CN106146518A - A kind of bruton's tyrosine kinase inhibitor intermediate and preparation method thereof - Google Patents
A kind of bruton's tyrosine kinase inhibitor intermediate and preparation method thereof Download PDFInfo
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- CN106146518A CN106146518A CN201610497404.5A CN201610497404A CN106146518A CN 106146518 A CN106146518 A CN 106146518A CN 201610497404 A CN201610497404 A CN 201610497404A CN 106146518 A CN106146518 A CN 106146518A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present invention relates to a kind of bruton's tyrosine kinase inhibitor intermediate, described bruton's tyrosine kinase inhibitor intermediate is to be the compound shown in I, II, III, IV, V or its pharmaceutically acceptable salt, and the structural formula of I is:The structural formula of II is:The structural formula of III is:The structural formula of IV is:The structural formula of V is:
Description
Technical field
Present invention relates particularly to a kind of bruton's tyrosine kinase inhibitor intermediate and preparation method thereof.
Background technology
Immunocyte can be divided into T cell and B cell two class, and wherein the major function of B cell is to secrete various antibody, helps
Human body resists the invasion of various exopathogen.Bruton tyrosine kinase (BTK) is main to be expressed in B cell, is distributed in lymphsystem, makes
Blood and blood system.In recent years about B cell especially for B cell non-Hodgkin′s lymphatic cancer and rheumatoid arthritis
Research finds, unconventionality expression often occurs in BTK.BTK is the Key kinases in B cell antigen receptor (BCR) signal path, energy
Enough regulate the maturation of normal B cells, differentiation, also closely related with multiple B cell lymphoid tissue disorders.The little molecule of BTK presses down
Preparation has good prospect for treatment hematologic malignancies and Autoimmune Disorders disease.Last decade, based on Showed Very Brisk
Property protein kinase targeted anticancer medicine had successful case, such as Pharmacyclics company and Johson & Johnson exploitation
Buddhist nun (ibrutinib) is replaced to be the most noticeable current BTK targeted inhibition agent according to Shandong, in November, 2013 and in February, 2014 quilt
U.S. FDA approval listing, is used for treating MCL and CLL.
Additionally, that has reported both at home and abroad is grinding according to Shandong for the derivant of Buddhist nun, analog, the most substituted Phenoxyphenyl
Derivant shows the highest BTK inhibitory activity, great exploitation potential in biological activity test.(see document: WO
2014187319;WO 2015165279;CN 105017256;CN 104844609).
Summary of the invention
The technical problem to be solved is to provide a kind of dibit point irreversible bruton's tyrosine kinase suppression
Agent intermediate and preparation method thereof.
For solving above technical problem, the present invention adopts the following technical scheme that:
A kind of bruton's tyrosine kinase inhibitor intermediate, described bruton's tyrosine kinase inhibitor intermediate is
It is the compound shown in I, II, III, IV, V or its pharmaceutically acceptable salt,
The structural formula of I is:The structural formula of II is:The structural formula of III is:The structural formula of IV is:The structural formula of V is:
Wherein, R1To R8It is independently selected from H, halogen, CF3、CN、NO2、OH、NH2、(C1-C6) alkyl, L-(C1-C6) alkane
Base, L-(C1-C6) alkyl-L-(C1-C6) alkyl, L-(C2-C6) thiazolinyl, L-replaces or non-substituted aryl or L-take
Generation or non-substituted heterocycle;Wherein L is O, S (=O), S (=O)2、NHC(O)CH2, NHC (O) O, NHC (O) or C (O) NH, X be
Halogen.
Term explanation
Terms used herein aryl refers to full carbon monocycle or the fused polycycle group of 5~12 carbon, has the π of total conjugated
Electronic system.The limiting examples of aryl has: phenyl ring, naphthalene nucleus and anthracene nucleus.Aromatic ring can be substituted or non-substituted.Virtue
The substituent group of ring is selected from halogen, nitro, amino, (C1-C6) alkyl, (C1-C6) alkoxyl, halo (C1-C6) alkyl, halo (C1-
C6) alkoxyl, (C3-C6) cycloalkyl, halo (C3-C6) cycloalkyl.
Term heterocycle refers to monocycle or fused ring group, has 5-9 annular atoms in ring, one of them annular atoms or
Two annular atomses are selected from N, O or S (O)m, wherein m is the hetero atom of integer of 0~2, and remaining annular atoms is C.These rings are permissible
There is one or more double bond, but these rings do not have the pi-electron system of total conjugated.Unsubstituted Heterocyclylalkyl can be pyrrole
Coughing up alkyl, piperidyl, piperazinyl, morpholino base, thio-morpholinyl, homopiperazine base, heterocycle can be unsubstituted or substituted.
The substituent group of heterocycle is selected from halogen, nitro, amino, (C1-C6) alkyl, (C1-C6) alkoxyl, halo (C1-C6) alkyl, halo
(C1-C6) alkoxyl, (C3-C6) cycloalkyl, halo (C3-C6) cycloalkyl.
Terms used herein alkoxyl refers to-O-alkoxy grp.The example of alkoxyl used herein includes but not limited to first
Epoxide, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy.Alkoxyl also includes substituted alkoxy;Alkoxyl
Can optionally be optionally substituted by halogen one or many.
Term thiazolinyl refers to that two initial atoms of alkyl form double bond, and this double bond is not the ingredient of aromatic radical.
It is to say, thiazolinyl starts from atom-C (R)=C (R)-R, wherein R refers to the remainder of thiazolinyl.Each R can be identical or not
With.Alkenyl part can be side chain straight chain ring-type (the most also can be called cycloalkenyl group).According to structure, thiazolinyl can
To be monoradical, or bivalent radical (alkenylene).Thiazolinyl can be optionally substituted.The limiting examples of thiazolinyl includes-
CH=CH2、–C(CH3)=CH2, CH=CH (CH3)、-C(CH3)=CHCH3;Alkenylene includes but not limited to-CH=CH-,-C
(CH3)=CH-,-CH=CHCH2,-CH=CHCH2CH2-、-C(CH3)=CHCH2-, thiazolinyl can have 2-10 carbon atom.
Thiazolinyl alternatively has the low-grade alkenyl of 2-6 carbon atom.
Term halogen represents fluorine, chlorine, bromine, iodine.
The present invention uses method well-known to those skilled in the art can prepare the salt of compound of the present invention.Described
Salt can be acylate, inorganic acid salt etc..Described acylate includes citrate, fumarate, oxalates, Fructus Mali pumilae
Hydrochlorate, lactate, camsilate, tosilate, mesylate.Described inorganic salt include halogen acid salt, sulfate,
Phosphate, nitrate etc..Such as, mesylate, trifluoro can be formed with lower alkanesulfonic acid such as methanesulfonic acid, trifluoromethanesulfonic acid etc.
