CN105418678A - Preparation method for tedizolid phosphate - Google Patents
Preparation method for tedizolid phosphate Download PDFInfo
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- CN105418678A CN105418678A CN201410476920.0A CN201410476920A CN105418678A CN 105418678 A CN105418678 A CN 105418678A CN 201410476920 A CN201410476920 A CN 201410476920A CN 105418678 A CN105418678 A CN 105418678A
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Abstract
The invention belongs to the field of medicine chemical industry and particularly relates to a preparation method for tedizolid phosphate. According to the preparation method provided by the invention, intermediates in the steps and the final product are high in purity. In addition, by using diiso-propylamido dibenzyl phosphite as a phosphorylation reagent, a dimerized product is further avoided, so that the preparation method provided by the invention is higher in yield. The preparation method provided by the invention is relatively short in route and mild in reaction condition, and further avoids use of toxic, irritant and strongly corrosive reagents, so that the preparation method is green and environmentally friendly. Meanwhile, ultralow temperature reaction is avoided, so that the preparation method is simple to operate, and the tedizolid phosphate is easy to prepare and high in production efficiency. Thereofe, the preparation method provided by the invention is suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, in particular to the new preparation method of a kind of phosphoric acid specially azoles amine.
Background technology
Phosphoric acid is azoles amine (tedizolidphosphate) specially, (R)-3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base) 3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone dihydrogen phosphoric acid ester (formula I), this medicine is used for the treatment of gram positive bacteria infection, the infection that such as acute bacterial skin infections, MRSA cause and pulmonary infection etc.
At present, the preparation method of disclosed phosphoric acid specially azoles amine mainly contains following two kinds:
Route 1:CN1894242 discloses following preparation method:
The reaction of this route the first step uses poisonous organotin reagent, the yield that key intermediate (R)-3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base) 3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone is prepared in second step condensation reaction is low to moderate 26%, carry out at three-step reaction preparation (R)-[3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base)-3-fluorophenyl)-2-oxygen-5-oxazolidinyl] methyl acid phosphate two (tetrabutyl ester) needs-78 DEG C, and long reaction time, final step needs use to have pungent odor, the trifluoroacetic acid of severe corrosive.Therefore, this route total recovery is low, and production cost is high, severe reaction conditions, and generating period is long, and agents useful for same is poisonous or pungency corrodibility strong, is not suitable for suitability for industrialized production.
Route 2:CN102177156 discloses following synthetic route:
This route is long by starting raw material building-up reactions route, wherein the reaction of second step boronation need be carried out at-72 DEG C of low temperature and the yield of product 4-(the benzyloxycarbonyl amino)-2-fluorobenzoic boric acid obtained is only 66% and very impure, 4th step annulation complex operation step and long reaction time, final step phosphorylation adopts the fuming liquid phosphorus oxychloride of severe toxicity.Therefore, this route is also not suitable with industrialization scale operation.
There is many defects in the synthetic method of the specially azoles amine of phosphoric acid disclosed in prior art, therefore still needs to prepare the novel method of phosphoric acid specially azoles amine.
Summary of the invention
On the one hand, the invention provides a kind of preparation method of type I compound, comprising: under catalyzer and hydrogen source exist, formula VII compound reacts,
Wherein said catalyzer is selected from Pd (OH)
2/ C, Pd/C, PdCl
2, Pd (OAc)
2, Pd (OH)
2or Raney nickel, be preferably Pd/C.
Wherein said hydrogen source is selected from H
2, HCOOH, HCOONH
4, NH
2nH
2or cyclohexene, be preferably H
2.
Be to be understood that; formula VII compound of the present invention also contains phenyl ring on benzyl by monosubstituted or polysubstituted compound; as long as above-mentioned reaction can be carried out, described substituting group includes but not limited to halogen, hydroxyl, amino, cyano group, carboxyl, alkylsulfonyl, sulfydryl, trifluoromethyl, nitro, phenyl, benzyl, benzyloxy, pyridyl, piperidyl, methylol, hydroxyethyl, hydroxypropyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl-carbonyl, C
1-C
6alkylamino, C
1-C
6alkyl-carbonyl oxygen base, C
3-C
7cycloalkyl, C
3-C
7cycloalkyloxy or C
3-C
7cycloalkylmethoxy.
The preparation of type I compound can select suitable solvent to react as required, and described solvent is selected from water, C
1~ C
8alcohol, 1,4-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, pimelinketone, ether, ethyl acetate, butylacetate, tetrahydrofuran (THF), acetonitrile, benzene,toluene,xylene, DMF, DMAC or DMSO one or more, be preferably ethyl acetate, butylacetate or C
1~ C
8one or more of alcohol, most preferably be one or more in ethyl acetate, methyl alcohol or ethanol.In a specific embodiments of the present invention, solvent is methyl alcohol.
