A kind of Ba Rui replaces the preparation method of Buddhist nunTechnical field
The invention belongs to field of medicine preparing technology, and in particular to a kind of selectivity JAK1 and JAK2 inhibitor Ba Rui replaces Buddhist nunPreparation method.
Technical background
Ba Rui replaces Buddhist nun (Baricitinib), and [(7H- pyrrolo-es [2,3-D] are phonetic by 4- by entitled 1- (the ethylsulfonyl) -3- of chemistryPyridine -4- bases) -1H- pyrazol-1-yls] -3- azetidine acetonitriles are that Lilly drugmaker closes with Incyte drugmakersThe selectivity for making to develop takes orally JAK1/JAK2 depressants, can inhibit the intracellular of a variety of inflammatory cytokines such as IL-6 and IL-23Signal transduction, this product can be used for treatment of the moderate to severe rheumatoid arthritis.Have what more than 1300 patient participated at oneIn research, Li Lai companies compare placebo with the Ba Rui of Incyte companies daily for Buddhist nun (Baricitinib), make after 12 weeksRA symptoms significantly improve, and meet Primary Endpoint requirement.For two kinds of common clinical indices of RA, which is also proved to better than Ah reachingWooden monoclonal antibody (Humira), has reached the by-end of the research, and Short Term Clinical result of study shows significant in efficacy.At present includingMultiple countries such as China, the U.S. carry out the clinical research of 3 phases so that Ba Rui surpasses standard for Buddhist nun (Baricitinib) as firstInjection treatment (including Humira and Enbrel) oral medication medicine.Structural formula is as follows：
It is less for the technology of Buddhist nun that Ba Rui is prepared at present, mainly includes patent CN105294699 and PCT Patent
WO2009114512 (corresponding Chinese patent CN102026999A or CN102026999B).
It is as follows for the method for Buddhist nun that Ba Rui is prepared in CN105294699：
This method is using 4- pyrazoles pinacol borate and 3- (cyanomethylene) azetidine -1- t-butyl formates to riseCompound 9 is made through Michael addition reaction in beginning raw material, and compound 9 is again with starting material compound 10 through catalyzed coupling reactionIntermediate 11 is made；Intermediate 12 is made through de- two molecule t-butyl formates in intermediate 11；Intermediate 12 exists with ethyl chlorideFinal product Ba Rui is made for Buddhist nun's (compound 1) through sulfonamide reaction in organic solvent.The route starting material compound 7 and changeObject 8 is closed to be difficult to buy, and in the invention final step because containing there are two the preferable amino of activity, when being reacted with ethyl chlorideDisubstituted or ethyl chloride easily occurs easily to react with the amino on pyrrole ring, thus for should walking, by-product is more.ThisOutside, precious metal palladium is used in reaction, totle drilling cost is relatively high, is not suitable for industrialized production.
Preparation bar in PCT Patent WO2009114512 (corresponding Chinese patent CN102026999A or CN102026999B)The auspicious method for Buddhist nun is as follows：
The route is first protected using 4- chloropyrrolo [2,3-ds as raw material with 2- (trimethylsilyl) ethoxymethyl chlorine (SEMCl)Shield obtains SEM protection 4- chloropyrrolo [2,3-ds, and compound is prepared through Suzuki coupling reactions with boric acid ester compound 17 afterwards18, compound 18 takes off the protection of 1- ethoxyethyl groups through aqueous hydrochloric acid solution again and pyrazole compound 19 is prepared, and prepares the change of gainedIt closes object 6 and compound 20 is prepared through Michael addition reaction under DBU catalysis with compound 19, compound 20 most passes through afterwardsLIBF4And NH4Two steps of OH are deprotected to obtain final product Ba Rui for Buddhist nun.The reaction route is long, and total recovery is low, cumbersome, andPalladium is used in reaction twice, finished product is relatively high, is not suitable for industrialized production.
Invention content
Part against the above deficiency of the invention, provides the preparation method that a kind of Ba Rui replaces Buddhist nun, this method raw materialIt is easy to get, easily operated, the relatively low preparation method of finished product.