Mesylate;Benzene sulfonate and tosilate is formed with aryl sulfonic acid such as benzenesulfonic acid and p-methyl benzenesulfonic acid.With organic carboxyl acid
As acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid form corresponding salt;With aminoacid such as
Glutamic acid and aspartic acid form corresponding glutamate, Glu and aspartate.With mineral acid such as halogen acids (Fluohydric acid., hydrogen bromine
Acid, hydroiodic acid, hydrochloric acid), sulphuric acid, phosphoric acid, carbonic acid, nitric acid can also form corresponding salt.
Preferably, R1、R2、R4、R6Independently selected from H or halogen, R3For selected from H, halogen, CF3、Methoxyl group or
OC2H4OCH3, wherein, halogen is fluorine, chlorine or bromine;R5、R7、R8For H;X is selected from bromine or iodine.
It is further preferred that R1、R2、R3、R4、R6In halogen be different halogens from X.
Most preferably, described bruton's tyrosine kinase inhibitor intermediate is the compound shown in following structural formula
In any one:
The preparation method of a kind of bruton's tyrosine kinase inhibitor intermediate, changes compound shown in formula A with shown in formula B
Compound is in the presence of alkali and solvent, and at 80~110 DEG C, nucleo philic substitution reaction obtains compound shown in formula II, wherein, formula A
Shown compound isCompound shown in formula B isCompound shown in formula II isR1~R8Definition as shown in claim 1, X, X1、X2Independently be halogen;Described solvent is for being selected from
Dioxane, toluene, acetonitrile, dimethylformamide, dimethyl acetylamide, dimethyl sulfoxide, ethanol, methanol, isopropanol, tetrahydrochysene
The combination of one or more in furan;Described alkali is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, carbonic acid
One or more in caesium, sodium hydroxide, Lithium hydrate, potassium hydroxide, potassium fluoride, triethylamine, diisopropyl ethyl amine, DBU
Combination.
Preferably, the reactant obtained nucleophilic substitution uses solvent to carry out post processing and crystallization processes obtains described
Formula II shown in compound, described solvent is selected from ethyl acetate, petroleum ether, normal hexane, normal heptane, ethanol, methanol, isopropyl
The combination of one or more in alcohol, water, acetone, toluene, dioxane, dimethylformamide.
The preparation method of a kind of bruton's tyrosine kinase inhibitor intermediate, by compound shown in formula II at alkali and solvent
In the presence of, after slaine is made in-78~80 DEG C of reactions, after having reacted at-78~80 DEG C with boric acid three ester, then pass through
Hydrolysis obtains compound shown in formula III, and wherein, compound shown in formula II isCompound shown in formula III isR1~R8, X definition as shown in claim 1;Described solvent is selected from ether, oxolane, first
The combination of one or more in base oxolane, normal hexane, normal heptane, described alkali is to try selected from chloroisopropane grignard
Agent, ethylmagnesium bromide Grignard reagent, methyl-magnesium-chloride Grignard reagent, isopropylmagnesium chloride Grignard reagent, phenyl-magnesium-bromide form
Reagent, n-BuLi, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine (LDA), LHMDS, hexamethyl
The combination of one or more in two silica-based amido sodium, potassium hexamethyldisilazide, described boric acid three ester is boron triethylenetetraminehexaacetic acid
Ester, methyl borate. or triisopropyl borate ester.
Preferably, the pH using acid regulation reaction system is 5~7 to carry out described hydrolysis, described acid be hydrochloric acid,
Any one in sulphuric acid, nitric acid, acetic acid, formic acid, benzoic acid.
A kind of preparation method of bruton's tyrosine kinase inhibitor intermediate, compound shown in formula III is iodo-with 3-
1H-pyrazoles [3,4-d] pyrimidine-4-amine, in the presence of solvent, alkali, palladium catalyst and part, passes through at 25~100 DEG C
Suzuki coupling obtains compound shown in formula IV, and compound shown in formula III isCompound shown in formula IV isR1~R8Definition as shown in claim 1;Described palladium catalyst be selected from palladium, four or three
The combination of one or more in phenyl phosphorus palladium, Palladous chloride., palladium carbon;Described part be selected from triphenyl phosphorus, three normal-butyl phosphorus,
The combination of one or more in thricyclohexyl phosphorus s-phos, x-phos;Described alkali is selected from potassium carbonate, sodium carbonate, carbonic acid
One or more in hydrogen sodium, potassium bicarbonate, cesium carbonate, ammonium carbonate, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, pyridine
Combination;Described solvent is one or more in dioxane, acetone, water, toluene, dimethylbenzene, oxolane
Combination.
Preferably, the reactant organic solvent extraction obtained through Suzuki coupling, washing are removed inorganic salt and water
Solubility impurity;The thick product of gained crystallizes in organic solvent or mixed solvent, thus realizes the purification of product, and described is organic molten
Agent is selected from ethyl acetate, petroleum ether, normal hexane, normal heptane, ethanol, methanol, isopropanol, acetic acid, water, acetone, toluene, dioxy
One or more in six rings, dimethylformamide.
The preparation method of a kind of bruton's tyrosine kinase inhibitor intermediate, by compound shown in formula IV and N-Boc-3-
Hydroxy piperidine, in the presence of solvent, condensing agent, alkylphosphines, obtains Formula V institute through Mitsunobu reaction at-20~40 DEG C
Showing compound, compound shown in formula IV isCompound shown in Formula V isR1
~R8Definition as shown in claim 1;Described solvent is the one in oxolane, ether, dichloromethane or many
The combination planted, described condensing agent is azo acid dimethyl ester, diethyl azodiformate or diisopropyl azodiformate,
Described alkylphosphines is triphenylphosphine or tributylphosphine.
The preparation method of a kind of bruton's tyrosine kinase inhibitor intermediate, by compound shown in Formula V in sour existence
Under, at 0~100 DEG C, the de-Boc of hydrolysis obtains compound shown in formula I, and compound shown in Formula V isFormula I
Shown compound isR1~R8Definition as shown in claim 1;Described acid be sulphuric acid, hydrochloric acid,
The mixing of one or more in nitric acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid.
Preferably, by principle soluble in water for the hydrochlorate of the reactant foundation amine obtained after hydrolysis, pickling alkali is carried out
Carry, and recrystallization purifying in a suitable solvent, described solvent be selected from ethyl acetate, petroleum ether, normal hexane, normal heptane,
The combination of one or more in ethanol, methanol, isopropanol, water, acetone, toluene, dioxane, dimethylformamide.
A kind of described bruton's tyrosine kinase inhibitor intermediate is at preparation treatment hematologic malignancies or self exempts from
Purposes in the medicine of epidemic disease disorders.
Due to the enforcement of above technical scheme, the present invention compared with prior art has the advantage that
The invention provides new bruton's tyrosine kinase inhibitor intermediate, the preparation method of those intermediate is just
Prompt, efficient, the preparation and the further investigation that contribute to novel B TK inhibitor even list.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following enforcement
Example.The implementation condition used in embodiment can do further adjustment, not marked enforcement according to specifically used different requirement
Condition is the condition in normal experiment.
