CN106554363A - A kind of preparation method of Baricitinib intermediates - Google Patents
A kind of preparation method of Baricitinib intermediates Download PDFInfo
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- CN106554363A CN106554363A CN201510628431.7A CN201510628431A CN106554363A CN 106554363 A CN106554363 A CN 106554363A CN 201510628431 A CN201510628431 A CN 201510628431A CN 106554363 A CN106554363 A CN 106554363A
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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
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Abstract
The invention belongs to field of medicine and chemical technology, in particular to a kind of preparation method of Baricitinib intermediates, the preparation method of the present invention, key intermediate 2- [1- ethylsulfonyl -3- [4- (4 are prepared by 4- pyrazoles boride and 2- [1- (ethylsulfonyl) -3- azetidin subunits] acetonitrile reaction, 4, 5, 5- tetramethyls -1, 3, penta ring -2- bases of 2- dioxos boron) -1H- pyrazol-1-yls] azetidin -3- bases] acetonitrile, without the need for protecting to the nitrogen on 4- pyrazoles boride pyrazole rings, so as to subsequently not slough the corresponding protection group step yet, therefore whole reaction scheme is short, raw material is more easy to obtain, low production cost, it is particularly suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, in particular to a kind of preparation method of Baricitinib intermediates.
Background technology
Baricitinib, entitled { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo-es [2,3-d] the pyrimidine-4-yl) -1H- pyrazol-1-yls] nitrogen of chemistry
Azetidine -3- bases } acetonitrile, it is small molecule JAK-1 and JAK2 kinase inhibitors developed by Eli Lilly and Incyte companies,
For oral medication rheumatoid arthritis, psoriasis and other diseases associated with inflammation, and diabetic nephropathy.
CN102026999A discloses Baricitinib and its intermediate 2- [1- ethylsulfonyl -3- [4- (7- [(2- (trimethyl silyl)
Ethyoxyl) methyl] -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azetidine -3- bases] and acetonitrile (formula I) system
Preparation Method, the middle preparation are as follows：
Method 1：
Method 2：
Method 1 and method 2 are required to compound 2 first with compound 3 in Pd (PPh3)4In the presence of reaction prepare intermediate
4- (1- (1- ethoxyethyl groups) -1H- pyrazoles -4- bases) -7- ((2- (trimethyl silyl) ethyoxyl) methyl) -7H- pyrrolo-es [2,3-d] are phonetic
Pyridine (compound 6), then sloughs 1- ethoxyethyl group protection groups and obtains intermediate 4- (1H- pyrazoles -4- bases) -7- ((2- (trimethyl first silicon
Alkyl) ethyoxyl) methyl) -7H- pyrrolo-es [2,3-d] pyrimidine (compound 5), then subsequent reactions are carried out by the intermediate；Due to changing
Compound 3 is by connecting " 1- ethoxyethyl groups " and " 4,4,5,5- tetramethyls on the relevant position of the structure of 1H- pyrazoles respectively
- 1,3,2- dioxaborolan alkane -2- bases " structure fragment is prepared (such as Qiyan Lin etc., Enantioselective
Synthesis of Janus Kinase Inhibitor INCB018424via an Organocatalytic Aza-Michael Reaction,
Organic Letters, 2009,11 (9), pp 1999-2002), therefore the reaction scheme of method 1 and method 2 has " 1- ethyoxyls
The connection of ethyl " protection group and two steps are sloughed, reaction scheme is long, production cost is high, does not accommodate industrialized production, therefore
New preparation method is remained a need for, to adapt to the demand of industrialized production.
The content of the invention
On the one hand, the present invention provides a kind of preparation method of type I compound, including：II compound of formula is being urged with III compound of formula
Reaction is carried out in the presence of agent and prepares type I compound,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 units are formed together with the oxygen atom being connected with them and boron atom miscellaneous
Ring, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, miscellaneous
Cycloalkyl, aryl or heteroaryl replace；
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom being connected with them and boron
Atom forms 5-8 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl replaces；
It is furthermore preferred that R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms 5-6 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-6 C1-6Alkyl replaces；
Most preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms following structure division together,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl；
In some specific embodiments of the present invention, R1And R2Formed together with the oxygen atom being connected with them and boron atom with
Lower structure division,
In some more specific embodiments of the present invention, the structure of II compound of formula is IV compound of formula, accordingly, formula I
Compound structure is V compound of formula,
It should be appreciated that II compound of formula can also be II compound pharmaceutically acceptable salt of formula or boric anhydride, as long as above-mentioned reaction
Can carry out；The oxygen that II compound of formula and type I compound are connected with boron atom can also be other atoms, as long as above-mentioned anti-
Should be able to carry out.
II compound of formula can be prepared by commercially available acquisition or by the method for prior art, and such as II compound of formula can pass through
Pyrazoles is prepared with the reagent reacting of appropriate boracic, specific example, and for example IV compound of formula can be by pyrazoles and connection boron
Sour pinacol ester reaction is prepared.
