CN110256441A - A kind of Ba Ruike replaces the preparation method of Buddhist nun - Google Patents
A kind of Ba Ruike replaces the preparation method of Buddhist nun Download PDFInfo
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- CN110256441A CN110256441A CN201910546711.1A CN201910546711A CN110256441A CN 110256441 A CN110256441 A CN 110256441A CN 201910546711 A CN201910546711 A CN 201910546711A CN 110256441 A CN110256441 A CN 110256441A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention relates to the preparation methods that Ba Ruike replaces Buddhist nun.Condensation reaction occurs by starting material and Wittig-Horner reagent of N- tertbutyloxycarbonyl -4- piperidones, obtains 3- (2- Oxymethylene) azetidine -1- t-butyl formate, then Michael addition reaction occurs with pyrazoles -4- pinacol borate.Simultaneously under the action of metallic catalyst cross-coupling reaction occurs gained pinacol ester intermediate for pyrimidine derivatives with 4- chlorobenzene again.Finally, passing through functional group conversions for R1Be converted into cyano and deprotection and etc. i.e. complete Ba Ruike replace Buddhist nun preparation.
Description
Technical 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 by
A kind of selectivity of EliLilly and Incyte company R & D Cooperation, invertibity JAK1 and JAK2 inhibitor, IC50Respectively
5.9nM and 5.7nM.Clinically treatment of the exploitation for inflammation disease and autoimmune disease, including class wind at present
Wet 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 for
Moderate 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.2018
June, 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 sulphur
Acyl 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 molecule
Structure 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, indyl
Deng.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 Rui
Gram replace Buddhist nun.Specific route is as follows:
2016, there is document (Journal of Chemical Research, 2016,40,205-208.) report to this
Patent synthetic route optimizes, and author successively passes through Wittig- using N- tertbutyloxycarbonyl -4- piperidones as starting material
Horner (Wittig-Huo Naer) reaction, the removing of N-Boc protecting group, sulfuryl amine, pyrazoles -4- pinacol borate
Michael addition reaction finally prepares Ba Ruike by Suzuki coupling reaction with 4- chloropyrrolo [2,3-d again and replaces Buddhist nun.It is synthesizing
Eliminated 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, always
Yield can achieve 49%.
2016, EliLilly (WO2016205487) proposed that a kind of synthesis Ba Ruike replaces the side of Buddhist nun and its key intermediate
Method.Central synthetic steps include: pyrazoles -4- pinacol borate to 2- [1- (ethylsulfonyl) -3- azetidin subunit] second
Then 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 again
Reaction 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] acetonitrile
Michael addition reaction, obtained intermediate removes Boc protecting group in acid condition, then reacts through ethyl sulfonamide
And 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 nun
At 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 it
Between 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 metaplasia
The 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 reagent
Addition 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 methylene
Base triphenylphosphine, phosphonium mesitoyl methyl acetate diethyl, ethoxycarbonyl methylene triphenyl phosphine, (N- methoxyl group-N- first carbonyl first
Base) 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), methylene
Base (=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}].Reaction
Ligand 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 invention
Range.
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.).Gained
Mixture, 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 progress
It 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 1L
Product, 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 instead
It 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 purifying
Body 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) with
And 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 separates
Organic 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 plus
Enter I2(125g,493mmol,1.1eq.).Gained mixture is stirred at room temperature detection in about 2 hours or so to reaction and has carried out
Entirely.Na is added2S2O3Solution quenching reaction is extracted with ethyl acetate (2 × 300mL) twice, merges organic phase, through column after concentration
Chromatography 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 excessively
Sour 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 C
Forced air drying about obtains Ba Ruike for 24 hours and replaces Buddhist nun (100g, 94%).
Claims (8)
1. a kind of method for preparing Ba Ruike and replacing Buddhist nun, reaction equation are as follows:
2. having 3- (R as shown in claim 11Methylene) azetidine -1- t-butyl formate (Formula II) preparation side
Method, it is characterised in that addition condensation reaction occurs for N- tertbutyloxycarbonyl -4- piperidones (Formulas I) and Wittig-Horner reagent, obtains
To 3- substituted azetidine -1- t-butyl formate (Formula II).