On the other hand, the invention provides formula VII compound,
Be to be understood that; formula VII compound of the present invention also contains phenyl ring on benzyl by monosubstituted or polysubstituted compound, and described substituting group includes but not limited to halogen, hydroxyl, amino, cyano group, carboxyl, alkylsulfonyl, sulfydryl, trifluoromethyl, nitro, phenyl, benzyl, benzyloxy, pyridyl, piperidyl, methylol, hydroxyethyl, hydroxypropyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl-carbonyl, C
1-C
6alkylamino, C
1-C
6alkyl-carbonyl oxygen base, C
3-C
7cycloalkyl, C
3-C
7cycloalkyloxy or C
3-C
7cycloalkylmethoxy.
Again on the one hand, the invention provides a kind of preparation method of formula VII compound, comprising: formula V compound and formula VI compound react under existing at catalyzer, oxygenant,
Wherein R
1and R
2be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl independently of one another; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace phenyl; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace benzyl.Preferred R
1and R
2be sec.-propyl or ethyl, most preferably R simultaneously
1and R
2it is sec.-propyl simultaneously.
Wherein said catalyzer be selected from 1H-tetrazole or
be preferably 1H-tetrazole.
Wherein said oxygenant is selected from metachloroperbenzoic acid (mCPBA), hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide or tertbutyl peroxide (TBHP), is preferably metachloroperbenzoic acid (mCPBA).
The preparation of formula VII compound can select suitable solvent to react as required, and described solvent is selected from water, C
1~ C
8alcohol, Isosorbide-5-Nitrae-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, pimelinketone, ether, ethyl acetate, butylacetate, tetrahydrofuran (THF), acetonitrile, benzene,toluene,xylene, one or more in DMF, DMAC or DMSO.In a specific embodiments of the present invention, solvent is methylene dichloride.Described formula VI compound by commercially available acquisition, also can be prepared by the method for prior art, such as, prepare by the following method,
In a specific embodiments of the present invention, formula VI compound is diisopropylaminoethyl dibenzyl phosphite (formula II),
Be to be understood that; formula VI compound of the present invention or formula II compound also contain phenyl ring on benzyl by monosubstituted or polysubstituted compound, and described substituting group includes but not limited to halogen, hydroxyl, amino, cyano group, carboxyl, alkylsulfonyl, sulfydryl, trifluoromethyl, nitro, phenyl, benzyl, benzyloxy, pyridyl, piperidyl, methylol, hydroxyethyl, hydroxypropyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkyl, optionally by halogen or C
1-C
6the C that alkoxyl group replaces
1-C
6alkoxyl group, C
1-C
6alkylthio, C
1-C
6alkoxy carbonyl, C
1-C
6alkyl-carbonyl, C
1-C
6alkylamino, C
1-C
6alkyl-carbonyl oxygen base, C
3-C
7cycloalkyl, C
3-C
7cycloalkyloxy or C
3-C
7cycloalkylmethoxy.
Another aspect, the invention provides a kind of preparation method of formula V compound, comprising:
(1) formula III compound and borating agent react under palladium catalyst and alkali exist,
(2) product of step (1) and formula IV compound react under palladium catalyst and alkali exist,
Wherein X
1and X
2be selected from F, Cl, Br or I independently of one another, be preferably Br or I, most preferably be Br.
In a specific embodiments of the present invention, formula III compound is (5R)-3-(4-bromine-3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone.
In a specific embodiments of the present invention, formula IV compound is the bromo-2-of 5-(2-methyl-2H-tetrazolium-5-base) pyridine.
The borating agent of described step (1) is selected from connection boric acid pinacol ester
triisopropyl boric acid ester, tripropylborane acid esters, trimethyl borate or triethyl-boron acid esters, be preferably connection boric acid pinacol ester,
or
be more preferably connection boric acid pinacol ester.
The palladium catalyst of described step (1) is selected from [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2, be preferably [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex.
The palladium catalyst of described step (2) is selected from [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2, be preferably [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex.
Should be appreciated that palladium catalyst of the present invention can also be various palladium complex compounds prepared by various palladium catalyst and part, described part includes but not limited to PCy
3, AsPh
3, n-Bu
3p, (MeO)
3p, Ph
2p (CH
2)
2pPh
2or Ph (dppe)
2p (CH
2)
3pPh
2(dppp).
