CN105418678B - A kind of preparation method of Tedizolid Phosphate - Google Patents
A kind of preparation method of Tedizolid Phosphate Download PDFInfo
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- 0 COCC(CN1c2cc(F)c(*)cc2)OC1=O Chemical compound COCC(CN1c2cc(F)c(*)cc2)OC1=O 0.000 description 2
- GQKZBCPTCWJTAS-UHFFFAOYSA-N COCc1ccccc1 Chemical compound COCc1ccccc1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 description 1
- XFALPSLJIHVRKE-GFCCVEGCSA-N C[n]1nnc(-c(cc2)ncc2-c(ccc(N(C[C@H](CO)O2)C2=O)c2)c2F)n1 Chemical compound C[n]1nnc(-c(cc2)ncc2-c(ccc(N(C[C@H](CO)O2)C2=O)c2)c2F)n1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 description 1
Abstract
The invention belongs to field of medicine and chemical technology, in particular to a kind of preparation method of Tedizolid Phosphate.Preparation method of the invention, the intermediate and final products of each step all have high-purity.In addition, also can avoid generating dimerization product using diisopropylamino dibenzyl phosphite as phosphorus esterification reagent, so that preparation method of the invention has higher yield.Preparation method route of the invention is shorter, and reaction condition is mild, also avoids using toxic, irritant and strong corrosive reagent, environmentally protective;It avoids reacting using ultralow temperature simultaneously, easy preparation easy to operate, high production efficiency.Therefore, preparation method of the invention especially adapts to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, in particular to a kind of new preparation method of Tedizolid Phosphate.
Background technique
Tedizolid Phosphate (tedizolid phosphate), (R) -3- (4- (2- (2- methyl tetrazolium -5- base) pyridine -
5- yl) 3- fluorophenyl) -5- hydroxyl first base oxazolidine -2- ketone dihydrogen phosphoric acid ester (formula I), the medicine is for treating gram-positive bacteria sense
Dye, such as infection and pulmonary infection etc. caused by acute bacterial skin infection, MRSA.
Currently, there are mainly two types of for the preparation method of disclosed Tedizolid Phosphate:
Route 1:CN1894242 is disclosed following preparation method:
Route first step reaction uses toxic organotin reagent, and second step condensation reaction prepares key intermediate (R)-
The yield of 3- (4- (2- (2- methyl tetrazolium -5- base) pyridine -5- base) 3- fluorophenyl) -5- Qiang Jia Ji oxazolidine -2- ketone down to
26%, third step reaction prepares (R)-[3- (4- (2- (2- methyl tetrazolium -5- base) pyridine -5- base) -3- fluorophenyl) -2- oxygen -5-
Oxazolidinyl] methyl acid phosphate bis- (tetrabutyl esters) needs to carry out at -78 DEG C, and the reaction time is long, and final step is needed using with thorn
Swash the trifluoroacetic acid of stink, strong corrosive.Therefore, the route total recovery is low, high production cost, severe reaction conditions, generates week
Phase is long, and agents useful for same is toxic or irritation corrosivity is strong, is not suitable for industrialized production.
Route 2:CN102177156 discloses following synthetic route:
The route is long by starting material synthetic reaction route, and wherein the reaction of second step boronation need to be carried out in -72 DEG C of low temperature
And the yield of obtained product 4- (benzyloxycarbonyl amino) -2- fluorobenzoic boric acid is only 66% and very impure, the 4th step cyclization is anti-
Answer the complex for operation step and reaction time long, final step phosphorylation is using hypertoxic fuming liquids phosphorus oxychloride.Therefore, the road
Line is also not suitable with industrialization large-scale production.
There are many defects for the synthetic method of Tedizolid Phosphate disclosed in the prior art, therefore still need to prepare phosphoric acid specially
The new method of azoles amine.
Summary of the invention
On the one hand, the present invention provides a kind of preparation method of type I compound, including:In the presence of catalyst and hydrogen source, formula
VII compound is reacted,
Wherein the catalyst is selected from Pd (OH)2/C、Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2Or Raney nickel, preferably
For Pd/C.