3. the Wittig-Horner reagent in claim 2 includes: cyanogen methyl acid phosphate diethylester, methoxycarbonyl methylene three
Phenylphosphine, phosphonium mesitoyl methyl acetate diethyl, ethoxycarbonyl methylene triphenyl phosphine, (N- methoxyl group-N- first carbonvlmethyl)
Diethyl phosphate phosphine acyl acetic acid three ethyl, (formyl methylene) triphenyl phosphine.
4. the compound with Formula IV as shown in claim 1.
5. the preparation method with Formula IV compound as shown in claim 1, it is characterised in that pyrazoles -4- pinacol borate
Michael addition reaction occurs for (formula III) and 3- (aldehyde radical methylene) azetidine -1- t-butyl formate (Formula II).
6. the preparation method with Formula VII compound as shown in claim 1, it is characterised in that function occurs for Formula IV compound
Group's conversion forms cyano compound (Formula VII).
7. the R of claim 6 compound of formula VI1Group be aldehyde radical (- CHO), carboxyl ester (- CO2Me), methylene (=
CH2)。
8. replacing the preparation method of Buddhist nun with as shown in claim 1 bar of Rake, it is characterised in that removed by Formula VII compound
Amino protecting group realizes that Ba Ruike replaces the preparation of Buddhist nun.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114302886A (en) * | 2019-12-16 | 2022-04-08 | 上海赛默罗生物科技有限公司 | Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof |
| CN117355527A (en) * | 2021-07-20 | 2024-01-05 | 上海椿安生物医药科技有限公司 | External anti-inflammatory coupling compound medicine and preparation method and application thereof |
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| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
| CN105294699A (en) * | 2015-12-04 | 2016-02-03 | 上海勋和医药科技有限公司 | Method for preparing baricitinib |
| CN106554363A (en) * | 2015-09-28 | 2017-04-05 | 正大天晴药业集团股份有限公司 | A kind of preparation method of Baricitinib intermediates |
| CN106946917A (en) * | 2017-03-20 | 2017-07-14 | 杭州科巢生物科技有限公司 | A kind of JAK inhibitor Ba Rui is for Buddhist nun and its novel synthesis of intermediate |
| CN107176955A (en) * | 2017-03-24 | 2017-09-19 | 南京优科制药有限公司 | A kind of Ba Rui replaces the preparation method of Buddhist nun |
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2019
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102026999A (en) * | 2008-03-11 | 2011-04-20 | 因塞特公司 | Azetidine and cyclobutane derivatives as JAK inhibitors |
| CN106554363A (en) * | 2015-09-28 | 2017-04-05 | 正大天晴药业集团股份有限公司 | A kind of preparation method of Baricitinib intermediates |
| CN105294699A (en) * | 2015-12-04 | 2016-02-03 | 上海勋和医药科技有限公司 | Method for preparing baricitinib |
| CN106946917A (en) * | 2017-03-20 | 2017-07-14 | 杭州科巢生物科技有限公司 | A kind of JAK inhibitor Ba Rui is for Buddhist nun and its novel synthesis of intermediate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114302886A (en) * | 2019-12-16 | 2022-04-08 | 上海赛默罗生物科技有限公司 | Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof |
| CN114302886B (en) * | 2019-12-16 | 2024-03-22 | 上海赛默罗生物科技有限公司 | Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof |
| CN117355527A (en) * | 2021-07-20 | 2024-01-05 | 上海椿安生物医药科技有限公司 | External anti-inflammatory coupling compound medicine and preparation method and application thereof |
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Address after: 223800 No. 38 Yangzi Road, Eco-chemical Science and Technology Industrial Park, Suyu District, Suqian City, Jiangsu Province Applicant after: Jiangsu junruo Pharmaceutical Co., Ltd Applicant after: HAIMEN BAIKANG PHARMACEUTICAL Co.,Ltd. Applicant after: Nanjing Junruo Biomedical Research Institute Co.,Ltd. Address before: 223800 No. 38 Yangzi Road, Eco-chemical Science and Technology Industrial Park, Suyu District, Suqian City, Jiangsu Province Applicant before: JIANGSU JUNRUO PHARMACEUTICAL Co.,Ltd. Applicant before: HAIMEN BAIKANG PHARMACEUTICAL Co.,Ltd. Applicant before: Nanjing Junruo Biomedical Research Institute Co.,Ltd. |
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