Below in embodiment, agents useful for same is commercially available product, and involved column chromatography silica gel is Qingdao Haiyang chemical industry
The silica gel of the 100-200 mesh that factory produces.
Present invention also offers formula I and the industrial process of pharmaceutically acceptable derivant thereof, synthesize with following scheme
Route synthesizes.Reaction equation is:
Embodiment 1
Preparation 5-bromo-2-phenoxypyridines (II-1)
In 100 liters of reactors, be sequentially added into phenol (0.94kg, 10mol), dimethylformamide (20kg), 2,5-bis-
Bromopyridine (2.37kg, 10mol), natrium carbonicum calcinatum (1.27kg, 12mol), reactant mixture is heated to 105 DEG C also by chuck
Stirring reaction 24 hours.Treating 2,5-dibromo pyridine consumes completely, and reaction is cooled to room temperature, discharging, sucking filtration.Filtrate is returned to reaction
It is cooled under 0 DEG C, stirring be dividedly in some parts trash ice (40kg) in still and by chuck, controls temperature 5-8 DEG C, within 0.5 hour, add, analysis
Going out light yellow solid, mixture continues to stir 2 hours at this temperature, discharging, sucking filtration.Take out after filter cake frozen water (10kg) washing
Filter cake, to dry, is dissolved in normal heptane (10kg), sucking filtration removes insoluble matter by filter, and gained filtrate is concentrated to dryness, and adds dimethyl
Methanamide (8kg) dissolves, and this solution added trash ice (10kg) after cooling to 0 DEG C in 1 hour, controlled temperature 3-5 DEG C, separated out solid
Body, 2 hours aging, sucking filtration of stirring, filter cake frozen water washs (10kg), drains to obtain yellow solid 2.05kg, and yield: 82% is pure
Degree: 95.4%.
1H NMR(400MHz,CDCl3)δ8.22(d,1H),7.75(dd,1H),7.40(t,2H),7.23(m,1H),7.11
(d,2H),6.82(d,1H)。
Embodiment 2
Preparation 6-phenoxypyridines-3-ylboronic acid (III-1)
In 50 liters of stills, adding fresh magnesium rod (288g, 12mol), iodine (10g), after evacuation, nitrogen replace 3 times, nitrogen is protected
Protect down, add anhydrous tetrahydro furan (10kg), start mechanical agitation, reactant liquor is heated to 50 DEG C, instill a small amount of chloro isopropyl
Alkane (39g, 0.5mol), continues to be heated to reaction and causes.After having caused, by remaining chloroisopropane (824g, 10.5mol)
It is slowly added to, within about 1 hour, adds, add backflow 1 hour.Gained chloroisopropane Grignard reagent is cooled to DEG C, is slowly dropped into
5-bromo-2-phenoxypyridines (2.5kg, 10mol), temperature control less than 10 DEG C.Add, stir 1.5 hours under room temperature, until having exchanged
Become.Reaction being cooled to 0 DEG C, drips triisopropyl borate ester (2.82kg, 15mol) in reactant liquor, temperature control less than 10 DEG C, 1 is little
Time add, then at stirred overnight at room temperature.Reactant liquor is cooled to-5 DEG C, is slowly added dropwise 6M hydrochloric acid and adjusts pH=6, separate out light yellow solid
Body, sucking filtration, washing (10L), be dried, light yellow solid 1.89kg, yield: 88%, purity: 97.2%.
1H NMR(400MHz,DMSO-d6)δ8.48(d,1H),8.26(d,2H),8.16(dd,1H),7.43(t,2H),
7.22(t,1H),7.13(d,2H),6.98(d,1H)。
Embodiment 3
Preparation 3-(6-phenoxypyridines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-1)
Iodo-for 3-1H-pyrazoles [3,4-d] pyrimidine-4-amine (440g, 1.68mol) is dissolved in dioxane (5L), adds
6-phenoxypyridines-3-ylboronic acid (480g, 2.23mol), Anhydrous potassium carbonate (700g, 5.07mol) and water (1L).Will reaction
Mixture evacuation 30 minutes, with nitrogen replace 3 times, add palladium (7.5g, 33.6mmol) and triphenylphosphine (17.6g,
67.2mmol), evacuation, nitrogen are replaced 3 times again.Reactant liquor refluxes overnight under nitrogen protection, and question response terminates, and is cooled to
Room temperature, sucking filtration removes insoluble matter, by filtrate reduced in volume to dry, adds water (5L), is extracted with ethyl acetate three times (3 × 2L),
Organic facies is dried with anhydrous sodium sulfate, filters, is evaporated to about 1.5kg after merging, and sucking filtration removes insoluble matter, adds in filtrate
Normal hexane (5kg), separates out solid, and gained slurry is stirred overnight, sucking filtration, is thick product after filtration cakes torrefaction.This thick product continues
Yellow solid 316 grams, yield: 62%, purity: 95.8% is obtained with acetone recrystallization.
1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.39(d,1H),8.23(s,1H),8.10(d,1H),
7.45(t,2H),7.30-7.15(m,4H),7.35–6.66(br,2H)。
Embodiment 4
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-1-
Base) piperidines-1-carbonic ester (V-1)
Under nitrogen protection, N-Boc-3-hydroxy piperidine (201g, 1mol) is dissolved in methyltetrahydrofuran (3kg), reacts cold
But to 0 DEG C, stirring disposably adds triphenylphosphine (327g, 1.25mol).Azoformic acid is dripped again with constant pressure funnel
Diisopropyl ester (232g, 1.15mol), temperature control 0-5 DEG C, at this temperature stirring 1 hour.Add 3-(6-phenoxypyridines-3-
Base)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (152g, 0.5mol), reaction is raised to room temperature and is stirred overnight.Question response terminates, and uses
4M sodium hydroxide solution washing (2 × 500g), saturated nacl aqueous solution washing (500g), separate organic layer, use anhydrous sodium sulfate
It is dried 2 hours, filters, in filtrate, add normal hexane (8kg), separate out light yellow solid, sucking filtration, i.e. obtain after filtration cakes torrefaction and slightly produce
Product V-1, can be directly used for next step reaction.In order to obtain analysis sterling, take a small amount of crude product and carry out silica gel column chromatography, with acetic acid
Ethyl ester and petroleum ether are eluant, obtain light yellow solid.