The alkali of described step (1) is selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol, be preferably Potassium ethanoate.
The alkali of described step (2) is selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol, be preferably cesium carbonate.
The preparation of formula V compound can select suitable solvent to react as required, and described solvent includes but not limited to water, C
1~ C
8alcohol, Isosorbide-5-Nitrae-dioxane, formic acid, acetic acid, butyric acid, valeric acid, acetone, butanone, pentanone, cyclopentanone, hexanone, pimelinketone, ether, ethyl acetate, butylacetate, tetrahydrofuran (THF), acetonitrile, benzene,toluene,xylene, DMF, DMAC, DMSO or NMP one or more.In a specific embodiments of the present invention, the solvent of step (1) is DMSO, and the solvent of step (2) is the mixed solvent of Isosorbide-5-Nitrae-dioxane and water.
Optionally, the reaction of step (1) and step (2) can at N
2or carry out under the protection of argon gas.
On the other hand, the invention provides the preparation method of a kind of type I compound (phosphoric acid is azoles amine specially), comprising:
I) formula III compound and borating agent react under palladium catalyst and alkali exist,
Ii) step I) product and formula IV compound under palladium catalyst and alkali exist, carry out reaction preparation formula V compound,
Iii) formula V compound and formula VI compound carry out reaction preparation formula VII compound at catalyzer, oxygenant under existing,
Iv) formula VII compound carries out reaction preparation I compound under catalyzer and hydrogen source exist,
Wherein X
1and X
2be selected from F, Cl, Br or I independently of one another, be preferably Br or I, most preferably be Br;
Wherein R
1and R
2independently of one another for being selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace phenyl; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace benzyl.Preferred R
1and R
2be sec.-propyl or ethyl, most preferably R simultaneously
1and R
2it is sec.-propyl simultaneously;
Described step I) borating agent be selected from connection boric acid pinacol ester
triisopropyl boric acid ester, tripropylborane acid esters, trimethyl borate or triethyl-boron acid esters, be preferably connection boric acid pinacol ester,
or
be more preferably connection boric acid pinacol ester;
Described step I) palladium catalyst be selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2, be preferably [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex;
Described step I) alkali be selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol, be preferably Potassium ethanoate.
Described step I i) palladium catalyst be selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2, be preferably [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex;
Described step I i) alkali be selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol, be preferably cesium carbonate.
Described step I ii) catalyzer be 1H-tetrazole or
be preferably 1H-tetrazole.
Described step I ii) oxygenant be selected from metachloroperbenzoic acid (mCPBA), hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide or tertbutyl peroxide (TBHP), be preferably metachloroperbenzoic acid (mCPBA).
Described step I v) catalyzer be selected from Pd (OH)
2/ C, Pd/C, PdCl
2, Pd (OAc)
2, Pd (OH)
2or Raney nickel, be preferably Pd/C.
Described step I v) hydrogen source be selected from H
2, HCOOH, HCOONH
4, NH
2nH
2or cyclohexene, be preferably H
2.
" dppf " of the present invention is two (diphenylphosphine) ferrocene of 1,1'-.
" dba " of the present invention is dibenzalacetone.
" PCy of the present invention
3" be tricyclohexyl phosphine.
" dppe " of the present invention is two (diphenylphosphine) ethane of 1,2-.
" dppp " of the present invention is two (diphenylphosphine) propane of 1,3-.
Preparation method of the present invention, intermediate and the finished product of each step all have high purity.In addition, adopt diisopropylamino dibenzyl phosphite as phosphorus esterification reagent, also can avoid producing dimerization product, make preparation method of the present invention have higher yield.Preparation method's route of the present invention is shorter, and reaction conditions is gentle, also avoids using poisonous, irritant and severe corrosive reagent, environmental protection; Avoid using very low temperature reaction, easy preparation easy and simple to handle, production efficiency is high simultaneously.Therefore, preparation method of the present invention adapts to suitability for industrialized production especially.
Embodiment
The present invention is by following examples, and they are only embodiments, do not limit the present invention, and every technology realized based on the present invention, all belongs to scope of the present invention.
The preparation of embodiment 1 (R)-3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base) 3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone (formula V compound)
DMSO (100ml) is added in 250ml reaction flask; (5R)-3-(4-bromine-3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone (10g; 34.5mmol), boric acid pinacol ester (17.52g is joined; 69mmol), [1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex (1.41g; 1.73mmol) with Potassium ethanoate (13.5g; 138mmol); under nitrogen protection; be warming up to 80 DEG C, react 14 hours.Stop heating, be down to room temperature, water/extraction into ethyl acetate 3 times, merge organic layer, organic layer saturated common salt water washing 3 times, anhydrous sodium sulfate drying, suction filtration concentrates.