The present invention first carries out amido protecting using 4- chloropyrrolo [2,3-ds as starting material, directly or is evaporated off after solvent and waterIt closes hydrazine and methacrylaldehyde " one kettle way " substitution, cyclization obtains centre 4.During starting material 1,3-DBA and ethylene glycol are condensed to yieldMesosome 5, intermediate 5 are condensed to yield intermediate 6 with ethyl sulfonamide, and intermediate 6 disappears with cyanogen methyl acid phosphate diethylester under highly basicIt removes to obtain intermediate 7, intermediate 4 and intermediate 7 and addition reaction, deprotection much target products occurs in catalyst action, alwaysYield is 40~55%.Avoid in the preparation method of current routine that route is long, cumbersome or raw material is not easy to obtain or adoptsMichael's addition, which is carried out, with precious metal palladium brings the drawbacks of of high cost.
Based on this, the present invention provides the preparation method that a kind of Ba Rui replaces Buddhist nun.
Realize that the technical solution of above-mentioned purpose is as follows：
A kind of Ba Rui replaces the preparation method of Buddhist nun, includes the following steps：
(1) using 4- chloropyrrolo [2,3-ds as raw material, intermediate state compound is obtained after carrying out amido protecting with amino protecting group3, after under oxygen, in organic solvent with hydrazine hydrate and methacrylaldehyde with certain proportion through " one kettle way " substitution, cyclization, recrystallizeTo compound 4；The structural formula of the compound 4 is：
R is amino protecting compound, such as alkoxy carbonyl group class, including di-tert-butyl dicarbonate, ((Boc) 2O), fluorenes methoxy carbonylAcyl chlorides (Fmoc-Cl), benzyloxycarbonyl group (Cbz-Cl)；Acyl group class, including paratoluensulfonyl chloride (TS-Cl), trifluoro-acetyl chloride (Tfa-Cl)；Alkyls, including chloro triphenylmenthane (Trt-Cl), to methoxybenzyl bromine (or chlorine) (PMB-Br or PMB-Cl)
R ' is the corresponding blocking groups of R, such as tertbutyloxycarbonyl (Boc), tablet held before the breast by officials methoxycarbonyl group (Fomc), and benzyloxycarbonyl group (Cbz),To mesyl (TS), trifluoro-acetyl chloride (Tfa), chloro triphenylmenthane (Trt), to methoxy-benzyl (PMB)
(2) using 1,3-DBA and ethylene glycol as raw material, carbonyl-protection compounds are condensed to yield under strong acid catalyst5；The structural formula of the compound 5 is：
(3) by compound 5 obtained by step (2) and ethyl sulfonamide under alkali effect, cyclization occurs for heating, obtains compound6；The structural formula of the compound 6 is：
(4) raw material cyanogen methyl acid phosphate diethylester eliminates under highly basic with compound 6 in step (3) and obtains compound 7；It is describedThe structural formula of compound 7 is：
(5) by compound 4 obtained by step (1) and compound 7 obtained by step (4) in organic solvent under catalyst actionAddition occurs, deamination protecting group obtains Ba Rui for Buddhist nun.
In wherein some embodiments, organic solvent described in step (1) is tetrahydrofuran, toluene, dimethylbenzene, neighbour twoOne kind in chlorobenzene；
In wherein some embodiments, the 4- chloropyrrolo [2,3-ds described in step (1), hydrazine hydrate, mole of methacrylaldehydeThan being 1: 1: 1-1: 4: 4.
In wherein some embodiments, strong acid catalyst described in step (2) is p-methyl benzenesulfonic acid, one in sulfuric acidKind.
In wherein some embodiments, alkali described in step (3) is potassium carbonate, sodium carbonate, and one kind in cesium carbonate is excellentSelect cesium carbonate；Reaction temperature is 50~80 DEG C
In wherein some embodiments, the alkali described in step (3) is cesium carbonate, and reaction temperature is 65 DEG C；
In wherein some embodiments, highly basic described in step (4) is sodium hydride, hydrofining, sodium methoxide, in sodium ethoxideOne kind；Reaction temperature is 10~40 DEG C.
In wherein some embodiments, catalyst described in step (5) is DBU, one kind in TBAB, TEBA；ReactionTemperature is 40~70 DEG C.