Wherein the hydrogen source is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene, preferably H2。
It is mono-substituted or polysubstituted chemical combination it should be appreciated that VII compound of formula of the invention also covers the phenyl ring on benzyl
Object, as long as above-mentioned reaction is able to carry out, the substituent group includes but is not limited to halogen, hydroxyl, amino, cyano, carboxyl, sulphur
Acyl group, sulfydryl, trifluoromethyl, nitro, phenyl, benzyl, benzyloxy, pyridyl group, piperidyl, methylol, ethoxy, hydroxypropyl,
Optionally by halogen or C1-C6The C that alkoxy replaces1-C6Alkyl, optionally by halogen or C1-C6The C that alkoxy replaces1-C6Alkoxy,
C1-C6Alkylthio group, C1-C6Alkoxy carbonyl, C1-C6Alkyl-carbonyl, C1-C6Alkyl amino, C1-C6Alkyl carbonyl epoxide, C3-C7Ring
Alkyl, C3-C7Cycloalkyloxy or C3-C7Cycloalkylmethoxy.
The preparation of type I compound can according to need the suitable solvent of selection and be reacted, and the solvent is selected from water, C1~
C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone, second
The one or more of ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, DMF, DMAC or DMSO,
Preferably ethyl acetate, butyl acetate or C1~C8Alcohol one or more, most preferably in ethyl acetate, methanol or ethyl alcohol
One or more.In one embodiment of the invention, solvent is methanol.
On the other hand, the present invention provides VII compound of formula,
It is mono-substituted or polysubstituted chemical combination it should be appreciated that VII compound of formula of the invention also covers the phenyl ring on benzyl
Object, the substituent group include but is not limited to halogen, hydroxyl, amino, cyano, carboxyl, sulfonyl, sulfydryl, trifluoromethyl, nitro,
Phenyl, benzyl, benzyloxy, pyridyl group, piperidyl, methylol, ethoxy, hydroxypropyl, optionally by halogen or C1-C6Alkoxy takes
The C in generation1-C6Alkyl, optionally by halogen or C1-C6The C that alkoxy replaces1-C6Alkoxy, C1-C6Alkylthio group, C1-C6Alkoxy carbonyl
Base, C1-C6Alkyl-carbonyl, C1-C6Alkyl amino, C1-C6Alkyl carbonyl epoxide, C3-C7Naphthenic base, C3-C7Cycloalkyloxy or C3-C7
Cycloalkylmethoxy.
In another aspect, the present invention provides a kind of preparation method of VII compound of formula, including:VI chemical combination of V compound of formula and formula
Object is reacted in the presence of catalyst, oxidant,
Wherein R1And R2It is each independently selected from methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or uncle
Butyl;Or R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace phenyl;Or
Person R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace benzyl.It is preferred that R1And R2
It is simultaneously isopropyl or ethyl, most preferably R1And R2It is simultaneously isopropyl.
Wherein the catalyst be selected from 1H- tetrazole orPreferably 1H- tetrazole.
Wherein the oxidant be selected from metachloroperbenzoic acid (mCPBA), hydrogen peroxide, Peracetic acid, benzoyl hydroperoxide or
Tert-butyl hydroperoxide (TBHP), preferably metachloroperbenzoic acid (mCPBA).
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, C1
~C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone,
One of ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, DMF, DMAC or DMSO or
It is several.In one embodiment of the invention, solvent is methylene chloride.VI compound of formula can be obtained by commercially available
, it can also be prepared by the method for the prior art, such as be prepared via a method which,
In one embodiment of the invention, VI compound of formula is diisopropylaminoethyl dibenzyl phosphite (formula
II),
It is mono-substituted or more it should be appreciated that VI compound of formula or II compound of formula of the invention also covers the phenyl ring on benzyl
Substituted compound, the substituent group include but is not limited to halogen, hydroxyl, amino, cyano, carboxyl, sulfonyl, sulfydryl, trifluoro
Methyl, nitro, phenyl, benzyl, benzyloxy, pyridyl group, piperidyl, methylol, ethoxy, hydroxypropyl, optionally by halogen or C1-
C6The C that alkoxy replaces1-C6Alkyl, optionally by halogen or C1-C6The C that alkoxy replaces1-C6Alkoxy, C1-C6Alkylthio group, C1-
C6Alkoxy carbonyl, C1-C6Alkyl-carbonyl, C1-C6Alkyl amino, C1-C6Alkyl carbonyl epoxide, C3-C7Naphthenic base, C3-C7Cycloalkanes
Oxygroup or C3-C7Cycloalkylmethoxy.
