CN106554363B - A kind of preparation method of Baricitinib intermediate - Google Patents
A kind of preparation method of Baricitinib intermediate Download PDFInfo
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- CN106554363B CN106554363B CN201510628431.7A CN201510628431A CN106554363B CN 106554363 B CN106554363 B CN 106554363B CN 201510628431 A CN201510628431 A CN 201510628431A CN 106554363 B CN106554363 B CN 106554363B
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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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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to field of medicine and chemical technology, in particular to a kind of preparation method of Baricitinib intermediate, preparation method of the invention, key intermediate 2- [1- ethylsulfonyl -3- [4- (4 is prepared by 4- pyrazoles boride and 2- [1- (ethylsulfonyl) -3- azetidin subunit] acetonitrile reaction, 4, 5, 5- tetramethyl -1, 3, penta ring -2- base of 2- dioxo boron) -1H- pyrazol-1-yl] azetidin -3- base] acetonitrile, without being protected to the nitrogen on 4- pyrazoles boride pyrazole ring, the corresponding protecting group step is not sloughed yet to subsequent, therefore entire reaction route is short, raw material is easier to obtain, production cost is low, 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 intermediate.
Background technique
Baricitinib, entitled { 1- (ethylsulfonyl) -3- [4- (7H- pyrrolo- [2,3-d] pyrimidine-4-yl)-of chemistry
1H- pyrazol-1-yl] azetidine -3- base } acetonitrile is the small molecule JAK-1 developed by Eli Lilly and Incyte company
With JAK2 kinase inhibitor, it to be used for oral medication rheumatoid arthritis, psoriasis and other diseases associated with inflammation and diabetes
Nephrosis.
CN102026999A discloses Baricitinib and its intermediate 2- [1- ethylsulfonyl -3- [4- (7- [(2- (three
Methyl silicane base) ethyoxyl) methyl] -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazol-1-yl] azetidin
Alkane -3- base] acetonitrile (formula I) preparation method, the intermediate the preparation method is as follows:
Method 1:
Method 2:
Method 1 and method 2 are required to first by compound 2 and compound 3 in Pd (PPh3)4In the presence of reaction prepare intermediate
4- (1- (1- ethoxyethyl group) -1H- pyrazoles -4- base) -7- ((2- (trimethyl silyl) ethyoxyl) methyl) -7H- pyrroles
And [2,3-d] pyrimidine (compound 6), it then sloughs 1- ethoxyethyl group protecting group and obtains intermediate 4- (1H- pyrazoles -4- base) -
7- ((2- (trimethyl silyl) ethyoxyl) methyl) -7H- pyrrolo- [2,3-d] pyrimidine (compound 5), then by this
Mesosome carries out subsequent reactions;Since compound 3 is by being separately connected " 1- ethoxy on the corresponding position of the structure of 1H- pyrazoles
Base ethyl " and " 4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- base " structure fragment be 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), because the reaction route of the method 1 and method 2 has the connection of " 1- ethoxyethyl group " protecting group
With slough two steps, reaction route is long, high production cost, does not accommodate industrialized production, therefore there is still a need for new preparation sides
Method, to adapt to the demand of industrialized production.
Summary of the invention
On the one hand, the present invention provides a kind of preparation method of type I compound, comprising: II compound of formula and III compound of formula
Reaction preparation type I compound is carried out in the presence of a catalyst,
Wherein R1And R2It is each independently selected from hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl
Base, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, nitroso, carboxyl,
The lower alkyl that amino, alkyl, the alkyl of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, lower alkoxy, halogen replace
Oxygroup, lower alkylthio, halogen replace lower alkylthio, mono- 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 alkylthio
Substituted aryl or heteroaryl;Or R1And R2It is miscellaneous that oxygen atom connected to them and boron atom are formed together 5-12 member
Ring, the heterocycle are unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, naphthenic base, miscellaneous
Naphthenic base, aryl or heteroaryl replace;
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom connected to them
And boron atom is formed together 5-8 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together 5-6 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together following structure division,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl;
In some specific embodiments of the invention, R1And R2Oxygen atom connected to them and boron atom are together
Following structure division is formed,
In some more specific embodiments of the invention, the structure of II compound of formula is IV compound of formula, correspondingly,
Type I compound structure is V compound of formula,
It should be appreciated that II compound of formula is also possible to II compound pharmaceutically acceptable salt of formula or boric anhydride, as long as on
Reaction is stated to be able to carry out;The oxygen that II compound of formula and type I compound are connected with boron atom is also possible to other atoms, only
Above-mentioned reaction is wanted to be able to carry out.
II compound of formula can be prepared by commercially available acquisition or by the method for the prior art, such as II compound of formula can
It is prepared with being reacted by pyrazoles with the reagent of boracic appropriate, specific example, such as IV compound of formula can pass through pyrrole
Azoles is reacted with connection boric acid pinacol ester to be prepared.
Wherein the catalyst is selected from tetramethylguanidine, 11 carbon -7- alkene (DBU) of 1,8- diazabicyclo (5.4.0), 1,5-
Diazabicyclo (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclo (2.2.2) octane, t-butyl ammonium hydroxide, sodium hydroxide,
Potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate,
One or more of saleratus, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate, preferably 1,8-
11 carbon -7- alkene of diazabicyclo (5.4.0).
It should be appreciated that the present invention prepare type I compound catalyst further include it is above-mentioned it is unlisted it is various can promote it is anti-
The reagent that should be carried out, as long as the reaction is able to carry out.
Wherein the preparation of type I compound selects suitable solvent to be reacted as needed, and the solvent is selected from acetonitrile, first
Alcohol, ethyl alcohol, 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, toluene, two
Toluene, n,N-Dimethylformamide, the one or more of n,N-dimethylacetamide or dimethyl sulfoxide, preferably acetonitrile, N, N-
The one or more of dimethylformamide or n,N-dimethylacetamide, most preferably acetonitrile.
