CN108358866A - A kind of preparation method of Febustat intermediate and its application in preparing Febustat - Google Patents
A kind of preparation method of Febustat intermediate and its application in preparing Febustat Download PDFInfo
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- CN108358866A CN108358866A CN201810025214.2A CN201810025214A CN108358866A CN 108358866 A CN108358866 A CN 108358866A CN 201810025214 A CN201810025214 A CN 201810025214A CN 108358866 A CN108358866 A CN 108358866A
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- 0 CCCCCCC(C)(CC)C(C)([C@](C)*)*(C*)(C(CC1)CC1C(C)CCC)C1=CCCC1 Chemical compound CCCCCCC(C)(CC)C(C)([C@](C)*)*(C*)(C(CC1)CC1C(C)CCC)C1=CCCC1 0.000 description 3
- KNSUIJPSCZNNAZ-UHFFFAOYSA-N CC(C)COc(c(C#N)c1)c(C)cc1C(N)=S Chemical compound CC(C)COc(c(C#N)c1)c(C)cc1C(N)=S KNSUIJPSCZNNAZ-UHFFFAOYSA-N 0.000 description 1
- XKZDBXMBJANBMB-UHFFFAOYSA-N CC(C)COc(c(C#N)c1)ccc1C1=NC(C)C(C(O)=O)S1 Chemical compound CC(C)COc(c(C#N)c1)ccc1C1=NC(C)C(C(O)=O)S1 XKZDBXMBJANBMB-UHFFFAOYSA-N 0.000 description 1
- RTWFSTQYINZYMD-UHFFFAOYSA-N CC(C)COc(ccc(Br)c1)c1Br Chemical compound CC(C)COc(ccc(Br)c1)c1Br RTWFSTQYINZYMD-UHFFFAOYSA-N 0.000 description 1
- QEVXAIAKBNBIOM-UHFFFAOYSA-N CC(COC1C=CC(C#N)=CC1)=C Chemical compound CC(COC1C=CC(C#N)=CC1)=C QEVXAIAKBNBIOM-UHFFFAOYSA-N 0.000 description 1
- ANQNRYAHRYSSEA-UHFFFAOYSA-N CC(COc(c(C#N)c1)ccc1C#N)=C Chemical compound CC(COc(c(C#N)c1)ccc1C#N)=C ANQNRYAHRYSSEA-UHFFFAOYSA-N 0.000 description 1
- WBASZWNYMUQGLG-UHFFFAOYSA-N CCOC(C1SC(c(cc2C#N)ccc2OCC(C)C)=NC1C)=O Chemical compound CCOC(C1SC(c(cc2C#N)ccc2OCC(C)C)=NC1C)=O WBASZWNYMUQGLG-UHFFFAOYSA-N 0.000 description 1
- OGAZOYHQFBSRMC-UHFFFAOYSA-N CCOC(c1c(C)nc(-c(cc2C#N)ccc2OCC(C)C)[s]1)=O Chemical compound CCOC(c1c(C)nc(-c(cc2C#N)ccc2OCC(C)C)[s]1)=O OGAZOYHQFBSRMC-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N N#Cc(cc1)ccc1O Chemical compound N#Cc(cc1)ccc1O CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- FAXWFCTVSHEODL-UHFFFAOYSA-N Oc(c(Br)c1)ccc1Br Chemical compound Oc(c(Br)c1)ccc1Br FAXWFCTVSHEODL-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of preparation methods of the compound of formula II, include the following steps：1) compound of structural formula VI is obtained by the reaction under the action of alkylating agent and alkali in the compound of structural formula VII；2) compound of structural formula VI is reacted obtains the compound of structural formula V；3) it is not necessarily to solvent, the compound of structural formula V is reacted with methenamine in acid condition, obtains the compound of structural formula IV；4) compound of structural formula IV and hydroxylamine hydrochloride react in the presence of a base, and dehydration obtains the compound of formula II I；5) compound of formula II I and the compound of structural formula VIII carry out ring closure reaction and obtain the compound of formula II.The present invention also provides application of the above-mentioned preparation method in synthesizing Febustat.The method of the present invention is easy to operate, high income, side reaction is few, toxic articles are not used, and as a kind of method prepared by novel Febustat intermediate, is suitable for industrialized production.Wherein, R=C1~C4Alkyl.
Description
Technical field
The invention belongs to organic chemistry fileds, and in particular to a kind of new preparation method of Febustat intermediate and its
Prepare the application in Febustat.
