A kind of Ba Ruike replaces the preparation method of Buddhist nunTechnical field
The present invention relates to raw material medicament preparation technical fields, and in particular to drug Ba Ruike replaces the preparation method of Buddhist nun.
Background technique
Ba Ruike replace Buddhist nun (Baricitinib, LY3009104 or INCB028050), trade name: Olumiant, be byA kind of selectivity of EliLilly and Incyte company R & D Cooperation, invertibity JAK1 and JAK2 inhibitor, IC50Respectively5.9nM and 5.7nM.Clinically treatment of the exploitation for inflammation disease and autoimmune disease, including class wind at presentWet arthritis (RA), ankylosing spondylitis (AS), psoriasis, atopic dermatitis, systemic loupus erythematosus, ulcerative enteritis(UC), alopecia areata etc..2 months 2017, Ba Ruike obtained European Union's approval for Buddhist nun, as a kind of single medicine or joint methotrexate (MTX), was used forModerate that is insufficient or not tolerating is alleviated to severe activity rheumatoid to one or more disease-modifying antirheumatic drugs (DMARD)The treatment of property arthritis adult patient.This is also the first JAK inhibitor of European Union's approval treatment rheumatoid arthritis.2018June, U.S. FDA have approved Ba Ruike for Buddhist nun's listing, suffer from moderate to severe rheumatoid arthritis for treating.
Ba Ruike replaces Buddhist nun's chemistry English name are as follows: 1- (Ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d]Pyrimidin-4-yl) -1H-pyrazol-1-yl] -3-azetidineacetonitril e, Chinese: 1- (ethyl sulphurAcyl group) -3- [4- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl] -3- azetidine acetonitrile.CAS:1187594-09-7, molecular formula C16H17N7O2S contains pyrrolopyrimidine, pyrazoles, azetidine core in the drug moleculeStructure fragment and possess a quaternary carbon center, structural formula is as follows:
Most early in 2007, Incyte company report for the first time Ba Ruike for Buddhist nun synthetic method (US20070135461,WO2009114512 patent protection), and to Ba Ruike for the structure of Buddhist nun is carried out, as follows:
Wherein, L=SO2Or CO；R1=(non-) substitution alkyl, cyclic alkyl, phenyl, 5,6- member heteroaryl perfume bases, indylDeng.From N- tertbutyloxycarbonyl -4- piperidones and cyanogen methyl acid phosphate diethylester by series reaction, comprising: Wittig-Horner reaction, Suzuki coupling reaction, Michael addition reaction and protection and removing and protection and etc. synthesis Ba RuiGram replace Buddhist nun.Specific route is as follows:
2016, there is document (Journal of Chemical Research, 2016,40,205-208.) report to thisPatent synthetic route optimizes, and author successively passes through Wittig- using N- tertbutyloxycarbonyl -4- piperidones as starting materialHorner (Wittig-Huo Naer) reaction, the removing of N-Boc protecting group, sulfuryl amine, pyrazoles -4- pinacol borateMichael addition reaction finally prepares Ba Ruike by Suzuki coupling reaction with 4- chloropyrrolo [2,3-d again and replaces Buddhist nun.It is synthesizingEliminated in route to the protection of the SEM silicon substrate of 4- chloropyrrolo [2,3-d and Deprotection and etc., synthetic route is more brief, alwaysYield can achieve 49%.
2016, EliLilly (WO2016205487) proposed that a kind of synthesis Ba Ruike replaces the side of Buddhist nun and its key intermediateMethod.Central synthetic steps include: pyrazoles -4- pinacol borate to 2- [1- (ethylsulfonyl) -3- azetidin subunit] secondThen the cross-coupling of metal catalytic is passed through in the Michael addition reaction of nitrile with 4- chloropyrrolo [2,3-d -7- carboxylic acid tert-butyl ester againReaction preparation Ba Ruike replaces Buddhist nun, and the synthetic route is as follows:
2017, Egis company (WO2017109524A1) reported (4- (1H-pyrazol-3-yl) -7H-pyrrolo[2,3-d] pyrimidin-7-yl) methyl pivalate and 2- [1- (ethylsulfonyl) -3- azetidin subunit] acetonitrileMichael addition reaction, obtained intermediate removes Boc protecting group in acid condition, then reacts through ethyl sulfonamideAnd etc. preparation Ba Ruike replace Buddhist nun, patent synthetic route is as follows:
In addition, there are also other many patents to Ba Ruike for synthetic method (such as CN108129482 conjunction of each segment of Buddhist nunAt pyrrole ring and aza cyclo-butanone) etc., different protecting groups (such as CN106946917 protects pyrrolopyrimidine with BOC,CN107176955 with benzenesulfonyl protect pyrrolopyrimidine, WO2016088094A1 with SEM protect pyrrolopyrimidine) and segment itBetween the order of connection (CN106496195A) optimize combination etc..