Wherein the preparation of type I compound can according to need the suitable reaction temperature of selection, such as reaction temperature can be from 0
DEG C to reaction system boiling point, in some specific embodiments of the invention, the reaction temperature be 25 DEG C.
Wherein the reaction can according to need the selection suitable reaction time, such as the reaction time can be small for 0-48
When, or 2-12 hours, in some specific embodiments of the invention, the reaction time was 2 hours.
Wherein the molar ratio of III compound of formula and II compound of formula can be 1, can also be greater than 1 or less than 1;Such as formula
The molar ratio of III compound and II compound of formula can be about 0.1-10, or about 0.8-1.5;Of the invention some specific
In embodiment, the molar ratio of III compound of formula and II compound of formula is about 1.34.
Optionally, the preparation of type I compound can carry out under the protection of nitrogen or argon gas.
Optionally, type I compound can further include following steps:
I. organic solvent extraction unmixing with water is added into reaction solution after reaction,
Ii. it is concentrated,
Wherein the organic solvent unmixing with water includes but is not limited to ethyl acetate, butyl acetate, methylene chloride, three
Chloromethanes or ether etc., in one embodiment of the invention, the organic solvent unmixing with water is acetic acid second
Ester.
On the other hand, the present invention provides a kind of preparation methods of VII compound of formula, comprising: type I compound and formula VI are changed
It closes object and carries out reaction VII compound of preparation formula in the presence of palladium catalyst and alkali,
Wherein R1And R2It is each independently selected from hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl
Base, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, nitroso, carboxyl,
The lower alkyl that amino, alkyl, the alkyl of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, lower alkoxy, halogen replace
Oxygroup, lower alkylthio, halogen replace lower alkylthio, mono- 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 alkylthio
Substituted aryl or heteroaryl;Or R1And R2It is miscellaneous that oxygen atom connected to them and boron atom are formed together 5-12 member
Ring, the heterocycle are unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, naphthenic base, miscellaneous
Naphthenic base, aryl or heteroaryl replace;
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom connected to them
And boron atom is formed together 5-8 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together 5-6 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together following structure division,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl;
In some specific embodiments of the invention, R1And R2Oxygen atom connected to them and boron atom are together
Following structure division is formed,
In some more specific embodiments of the invention, type I compound structure is V compound of formula,
Wherein X be selected from fluorine, chlorine, bromine, iodine, tosylate group or trifluoromethanesulfonic acid 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- (trimethylsilyl) ethoxyl methyl
(SEM), N- pentanoyloxymethyl (POM), benzyloxycarbonyl (Cbz), 2,2,2- tri-chloroethoxy base carbonyl (Troc), 2- (front three
Base silane base) ethoxy carbonyl (Teoc), 2- (4- trifluoromethyl sulfonyl) ethoxy carbonyl (Tsc), tert-butoxy carbonyl
Base (BOC), 1- adamantyloxycarbonyl (Adoc), 2- adamantyl carbonyl (2-Adoc), 2,4- dimethyl-penten -3- base oxygen
Base carbonyl (Doc), cyclohexyl Epoxide carbonyl (Hoc), 1,1- dimethyl -2,2,2- tri-chloroethoxy base carbonyl (TcBOC), ethylene
Base, 2- chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, 2- nitrobenzyl, 4- nitrobenzyl, diphenyl -4- pyridine
Ylmethyl, N ', N '-dimethyl diazanyl, methoxy, t-butoxymethyl (Bum), benzyloxymethyl (BOM) or 2- tetrahydro
Pyranose (THP), preferably 2- (trimethylsilyl) ethoxyl methyl or N- pentanoyloxymethyl, most preferably 2- (three
Methyl-monosilane base) ethoxyl methyl.
In some specific embodiments of the invention, VI compound of formula is VIII compound of formula, preferably Ⅸ compound of formula,
Correspondingly, VII compound of formula is Ⅺ compound of formula,
Wherein the 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 invention
In, palladium catalyst is Pd (PPh3)4。
It should be appreciated that palladium catalyst of the invention can also be the various palladium complexes of various palladium catalysts and ligand preparation
Compound, the ligand include but is not limited to PCy3、AsPh3、n-Bu3P、(MeO)3P、Ph2P(CH2)2PPh2(dppe) or
Ph2P(CH2)3PPh2(dppp)。
Wherein the alkali is selected from N, N- diisopropylethylamine, triethylamine, diethylamine, ethylenediamine, sodium methoxide, sodium ethoxide, just
Sodium propoxide, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, the tert-butyl alcohol
Lithium, lithium diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate or carbon
The one or more of the one or more of potassium hydrogen phthalate, preferably potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus, most preferably
For potassium carbonate.
Wherein the preparation of VII compound of formula can according to need the suitable solvent of selection and be reacted, and the solvent is selected from
Water, methanol, ethyl alcohol, propyl alcohol, isopropanol, 1,2- dimethoxy-ethane, 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 dimethyl sulfoxide
One or more, preferably n-butanol or 1, one or both of 2- dimethoxy-ethane, most preferably n-butanol.
Wherein the reaction can according to need the suitable reaction temperature of selection and carry out, such as reaction temperature can be for from 0 DEG C
To the boiling point of reaction system, preferably in some specific embodiments of the invention, the reaction temperature is the boiling of reaction system
Point.
Wherein the reaction can according to need the selection suitable reaction time, such as the reaction time can be small for 0-48
When, or 2-12 hours, in some specific embodiments of the invention, the reaction time was 2 hours.
