A kind of preparation method of -2 inhibitor ABT-199 of the B cell lymphoma factorTechnical field
The invention belongs to technical field of medicine synthesis, inhibit more particularly to a kind of B cell lymphoma factor -2 (BCL-2)The preparation method of agent.
Background technique
ABT-199 (venetoclax) has the following structure formula:
Molecular formula C45H50ClN7O7S, molecular weight 868.44, English trade name Venclexta, English drug nameVenetoclax, Chinese drug name ABT-199, Chinese chemical name are 4- [4- [[2- (4- chlorphenyl -4,4- dimethyl -1- hexamethyleneBase -1- base] methyl] -1- piperazinyl]-N- [[3- nitro -4- [[(tetrahydro -2H- pyrans -4- base) methyl] amino] phenyl] sulfonic acidBase] -2- (1H- pyrroles [2,3-b] pyridine -5- oxygroup) benzamide.
Venclexta is by a breakthrough anticarcinogen of Ai Baiwei (AbbVie) and Roche (Roche) cooperative development.It isThe first B cell lymphoma factor -2 (BCL-2) inhibitor of FDA approval, has harvested 4 indications in the U.S..Venclexta isA kind of oral B cell lymphoma factor -2 (BCL-2) inhibitor, BCL-2 hair in Apoptosis (apoptosis)Important function is waved, the apoptosis of some cells (including lymphocyte) can be prevented, and over-express in certain types of cancer, withThe formation of drug resistance is related.Venetoclax is intended to the function of selective depression BCL-2, restores the communication system of cell, allows cancerCell self-destruction achievees the purpose that treat tumour.The mono- medicine of venetoclax and combination therapy to treat multiple types leukemia, includingCLL, NHL, diffusivity large B cell lymph cancer (DLBCL), acute myeloid leukaemia (AML) and Huppert's disease (MM).
The document of synthesis Venclexta mainly includes US2014/275540, WO2012/71336, US2010/ at present305122 (corresponding China Patent No. is CN103153993), WO2016/24230, WO 2011/150016.In several patentsSynthetic method about Venclexta is mainly as follows.General line is too long, a total of 10 step.Change in the starting material of reactionObject 1 is closed, compound 9 is the raw material for being difficult to buy or synthesize, which is difficult to amplify production.In addition, whole route is always receivedRate is too low (less than 10%), and using the palladium class catalyst to anti-valuableness in compound 3 and the reaction of compound 4, totle drilling cost is oppositeIt is higher.Using a large amount of potassium phosphate is arrived in compound 8 and the reaction of compound 9, a large amount of phosphorus can be generated under system acid conditionAcid, it is larger to the pollution of environment.
Summary of the invention
The purpose of the present invention is to provide the synthetic method of synthesis Venclexta a kind of new, a kind of B cell lymphoma becauseThe preparation method of -2 (BCL-2) inhibitor ABT-199 (venetoclax) of son expects that this method has at least one following sideThe advantages of face: synthesis step is short, high income, avoid using severe toxicity and/or expensive reagent, suitable for industrialized production, avoidUse environment pollutes biggish solvent and/or reaction reagent, and raw material is easy to get or easily prepared etc..The present invention is unexpectedly sent outIt is existing, have the advantages that the method for synthesis step feature of the present invention can obtain at least one above-mentioned aspect.The present invention is based on this hairsNow it is accomplished.Realize that above-mentioned purpose includes the following steps:
(a) make following formula II and formula III compound:
It reacts under phase transfer catalyst effect, obtains the compound of following formula IV:
X: for halogen
(b) self-control obtains the compound of following formula V:
In acid condition, the compound deamination protecting group of formula IV, with the Formula V compound in step (b) in catalystThe compound of following formula VI is obtained through reductive amination process under effect:
(c) make the compound 5- bromo-7-azaindole of following formula VII:
Compound with the Formula IV in step (b) replaces in the presence of catalyst in alkali systems and obtains following formula VIII'sCompound:
(d) make the compound of following formula Ⅸ:
Under alkaline condition with the Formula VIII compound in step (c), acyl is carried out under dehydrating agent and catalyst collective effectAminating reaction obtains the target product ABT-199 of Formulas I.