Another aspect, the present invention provide a kind of preparation method of V compound of formula, including:
(1) III compound of formula is reacted in the presence of palladium catalyst and alkali with borating agent,
(2) product of step (1) is reacted in the presence of palladium catalyst and alkali with IV compound of formula,
Wherein X1And X2It is each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br.
In one embodiment of the invention, III compound of formula is (5R) -3- (4- bromine-3-fluorophenyl) -5- hydroxyl
Jia Ji oxazolidine -2- ketone.
In one embodiment of the invention, IV compound of formula is the bromo- 2- of 5- (2- methyl -2H- tetrazolium -5- base)
Pyridine.
The borating agent of the step (1) is selected from connection boric acid pinacol ester Triisopropyl
Borate, tripropylborane acid esters, trimethyl borate or boron triethyl acid esters, preferably connection boric acid pinacol ester,
OrMore preferably connection boric acid pinacol ester.
The palladium catalyst of the step (1) is selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride network
Close object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2, preferably [1,1'- bis- (diphenyl
Phosphine) ferrocene] palladium chloride dichloromethane complex.
The palladium catalyst of the step (2) is selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride network
Close object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2, preferably [1,1'- bis- (diphenyl
Phosphine) ferrocene] palladium chloride dichloromethane complex.
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)。
The alkali of the step (1) is selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, uncle
Butanol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three
One of ethamine, diethylamine or ethylenediamine are a variety of, preferably potassium acetate.
The alkali of the step (2) is selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, uncle
Butanol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three
One of ethamine, diethylamine or ethylenediamine are a variety of, preferably cesium carbonate.
The preparation of V compound of formula can according to need the suitable solvent of selection and be reacted, and the solvent includes but unlimited
Yu Shui, C1~C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, ring
Hexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, DMF, DMAC, DMSO or NMP
It is one or more of.In one embodiment of the invention, the solvent of step (1) is DMSO, and the solvent of step (2) is 1,
The mixed solvent of 4- dioxane and water.
Optionally, the reaction of step (1) and step (2) can be in N2Or it is carried out under the protection of argon gas.
On the other hand, the present invention provides a kind of preparation method of type I compound (Tedizolid Phosphate), including:
I) III compound of formula is reacted in the presence of palladium catalyst and alkali with borating agent,
Ii) product of step i) carries out reacting V chemical combination of preparation formula in the presence of palladium catalyst and alkali with IV compound of formula
Object,
Iii) V compound of formula and VI compound of formula carry out reaction VII chemical combination of preparation formula in the presence of catalyst, oxidant
Object,
Iv) VII compound of formula carries out reaction preparation of compounds of formula I in the presence of catalyst and hydrogen source,
Wherein X1And X2It is each independently selected from F, Cl, Br or I, preferably Br or I, most preferably Br;
Wherein R1And R2Be each independently selected from methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or
Tert-butyl;Or R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace phenyl;
Or R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace benzyl.It is preferred that R1
And R2It is simultaneously isopropyl or ethyl, most preferably R1And R2It is simultaneously isopropyl;
The borating agent of the step i) is selected from connection boric acid pinacol ester Triisopropyl
Borate, tripropylborane acid esters, trimethyl borate or boron triethyl acid esters, preferably connection boric acid pinacol ester,
OrMore preferably connection boric acid pinacol ester;
The palladium catalyst of the step i) is complexed selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride
Object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2, preferably [1,1'- bis- (diphenylphosphines)
Ferrocene] palladium chloride dichloromethane complex;
The alkali of the step i) is selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, tertiary fourth
Lithium alkoxide, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three second
One of amine, diethylamine or ethylenediamine are a variety of, preferably potassium acetate.
The step ii) palladium catalyst be selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride network
Close object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2, preferably [1,1'- bis- (diphenyl
Phosphine) ferrocene] palladium chloride dichloromethane complex;
The step ii) alkali be selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, uncle
Butanol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three
One of ethamine, diethylamine or ethylenediamine are a variety of, preferably cesium carbonate.
The step iii) catalyst be 1H- tetrazole orPreferably 1H- tetrazole.
The step iii) oxidant be selected from metachloroperbenzoic acid (mCPBA), hydrogen peroxide, Peracetic acid, peroxide benzene
Formic acid or tert-butyl hydroperoxide (TBHP), preferably metachloroperbenzoic acid (mCPBA).
The step iv) catalyst be selected from Pd (OH)2/C、Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2Or Raney nickel,
Preferably Pd/C.
