCMS monitoring display is anti-after two hours
It answers raw material to disappear, post-reaction treatment: being cooled to room temperature, filter, the elution of 300mL15% acetic acid aqueous solution, the leaching of 200mL petroleum ether
It washes, is spin-dried for obtaining 459g yellow solid, as compound s 6-3b, yield 88%.
Step 7: the preparation of Compound Compound S6-3c
688mL phosphorus oxychloride, 183g triethanolamine are sequentially added in 2L reaction flask, are added portionwise again after covering drying tube
459g compound s 6-3b after 10min is stirred at room temperature, reacts 12-16 hours at 105 DEG C, LCMS monitoring display fully reacting, instead
Should post-process: room temperature filtering, filter cake pour into 500mL water, cooling on the rocks, and 5min, filter 23 00mL washing, 300mL is stirred at room temperature
Petroleum ether elution, drains for 50 DEG C to obtain 300g yellow solid, as compound s 6-3c, yield 61%.
Step 8: the preparation of compound s 6-3d
338g compound s 6-3c, 203g N-bromosuccinimide, 2.4L acetonitrile, 50mL are sequentially added in reaction flask
Fluoboric acid ether, LCMS monitors the complete 40g N-bromosuccinimide of adding of unreacted and stays overnight after 5 hours, and LCMS is supervised after 1 hour
Unreacted is complete adds 40g N-bromosuccinimide for control, and unreacted is complete adds 50g N- bromo amber for LC-MS monitoring after 1 hour
Acid imide, LC-MS monitoring unreacted is complete after 2 hours adds 50g N-bromosuccinimide, and LCMS monitoring shows fully reacting,
Post-reaction treatment: room temperature filtering, filter cake are eluted with 400mL acetonitrile, drain for 50 DEG C to obtain 379g yellow solid, as compound
S6-3d, yield 88%.
Step 9: the preparation of compound s 6-5
1L is added in 60.07g acetic acid -2- methylbenzene base ester, 106.8g N-bromosuccinimide and 500ml hexamethylene
In flask, 3.284g azodiisobutyronitrile is then added with vigorous stirring and stirs 30 minutes, is mixed at 80 DEG C straight
To conversion is not further observed that, post-reaction treatment: being then cooled to room temperature, and is filtered to remove sediment and is washed with hexamethylene
Filtrate obtains compound s 6-5, yield 90%.
Step 10: the preparation of compound s 6-6
2L reaction flask is added in 23.10g anhydrous lithium chloride and 65.36g anhydrous zinc chloride, then the 0.1mmHG at 160 DEG C
1 hour dry under pressure, protection is cooled to room temperature under argon gas, and reaction flask is added in 26.49g magnesium chip, is cooled to 0 DEG C of addition in advance
Mixture is stirred 30 minutes under ice bath, forms the inorganic matter of precooling by tetrahydrofuran；Then by 100g2- (bromomethyl) second
Acid phenenyl ester (S6-5) is dissolved in 120mL tetrahydrofuran, and the inorganic matter of above-mentioned precooling, the mixing of generation are added in 15 minutes
Object stirs 45 minutes, and temperature is maintained between 0-5 DEG C, adds the toluene solution of 64.82mL glyoxylic acid ethyl ester in 5 minutes, then
It is stirred 15 minutes, is then removed by filtration insoluble inorganic matter, filtrate is stirred mixture with the methanol dilution of 500mL
It mixes, 30mL acetic acid fugitive constituent is then added, solvent is distilled off under reduced pressure, 350mL water, mixture acetic acid second is then added
Ester extracts, then washes organic phase with saturated sodium bicarbonate aqueous solution, and anhydrous sodium sulfate dries, filters, filtrate decompression concentration, then
100mL n-hexane is added, is stirred 30 minutes at 0 DEG C, using filtering and WATER-WASHING METHOD, fractionation obtains white crystal, as chemical combination
Object S6-6, yield 40%.