Wherein described catalyst is double selected from TMG, 11 carbon -7- alkene (DBU) of 1,8- diazabicyclos (5.4.0), 1,5- diazas
Ring (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclos (2.2.2) octane, t-butyl ammonium hydroxide, NaOH, potassium hydroxide, methyl alcohol
Sodium, caustic alcohol, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus,
One or more in potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate, preferably 1,8- diazabicyclos
(5.4.0) 11 carbon -7- alkene.
It should be appreciated that the present invention prepares the catalyst of type I compound also to include above-mentioned unrequited various reaction being promoted to carry out
Reagent, as long as the reaction can be carried out.
The wherein preparation of type I compound selects suitable solvent to be reacted as needed, the solvent selected from acetonitrile, methyl alcohol,
Ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid,
Acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, benzene,
One or more of toluene, dimethylbenzene, DMF, DMA or dimethyl sulfoxide, preferably second
One or more of nitrile, DMF or DMA, most preferably acetonitrile.
The wherein preparation of type I compound can select suitable reaction temperature as needed, such as reaction temperature can be from 0 DEG C to
The boiling point of reaction system, in some specific embodiments of the present invention, the reaction temperature is 25 DEG C.
Wherein described reaction can select the suitable reaction time as needed, and such as reaction time can be 0-48 hours, also may be used
Think 2-12 hours, in some specific embodiments of the present invention, the reaction time is 2 hours.
Wherein III compound of formula and the mol ratio of II compound of formula can be 1, it is also possible to more than 1 or less than 1；For example formula III is changed
Compound can be about 0.1-10, or about 0.8-1.5 with the mol ratio of II compound of formula；In some specific embodiments of the present invention
In, III compound of formula is about 1.34 with the mol ratio of II compound of formula.
Optionally, the preparation of type I compound can be carried out under the protection of nitrogen or argon gas.
Optionally, type I compound can further include following steps：
I. reaction is added in terminating backward reactant liquor and the immiscible organic solvent extraction of water,
Ii. concentrate,
It is wherein described to include but is not limited to ethyl acetate, butyl acetate, dichloromethane, three chloromethanes with the immiscible organic solvent of water
Alkane or ether etc., in one embodiment of the invention, described is ethyl acetate with the immiscible organic solvent of water.
On the other hand, the invention provides a kind of preparation method of VII compound of formula, including：VI compound of type I compound and formula
Carry out reacting VII compound of formula in the presence of palladium catalyst and alkali,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 units are formed together with the oxygen atom being connected with them and boron atom miscellaneous
Ring, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, miscellaneous
Cycloalkyl, aryl or heteroaryl replace；
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom being connected with them and boron
Atom forms 5-8 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl replaces；
It is furthermore preferred that R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms 5-6 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-6 C1-6Alkyl replaces；
Most preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms following structure division together,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl；
In some specific embodiments of the present invention, R1And R2Formed together with the oxygen atom being connected with them and boron atom with
Lower structure division,
In some more specific embodiments of the present invention, type I compound structure is V compound of formula,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or TFMS foundation group, preferably chlorine, bromine or iodine,
Most preferably chlorine.
Wherein P is blocking group, and the blocking group includes but is not limited to 2- (TMS) ethoxyl methyl (SEM), N-
Pentanoyloxymethyl (POM), benzyloxycarbonyl (Cbz), 2,2,2- tri-chloroethoxies base carbonyl (Troc), 2- (TMS) ethoxy
Base carbonyl (Teoc), 2- (4- trifluoromethyl sulfonyls) ethoxy carbonyl (Tsc), tert-butoxycarbonyl (BOC), 1- adamantyls
Epoxide carbonyl (Adoc), 2- adamantyl carbonyls (2-Adoc), 2,4- dimethyl-pentens -3- base Epoxide carbonyls (Doc), cyclohexyl epoxide carbonyl
Base (Hoc), 1,1- dimethyl -2,2,2- tri-chloroethoxies base carbonyl (TcBOC), vinyl, 2- chloroethyls, 2- phenylsulfonylethyls,
Pi-allyl, benzyl, 2- nitrobenzyls, 4- nitrobenzyls, diphenyl -4- pyridylmethyls, N ', N '-dimethyl diazanyl, methoxyl group
Methyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM) or 2- THP trtrahydropyranyls (THP), preferably 2- (trimethyl silanes
Base) ethoxyl methyl or N- pentanoyloxymethyls, most preferably 2- (TMS) ethoxyl methyl.
In some specific embodiments of the present invention, VI compound of formula is VIII compound of formula, preferably Ⅸ compound of formula, accordingly
, VII compound of formula is Ⅺ compound of formula,
Wherein described palladium catalyst can be palladium (0) and palladium (II) catalyst, including but not limited to Pd (PPh3)4、Pd(OAc)2、
PdCl2(dppf)、Pd2(dba)3、Pd(dba)2Or Pd (dppf)2Cl2, in some specific embodiments of the present invention, palladium chtalyst
Agent is Pd (PPh3)4。
It should be appreciated that the palladium catalyst of the present invention can also be the various palladium complex compounds that various palladium catalysts are prepared with part,
The part includes but is not limited to PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or
Ph2P(CH2)3PPh2(dppp)。
Wherein described alkali be selected from N, N- diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, sodium methoxide, caustic alcohol, positive third
Sodium alkoxide, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, tertiary fourth
Lithium alkoxide, lithium diisopropylamine, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, bicarbonate
One or more of one or more of sodium or saleratus, preferably potassium carbonate, sodium carbonate, sodium acid carbonate or saleratus,
Most preferably potassium carbonate.