The step iv) hydrogen source be selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene, preferably H2。
" dppf " of the present invention is bis- (diphenylphosphine) ferrocene of 1,1'-.
" dba " of the present invention is dibenzalacetone.
" PCy of the present invention3" it is tricyclohexyl phosphine.
" dppe " of the present invention is bis- (diphenylphosphine) ethane of 1,2-.
" dppp " of the present invention is bis- (diphenylphosphine) propane of 1,3-.
Preparation method of the invention, the intermediate and final products of each step all have high-purity.In addition, using diisopropyl
Amido dibenzyl phosphite also can avoid generating dimerization product, so that preparation method of the invention has as phosphorus esterification reagent
There is higher yield.Preparation method route of the invention is shorter, and reaction condition is mild, also avoids using toxic, irritant and strong
Corrosive reagents, it is environmentally protective;It avoids reacting using ultralow temperature simultaneously, easy preparation easy to operate, high production efficiency.Therefore, originally
The preparation method of invention especially adapts to 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.
Embodiment 1 (R) -3- (4- (2- (2- methyl tetrazolium -5- base) pyridine -5- base) 3- fluorophenyl) -5- Qiang Jia Ji oxazole
The preparation of alkane -2- ketone (V compound of formula)
DMSO (100ml) is added in 250ml reaction flask, (5R) -3- (4- bromine-3-fluorophenyl) -5- Qiang Jia Ji oxazolidine -2-
Ketone (10g, 34.5mmol), connection boric acid pinacol ester (17.52g, 69mmol), [1,1'- bis- (diphenylphosphine) ferrocene] dichloro
Change palladium dichloromethane complex (1.41g, 1.73mmol) and potassium acetate (13.5g, 138mmol), under nitrogen protection, is warming up to 80
DEG C, it reacts 14 hours.Stop heating, be down to room temperature, water/ethyl acetate extracts 3 times, merges organic layer, organic layer saturation food
Salt water washing 3 times, anhydrous sodium sulfate is dry, filters concentration.
The enriched product of above-mentioned steps is added in 250ml reaction flask, addition Isosorbide-5-Nitrae-dioxane (100ml), 5- are bromo-
2- (2- methyl -2H- tetrazolium -5- base) pyridine (8.28g, 34.5mmol), [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride
Dichloromethane complex (0.56g, 0.69mmol) and cesium carbonate aqueous solution (50ml, cesium carbonate containing 33.72g, 103.5mmol),
Under nitrogen protection, 70 DEG C are warming up to, is reacted 3 hours, methylene chloride extraction is added.Separating obtained organic phase saturated salt solution
Washing, filtering, is concentrated in vacuo simultaneously through column chromatography purifying anhydrous sodium sulfate dehydration, obtains 10.6g solid, yield 83.0%,
It is 98.34% (area normalization method) that HPLC, which detects purity,.
1H NMR (500 MHz, DMSO-d6):δ8.9328(s,1H),8.2019(m,2H),7.7153(m,2H),
7.5227(m,1H),5.1824(t,1H),4.7675(m,1H),4.4782(s,3H),4.1671(t,1H),3.9184(m,
1H),3.7203(m,1H),3.6122(m,1H)。
13C NMR (125 MHz, DMSO-d6):δ163.75,159.1925,154.147,149.235,144.983,
140.434,136.91,131.475,130.69,121.918,118.483,113.89,105.292,73.314,61.507,
45.907,39.519。
ESI-MS[M+H]+:371.1264。
Embodiment 2 (R)-[3- (4- (2- (2- methyl tetrazolium -5- base) pyridine -5- base) -3- fluorophenyl) -2- oxygen -5- oxazolidine
Base] methyl acid phosphate bis- (benzyl esters) (VII compound of formula) preparation
Methylene chloride (100ml), V chemical combination of 1H- tetrazole (5.97g, 85.2mmol) and formula are added in 500ml there-necked flask
Object (10.5g, 28.4mmol), temperature control in 30 DEG C or less dropwise addition diisopropylamino dibenzyl phosphites (19.6g, 56.8mmol),
Maintain the temperature at 25~30 DEG C of reaction 30min.Be cooled to 0~10 DEG C, be added 85% metachloroperbenzoic acid (8.08g,
39.8mmol), 5~10 DEG C of reaction 30min.