Step 11: the preparation of compound s 6-6b
10.0g compound s 6-6,14.3g (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) are added in 500mL reaction flask
Base) methanol, 20.8g triphenyl phosphorus, 200mL toluene, 18.3g tert-butyl azodicarboxylate, it is small that system nitrogen protection reacts 12
When, 50 DEG C of reaction temperature, LCMS monitors fully reacting, post-reaction treatment: 50g silica gel dry powder is added and mixes sample, column chromatographs (petroleum
Ether/ethyl acetate=20%) obtain 10.0g weak yellow liquid, as compound s 6-6b, yield: 60%.
Step 12: the preparation of compound s 6-6c
10g compound s 6-6b, 50mL ethyl alcohol, 0.08g sodium ethoxide, room temperature under system nitrogen protection are added in reaction flask
Post-reaction treatment: reaction 12-16 hours, LCMS monitoring display fully reacting add 100mL ammonium chloride solution, ethyl acetate extraction
Three times, merge organic phase, the washing of 60mL saturated common salt is primary, and anhydrous sodium sulfate is dry, solvent evaporated, and column chromatographs to obtain 8.8g light
Yellow liquid, as compound s 6-6c, yield 98%.
Step 13: the preparation (since step 13 and step 14 merge, being not drawn into the structural formula of S6-6d) of compound s 6-6d
In 500mL reaction flask put into 16.6g compound s 6-6c, 15.2g compound s 6-3d, 18.5g cesium carbonate,
The 300mL tert-butyl alcohol, system nitrogen protection are reacted 12-16 hours, and reaction temperature is 35 DEG C, LCMS monitoring display fully reacting, instead
It should post-process: add 1.5L aqueous ammonium chloride solution, 300mL ethyl acetate extracts three times, uses 300mL saturated common salt after merging organic phase
Washing is primary, and anhydrous sodium sulfate is dry, solvent evaporated, gained grease silica gel breading column chromatography (petrol ether/ethyl acetate=
10%-30%) obtain 24.5g white solid, as compound s 6-6d, yield 85%.
Step 14: the preparation of compound s 6-6e
12g compound s 6-6d, 8.3g cesium carbonate, 1.2g bi triphenyl phosphorus dichloride are sequentially added in 500mL single port bottle
Palladium, 200mLN, dinethylformamide, 40mL water, 8g compound s 6-3e, the displacement of system nitrogen are heated to 70 DEG C in oil bath
Reaction 2 hours, is placed at room temperature for 12-16 hours, and LCMS monitoring display fully reacting, post-reaction treatment: being added 1L water quenching reaction,
300mL ethyl acetate extracts three times, merges organic phase, and the washing of 300mL saturated common salt is primary, and anhydrous sodium sulfate is dry, and silica gel is mixed
Powder revolves dry chromatography (petrol ether/ethyl acetate=0-20%), obtains 20.8g yellow solid, as compound s 6-6e, yield
92%.
Step 15: the preparation of compound s 6-6f
In 1L reaction flask put into 18g compound s 6-6e, 18g compound s 6-2f, 360mL tetrahydrofuran, 120mL water,
Bis- [di-t-butyl-(4- dimethylaminophenyl) phosphine] palladiums (II) of 14.9g cesium carbonate, 0.76g dichloro, system nitrogen protection constant temperature
90 DEG C react 2 hours, LCMS monitoring display fully reacting, post-reaction treatment: saturated common salt water washing three times (400mL × 3), nothing
Aqueous sodium persulfate is dry, is spin-dried for, and column chromatographs (methylene chloride/methanol=0-5%), obtains 20.5g yellow, viscous liquid, as changes
Close object S6-6f, yield 89%.
Step 16: the preparation of compound s 6-6g
22g compound s 6-6f, 220mL1,4- dioxane, 220mL water, 7.54g hydrogen are sequentially added in 1L reaction flask
Lithia monohydrate reacts at room temperature 1 hour, post-reaction treatment: LCMS monitoring display fully reacting is spin-dried for removing Isosorbide-5-Nitrae-dioxy
100mL methyl tertiary butyl ether(MTBE) is added in six rings, and three times, it is 7 that water phase, which is adjusted to pH value with 1mol hydrochloric acid, then with 150mL dichloromethane for extraction
Alkane extraction merges organic phase, and anhydrous sodium sulfate is dry, is spin-dried for obtaining 15g crude product, 10g compound s 6-is prepared in chiral HPLC
6g, 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 preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In being heated to 45 DEG C in step 4.