Summary of the invention
The present invention relates to the variation routes that Ba Ruike replaces Buddhist nun, and preparation method is simple, wide application range of substrates, are suitble to industry metaplasiaThe features such as production, has apparent technical advantage.
Synthetic route of the invention is as follows:
The first step of the present invention is related to starting material N- tertbutyloxycarbonyl -4- piperidones (Formulas I) and Wittig-Horner reagentAddition condensation reaction occurs, obtains 3- substituted azetidine -1- t-butyl formate (Formula II).
The Wittig-Horner reagent that first step reaction uses includes: cyanogen methyl acid phosphate diethylester, methoxycarbonyl base methyleneBase triphenylphosphine, phosphonium mesitoyl methyl acetate diethyl, ethoxycarbonyl methylene triphenyl phosphine, (N- methoxyl group-N- first carbonyl firstBase) diethyl phosphate phosphine acyl acetic acid three ethyl, (formyl methylene) triphenyl phosphine.
R in compound Formula II1For cyano (- CN), aldehyde radical (- CHO), carboxyl ester (- CO2Me), methylene (=CH2)；Compound Formula II are as follows: 3- (cyanomethylene) azetidine -1- t-butyl formate, 3- (aldehyde radical methylene) azetidine -1- t-butyl formate, 3- (carboxyl ester methylene) azetidine -1- t-butyl formate, 3- (connection alkenyl) azetidine -1- t-butyl formate.
The solvent that first step reaction uses is THF, chlorobenzene, toluene, 2- methyltetrahydrofuran, Isosorbide-5-Nitrae-dioxane.
Reaction second step is related to Formula II compound and pyrazoles -4- pinacol borate (formula III) generation Michael addition is anti-It answers, obtains formula IV compound.R in compound formula IV1For cyano (- CN), aldehyde radical (- CHO), carboxyl ester (- CO2Me), methyleneBase (=CH2)。
React second step Michael addition reaction involved in alkali be NaOH, NaOMe, NaOEt, t-BuOK, DBU,DBACO。
Reacting catalyst involved in second step addition reaction is [{ Rh (cod) Cl }2],[{Rh(CO)2acac}].ReactionLigand involved in second step addition reaction is DPEphos, JoSPOphos, 6-DPPon.
Reaction third step is related to the cross-coupling reaction of formula IV compound and 4- chlorobenzene and pyrimidine derivatives Formula V compound,Prepare intermediate compound of formula VI.
R in Formula V2For trimethyl silicon substrate ethyl, special penta carbonyl.
R in compound Formula IV1For cyano, aldehyde radical, carboxyl ester, methylene.
The solvent that third step reaction uses is THF, toluene, 2- methyltetrahydrofuran, dioxane.
The metallic catalyst that third step reaction uses includes Pd2(dba)3,PdCl2(PPh3)2,Pd(dppf)Cl2,Fe(PtBu2)-HBF4,PdCl2[dtbpf],Pd(PPh3)4。
It reacts the 4th step and is related to Formula IV compound functional group conversions reaction preparation formula VII compound.
Four-step reaction institute includes THF using solvent, DMSO, 1,4-dixoane, H2O, toluene, chloroform, acetonitrile.
Four-step reaction institute includes 9-BBN using reagent, H2O2,(COCl)2,NH4OH,I2。
It reacts the 5th step and is related to the preparation that Formula VII compound removal amino protecting group completion Ba Ruike replaces Buddhist nun.
5th step reaction institute using solvent include ethyl alcohol, methanol, isopropanol, THF, ethyl acetate, 2- methyltetrahydrofuran,Dioxane, toluene, acetonitrile.