Content according to a first aspect of the present invention, wherein the compound of Formula II compound and formula III is anti-in step (a)The organic solvent that should be used is toluene, tetrahydrofuran (THF), one of DMSO or DMF；
Content according to a first aspect of the present invention, wherein the compound of Formula II compound and formula III is anti-in step (a)Phase transfer catalyst used in answering is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, preferably tetrabutyl iodineChange ammonium；
Content according to a first aspect of the present invention, wherein in step (a), the compound of Formula II compound and formula IIIReaction is carried out at 30-100 DEG C.
Content according to a first aspect of the present invention, wherein in step (a), the compound of Formula II compound and formula IIIBronsted acid is added after reaction to be deprotected, Bronsted acid used is selected from hydrochloric acid solution, hydrobromic acid solution or its gas；
Content according to a first aspect of the present invention, wherein reacting the solvent used in step (b) and being selected from toluene, diformazanBenzene, one of Isosorbide-5-Nitrae-dioxane；
Content according to a first aspect of the present invention, wherein in step (b), the compound of formula IV deamination and the change of Formula VThe catalyst that reduction amination is used in object reaction is closed, the reduction amination catalyst is sodium triacetoxy borohydride；
Content according to a first aspect of the present invention, wherein the temperature that catalyst is added is -30-5 DEG C in step (b).RootAccording to the content of first aspect present invention, wherein in step (c), the reacting of Formula VII compound and Formula IV compound uses moltenAgent is selected from toluene, Isosorbide-5-Nitrae-dioxane, DMF, one of DMSO；
Content according to a first aspect of the present invention, wherein Formula VII compound is anti-with Formula IV compound in step (c)Alkali used in answering is potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide etc., preferably cesium carbonate；
Content according to a first aspect of the present invention, wherein Formula VII compound is anti-with Formula IV compound in step (c)The catalyst answered is cuprous bromide, cuprous iodide, one of stannous chloride.
Content according to a first aspect of the present invention, wherein the compound and Formula VIII compound of formula Ⅸ exist in step (d)It reacts at a temperature of 0-40 DEG C；
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII chemical combination alkaloids of formula ⅨProperty under the conditions of it is acylated, selected alkali is triethylamine, and pyridine, ammonium hydroxide is medium, preferably triethylamine.
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII compound acyl of formula ⅨChange reaction, the dehydrating agent used is 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDCI), dicyclohexylcarbodiimide(DCC), diisopropylcarbodiimide (DIC)；
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII compound acyl of formula ⅨChange reaction, the catalyst used is DMAP.
Content according to a first aspect of the present invention, wherein the recrystallization solvent of target product Formulas I is first in step (d)Alcohol/ethyl acetate system, ethyl alcohol/ethyl acetate system, methanol/acetonitrile system, one of ethanol/acetonitrile system；
Content according to a first aspect of the present invention, wherein the recrystallization temperature of target product Formulas I is 30- in step (d)80℃。
Formula V compound can be prepared according to the method for US20140275540.
The utility model has the advantages that
The present invention provides a kind of new method for preparing Venclexta, this method can not only shorten linear synthetic routeReaction step, and used reagent is safer and cheap and easily-available, which employs mild reaction condition and it is simple afterProcessing method reduces production cost so that the total recovery of linear synthetic route can be improved, therefore is more suitable for industrialization amplification lifeIt produces.In particular, the method for the present invention has the advantages that at least one following aspect: synthesis step is short, high income, avoids using severe toxicityAnd/or it expensive reagent, is easy to get suitable for industrialized production, raw material or easily prepared etc..It is embodied in:
1) raw material that the present invention uses are to be easy to purchase or homemade raw material, avoid use cost in existing literatureHigher fluorine-containing raw material；
2) present invention is ingenious reacts with compound III, that is, one end amido protecting piperazine with compound II, can avoid piperazineThe drawbacks of piperazine both ends react with compound II respectively avoids the generation of by-product to improve the specificity of reaction；
3) when compound II and compound III reacts, the present invention can on the basis of specificity with phase transfer catalystLargely improve the yield of the step；
4) the compounds of this invention IV and compound V reaction is catalyzed with sodium triacetoxy borohydride as reduction aminationAgent, more other reductive amination process effects are much higher, not only can guarantee the generation for effectively avoid by-product of reaction, simultaneouslyThe yield of this step can be improved；
5) compound Ⅸ and when compound VIII amidation in step d of the present invention, it is same using dehydrating agent and catalyst DMAPShi Zuoyong can avoid compound VIII chlorine by-product in conjunction with the amino of compound Ⅸ, largely improve the exclusive of reactionProperty and this step efficiency.