Advantageous effect：
(1) the invention avoids Ba Rui for being used in the prior synthesizing method of Buddhist nun using in Suzuki coupling reactions to metalPalladium and cause the problem of of high cost；
(2) present invention is ingenious with amino protecting group, and the amino in pyrrole ring is avoided to participate in reaction, reduces by-product produceRaw possibility improves the quality and total recovery of intermediate and finished product；
(3) it is directly evaporated off with ammonium hydroxide and methacrylaldehyde " one kettle way " replacing after solvent after 2 amido protecting of the compounds of this invention, closeRing obtains centre 4, simplifies operating procedure；
(4) what the present invention used is cheap and easily-available starting material, and reaction route is compared with traditional route briefly much, insteadMild condition is answered, is suitble to industrialized production.
Specific embodiment
Embodiment 1
The synthesis of compound 4
15.4g (0.1mol) compound 2,11.4g (0.05mol) dipotassium hydrogen phosphate, 26.2g are put into 1L reaction bulbsMiddle control after 12h is stirred at room temperature in (0.12mol) di-tert-butyl dicarbonate, 300g tetrahydrofurans and 70g water, and the reaction was complete for raw material, pointLiquid, water layer are extracted with 200g tetrahydrofurans, merge organic layer, and organic layer is directly used in lower step.
5.1g (0.1mol) hydrazine hydrates and 5.6g (0.1mol) methacrylaldehyde are added in into above-mentioned system, oxygen atmosphere is next timeStream reaction 8h.Middle control raw material stops heating after the reaction was complete, and system is cooled to room temperature, system is poured into 100g ice water under stirringIn, it is layered after stirring 10min, organic layer dry filter, filtrate revolving obtains crude product sticky matter, crude product methyl tertiary butyl ether(MTBE)The about 24.9g of compound 4, yield are recrystallized to give with n-hexane：87.2%, HPLC >=98.0%.
The synthesis of compound 5
500g toluene is added in 2L reaction bulbs, is added with stirring 43.2g (0.2mol) 1,3-DBA, 24.3g(0.4mol) ethylene glycol and 0.3g p-methyl benzenesulfonic acid, system are warming up to 110 DEG C of reflux, and generation is separated with water knockout drum in reflux courseWater, after insulation reaction 12h decompression steam toluene, 450g ethyl acetate, system use are added in into system after no liquid oozesOrganic layer drying after 450g washings twice.Organic layer is crossed after fibre active carbon and steams second after diatomite, gained filtrate after dryingEthyl acetate layer, it is final to obtain colourless transparent liquid 41.9g, HPLC >=99.0%, yield：80.7%.1HNMR (400MHz, CDCl3),δ ppm3.61 (s, 4H), 4.14 (s, 4H).
The synthesis of compound 6
500g1,4- dioxane, 39.0g (0.15mol) compound 5,97.7g (0.3mol) are added in into 2L reaction bulbsCesium carbonate and 18.0g (0.17mol) ethyl sulfonamide, system are warming up to 80 DEG C, insulation reaction 20h, middle control, raw material compound 5Fundamental reaction is complete.Stopping reaction, system is cooled to room temperature, and 500g water and 500g ethyl acetate are added in into system, stirs, pointLayer, water layer are extracted with 300gX2 ethyl acetate, merge organic layer, and organic layer is washed with 500g.It is clean that organic layer is packed into 2L againReaction bulb in, be stirred at room temperature it is lower dropwise addition 30.4g concentrated hydrochloric acids.Drop finishes, and is layered after stirring 1h, and organic layer is done after being washed with 500gDry, filtering, filtrate concentration half adds in 300g normal heptanes, and system is cooled to 0-10 DEG C, and heat preservation is beaten filtering filter cake drying after 2hTo the about 22.6g of chemical combination 6, yield：92.4%, HPLC >=98.0%.
M/z-164.1 (M+1),1HNMR (300MHz, CDCl3)：δ 4.08 (d, J=2.4Hz, 2H), 3.94 (d, J=2.6Hz, 2H), 3.35-3.10 (m, 2H), 1.40-1.20 (m, 3H) ppm.