Background technology
Febustat (Febuxostat also known as Febuxostat, No. CAS:144060-53-7) chemical name：2- (3- cyano-
4- isobutoxy phenyls) -4- methyl-1s, 3- thiazole -5- formic acid, structure is shown in formula I.
Febustat is the drug that latest generation inhibits uric acid synthesis, is developed at first by Japanese Supreme Being people (TAP) drugmaker,
In May, 2008 in the granted listing of European Union, is ratified to list in the U.S. for 2 months 2009 through FDA, is promoted in the whole world at present.Fei Busi
His mechanism of action is novel, is novel non-purines xanthine oxidase (XOR) inhibitor, has the selectivity of height to XOR,
And there is significant inhibiting effect to the XOR of oxidized form and reduced form.Febustat is curative for effect, and adverse reaction is mostly slight,
And there is self limiting.Currently, Febustat has been included in U.S. ACR gout diagnosis and treatment guides, as anti-trioxypurine drug of first choice.
Original grinds pharmaceutical factory --- and several patents of invention of Japanese Supreme Being people's pharmacy disclose the preparation route of several Febustats.Such as
Synthetic route is disclosed in the patent of invention of notification number JP2725886 (B2) (March 11 1998 day for announcing)：
It is starting material and hydroxylamine hydrochloride, sodium acetate in formic acid solvent using the 3- nitro -4- hydroxy benzaldehydes of structural formula 1
It is middle to heat the compound that structural formula 2 is obtained by the reaction, the compound of structural formula 3 is then obtained by the reaction with thioacetamide, the chemical combination
Object obtains the compound of structural formula 4 with 2- chloroacetyl acetacetic ester cyclizations structure thiazole ring, and then hydroxyl is under the conditions of potassium carbonate
O-alkylation occurs and obtains the compound of structural formula 5, is then changed into after nitro catalytic hydrogenation after amino, amino diazotising and cyanogen
Change the compound that structural formula 6 is obtained by the reaction in cuprous and potassium cyanide, most obtains Febustat after hydrolyzing, being acidified afterwards.Reaction route
As follows：
Although the route, which is the original of Febustat, grinds synthetic route, precious metal catalyst hydrogen has been used in entire route
Change, the hazardous reactions such as diazo reaction, the cuprous cyanide and potassium cyanide of severe toxicity have been used when introducing cyano.Therefore, integrated artistic is given birth to
Produce of high cost, operational danger is big, is unsuitable for industrialized production.
The patent of invention of Supreme Being people's pharmacy notification number JP3169735B2 (May 28 2001 day for announcing) discloses one kettle way
The synthetic route of the intermediate of preparation structure formula 6：Using the 4- p-nitriles of structural formula 7 as starting material, with thioacetamide or
P4S10The thio phenyl acetamide of 4- nitros for reacting generating structure formula 8, the change of structural formula 9 is obtained with 2- chloroacetyl acetacetic ester cyclizations
Close object, the intermediate of structural formula 6 is then prepared with potassium cyanide, isobutane bromide one kettle way in DMSO, most afterwards through hydrolysis,
Febustat is prepared in acidification.Reaction route is as follows：
The route advantage is that route is short, but starting material 4- p-nitriles price is high, and can not largely purchase in the market,
It is excessively high that this directly results in Febustat production cost.In addition, having used high boiling DMSO in technique, can bring a large amount of useless
Water；The use of toxic articles potassium cyanide, increases the danger of operation, is equally unsuitable for industrially amplifying production.
Also occur preparing the patent application of Febustat or in which mesosome, such as publication number successively in the prior art
The Chinese invention patent application of CN102120733A (publication date on July 13rd, 2011), disclosed synthetic route are：With structural formula
10 2,4- dibromophenols are starting material, are alkylated to obtain the compound of structural formula 11 with isopropyl bromo-derivative, the change
The bromine of conjunction object 2,4, which is reacted with cuprous cyanide under CuI catalysis, is changed into cyano, obtains the compound of structural formula 12, structural formula
12 compound selectively carries out cyano thioformamide under thioacetamide effect and obtains the compound of structural formula 13, should
Compound obtains the intermediate of structural formula 6 with 2- chloroacetyl acetacetic ester cyclizations again, finally hydrolyzes, acidification obtains Febustat.
The route has used toxic articles cuprous cyanide.In addition, there are two cyano, 4 ' position cyano for the compound of structural formula 12
In selective thioformamide, the cyano of 2 ' positions can also be converted generation by-product, and the by-product structure is similar with product,
It causes to isolate and purify difficulty.