Detailed description of the invention
Fig. 1 is the HPLC map of the ABT-199 in embodiment 1
Fig. 2 is the nuclear magnetic resonance spectroscopy of the ABT-199 in embodiment 1
Fig. 3 is the mass spectrogram of the ABT-199 midbody compound VIII cation in embodiment 1
Fig. 4 is the mass spectrogram of the ABT-199 midbody compound VIII anion in embodiment 1
Fig. 5 is the nuclear magnetic resonance spectroscopy of the ABT-199 midbody compound VIII in embodiment 1
Fig. 6 is the nuclear magnetic resonance spectroscopy of the ABT-199 midbody compound V in embodiment 1
Specific embodiment
Embodiment 1
The synthesis of compound IV
34.2g (0.20mol) compound II, 3.1g (8.4mmol) tetra-tert ammonium iodide is added in 1L reaction flask(TBAI), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 350mLDMSO.It finishes, system heatingTo 100 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 10h, HPLC or TLC, raw material fully reacting stops anti-It answers.300mL ethyl acetate is added into filtrate for filtering, and 1h is stirred at room temperature in 83mL concentrated hydrochloric acid solution, filters, obtains compound IVFaint yellow solid crude product 47.0g.It is directly used in lower step, HPLC:97.8%, yield: 86.3%.
The synthesis of compound V
The DMF that 33.4g (0.46mol) Non-aqueous processing is crossed, 80mL methylene chloride, system cooling are added in 500mL reaction flaskTo -5 DEG C, 64.7g (0.42mol) POCl is added dropwise after temperature is stablized3, drop is complete, is to slowly warm up to 20 DEG C of stirring 1h, system is againIt is cooled to 0 DEG C, the about 41.0g of compound 1 is added into system, while 20mL methylene chloride is added, finishes, is delayed after stirring 30minSlowly it is warming up to system reflux 6h.System reaction terminates, and system is cooled to after room temperature and is poured slowly into 500mL ice water, stirs30min.Layering, upper organic layer are extracted with 200mLX3 methylene chloride, merge all organic layers, organic layer saturated salt solutionWashing is evaporated off solvent after organic layer is dry, obtains 54.9g light yellow oil compound 2, be directly used in lower step.Yield:97.9%.30.0g (0.17mol) compound 2, tetrabutylammonium bromide 56.0g, 30mL acetonitrile are added in 1L reaction flask, room temperature is stirred25% solution of potassium carbonate 63.9g is added after mixing 10min.It finishes, 28.6g compound 3 is added after 10min is stirred at room temperature.It finishes, bodyIt is that 30 DEG C are heated under nitrogen protection, room temperature when system is cooling after insulation reaction 12h.300mL toluene and 5% is added into systemSodium bicarbonate solution 300mL, be layered after stirring 5-10min, organic layer is layered after being washed with 300mL saturated common salt, dry, mistakeFilter, filtrate are concentrated to dryness, and the brown oil 40.5g for obtaining compound V is directly used in lower step, yield: 93.7%.1HNMR(CDCl3): δ 1.00 (s, 6H), 1.49 (t, J=6.6Hz, 2H), 2.28 (t, J=2.1Hz, 2H), 2.38 (m, 2H), 7.13(m, 2H), 7.34 (m, 2H), 9.49 (s, 1H).
The synthesis of compound VI
It is added in 1L reaction flask
Compound V30.0g (0.12mol) is added in 2L reaction flask, 240mL toluene solution is added with stirring 40.8g240mL anhydrous tetrahydro furan is added simultaneously in (0.15mol) compound IV.System is cooled to -30 DEG C after stirring 10min at room temperature,Sodium triacetoxy borohydride 31.6g (0.15mol) is added portionwise after temperature is stablized.It finishes, 4h, HPLC is stirred at room temperature in systemOr it is controlled in TLC, raw material fully reacting.12.5% saline solution 300g is added into filtrate, is layered after stirring 30min for filtering.OnLayer organic layer is washed with 10% citric acid solution 300gX2, then is washed with the sodium bicarbonate solution of 300g concentration 5%, finally full with 300gIt is washed with salt.Organic layer filters the inorganic salts of precipitation after being cooled to -30 DEG C of heat preservation 30min.It is added after organic layer concentration half240mL acetonitrile, system are heated to 80 DEG C, refilter after solid dissolved clarification, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C, thisWhen system in there are a large amount of solids to be precipitated, filtering, filter cake wash with cold acetonitrile 50mL, obtains refining wet product 66.8g, must after drying49.5g compound VI, HPLC:99.3%.Yield: 88.0%.The synthesis of compound VIII
Compound Compound VI47.0g (0.10mol) is added in 1L reaction flask, 500gDMF, 24.3g (0.12mol) chemical combinationObject VII, 29.7g (0.16mol) cuprous iodide and 78.2g (0.24mol) cesium carbonate.After system is heated to 60 DEG C of reaction 4-6hIt is controlled in TLC or HPLC, raw material fully reacting.System filtering sequentially adds 500g methylene chloride and 500g saturation food into filtrateSalt water is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g is added into systemMethanol, while it is 20% sodium hydroxide that 40g weight content, which is added, is warming up to HPLC or TLC hydrolysis after 65 DEG C of stirring 2-3hTerminate.Stopping reaction, stirs lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h,Obtain the faint yellow solid object 48.7g of compound VIII, yield: 82.5%, HPLC:98.9%.