The enriched product of above-mentioned steps is joined in 250ml reaction flask; add 1; 4-dioxane (100ml), the bromo-2-of 5-(2-methyl-2H-tetrazolium-5-base) pyridine (8.28g; 34.5mmol), [1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex (0.56g; 0.69mmol) with cesium carbonate aqueous solution (50ml; containing 33.72g cesium carbonate; 103.5mmol); under nitrogen protection; be warming up to 70 DEG C, react 3 hours, add dichloromethane extraction.Separating obtained organic phase saturated common salt water washing, anhydrous sodium sulfate dehydration, filtration, vacuum concentration also by purification by column chromatography, obtain 10.6g solid, and it is 98.34% (area normalization method) that yield 83.0%, HPLC detects purity.
1HNMR(500MHz，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)。
13CNMR(125MHz，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。
The preparation of two (benzyl ester) (formula VII compound) of embodiment 2 (R)-[3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base)-3-fluorophenyl)-2-oxygen-5-oxazolidinyl] methyl acid phosphate
Methylene dichloride (100ml), 1H-tetrazole (5.97g is added in 500ml there-necked flask, 85.2mmol) with formula V compound (10.5g, 28.4mmol), temperature control drips diisopropylamino dibenzyl phosphite (19.6g below 30 DEG C, 56.8mmol), 25 ~ 30 DEG C of reaction 30min are maintained the temperature at.Be cooled to 0 ~ 10 DEG C, add 85% metachloroperbenzoic acid (8.08g, 39.8mmol), 5 ~ 10 DEG C of reaction 30min.
Reaction solution uses saturated NaHCO successively
3wash twice, once, anhydrous sodium sulfate drying, filters, concentrated, by purification by column chromatography, obtains 14.89g title compound, and it is 99.62% (area normalization method) that yield 83.1%, HPLC detects purity in saturated NaCl washing.
1HNMR(500MHz，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)。
13CNMR(125MHz，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 embodiment 3 phosphoric acid specially azoles amine (formula I)
Methyl alcohol (1000ml) is added in 2L reaction flask, formula VII compound (12.8g) and 10%Pd/C (50% water, 1.28g), 50 DEG C of atmospheric hydrogenation reaction 12h, filter, evaporate to dryness, obtains 8.78g title compound, it is 99.66% (area normalization method) that yield 96.0%, HPLC detects purity.
1HNMR(500MHz，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)。
13CNMR(125MHz，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-MSm/z[M+H]
+:451.0927。
Claims (10)
1. a preparation method for type I compound, comprising: under catalyzer and hydrogen source exist, formula VII compound reacts,
Wherein said catalyzer is selected from Pd (OH)
2/ C, Pd/C, PdCl
2, Pd (OAc)
2, Pd (OH)
2or Raney nickel,
Wherein said hydrogen source is selected from H
2, HCOOH, HCOONH
4, NH
2nH
2or cyclohexene.
2. the preparation method of claim 1, wherein said catalyzer is selected from Pd/C, and described hydrogen source is selected from H
2.
3. formula VII compound,
4. the preparation method any one of claim 1 or 2, also comprises: formula V compound and formula VI compound react under existing at catalyzer, oxygenant, prepare formula VII compound,
Wherein R
1and R
2be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl independently of one another; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace phenyl; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace benzyl,
Wherein said catalyzer be selected from 1H-tetrazole or
Wherein said oxygenant is selected from metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide or tertbutyl peroxide.
5. the preparation method of claim 4, further comprising the steps of come preparation formula V compound:
(1) formula III compound and borating agent react under palladium catalyst and alkali exist,
(2) product of step (1) and formula IV compound react under palladium catalyst and alkali exist,
Wherein X
1and X
2be selected from F, Cl, Br or I independently of one another,
The borating agent of wherein said step (1) be selected from connection boric acid pinacol ester,
triisopropyl boric acid ester, tripropylborane acid esters, trimethyl borate or triethyl-boron acid esters,
The palladium catalyst of wherein said step (1) is selected from [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2,
The alkali of wherein said step (1) is selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol
The palladium catalyst of wherein said step (2) is selected from [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2,
The alkali of wherein said step (2) is selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol.
6. the preparation method of claim 5, wherein X
1be selected from Br, X
2be selected from Br.