Wherein the molar ratio of VI compound of formula and type I compound can be 1, can also be greater than 1 or less than 1;Such as formula
The molar ratio of VI compound and type I compound can be about 0.1-10, or about 1-3;In some specific embodiment parties of the invention
In case, the molar ratio of VI compound of formula and type I compound is about 2.
Wherein the mass ratio of type I compound and palladium catalyst is not particularly limited, in some embodiments of the present invention, formula
The mass ratio of I compound and palladium catalyst can be about 0.0001-10, or about 0.05-0.5;Of the invention some specific
In embodiment, the mass ratio of type I compound and palladium catalyst is about 0.2.
Optionally, the preparation of VII compound of formula can further include following steps:
I. organic solvent extraction unmixing with water is added into reaction solution after reaction,
Ii. it is concentrated,
Wherein the organic solvent unmixing with water includes but is not limited to ethyl acetate, butyl acetate, methylene chloride, three
Chloromethanes or ether etc., in one embodiment of the invention, the organic solvent unmixing with water is acetic acid second
Ester.
VI compound of formula of the invention can also be prepared by commercially available acquisition by the method for the prior art, such as
Method disclosed in CN102026999A, VI compound of formula by protecting formula Ⅻ compound to be formed with P blocking group,
Wherein for P blocking group as described above, in certain specific embodiments of the invention, the P blocking group is 2-
(trimethylsilyl) ethoxyl methyl or N- pentanoyloxymethyl, preferably 2- (trimethylsilyl) ethoxyl methyl.
In some specific embodiments of the invention, VI compound of formula is VIII compound of formula, and VIII compound of formula is by such as
The preparation of lower section method,
Wherein X be selected from fluorine, chlorine, bromine, iodine, tosylate group or trifluoromethanesulfonic acid 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 according to need the suitable alkali of selection, such as sodium hydride (NaH).
The preparation of VIII compound of formula can according to need the suitable solvent of selection, such as n,N-dimethylacetamide, tetrahydro
Furans, 1,2- dimethoxy-ethane or 1,4- dioxane etc..
On the one hand, the present invention provides a kind of preparation methods of VII compound of formula, comprising:
(1) II compound of formula carries out reacting preparation type I compound with III compound of formula in the presence of a catalyst,
(2) type I compound and VI compound of formula carry out reaction VII compound of preparation formula in the presence of palladium catalyst and alkali,
Wherein R1And R2It is as defined above, in some specific embodiments of the invention, R1And R2With their companies, institute
The oxygen atom and boron atom connect is formed together following structure division,
Wherein X be selected from fluorine, chlorine, bromine, iodine, tosylate group or trifluoromethanesulfonic acid foundation group, preferably chlorine, bromine or
Iodine, most preferably chlorine.
Wherein for P blocking group as described above, in certain specific embodiments of the invention, the P blocking group is 2-
(trimethylsilyl) ethoxyl methyl or N- pentanoyloxymethyl, preferably 2- (trimethylsilyl) ethoxyl methyl.
Wherein catalyst described in step (1) be selected from tetramethylguanidine, 11 carbon -7- alkene of 1,8- diazabicyclo (5.4.0),
1,5- diazabicyclo (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclo (2.2.2) octane, t-butyl ammonium hydroxide, hydroxide
Sodium, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, potassium carbonate, bicarbonate
One or more of sodium, saleratus, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate, preferably 1,
11 carbon -7- alkene of 8- diazabicyclo (5.4.0).
Wherein palladium catalyst 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 tools of the invention
In body embodiment, 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, butyl lithium,
Tert-butyl alcohol lithium, lithium diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, bicarbonate
The one or more of the one or more of sodium or saleratus, preferably potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus,
Most preferably potassium carbonate.
Another aspect, the present invention provides type I compound or its pharmaceutically acceptable salt,
Wherein R1And R2It is each independently selected from hydrogen, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl
Base, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, nitroso, carboxyl,
The lower alkyl that amino, alkyl, the alkyl of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, lower alkoxy, halogen replace
Oxygroup, lower alkylthio, halogen replace lower alkylthio, mono- 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 alkylthio
Substituted aryl or heteroaryl;Or R1And R2It is miscellaneous that oxygen atom connected to them and boron atom are formed together 5-12 member
Ring, the heterocycle are unsubstituted or optionally by 1-20 selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, naphthenic base, miscellaneous
Naphthenic base, aryl or heteroaryl replace;
Preferably, R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom connected to them
And boron atom is formed together 5-8 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together 5-6 circle heterocyclic ring, 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 R2Oxygen connected to them is former
Son and boron atom are formed together following structure division,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl;
In some specific embodiments of the invention, R1And R2Oxygen atom connected to them and boron atom are together
Following structure division is formed,
In some more specific embodiments of the invention, type I compound structure is V compound of formula,
Another aspect, the present invention provides type I compounds or its pharmaceutically acceptable salt in VII compound of preparation formula
Purposes.
Also on the one hand, the present invention provides type I compounds or its pharmaceutically acceptable salt in preparation 2- [1- ethylsulfonyl
- 3- [4- (7- [(2- (trimethyl silyl) ethyoxyl) methyl] -7H- pyrrolo- [2,3-d] pyrimidine-4-yl) -1H- pyrazoles -
1- yl] azetidine -3- base] acetonitrile purposes.
Unless otherwise stated, general chemical terms used, such as, but not limited to, " alkyl ", " amine ", " aryl " etc.
It is same as its form optionally replaced.For example, " alkyl " used herein includes substitution and unsubstituted alkyl.
Terms used herein " group " refers to specific fragment or functional group in molecule.Chemical part is typically considered embedding
The chemical entities for entering or being attached on molecule.
Term " optional " " optionally " refers to that the event then described or situation may occur or may not occur, this is retouched
It states including the event or situation occurs and the event or situation do not occur.