1HNMR (DMSO-d6): δ 0.94 (s, 6H), 1.13t, J=6.2Hz, 2H), 1.98 (s, br, 2H), 2.20 (m,6H), 2.74 (s, br, 2H), 3.13 (m, 4H), 6.36 (d, J=1.75Hz, 2H), 6.72 (dd, J=8.55,2.4Hz, 1H),7.06 (m, J=7.65,2H), 7.36 (m, J=7.55,2H), 7.40 (d, J=2.35Hz, 1H), 7.46 (t, J=5.5Hz,1H), 7.74 (d, J=8.8Hz, 1H), 7.98 (d, J=2.5Hz, 1H), 11.59 (m, 1H), 12.1 (s, 1H) compound I'sSynthesis
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 22.7g(0.11mol) DCC and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5g (0.064mol)The solution of compound VIII and 23.7g (0.23mol) triethylamine and 80mL methylene chloride is slowly dropped in above-mentioned system, dropFinish, is controlled in HPLC or TLC after 40 DEG C of stirring 2h, raw material fully reacting.14.1g N, N '-dimethyl second two are added into systemAmine.System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12% is added after temperature is stablized, stirs 10minAfterwards, it is layered, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.Organic layer is dryDry, 300mL ethyl acetate is added after solvent is evaporated off in filtering, and methanol solution is added dropwise after being heated to 50 DEG C in system, after system clarificationStart to be cooled to 0-5 DEG C, and insulated and stirred 1h, filter, obtains compound as white solid I about 45.4g, yield after worry biscuit is dry81.6%, HPLC >=99.0%.(
1HNMR (500MHz, DMSO-d6): δ 0.92 (s, 6H), 1.26 (m, 2H), 1.38 (t, J=12.7Hz, 2H),1.61 (d, 2H), 1.90 (m, 1H), 1.95 (s, 2H), 2.15 (s, br, 2H), 2.20 (s, 4H), 2.75 (s, br, 2H), 3.07(s, 4H), 3.26 (m, 4H), 3.84 (dd, 2H), 6.19 (d, J=1.8Hz, 1H), 6.39 (dd, J=1.8,1.9Hz, 1H),6.67 (dd, J=2.0,1.9Hz, 1H), 7.03 (m, 2H), 7.11 (d, 2H), 7.33 (d, 2H), 7.49 (m, 2H), 7.54 (d, J=2.3,1H), 7.81 (dd, J=1.7,2.3Hz, 1H), 8.04 (d, J=2.5Hz, 1H), 8.56 (d, J=2.25Hz, 1H),8.58 (t, 1H), 11.65 (m, 1H)
Embodiment 2
The synthesis of compound IV
34.2g (0.20mol) compound II, 3.4g (10.5mmol) tetra-tert ammonium bromide is added in 1L reaction flask(TBAB), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mLTHF.It finishes, system heatingTo 30 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 12h, HPLC or TLC, raw material fully reacting stops reaction.Filtering, be stirred at room temperature it is lower HCl gas is passed through into filtrate, until system in again without solid precipitation.Filtering, obtains compound IV'sFaint yellow solid crude product 44.2g.It is directly used in lower step, HPLC:97.8%, yield: 81.2%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V30.0g (0.12mol) is added in 2L reaction flask, 300mL xylene solution is added with stirring 40.8g240mL anhydrous tetrahydro furan is added simultaneously in (0.15mol) compound IV.System is cooled to -15 DEG C after 10min is stirred at room temperature, toTemperature is added portionwise sodium triacetoxy borohydride 31.6g (0.15mol) after stablizing, and system temperature is no more than 5 in adition process℃.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.12.5% food is added into filtrate for filteringSalt water 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 300gX2, then with 300g concentration 5%Sodium bicarbonate solution is washed, and is finally washed with 300g saturated common salt.Organic layer filters precipitation after being cooled to -30 DEG C of heat preservation 30minInorganic salts.240mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate is slowInsulated and stirred 2-4h after being cooled to 10 DEG C has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 50mLIt washs, obtains purification wet product 60.1g, 43.8g compound VI, HPLC:99.2% are obtained after drying.Yield: 80.4%.
