CN104496979A - Method for preparing oxazolidinone compound and intermediate thereof - Google Patents
Method for preparing oxazolidinone compound and intermediate thereof Download PDFInfo
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- CN104496979A CN104496979A CN201410819173.6A CN201410819173A CN104496979A CN 104496979 A CN104496979 A CN 104496979A CN 201410819173 A CN201410819173 A CN 201410819173A CN 104496979 A CN104496979 A CN 104496979A
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- 0 C[n]1nnc(-c2ccc(*)cn2)n1 Chemical compound C[n]1nnc(-c2ccc(*)cn2)n1 0.000 description 2
- XYUGDJIYKLSISX-SECBINFHSA-N OC[C@@H](CN1c2cc(F)ccc2)OC1=O Chemical compound OC[C@@H](CN1c2cc(F)ccc2)OC1=O XYUGDJIYKLSISX-SECBINFHSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a method for preparing an oxazolidinone compound and an intermediate thereof. Specifically, two fragments are coupled to prepare the oxazolidinone compound by virtue of Suzuki reaction. The method is simple in process, short in reaction time and high in yield and is suitable for industrial production. Furthermore, the method for preparing the intermediate of the oxazolidinone compound has the advantages of simplicity in operation, high yield and low cost.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, be specifically related to the preparation method of Yi Zhong oxazolidinone compounds and intermediate thereof.
Background technology
Oxazolidone finds in treatment as a class chemical composition and prevents to be widely used in the medicine of such as bacteriological infection and atherosclerotic medical conditions.The various structures of oxazolidinone derivative are known.Such as, disclose the monosubstituted or disubstituted derivatives of 3-phenyl-2-oxazolidone in US4461773, US4476136, US4250318 etc.
Safe ground azoles amine (Tedizolid) is a kind of novel oxazolidinone antibiotics, its phosphoric acid salt (tedizolid phosphate) has obtained FDA approval and has been used for the treatment of the acute bacterial skin and skin structure infection (ABSSSI) that streptococcus aureus (comprising methicillin resistant strains, methicillin sensitive strain) and the gram positive bacterium such as various streptococcus and enterococcus faecalis cause.Safe ground azoles amine structure formula as shown in the formula shown in TD,
，
Chemical name: (R)-3-(4-(2-(2-methyl tetrazolium-5-base) pyridine-5-base)-3-fluorophenyl)-5-Qiang Jia Ji oxazolidine-2-ketone.
Chinese patent CN102516238A and CN102702184A discloses the preparation method of safe ground azoles amine and phosphoric acid safe ground azoles amine general formula compound, as reaction formula (1):
Reaction formula (1)
The method first replaces the hydrogen atom on the phenyl of Qiang methyl oxazolidinone derivative (II) with halogen atom, generate derivative (III); Then adding palladium catalyst makes derivative (III) replace with hexa methyl ditin or tri-butyl tin hydride, generates derivative (IV), this step yield about 61%; 3rd step, makes derivative (IV) react with the pyridine derivate replaced by bromine or iodine under palladium catalyst condition, generates and have pyridine ring oxazolidinone derivative (V).The method preparation safe ground azoles amine, need to use palladium catalyst twice, and three-step reaction is reacted by (R)-3-(4-tributyl tinbase-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol and 2-(2-methyl tetrazolium-5-base)-5-bromopyridine and generates safe ground azoles amine, and yield only can reach 26%.Whole piece route cost is high, and yield is low, is not suitable for suitability for industrialized production; On the other hand, present method relates to the route of synthesis of organotin coupling, easily causes the residual of tin in finished product, is not suitable for preparing patent medicine.
US8604209B2 discloses the preparation method of the safe ground azoles amine shown in following reaction formula (2):
Reaction formula (2)
Wherein Y is from ZnCl, BF
3and BR
3r
4, wherein R
3and R
4independently selected from OH and any C replaced
1-C
6unitary and dibasic alcohol, wherein R
3and R
4together can Cheng Huan.
The method will obtain compound 3 and react with Glycidyl Butyrate in the basic conditions after first compound 1 and compound 2 being carried out linked reaction, generate safe ground azoles amine (TD).Wherein, the first step reacts intermediate 3 purity and yield all lower (HPLC:89.8%, the yield: 66%) of preparation; Final step linked reaction, uses highly basic (hexamethyl two lithium silicide) to cause side reaction many, introduces impurity more, aftertreatment difficulty, complex operation; Final step long reaction time, the safe ground azoles amine purity prepared is low, and need through repeatedly purifying, complex operation, after purifying, Pd residual quantity is still higher; Reaction needed uses anhydrous solvent, is not suitable for industrialization and generates.
At present about preparation method's bibliographical information fewer of safe ground azoles amine, existing method, complicated operation, long reaction time, production cost is high, and total recovery is low, and purity is lower, is not suitable for industrialization and generates.
Summary of the invention
It is low that the object of the invention is to provide a kind of production cost, simple to operate, yield and purity higher, the reaction times is short, is applicable to the method for oxazolidinones compounds processed of suitability for industrialized production, is specifically related to the method preparing safe ground azoles amine.
For achieving the above object, the invention provides following technical scheme:
The preparation method of compound shown in a kind of following formula TD
，
Comprise compound shown in following formula I
With compound shown in formula II
Reaction, generates compound shown in following formula TD-1
；
Wherein, R is hydrogen or hydroxyl protecting group; L and R
1in one be leavings group, another is BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan; Optional, slough the hydroxyl protecting group R of compound shown in TD-1, generate compound shown in TD.
In one embodiment, preferred L is leavings group, R
1for BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan.
In another embodiment, preferential L is BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan, R
1for leavings group.