1H NMR(400MHz,CDCl3)δ8.51(s,1H),8.37(s,1H),8.44(d,1H),7.44(t,2H),7.22
(m,1H),7.19(d,2H),7.08(d,1H),5.80(br,2H),4.85(m,1H),4.50-4.40(m,2H),3.50-3.30
(m,1H),2.86(t,1H),2.35–2.15(m,2H),1.90(m,1H),1.70(m,1H),1.44(s,9H)。
Embodiment 5
Preparation (R)-3-(6-phenoxypyridines-3-base)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-4-amine
Hydrochlorate (I-1)
By previous step obtain thick product V-1 [((R)-tert-butyl group-3-(4-amino-3-(6-phenoxypyridines-3-base)-
1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidines-1-carbonic ester)] be dissolved in ethanol (4kg), add 6M hydrochloric acid (600g), heating
Reflux 1 hour.Question response is complete, is cooled to room temperature, is evaporated to do.Concentrate is dissolved in 2M hydrochloric acid (1kg), uses acetic acid second
Ester abstraction impurity removal (3 × 500mL), aqueous phase sodium hydroxide adjusts pH=9 to dissociate thick product, with dichloromethane extraction (3 ×
500mL), combined dichloromethane layer, being dried with anhydrous sodium sulfate, filter, be passed through dry hydrogen chloride gas in filtrate, it is heavy to separate out
Form sediment, sucking filtration, be dried to obtain off-white color solid 108 grams, two step total recoverys: 51%, purity: 95.9%.
1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),9.47(s,1H),8.60(s,1H),8.41(d,1H),
8.11(dd,1H),7.60-7.50(m,3H),7.47(t,2H),7.30–7.20(m,4H),5.23(m,1H),3.53(d,1H),
3.41(m,1H),3.30(d,1H),3.00(m,1H),2.13(m,2H),1.96(m,2H).LC-MS found 388.1,
calc.forC21H21N7O 387.2([M+H]+)。
Embodiment 6
The preparation bromo-2-of 5-(3-fluorophenoxy) pyridine (II-2)
3-fluorophenol (600g, 5.35mol) is dissolved in dimethylformamide (4L), adds 2,5-dibromo pyridine (1.05kg,
4.43mol) with Anhydrous potassium carbonate (800g, 5.79mol), reaction is heated to reflux 12 hours.Question response is complete, is cooled to room temperature,
Adding water (10L) and be extracted with ethyl acetate (3 × 5L), organic facies is washed with 2M sodium hydroxide (3 × 2L) after merging, saturated food
Salt washing (3 × 2L), anhydrous sodium sulfate are dried, filter, and filtrate reduced in volume is the most dry, and silica gel column chromatography purification obtains light yellow oil
Shape thing 1.0kg, yield: 85%, purity: 96.6%.
1H NMR(400MHz,CDCl3)δ8.23(d,1H),7.80(dd,1H),7.37(m,1H),6.90(m,4H)。
Embodiment 7
Preparation 6-(3-fluorophenoxy) pyridin-3-yl boric acid (III-2)
Preparation method is with reference to embodiment 2, and compound III-2 is light yellow solid, yield 86%, purity: 96.0%.
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.29(brs,2H),8.16(dd,1H),7.45(m,1H),
7.04(m,4H。
Embodiment 8
Preparation 3-(6-(3-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-2)
Preparation method is with reference to embodiment 3, and compound IV-2 is light yellow solid, yield: 78%, purity: 94.8%.
1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.40(d,1H),8.23(s,1H),8.11(dd,1H),
7.53(m,1H),7.24(d,1H),7.20–7.02(m,3H),6.95(brs,2H)。
Embodiment 9
(4-amino-3-(6-(3-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] is phonetic for preparation (R)-tert-butyl group-3-
Pyridine-1-base) piperidines-1-carbonic ester (V-2)
Preparation method reference example 4, compound V-2 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.52(d,1H),8.37(s,1H),8.07(dd,1H),7.46(m,1H),7.12
(d,1H),7.00-6.90(m,3H),6.00(brs,2H),4.85(m,1H),4.45–4.00(m,2H),3.40(m,1H),
2.75(t,1H),2.20(m,2H),1.90(m,1H),1.70(m,1H),1.45(s,9H)。
Embodiment 10
Preparation (R)-3-(6-(3-fluorophenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-
4-amine hydrochlorate (I-2)
Preparation method reference example 5, compound I-2 is light yellow solid, two step total recoverys 45%, purity: 94.4%.
1H NMR(400MHz,DMSO-d6)δ10.01(m,1H),9.73(m,1H),9.50(brs,1H),8.68(s,1H),
8.45(d,1H),8.17(dd,1H),7.52(m,1H),7.29(d,1H),7.17–7.05(m,3H),5.30(m,1H),3.55–
3.25(m,3H),3.00(m,1H),2.16(m,2H),1.92(m,2H).LC-MS found 406.0,
calc.forC21H21FN7O 406.2([M+H]+)。
Embodiment 11
Preparation 2-(4-fluorophenoxy)-5-iodine pyridine (II-3)
Preparation method reference example 1, carries out nucleophilic substitution with 2-bromo-5-iodine pyridine and 3-fluorophenol, obtains chemical combination
Thing II-3 is white solid, yield 75%, purity: 95.7%.
1H NMR(400MHz,CDCl3)δ8.34(d,1H),7.91(dd,1H),7.08(m,4H),6.76(d,1H)。
Embodiment 12
Preparation 6-(4-fluorophenoxy) pyridin-3-yl boric acid (III-3)
Preparation method reference example 2, compound III-3 is light yellow solid, yield 83%, purity: 95.6%.
1H NMR(400MHz,CDCl3)δ8.60(m,1H),8.20(m,1H),7.00(m,4H),6.75(m,1H)。
Embodiment 13
Preparation 3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-3)
Preparation method reference example 3, compound IV-3 is yellow solid, yield 65%, purity: 95.9%.
1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),8.36(d,1H),8.22(s,1H),8.09(dd,1H),
7.25(m,4H),7.18(d,1H),6.98(brs,2H)。
Embodiment 14
(4-amino-3-(6-(4-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] is phonetic for preparation (R)-tert-butyl group-3-
Pyridine-1-base) piperidines-1-carbonic ester (V-3)
Preparation method reference example 4, compound V-3 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.48(d,1H),8.35(s,1H),8.05(dd,1H),7.20-7.07(m,
4H),5.96(brs,2H),4.84(m,1H),4.45–4.00(m,2H),3.40(m,1H),2.87(t,1H),2.20(m,2H),
1.90(m,1H),1.70(m,1H),1.44(s,9H)。
Embodiment 15
Preparation (R)-3-(6-(4-fluorophenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-
4-amine hydrochlorate (I-3)
Preparation method reference example 5, compound I-3 is light yellow solid, two step total recoverys 39%, purity: 96.3%.
1H NMR(400MHz,DMSO-d6)δ9.82(m,1H),9.55(m,1H),8.61(s,1H),8.40(d,1H),
8.13(dd,1H),7.33–7.23(m,4H),5.25(m,1H),3.61–3.29(m,3H),3.01(m,1H),2.14(m,2H),
1.98(m,2H).LC-MS found 406.0,calc.for C21H21FN7O 406.2([M+H]+)。
Embodiment 16
The preparation bromo-2-of 5-(3,4-difluorobenzene epoxide) pyridine (II-4)
Preparation method reference example 6, compound II-4 is light yellow oil thing, yield 79%, purity: 96.1%.