The wherein preparation of III compound of formula can select suitable solvent to be reacted as needed, the solvent selected from water, methyl alcohol,
Ethanol, propyl alcohol, isopropanol, 1,2- dimethoxy-ethanes, n-butanol, isobutanol, the tert-butyl alcohol, 1,4- dioxane, formic acid,
Acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, acetic acid fourth
Ester, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or diformazan are sub-
One or two in one or more of sulfone, preferably n-butanol or 1,2- dimethoxy-ethane, most preferably n-butanol.
Wherein described reaction can select suitable reaction temperature to carry out as needed, and such as reaction temperature can be from 0 DEG C to reaction
The boiling point of system, preferably in some specific embodiments of the present invention, boiling point of the reaction temperature for reaction system.
Wherein described reaction can select the suitable reaction time as needed, and such as reaction time can be 0-48 hours, also may be used
Think 2-12 hours, in some specific embodiments of the present invention, the reaction time is 2 hours.
Wherein VI compound of formula and the mol ratio of type I compound can be 1, it is also possible to more than 1 or less than 1；For example formula VI is changed
Compound can be about 0.1-10, or about 1-3 with the mol ratio of type I compound；In some specific embodiments of the present invention,
VI compound of formula is about 2 with the mol ratio of type I compound.
Wherein type I compound is not particularly limited with the mass ratio of palladium catalyst, and in some embodiments of the present invention, formula I is changed
Compound can be about 0.0001-10, or about 0.05-0.5 with the mass ratio of palladium catalyst；In some specific embodiment parties of the present invention
In case, type I compound is about 0.2 with the mass ratio of palladium catalyst.
Optionally, the preparation of VII compound of formula can further include following steps：
I. reaction is added in terminating backward reactant liquor and the immiscible organic solvent extraction of water,
Ii. concentrate,
It is wherein described to include but is not limited to ethyl acetate, butyl acetate, dichloromethane, three chloromethanes with the immiscible organic solvent of water
Alkane or ether etc., in one embodiment of the invention, described is ethyl acetate with the immiscible organic solvent of water.
VI compound of formula of the present invention can be by commercially available acquisition, it is also possible to prepared by the method for prior art, for example
Method disclosed in CN102026999A, VI compound of formula are formed by protecting Ⅻ compound of formula with P blocking groups,
Wherein P blocking groups are as described above, in certain specific embodiments of the invention, the P blocking groups are 2- (front threes
Base silane base) ethoxyl methyl or N- pentanoyloxymethyls, preferably 2- (TMS) ethoxyl methyl.
In some specific embodiments of the present invention, VI compound of formula is VIII compound of formula, and VIII compound of formula is by the following method
Prepare,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or TFMS foundation group, preferably chlorine, bromine or iodine,
Most preferably chlorine.
Wherein Y is selected from fluorine, chlorine, bromine or iodine, preferably chlorine, bromine or iodine, most preferably chlorine.
The preparation of VIII compound of formula can select suitable alkali, such as sodium hydride (NaH) as needed.
The preparation of VIII compound of formula can select suitable solvent as needed, for example DMA, tetrahydrofuran,
1,2- dimethoxy-ethanes or 1,4- dioxane etc..
On the one hand, the invention provides a kind of preparation method of VII compound of formula, including：
(1) II compound of formula carries out reaction in the presence of a catalyst with III compound of formula and prepares type I compound,
(2) type I compound and VI compound of formula carry out reacting VII compound of formula in the presence of palladium catalyst and alkali,
Wherein R1And R2It is as defined above, in some specific embodiments of the present invention, R1And R2It is connected with them
Oxygen atom and boron atom form following structure division together,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or TFMS foundation group, preferably chlorine, bromine or iodine,
Most preferably chlorine.
Wherein P blocking groups are as described above, in certain specific embodiments of the invention, the P blocking groups are 2- (trimethyls
Silylation) ethoxyl methyl or N- pentanoyloxymethyls, preferably 2- (TMS) ethoxyl methyl.
Catalyst wherein described in step (1) is selected from TMG, 11 carbon -7- alkene of 1,8- diazabicyclos (5.4.0), 1,5- phenodiazines
Miscellaneous bicyclic (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclos (2.2.2) octane, t-butyl ammonium hydroxide, NaOH, potassium hydroxide,
Sodium methoxide, caustic alcohol, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium acid carbonate, carbonic acid
One or more in hydrogen potassium, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate, preferably 1,8- phenodiazines
Miscellaneous bicyclic (5.4.0) 11 carbon -7- alkene.