Wherein, described leavings group comprises halogen as chlorine, bromine, iodine, and sulfonyloxy is as trifluoro-methanesulfonyl oxy, mesyloxy, phenylsulfonyloxy, or by the phenylsulfonyloxy that one or more substituting group replaces, described substituting group is selected from: halogen, C
1 ~ 6alkyl and C
1 ~ 6the group of alkoxyl group composition; Preferred leavings group is chlorine, bromine, iodine; More preferably leavings group is bromine or iodine.
Wherein, described R is hydrogen, or hydroxyl protecting group, and described hydroxyl protecting group comprises: alkyl, acyl group, alkyl silyl, and preferably described hydroxyl protecting group is benzyl, by the benzyl that one or more substituting group replaces, and C
1 ~ 4alkyl acyl, or trimethyl silicon based, and described substituting group is selected from by C
1 ~ 6alkyl, C
1 ~ 6the group of alkoxyl group and halogen composition.Further preferably, R is hydrogen, benzyl, to methyl-benzyl, and ethanoyl, propionyl, or butyryl radicals.
Wherein, described BR
2r
3, be preferably B (OH)
2or
.
In another embodiment, preferred L is bromine or iodine, R
1for BF
3, B (OH)
2or
, shown in the following reaction formula of the preparation method of compound shown in described formula TD:
，
Compound shown in compound and formula II shown in formula I reacts, preferably under palladium catalyst catalytic condition, react under alkalescence (as sodium carbonate, salt of wormwood, sodium hydroxide or potassium hydroxide etc.) environment, solvent is preferably toluene, THF, DMF, DMSO, dioxane, Virahol or ethanol etc., temperature of reaction is about 60 ~ 80 DEG C, and it is hydroxyl protecting group that coupling obtains compound TD-1(R) or TD(R be hydrogen); Optional sloughs hydroxyl protecting group R by compound TD-1, obtains compound TD.Wherein compound shown in intermediate formula II:
, wherein R
1for BF
3, B (OH)
2or
, can prepare by the following method:
Intermediate ii, wherein X is chlorine, bromine or iodine, with the highly basic of 2 equivalents (as C
1 ~ 6lithium alkylide is as n-Butyl Lithium or tert-butyl lithium) reaction, then add suitable electrophilic reagent as B (OR
2)
3, concrete, as C
1 ~ 6tri-alkoxy boric acid ester (as triisopropyl borate ester), preferred solvent is THF or toluene, and temperature of reaction is about-75 DEG C ~-65 DEG C.When electrophilic reagent is tri-alkoxy boric acid ester, gained reaction mixture obtains boric acid IIa through aftertreatment.The dianion of intermediate ii and ring boric acid ester are reacted, then namely separablely obtains ring boric acid ester IIb.Boronic acid compounds IIa can also prepare with reference to " the pyrimidine chloro thing of palladium chtalyst and the Suzuki linked reaction of pyridine boronic acid ester " (Xiao Wenjing, 2011-Zhengzhou University: pharmaceutical chemistry, master thesis) disclosed method.Or diborate (as diborated two tetramethyl ethylene ketones) is coupled to halohydrocarbon under palladium catalyst effect (ii) go up, the boric acid ester IIb of generation can be hydrolyzed and become boric acid IIa in sour water; Trifluoro boric acid derivatives IIc can by IIa and KF and/or KHF
2reaction generates; Or trifluoro boric acid derivatives IIc through type ii and boric acid ester (as triisopropyl borate ester) in the basic conditions (as n-Butyl Lithium) react, and solvent is preferably THF, generate boric acid triisopropyl lithium salts, and then and KHF
2reaction prepares, concrete grammar can (be appointed big see " under palladium chtalyst 2-pyridine three potassium fluoborate and virtue mix the Suzuki-Miyaura linked reaction of halides ", 2011-Zhengzhou University: organic chemistry, Master's thesis), the document is attached in this patent by reference.
Concrete, described IIa prepares by method shown in following reaction formula:
Shown in its Chinese style (1-4), compound can prepare with reference to method disclosed in CN1894242B, and disclosed in this patent, content is attached in the present invention by reference.Such as, include but not limited to that shown in (1-4), compound reacts with boric acid ester compound under strong basicity (as n-Butyl Lithium) condition, prepare compound shown in formula IIa, preferred reaction solvent is THF, and temperature of reaction is about-70 DEG C ~-65 DEG C.
In another embodiment, preferential R
1for bromine or iodine, L is BF
3, B (OH)
2or
, the following reaction formula of the preparation method of compound shown in described formula TD:
Compound shown in compound and formula II shown in formula I reacts; preferably react under palladium catalyst catalytic condition; solvent is preferably DMF; temperature of reaction is about 60 ~ 80 DEG C; preparing compound TD-1(R is hydroxyl protecting group) or TD(R be hydrogen); optional, compound TD-1 is sloughed hydroxyl protecting group R, obtains compound TD.Wherein compound shown in intermediate formula I:
, wherein, L is BF
3, B (OH)
2or
preparation method and previously described formula II shown in compound work as R
1for boric acid ester or BF
3time preparation method similar, concrete reaction formula is as follows:
。
In its Chinese style i, X is chlorine, bromine or iodine; Described R is hydrogen, benzyl, to methyl-benzyl, and ethanoyl, propionyl, or butyryl radicals.Further preferably X is bromine or iodine, and R is hydrogen.
In another embodiment, preferred described L is bromine or iodine, and described R is hydrogen, concrete, shown in the following reaction process of the preparation method of compound shown in described formula TD:
，
Described reaction is preferably reacted under palladium catalyst catalytic condition, and solvent is preferably DMF, and temperature of reaction is about 60 ~ 80 DEG C, and preferable reaction temperature is 70 DEG C.
Halogen of the present invention comprises fluorine, chlorine, bromine, iodine; Described alkyl comprises straight or branched alkyl (as ethyl, sec.-propyl etc.), the moieties (as benzyl etc.) that aryl replaces.