The synthesis of compound 7
Add in 450g tetrahydrofurans in 2L reaction bulbs, 21.3g (0.12mol) cyanogen methyl acid phosphate diethylester, system is cooled to-5-5 DEG C, sodium hydride (content 60%) 5.3g (0.13mol) is added portionwise under nitrogen protection, 30min is finished, and system gradually heats upTo 20 DEG C.Stir 45min.Continue the solution for 16.3g (0.1mol) compound 6 being added dropwise into system and 80g tetrahydrofurans are made into.Drop finishes in 1h, reaction 12h is stirred at room temperature, middle control raw material reaction is substantially completely.System adds in 500g ethyl acetate after being cooled to 0 DEG CWith 300g saturated salt solutions, it is layered after stirring 5min.Water layer is extracted with 300gX3 ethyl acetate, merges organic layer.Organic layer is used500g is washed.Organic layer is dried, filtering, filtrate concentration, obtains the crude product of compound 7, and a small amount of n-hexane rinse of crude product is driedIt is dry, obtain 15.2g compounds 7, yield：88.2%, HPLC >=98.0%.
The synthesis of target product 1
200g acetonitriles are added in 1L reaction bulbs, 14.3g (0.05mol) compound 4 is added with stirring 6.9g (0.05mol)Potassium carbonate adds in 9.3g (0.05mol) compound 7 after 30min is stirred at room temperature and 8.1g (0.025mol) TBAB, system is warming up toMiddle control after 40 DEG C of reaction 8h, the reaction was complete for raw material, stops reaction.It removes under reduced pressure and adds in 100g water quenchings into system after solvent and go out insteadShould after add 200g ethyl acetate, stir, layering, water layer again with 100gX3 ethyl acetate extract, the organic layer being obtained by extraction10.2g concentrated hydrochloric acids are added in after merging at room temperature, after stirring 30min, filtering considers and the fresh ethyl acetate of 300g is added in cake, stirsLower 10% solution of potassium carbonate tune pH to neutrality is mixed, is layered, is filtered after organic layer drying, cake is considered and dries to obtain white solid16.6g, HPLC >=99.0%, yield：89.3%.
Embodiment 2
The synthesis of compound 4
15.4g (0.1mol) compound 2,11.4g (0.05mol) dipotassium hydrogen phosphate, fluorenes methoxy carbonyl are put into 1L reaction bulbsMiddle control after 12h is stirred at room temperature in acyl chlorides 31.0g (0.12mol), dichloromethane 400g, and the reaction was complete for raw material, filtering, adds in filtrateEnter 300g ice water, stir liquid separation after 10min, water layer is extracted with 200g, merges organic layer, and organic layer is spin-dried for, and gained system is directFor the next step.
10.2g (0.2mol) hydrazine hydrate, 500g toluene and 11.2g (0.2mol) methacrylaldehyde, oxygen are added in into above-mentioned systemAtmosphere encloses lower back flow reaction 8h.Middle control raw material stops heating after the reaction was complete, and system is cooled to room temperature, pours into system under stirringIt in 100g ice water, is layered after stirring 10min, is filtered after organic layer drying, filtrate revolving obtains crude product sticky matter, crude product firstBase tertbutyl ether and n-hexane are recrystallized to give the about 41.7g of compound 4, yield：80.5%, HPLC >=98.0%.
The synthesis of compound 5
500g toluene is added in 2L reaction bulbs, is added with stirring 43.2g (0.2mol) 1,3-DBA, 24.3g(0.4mol) ethylene glycol and the 2.0g concentrated sulfuric acids, system are warming up to 110 DEG C of reflux, and generation is separated with water knockout drum in reflux courseWater, after insulation reaction 12h decompression steam toluene, 450g ethyl acetate, system use are added in into system after no liquid oozesOrganic layer drying after 450g washings twice.Organic layer is crossed after fibre active carbon and steams second after diatomite, gained filtrate after dryingEthyl acetate layer, it is final to obtain colourless transparent liquid 42.1g, HPLC >=99.0%, yield：81.1%.
The synthesis of compound 6
500g1,4- dioxane, 39.0g (0.15mol) compound 5,41.5g (0.3mol) are added in into 2L reaction bulbsPotassium carbonate and 18.0g (0.17mol) ethyl sulfonamide, system are warming up to 70 DEG C, insulation reaction 20h, middle control, raw material compound 5Fundamental reaction is complete.Stopping reaction, system is cooled to room temperature, and 500g water and 500g ethyl acetate are added in into system, stirs, pointLayer, water layer are extracted with 300gX2 ethyl acetate, merge organic layer, and organic layer is washed with 500g.It is clean that organic layer is packed into 2L againReaction bulb in, be stirred at room temperature it is lower dropwise addition 30.4g concentrated hydrochloric acids.Drop finishes, and is layered after stirring 1h, and organic layer is done after being washed with 500gDry, filtering, filtrate concentration half adds in 300g normal heptanes, and system is cooled to 0-10 DEG C, and heat preservation is beaten filtering filter cake drying after 2hTo the about 22.8g of chemical combination 6, yield：93.1%, HPLC >=98.0%.