1H NMR(400MHz,CDCl3)δ8.25(d,1H),7.94(dd,1H),6.94-7.13(m,3H),6.69(d,
1H)。
Embodiment 17
Preparation 6-(3,4-difluorobenzene epoxide) pyridin-3-yl boric acid (III-4)
Preparation method reference example 2, compound III-4 is light brown solid, yield 91%, purity: 96.5%.
1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.21(brs,2H),8.14(dd,1H),7.12(m,1H),
7.05(m,2H),6.91(d,1H)。
Embodiment 18
Preparation 3-(6-(3,4-difluorobenzene epoxide) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-4)
Preparation method is with reference to embodiment 3, and compound IV-4 is light yellow solid, yield 55%, purity: 96.8%.
1H NMR(400MHz,DMSO-d6)δ13.65(s,1H),8.35(d,1H),8.23(s,1H),8.09(dd,1H),
7.37(m,1H),7.31-7.21(m,2H),7.10(d,1H),6.82(brs,2H)。
Embodiment 19
Preparation (R)-tert-butyl group 3-(4-amino-3-(6-(3,4-difluorobenzene epoxide) pyridin-3-yl)-1H-pyrazoles [3,4-
D] pyrimidine-1-base) piperidines-1-carbonic ester (V-4)
Preparation method is with reference to embodiment 4, and compound V-4 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.44(d,1H),8.33(s,1H),8.05(dd,1H),7.36(m,1H),
7.20-7.09(m,3H),6.00(brs,2H),4.81(m,1H),4.48–4.05(m,2H),3.42(m,1H),2.85(t,
1H),2.21(m,2H),1.89(m,1H),1.70(m,1H),1.43(s,9H)。
Embodiment 20
Preparation (R)-3-(6-(3,4-difluorobenzene epoxide) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d]
Pyrimidine-4-amine hydrochlorate (I-4)
Preparation method is with reference to embodiment 5, and compound I-4 is light yellow solid, two step yields 42%, purity: 96.5%.
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.80(m,1H),9.46(brs,1H),8.68(s,1H),
8.45(d,1H),8.17(dd,1H),7.45(m,1H),7.25(d,1H),7.17–7.06(m,2H),5.32(m,1H),3.52–
3.25(m,3H),3.02(m,1H),2.18(m,2H),1.94(m,2H).LC-MS found 424.1,calc.for
C21H20F2N7O 424.2([M+H]+)。
Embodiment 21
The preparation bromo-2-of 5-(2-fluorophenoxy) pyridine (II-5)
Preparation method is with reference to embodiment 6, and compound II-5 is light yellow oil, yield 85%, purity: 97.6%.
1H NMR(400MHz,CDCl3)δ8.19(d,1H),7.87(dd,1H),7.16-7.98(m,4H),6.75(d,
1H)。
Embodiment 22
Preparation 6-(2-fluorophenoxy) pyridin-3-yl boric acid (III-5)
Preparation method is with reference to embodiment 2, and compound III-5 is light yellow solid, yield 89%, purity: 97.6%.
1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),8.15(brs,2H),7.97(dd,1H),7.12-6.95
(m,4H),6.78(d,1H)。
Embodiment 23
Preparation 3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-5)
Preparation method is with reference to embodiment 3, and compound IV-5 is light yellow solid, yield 86%, purity: 96.3%.
1H NMR(400MHz,DMSO-d6)δ13.49(s,1H),8.42(d,1H),8.31(s,1H),8.09(dd,1H),
7.19-6.85(m,5H),7.20-6.70(brs,2H)。
Embodiment 24
(4-amino-3-(6-(2-fluorophenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] is phonetic for preparation (R)-tert-butyl group-3-
Pyridine-1-base) piperidines-1-carbonic ester (V-5)
Preparation method is with reference to embodiment 4, and compound V-5 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.45(s,1H),8.38(d,1H),8.09(dd,1H),7.11-6.88(m,
5H),6.10(brs,2H),4.80(m,1H),4.38-4.12(m,2H),3.45(m,1H),2.86(t,1H),2.30–2.15
(m,2H),1.90(m,1H),1.70(m,1H),1.47(s,9H)。
Embodiment 25
Preparation (R)-3-(6-(2-fluorophenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-
4-semicarbazide hydrochloride (I-5)
Preparation method is with reference to embodiment 5, and compound I-5 is light yellow solid, two step total recoverys 49%, purity: 96.2%.
1H NMR(400MHz,DMSO-d6)δ10.03(m,1H),9.77(m,1H),9.50(brs,1H),8.60(s,1H),
8.39(d,1H),8.15(dd,1H),7.25-7.03(m,5H),5.29(m,1H),3.50(m,1H),3.42(m,1H),3.29
(m,1H),3.09(m,1H),2.15(m,2H),1.90(m,2H).LC-MS found 406.0,calc.for C21H21FN7O
406.2([M+H]+)。
Embodiment 26
The preparation bromo-2-of 5-(4-(trifluoromethyl) phenoxy group) pyridine (II-6)
Preparation method is with reference to embodiment 1, and compound II-6 is light yellow solid, yield 75%, purity: 96.7%.
1H NMR(400MHz,CDCl3)δ8.26(d,1H),8.01(dd,1H),7.65(d,2H),7.08(d,2H),6.82
(d,1H)。
Embodiment 27
Preparation 6-(4-(trifluoromethyl) phenoxy group) pyridin-3-yl boric acid (III-6)
Preparation method is with reference to embodiment 2, and compound III-6 is light yellow solid, yield 90%, purity: 97.4%.
1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),8.12(brs,2H),8.05(dd,1H),7.58(d,2H),
7.04(d,2H),6.89(d,1H)。
Embodiment 28
Preparation 3-(6-(4-(trifluoromethyl) phenoxy group) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-6)
Preparation method is with reference to embodiment 3, and compound IV-6 is light yellow solid, yield 51%, purity: 95.8%.
1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.44(d,1H),8.21(s,1H),8.05(dd,1H),
7.54(d,2H),7.21(d,2H),7.10(d,1H),6.96(brs,2H)。
Embodiment 29
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-(4-(trifluoromethyl) phenoxy group) pyridin-3-yl)-1H-pyrazoles
[3,4-d] pyrimidine-1-base) piperidines-1-carbonic ester (V-6)
Preparation method is with reference to embodiment 4, and compound V-6 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.50(d,1H),8.37(s,1H),8.04(dd,1H),7.66(d,2H),7.09
(d,2H),7.01(d,1H),5.90(brs,2H),4.83(m,1H),4.50–4.09(m,2H),3.41(m,1H),2.91(t,
1H),2.23(m,2H),1.88(m,1H),1.65(m,1H),1.47(s,9H)。
Embodiment 30
Preparation (R)-1-(piperidines-3-base)-3-(6-(4-(trifluoromethyl) phenoxy group) pyridin-3-yl)-1H-pyrazoles [3,
4-d] pyrimidine-4-amine hydrochlorate (I-6)
Preparation method is with reference to embodiment 5, and compound I-6 is light yellow solid, two step yields 41%, purity: 97.0%.