The Chinese invention patent application of publication number CN102229581A (publication date on November 2nd, 2011) is disclosed to tie
3- methyl -4- the hydroxy benzaldehydes of structure formula 14 are starting material, through it is cyanalation, at ether, carbonylation, thioamides and cyclization,
Obtain Febustat key intermediate：2- (3- formoxyl -4- isobutoxy phenyls) -4- methylthiazole-5-carboxylates (knot
The compound of structure formula 19).Reaction route is as follows：
In above-mentioned preparation method, the compound of structural formula 16 in carbon tetrachloride through N- bromo-succinimides (NBS) with
And dibenzoyl peroxide ((PhCO2)2) it is catalyzed reaction, the methyl on phenyl ring first generates dibromo, and for object, hydrolysis is aldehyde radical again；
Period can generate a bromo-derivative simultaneously, it is similar with the compound structure of structural formula 17 hydrolyze the by-product generated, it is difficult to detach
Purifying.The generation of one bromo-derivative and hydrolysis formula are as described below：
In addition, just introducing unstable aldehyde radical before building thiazole ring, keep aldehyde radical easy under subsequent high temperature counterflow condition
By oxidation stain, increase subsequent purification difficulty and cost.And the reaction solvent for use carbon tetrachloride is more toxic.
Invention content
For overcome the deficiencies in the prior art, the present invention provides a kind of preparation side of new Febustat key intermediate
Method.The preparation method raw material is cheap and easy to get, the risky operation such as non precious metal catalytic hydrogenation, diazotising and toxic articles；And it reacts
High selectivity, side reaction is few, and post-processing is simple.This method is applied to the preparation of Febustat, final product (Febustat) is pure
Degree height, high income.
For achieving the above object, present invention employs the following technical solutions：
A kind of preparation method of the compound of formula II,
Wherein, R=C1~C4Alkyl；
The preparation method includes the following steps：
1) chemical combination of structural formula VI is obtained by the reaction under the action of alkylating agent and alkali in the para hydroxybenzene nitrile of structural formula VII
Object；
2) cyano of the compound of structural formula VI is changed into thioformamide, obtains the compound of structural formula V；
3) it is not necessarily to solvent, the compound of structural formula V is reacted with methenamine in acid condition, obtains structural formula IV's
Compound；
4) compound of structural formula IV and hydroxylamine hydrochloride react in the presence of a base, and dehydration obtains formula II I's
Compound；
5) the 2- haloacetyl acetate compounds of the compound of formula II I and structural formula VIII carry out ring closure reaction
Obtain the compound of formula II；
Wherein, X=Cl, Br, I, R=C1~C4Alkyl.
The synthetic route of the compound of above structure Formula II is：
Preferably, R=methyl, ethyl or tertiary butyl.
Preferably, in the step 1), the alkylating agent is 1- isobutane bromides or 1- iodo isobutanes, more preferably 1-
Isobutane bromide.
Preferably, in the step 1), the molar ratio of the para hydroxybenzene nitrile of the alkylating agent and structural formula VII is：1~
5:1, preferably 1.2~2:1.
Preferably, in the step 1), the alkali is organic base or inorganic base；The organic base is selected from 1,8- diazas two
11 carbon -7- alkene (DBU) of ring, lithium diisopropylamine (LDA), morpholine, 4-dimethylaminopyridine (DMAP), n-BuLi (n-
BuLi), potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), two silicon methylamino lithium of hexamethyl
(LiHMDS) one kind in；The inorganic base selects NaH, KOH, NaOH, Na2CO3、 K2CO3, in t-BuOK and t-BuONa one
Kind.
It is furthermore preferred that in the step 1), the alkali is inorganic base, most preferably K2CO3。
Preferably, in the step 1), the molar ratio of the alkali and para hydroxybenzene nitrile is 1~10:1, more preferably 1.5
~2.5:1.
In the step 1), solvent used is the organic solvent for not influencing reaction, and such as esters can be selected from acetic acid second
Ester, methyl acetate, tert-butyl acetate, isopropyl acetate etc.；Such as ethers, tetrahydrofuran, ether, methyl tertiary butyl ether(MTBE) can be selected from
Deng；Such as amides, n,N-Dimethylformamide (DMF), n,N-dimethylacetamide (DMAC) etc. can be selected from；It can also be two
First sulfoxide (DMSO), acetone etc.；Preferably, solvent for use is n,N-Dimethylformamide (DMF) in step 1).