The synthesis of compound 7
450g tetrahydrofurans, 21.3g (0.12mol) cyanogen methyl acid phosphate diethylester are added in 2L reaction bulbs, system is cooled to10 DEG C, nitrogen protection is lower to add in sodium methoxide 7.0g (0.13mol), finishes, system is gradually heating to 20 DEG C.Stir 45min.ContinueThe solution that dropwise addition 16.3g (0.1mol) compound 6 and 80g tetrahydrofurans are made into system.Drop finishes in 1h, and 30 DEG C are stirred to react10h, middle control raw material reaction is substantially completely.System adds in 500g ethyl acetate and 300g saturated salt solutions after being cooled to 10 DEG C, stirsIt is layered after mixing 5min.Water layer is extracted with 300gX3 ethyl acetate, merges organic layer.Organic layer is washed with 500g.Organic layer is dried,Filtering, filtrate concentration obtain the crude product of compound 7, a small amount of n-hexane rinse of crude product, and drying obtains 16.6g compounds 7, producesRate：96.4%, HPLC >=98.0%.
The synthesis of target product 1
200g acetonitriles are added in 1L reaction bulbs, 20.4g (0.05mol) compound 4 is added with stirring 6.9g (0.05mol)Potassium carbonate adds in 9.3g (0.05mol) compound 7 after 30min is stirred at room temperature and 8g (0.05mol) DBU, system is warming up to 40 DEG CMiddle control after reaction 8h, the reaction was complete for raw material, stops reaction.It removes under reduced pressure after solvent and 100g water quenchings are added in into system goes out after reaction200g ethyl acetate is added, stirs 30min, cake ethyl acetate rinse fresh 100g is considered in filtering, and filter cake is dried to obtain whiteColor solid 17.0g, HPLC >=99.0%, yield：91.2%.
Embodiment 3
The synthesis of compound 4
15.4g (0.1mol) compound 2,27.6g (0.2mol) potassium carbonate, 19.1g (0.1mol) are put into 1L reaction bulbsMiddle control after 8h is stirred at room temperature in paratoluensulfonyl chloride, 500g acetonitriles, and the reaction was complete for raw material, and filtering, filtrate decompression is spin-dried for, and directly usesIn lower step.
20.4g (0.4mol) hydrazine hydrate, 450g o-dichlorohenzenes and 22.4g (0.4mol) propylene are added in into above-mentioned systemAldehyde, back flow reaction 4h under oxygen atmosphere.Middle control raw material stops heating after the reaction was complete, and system is cooled to room temperature, by body under stirringSystem is poured into 100g ice water, is layered after stirring 10min, the dried filtration of organic layer, and filtrate revolving obtains crude product sticky matter, slightlyProduct methyl tertiary butyl ether(MTBE) and n-hexane are recrystallized to give the about 27.7g of compound 4, yield：81.6%, HPLC >=98.0%.
The synthesis of compound 5
500g toluene is added in 2L reaction bulbs, is added with stirring 43.2g (0.2mol) 1,3-DBA, 24.3g(0.4mol) ethylene glycol and 0.3g p-methyl benzenesulfonic acid, system are warming up to 110 DEG C of reflux, and generation is separated with water knockout drum in reflux courseWater, after insulation reaction 12h decompression steam toluene, 450g ethyl acetate, system use are added in into system after no liquid oozesOrganic layer drying after 450g washings twice.Organic layer is crossed after fibre active carbon and steams second after diatomite, gained filtrate after dryingEthyl acetate layer, it is final to obtain colourless transparent liquid 42.6g, HPLC >=99.0%, yield：82.0%.1HNMR (400MHz,CDCl3), δ ppm3.61 (s, 4H), 4.14 (s, 4H).