Shown in described formula I, shown in compound and formula IIa, compound preferably carries out linked reaction under the catalytic condition of palladium catalyst, described palladium catalyst can comprise two (triphenylphosphine) palladium (II) of dichloro, tetrakis triphenylphosphine palladium (0), palladium carbon, Pd (OAc)
2and PCy
3/ Pd
2(dba)
3(dba=BENZALACETONE) etc., preferably this reaction solvent is dimethyl formamide (DMF), 1-Methyl-2-Pyrrolidone, tetrahydrofuran (THF) (THF), toluene, methyl-sulphoxide, toluene, Virahol, ethanol etc., and temperature is about 60 DEG C ~ 150 DEG C.
When R is hydroxyl protecting group, according to the method for the dehydroxylation protecting group of this area routine, sloughs protecting group R, obtain compound shown in formula TD.Such as, when R be benzyl or substituted benzyl time can select Pb-C/H
2the method of catalytic hydrogenation sloughs protecting group, and reaction solvent is preferably THF, methyl alcohol, toluene or hexane etc.; When R is alkyl silyl (as trimethyl silicon based), preferably in acid condition in organic solvent (as HCl-MeOH, HCl-dioxane system, or AcOH-THF system) slough alkyl silyl protecting group; When R is alkyl acyl (ethanoyl, propionyl, butyryl radicals etc.), can select is hydrolyzed under pickling or alkaline condition sloughs, and as under sodium methylate condition, is that solvent stirring at room temperature sloughs corresponding alkyl acyl with methyl alcohol.
On the other hand, the invention provides compound shown in formula I, preferred L is chlorine, preparation method during bromine or iodine, and it is reacted by compound shown in formula III and carbonyl dimidazoles and changes into,
Described reaction solvent is preferably methylene dichloride, DMF, Virahol or THF etc., and temperature of reaction is about 25 DEG C ~ 40 DEG C.After reaction terminates, optional Compound I and hydroxyl protecting group (such as Benzyl Chloride by not containing protecting group, diethylaminoethanol, C1 ~ 6 alkyl carboxylic acid, dimethyl tertiary butyl silicon chlorides, trimethylsilyl chloride or dimethyl tertiary butyl silicon chlorides etc.) reaction, obtain the Compound I that corresponding R is hydroxyl protecting group; Wherein preferably R is hydrogen, benzyl, to methyl-benzyl, and ethanoyl, propionyl, butyryl radicals, dimethyl tertiary butyl silicon chlorides, trimethylsilyl chloride or dimethyl tertiary butyl silicon chlorides.
Further, compound shown in formula IV shown in described formula III
React with Racemic glycidol butyl ester, generate, wherein, L is chlorine, bromine or iodine; Described reaction is preferably carried out being back to reaction and is terminated in Virahol.
In certain embodiments, the method for the invention also comprises, and compound shown in the formula TD using the method for the invention to prepare, with POCl
3, POCl (OBn)
2or P (N-iPr
2) (O-tBu)
2generate compound shown in TD-P at reaction conditions
；
Further, described method also comprises and uses compound shown in TD-P to generate compound shown in following formula TD-PN with alkali reaction at reaction conditions
Wherein, M is PO (OH)
2pharmacy acceptable salt.The technician of medicinal chemistry art can understand, and term " pharmacy acceptable salt " refers to and the salt that suitable biocompatible positively charged ion and/or negatively charged ion generate.Described positively charged ion comprises metallic element positively charged ion, and such as the quaternary ammonium cation of sodium, lithium, potassium, magnesium, aluminium, calcium, zinc and alkaloid comprises metallic element positively charged ion, such as N, N-dibenzyl-ethylenediamin.Chloroprocaine, choline, diethyl hydramine, quadrol, PROCAINE HCL, PHARMA GRADE and N-methyl glucose osamine etc.Described negatively charged ion comprises the negatively charged ion of mineral acid, described mineral acid than example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, oxyacetic acid, formic acid, lactic acid, toxilic acid, tartrate, citric acid, palmitinic acid, propanedioic acid, tartronic acid, toluylic acid, L-glutamic acid, benzoic acid salicylic acid, toluenesulphonic acids, oxysuccinic acid and class acidoid.Preferably described alkali is the alkali containing sodium, and preferred described M is PO
3na
2.
The third aspect, the invention provides following formula: compound
,
with
,
Wherein, L is bromine or iodine.
On the other hand, compound (during R=H) shown in formula i ' of the present invention, can also be prepared by method following reaction formula (4) Suo Shi:
Reaction formula (4)
Bromo-for 4-3-fluoroaniline and chloroformic acid benzyl ester react by step 1) under alkalescence (as sodium bicarbonate) condition, prepare Benzylcarbamate compounds (1-7); Step 2) Benzylcarbamate compounds (1-7) is reacted with Racemic glycidol butyl ester under strong basicity (as n-Butyl Lithium) condition, obtain compound shown in formula (1-9); Finally, according to the different choice of X at reaction conditions by compound converting compounds accepted way of doing sth i ' formula (1-9) Suo Shi Suo Shi.Optional, compound formula i ' Suo Shi and hydroxy-protecting agent are reacted the compound preparing hydroxyl protecting group R.
Concrete, when X is halogen (that is, when preferred L is bromine or iodine), shown in formula (1-9), compound and halide reagent are (as ICl/CF
3cOOAg, BrCl/ CF
3cOOAg) react, solvent is preferably acetonitrile, reacts compound shown in preparation formula i ' under room temperature condition.
Compound i ' optional with hydroxy-protecting agent (such as Benzyl Chloride, diethylaminoethanol, C
1 ~ 6alkyl carboxylic acid etc.) reaction, obtain the Compound I that corresponding R is hydroxyl protecting group,
。
On the other hand, Compound I ' in halogen X change into methylsulfonic acid acid anhydride class group by this area ordinary method, and then obtain compound TD with Compound II per a by linked reaction.