Preferably, in the step 1), reaction temperature is 50 DEG C~120 DEG C, more preferable 60 DEG C~100 DEG C.
It in the step 1), can be added, can also be added without potassium iodide and make catalysts.
Preferably, in the step 2), under conditions of selected from following any, the cyano of the compound of structural formula VI changes
For thioformamide, the compound of structural formula V is obtained：
A. in acid condition, the compound of structural formula VI reacts with thioacetamide；It is described acid selected from glacial acetic acid,
Polyphosphoric acids, HCl gases or HBr gases etc., preferably HCl gases；The acid is gas, and sour dosage is the saturation of solvent
Amount, the solvent are selected from n,N-Dimethylformamide (DMF), DMSO, N-Methyl pyrrolidone (NMP) etc., preferably DMF；It is described
Acid is liquid, directly makees solvent with the acid；Or
B. under alkaline condition, the compound of structural formulas VI and ammonium sulfide reaction；The alkali be selected from pyridine, triethylamine,
1,8- diazabicylo, 11 carbon -7- alkene (DBU), lithium diisopropylamine (LDA), morpholine, 4-dimethylaminopyridine (DMAP)
Or n,N-diisopropylethylamine (DIEA), more preferably triethylamine；The molar ratio of the compound of the alkali and structural formula VI is 1.5
~10:1, more preferably 2~3:1；Or
C. under the conditions of existing for lewis acid, the compound and NaHS of structural formula VI are reacted；The lewis acid
Selected from magnesium chloride, zinc bromide, alchlor, titanium tetrachloride or zinc chloride, preferably zinc chloride；The lewis acid and structural formula
The molar ratio of the compound of VI is 0.5~5:1, preferably 0.5~2:1；Or
D. the compound of structural formula VI and (1- Methylethyls) ester of phosphordithiic acid-O, O- bis- or P4S10Reaction.
Preferably, in the step 2), the thioacetamide, NaHS, ammonium sulfide, phosphordithiic acid-O, O- bis-
(1- Methylethyls) ester or P4S10Molar ratio with the compound of structural formula VI is 1~10:1, more preferably 1.5~2.5:1.
It is furthermore preferred that in the step 2), the compound of structural formula VI is reacted at the condition A, obtains structural formula V's
Compound.
Preferably, in the step 2), reaction temperature is 0 DEG C~120 DEG C, more preferable 20 DEG C~80 DEG C.
Preferably, in the step 3), the molar ratio of the compound of the methenamine and structural formula V is 1~10:1, more
Preferably 3~5:1.
Preferably, in the step 3), it is described acid selected from glacial acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, formic acid, methanesulfonic acid or
Polyphosphoric acids, more preferably methanesulfonic acid；The volume ratio of the acid and the compound of structural formula V is 1~20:1, preferably 5~8:1.
The scheme substituted as one, in the step 3), under the conditions of existing for lewis acid, the chemical combination of structural formula V
Object and 1,1- dichloroether, DMF/ pyrophosphoryl chlorides and acetone cyanohydrin one react, and obtain the compound of structural formula IV；Wherein, institute
It states lewis acid and is selected from zinc chloride, zinc bromide, titanium tetrachloride, magnesium chloride or alchlor, preferably alchlor；The Louis
The molar ratio of this acid and the compound of structural formula V is 1~10:1, preferably 2~3:1.
Preferably, in the step 3), reaction temperature is 0 DEG C~120 DEG C, more preferable 0 DEG C~80 DEG C.
Preferably, in the step 4), the molar ratio of the compound of the hydroxylamine hydrochloride and structural formula IV is 1~10:1,
More preferably 1.2~2.5:1.
Preferably, in the step 4), the alkali is selected from sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide or hydroxide
Potassium, more preferably sodium acetate；The molar ratio of the compound of the alkali and structural formula IV is 1~10:1, more preferably 1.5~3:1.
The scheme substituted as one, in the step 4), the compound and O- arylamine formyl hydroxylamines pair of structural formula IV
Toluenesulfonic acid reactant salt obtains the compound of formula II I after dehydration；Wherein, the O- arylamine formyl hydroxylamine p-methyl benzenesulfonic acid
Salt is selected from O- aniline formyl hydroxylamines tosilate, O-2- methoxybenzoyl base azanols tosilate, O-3- first
Oxygroup benzoyl azanol tosilate, O-4- methoxybenzoyls base azanol tosilate or O-2- nitrobenzoyls
Acyl group azanol tosilate；Mole of the O- arylamine formyl hydroxylamine tosilate and the compound of structural formula IV
Than being 1~3:1, more preferably 1~1.5:1.