The term " hydrocarbon " being used alone or in combination herein refers to compound or chemical base only comprising carbon atom and hydrogen atom
Group.
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 is only
It is on the spot 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, some in described two or more hetero atoms can be mutually the same or described two or more hetero atom or
It is all different from each other.
The term " alkyl " being used alone or in combination herein refers to the one of the straight chain optionally replaced or the branch optionally replaced
Valence saturated hydrocarbons." alkyl " of this paper can have about 18 carbon atoms of 1-, or have about 10 carbon atoms of 1-, and preferably 1-6 carbon is former
Son.The examples of alkyl of this paper includes but is not limited to methyl, ethyl, n-propyl, isopropyl, 2- methyl-l- propyl, 2- methyl -2-
Propyl, 2-methyl-1-butene base, 3- methyl-l- butyl, 2- methyl -3- butyl, 2,2- dimethyl -1- propyl, 2- methyl-1-pentene
Base, 3- methyl-1-amyl, 4- methyl-l- amyl, 2- methyl-2- amyl, 3- methyl-2- amyl, 4- methyl-2- amyl, 2,
2- dimethyl-l- butyl, 3,3- dimethyl -1- butyl, 2- ethyl -1- butyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl,
N-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl and longer alkyl group, such as heptyl and octyl.Go out herein
When existing digital scope, such as " C1-6Alkyl " refers to can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5
The alkyl that a carbon atom or 6 carbon atoms are constituted, " C1-6Alkyl " includes " C1-2Alkyl ", " C1-3Alkyl ", " C1-4Alkyl " or
“C1-5The case where alkyl ", the alkyl of this paper also includes not specified digital scope.
" alkyl " being applied in combination herein includes but is not limited to be included in " alkoxy ", " alkylthio group ", " mono- alkyl amino "
" alkyl " in " di-alkyl amino " etc..
The term " alkenyl " being used alone or in combination herein refers to the one of the straight chain optionally replaced or the branch optionally replaced
Valence hydrocarbon has one or more carbon-to-carbon double bonds.The alkenyl is for example with about 18 carbon atoms of 2-, or has 2- about 10
Carbon atom, about 6 carbon atoms of more preferable 2-.Double bond in these groups can be cis or trans configuration, and should be understood
Include described two isomers.Example includes but is not limited to vinyl (- CH=CH2), 1- acrylic (- CH2CH=CH2), it is different
Acrylic (- C (CH3)=CH2), cyclobutenyl and 1,3- butadienyl etc..
The term " alkynyl " being used alone or in combination herein refers to the one of the straight chain optionally replaced or the branch optionally replaced
Valence hydrocarbon has one or more carbon-carbon triple bonds.Such as the alkynyl has about 10 carbon originals of about 18 carbon atoms of 2- or 2-
Son, about 6 carbon atoms of more preferable 2-.The alkynyl example of this paper include but is not limited to acetenyl, 2-propynyl, 2- butynyl and
1,3- diacetylene base etc..
The term " alkyl that halogen replaces " being used alone or in combination herein refers to the alkyl group optionally replaced, as above fixed
Justice, wherein one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atom or combinations thereof.In some embodiments,
Two or more hydrogen atoms (such as difluoromethyl, trifluoromethyl) are replaced using mutually the same halogen atom;In other implementations
Using not fully identical halogen atom replaces two or more hydrogen atoms (such as fluoro- 1- iodine of the chloro- 1- of 1- each other in mode
Ethyl).The non-limiting example for the alkyl that halogen replaces is methyl fluoride and bromoethyl.
The term " ring " that is used alone or in combination herein and " ... member ring " refer to and arbitrarily covalently close as described herein
The structure of conjunction comprising alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring and polycyclic condensed ring system or polycyclic non-condensed ring system.Ring can be appointed
Meaning replaces.Ring can form fused rings pastern point.Term " member " refers to a group number for cyclic skeletal atom.Therefore, citing and
Speech, hexamethylene, pyridine, pyrans and pyrimidine are hexatomic ring, and pentamethylene, pyrroles, tetrahydrofuran and thiophene are five-membered ring.
The term " naphthenic base " being used alone or in combination herein refers to the monovalence saturation hydrocarbon ring optionally replaced, and it includes 3- about
About 10 ring carbons of 15 ring carbons or 3-, may also comprise as substituent group other non-ring carbons (such as
Methylcyclopropyl groups).Naphthenic base can have 3 to about 10 or 3- about 8 or 3- about 6 or 3-5 ring member nitrogen atoms, naphthenic base
Example includes but is not limited to cyclopropane, cyclobutane, pentamethylene and hexamethylene.
The non-limiting example for the term " Heterocyclylalkyl " being used alone or in combination herein includes azine (azinyl), nitrogen
Azetidinyl (azetidinyl), oxetanylmethoxy (oxetanyl), thietanyl (thietanyl), homopiperidinyl
(homopiperidinyl), oxetane (oxepanyl), thiocycloheptyl (thiepanyl), azepine oxepane three
Alkenyl (oxazepinyl), diazacyclo heptantriene (diazepinyl), azepine thia cycloheptatriene (thiazepinyl), 1,
2,3,6- tetrahydro pyridyl, 2- pyrrolinyl, 3- pyrrolinyl, indolinyl, 2H- pyranose, 4H- pyranose, dioxa
Cyclohexyl (dioxanyl), 1,3- dioxolanyl (1,3-dioxolanyl), pyrazolinyl, two sulphur cyclohexyl
(dithianyl), two sulphur cyclopenta (dithiolanyl), dihydro pyranyl, dihydrothiophene, dihydrofuryl, pyrazolidine
Base, imidazolinyl, imidazolidinyl (imidazolidinyl), 3- azabicyclo [3.1.0] hexyl, 3- azabicyclo [4.1.0]
Heptyl, 3H- indyl and quinazinyl etc..The term further includes all annular forms of carbohydrate, including but not limited to monosaccharide, two
Sugar and oligosaccharides.