In the present invention, described " hydroxy-protecting agent " refers to and can generate ester class protecting group with hydroxyl reaction, silicon ether protecting group, the reagent of alkyl oxide protecting group, such as, the hydroxy-protecting agent of ester class protecting group can be generated with hydroxyl reaction, include but not limited to, formic acid, acetic acid, butyric acid, propionic acid etc.; The hydroxy-protecting agent of described formation silicon ethers protecting group, include but not limited to, trifluoromethyl is silica-based, trimethyl silicon based, and 3,5-dimethylphenyl is silica-based, and dimethyl tertiary butyl is silica-based; Describedly can form the hydroxy-protecting agent of alkyl oxide with hydroxyl, include but not limited to, benzyl, to methyl-benzyl etc.
" optional " described in the present invention, refer to according to reaction needed, yes or no can be selected, illustrational, in the present invention, Compound I and Compound II per react the process preparing compound TD, when R is H, the structure of TD-1 and TD is identical, then TD-1 does not need to slough hydroxyl protecting group further and prepares TD; When R be benzyl or silicon-based protecting group time, Compound I and Compound II per react and first obtain compound TD-1, then need select further hydroxyl protecting group R in TD-1 is sloughed, prepare TD.
The invention provides a kind of new synthetic method of safe ground azoles amine (TD), described method compared with prior art has significant technique effect, first, raw material used by the present invention is easy to get, compound shown in formula I used by the present invention, prepare, and yield is all higher by multiple method; Compound shown in formula II used by the present invention, preparation method is simple, easily obtains; Secondly, prepare safe ground azoles amine (compound TD) by compound coupling shown in compound and formula II shown in this formula I, yield significantly improves (being not less than 87%), and the reaction times significantly shortens.3rd, method provided by the invention, agents useful for same is easy to get, and cost is low, and each intermediate of preparation is solid, and aftertreatment is simple.
Specific embodiment
In order to make technical problem solved by the invention, technical scheme and beneficial effect clearly understand, below in conjunction with specific embodiment, the present invention is further illustrated, and given specific embodiment is the preferred embodiments of the present invention.
embodiment 1: the preparation of compound shown in formula IIa
(1), the preparation of 2-cyano group-5-bromopyridine:
100 gram of 2,5-dibromo pyridine is dissolved in 1 liter of dimethyl formamide, at room temperature 32 grams of cupric cyanides and 17.8 grams of sodium cyanides is added in solution, at temperature is 150 DEG C, solution stirring is reacted for 7 hours.After being cooled to room temperature, in reaction mixture, add water, and be extracted with ethyl acetate.Organic layer washed with brine also dewaters, filters and vacuum concentration, obtains 54 grams of title compounds, yield 70%.
1H-NMR(CDCl
3)δ8.76(s，1H)，7.98(dd，1H)，7.58(dd，1H)。
(2), the preparation of 2-(tetrazolium-5-base)-5-bromopyridine:
Be dissolved in 100 milliliters of dimethyl formamides by 10 grams of 2-cyano group-5-bromopyridines, at room temperature join in solution by 5.33 grams of sodiumazide and 4.4 grams of ammonium chlorides, solution stirs and reacts for 3 hours at temperature is 110 DEG C.Add water in reaction mixture, be then extracted with ethyl acetate, separating obtained organic layer washed with brine, dehydration, filtration vacuum concentration, obtain 10.5 grams of title compounds, yield 85% thus.
(3), the preparation of 2-(1-methyl tetrazolium-5-base)-5-bromopyridine and 2-(2-methyl tetrazolium-5-base)-5-bromopyridine
10.5 grams of 2-(tetrazolium-5-base)-5-bromopyridine is dissolved in 100 milliliters of dimethyl formamides, then 6.5 grams of sodium hydroxide is joined in solution, and at 0 DEG C, 9.3 grams of methyl iodides are slowly joined in solution.Solution at room temperature stirs 6 hours, then adds water, and is extracted with ethyl acetate.Then gained organic layer washed with brine, dehydration, filtration, vacuum concentration also by chromatography over CC, obtain 4 grams of 2-(1-methyl tetrazolium-5-base)-5-bromopyridine and 5 grams of 2-(2-methyl tetrazolium-5-base)-5-bromopyridines.
(4), the preparation of compound shown in formula IIa:
Under nitrogen protection; 240 grams of 2-(2-methyl tetrazolium-5-base)-5-bromopyridine is dissolved in 2.4 liters of tetrahydrofuran (THF)s; add 207g triisopropyl borate ester;-75 DEG C are cooled in liquid nitrogen/ethanol bath; the n-Butyl Lithium tetrahydrofuran solution of slow dropping 840ml 2.5M, control temperature, below-65 DEG C, reacts 2h in-75 ~-65 DEG C; HPLC detection reaction, until completely.Drip 1.3L 20% aqueous ammonium chloride solution, control temperature, below 0 DEG C, drips and finishes, and stirs 0.5h, stratification, organic over anhydrous dried over sodium sulfate, draws dry, adds 600ml ethyl acetate making beating 2h, filter, dry, obtain 149.7g target compound, yield is 73%.
embodiment 2: the preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (that is, compound i '):
(1), the preparation of N-benzyloxycarbonyl-3-fluoroaniline (1-7):
100 grams of 3-fluoroanilines are dissolved in 1 liter of tetrahydrofuran (THF) (THF), and by 150 grams of (1.8 moles) hydrogen-carbonates
Sodium (NaHCO
3) join in this solution, after being cooled to 0 DEG C, 154 milliliters of N-carbobenzoxy chlorides (CbzCl) slowly being added in solution and reacts.Under agitation by reaction mixture sustained reaction 2 hours at 0 DEG C, use 0.5 liter of extraction into ethyl acetate reaction system afterwards, after separation, organic layer washed with brine, with anhydrous magnesium sulfate (MgSO
4) dry also vacuum concentration, residue n-hexane twice, obtains 132 grams of title compounds into white crystal, yield 85%.