Preferably, in the step 4), the dehydration carries out in formic acid or acetic anhydride.
Preferably, in the step 4), reaction temperature is 40 DEG C~120 DEG C, more preferable 60 DEG C~80 DEG C.
Preferably, in the step 5), the 2- haloacetyls acetate compounds and formula II I of structural formula VIII
Compound molar ratio be 1~10:1, more preferably 1.2~3:1.
Preferably, in the step 5), X=Cl or Br.
Preferably, in the step 5), reaction temperature is -20 DEG C~120 DEG C, more preferably -10 DEG C~100 DEG C.
It is also an object of the present invention to provide the preparation methods of the compound of above structure Formula II in synthesis Fei Busi
Application in him；Specifically, the compound of formula II is prepared by above-mentioned preparation method, through hydrolysis, Fei Busi is obtained
He.
Preferably, when R=methyl or ethyl, the mixing of the compound of formula II in corresponding methanol or second alcohol and water
In solvent, hydrolyzed under sodium hydroxide effect, it is acidified rear up to Febustat crude product；When R=tertiary butyls, formula II
Compound is in methylene chloride through trifluoroacetic acid hydrolysis, you can obtains Febustat crude product.
The Febustat crude product is through recrystallizing to obtain refined Febustat；The refined Febustat purity 99.5% with
On, single contaminant is below 0.1%.
Method provided by the invention, starting material para hydroxybenzene nitrile is cheap and easy to get, and structural formula is just only prepared with the reaction of 5 steps
The Febustat key intermediate of II.The method of the present invention, first carries out o-alkylation to starting material, can avoid exposed hydroxyl
Base and the ortho position aldehyde radical that subsequently introduces reduce alkylating agent dosage, reduce production because intramolecular hydrogen bond increases o-alkylation difficulty
Cost.In addition, the preparation method of the present invention is also avoided that in the patent application of publication number CN102120733A while generating two
Cyano increases the problem of subsequent selective reaction difficulty, to reduce the generation of the similar by-product of structure, is conducive to prepare high
The Febustat key intermediate II of purity, is finally prepared high-purity Febustat.
In step 2) of the present invention, so that the cyano of the compound of structural formula VI is converted to thioformamide and (obtain
The compound of structural formula V), it is re-introduced into aldehyde radical (obtaining the compound of structural formula IV), so as to avoid patent publication No.
It introduces unstable aldehyde radical in the patent application of CN102229581A too early on phenyl ring, avoids aldehyde radical under the conditions of subsequent high temperature
The unfavorable factor not tolerated reduces subsequent purification difficulty.For the prior art of publication number CN102229581A, if to protect
The aldehyde radical that introduces too early and be translated into cyano, then there are two cyano in molecular structure, are unfavorable for the general of subsequent selective
Cyano is converted into the progress of thioformamide reaction.
In addition, the present invention is that solvent is introduced directly on the phenyl ring of structural formula V in the step 3) of aldehyde radical with acid, not only it is not necessarily to
In addition addition solvent (the solvent carbon tetrachloride of such as CN102229581A), and overcome showing for publication number CN102229581A
The defect for bringing monobromide by-product when thering is technology is existing to convert methyl to aldehyde radical into, so as to better ensure that whole production
The purity of object Febustat.
In short, the method for the present invention is easy to operate, high income, side reaction is few, toxic articles are not used, is environmental-friendly, as
A kind of method prepared by novel Febustat intermediate, is suitable for industrialized production.
Description of the drawings
Below in conjunction with the accompanying drawings, the present invention will be further described.
Fig. 1 shows the HPLC collection of illustrative plates of the compound (Febustat ethyl ester) of formula II prepared by embodiment 14, figure
The chromatographic peak of middle retention time~18.5min is the absorption peak of the compound.
Fig. 2 shows be embodiment 15 prepare formula II compound (Febustat methyl esters) HPLC collection of illustrative plates, figure
The chromatographic peak of middle retention time~20min is the absorption peak of the compound.
Fig. 3 shows the HPLC collection of illustrative plates of Febustat prepared by embodiment 17, the color of retention time~7.5min in figure
Spectral peak is the absorption peak of the compound.