Embodiment 3: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In being heated to 55 DEG C in step 4.
Embodiment 4: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 1 hour in step 4.
Embodiment 5: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 3 hours in step 4.
Embodiment 6: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 14 hours in step 11.
Embodiment 7: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 16 hours in step 11.
Embodiment 8: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 45 DEG C in step 11.
Embodiment 9: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 55 DEG C in step 11.
Embodiment 10: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 30 DEG C in step 13.
Embodiment 11: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 40 DEG C in step 13.
Embodiment 12: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In oil bath heating is to 65 DEG C in step 14.
Embodiment 13: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In oil bath heating is to 75 DEG C in step 14.
Embodiment 14: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 1 hour in step 14.
Embodiment 15: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 3 hours in step 14.
Embodiment 16: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In 85 DEG C of constant temperature in step 15.
Embodiment 17: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In 95 DEG C of constant temperature in step 15.
Embodiment 18: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 1 hour in step 15.
Embodiment 19: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In the reaction time is 3 hours in step 15.
Comparative example 1: using method prepare compound S63845 disclosed in European patent EP 2886545A1, preparation method
Reaction equation as shown in Figure 1 carries out.
Comparative example 2: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In being heated to 40 DEG C in step 4.
Comparative example 3: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 40 DEG C in step 11.
Comparative example 4: a kind of preparation method of multiple target point small molecule compound S63845 exists with the difference of embodiment 1
In reaction temperature is 25 DEG C in step 13.
Comparative example 5: a kind of preparation method of multiple target point small molecule compound S63845 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 preparation method of multiple target point small molecule compound S63845 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 comparison
The compound s 6 3845 obtained in example 1-6 is used as control sample 1-6, calculates separately test specimen 1-19's and control sample 1-6
Total recovery simultaneously measures its purity, and total recovery is the product of every step yield in step 9-16.
Test result: the measurement result of test specimen 1-19 and control sample 1-6 are as shown in table 1.As seen from table, control sample
The total recovery of product 1-6 is 4.7-5.3%, and purity is 96.5 or so；The total recovery of test specimen 1-19 is 5.7-6.7%, is higher than
Control sample 1, purity are higher than control sample 1-6 98% or so.Illustrate that the application passes through the synthesis road to compound s 6 3845
Line improves, and significantly improves the total recovery of compound s 6 3845, while preparation method is reduced to 16 steps by 18 original steps,
Reduce protecting group (THP) and deprotection base (THP) two-step reaction, reduce cost of material, improves product economy benefit.
The measurement result of table 1 test specimen 1-19 and control sample 1-6
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (11)
1. a kind of preparation method of multiple target point small molecule compound S63845, which comprises the following steps:
Step 1: the preparation of compound s 6-2b
Raw material compound S6-2, tri isopropyl chlorosilane, imidazoles, methylene chloride are added in reaction flask, is stirred at room temperature anti-
It answers, post-reaction treatment, obtains compound s 6-2b；
Step 2: the preparation of compound s 6-2c
N,N-diisopropylethylamine, tetrahydrofuran are added in the reactor, is cooled to -30 DEG C after the displacement of system nitrogen and positive fourth is added dropwise
Base lithium, stirring is cooled to the tetrahydrofuran solution of-78 DEG C of dropwise addition compound s 6-2b, stirring, then iodomethane is added dropwise, and heats up naturally
Reaction, post-reaction treatment obtain compound s 6-2c；
Step 3: the preparation of compound s 6-2d
Compound s 6-2c, tetrabutyl ammonium fluoride are put into reaction flask, are stirred at room temperature reaction under nitrogen protection, post-reaction treatment,
Obtain compound s 6-2d；
Step 4: the preparation of compound s 6-2e
Compound s 6-2d, 1- ethoxy-4- methyl piperazine, triphenyl phosphorus is added into reaction flask under nitrogen protection, injects first
Benzene stirring and dissolving adds tert-butyl azodicarboxylate, heating stirring reaction after becoming limpid, post-reaction treatment obtains chemical combination
Object S6-2e；
Step 5: the preparation of compound s 6-2f
Compound s 6-2e, tetrahydrofuran are put into reaction flask, system nitrogen protection is cooled to-78 DEG C of dropwise addition n-BuLis, adds