1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),9.75(m,1H),9.44(brs,1H),8.65(s,1H),
8.42(d,1H),8.11(dd,1H),7.65(d,2H),7.27(d,2H),7.17(d,1H),5.22(m,1H),3.60–3.27
(m,3H),3.05(m,1H),2.17(m,2H),1.92(m,2H).LC-MS found 456.3,calc.for C22H21F3N7O
456.2([M+H]+)。
Embodiment 31
The preparation bromo-2-of 5-(4-cyclopropyl-phenyl epoxide) pyridine (II-7)
Preparation method is with reference to embodiment 6, and compound II-7 is colorless oil, yield 73%, purity: 96.8%.
1H NMR(400MHz,CDCl3)δ8.12(d,1H),7.91(dd,1H),7.15(d,2H),6.95(d,2H),6.68
(d,1H),1.85(m,1H),0.84(m,2H),0.68(m,2H)。
Embodiment 32
Preparation 6-(4-cyclopropyl-phenyl epoxide) pyridin-3-yl boric acid (III-7)
Preparation method is with reference to embodiment 2, and compound III-7 is light yellow solid, yield 94%, purity: 96.0%.
1H NMR(400MHz,DMSO-d6)δ8.36(d,1H),8.20(brs,2H),7.91(dd,1H),7.09(d,2H),
6.94(d,2H),6.70(d,1H),1.87(m,1H),0.85(m,2H),0.65(m,2H)。
Embodiment 33
Preparation 3-(6-(4-cyclopropyl-phenyl epoxide) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-7)
Preparation method is with reference to embodiment 3, and compound IV-7 is light yellow solid, yield 72%, purity: 94.8%.
1H NMR(400MHz,DMSO-d6)δ13.43(s,1H),8.39(d,1H),8.25(s,1H),7.95(dd,1H),
7.25(d,2H),7.06(d,2H),6.95(d,1H),6.90(brs,2H),1.69(m,1H),0.72(m,2H),0.58(m,
2H)。
Embodiment 34
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-(4-cyclopropyl-phenyl epoxide) pyridin-3-yl)-1H-pyrazoles [3,4-
D] pyrimidine-1-base) piperidines-1-carbonic ester (V-7)
Preparation method is with reference to embodiment 4, and compound V-7 is light yellow solid, is directly used in next step reaction.
1H NMR(400MHz,CDCl3)δ8.51(d,1H),8.36(s,1H),8.03(dd,1H),7.13(d,2H),7.01
(d,2H),6.87(d,1H),6.00(brs,2H),4.90(m,1H),4.50-4.10(m,2H),3.41(m,1H),2.83(t,
1H),2.25(m,2H),1.88(m,2H),1.65(m,1H),1.45(s,9H),0.75(m,2H),0.60(m,2H)。
Embodiment 35
Preparation (R)-3-(6-(4-cyclopropyl-phenyl epoxide) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d]
Pyrimidine-4-amine hydrochlorate (I-7)
Preparation method is with reference to embodiment 5, and compound I-7 is light yellow solid, two step total recoverys 35%, purity: 96.6%.
1H NMR(400MHz,DMSO-d6)δ9.92(m,1H),9.75(m,1H),9.45(brs,1H),8.52(s,1H),
8.26(d,1H),8.06(dd,1H),7.21(d,2H),7.05(d,2H),6.85(d,1H),5.10(m,1H),3.65(m,
1H),3.40(m,1H),3.21(m,1H),3.00(m,1H),2.12(m,2H),1.95(m,3H),0.86(m,2H),0.67(m,
2H).LC-MS found 428.3,calc.for C24H26N7O 428.2([M+H]+)。
Embodiment 36
The preparation bromo-2-of 5-(4-methoxyphenoxy) pyridine (II-8)
Preparation method is with reference to embodiment 1, and compound II-8 is white solid, yield 92%, purity: 95.0%.
1H NMR(400MHz,CDCl3)δ8.19(d,1H),7.92(dd,1H),7.05(d,2H),6.85-6.78(m,
3H),3.81(s,3H)。
Embodiment 37
Preparation 6-(4-methoxyphenoxy) pyridin-3-yl boric acid (III-8)
Preparation method is with reference to embodiment 2, and compound III-8 is light yellow solid, yield 84%, purity: 97.3%.
1H NMR(400MHz,DMSO-d6)δ8.43(d,1H),8.11(brs,2H),8.01(dd,1H),7.06(d,2H),
6.92(d,2H),6.81(d,1H),3.80(s,3H)。
Embodiment 38
Preparation 3-(6-(4-methoxyphenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-8)
Preparation method is with reference to embodiment 3, and compound IV-8 is light yellow solid, yield 81%, purity: 95.1%.
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.41(d,1H),8.20(s,1H),8.01(dd,1H),
7.14(d,2H),6.99(d,2H),6.94(d,1H),6.50(brs,2H),3.81(s,3H)。
Embodiment 39
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-(4-methoxyphenoxy) pyridin-3-yl)-1H-pyrazoles [3,4-
D] pyrimidine-1-base) piperidines-1-carbonic ester (V-8)
Preparation method is with reference to embodiment 4, and compound V-8 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.47(d,1H),8.35(s,1H),8.04(dd,1H),7.06(m,3H),7.01
(d,2H),5.92(brs,2H),4.80(m,1H),4.43–4.05(m,2H),3.76(s,3H),3.45(m,1H),2.85(t,
1H),2.30(m,2H),1.92(m,1H),1.60(m,1H),1.44(s,9H)。
Embodiment 40
Preparation (R)-3-(6-(4-methoxyphenoxy) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d]
Pyrimidine-4-amine hydrochlorate (I-8)
Preparation method is with reference to embodiment 5, and compound I-8 is light yellow solid, two step yields 56%, purity: 95.6%.
1H NMR(400MHz,DMSO-d6)δ10.05(m,1H),9.81(m,1H),9.41(brs,1H),8.59(s,1H),
8.37(d,1H),8.06(dd,1H),7.21(d,2H),7.16(d,2H),7.08(d,1H),5.23(m,1H),3.81(s,
3H),3.49–3.22(m,3H),3.02(m,1H),2.16(m,2H),1.93(m,2H).LC-MS found 418.2,
calc.for C22H24N7O2 418.2([M+H]+)。
Embodiment 41
The preparation bromo-2-of 5-(4-(2-methoxy ethoxy) phenoxy group) pyridine (II-9)
Preparation method is with reference to embodiment 6, and compound II-9 is colourless liquid, yield 76%, purity: 97.3%.
1H NMR(400MHz,CDCl3)δ8.21(d,1H),7.85(dd,1H),7.11(d,2H),6.95(d,2H),6.71
(d,1H),4.22(t,2H),3.85(t,2H),3.63(s,3H)。
Embodiment 42
Preparation 6-(4-(2-methoxy ethoxy) phenoxy group) pyridin-3-yl boric acid (III-9)
Preparation method is with reference to embodiment 2, and compound III-9 is pale yellow semi-solid, yield 85%, purity: 96.6%.