The synthesis of compound VIII
Compound VI47.0g (0.10mol) is added in 1L reaction flask, 600g Isosorbide-5-Nitrae-dioxane, 24.3g (0.12mol)Compound VII, 23.0g (0.16mol) cuprous bromide and 33.2g (0.24mol) potassium carbonate.After system is heated to 60 DEG C of reaction 6hIt is controlled in TLC or HPLC, raw material fully reacting.System filtering sequentially adds 500g methylene chloride and 500g saturation food into filtrateSalt water is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g is added into systemMethanol, while the sodium hydroxide that 40g weight content is 20% is added, HPLC or TLC hydrolysis is anti-after being warming up to 65 DEG C of stirring 2-3hIt should terminate.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, mistake after insulated and stirred 1hFilter, obtains the faint yellow solid object 44.3g of compound VIII, yield: 75.2%, HPLC:98.3%.The synthesis of compound I
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 20.9g(0.1lmol) EDCI and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5gThe solution of (0.064mol) compound VIII and 23.7g (0.23mol) triethylamine and 200mL methylene chloride is slowly dropped to above-mentionedIn system, drop finishes, and controls in HPLC or TLC after 20 DEG C of stirring 3h, raw material fully reacting.14.1gN, N '-diformazan are added into systemBase ethylenediamine.System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12%, stirring are added after temperature is stablizedAfter 10min, layering, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.It is organicLayer dries, filters, and 200mL acetonitrile is added after solvent is evaporated off, and methanol solution is added dropwise after being heated to 30 DEG C in system, after system clarificationStart to be cooled to 0-5 DEG C, and insulated and stirred 1h, filter, obtains compound as white solid I about 50.8g, yield after worry biscuit is dry91.4%, HPLC >=99.0%.
Embodiment 3
The synthesis of compound IV
34.2g (0.20mol) compound II, 2.9g (10.5mmol) tetra-tert ammonium chloride is added in 1L reaction flask(TBAC), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mL toluene.It finishes, system heatingTo 80 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 10h, HPLC or TLC, raw material fully reacting stops reaction.Filtering, filtrate decompression are spin-dried for.Into system be added 200mL tetrahydrofuran, be stirred at room temperature it is lower HBr gas is passed through into filtrate, directlyIt is precipitated again without solid into system.Filtering, obtains the yellow solid crude product 49.2g of compound IV.It is directly used in lower step, HPLC:97.6%, yield: 77.9%.The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V30.0g (0.12mol) is added in 2L reaction flask, 300mL1,4- dioxane solution is added with stirring240mL anhydrous tetrahydro furan is added simultaneously in 47.4g (0.15mol) compound IV.System is cooled to 0 after 10rmin is stirred at room temperatureDEG C, it is added portionwise sodium triacetoxy borohydride 31.6g (0.15mol) after temperature is stablized, system temperature is not in adition processMore than 5 DEG C.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.Filtering, is added into filtrate12.5% saline solution 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 300gX2, then is usedThe sodium bicarbonate solution of 300g concentration 5% is washed, and is finally washed with 300g saturated common salt.Organic layer is cooled to -30 DEG C of heat preservation 30minThe inorganic salts of precipitation are filtered afterwards.240mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, after solid dissolved clarification againFiltering, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C have a large amount of solids to be precipitated at this time in system, filtering, and filter cake is with coldAcetonitrile 50mL washing, obtain purification wet product 63.5g, after drying 45.4g compound VI, HPLC:99.0%.Yield:80.8%.