5th step reaction institute includes HCl, HOAc, CF using deprotection base reagent3CO2H、AcCl。
Specific embodiment
The present invention can be more specifically understood by the following examples, but it illustrates rather than the limitation present inventionRange.
Embodiment
1,3- (2- Oxymethylene) azetidine -1- t-butyl formate (Formula II, R are prepared1=CHO)
Anhydrous CH is added in the flask bottle of 1000mL2Cl2(300ml) sequentially adds N- tertbutyloxycarbonyl -4- piperidones(100g, 584.1mmol, 1.0eq.) and methoxycarbonyl methylene triphenylphosphine (177g, 584.1mmol, 1.0eq.).GainedMixture, which is heated at 40 DEG C heating reaction 5 hours to reaction, to be terminated.Solvent concentration, it is anti-in next step that residue drains directly progressIt answers.
2, key intermediate (formula IV, R are prepared1=CHO)
It is (thick that 3- (2- Oxymethylene) azetidine -1- t-butyl formate is added under nitrogen protection, in the reaction flask of 1LProduct, ca.580mmol, 1.0eq.), pyrazoles -4- pinacol borate (formula III) (112g, 580mmol, 1.0eq.) and benzoic acid(2.0g, cat.) and toluene (300mL).Mixed system is reacted to stir to reaction progress completely.System is added water (250mL) and is quenched insteadIt answers, then system is extracted three times (3x100mL) using toluene, merging organic phase, organic phase saturated common salt water washing (200mL),Gained residue after organic phase removed under reduced pressure organic solvent.Residue obtains crucial centre using silica gel column chromatography fast separating and purifyingBody formula IV (226g, 86%) is colorless oil.
3, key intermediate (Formula IV, R are prepared1=CHO)
In 1000mL reaction flask, it is added key intermediate formula IV (200g, 512mmol, 1.0eq.), CH3CN (300mL) withAnd 4- chloropyrrolo [2,3-d derivative (Formula V, R2=CH2CH2TMS)(145g,512mmol,1.0eq.).Add Pd (dppf)Cl2(20g, 5mol%) and KOAc (60g, 1.2eq.).Mixture is heated to reacting 6 hours at 80 DEG C to reaction progress completely.Ethyl acetate (200mL) and H are added into residue2O (150mL), stands after stirring, is filtered to remove solid insoluble.It separatesOrganic phase, water phase are extracted with ethyl acetate (2 × 300mL) twice again, merging organic phase, organic phase removed under reduced pressure organic solvent,Residue column chromatography rapidly purifies (ethyl acetate/normal heptane=1/4-1/1) and obtains white solid (formula IV, R1=CHO, R2=CH2CH2TMS) (236g, 90%).
4, key intermediate (Formula VII, R are prepared1=CN, R2=CH2CH2TMS)
In 1000mL reaction flask, key intermediate Formula IV (R1=CHO, R2=CH2CH2TMS)(230g,448mmol,1.0eq.) it is dissolved in THF (300mL) and H2The solution of O (50mL) is slowly added to 25% ammonium hydroxide (160mL, 1.2mol), then plusEnter I2(125g,493mmol,1.1eq.).Gained mixture is stirred at room temperature detection in about 2 hours or so to reaction and has carried outEntirely.Na is added2S2O3Solution quenching reaction is extracted with ethyl acetate (2 × 300mL) twice, merges organic phase, through column after concentrationChromatography rapidly purifies (ethyl acetate/normal heptane=1/5-1/3) and obtains white solid (formula IV, R1=CHO, R2=CH2CH2TMS)(173g, 76%).
5, preparation Ba Ruike replaces Buddhist nun
In 1000mL reaction flask, key intermediate (Formula VII, R1=CN, R2=CH2CH2TMS)(170g,334mmol,It 1.0eq.) is dissolved in methanol (300mL), is cooled at 0 DEG C, chloroacetic chloride (48mL, 2.0eq.) is slowly added dropwise.After being added dropwise,Detection reaction carries out completely after system is heated to (65 DEG C) reaction 6h of reflux.It is naturally cooling to room temperature.It is concentrated under reduced pressure and removes excessivelySour gas and most of solvent, filter, and filter cake elutes 2 times (100mL) with cold methanol, and gained white solid powder is placed in 50 DEG CForced air drying about obtains Ba Ruike for 24 hours and replaces Buddhist nun (100g, 94%).