Palladium catalyst wherein described in step (2) can be palladium (0) and palladium (II) catalyst, including but not limited to Pd (PPh3)4、
Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3、Pd(dba)2Or Pd (dppf)2Cl2, in some specific embodiments of the present invention,
Palladium catalyst is Pd (PPh3)4。
Wherein step (2) alkali is selected from N, N- diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, sodium methoxide, second
Sodium alkoxide, normal propyl alcohol sodium, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, fourth
Base lithium, tert-butyl alcohol lithium, lithium diisopropylamine, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, acetic acid
One or more of potassium, sodium acid carbonate or saleratus, preferably potassium carbonate, sodium carbonate, the one of sodium acid carbonate or saleratus
Plant or several, most preferably potassium carbonate.
Another aspect, the invention provides type I compound or its pharmaceutically acceptable salt,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 units are formed together with the oxygen atom being connected with them and boron atom miscellaneous
Ring, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, miscellaneous
Cycloalkyl, aryl or heteroaryl replace；
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom being connected with them and boron
Atom forms 5-8 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl replaces；
It is furthermore preferred that R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms 5-6 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-6 C1-6Alkyl replaces；
Most preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2The oxygen atom that is connected with them and
Boron atom forms following structure division together,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl；
In some specific embodiments of the present invention, R1And R2Formed together with the oxygen atom being connected with them and boron atom with
Lower structure division,
In some more specific embodiments of the present invention, type I compound structure is V compound of formula,
Another aspect, the invention provides the purposes of type I compound or its pharmaceutically acceptable salt in VII compound of formula.
Further aspect, the invention provides type I compound or its pharmaceutically acceptable salt are preparing 2- [1- ethylsulfonyls
- 3- [4- (7- [(2- (trimethyl silyl) ethyoxyl) methyl] -7H- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yls] azacyclo-
Butane -3- bases] acetonitrile purposes.
Unless otherwise stated, general chemical terms used, such as but not limited to, " alkyl ", " amine ", " aryl " equivalent
In its optionally substituted form.For example, " alkyl " used herein includes replace and unsubstituted alkyl.
Terms used herein " group " refers to the specific fragment in molecule or functional group.Chemical part be typically considered it is embedded or
The chemical entities being attached on molecule.
Term " optional " or " optionally " refer to that the event or situation of subsequent description may occur or may not occur, the description
Including there is the event or situation and the event or situation not occurring.
The term " hydrocarbon " being used alone or in combination herein refers to the compound or chemical group only comprising carbon atom and hydrogen atom.
The term " hetero atom " being used alone or in combination herein or " miscellaneous " refer to the atom in addition to carbon and hydrogen.Hetero atom independence
Ground is selected from boron, oxygen, nitrogen, sulphur, phosphorus, silicon, selenium and tin, but is not limited to these atoms.It is heteroatomic there are two or more
In embodiment, described two or more hetero atoms can be mutually the same, or in described two or more hetero atoms some or it is complete
Portion is different from each other.
The term " alkyl " being used alone or in combination herein refers to the monovalence saturation of optionally substituted straight chain or optionally substituted side chain
Hydrocarbon." alkyl " of this paper can have about 18 carbon atoms of 1-, or have about 10 carbon atoms of 1-, preferred 1-6 carbon atom.
The examples of alkyl of this paper include but is not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl-l- propyl group, 2- methyl-2-propyls,
2-methyl-1-butene base, 3- methyl-l- butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- propyl group, 2- methyl-1-pentene bases, 3- methyl isophthalic acids -
Amyl group, 4- methyl-l- amyl groups, 2- methyl -2- amyl groups, 3- methyl -2- amyl groups, 4- methyl -2- amyl groups, 2,2- dimethyl-l- butyl, 3,3-
Dimethyl -1- butyl, 2- ethyl -1- butyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, new penta
Base, tertiary pentyl and hexyl, and longer alkyl group, such as heptyl and octyl group etc..During herein presented digital scope, for example
“C1-6Alkyl " is referred to can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6
The alkyl that individual carbon atom is constituted, " C1-6Alkyl " includes " C1-2Alkyl ", " C1-3Alkyl ", " C1-4Alkyl " or " C1-5Alkyl ",
The alkyl of this paper also includes the situation of not specified digital scope.
" alkyl " being applied in combination herein be included in " alkoxyl ", " alkylthio group ", " list-alkyl amino " and
" alkyl " in " di-alkyl amino " etc..
The term " thiazolinyl " being used alone or in combination herein refers to the monovalent hydrocarbon of optionally substituted straight chain or optionally substituted side chain,
Which has one or more carbon-to-carbon double bonds.The thiazolinyl for example has about 18 carbon atoms of 2-, or has about 10 carbon atoms of 2-,
About 6 carbon atoms of more preferably 2-.Double bond in these groups can be cis or trans configuration, and should be understood comprising described
Two kinds of isomers.Example includes but is not limited to vinyl (- CH=CH2), 1- acrylic (- CH2CH=CH2), isopropenyl
(-C(CH3)=CH2), cyclobutenyl and 1,3- butadienyls etc..