The term " aryl " being used alone or in combination herein refers to the aryl radical optionally replaced, with 6- about 20 at
Ring carbon atom, and including fused rings and non-condensed aryl rings.Fused-aryl includes 2-4 condensed rings, and wherein connection ring is virtue
Ring, other each rings can be alicyclic ring, heterocycle, aromatic ring, hetero-aromatic ring or any combination thereof.Further, term aryl includes thick
It closes and non-condensed ring.In addition, term aryl includes but is not limited to monocycle, bicyclic, tricyclic or more.Aryl (such as monocycle virtue
Base) it include such as 6 to about 12,6 to about 10 or 6 to about 8 ring carbons.The non-limiting example packet of monocyclic aryl
Phenyl is included, fused rings aryl includes naphthalene, phenanthryl, anthryl, azulenyl (azulenyl), and double-aryl of non-condensed includes xenyl.
The term " heteroaryl " being used alone or in combination herein refers to any substituted monovalence aryl, it 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.In ring
In occur in two or more heteroatomic embodiments, described two or more hetero atoms can be mutually the same or described two
Some or all of a or more hetero atom is different from each other.Term heteroaryl includes that at least one is miscellaneous for having of optionally replacing
Condensed or non-condensed the heteroaryl of atom.Term heteroaryl further includes condensed containing 5 to about 12 skeleton ring member nitrogen atoms
With the heteroaryl of non-condensed, and condensed and non-condensed the heteroaryl containing 5 to about 10 skeleton ring member nitrogen atoms.It can pass through
Carbon atom or hetero atom are in conjunction with heteroaryl.Therefore, unrestricted citing, imidazole radicals can pass through its any carbon atom (miaow
Azoles -2- base, imidazol-4 yl or imidazoles -5- base) or its nitrogen-atoms (imidazoles -1- base or imidazo-3-yl) be connected with parent molecule.
Similarly, heteroaryl any or whole carbon atoms and/or any or whole hetero atoms can be further substituted by its.It is condensed
Heteroaryl may include 2-4 fused rings, wherein connection ring is hetero-aromatic ring, other each rings can for alicyclic ring, heterocycle, aromatic ring,
Hetero-aromatic ring or any combination thereof.Bicyclic heteroaryl includes but is not limited to have 5 to about 12,5 to about 10,5 to about 7 or 6
The bicyclic heteroaryl of a ring member nitrogen atoms.The non-limiting example of bicyclic heteroaryl includes pyridyl group, and fused ring heteroaryl includes benzene
And imidazole radicals, quinolyl, acridinyl, double-heteroaryl of non-condensed includes bipyridyl.Other examples of heteroaryl include but
Be not limited to: furyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl,
Benzothiazolyl, diazosulfide base (benzothiadiazolyl), benzothienyl (benzothiophenyl), benzo
Oxadiazoles base, benzotriazole base, imidazole radicals, indyl, isoxazolyl, isoquinolyl, indolizine base (indolizinyl), different thiophene
Oxazolyl, isoindolyl oxadiazoles base, indazolyl, pyridyl group, pyridazinyl (pyridazyl), pyrimidine radicals, pyrazinyl, pyrrole radicals,
Pyrazolyl, purine radicals, phthalazinyl, pteridyl (pteridinyl), quinolyl, quinazolyl, quinoxaline base
(quinoxalinyl), triazolyl, tetrazole radical, thiazolyl, triazine radical and thiadiazolyl group (thiadiazolyl) etc. and its oxygen
Compound, 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 in the ring
One non-carbon (hetero atom).As the name of " 5-n circle heterocyclic ring " be total atom number contained in finger ring (i.e. five or n member ring,
Wherein at least one atom is carbon atom, at least one atom is hetero atom, and remaining 3- (n subtracts 2) a atom is carbon atom
Or hetero atom, the n are greater than 5, such as can be 6,8 or 12);If the atom in " heterocycle " middle ring is existing one or more former
Son is fixed, and at least contains a hetero atom, then the atom on remaining ring is carbon atom or hetero atom.For having two
For a or more heteroatomic heterocycle, described two or more hetero atoms be can be the same or different from each other.
The term " alkoxy " being used alone or in combination herein refers to alkylether radicals, O- alkyl comprising O- aliphatic radical and O-
Carbocylic radical, wherein alkyl, aliphatic radical and carbocylic radical can be optionally substituted, and term alkyl, aliphatic radical and carbocylic radical therein are such as
Definition above.The non-limiting example of alkoxy include methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy and tert-butoxy etc..
The term " halogen ", " halogenated " 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 " comprising-S- aliphatic radical and-S- carbocyclic ring
Base.Alkyl, aliphatic radical and carbocylic radical therein definition for example above.The non-limiting example of alkylthio group includes methyl mercapto, second sulphur
Base, rosickyite base and butylthio etc..
The term " dppf " being used alone or in combination herein is bis- (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" it is tricyclohexyl phosphine.
The term " dppe " being used alone or in combination herein is bis- (diphenylphosphine) ethane of 1,2-.
The term " dppp " being used alone or in combination herein is bis- (diphenylphosphine) propane of 1,3-.