The synthesis of compound 6
500g1,4- dioxane, 39.0g (0.15mol) compound 5,31.8g (0.3mol) are added in into 2L reaction bulbsSodium carbonate and 18.0g (0.17mol) ethyl sulfonamide, system are warming up to 65 DEG C, insulation reaction 16h, middle control, raw material compound 5Fundamental reaction is complete.Stopping reaction, system is cooled to room temperature, and 500g water and 500g ethyl acetate are added in into system, stirs, pointLayer, water layer are extracted with 300gX2 ethyl acetate, merge organic layer, and organic layer is washed with 500g.It is clean that organic layer is packed into 2L againReaction bulb in, be stirred at room temperature it is lower dropwise addition 30.4g concentrated hydrochloric acids.Drop finishes, and is layered after stirring 1h, and organic layer is done after being washed with 500gDry, filtering, filtrate concentration half adds in 300g normal heptanes, and system is cooled to 0-10 DEG C, and heat preservation is beaten filtering filter cake drying after 2hTo the about 23.0g of chemical combination 6, yield：94.1%, HPLC >=98.0%.
The synthesis of compound 7
450g tetrahydrofurans, 21.3g (0.12mol) cyanogen methyl acid phosphate diethylester are added in 2L reaction bulbs, system is cooled to10 DEG C, nitrogen protection is lower to add in sodium ethoxide 10.2g (0.15mol), finishes, system is gradually heating to 20 DEG C.Stir 45min.AfterContinue the solution that dropwise addition 16.3g (0.1mol) compound 6 and 80g tetrahydrofurans are made into system.Drop finishes in 1h, and 40 DEG C of stirrings are anti-10h is answered, middle control raw material reaction is substantially completely.System adds in 500g ethyl acetate and 300g saturated salt solutions after being cooled to 10 DEG C,It is layered after stirring 5min.Water layer is extracted with 300gX3 ethyl acetate, merges organic layer.Organic layer is washed with 500g.Organic layer is doneDry, filtering, filtrate concentration obtains the crude product of compound 7, a small amount of n-hexane rinse of crude product, and drying obtains 16.3g compounds7, yield：94.3%, HPLC >=98.0%.
The synthesis of target product 1
200g acetonitriles are added in 1L reaction bulbs, 17.0g (0.05mol) compound 4 is added with stirring 6.9g (0.05mol)Potassium carbonate adds in 9.3g (0.05mol) compound 7 after 30min is stirred at room temperature and 5.7g (0.025mol) TEBA, system is warming up toMiddle control after 70 DEG C of reaction 6h, the reaction was complete for raw material, stops reaction.It removes under reduced pressure and adds in 100g water quenchings into system after solvent and go out insteadShould after add 400g acetone, at room temperature be added dropwise 9.8g (0.1mol) concentrated sulfuric acid, 40 DEG C stirring 1h, after be cooled to 0 DEG C of filtering, filterCake 50g acetone rinses, filtrate decompression is rotated adds in 300g ethyl acetate to after doing, and is filtered after 2h is stirred at room temperature, filter cake dryingObtain white solid 16.0g, HPLC >=99.0%, yield：85.9%.
Embodiment 4
The synthesis of compound 4
15.4g (0.1mol) compound 2,20.2g (0.2mol) triethylamine, 27.9g (0.1mol) are put into 1L reaction bulbsMiddle control after 4h is stirred at room temperature in triphenyl chloromethane, 600g acetonitriles, and the reaction was complete for raw material.Filtering, filtrate decompression are spin-dried for, are directly used inLower step.
20.4g (0.4mol) hydrazine hydrate, 450g o-dichlorohenzenes and 22.4g (0.4mol) propylene are added in into above-mentioned systemAldehyde, back flow reaction 4h under oxygen atmosphere.Middle control raw material stops heating after the reaction was complete, and system is cooled to room temperature, by body under stirringSystem is poured into 100g ice water, is layered after stirring 10min, the dried filtration of organic layer, and filtrate revolving obtains crude product sticky matter, slightlyProduct ether and n-hexane are recrystallized to give the about 35.6g of compound 4, yield：83.2%, HPLC >=98.0%.
The synthesis of compound 5
500g toluene is added in 2L reaction bulbs, is added with stirring 43.2g (0.2mol) 1,3-DBA, 24.3g(0.4mol) ethylene glycol and 0.3g p-methyl benzenesulfonic acid, system are warming up to 110 DEG C of reflux, and generation is separated with water knockout drum in reflux courseWater, after insulation reaction 12h decompression steam toluene, 450g ethyl acetate, system use are added in into system after no liquid oozesOrganic layer drying after 450g washings twice.Organic layer is crossed after fibre active carbon and steams second after diatomite, gained filtrate after dryingEthyl acetate layer, it is final to obtain colourless transparent liquid 42.6g, HPLC >=99.0%, yield：82.0%.