(2), the preparation of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (1-9):
132 grams of N-benzyloxycarbonyl-3-fluoroanilines are dissolved in 1.3 liters of tetrahydrofuran (THF)s, and solution is cooled to-78 DEG C.370 milliliters of n-Butyl Lithiums (1.6 mol/L, normal hexane) are slowly joined in solution in a nitrogen atmosphere, then stirs 10 minutes.84 milliliters of (R)-(-)-Glycidyl butyrates are slowly joined in reaction mixture, stirs 2 hours at that same temperature, then at room temperature react 24 hours.After having reacted, in solution, add ammonium chloride solution, and at room temperature use 0.5 liter of extraction into ethyl acetate.With the organic layer that salt water washing is separating obtained, and with anhydrous magnesium sulfate drying, vacuum concentration.Be dissolved in by gained residue also with n-hexane in 100 milliliters of ethyl acetate, obtain white crystal, this white crystal purifying is 80 grams of title compounds, yield 70%;
1h-NMR (DMSO-d
6) δ 7.85 (t, 1H), 7.58 (dd, 1H), 7.23 (dd, 1H), 4.69 (m, 1H), 4.02 (t, 1H), 3.80 (dd, 1H), 3.60 (br dd, 2H).
(3), the preparation of (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (formula i ' shown in compound):
30 grams of (R)-3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol are dissolved in 300 milliliters of acetonitriles, and by 46 grams of trifluoroacetic acid silver salt (CF
3cOOAg) and 43 grams of iodate chlorine join in solution, and at room temperature stir after 1 day, in solution, add water, and be extracted with ethyl acetate, separating obtained organic layer washed with brine also dewaters.Then residue filtration, vacuum concentration is also dry, obtain 44 grams of title compounds thus, yield 94%;
1h-NMR (DMSO-d
6) δ 7.77 (t, 1H), 7.56 (dd, 1H), 7.20 (dd, 1H), 5.20 (m, 1H), 4.70 (m, 1H), 4.07 (t, 1H), 3.80 (m, 1H), 3.67 (m, 2H), 3.56 (m, 3H).
(R)-3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (formula I ' shown in compound, when L is bromine) the preparation method of preparation method similar (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol, difference is the iodide (iodate chlorine) replaced with the bromide of response in step (3).
embodiment 3: the preparation on safe ground azoles amine (shown in TD compound):
In the there-necked flask of 500ml being configured with reflux condensing tube and thermometer, add 1.57g Pd (OAc)
2, 3.7g PPh
3be dissolved in 150 ml DMF; be replaced as nitrogen; then 33.75 ml triethylamines are added; stir until solution becomes reddish black at 70 DEG C, add compound shown in (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (compound i ') of 47.2 g embodiments 2 preparations and the formula IIa of 34.4g embodiment 1 preparation, be dissolved in 100ml DMF solution; under nitrogen protection; at 90 DEG C of stirring reaction 2h, TLC monitors reaction, while hot through diatomite filtration.Be concentrated into 50ml at 70 DEG C, add 500ml purified water, stir 1.0h, filter, filter cake 50ml 50% methanol aqueous solution (volumetric concentration) washing, 50 DEG C of dry 8h.In gained solid, add 430ml 50% methanol aqueous solution (volumetric concentration), be heated to 70 degree of making beating 2h, be cooled to room temperature, filter, 30ml methanol rinses, obtains the 45g of compound shown in TD in 50 degree of dryings, and yield is 87%, and purity is 98.6%; 1H-NMR(DMSO-d6) δ 8.89(s, 1H), 8.16 (m, 2H), (7.69 m, 2H), 7.49 (dd, 1H), (5.25 t, 1H), 4.73 (m, 1H), (4.45 s, 3H), 4.13 (t, 1H), 3.86 (dd, 1H), 3.67 (m, 1H), 3.58 (m, 1H).
embodiment 4: the preparation of (2R)-(4-bromine-3-fluorophenyl amino)-2-hydrox y-propanol butyric ester (compound III ')
Bromo-for 19.0g 4-3-fluoroaniline is dissolved in 200ml Virahol, adds 14.4g (R)-Glycidyl butyrate, reflux, insulation reaction 12h.Remove solvent under reduced pressure, obtain product (2R)-(4-bromine-3-fluorophenyl is amino)-2-hydrox y-propanol butyric ester, product, without the need to purifying, can be directly used in next step reaction.
embodiment 5: the preparation of (R)-3-(4-bromo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol (Compound I ' ')
33.4g (2R)-(4-bromine-3-fluorophenyl is amino)-2-hydrox y-propanol butyric ester is dissolved in 150ml methylene dichloride, adds 17.8g carbonyl dimidazoles, be heated to 30 ~ 35 DEG C, insulation reaction 16h.Add 100ml water, stir 0.5h, separate organic layer, anhydrous sodium sulfate drying, concentrated.Add 100ml dissolve with methanol resistates, after dissolving clarification, add 5.94g sodium methylate, in stirred at ambient temperature 2h, remove solvent under reduced pressure, add 200ml methylene dichloride, respectively with 50ml 5% dilute hydrochloric acid, 50ml 7% sodium bicarbonate aqueous solution, the washing of 50ml purified water, organic over anhydrous dried over sodium sulfate, filter, concentrated obtain title compound 31.5g, yield is 85%.