Fig. 4 shows the HPLC collection of illustrative plates of Febustat prepared by embodiment 18, the color of retention time~7.5min in figure
Spectral peak is the absorption peak of the compound.
Specific implementation mode
The present invention provides a kind of preparation method of the compound of formula II, and reaction route is：
Wherein R=C1~C4Alkyl, preferably methyl, ethyl or tertiary butyl.
The preparation method is preferably realized by following reaction step：
1) effect of the para hydroxybenzene nitrile of structural formula VII in alkylating agent (1- isobutane bromides or 1- iodo isobutanes) and alkali
Under, the compound of structural formula VI is obtained by the reaction at 60 DEG C~100 DEG C；The molar ratio of the alkylating agent and para hydroxybenzene nitrile is 1.2
~2:1；The alkylating agent is preferably 1- isobutane bromides；The molar ratio of the alkali and para hydroxybenzene nitrile is 1.5~2.5:1, institute
It is inorganic base, preferably K to state alkali2CO3；Reaction dissolvent is N,N-dimethylformamide (DMF)；
2) in acid condition, the compound of structural formula VI and thioacetamide are in N, N- dissolved with saturation HCl gases
In dimethylformamide (DMF), reacts at 20 DEG C~80 DEG C, obtain the compound of structural formula V；Thioacetamide and structure
The molar ratio of the compound of Formula IV is 1.5~2.5:1；
3) it is not necessarily to solvent, under the conditions of existing for methanesulfonic acid, 0 DEG C~80 DEG C, the compound and methenamine of structural formula V is anti-
It answers, obtains the compound of structural formula IV；The volume ratio of methanesulfonic acid and the compound of structural formula V is 5~8:1；
Alternatively,
Without solvent, under the conditions of existing for alchlor, 0 DEG C~80 DEG C, compound and 1,1-, bis- chloroethenes of structural formula V
Ether, DMF/ pyrophosphoryl chlorides and acetone cyanohydrin one react, and obtain the compound of structural formula IV；The change of alchlor and structural formula V
The molar ratio for closing object is 2~3:1；
4) it 60 DEG C~80 DEG C, is reacted under the conditions of the compound and hydroxylamine hydrochloride of structural formula IV are existing for sodium acetate；Product
Dehydration obtains the compound of formula II I in formic acid or acetic anhydride；Sodium acetate and molar ratio with the compound of structural formula IV
It is 1.5~3:1；Alternatively,
It reacts, is tied at 60 DEG C~80 DEG C of the compound and O- arylamine formyl hydroxylamines tosilate of structural formula IV
The compound of structure formula III；The molar ratio of the O- arylamine formyl hydroxylamine tosilate and the compound of structural formula IV is 1
~1.5:1；
5) the 2- haloacetyl acetate compounds of the compound of formula II I and structural formula VIII carry out ring closure reaction
Obtain the compound of formula II；The compound of the 2- haloacetyls acetate compounds and formula II I of structural formula VIII
Molar ratio be 1.2~3:1；The 2- haloacetyls acetate compounds are selected from 2- chloroacetyls methyl acetate, 2- chloros
Ethyl acetoacetate, 2- chloroacetyls tert-butyl acetate, 2- bromoacetyls methyl acetate, 2- bromo-acetoacetic esters and 2- bromines
For one kind in tert-butyl acetoacetate.
The compound of formula II is prepared using above-mentioned preparation method, through hydrolysis, obtains Febustat crude product；Non- cloth
Refined Febustat is obtained after taking charge of his crude product recrystallization.
The present invention is described below with reference to specific embodiments.It will be appreciated by those skilled in the art that these embodiments are only
For illustrating the present invention, do not limit the scope of the invention in any way.
Experimental method in following embodiments is unless otherwise specified conventional method.Original as used in the following examples
Material, reagent material etc. are commercially available products unless otherwise specified.
In following examples, unless otherwise specified, room temperature refers to 20 DEG C~35 DEG C." purity " is liquid chromatogram
The purity for the compound that peak area normalization method measures.
Embodiment 1The preparation of the compound of structural formula VI
Para hydroxybenzene nitrile 12g (1eq), K2CO321g (1.5eq), 1- isobutane bromides 18g (1.3eq), KI 1.7g (0.1
Eq) 60 DEG C are heated to and is reacted 10 hours with the reaction system of DMF 120ml, water and each 100ml of ethyl acetate, liquid separation, water is added
Mutually continue to be extracted with ethyl acetate, merge organic phase, dry, decompression is spin-dried for obtaining 17.7g title compounds, and yield about 100% is pure
Degree 98%.