The term " alkynyl " being used alone or in combination herein refers to the monovalent hydrocarbon of optionally substituted straight chain or optionally substituted side chain,
Which has one or more carbon-to-carbon triple bonds.Such as described alkynyl has about 10 carbon atoms of about 18 carbon atoms of 2- or 2-, more excellent
Select about 6 carbon atoms of 2-.The alkynyl example of this paper includes but is not limited to acetenyl, 2-propynyl, 2- butynyls and 1,3- diacetylene
Base etc..
The term " alkyl of halogen substiuted " being used alone or in combination herein refers to optionally substituted alkyl group, as defined above,
Wherein one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atom or its combination.In some embodiments, that are used
This identical halogen atom replaces two or more hydrogen atoms (such as difluoromethyl, trifluoromethyl)；Make in other embodiments
With not fully identical halogen atom replaces two or more hydrogen atoms (such as the fluoro- 1- iodine ethyls of the chloro- 1- of 1-) each other.Halogen substiuted
The non-limiting example of alkyl be methyl fluoride and bromoethyl.
The term " ring " that is used alone or in combination herein and " ... yuan of rings " refer to arbitrarily covalence closed as described herein
Structure, which includes alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring and polycyclic condenses ring system or polycyclic non-condensed ring system.Ring arbitrarily can be taken
Generation.Ring can form fused rings pastern point.Term " unit " refers to the number of the skeletal atom of composition ring.Therefore, for example,
Hexamethylene, pyridine, pyrans and pyrimidine are hexatomic ring, and pentamethylene, pyrroles, tetrahydrofuran and thiophene are five-membered ring.
The term " cycloalkyl " being used alone or in combination herein refers to optionally substituted monovalence saturation hydrocarbon ring, and which includes 3- about 15
About 10 ring carbons of ring carbons or 3-, may also comprise other non-ring carbons (such as methyl rings as substituent
Propyl group).Cycloalkyl can have 3 to about 10 or 3- about 8 or 3- about 6 or 3-5 ring member nitrogen atoms, the example of cycloalkyl
Including but not limited to cyclopropane, cyclobutane, pentamethylene and hexamethylene.
The non-limiting examples of the term " Heterocyclylalkyl " being used alone or in combination herein include azine (azinyl), azetidin
Alkyl (azetidinyl), oxetanylmethoxy (oxetanyl), thietanyl (thietanyl), homopiperidinyl (homopiperidinyl),
Oxepane base (oxepanyl), thia suberyl (thiepanyl), azepine oxepin base (oxazepinyl), diazacyclo
Heptantriene (diazepinyl), azepine thia cycloheptatriene (thiazepinyl), 1,2,3,6- tetrahydro pyridyls, 2- pyrrolinyls, 3- pyrroles
Cough up quinoline base, indolinyl, 2H- pyranoses, 4H- pyranoses, dioxane hexyl (dioxanyl), 1,3- dioxolanyls
(1,3-dioxolanyl), pyrazolinyl, two sulphur cyclohexyl (dithianyl), two sulphur cyclopenta (dithiolanyl), dihydro pyranyl,
Dihydro-thiophene base, dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl (imidazolidinyl), 3- azabicyclos [3.1.0]
Hexyl, 3- azabicyclos [4.1.0] heptyl, 3H- indyls and quinolizine base etc..All annular forms of the term also including carbohydrate,
Including but not limited to monose, disaccharides and oligosaccharides.
The term " aryl " being used alone or in combination herein refers to optionally substituted aryl radical, and which has 6- about 20 into ring carbon
Atom, and including fused rings and non-condensed aryl rings.Fused-aryl includes the 2-4 ring for condensing, and wherein connection ring is aromatic ring,
Other each rings can be alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring or its any combination.Further, term aryl includes condensing
With non-condensed ring.Additionally, term aryl is including but not limited to monocyclic, bicyclic, three rings or more polycyclic.Aryl (such as monocyclic aryl)
Including such as 6 to about 12,6 to about 10 or 6 to about 8 ring carbons.The non-limiting examples bag of monocyclic aryl
Phenyl is included, fused rings aryl includes naphthyl, phenanthryl, anthryl, azulenyl (azulenyl), and the double-aryl of non-condensed includes xenyl.
The term " heteroaryl " being used alone or in combination herein refers to the monovalence aryl of any replacement, and which includes about 5 to about 20
Skeleton ring member nitrogen atoms, wherein one or more ring member nitrogen atoms be hetero atom, the hetero atom independently selected from oxygen, nitrogen, sulphur, phosphorus,
Silicon, selenium and tin, but not limited to this；With the proviso that the ring of the group does not include two adjacent O or S atom.Go out in ring
In existing two or more heteroatomic embodiments, described two or more hetero atoms can be mutually the same, or described two or more
Some or all in many hetero atoms are different from each other.Term heteroaryl includes optionally substituted having at least one heteroatomic to condense
Or non-condensed heteroaryl.Term heteroaryl also includes the miscellaneous of the condense and non-condensed containing 5 to about 12 skeleton ring member nitrogen atoms
Aryl, and the heteroaryl of the condense and non-condensed containing 5 to about 10 skeleton ring member nitrogen atoms.Carbon atom or hetero atom can be passed through
Combined with heteroaryl.Therefore, nonrestrictive citing, imidazole radicals can pass through its arbitrary carbon atom (imidazoles -2- bases, imidazol-4 yl
Or imidazoles -5- bases) or its nitrogen-atoms (imidazoles -1- bases or imidazo-3-yl) be connected with parent molecule.Similarly, heteroaryl can pass through which
Meaning or whole carbon atoms and/or any or whole hetero atoms are further substituted.The heteroaryl for condensing can include 2-4 fused rings,
Wherein connection ring is hetero-aromatic ring, and other each rings can be alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring or its any combination.It is monocyclic miscellaneous
Bicyclic heteroaryl of the aryl including but not limited to 5 to about 12,5 to about 10,5 to about 7 or 6 ring member nitrogen atoms.