Reaction solution is successively with saturation NaHCO3It washing twice, saturation NaCl washed once, and anhydrous sodium sulfate dries, filters,
Concentration, is purified by column chromatography, obtains 14.89g title compound, yield 83.1%, it is 99.62% (face that HPLC, which detects purity,
Product normalization method).
1H NMR (500 MHz, DMSO-d6):δ8.9318(s,1H),8.241(m,1H),8.1938(m,1H),7.7457
(t,1H),7.6669(m,1H),7.4924(m,1H),7.3442(m,10H),5.0336(m,5H),4.4859(s,3H),
3.3063(m,3H),3.9175(m,1H)。
13C NMR (125 MHz, DMSO-d6):δ163.811,159.234,153.752,149.343,145.068,
140.087,137.079,135.778,131.5,130.75,128.358,127.733,122.037,118.804,114.055,
105.463,70.977,68.741,67.288,45.698,39.53。
ESI-MS[M+H]+:631.1852。
The preparation of 3 Tedizolid Phosphate of embodiment (compound of formula I)
Methanol (1000ml) is added in 2L reaction flask, VII compound of formula (12.8g) and 10%Pd/C (50% water, 1.28g),
50 DEG C of atmospheric hydrogenations react 12h, and filtering is evaporated, and obtain 8.78g title compound, yield 96.0%, and HPLC detection purity is
99.66% (area normalization method).
1H NMR (500 MHz, DMSO-d6):δ8.9367(s,1H),8.2052(m,2H),7.72(m,2H),7.5162
(m,1H),4.99(m,1H),4.4961(s,3H),4.2546(t,1H),4.1714(m,1H),4.1035(m,1H),3.9521
(m,1H)。
13C NMR (125 MHz, DMSO-d6):δ163.854,159.2905,153.925,149.382,145.069,
140.286,137.083,131.558,130.87,122.044,118.764,114.079,105.509,71.467,65.457,
45.833,39.549。
ESI-MS m/z[M+H]+:451.0927。
Claims (30)
1. a kind of preparation method of type I compound, including:In the presence of catalyst and hydrogen source, VII compound of formula is reacted,
The catalyst that wherein VII compound of formula is reacted is selected from Pd (OH)2/C、Pd/C、PdCl2、Pd(OAc)2、Pd(OH)2
Or Raney nickel,
The hydrogen source that wherein VII compound of formula is reacted is selected from H2、HCOOH、HCOONH4、NH2NH2Or cyclohexene,
Wherein the preparation method further includes:V compound of formula and VI compound of formula carry out anti-in the presence of catalyst, oxidant
It answers, VII compound of formula is prepared,
Wherein R1And R2It is each independently selected from methyl, ethyl, propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tertiary fourth
Base;Or R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace phenyl;Or
R1And R2It is each independently selected from optionally by halogen, C1-C4Alkyl or C1-C4Alkoxy replace benzyl,
Wherein the catalyst of VII compound of preparation formula be selected from 1H- tetrazole or
Wherein the oxidant of VII compound of preparation formula is selected from metachloroperbenzoic acid, hydrogen peroxide, Peracetic acid, peroxide benzene first
Acid or tert-butyl hydroperoxide.
2. the preparation method of claim 1, wherein the catalyst is selected from Pd/C, the hydrogen source is selected from H2。
3. the preparation method of claim 1, wherein VII compound of formula carries out the reaction of reaction preparation type I compound in solvent
Middle progress, the solvent are selected from water, C1~C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, penta
Ketone, cyclopentanone, hexanone, cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene,
The one or more of DMF, DMAC or DMSO.
4. the preparation method of claim 3, the solvent that wherein VII compound of formula carries out reaction preparation type I compound is selected from second
Acetoacetic ester, butyl acetate or C1~C8Alcohol one or more.
5. the preparation method of claim 4, the solvent that wherein VII compound of formula carries out reaction preparation type I compound is selected from second
One or more of acetoacetic ester, methanol or ethyl alcohol.
6. the preparation method of claim 5, the solvent that wherein VII compound of formula carries out reaction preparation type I compound is selected from first
Alcohol.
7. the preparation method of claim 1, wherein R1And R2It is simultaneously isopropyl or ethyl.
8. the preparation method of claim 2, wherein R1And R2It is simultaneously isopropyl.
9. the preparation method of claim 1, wherein the catalyst is selected from 1H- tetrazole.
10. the preparation method of claim 1, wherein the oxidant is selected from metachloroperbenzoic acid.