Shown in formula II prepared by (R)-3-(4-bromo-3-the fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol using embodiment 5 method to prepare and embodiment 1 method, compound reacts, and prepares the method similar embodiment 3 on safe ground azoles amine (shown in TD compound).
embodiment 6: the preparation of compound shown in following formula (I-2)
(2R) that 33.4g embodiment prepared-(4-bromine-3-fluorophenyl is amino)-2-hydrox y-propanol butyric ester is dissolved in 150ml methylene dichloride, adds 17.8g carbonyl dimidazoles, be heated to 30 ~ 35 DEG C, insulation reaction 16h.Add 100ml water, stir 0.5h, separate organic layer, anhydrous sodium sulfate drying, concentrated, obtain title compound 31.5g, yield is 85%.
embodiment 7: the preparation of safe ground azoles amine
In the there-necked flask of 500ml being configured with reflux condensing tube and thermometer, add 1.57g Pd (OAc)
2, 3.7g PPh
3be dissolved in 150 ml DMF; be replaced as nitrogen; then 33.75 ml triethylamines are added; stir until solution becomes reddish black at 70 DEG C, add compound shown in the shown compound of formula (I-2) of 47.2 g embodiments 6 preparations and the formula II of 34.4g embodiment 1 preparation, be dissolved in 100ml DMF solution; under nitrogen protection; at 90 DEG C of stirring reaction 2h, TLC monitors reaction, while hot through diatomite filtration.Be concentrated into 50ml at 70 DEG C, add 500ml purified water, stir 1.0h, filter, filter cake 100ml dissolve with methanol, adds 5.94g sodium methylate, in stirred at ambient temperature 2h, remove solvent under reduced pressure, filter cake 50ml 50% methanol aqueous solution (volumetric concentration) washing, 50 DEG C of dry 8h.430ml 50% methanol aqueous solution (volumetric concentration) is added in gained solid, be heated to 70 degree of making beating 2h, be cooled to room temperature, filter, 30ml methanol rinses, obtains the 45g of compound shown in TD in 50 DEG C of dryings, and yield is 87%, purity is 98.6%, Pd content: < 2 ppm.
embodiment 8the preparation of following formula: compound TD-1
1) preparation of compound (I-3):
By 14.5 g chemical compounds Is " be dissolved in 70mL tetrahydrofuran (THF) (THF), and 6.33g (1.2eq.) Benzyl Chloride is joined in this solution, after being cooled to 0 DEG C, slowly add 1.2g(1.0eq in batches) sodium hydride.Sustained reaction 5 hours under agitation reaction mixture being warming up to 40 DEG C, step-down concentrates, and adds 300mL ethyl acetate, organic layer washed with brine, with anhydrous sodium sulfate drying, filtration, concentrate, obtain the 15.6g title compound into white crystal, yield 82%.
2), chemical combination TD-1 is prepared by compound (I-3)
In the there-necked flask of 250ml; add 11.41g compound 1-3,6.46g (1.05eq.) compound ii a, 1.14g Pd/C; 9.09g triethylamine, 80ml DMF; nitrogen protection; be heated to 80 DEG C; insulation reaction 3h; pass through diatomite filtration; add 400ml 7% sodium bicarbonate aqueous solution; stir 10min; use 150ml*3 extraction into ethyl acetate, successively with 150ml distilled water, the washing of 150ml saturated sodium-chloride water solution, anhydrous sodium sulfate drying, filtration, concentrated obtain target compound TD-1 9.26g, yield is 67%.
React by compound (I-3) and Compound II per a that to prepare compound TD-1(hydroxyl protecting group R be benzyl) method similar embodiment 7 in compound (I-2) and IIa react that to prepare compound TD-1(R be positive butyryl radicals) method.
embodiment 9: the preparation (in compound shown in TD-1 during R=benzyl) of safe ground azoles amine:
During by TD-1(R=benzyl): 10g TD-1 is dissolved in 80ml methyl alcohol, adds 0.5gPb-C/H
2, nitrogen replacement 3 times, hydrogen exchange three times, hydrogen pressure is 0.5Mpa, reflux, and HPLC monitors reaction, reacts completely, and is cooled to room temperature, through filtering with microporous membrane twice, concentrated, dry, obtains compound described in title.
embodiment 10: following formula I ' shown in the preparation of compound
Compound (1-9) (0.9eq) is dissolved in 1L tetrahydrofuran (THF) (THF), sodium hydrogen (1.1eq) is joined in this solution, after being cooled to about 0 DEG C, Benzyl Chloride (1.0eq) is joined in reaction solution, is stirred to reaction and terminates, extraction into ethyl acetate, be separated, after concentrated, obtain benzyl oxide.The preparation method of similar embodiment 2 step (3) (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl alcohol subsequently; act on 4 iodine replacements of phenyl ring through trifluoroacetic acid silver and iodine monochloride in acetonitrile; obtain 4 and replaced oxazolidone hydroxyl by the compound formula of benzyl protection (1-9) Suo Shi by iodine; then the synthetic method with reference to embodiment 1 step (4) prepares corresponding boric acid; the last benzyl that removes in concentrated hydrochloric acid obtains compound shown in target compounds of formula I ', MS ESI [M]
+: 255.
embodiment 11: the preparation on safe ground azoles amine (shown in TD compound)
In the there-necked flask of 500ml being configured with reflux condensing tube and thermometer, add 1.83g Pd
2(dba)
3, 1.12g PCy
3be dissolved in 400ml DMF, be replaced as nitrogen, stirred at ambient temperature 0.5h, then add 60.6g triethylamine, add 51.0 g formulas I
'shown compound and 57.6g formula II
'shown compound, under nitrogen protection, at 70 DEG C of stirring reactions, HPLC monitors reaction, while hot through diatomite filtration.Be concentrated into 50ml at 70 DEG C, add 500ml purified water, extract with methylene dichloride 400ml*2, anhydrous sodium sulfate drying, filters, and concentrates and obtains solid, 500ml 50% methanol aqueous solution (volumetric concentration) is added in gained solid, be heated to 70 degree of making beating 2h, be cooled to room temperature, filter, 40ml methanol rinses, obtain the 65.9g of compound shown in TD in 50 DEG C of dryings, yield is 89%, and purity is 98.8%.