The non-limiting example of bicyclic heteroaryl includes pyridine radicals, and fused ring heteroaryl includes benzimidazolyl, quinolyl, acridinyl,
Double-the heteroaryl of non-condensed includes bipyridyl.Other examples of heteroaryl are included but is not limited to：Furyl, thienyl, oxazoles
Base, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, diazosulfide base
(benzothiadiazolyl), benzothienyl (benzothiophenyl), Ben Bing oxadiazolyl, BTA base, imidazole radicals, Yin
Diindyl base, isoxazolyls, isoquinolyl, indolizine base (indolizinyl), isothiazolyl, iso-indoles oxadiazole base, indazolyl,
Pyridine radicals, pyridazinyl (pyridazyl), pyrimidine radicals, pyrazinyl, pyrrole radicals, pyrazolyl, purine radicals, phthalazinyl, pteridyl
(pteridinyl), quinolyl, quinazolyl, quinoxalinyls (quinoxalinyl), triazolyl, tetrazole radical, thiazolyl, triazine radical
With thiadiazolyl group (thiadiazolyl) etc., and its oxide, such as pyridinyl-N-oxide etc..
The term " heterocycle " being used alone or in combination herein refers to heterolipid ring or hetero-aromatic ring, certainly exists at least one in the ring
Non-carbon (hetero atom).Name such as " 5-n circle heterocycles " is contained total atom number (i.e. five or n yuan of rings, wherein extremely in finger ring
A few atom is carbon atom, and at least one atom is hetero atom, and the individual atoms of remaining 3- (n subtracts 2) are carbon atom or miscellaneous original
Son, the n are more than 5, for example, can be 6,8 or 12)；If existing one or more atoms of the atom in " heterocycle " middle ring
It is fixed, and at least contain a hetero atom, then the atom on remaining ring is carbon atom or hetero atom.For with two or
For more heteroatomic heterocycles, described two or more hetero atoms can be same to each other or different to each other.
The term " alkoxyl " being used alone or in combination herein refers to alkylether radicals, O- alkyl, and which includes O- aliphatic radicals and O- carbocyclic rings
Base, wherein alkyl, aliphatic radical and carbocylic radical can be optionally substituted, and term alkyl therein, aliphatic radical and carbocylic radical are as above
Definition.The non-limiting example of alkoxyl includes methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, different
Butoxy, sec-butoxy and tert-butoxy etc..
The term " halogen ", " halo " or " halide " being used alone or in combination herein refers to fluorine, chlorine, bromine and iodine.
The term " alkylthio group " being used alone or in combination herein refers to "-S- alkyl ", and which includes-S- aliphatic radicals and-S- carbocylic radicals.Its
In alkyl, aliphatic radical and carbocylic radical such as definition above.The non-limiting example of alkylthio group includes methyl mercapto, ethylmercapto group, rosickyite
Base and butylthio etc..
The term " dppf " being used alone or in combination herein is double (diphenylphosphine) ferrocene of 1,1'-.
The term " dba " being used alone or in combination herein is dibenzalacetone.
Term " the PCy being used alone or in combination herein3" for tricyclohexyl phosphine.
The term " dppe " being used alone or in combination herein is double (diphenylphosphine) ethane of 1,2-.
The term " dppp " being used alone or in combination herein is double (diphenylphosphine) propane of 1,3-.
The preparation method of the present invention, with the 4- pyrazoles borides shown in II compound of formula as raw material, with 2- [1- (ethylsulfonyl) -3-
Azetidin subunit] acetonitrile reaction prepares key intermediate 2- [1- ethylsulfonyl -3- [4- (4,4,5,5- tetramethyl -1,3,2- dioxos boron penta
Ring -2- bases) -1H- pyrazol-1-yls] azetidin -3- bases] acetonitrile, without the need for protecting to the nitrogen on II compound pyrazole ring of formula, so as to
It is follow-up also not slough the corresponding protection group step, therefore whole reaction scheme is short, raw material is more easy to obtain, low production cost, together
When, the preparation method reaction time using the present invention is short, and reaction condition is gentle, it is to avoid using poisonous, irritant and deep-etching
Property reagent, environmental protection prepares simple to operation, and products obtained therefrom has in high yield and high-purity, can be directly used for further
Baricitinib is prepared, is particularly suitable for industrialized production.