7. the preparation method of claim 5, wherein the borating agent of step (1) is selected from connection boric acid pinacol ester, the palladium catalyst of step (1) is selected from [1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride dichloromethane complex, the alkali of step (1) is selected from Potassium ethanoate.
8. the preparation method of claim 5, wherein the palladium catalyst of step (2) is selected from [two (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex, and the alkali of step (2) is selected from cesium carbonate.
9. a preparation method for type I compound, comprising:
I) formula III compound and borating agent react under palladium catalyst and alkali exist,
Ii) step I) product and formula IV compound under palladium catalyst and alkali exist, carry out reaction preparation formula V compound,
Iii) formula V compound and formula VI compound carry out reaction preparation formula VII compound at catalyzer, oxygenant under existing,
Iv) formula VII compound carries out reaction preparation I compound under catalyzer and hydrogen source exist,
Wherein X
1and X
2be selected from F, Cl, Br or I independently of one another,
Wherein R
1and R
2be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-or the tertiary butyl independently of one another; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace phenyl; Or R
1and R
2be selected from independently of one another optionally by halogen, C
1-C
4alkyl or C
1-C
4alkoxyl group replace benzyl.
10. the preparation method of claim 9, wherein
Described step I) borating agent be selected from connection boric acid pinacol ester,
triisopropyl boric acid ester, tripropylborane acid esters, trimethyl borate or triethyl-boron acid esters,
Described step I) palladium catalyst be selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2,
Described step I) alkali be selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol
Described step I i) palladium catalyst be selected from [1,1'-two (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex, Pd (PPh
3)
4, Pd (OAc)
2, PdCl
2(dppf), Pd
2(dba)
3or Pd (dba)
2,
Described step I i) alkali be selected from C
1~ C
8sodium alkoxide, cesium carbonate, Quilonum Retard, sodium hydride, sodium amide, butyllithium, trimethyl carbinol lithium, LDA, sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium-acetate, Potassium ethanoate, sodium bicarbonate, saleratus, triethylamine, one or more in diethylamine or quadrol
Described step I ii) catalyzer be selected from 1H-tetrazole or
Described step I ii) oxygenant be selected from metachloroperbenzoic acid, hydrogen peroxide, Peracetic Acid, benzoyl hydroperoxide or tertbutyl peroxide,
Described step I v) catalyzer be selected from Pd (OH)
2/ C, Pd/C, PdCl
2, Pd (OAc)
2, Pd (OH)
2or Raney nickel, described step I v) hydrogen source be selected from H
2, HCOOH, HCOONH
4, NH
2nH
2or cyclohexene.
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| CN105085570A (en) * | 2015-09-12 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Tedizolid phosphate compound and preparation method thereof |
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| CN111518135A (en) * | 2019-12-06 | 2020-08-11 | 山东中医药大学 | Preparation method of high-purity tedizolid phosphate |
| CN114105968A (en) * | 2020-08-28 | 2022-03-01 | 河北明吉化工科技有限公司 | Method for removing palladium residue of tedizolid |
| CN114933596A (en) * | 2022-05-12 | 2022-08-23 | 河北广祥制药有限公司 | Preparation method of tedizolid |
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| CN105085570A (en) * | 2015-09-12 | 2015-11-25 | 山东罗欣药业集团股份有限公司 | Tedizolid phosphate compound and preparation method thereof |
| CN105085570B (en) * | 2015-09-12 | 2017-11-28 | 山东罗欣药业集团股份有限公司 | A kind of Tedizolid Phosphate compound and preparation method thereof |
| CN107353304A (en) * | 2017-07-12 | 2017-11-17 | 浙江普洛得邦制药有限公司 | Phosphoric acid safe ground azoles amine trishydroxymethylaminomethane salt and its crystal formation A, preparation method and application |
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| CN111518135B (en) * | 2019-12-06 | 2022-05-06 | 山东中医药大学 | Preparation method of high-purity tedizolid phosphate |
| CN114105968A (en) * | 2020-08-28 | 2022-03-01 | 河北明吉化工科技有限公司 | Method for removing palladium residue of tedizolid |
| CN114105968B (en) * | 2020-08-28 | 2024-04-16 | 河北明吉化工科技有限公司 | Method for removing residual palladium of tedizolid |
| CN114933596A (en) * | 2022-05-12 | 2022-08-23 | 河北广祥制药有限公司 | Preparation method of tedizolid |
| CN114933596B (en) * | 2022-05-12 | 2023-09-05 | 河北广祥制药有限公司 | Preparation method of tedizolid |
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