The synthesis of compound VIII
Compound VI47.0g (0.10mol) is added in 2L reaction flask, 800g toluene, 24.3g (0.12mol) compoundVII, 15.8g (0.16mol) stannous chloride and 7.2g (0.18mol) sodium hydroxide.System be heated to after 40 DEG C of reaction 5h TLC orIt is controlled in HPLC, raw material fully reacting.System filtering, 500g saturated salt solution is added into filtrate, is layered after stirring 10min, onLayer organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g methanol is added into system, while 40g weight is added and containsThe sodium hydroxide that amount is 20%, HPLC or TLC hydrolysis terminates after being warming up to 65 DEG C of stirring 2-3h.Stop reaction, under stirringAcetum tune pH to 5-6 is added dropwise, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, obtains the yellowish of compound VIIIColor solids 42.6g, yield: 72.3%, HPLC:97.9%.
The synthesis of compound I
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 13.9g(0.11mol) DIC and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5g (0.064mol)The solution of compound VIII and 23.7g (0.23mol) triethylamine and 200mL methylene chloride is slowly dropped in above-mentioned system, dropFinish, is controlled in HPLC or TLC after 0 DEG C of stirring 6h, raw material fully reacting.14.1gN, N '-dimethyl-ethylenediamine are added into system.System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12% is added after temperature is stablized, after stirring 10min, pointLayer, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.Organic layer is dry, mistake300mL ethyl acetate is added after solvent is evaporated off in filter, and ethanol solution is added dropwise after being heated to 55 DEG C in system, starts after system clarificationIt is cooled to 0-5 DEG C, and insulated and stirred 1h, is filtered, obtains compound as white solid I about 49.7g, yield after worry biscuit is dry89.5%, HPLC >=99.0%.
Embodiment 4
The synthesis of compound IV
17.0g (0.10mol) compound II, 1.6g (4.2mmol) tetra-tert ammonium iodide is added in 1L reaction flask(TBAI), 15.2g (0.11mol) potassium carbonate and 20.5g (0.11mol) compound III and 200mLDMF.It finishes, system heatingTo 90 DEG C of reaction 3h or so, controlled in be cooled to after room temperature that the reaction was continued 6h, HPLC or TLC, raw material fully reacting stops reaction.Filtering, 200mL ethyl acetate is added into filtrate, and 1h is stirred at room temperature in 24mL40% hydrobromic acid solution.Filtering, obtains compoundThe yellow solid crude product 27.6g of IV.It is directly used in lower step, HPLC:98.0%, yield: 87.1%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V 12.5g (0.05mol) is added in 2L reaction flask, 200mL toluene solution is added with stirring 20.0g200mL anhydrous tetrahydro furan is added simultaneously in (0.063mol) compound IV.System is cooled to -20 DEG C after stirring 10min at room temperature,Sodium triacetoxy borohydride 13.4g (0.063mol) is added portionwise after temperature is stablized.It finishing, 4h is stirred at room temperature in system,It is controlled in HPLC or TLC, raw material fully reacting.12.5% saline solution 150g is added into filtrate for filtering, divides after stirring 30minLayer.Upper organic layer is washed with 10% citric acid solution 150gX2, then is washed with the sodium bicarbonate solution of 150g concentration 5%, is finally usedThe washing of 150g saturated common salt.Organic layer filters the inorganic salts of precipitation after being cooled to -30 DEG C of heat preservation 30min.Half is concentrated in organic layer150mL acetonitrile is added afterwards, system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate slow cooling to insulated and stirred after 10 DEG C2-4h has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 50mL, obtains 19.5gization after filter cake dryingClose object VI, HPLC:99.1%.Yield: 83.3%.
The synthesis of compound VIII
Compound VI18.8g (0.04mol) is added in 1L reaction flask, 200gDMSO, 9.5g (0.048mol) compoundVII, 12.2g (0.064mol) cuprous iodide and 31.3g (0.096mol) cesium carbonate.System is heated to TLC after 80 DEG C of reaction 3hOr it is controlled in HPLC, raw material fully reacting.System filtering, 400g methylene chloride and 200g saturated common salt are sequentially added into filtrateWater is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 200gX2, and solvent is evaporated off.200g first is added into systemAlcohol, while it is 20% sodium hydroxide that 16g content, which is added, HPLC or TLC hydrolysis terminates after being warming up to 65 DEG C of stirring 2-3h.StopIt only reacts, stirs lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, changedClose the faint yellow solid object 19.0g of object VIII, yield: 83.0%, HPLC:98.6%.