Preparation method of the invention, using 4- pyrazoles boride shown in II compound of formula as raw material, with 2- [1- (ethyl sulphur
Acyl group) -3- azetidin subunit] acetonitrile reaction prepares key intermediate 2- [1- ethylsulfonyl -3- [4- (4,4,5,5- tetramethyl
Base -1,3, penta ring -2- base of 2- dioxo boron) -1H- pyrazol-1-yl] azetidin -3- base] acetonitrile, without to II compound of formula
Nitrogen on pyrazole ring is protected, so that subsequent do not slough the corresponding protecting group step yet, therefore entire reaction route is short,
Raw material is easier to obtain, and production cost is low, meanwhile, short using the preparation method reaction time of the invention, reaction condition is mild, keeps away
Exempt from using toxic, irritant and strong corrosive reagent, it is environmentally protective, prepare simple to operation, products obtained therefrom has in high yield
And high-purity, it can be directly used for further preparing Baricitinib, be particularly suitable for industrialized production.
Specific embodiment
For the present invention by following embodiment, they are only embodiment, are not intended to limit the present invention, all to be based on institute of the present invention
The technology of realization, all belongs to the scope of the present invention.
The chloro- 7- of 1 4- of embodiment [(2- (trimethylsilyl) ethyoxyl) methyl] -7H- pyrroles [2,3-d] pyrimidine (formula Ⅸ
Compound) preparation
In 2 liters of there-necked flasks, 4- chloropyrrolo [2,3-d (280g, 1.83mol) and n,N-dimethylacetamide is added
(500mL) is cooled to -10 DEG C, and NaH (84g) is added in three times, finishes, insulated and stirred 0.5 hour.It is added 2- (trimethyl silicane)
Ethoxyl methyl chlorine (385mL, 1.98mol), finishes, and after room temperature reaction 2 hours, reaction solution is poured into 1L water, is added
500mL ethyl acetate, stirring extraction separate ester layer, are washed once with 300mL saturated sodium-chloride, and anhydrous sodium sulfate dries, filters,
It is concentrated under reduced pressure to give red product 390g, yield 75%.
2 2- of embodiment [1- ethylsulfonyl -3- [4- (penta ring -2- base of 4,4,5,5- tetramethyl -1,3,2- dioxo boron) -
1H- pyrazol-1-yl] azetidin -3- base] acetonitrile (V compound of formula) preparation
4- pyrazoles pinacol borate (14g, 72.1mmol) is added in 100mL acetonitrile at room temperature, 2- [1- is added
(ethylsulfonyl) -3- azetidin subunit] acetonitrile (18g, 96.7mmol) and DBU (20mL), reaction 2 hours is stirred at room temperature
Afterwards, ethyl acetate (500mL) and water (500mL) is added, extracts liquid separation, water layer 50mL ethyl acetate extracts primary, merging
Organic layer, then washed once with 50mL saturated sodium-chloride, anhydrous sodium sulfate dries, filters, and is 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- pyrrole
Cough up simultaneously [2,3-d] pyrimidine -4- base) -1H- pyrazol-1-yl] azetidine -3- base] and acetonitrile (Ⅺ compound of formula) preparation
At room temperature by the chloro- 7- of 4- [(2- (trimethylsilyl) ethyoxyl) methyl] -7H- pyrroles [2,3-d] pyrimidine (50g,
0.176mol) and 2- [1- ethylsulfonyl -3- [4- (penta ring -2- base of 4,4,5,5- tetramethyl -1,3,2- dioxo boron) -1H- pyrrole
Azoles -1- base] azetidin -3- base] acetonitrile (67g, 0.176mol) is added in 2L eggplant type bottle, sequentially add n-butanol
(500mL), potassium carbonate (50g, 0.352mol), tetrakis triphenylphosphine palladium (0) (Pd (PPh3)4, 10g) and water (100mL) after, rise
500mL ethyl acetate and 500mL water were added into reaction solution to back flow reaction 2 hours for temperature, extracted liquid separation, separated organic layer,
It is washed once with 200mL saturated sodium chloride solution again, anhydrous sodium sulfate dries, filters, it 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 (61)
1. a kind of preparation method of type I compound, comprising: II compound of formula carries out in the presence of a catalyst with III compound of formula
Reaction preparation type I compound,
Wherein R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom and boron connected to them are former
Son is formed together 5-8 circle heterocyclic ring, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl replaces.
2. the preparation method of claim 1, wherein R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2With them
The oxygen atom and boron atom connected is formed together 5-6 circle heterocyclic ring, and the heterocycle is unsubstituted or optionally by 1-6 C1-6Alkane
Base replaces.
3. the preparation method of claim 2, wherein R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2With them
The oxygen atom and boron atom connected is formed together following structure division,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl.
4. the preparation method of claim 2, wherein R1And R2Oxygen atom connected to them and boron atom are formed together following
Structure division,
5. the preparation method of claim 1, wherein the structure of II compound of formula is IV compound of formula, correspondingly, type I compound knot
Structure is V compound of formula,
6. the preparation method of claim 1, wherein the catalyst is selected from tetramethylguanidine, 1,8- diazabicyclo (5.4.0) ten
One carbon -7- alkene, 1,5- diazabicyclo (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclo (2.2.2) octane, tert-butyl hydroxide
Ammonium, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine, sodium carbonate, carbonic acid
One or more of potassium, sodium bicarbonate, saleratus, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate.
7. the preparation method of claim 6, wherein the catalyst is selected from 1,8- diazabicyclo (5.4.0) 11 carbon -7- alkene.
8. the preparation method of claim 1 carries out in a solvent wherein preparing type I compound, the solvent is selected from acetonitrile, first
Alcohol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, third
Ketone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, benzene, toluene, diformazan
The one or more of benzene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide.
9. the preparation method of claim 8, wherein the solvent is selected from acetonitrile, n,N-Dimethylformamide or N, N- dimethyl second
The one or more of amide.
10. the preparation method of claim 9, wherein the solvent is selected from acetonitrile.
11. the preparation method of claim 1, wherein the reaction temperature for preparing type I compound is from 0 DEG C to the boiling of reaction system
Point.
12. the preparation method of claim 11, wherein the reaction temperature for preparing type I compound is 25 DEG C.