The synthesis of compound 6
500g1,4- dioxane, 39.0g (0.15mol) compound 5,31.8g (0.3mol) are added in into 2L reaction bulbsSodium carbonate and 18.0g (0.17mol) ethyl sulfonamide, system are warming up to 50 DEG C, insulation reaction 16h, middle control, raw material compound 5Fundamental reaction is complete.Stopping reaction, system is cooled to room temperature, and 500g water and 500g ethyl acetate are added in into system, stirs, pointLayer, water layer are extracted with 300gX2 ethyl acetate, merge organic layer, and organic layer is washed with 500g.It is clean that organic layer is packed into 2L againReaction bulb in, be stirred at room temperature it is lower dropwise addition 30.4g concentrated hydrochloric acids.Drop finishes, and is layered after stirring 1h, and organic layer is done after being washed with 500gDry, filtering, filtrate concentration half adds in 300g normal heptanes, and system is cooled to 0-10 DEG C, and heat preservation is beaten filtering filter cake drying after 2hTo the about 22.1g of chemical combination 6, yield：90.2%, HPLC >=98.0%.
The synthesis of compound 7
450g tetrahydrofurans, 21.3g (0.12mol) cyanogen methyl acid phosphate diethylester are added in 2L reaction bulbs, system is cooled to10 DEG C, nitrogen protection is lower to add in sodium ethoxide 10.2g (0.15mol), finishes, system is gradually heating to 20 DEG C.Stir 45min.AfterContinue the solution that dropwise addition 16.3g (0.1mol) compound 6 and 80g tetrahydrofurans are made into system.Drop finishes in 1h, and 40 DEG C of stirrings are anti-10h is answered, middle control raw material reaction is substantially completely.System adds in 500g ethyl acetate and 300g saturated salt solutions after being cooled to 10 DEG C,It is layered after stirring 5min.Water layer is extracted with 300gX3 ethyl acetate, merges organic layer.Organic layer is washed with 500g.Organic layer is doneDry, filtering, filtrate concentration obtains the crude product of compound 7, a small amount of n-hexane rinse of crude product, and drying obtains 16.3g compounds7, yield：94.3%, HPLC >=98.0%.
The synthesis of target product 1
400g acetonitriles are added in 1L reaction bulbs, 21.4g (0.05mol) compound 4 is added with stirring 6.9g (0.05mol)Potassium carbonate adds in 9.3g (0.05mol) compound 7 after 30min is stirred at room temperature and 5.7g (0.025mol) TEBA, system is warming up toMiddle control after 70 DEG C of reaction 6h, the reaction was complete for raw material, stops reaction.It removes under reduced pressure and adds in 100g water quenchings into system after solvent and go out insteadShould after add 400g acetone, be added dropwise 19.6g (0.2mol) concentrated sulfuric acid at room temperature, 40 DEG C of stirring 1h, after be cooled to 0 DEG C of heat preservation and stirIt is refiltered after mixing 1-2h, filter cake 50g acetone rinses, filtrate decompression is rotated adds in 300g ethyl acetate to after doing, and is stirred at room temperatureIt is filtered after 2h, filter cake dries to obtain white solid 16.7g, HPLC >=99.0%, yield：89.6%.
Embodiment 5
The synthesis of compound 4
15.4g (0.1mol) compound 2,20.2g (0.2mol) potassium carbonate, 24.1g (0.12mol) are put into 1L reaction bulbsMiddle control after 6h is stirred at room temperature in 4- methoxyl group bromobenzyls, 500g acetonitriles, and the reaction was complete for raw material.Filtering, filtrate decompression are spin-dried for, and are directly usedIn lower step.