embodiment 12: the preparation of phosphoric acid safe ground azoles amine (TD-P)
The round-bottomed flask of the jacket of 5L, is equipped with the machine mixer at top, additional funnel, thermocouple, nitrogen inlet and circulating cooling unit.Compound shown in TD (70.0g, 0.189mol), THF (1.4L, 20 volumes) and triethylamine (58.2g, 0.575mol) is added in flask.Slurry stirs, and jacket temperature is set as 0 DEG C.The phosphorus oxychloride (87.0g, 0.567mol) being dissolved in THF (70mL, 1 volume) is added in additional funnel.When internal temperature reaches 1 DEG C, POCl
3namely solution dropwise add in 44min.This mixture stirs 3 hours at 1-2 DEG C.To in three neck round-bottomed flasks, add water (1.4L), in ice, brine bath, be cooled to 3.8 DEG C.Reaction mixture pumped into quench water surface in 1 hour.Top temperature during cancellation is 11.9 DEG C.Yellow syrup stirs and spends the night, and filters, and filter cake use water (700mL) and methyl alcohol (700mL) rinse.Product under room temperature in vacuum-drying to constant weight.Obtain target product, yield be 83.4g (yield 98.1%), purity is 96.5%.
embodiment 13: the preparation of safe ground azoles amine disodic alkaliine
Phosphoric acid safe ground azoles amine (30.0g) prepared by embodiment 9 joins in the reactor of 1L, add methyl alcohol (360mL), slurry at room temperature stirs, and dropwise adds methyl alcohol (43.1g) solution of the sodium methylate of 25% at 10min.Slurry filters after at room temperature stirring 1h.Reactor and filter cake methyl alcohol (150mL) and acetone (150mL) rinse.Product at vacuum chamber inner drying, obtains 32.6g crude product safe ground azoles amine disodic alkaliine in 50-60 DEG C.Crude product water-soluble (325mL), adds gac, stirred at ambient temperature 30 minutes.2N NaOH regulates slurry pH value to 11.Slurry is by diatomite filtration, and filtrate is filtered again with the filter membrane of 0.45 μ.Filtrate dropwise adds in acetone (1.3L), gained slurry stirs and spends the night, then slurry by filtration, rinses with acetone (320mL), dry in vacuum chamber in 50 DEG C, by it again water-soluble (230mL), add sodium hydroxide solution and pH value is adjusted to 10, this solution is by the membrane filtration removing color of 0.45 μ, and filtrate dropwise adds in acetone (950ml), filter, then use acetone (230mL) to rinse.After product drying, be heavily 25.8g (total recovery is 79%), HPLC:99.6%.
embodiment 14: the preparation of following formula: compound Ib
In the there-necked flask of 500ml being configured with reflux condensing tube and thermometer, add 14.5g compound i, 13.97g (1.1eq.) tetramethyl ethylene ketone diborate, 1.83g(0.05eq.) PdCl
22 (dppf), 110ml DMF, under nitrogen protection, at 70 DEG C of stirring reactions, HPLC monitors reaction, while hot through diatomite filtration.Be concentrated into 50ml at 70 DEG C, add 400ml purified water, extract, anhydrous sodium sulfate drying with methylene dichloride 400ml*2, filter, concentrate and obtain compounds ib 12.74g, yield is 74%, and purity is 99.3%;
1h-NMR (DMSO-D
6): 1.32 (s, 12H), 4.45 (s, 3H), 8.13 (d, 1H), 8.18 (d, 1H), 8.90 (s, 1H).
embodiment 15the preparation on safe ground azoles amine (TD)
In the there-necked flask of 500ml being configured with reflux condensing tube and thermometer, add 1.83g Pd
2(dba)
3, 1.12g PCy
3be dissolved in 400ml DMF, be replaced as nitrogen, stirred at ambient temperature 0.5h, then add 60.6g triethylamine, add 51.0 g compound i and 85.2g compound lb, under nitrogen protection, at 70 DEG C of stirring reactions, HPLC monitors reaction, while hot through diatomite filtration.Be concentrated into 50ml at 70 DEG C, add 500ml purified water, extract with methylene dichloride 400ml*2, anhydrous sodium sulfate drying, filters, and concentrates and obtains solid, 500ml 50% methanol aqueous solution (volumetric concentration) is added in gained solid, be heated to 70 degree of making beating 2h, be cooled to room temperature, filter, 40ml methanol rinses, obtain the 61.2g of compound shown in TD in 50 DEG C of dryings, yield is 82.7%, and purity is 98.9%.
It should be noted that and the foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., all should be included within protection scope of the present invention.
Claims (13)
1. the preparation method of compound shown in a following formula TD
，
Comprise: by compound shown in following formula I
With compound shown in formula II
Reaction, generates compound shown in following formula TD-1
；
Wherein, R is hydrogen or hydroxyl protecting group; L and R
1in one be leavings group, another is BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan;
Optional, slough the hydroxyl protecting group R of compound shown in TD-1, generate compound shown in TD.
2. method according to claim 1, wherein L is leavings group, R
1for BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan.
3. method according to claim 1, wherein L is BF
3or BR
2r
3, wherein R
2and R
3independently be selected from the C by OH and replacement arbitrarily
1~ C
6the group of unitary and dibasic alcohol composition, wherein R
2and R
3together can Cheng Huan, R
1for leavings group.
4., according to the arbitrary described method of claim 1 ~ 3, wherein said leavings group is selected from halogen, trifluoro-methanesulfonyl oxy, mesyloxy, and the group that substituted or unsubstituted phenylsulfonyloxy group forms; Described R is hydrogen, benzyl, substituted benzyl, alkyl acyl, or alkyl silyl.