13. the preparation method of claim 1, wherein the molar ratio of III compound of formula and II compound of formula is 0.1-10.
14. the preparation method of claim 13, wherein the molar ratio of III compound of formula and II compound of formula is 0.8-1.5.
15. the preparation method of claim 14, wherein the molar ratio of III compound of formula and II compound of formula is 1.34.
16. the preparation method of claim 1, wherein the method for preparing type I compound further comprises following steps:
I. organic solvent extraction unmixing with water is added into reaction solution after reaction,
Ii. it is concentrated,
Wherein the organic solvent unmixing with water is selected from ethyl acetate, butyl acetate, methylene chloride, chloroform or second
Ether.
17. the preparation method of claim 16, wherein the organic solvent unmixing with water is ethyl acetate.
18. a kind of preparation method of VII compound of formula, comprising: what the preparation method of any one of claim 1-17 was prepared
Type I compound and VI compound of formula carry out reaction VII compound of preparation formula in the presence of palladium catalyst and alkali,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or trifluoromethanesulfonic acid foundation group,
Wherein P is blocking group.
19. the preparation method of claim 18, wherein X is selected from chlorine, bromine or iodine.
20. the preparation method of claim 19, wherein X is selected from chlorine.
21. the preparation method of claim 18, wherein the blocking group be selected from 2- (trimethylsilyl) ethoxyl methyl,
N- pentanoyloxymethyl, benzyloxycarbonyl, 2,2,2- tri-chloroethoxy base carbonyl, 2- (trimethylsilyl) ethoxy carbonyl, 2-
(4- trifluoromethyl sulfonyl) ethoxy carbonyl, tert-butoxycarbonyl, 1- adamantyloxycarbonyl, 2- adamantyl carbonyl
Base, 2,4- dimethyl-penten -3- base Epoxide carbonyl, cyclohexyl Epoxide carbonyl, 1,1- dimethyl -2,2,2- tri-chloroethoxy base carbonyl,
Vinyl, 2- chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, 2- nitrobenzyl, 4- nitrobenzyl, diphenyl -4-
Pyridylmethyl, N ', N '-dimethyl diazanyl, methoxy, t-butoxymethyl, benzyloxymethyl or 2- THP trtrahydropyranyl.
22. the preparation method of claim 21, wherein the blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl
Or N- pentanoyloxymethyl.
23. the preparation method of claim 22, wherein the blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl.
24. the preparation method of claim 18, wherein VI compound of formula is Ⅸ compound of formula, correspondingly, VII compound of formula is formula
Ⅺ compound,
25. the preparation method of claim 18, wherein the palladium catalyst is selected from Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、
Pd2(dba)3、Pd(dba)2Or Pd (dppf)2Cl2。
26. the preparation method of claim 25, wherein the palladium catalyst is selected from Pd (PPh3)4。
27. the preparation method of claim 18, wherein the alkali is selected from n,N-diisopropylethylamine, triethylamine, diethylamine, second two
Amine, sodium methoxide, sodium ethoxide, normal propyl alcohol sodium, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, sodium hydride, ammonia
Base sodium, butyl lithium, tert-butyl alcohol lithium, lithium diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, vinegar
The one or more of sour potassium, sodium bicarbonate or saleratus.
28. the preparation method of claim 27, wherein the alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate or saleratus
It is one or more of.
29. the preparation method of claim 28, wherein the alkali is selected from potassium carbonate.
30. the preparation method of claim 18, wherein VII compound of preparation formula carries out in a solvent, the solvent is selected from water, first
Alcohol, ethyl alcohol, propyl alcohol, isopropanol, 1,2- dimethoxy-ethane, 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, tetrahydro
Furans, acetonitrile, benzene,toluene,xylene, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide or dimethyl sulfoxide one kind or
It is several.
31. the preparation method of claim 30, wherein VII compound of preparation formula carries out in a solvent, the solvent is selected from n-butanol
Or one or both of 1,2- dimethoxy-ethane.
32. the preparation method of claim 31, wherein VII compound of preparation formula carries out in a solvent, the solvent is selected from positive fourth
Alcohol.
33. the preparation method of claim 18, wherein the reaction temperature of VII compound of preparation formula is from 0 DEG C to the boiling of reaction system
Point.
34. the preparation method of claim 33, wherein the reaction temperature of VII compound of preparation formula is the boiling point of reaction system.
35. the preparation method of claim 18, wherein the molar ratio of VI compound of formula and type I compound is 0.1-10.
36. the preparation method of claim 35, wherein the molar ratio of VI compound of formula and type I compound is 1-3.
37. the preparation method of claim 36, wherein the molar ratio of VI compound of formula and type I compound is 2.
38. the preparation method of claim 18, wherein the method for VII compound of preparation formula further comprises following steps:
I. organic solvent extraction unmixing with water is added into reaction solution after reaction,
Ii. it is concentrated,
Wherein the organic solvent unmixing with water includes but is not limited to ethyl acetate, butyl acetate, methylene chloride, three chloromethanes
Alkane or ether.
39. the preparation method of claim 38, wherein the organic solvent unmixing with water is ethyl acetate.
40. a kind of preparation method of VII compound of formula, comprising:
(1) II compound of formula carries out reacting preparation type I compound with III compound of formula in the presence of a catalyst,
(2) type I compound and VI compound of formula carry out reaction VII compound of preparation formula in the presence of palladium catalyst and alkali,
Wherein R1And R2Oxygen atom connected to them and boron atom are formed together following structure division,
Wherein X is selected from fluorine, chlorine, bromine, iodine, tosylate group or trifluoromethanesulfonic acid foundation group,
Wherein P is blocking group.
41. the preparation method of claim 40, wherein X is selected from chlorine, bromine or iodine.