1H-NMR(CDCI3)δ：1.06 (d, 6H), 2.30 (m, 1H), 3.94 (d, 2H), 6.95 (d, 2H), 7.45 (d,
2H).
Embodiment 2The preparation of the compound of structural formula VI
Para hydroxybenzene nitrile 12g (1eq), morpholine 22g (2.5eq), 1- isobutane bromides 25g (1.8eq), KI 1.7g (0.1
Eq) 60 DEG C are heated to and is reacted 12 hours with the reaction system of ethyl acetate 200ml, water and each 100ml of ethyl acetate is added, point
Liquid, water phase continue to be extracted with ethyl acetate, and merge organic phase, dry, depressurize and are spin-dried for obtaining 16g title compounds, yield about 90%,
Purity 93%.
1H-NMR(CDCI3)δ：1.04 (d, 6H), 2.32 (m, 1H), 3.97 (d, 2H), 6.99 (d, 2H), 7.50 (d,
2H).
Embodiment 3The preparation of the compound of structural formula VI
Para hydroxybenzene nitrile 12g (1eq), potassium hexamethyldisilazide 36g (1.8eq), 1- isobutane bromides 25g (1.8
Eq), the reaction system of DMF200ml is heated to 80 DEG C and reacts 15 hours, and water and each 100ml of ethyl acetate, liquid separation, water phase is added
Continue to be extracted with ethyl acetate, merge organic phase, dry, decompression is spin-dried for obtaining 15.6g title compounds, yield about 88%, purity
90%.
1H-NMR(CDCI3)δ：1.10 (d, 6H), 2.35 (m, 1H), 3.40 (d, 2H), 6.97 (d, 2H), 7.42 (d,
2H).
Embodiment 4The preparation of the compound of structural formula V
Compound 17.7g (1eq), the thioacetamide 12g (1.6eq) of structural formula VI prepared by embodiment 1 is dissolved in 200ml
In the DMF of hydrogen chloride gas saturation, it is heated to 80 DEG C and reacts 4 hours.After reaction, 5% sodium hydroxide solution tune is added
PH value is saved to 8-9, is collected by filtration obtained solid, dry 18g title compounds after ethyl alcohol recrystallization.Yield about 85%, purity
99%.
1H-NMR(CDCI3)δ：1.08 (d, 6H), 2.36 (m, 1H), 3.97 (d, 2H), 6.82 (d, 2H), 7.17 (d,
2H).
Embodiment 5The preparation of the compound of structural formula V
The compound 17.7g (1eq) of the structural formula VI prepared according to the method described in embodiment 2 is dissolved in pyridine 170mL
In, the ammonium sulfide solution 37.4g (1.1eq) of triethylamine 7.6g (1.1eq) and 20% is then added, is heated to 50 DEG C of reactions 6
Hour.After, the sodium hydroxide solution for being added 5% adjusts pH value to 8-9, is collected by filtration obtained solid, after ethyl alcohol recrystallization
Dry 17g title compounds.Yield about 80%, purity 95%.
1H-NMR(CDCI3)δ：1.02 (d, 6H), 2.33 (m, 1H), 3.90 (d, 2H), 6.75 (d, 2H), 7.13 (d,
2H).
Embodiment 6The preparation of the compound of structural formula V
The compound 17.7g (1eq) of the structural formula VI prepared according to method described in embodiment 3 adds to NaHS 11g
In the DMF solution 100mL of (2eq) and Magnesium dichloride hexahydrate 20.3g (1.0eq), react at room temperature 1.5 hours.After reaction, add
5% sodium hydroxide solution adjusts pH value to 8-9, is collected by filtration obtained solid, dry 17g title compounds after ethyl alcohol recrystallization
Object.Yield about 80%, purity 96%.
1H-NMR(CDCI3)δ：1.06 (d, 6H), 2.31 (m, 1H), 3.95 (d, 2H), 6.80 (d, 2H), 7.17 (d,
2H).
The preparation of the compound of 7 structural formula V of embodiment
According to compound 17.7g (1eq), the phosphordithiic acid-O, O- of structural formula VI prepared by method described in embodiment 1
Two (1- Methylethyls) ester 21.5g (1eq) are dissolved in 100mL DMSO, are heated to 40 DEG C and are reacted 10 hours.After reaction, add
Enter in 500mL water, ethyl acetate extracts three times, and each 100mL, organic phase is washed with NaHCO3 saturated solutions (200mL) again.