20.4g (0.4mol) hydrazine hydrate, 450g o-dichlorohenzenes and 22.4g (0.4mol) propylene are added in into above-mentioned systemAldehyde, back flow reaction 4h under oxygen atmosphere.Middle control raw material stops heating after the reaction was complete, and system is cooled to room temperature, by body under stirringSystem is poured into 100g ice water, is layered after stirring 10min, the dried filtration of organic layer, and filtrate revolving obtains crude product sticky matter, slightlyProduct methyl tertiary butyl ether(MTBE) and n-hexane are recrystallized to give the about 24.6g of compound 4, yield：80.5%, HPLC >=98.0%.
The synthesis of compound 5
500g toluene is added in 2L reaction bulbs, is added with stirring 43.2g (0.2mol) 1,3-DBA, 24.3g(0.4mol) ethylene glycol and 0.3g p-methyl benzenesulfonic acid, system are warming up to 110 DEG C of reflux, and generation is separated with water knockout drum in reflux courseWater, after insulation reaction 12h decompression steam toluene, 450g ethyl acetate, system use are added in into system after no liquid oozesOrganic layer drying after 450g washings twice.Organic layer is crossed after fibre active carbon and steams second after diatomite, gained filtrate after dryingEthyl acetate layer, it is final to obtain colourless transparent liquid 42.6g, HPLC >=99.0%, yield：82.0%.
The synthesis of compound 6
500g1,4- dioxane, 39.0g (0.15mol) compound 5,31.8g (0.3mol) are added in into 2L reaction bulbsSodium carbonate and 18.0g (0.17mol) ethyl sulfonamide, system are warming up to 60 DEG C, insulation reaction 16h, middle control, raw material compound 5Fundamental reaction is complete.Stopping reaction, system is cooled to room temperature, and 500g water and 500g ethyl acetate are added in into system, stirs, pointLayer, water layer are extracted with 300gX2 ethyl acetate, merge organic layer, and organic layer is washed with 500g.It is clean that organic layer is packed into 2L againReaction bulb in, be stirred at room temperature it is lower dropwise addition 30.4g concentrated hydrochloric acids.Drop finishes, and is layered after stirring 1h, and organic layer is done after being washed with 500gDry, filtering, filtrate concentration half adds in 300g normal heptanes, and system is cooled to 0-10 DEG C, and heat preservation is beaten filtering filter cake drying after 2hTo the about 24.5g of chemical combination 6, yield：93.4%, HPLC >=98.0%.
The synthesis of compound 7
450g tetrahydrofurans, 21.3g (0.12mol) cyanogen methyl acid phosphate diethylester are added in 2L reaction bulbs, system is cooled to10 DEG C, nitrogen protection is lower to add in sodium ethoxide 10.2g (0.15mol), finishes, system is gradually heating to 20 DEG C.Stir 45min.AfterContinue the solution that dropwise addition 16.3g (0.1mol) compound 6 and 80g tetrahydrofurans are made into system.Drop finishes in 1h, and 40 DEG C of stirrings are anti-10h is answered, middle control raw material reaction is substantially completely.System adds in 500g ethyl acetate and 300g saturated salt solutions after being cooled to 10 DEG C,It is layered after stirring 5min.Water layer is extracted with 300gX3 ethyl acetate, merges organic layer.Organic layer is washed with 500g.Organic layer is doneDry, filtering, filtrate concentration obtains the crude product of compound 7, a small amount of n-hexane rinse of crude product, and drying obtains 16.3g compounds7, yield：94.3%, HPLC >=98.0%.
The synthesis of target product 1
400g acetonitriles are added in 1L reaction bulbs, 15.3g (0.05mol) compound 4 is added with stirring 6.9g (0.05mol)Potassium carbonate adds in 9.3g (0.05mol) compound 7 after 30min is stirred at room temperature and 5.7g (0.025mol) TEBA, system is warming up toMiddle control after 70 DEG C of reaction 6h, the reaction was complete for raw material, stops reaction.It removes under reduced pressure and adds in 100g water quenchings into system after solvent and go out insteadShould after add 400g ethyl alcohol, system is cooled to 0~10 DEG C, keep the temperature it is lower 17.1g (0.15mol) trifluoroacetic acid is added dropwise, room temperature is stirredMix 1h, after be cooled to 0 DEG C of insulated and stirred 1-2h after refilter, filter cake 50g ethyl alcohol rinses, afterwards into system addition 400g dichlorosMethane, system filter after being cooled to 0~10 DEG C of stirring 2h, and filter cake dries to obtain white solid 15.2g, HPLC >=99.0%, productionRate：81.8%.