1H NMR(400MHz,DMSO-d6)δ8.48(d,1H),8.30(brs,2H),8.08(dd,1H),7.25(d,2H),
7.06(d,2H),6.89(d,1H),4.18(t,2H),3.88(t,2H),3.77(s,3H)。
Embodiment 43
Preparation 3-(6-(4-(2-methoxy ethoxy) phenoxy group) pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine
(IV-9)
Preparation method is with reference to embodiment 3, and compound IV-9 is light yellow solid, yield 61%, purity: 96.3%.
1H NMR(400MHz,DMSO-d6)δ13.41(s,1H),8.35(d,1H),8.27(s,1H),7.91(dd,1H),
7.18(d,2H),7.01(d,2H),6.95(d,1H),6.88(brs,2H),4.31(t,2H),3.79(t,2H),3.72(s,
3H)。
Embodiment 44
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-(4-(2-methoxy ethoxy) phenoxy group) pyridin-3-yl)-
1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidines-1-carbonic ester (V-9)
Preparation method is with reference to embodiment 4, and compound V-9 is pale yellow semi-solid.
1H NMR(400MHz,CDCl3)δ8.45(d,1H),8.38(s,1H),8.07(dd,1H),7.10(d,2H),6.97
(d,2H),6.91(d,1H),6.05(brs,2H),4.81(m,1H),4.48-4.10(m,4H),3.70(t,2H),3.62(s,
3H),3.35(m,1H),2.83(t,1H),2.20(m,2H),1.85(m,2H),1.69(m,1H),1.41(s,9H)。
Embodiment 45
Preparation (R)-3-(6-(4-(2-methoxy ethoxy) phenoxy group) pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrrole
Azoles [3,4-d] pyrimidine-4-amine hydrochlorate (I-9)
Preparation method is with reference to embodiment 5, and compound I-9 is light yellow solid, two step yields 56%, purity: 95.8%.
1H NMR(400MHz,DMSO-d6)δ9.95-9.80(m,2H),9.40(brs,1H),8.43(s,1H),8.25(d,
1H),8.12(dd,1H),7.17(d,2H),7.01(d,2H),6.93(d,1H),5.21(m,1H),4.40(m,1H),3.90
(t,1H),3.78(t,1H),3..70(s,3H),3.55(m,1H),3.42(m,1H),3.28(m,1H),2.92(m,1H),
2.10(m,2H),1.88(m,2H).LC-MS found 462.2,calc.for C24H28N7O3 462.2([M+H]+)。
Embodiment 46
The preparation bromo-2-of 5-(4-cyclopropyl-phenyl epoxide)-3-fluorine pyridine (II-10)
Preparation method is with reference to embodiment 5, and compound II-10 is light yellow oil, yield 65%, purity: 97.6%.
1H NMR(400MHz,CDCl3)δ8.40(d,1H),8.25(m,1H),7.21(d,2H),7.03(d,2H),1.90
(m,1H),0.85(m,2H),0.65(m,2H)。
Embodiment 47
Preparation 6-(4-cyclopropyl-phenyl epoxide)-5-fluorine pyridin-3-yl boric acid (III-10)
Preparation method is with reference to embodiment 2, and compound III-10 is light yellow solid, yield 86%, purity: 96.3%.
1H NMR(400MHz,DMSO-d6)δ8.45(d,1H),8.21(m,1H),8.10(brs,2H),7.18(d,2H),
7.05(d,2H),1.92(m,1H),0.75(m,2H),0.56(m,2H)。
Embodiment 48
Preparation 3-(6-(4-cyclopropyl-phenyl epoxide)-5-fluorine pyridin-3-yl)-1H-pyrazoles [3,4-d] pyrimidine-4-amine (IV-
10)
Preparation method is with reference to embodiment 3, and compound IV-10 is light yellow solid, yield 56%, purity: 97.2%.
1H NMR(400MHz,DMSO-d6)δ13.45(s,1H),8.36(d,1H),8.29(s,1H),8.18(m,1H),
7.16(d,2H),7.09(d,2H),6.85(brs,2H),1.80(m,1H),0.88(m,2H),0.67(m,2H)。
Embodiment 49
Preparation (R)-tert-butyl group-3-(4-amino-3-(6-(4-cyclopropyl-phenyl epoxide)-5-fluorine pyridin-3-yl)-1H-pyrazoles
[3,4-d] pyrimidine-1-base) piperidines-1-carbonic ester (V-10)
Preparation method is with reference to embodiment 4, and compound V-10 is light yellow solid.
1H NMR(400MHz,CDCl3)δ8.39(d,1H),8.25(m,1H),7.15(d,2H),6.98(d,2H),5.86
(brs,2H),4.85(m,1H),4.40-4.13(m,2H),3.45(m,1H),2.78(t,1H),2.21(m,2H),1.89(m,
3H),1.65(m,1H),1.45(s,9H),0.79(m,2H),0.61(m,2H)。
Embodiment 50
Preparation (R)-3-(6-(4-cyclopropyl-phenyl epoxide)-5-fluorine pyridin-3-yl)-1-(piperidines-3-base)-1H-pyrazoles [3,
4-d] pyrimidine-4-amine hydrochlorate (I-10)
Preparation method is with reference to embodiment 5, and compound I-10 is light yellow solid, two step yields 43%, purity: 96.4%.
1H NMR(400MHz,DMSO-d6)δ10.10-9.95(m,2H),8.35(s,1H),8.14(m,1H),7.23(d,
2H),7.09(d,2H),5.12(m,1H),3.59(m,1H),3.42(m,1H),3.25(m,1H),3.01(m,1H),2.14(m,
2H),1.90(m,3H),0.87(m,2H),0.59(m,2H).LC-MS found 446.2,calc.for C24H25FN7O
446.2([M+H]+)。
Embodiment 51
Compound 1 (R, E)-1-(3-(4-amino-3-(6-phenoxypyridines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-1-
Yl) piperidin-1-yl) preparation of but-2-ene-1-ketone (1)
Compound I-1 (10g, 23.6mmol) is dissolved in THF, adds trans .beta.-methylacrylic acid (2.4g, 28.3mmol), will mixing
Thing ice-water bath is cooled to 0 DEG C, is sequentially added into EDCI (6.8g, 35.4mmol), HOBT (4.8g, 35.4mmol), finishes, reaction
Naturally it is raised to room temperature, is stirred overnight.Reacting the cancellation (200mL) that adds water, ethyl acetate extracts (2 × 200mL), after organic facies merges
Being dried with saturated common salt washing (2 × 100mL), anhydrous sodium sulfate, filter, filtrate reduced in volume is the most dry, silica gel column chromatography purification,
Obtain light yellow solid 9.2 grams, yield 86%, purity 96.6%.1H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.20
(s,1H),7.91(d,1H),7.23-7.15(m,3H),7.00(d,2H),6.75(d,1H),6.54(m,1H),6.11(m,
1H),4.85(brs,2H),4.77(m,1H),4.52(m,0.5H),4.17(m,1H),4.05(m,0.5H),3.73(t,
0.5H),3.19(m,1H),3.01(t,0.5H),2.28(m,1H),2.18(m,1H),1.98(m,1H),1.92(s,3H),
1.60(m,1H).LC-MS found 456.3,calc.for C25H26N7O2456.2([M+H]+)。
The present invention is according to drug design principle, it is provided that the intermediate with phenoxypyridines structure can be further used for
Prepare bioactive compound, such as: after the nitrogen-atoms on these intermediate piperidine rings is carried out acrylamide derivatization,
Obtained by there is phenoxypyridines structure there is BTK inhibitory activity according to Shandong for Buddhist nun's analog.