Specific embodiment
By following examples, they are only embodiment to the present invention, are not intended to limit the present invention, every to be realized based on the present invention
Technology, belong to the scope of the present invention.
The preparation of the chloro- 7- of 1 4- of embodiment [(2- (TMS) ethyoxyl) methyl] -7H- pyrroles [2,3-d] pyrimidine (Ⅸ compound of formula)
In 2 liters of there-necked flasks, 4- chloropyrrolo [2,3-ds (280g, 1.83mol) and DMA (500mL), cooling are added
To -10 DEG C, NaH (84g) is added in three times, is finished, insulated and stirred 0.5 hour.Add 2- (trimethyl silicane) ethoxyl methyl chlorine
(385mL, 1.98mol), finishes, and room temperature reaction after 2 hours is poured reactant liquor in 1L water into, adds 500mL ethyl acetate,
Stirring extraction separates ester layer, is washed once with 300mL saturated sodium-chlorides, anhydrous sodium sulfate drying, filters, is concentrated under reduced pressure to give red
Color product 390g, yield 75%.
2 2- of embodiment [1- ethylsulfonyl -3- [4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxos boron) -1H- pyrazol-1-yls] azacyclo-s
Butyl- 3- yl] acetonitrile (V compound of formula) preparation
4- pyrazoles pinacol borates (14g, 72.1mmol) is added in 100mL acetonitriles under room temperature, adds 2- [1- (ethyls
Sulfonyl) -3- azetidin subunits] acetonitrile (18g, 96.7mmol) and DBU (20mL), after reaction being stirred at room temperature 2 hours,
Ethyl acetate (500mL) and water (500mL), extraction point liquid, water layer is added to be extracted once with 50mL ethyl acetate, merged
Organic layer, then washed once with 50mL saturated sodium-chlorides, anhydrous sodium sulfate drying, filter, be concentrated under reduced pressure to give yellow solid 23g.
Yield 85%.1H-NMR(300MHz,CDCl3),δ(ppm):1.32(12H,s,4×CH3), 1.37～1.41 (3H, t, J=7.4Hz,
CH3), 3.02～3.09 (2H, q, J=7.3Hz, CH2),3.33(2H,s,CNCH2), 4.15～4.18 (2H, d, J=9.1Hz, NCH2),
4.50～4.53 (2H, d, J=9.2Hz, NCH2), 7.87 (1H, s, N=CH-C), 7.91 (1H, s, N-CH=C) .MS (ESI, m/z):
381.1([M+H]+,base peak).
3 2- of embodiment [1- ethylsulfonyl -3- [4- (7- [(2- (trimethyl silyl) ethyoxyl) methyl] -7H- pyrrolo-es [2,3-d] pyrimidine -4-
Base) -1H- pyrazol-1-yls] azetidine -3- bases] and acetonitrile (Ⅺ compound of formula) preparation
Under room temperature by 4- chloro- 7- [(2- (TMS) ethyoxyl) methyl] -7H- pyrroles [2,3-d] pyrimidines (50g, 0.176mol) and
2- [1- ethylsulfonyl -3- [4- (penta ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxos boron) -1H- pyrazol-1-yls] azetidin -3- bases] second
Nitrile (67g, 0.176mol) is added in 2L eggplant type bottles, sequentially add n-butanol (500mL), potassium carbonate (50g, 0.352mol),
Tetrakis triphenylphosphine palladium (0) (Pd (PPh3)4, 10g) and water (100mL) after, be warming up to back flow reaction 2 hours, toward reactant liquor
500mL ethyl acetate and 500mL water, extraction point liquid is added to separate organic layer, then washed with 200mL saturated nacl aqueous solutions
Once, anhydrous sodium sulfate drying, filters, is concentrated under reduced pressure to give faint yellow solid 78g, yield 95%.1H-NMR(300MHz,
DMSO-d6),δ(ppm):0.00(9H,s,3×CH3), 0.90～0.96 (2H, t, J=8.1Hz, CH2), 1.32～1.37 (3H, t, J=7.4Hz,
CH3), 3.30～3.37 (2H, q, J=7.4Hz, CH2), 3.61～3.66 (2H, t, J=7.9Hz, CH3),3.80(2H,s,
CH2), 4.36～4.33 (2H, d, J=9.1Hz, CH2), 4.69～4.72 (2H, d, J=9.1Hz, CH2),5.74(2H,
s,CH2), 7.29～7.30 (1H, d, J=3.5Hz, ArH), 7.90～7.91 (1H, d, J=3.6Hz, ArH), 8.60 (1H, s, ArH),
8.89(1H,s,ArH),9.06(s,1H,ArH).MS(ESI,m/z):502.2([M+H]+,base peak).
Claims (10)
1. a kind of preparation method of type I compound, including：II compound of formula is carried out instead in the presence of a catalyst with III compound of formula
Type I compound should be prepared,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 is formed together with the oxygen atom being connected with them and boron atom first
Heterocycle, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl,
Heterocyclylalkyl, aryl or heteroaryl replace.