42. the preparation method of claim 41, wherein X is selected from chlorine.
43. the preparation method of claim 40, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl, N- valeryl
Oxygroup methyl, benzyloxycarbonyl, 2,2,2- tri-chloroethoxy base carbonyl, 2- (trimethylsilyl) ethoxy carbonyl, 2- (4- trifluoro
Methylphenylsulfonyl) ethoxy carbonyl, tert-butoxycarbonyl, 1- adamantyloxycarbonyl, 2- adamantyl carbonyl, 2,4-
Dimethyl-penten -3- base Epoxide carbonyl, cyclohexyl Epoxide carbonyl, 1,1- dimethyl -2,2,2- tri-chloroethoxy base carbonyl, vinyl,
2- chloroethyl, 2- phenylsulfonylethyl, allyl, benzyl, 2- nitrobenzyl, 4- nitrobenzyl, diphenyl -4- pyridyl group first
Base, N ', N '-dimethyl diazanyl, methoxy, t-butoxymethyl, benzyloxymethyl or 2- THP trtrahydropyranyl.
44. the preparation method of claim 43, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl or N-
Pentanoyloxymethyl.
45. the preparation method of claim 44, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl.
46. the preparation method of claim 40, wherein it is double to be selected from tetramethylguanidine, 1,8- diaza for catalyst described in step (1)
11 carbon -7- alkene of ring (5.4.0), 1,5- diazabicyclo (4.3.0) nonyl- 5- alkene, 1,4- diazabicyclo (2.2.2) octane,
T-butyl ammonium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, tripotassium phosphate, sodium metasilicate, calcium oxide, triethylamine,
In sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, potassium hydrogen phosphate, triphenyl phasphine, triethyl phosphine, potassium acetate or potassium acrylate
It is one or more of.
47. the preparation method of claim 46, wherein catalyst described in step (1) is selected from 1,8- diazabicyclo (5.4.0)
11 carbon -7- alkene.
48. the preparation method of claim 40, wherein palladium catalyst described in step (2) is selected from Pd (PPh3)4、Pd(OAc)2、
PdCl2(dppf)、Pd2(dba)3、Pd(dba)2Or Pd (dppf)2Cl2。
49. the preparation method of claim 48, wherein palladium catalyst described in step (2) is selected from Pd (PPh3)4。
50. the preparation method of claim 40, wherein step (2) alkali is selected from n,N-diisopropylethylamine, triethylamine, diethyl
Amine, ethylenediamine, sodium methoxide, sodium ethoxide, normal propyl alcohol sodium, sodium isopropylate, n-butanol sodium, sodium tert-butoxide, cesium carbonate, lithium carbonate, hydrogen
Change sodium, Sodamide, butyl lithium, tert-butyl alcohol lithium, lithium diisopropylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, vinegar
The one or more of sour sodium, potassium acetate, sodium bicarbonate or saleratus.
51. the preparation method of claim 50, wherein step (2) alkali is selected from potassium carbonate, sodium carbonate, sodium bicarbonate or carbonic acid
The one or more of hydrogen potassium.
52. the preparation method of claim 51, wherein step (2) alkali is selected from potassium carbonate.
53. type I compound or its pharmaceutically acceptable salt,
Wherein R1And R2It is each independently selected from hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom and boron connected to them are former
Son is formed together 5-8 circle heterocyclic ring, and the heterocycle is unsubstituted or optionally by 1-10 C1-6Alkyl replaces.
54. type I compound described in claim 53 or its pharmaceutically acceptable salt, wherein R1And R2It is each independently selected from
Hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom connected to them and boron atom are formed together 5-6 circle heterocyclic ring, the heterocycle
It is unsubstituted or optionally by 1-6 C1-6Alkyl replaces.
55. type I compound described in claim 54 or its pharmaceutically acceptable salt, wherein R1And R2It is each independently selected from
Hydrogen or C1-6Alkyl;Or R1And R2Oxygen atom connected to them and boron atom are formed together following structure division,
Wherein R11、R12、R13、R14、R21、R22、R23、R24、R25And R26It is independently selected from C1-6Alkyl.
56. type I compound described in claim 54 or its pharmaceutically acceptable salt, R1And R2Oxygen connected to them is former
Son and boron atom are formed together following structure division,
57. type I compound described in claim 56 or its pharmaceutically acceptable salt, wherein type I compound structure is formula V
Compound,
58. type I compound described in claim 53-57 or its pharmaceutically acceptable salt are in the use of VII compound of preparation formula
On the way,
Wherein P is blocking group.
59. the purposes of claim 58, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl, N- valeryl oxygroup
Methyl, benzyloxycarbonyl, 2,2,2- tri-chloroethoxy base carbonyl, 2- (trimethylsilyl) ethoxy carbonyl, 2- (4- trifluoromethyl
Phenyl sulfonyl) ethoxy carbonyl, tert-butoxycarbonyl, 1- adamantyloxycarbonyl, 2- adamantyl carbonyl, 2,4- diformazan
The amyl- 3- base Epoxide carbonyl of base, cyclohexyl Epoxide carbonyl, 1,1- dimethyl -2,2,2- tri-chloroethoxy base carbonyl, vinyl, 2- chlorine
Ethyl, 2- phenylsulfonylethyl, allyl, benzyl, 2- nitrobenzyl, 4- nitrobenzyl, diphenyl -4- pyridylmethyl,
N ', N '-dimethyl diazanyl, methoxy, t-butoxymethyl, benzyloxymethyl or 2- THP trtrahydropyranyl.
60. the purposes of claim 59, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl or N- valeryl
Oxygroup methyl.
61. the purposes of claim 60, wherein blocking group is selected from 2- (trimethylsilyl) ethoxyl methyl.
Priority Applications (1)
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