Therefore, the intermediate of present invention offer and preparation technology, contribute to preparing novel B TK inhibitor efficiently, right
Research and development in BTK inhibitor kind new medicine even list has the highest using value.
Above the present invention is described in detail, its object is to allow the personage being familiar with this art will appreciate that this
Invention content and be carried out, can not limit the scope of the invention with this, all spirit institutes according to the present invention
The equivalence change made or modification, all should contain within the scope of the present invention.
Claims (10)
1. a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: described bruton's tyrosine kinase suppression
Agent intermediate is the compound shown in I, II, III, IV, V or its pharmaceutically acceptable salt,
The structural formula of I is:The structural formula of II is:The structural formula of III is:The structural formula of IV is:The structural formula of V is:
Wherein, R1To R8It is independently selected from H, halogen, CF3、CN、NO2、OH、NH2、(C1-C6) alkyl, L-(C1-C6) alkyl, L-
(C1-C6) alkyl-L-(C1-C6) alkyl, L-(C2-C6) thiazolinyl, L-replace or non-substituted aryl or L-replace or
Non-substituted heterocycle;Wherein L is O, S (=O), S (=O)2、NHC(O)CH2, NHC (O) O, NHC (O) or C (O) NH, X be halogen.
Bruton's tyrosine kinase inhibitor intermediate the most according to claim 1, it is characterised in that: R1、R2、R4、R6Solely
On the spot selected from H or halogen, R3For selected from H, halogen, CF3、Methoxyl group or OC2H4OCH3, wherein, halogen is fluorine, chlorine or bromine;
R5、R7、R8For H;X is selected from bromine or iodine.
Bruton's tyrosine kinase inhibitor intermediate the most according to claim 2, it is characterised in that: R1、R2、R3、R4、R6
In halogen be different halogens from X.
Bruton's tyrosine kinase inhibitor intermediate the most according to any one of claim 1 to 3, it is characterised in that:
Described bruton's tyrosine kinase inhibitor intermediate is any one in the compound shown in following structural formula:
5. the preparation method of a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: by compound shown in formula A with
Compound shown in formula B is in the presence of alkali and solvent, and at 80~110 DEG C, nucleo philic substitution reaction obtains chemical combination shown in formula II
Thing, wherein, compound shown in formula A isCompound shown in formula B isFormula II shownization
Compound isR1~R8Definition as shown in claim 1, X, X1、X2Independently be halogen;Described solvent
For selected from dioxane, toluene, acetonitrile, dimethylformamide, dimethyl acetylamide, dimethyl sulfoxide, ethanol, methanol, isopropyl
The combination of one or more in alcohol, oxolane;Described alkali is selected from sodium bicarbonate, sodium carbonate, potassium carbonate, bicarbonate
One in potassium, cesium carbonate, sodium hydroxide, Lithium hydrate, potassium hydroxide, potassium fluoride, triethylamine, diisopropyl ethyl amine, DBU
Or multiple combination.
6. the preparation method of a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: by compound shown in formula II
In the presence of alkali and solvent, after slaine is made in-78~80 DEG C of reactions, react at-78~80 DEG C with boric acid three ester
Cheng Hou, then obtain compound shown in formula III through hydrolysis, wherein, compound shown in formula II isShown in formula III
Compound isR1~R8, X definition as shown in claim 1;Described solvent is selected from ether, tetrahydrochysene
The combination of one or more in furan, methyltetrahydrofuran, normal hexane, normal heptane, described alkali is selected from chloroisopropane
Grignard reagent, ethylmagnesium bromide Grignard reagent, methyl-magnesium-chloride Grignard reagent, isopropylmagnesium chloride Grignard reagent, phenyl bromination
Magnesium grignard reagent, n-BuLi, s-butyl lithium, tert-butyl lithium, lithium diisopropylamine (LDA), LHMDS,
The combination of one or more in sodium hexamethyldisilazide, potassium hexamethyldisilazide, described boric acid three ester is boron
Triethylenetetraminehexaacetic acid ester, methyl borate. or triisopropyl borate ester.
7. the preparation method of a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: by compound shown in formula III
1H-pyrazoles [3,4-d] pyrimidine-4-amine iodo-with 3-is in the presence of solvent, alkali, palladium catalyst and part, at 25~100 DEG C
Lower obtaining compound shown in formula IV through Suzuki coupling, compound shown in formula III isFormula IV shownization
Compound isR1~R8Definition as shown in claim 1;Described palladium catalyst is selected from acetic acid
The combination of one or more in palladium, four triphenyl phosphorus palladiums, Palladous chloride., palladium carbon;Described part is selected from triphenyl phosphorus, three just
The combination of one or more in butyl phosphorus, thricyclohexyl phosphorus s-phos, x-phos;Described alkali is selected from potassium carbonate, carbonic acid
In sodium, sodium bicarbonate, potassium bicarbonate, cesium carbonate, ammonium carbonate, triethylamine, tri-n-butylamine, diisopropyl ethyl amine, pyridine one
Kind or multiple combination;Described solvent is the one in dioxane, acetone, water, toluene, dimethylbenzene, oxolane
Or multiple combination.
8. the preparation method of a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: by compound shown in formula IV
With N-Boc-3-hydroxy piperidine in the presence of solvent, condensing agent, alkylphosphines, react through Mitsunobu at-20~40 DEG C
Obtaining compound shown in Formula V, compound shown in formula IV isCompound shown in Formula V isR1~R8Definition as shown in claim 1;Described solvent is selected from oxolane, ether, dichloro
The combination of one or more in methane, described condensing agent is azo acid dimethyl ester, diethyl azodiformate or idol
Nitrogen dioctyl phthalate diisopropyl ester, described alkylphosphines is triphenylphosphine or tributylphosphine.
9. the preparation method of a bruton's tyrosine kinase inhibitor intermediate, it is characterised in that: compound shown in Formula V is existed
In the presence of acid, at 0~100 DEG C, the de-Boc of hydrolysis obtains compound shown in formula I, and compound shown in Formula V isCompound shown in formula I isR1~R8Definition as shown in claim 1;Institute
The acid stated is the mixing of one or more in sulphuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid.
10. the bruton's tyrosine kinase inhibitor intermediate as according to any one of Claims 1-4 is in preparation treatment
Purposes in the medicine of hematologic malignancies or Autoimmune Disorders disease.
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