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 obtained compound s 6-2f；
Step 6: the preparation of compound s 6-3b
Acetic acid, sulfuric acid, water, compound s 6-3 are separately added into reaction flask under nitrogen protection, periodic acid, elemental iodine is added,
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: the preparation of compound s 6-3c
Phosphorus oxychloride, triethanolamine are sequentially added in reaction flask, and compound s 6-3b, room temperature are added portionwise again after covering drying tube
Stirring, reacts 12-16 hours, post-reaction treatment obtains compound s 6-3c at 105 DEG C；
Step 8: the preparation of compound s 6-3d
Compound s 6-3c, N-bromosuccinimide, acetonitrile, fluoboric acid ether are sequentially added in reaction flask, system nitrogen is protected
Shield is reacted at room temperature, and post-reaction treatment obtains compound s 6-3d；
Step 9: the preparation of compound s 6-5
Acetic acid -2- methylbenzene base ester, N-bromosuccinimide and hexamethylene are added in beaker, are added with vigorous stirring even
Nitrogen bis-isobutyronitrile simultaneously stirs, and reaction is mixed at 80 DEG C, and post-reaction treatment obtains compound s 6-5；
Step 10: the preparation of compound s 6-6
Reaction flask is added in anhydrous lithium chloride and anhydrous zinc chloride, it is then 1 hour dry under 0.1mmHG pressure at 160 DEG C,
It is cooled to room temperature under argon gas protection, reaction flask is added in magnesium chip, 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, above-mentioned pre-cooling is added
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, filtering removal
Insoluble inorganic matter, filtrate methanol dilution, stirs the mixture for, and acetic acid is then added, solvent is distilled off under reduced pressure, instead
It should post-process, fractionation obtains compound s 6-6；
Step 11: the preparation of compound s 6-6b
Compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base) methanol, triphenyl phosphorus, first are added in reaction flask
Benzene, tert-butyl azodicarboxylate, the reaction of system nitrogen protection, post-reaction treatment obtain compound s 6-6b；
Step 12: the preparation of compound s 6-6c
Compound s 6-6b, ethyl alcohol, sodium ethoxide are added in reaction flask, reacts at room temperature 12-16 hours under system nitrogen protection, instead
It should post-process, obtain compound s 6-6c；
Step 13: the preparation of compound s 6-6d
Compound s 6-6c, compound s 6-3d, cesium carbonate, the tert-butyl alcohol are put into reaction flask, system nitrogen protection reacts 12-16
Hour, post-reaction treatment obtains compound s 6-6d；
Step 14: the preparation of compound s 6-6e
Sequentially added in single port bottle compound s 6-6d, cesium carbonate, bi triphenyl phosphorus palladium chloride, n,N-Dimethylformamide,
Water, compound s 6-3e, the displacement of system nitrogen, heating reaction, post-reaction treatment obtain compound s 6-6e in oil bath；
Step 15: the preparation of compound s 6-6f
Compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, cesium carbonate, the bis- [di-t-butyls-of dichloro are put into reaction flask
(4- dimethylaminophenyl) phosphine] palladium (II), system nitrogen protection isothermal reaction, post-reaction treatment obtains compound s 6-6f；
Step 16: the preparation of compound s 6-6g
Compound s 6-6f, Isosorbide-5-Nitrae-dioxane, water, lithium hydroxide monohydrate room temperature reaction are sequentially added in reaction flask, instead
It should post-process, compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC；
The preparation method following reaction formula carries out:
2. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 1 in reaction flask specifically includes the following steps: be added raw material compound S6-2, tri isopropyl chlorosilane, imidazoles, dichloromethane
Alkane, the reaction system are stirred at room temperature 3 hours, thin-layer chromatography TLC, petrol ether/ethyl acetate=3/1, show fully reacting,
Post-reaction treatment: being first added saturated salt solution, stands liquid separation, and organic phase merges concentration and silica gel mixed sample is added, and column chromatography obtains
Colourless liquid, as compound s 6-2b；
The step 2 specifically includes the following steps: be added n,N-diisopropylethylamine, tetrahydrofuran, system nitrogen in the reactor
- 30 DEG C of dropwise addition n-BuLis are cooled to after gas displacement, drips off and stirs 45min under the conditions of -30-0 DEG C, be cooled to -78 DEG C of dropwise additions
The tetrahydrofuran solution of compound s 6-2b is stirred 1 hour under the conditions of-78 DEG C after dripping off, is then dripped again under the conditions of-78 DEG C
Add iodomethane, natural temperature reaction 12-16 hours after adding, TLC shows fully reacting, and post-reaction treatment: reaction solution is poured into
In ammonium chloride solution plus ethyl acetate liquid separation, water phase ethyl acetate are extracted twice, and are washed again with saturated common salt after merging organic phase
Once, anhydrous sodium sulfate is dry, obtains yellow liquid, as compound s 6-2c after solvent evaporated.
3. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 3 specifically includes the following steps: in reaction flask put into compound s 6-2c, tetrabutyl ammonium fluoride, reinject tetrahydrofuran, nitrogen
It is stirred at room temperature 12-16 hours, TLC shows that compound s 6-2c disappears, post-reaction treatment: being added into reaction solution full under gas shielded
With saline solution and ethyl acetate liquid separation, water phase is extracted with ethyl acetate twice, merges organic phase, then wash one with saturated common salt
Secondary, addition silica gel dry powder mixes sample, column chromatography, petrol ether/ethyl acetate=2/ after anhydrous sodium sulfate dries, filters removing desiccant
1, obtain yellow liquid, as compound s 6-2d；
The step 4 into reaction flask specifically includes the following steps: be added compound s 6-2d, 1- ethoxy-under nitrogen protection
4- methyl piperazine, triphenyl phosphorus, injection toluene stirring and dissolving add tert-butyl azodicarboxylate after becoming limpid, are heated to
45-55 DEG C is stirred to react 1-3 hours, and TLC shows compound s 6-2d fully reacting, generates the product point S6-2e that polarity increases,
Post-reaction treatment: 30% methanol hydrochloride solution is added and is stirred at room temperature two hours, filters 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. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 5 in reaction flask specifically includes the following steps: put into compound s 6-2e, tetrahydrofuran, and system nitrogen protection 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 -
It is stirred half an hour at 78 DEG C, natural temperature reaction 12-16 hours, TLC shows fully reacting, and post-reaction treatment: reaction solution is fallen
Enter in ammonium chloride solution and be quenched, adds ethyl acetate, water to extract 3 merging organic phases, saturated common salt washing is primary, anhydrous sodium sulfate
It is dry, it is spin-dried for, obtains liquid, as compound s 6-2f；
The step 6 into reaction flask specifically includes the following steps: be separately added into acetic acid, sulfuric acid, water, chemical combination under nitrogen protection
Object S6-3 is added periodic acid, elemental iodine, is heated with stirring to 60 DEG C and is reacted, LCMS monitoring display reaction raw materials after two hours
It disappears, post-reaction treatment: being cooled to room temperature, filtering, the elution of 15% acetic acid aqueous solution, and it is solid to be spin-dried for obtaining yellow for petroleum ether elution
Body, as compound s 6-3b.
5. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 7 in reaction flask specifically includes the following steps: sequentially add phosphorus oxychloride, triethanolamine, is added portionwise again after covering drying tube
Compound s 6-3b after 10min is stirred at room temperature, reacts 12-16 hours at 105 DEG C, LCMS monitoring display fully reacting, after reaction
Processing: room temperature filtering, filter cake are poured into water, cooling on the rocks, 5min are 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 the following steps: sequentially added in reaction flask compound s 6-3c, N-bromosuccinimide,
Acetonitrile, fluoboric acid ether, system nitrogen protection react at room temperature 8 hours, LCMS monitoring display fully reacting, 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. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 9 specifically includes the following steps: acetic acid -2- methylbenzene base ester, N-bromosuccinimide and hexamethylene are added in beaker, so
Azodiisobutyronitrile is added with vigorous stirring afterwards and stirs 30 minutes, is mixed at 80 DEG C until not further looking at
To conversion, post-reaction treatment: being then cooled to room temperature, and is filtered to remove sediment and is washed filtrate with hexamethylene, obtains compound
S6-5。
7. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 11 in reaction flask specifically includes the following steps: be added compound s 6-6, (5- (1- (2,2,2 ,-trifluoroethyl) pyrazoles) base)
Methanol, triphenyl phosphorus, toluene, tert-butyl azodicarboxylate, system nitrogen protection are reacted 12-16 hours, reaction temperature 45-55
DEG C, LCMS monitors fully reacting, post-reaction treatment: silica gel dry powder is added and mixes sample, column chromatographs, petrol ether/ethyl acetate=20%,
Obtain weak yellow liquid, as compound s 6-6b；
The step 12 in reaction flask specifically includes the following steps: be added compound s 6-6b, ethyl alcohol, sodium ethoxide, system nitrogen
Protection lower room temperature reaction 12-16 hours, LCMS monitoring display fully reacting, post-reaction treatment: adding ammonium chloride solution, ethyl acetate
Extraction three times, merges organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry, and solvent evaporated, column chromatographs to obtain faint yellow
Liquid, as compound s 6-6c.
8. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 13 in reaction flask specifically includes the following steps: put into compound s 6-6c, compound s 6-3d, cesium carbonate, the tert-butyl alcohol, system
Nitrogen protection is reacted 12-16 hours, and reaction temperature is 30-40 DEG C, LCMS monitoring display fully reacting, post-reaction treatment: chlorination
Change aqueous ammonium, ethyl acetate extracts three times, is washed once after merging organic phase with saturated common salt, anhydrous sodium sulfate is dry, steams
Dry solvent, gained grease silica gel breading column chromatography, petrol ether/ethyl acetate=10%-30% obtain white solid, as
Compound s 6-6d；
The step 14 in single port bottle specifically includes the following steps: sequentially add compound s 6-6d, cesium carbonate, bi triphenyl
Phosphorus palladium chloride, n,N-Dimethylformamide, water, compound s 6-3e, the displacement of system nitrogen, are heated to 65-75 DEG C in oil bath
Reaction 1-3 hours, LCMS monitoring display fully reacting, post-reaction treatment: being added water quenching reaction, and ethyl acetate extracts three times,
Merge organic phase, saturated common salt washing is primary, and anhydrous sodium sulfate is dry, silica gel breading, revolves dry chromatography, petroleum ether/acetic acid second
Ester=0-20% obtains yellow solid, as compound s 6-6e.
9. the preparation method of multiple target point small molecule compound S63845 according to claim 1, which is characterized in that the step
Rapid 15 in reaction flask specifically includes the following steps: put into compound s 6-6e, compound s 6-2f, tetrahydrofuran, water, carbonic acid
Bis- [di-t-butyl-(4- dimethylaminophenyl) phosphine] palladiums (II) of caesium, dichloro, system nitrogen protection isothermal reaction, LCMS monitoring
Show fully reacting, post-reaction treatment: three times, anhydrous sodium sulfate is dry for saturated common salt water washing, is spin-dried for, column chromatography, dichloromethane
Alkane/methanol=0-5% obtains yellow, viscous liquid, as compound s 6-6f；
The step 16 specifically includes the following steps: sequentially added in reaction flask compound s 6-6f, 1,4- dioxane, water,
Lithium hydroxide monohydrate reacts at room temperature 1 hour, post-reaction treatment: LCMS monitoring display fully reacting is spin-dried for removing Isosorbide-5-Nitrae-two
Methyl tertiary butyl ether(MTBE) is added in six ring of oxygen, and three times, it is 7 that water phase, which is adjusted to pH value with hydrochloric acid, then is extracted with dichloromethane for extraction, is merged
Organic phase, anhydrous sodium sulfate is dry, is spin-dried for obtaining crude product, compound s 6-6g, i.e. product S63845 is prepared in chiral HPLC.
10. the preparation method of multiple target point small molecule compound S63845 according to claim 9, which is characterized in that described
85-95 DEG C of constant temperature in step 15, reaction time are 1-3 hours.
11. the preparation method of multiple target point small molecule compound S63845 according to claim 10, which is characterized in that described
90 DEG C of constant temperature in step 15, reaction time are 2 hours.
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| 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 |
| CN115813929B (en) * | 2022-11-15 | 2023-07-21 | 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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