The synthesis of compound I
Compound IX9.5g (0.03mol) is added in 2L reaction flask, 7.3g (0.06mol) DMAP, 10.5g (0.051mol)DCC and 250mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 17.1g (0.03mol) compound VIIIIt is slowly dropped in above-mentioned system with the solution of 10.9g (0.11mol) triethylamine and 200mL methylene chloride, drop finishes, 0 DEG C of stirringIt is controlled in HPLC or TLC after 6h, raw material fully reacting.6.6gN, N '-dimethyl-ethylenediamine are added into system.System is heated to 35DEG C continue to stir, the acetum of 94mL concentration 12% is added after temperature is stablized, after stirring 10min, layering, organic layer is used5% sodium bicarbonate solution 100mL is washed, then is washed with 5% sodium chloride solution 100mL.Organic layer dries, filters, and solvent is evaporated off100mL acetonitrile is added afterwards, ethanol solution is added dropwise after being heated to 55 DEG C in system, starts to be cooled to 0-5 DEG C after system clarification, and protectTemperature stirring 1h, filtering, consider biscuit it is dry after obtain compound as white solid I about 21.5g (theoretical yield 26.1g), yield 82.3%,HPLC >=99.0%.
Embodiment 5
The synthesis of compound IV
17.0g (0.10mol) compound II, 1.7g (5.3mmol) tetra-tert ammonium bromide is added in 1L reaction flask(TBAB), 15.2g (0.22mol) potassium carbonate and 20.5g (0.11mol) compound III and 300mL toluene.It finishes, system heatingTo 30 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 12h, HPLC or TLC, raw material fully reacting stops reaction.Filtering, be stirred at room temperature it is lower HCl gas is passed through into filtrate, until system in again without solid precipitation.Filtering, obtains compound IV'sFaint yellow solid crude product 22.5g.It is directly used in lower step, HPLC:98.3%, yield: 82.5%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V15.0g (0.06mol) is added in 1L reaction flask, 200mL1,4- dioxane is added with stirring 20.4g120mL anhydrous tetrahydro furan is added simultaneously in (0.075mol) compound IV.System is cooled to -10 DEG C after 10min is stirred at room temperature, toTemperature is added portionwise sodium triacetoxy borohydride 15.8g (0.075mol) after stablizing, and system temperature is no more than 5 in adition process℃.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.12.5% food is added into filtrate for filteringSalt water 150g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 150gX2, then with 150g concentration 5%Sodium bicarbonate solution is washed, and is finally washed with 150g saturated common salt.Organic layer filters precipitation after being cooled to -30 DEG C of heat preservation 30minInorganic salts.120mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate is slowInsulated and stirred 2-4h after being cooled to 10 DEG C has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 30mLIt washs, obtains purification wet product 39.1g, 23.3g compound VI, HPLC:99.1% are obtained after drying.Yield: 83.0%.
The synthesis of compound VIII
Compound VI18.8g (0.04mol) is added in 1L reaction flask, 250g Isosorbide-5-Nitrae-dioxane, 9.5g (0.048mol)Compound VII, 12.2g (0.064mol) cuprous iodide and 5.4g (0.096mol) potassium hydroxide.System is heated to 60 DEG C of reactionsIt is controlled in TLC or HPLC after 3h, raw material fully reacting.System filtering, 300g methylene chloride is sequentially added into filtrate and 200g is fullAnd saline solution, it is layered after stirring 10min, lower organic layer is washed with saturated salt solution 200gX2, and solvent is evaporated off.It is added into system200g methanol, while the sodium hydroxide that 16g weight content is 20% is added, it is warming up to HPLC or TLC water after 65 DEG C of stirring 2-3hSolution reaction terminates.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, insulated and stirred 1hAfter filter, obtain the faint yellow solid object 18.8g of compound VIII, yield: 82.2%, HPLC:98.1%.The conjunction of compound IAt
Compound IX9.5g (0.03mol) is added in 1L reaction flask, 7.3g (0.06mol) DMAP, 9.8g (0.051mol)EDCI and 200mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 17.1g (0.03mol) compoundThe solution of VIII and 10.9g (0.11mol) triethylamine and 70mL methylene chloride is slowly dropped in above-mentioned system, and drop finishes, and 20 DEG CIt is controlled in HPLC or TLC after stirring 3h, raw material fully reacting.6.6gN, N '-dimethyl-ethylenediamine are added into system.System heatingContinue to stir to 35 DEG C, the acetum of 94mL concentration 12% is added after temperature is stablized, after stirring 10min, layering, organic layerIt is washed with 5% sodium bicarbonate solution 100mL, then is washed with 5% sodium chloride solution 100mL.Organic layer dries, filters, and is evaporated off molten100mL acetonitrile is added after agent, ethanol solution is added dropwise after being heated to 30 DEG C in system, start to be cooled to 0-5 DEG C after system clarification, andInsulated and stirred 1h, filtering obtain compound as white solid I about 23.6g, yield 90.5%, HPLC >=99.0% after worry biscuit is dry.