5., according to the arbitrary described method of claim 1 ~ 3, wherein said leavings group is selected from chlorine, bromine and iodine; Described R is hydrogen, benzyl, and to methyl-benzyl, ethanoyl, propionyl, butyryl radicals, dimethyl tertiary butyl is silica-based, trimethyl silicon based, or 3,5-dimethylphenyl is silica-based.
6. according to the arbitrary described method of claim 1 ~ 3, wherein leavings group is selected from bromine and iodine, and R is hydrogen.
7. method according to claim 1, wherein L is bromine or iodine, and R is hydrogen, R
1for BF
3, B (OH)
2or
; Or, R
1for bromine or iodine, R is hydrogen, and L is BF
3, B (OH)
2or
.
8. method according to claim 2, shown in its Chinese style I, compound shown in formula III and carbonyl dimidazoles react, optional, then react with hydroxy-protecting agent and generate,
，
Wherein, L is chlorine, bromine or iodine; R is hydrogen, benzyl, and to methyl-benzyl, ethanoyl, propionyl, butyryl radicals, dimethyl tertiary butyl is silica-based, trimethyl silicon based, or 3,5-dimethylphenyl is silica-based.
9. method according to claim 8, compound shown in formula IV shown in wherein said formula III
Wherein, L is chlorine, and bromine or iodine reacts with Racemic glycidol butyl ester, generates.
10., according to the arbitrary described method of claim 1 ~ 3, shown in its Chinese style I, shown in compound and formula II, compound reacts under palladium reagent catalysis.
11. 1 kinds of methods preparing compound shown in following formula TD-P, is characterized in that, compound shown in the formula TD using the arbitrary described method of claim 1 ~ 3 to prepare, with POCl
3, POCl (OBn)
2or P (N-iPr
2) (O-tBu)
2generate at reaction conditions:
。
12., according to method described in claim 11, is characterized in that, also comprise and use compound shown in TD-P to generate compound shown in following formula TD-PN with alkali reaction at reaction conditions
Wherein, M is PO (OH)
2pharmacy acceptable salt.
13. 1 kinds of following formula: compounds
,
with
,
Wherein, L is bromine or iodine.
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| WO2016041508A1 (en) * | 2014-09-17 | 2016-03-24 | 博瑞生物医药技术(苏州)有限公司 | Method for preparing oxazolidinone compound and intermediate thereof |
| CN104530128A (en) * | 2014-12-30 | 2015-04-22 | 石药集团中诺药业（石家庄）有限公司 | Disodium tedizolid phosphate and preparation method thereof |
| CN104892592A (en) * | 2015-03-30 | 2015-09-09 | 成都惟新医药科技有限公司 | Preparation method for tedizolid |
| CN106146559A (en) * | 2015-04-10 | 2016-11-23 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of oxazolidinones |
| CN106146559B (en) * | 2015-04-10 | 2019-08-09 | 博瑞生物医药（苏州）股份有限公司 | A kind of preparation method of Oxazolidinone derivative |
| CN106279281B (en) * | 2015-05-15 | 2018-08-03 | 重庆圣华曦药业股份有限公司 | The process for purification of oxazolidone antibiotics safe ground azoles amine phosphate |
| CN106279281A (en) * | 2015-05-15 | 2017-01-04 | 重庆圣华曦药业股份有限公司 | The process for purification of oxazolidinone antibacterial element Thailand ground azoles amine phosphate ester |
| CN106045934A (en) * | 2015-10-27 | 2016-10-26 | 博瑞生物医药（苏州）股份有限公司 | Crystal form of intermediate used for synthesis of tedizolid |
| US10385079B2 (en) | 2015-11-03 | 2019-08-20 | Zhejiang Huahai Pharmaceutical Co., Ltd | Preparation method for tedizolid, tedizolid intermediate, and preparation method therefor |
| WO2017076293A1 (en) * | 2015-11-03 | 2017-05-11 | 浙江华海药业股份有限公司 | Method for preparing oxazolidinone intermediate |
| WO2017076285A1 (en) * | 2015-11-03 | 2017-05-11 | 浙江华海药业股份有限公司 | Preparation method for tedizolid, tedizolid intermediate, and preparation method therefor |
| CN108368100A (en) * | 2015-11-03 | 2018-08-03 | 浙江华海药业股份有限公司 | A kind of Preparation Method And Their Intermediate and preparation method of safe ground azoles amine |
| CN108430999A (en) * | 2015-11-03 | 2018-08-21 | 浙江华海药业股份有限公司 | The preparation method of Yi Zhong oxazolidone intermediates |
| CN106632298A (en) * | 2015-11-03 | 2017-05-10 | 上海科胜药物研发有限公司 | Preparation method of tedizolid and intermediate of tedizolid |
| CN106632298B (en) * | 2015-11-03 | 2021-06-01 | 上海科胜药物研发有限公司 | Preparation method and intermediate of tedizolid |
| CN108368100B (en) * | 2015-11-03 | 2021-07-23 | 浙江华海药业股份有限公司 | Preparation method of tedizolid, intermediate and preparation method thereof |
| CN108430999B (en) * | 2015-11-03 | 2021-07-23 | 浙江华海药业股份有限公司 | Preparation method of oxazolidinone intermediate |
| CN105418681A (en) * | 2015-12-15 | 2016-03-23 | 南京艾德凯腾生物医药有限责任公司 | Preparation method of tedizolid phosphate |
| CN107382995A (en) * | 2017-09-01 | 2017-11-24 | 杭州新博思生物医药有限公司 | One pot process safe ground azoles amine |
| CN111518135A (en) * | 2019-12-06 | 2020-08-11 | 山东中医药大学 | Preparation method of high-purity tedizolid phosphate |
| CN111518135B (en) * | 2019-12-06 | 2022-05-06 | 山东中医药大学 | Preparation method of high-purity tedizolid phosphate |
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| WO2016041508A1 (en) | 2016-03-24 |
| CN106928214A (en) | 2017-07-07 |
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