11. the preparation method of claim 1, wherein the reaction of VII compound of preparation formula carries out in a solvent, the solvent
Selected from water, C1~C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone,
Cyclohexanone, ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, in DMF, DMAC or DMSO
It is one or more of.
12. the preparation method of claim 1, wherein the reaction of VII compound of preparation formula carries out in a solvent, the solvent
Selected from methylene chloride.
13. the preparation method of claim 1, it is further comprising the steps of come V compound of preparation formula:
(1) III compound of formula is reacted in the presence of palladium catalyst and alkali with borating agent,
(2) product of step (1) is reacted in the presence of palladium catalyst and alkali with IV compound of formula,
Wherein X1And X2It is each independently selected from F, Cl, Br or I,
Wherein the borating agent of the step (1) be selected from connection boric acid pinacol ester, Triisopropyl borate, 3 third
Ylboronic acid ester, trimethyl borate or boron triethyl acid esters,
Wherein the palladium catalyst of the step (1) is selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride network
Close object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2,
Wherein the alkali of the step (1) is selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, uncle
Butanol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three
One of ethamine, diethylamine or ethylenediamine are a variety of,
Wherein the palladium catalyst of the step (2) is selected from [bis- (diphenylphosphine) ferrocene of 1,1'-] palladium chloride methylene chloride network
Close object, Pd (PPh3)4、Pd(OAc)2、PdCl2(dppf)、Pd2(dba)3Or Pd (dba)2,
Wherein the alkali of the step (2) is selected from C1~C8Sodium alkoxide, cesium carbonate, lithium carbonate, sodium hydride, Sodamide, butyl lithium, uncle
Butanol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium bicarbonate, saleratus, three
One of ethamine, diethylamine or ethylenediamine are a variety of.
14. the preparation method of claim 13, wherein X1Selected from Br or I, X2Selected from Br or I.
15. the preparation method of claim 14, wherein X1Selected from Br, X2Selected from Br.
16. the preparation method of claim 14, wherein III compound of formula is (5R) -3- (4- bromine-3-fluorophenyl) -5- hydroxyl first base Evil
Oxazolidine -2- ketone.
17. the preparation method of claim 14, wherein IV compound of formula is the bromo- 2- of 5- (2- methyl -2H- tetrazolium -5- base) pyridine.
18. the preparation method of claim 14, wherein the borating agent of step (1) be selected from connection boric acid pinacol ester,
19. the preparation method of claim 18, wherein the borating agent of step (1) is selected from connection boric acid pinacol ester.
20. the preparation method of claim 13, wherein the palladium catalyst of step (1) is selected from [1,1'- bis- (diphenylphosphines) two cyclopentadienyl
Iron] palladium chloride dichloromethane complex.
21. the preparation method of claim 13, wherein the alkali of step (1) is selected from potassium acetate.
22. the preparation method of claim 13, wherein the borating agent of step (1) is selected from connection boric acid pinacol ester, step (1)
Palladium catalyst is selected from [1,1'- bis- (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, and the alkali of step (1) is selected from vinegar
Sour potassium.
23. the preparation method of claim 13, wherein the palladium catalyst of step (2) is selected from [1,1'- bis- (diphenylphosphines) two cyclopentadienyl
Iron] palladium chloride dichloromethane complex.
24. the preparation method of claim 13, wherein the alkali of step (2) is selected from cesium carbonate.
25. the preparation method of claim 13, wherein the palladium catalyst of step (2) is selected from [1,1'- bis- (diphenylphosphines) two cyclopentadienyl
Iron] palladium chloride dichloromethane complex, the alkali of step (2) is selected from cesium carbonate.
26. the preparation method of claim 13, wherein the preparation of V compound of formula carries out in a solvent, the solvent is selected from water, C1
~C8Alcohol, 1,4- dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, cyclohexanone,
One kind of ether, ethyl acetate, butyl acetate, tetrahydrofuran, acetonitrile, benzene,toluene,xylene, DMF, DMAC, DMSO or NMP
Or it is several.
27. the preparation method of claim 26, wherein the solvent of step (1) is DMSO.
28. the preparation method of claim 26, wherein the solvent of step (2) is the mixed solvent of Isosorbide-5-Nitrae-dioxane and water.
29. the preparation method of claim 13, wherein the reaction of step (1) and step (2) is in N2Or it is carried out under the protection of argon gas.
30. VII compound of formula,
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