2. the preparation method of claim 1, R1And R2It is each independently selected from hydrogen or C1-6Alkyl；Or R1And R2With they institute
The oxygen atom and boron atom of connection forms 5-8 circle heterocycles together, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl
Replace.
3. the preparation method of claim 1, wherein the catalyst is selected from TMG, 1,8- diazabicyclos (5.4.0), 11 carbon
- 7- alkene, 1,5- diazabicyclos (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclos (2.2.2) octane, t-butyl ammonium hydroxide, hydroxide
Sodium, potassium hydroxide, sodium methoxide, caustic alcohol, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate,
One or more in sodium acid carbonate, saleratus, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate.
4. the preparation method of VII compound of a kind of formula, including：I chemical combination of formula that the preparation method of any one of claim 1-3 is prepared
Thing and VI compound of formula carry out reacting VII compound of formula in the presence of palladium catalyst and alkali,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or TFMS foundation group,
Wherein P is blocking group.
5. the preparation method of claim 4, wherein described blocking group is selected from 2- (TMS) ethoxyl methyl, N- valeryls
Epoxide methyl, benzyloxycarbonyl, 2,2,2- tri-chloroethoxy base carbonyls, 2- (TMS) ethoxy carbonyl, 2- (4- fluoroforms
Base phenyl sulfonyl) ethoxy carbonyl, tert-butoxycarbonyl, 1- adamantyloxycarbonyls, 2- adamantyl carbonyls, 2,4- diformazans
The amyl- 3- bases Epoxide carbonyl of base, cyclohexyl Epoxide carbonyl, 1,1- dimethyl -2,2,2- tri-chloroethoxy base carbonyls, vinyl, 2- chloroethyls,
2- phenylsulfonylethyls, pi-allyl, benzyl, 2- nitrobenzyls, 4- nitrobenzyls, diphenyl -4- pyridylmethyls, N ', N ' -
Dimethyl diazanyl, methoxy, t-butoxymethyl, benzyloxymethyl or 2- THP trtrahydropyranyls.
6. the preparation method of claim 4, wherein the palladium catalyst selected from Pd (PPh3) 4, Pd (OAc) 2, PdCl2 (dppf),
Pd2(dba)3、Pd(dba)2Or Pd (dppf)2Cl2。
7. the preparation method of claim 4, wherein the alkali selected from DIPEA, triethylamine, diethylamine, ethylenediamine,
Sodium methoxide, caustic alcohol, normal propyl alcohol sodium, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride,
Sodamide, butyl lithium, tert-butyl alcohol lithium, lithium diisopropylamine, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, vinegar
One or more of sour sodium, potassium acetate, sodium acid carbonate or saleratus.
8. the preparation method of VII compound of a kind of formula, including：
(1) II compound of formula carries out reaction in the presence of a catalyst with III compound of formula and prepares type I compound,
(2) type I compound and VI compound of formula carry out reacting VII compound of formula in the presence of palladium catalyst and alkali,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 is formed together with the oxygen atom being connected with them and boron atom first
Heterocycle, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl,
Heterocyclylalkyl, aryl or heteroaryl replace,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or TFMS foundation group,
Wherein P is blocking group.
9. type I compound or its pharmaceutically acceptable salt,
Wherein R1And R2Hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl are each independently selected from,
Wherein above-mentioned group is optionally replaced by one or more following substituent：Halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, alkyl, the alkyl of halogen substiuted, cycloalkyl, the cycloalkyl of halogen substiuted, lower alkoxy, the lower alkyl of halogen substiuted
Epoxide, lower alkylthio, the lower alkylthio of halogen substiuted, list-alkyl amino, di-alkyl amino, cycloalkyl amino and appoint
Choosing is by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkyl
Aryl or heteroaryl that sulfenyl replaces；Or R1And R25-12 is formed together with the oxygen atom being connected with them and boron atom first
Heterocycle, the heterocycle it is unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl,
Heterocyclylalkyl, aryl or heteroaryl replace.
10. the purposes of type I compound described in claim 9 or its pharmaceutically acceptable salt in VII compound of formula,
Wherein P is blocking group.
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| CN110256441A (en) * | 2019-06-24 | 2019-09-20 | 江苏君若医药有限公司 | A kind of Ba Ruike replaces the preparation method of Buddhist nun |
| CN110283136A (en) * | 2019-06-13 | 2019-09-27 | 苏州莱安医药化学技术有限公司 | A kind of preparation method of RE-021 intermediate |
| US10766900B2 (en) | 2017-12-29 | 2020-09-08 | Formosa Laboratories, Inc. | Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof |
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| US10766900B2 (en) | 2017-12-29 | 2020-09-08 | Formosa Laboratories, Inc. | Baricitinib intermediate, method for forming Baricitinib intermediate, and method for preparing Baricitinib or pharmaceutically acceptable salt thereof |
| CN110283136A (en) * | 2019-06-13 | 2019-09-27 | 苏州莱安医药化学技术有限公司 | A kind of preparation method of RE-021 intermediate |
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| CN110256441A (en) * | 2019-06-24 | 2019-09-20 | 江苏君若医药有限公司 | A kind of Ba Ruike replaces the preparation method of Buddhist nun |
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