Embodiment 6
The synthesis of compound IV
17.1g (0.10mol) compound II, 1.5g (5.3mmol) tetra-tert ammonium chloride is added in 1L reaction flask(TBAC), 15.1g (0.11mol) potassium carbonate and 20.5g (0.11mol) compound III and 250mLTHF.It finishes, system heatingTo 30 DEG C of reaction 7h or so, controlled in be cooled to after room temperature that the reaction was continued 14h, HPLC or TLC, raw material fully reacting stops reaction.The lower dropwise addition 42mL concentrated hydrochloric acid solution into filtrate is stirred at room temperature, until being precipitated again without solid in system in filtering.Filtering, is changedClose the faint yellow solid crude product 23.7g of object IV.It is directly used in lower step, HPLC:97.1%, yield: 87.0%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V15.9g (0.064mol) is added in 1L reaction flask, 200mL tetrahydrofuran solution is added with stirring120mL anhydrous tetrahydro furan is added simultaneously in 22.0g (0.08mol) compound IV.System is cooled to -8 after 10min is stirred at room temperatureDEG C, it is added portionwise sodium triacetoxy borohydride 17.0g (0.08mol) after temperature is stablized, system temperature is not in adition processMore than 5 DEG C.It finishes, system is stirred at room temperature in 2h, HPLC or TLC and controls, raw material fully reacting.Filtering, is added into filtrate12.5% saline solution 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 200gX2, then is usedThe sodium bicarbonate solution of 200g concentration 5% is washed, and is finally washed with 200g saturated common salt.Organic layer is cooled to -30 DEG C of heat preservation 30minThe inorganic salts of precipitation are filtered afterwards.130mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, after solid dissolved clarification againFiltering, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C have a large amount of solids to be precipitated at this time in system, filtering, and filter cake is with coldAcetonitrile 30mL washing, obtain purification wet product 48.9g, after drying 25.7g compound VI, HPLC:99.1%.Yield:85.8%.
The synthesis of compound VIII
Compound VI23.5g (0.05mol) is added in 1L reaction flask, 260gDMF, 12.2g (0.06mol) compound VII,11.5g (0.08mol) cuprous bromide and 12.7g (0.12mol) sodium carbonate.System be heated to after 60 DEG C of reaction 6.5h TLC orIt is controlled in HPLC, raw material fully reacting.System filtering, 250g methylene chloride and 250g saturated salt solution are sequentially added into filtrate,It is layered after stirring 10min, lower organic layer is washed with saturated salt solution 150gX2, and solvent is evaporated off.250g methanol is added into system,The sodium hydroxide that 20g weight content is 20% is added simultaneously, is warming up to HPLC or TLC hydrolysis knot after 65 DEG C of stirring 2-3hBeam.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, obtainsTo the faint yellow solid object 21.2g of compound VIII, yield: 74.4%, HPLC:98.7%.
The synthesis of compound I
Ⅸ 15.8g of compound (0.05mol) is added in 1L reaction flask, 12.2g (0.1mol) DMAP, 10.7g(0.085mol) DIC and 250mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 28.6g (0.05mol)The solution of compound VIII and 18.2g (0.18mol) triethylamine and 100mL methylene chloride is slowly dropped in above-mentioned system, dropFinish, is controlled in HPLC or TLC after 20 DEG C of stirring 3h, raw material fully reacting.11.0gN, N '-dimethyl-ethylenediamine are added into system.System is heated to 35 DEG C and continues to stir, and the acetum of 160mL concentration 12% is added after temperature is stablized, after stirring 10min, pointLayer, organic layer is washed with 5% sodium bicarbonate solution 160mL, then is washed with 5% sodium chloride solution mL.Organic layer dries, filters,240mL ethyl acetate is added after solvent is evaporated off, methanol solution is added dropwise after being heated to 50 DEG C in system, starts to cool down after system clarificationTo 0-5 DEG C, and insulated and stirred 1h, filtering, consider biscuit it is dry after obtain compound as white solid I about 39.2g, yield 90.3%,HPLC >=99.0%.