Organic phase is concentrated under reduced pressure, obtained solid ethyl alcohol recrystallization, dry 16.4g title compounds.Yield about 78%, purity 92%.
1H-NMR(CDCI3)δ：1.05 (d, 6H), 2.33 (m, 1H), 3.92 (d, 2H), 6.78 (d, 2H), 7.15 (d,
2H).
Embodiment 8The preparation of the compound of structural formula IV
Methenamine 31g (2.5eq) is added slowly to the compound of the structural formula V prepared according to 4 the method for embodiment
In methanesulfonic acid 50g (6eq) solution of 18g (1eq), it is heated to 75 DEG C and stirs 10 hours.It is cooled to 30 DEG C after reaction, adds
Temperature is down to 0 DEG C and is stirred 1 hour again after entering 200ml water, the solid of precipitation is collected by filtration, water washing dries to obtain 16.3g titles
Compound.Yield 80%, purity 99.4%.
1H-NMR(CDCI3)δ：1.07 (d, 6H), 2.29 (m, 1H), 3.97 (d, 2H), 7.14 (d, 1H), 7.85 (dd,
1H), 7.96 (d, 1H)
Embodiment 9The preparation of the compound of structural formula IV
The compound 21g (1eq) of the structural formula V prepared according to 5 the method for embodiment is dissolved in anhydrous methylene chloride
In (210mL), 0 DEG C is cooled under nitrogen protection.TiCl441.8g (1eq) is slowly dropped into.After 0 DEG C is stirred 1 hour, 1,1- bis-
Dichloroethyl ether 12.5g (1eq) is slowly dropped into, and continues stirring 45 minutes.Saturated aqueous ammonium chloride 125mL is added to be quenched, room temperature
After stirring 2 hours, liquid separation, water saturation dichloromethane 100mL is extracted 2 times, merges organic phase, 0.1N hydrochloric acid (100mL × 1) and is satisfied
With saline solution 100mL × 1) it washs, organic phase reduced pressure is spin-dried for, and dries to obtain 14.3g title compounds.Yield 60%, purity
99%.
1H-NMR(CDCI3)δ：1.06 (d, 6H), 2.27 (m, 1H), 3.94 (d, 2H), 7.11 (d, 1H), 7.83 (dd,
1H), 7.92 (d, 1H)
Embodiment 10The preparation of the compound of structural formula IV
In 0 DEG C of compound 21g (1eq) and DMF 11g toward the structural formula V prepared according to 6 the method for embodiment
Pyrophosphoryl chloride 37.5g (1.5eq) is slowly added dropwise in the mixed solution of (1.5eq), is added dropwise, it is small to be heated to 100 DEG C of reactions 24
When.After reaction, reaction solution is cooled to room temperature, and slowly down in 200mL ice water, 2N sodium hydroxide solution tune is used at 0 DEG C
PH to 3-4 is saved, the solid of precipitation is collected by filtration, water washing dries to obtain 13g title compounds.Yield 54.8%, purity 99%.
1H-NMR(CDCI3)δ：1.02 (d, 6H), 2.23 (m, 1H), 3.90 (d, 2H), 7.08 (d, 1H), 7.78 (dd,
1H), 7.89 (d, 1H)
Embodiment 11The preparation of the compound of structural formula IV
According to the compound 21g (1eq) and acetone cyanohydrin 8.5g (1eq) of structural formula V prepared by 7 the method for embodiment
It is dissolved in 1,2- dichloroethanes 100mL, is cooled to 0 DEG C, alchlor 26.7g (2eq) is slowly added under stirring.Add rear temperature
It is warmed to room temperature, then flows back 24 hours.Water 10mL is added and continues stirring 2 hours.After adding water to wash, organic phase decompression is spin-dried for, and is dried
Title compound 10.6g, yield 45%, purity 98%.
1H-NMR(CDCI3)δ：1.06 (d, 6H), 2.27 (m, 1H), 3.94 (d, 2H), 7.11 (d, 1H), 7.83 (dd,
1H), 7.92 (d, 1H)
Embodiment 12The preparation of the compound of formula II I
Compound IV 16g (1eq), hydroxylamine hydrochloride 5.6g (1.2eq) and the acetic acid prepared according to 8 the method for embodiment
Sodium 10.6g (1.5eq) flows back 5 hours in formic acid, and temperature is cooled to room temperature plus elutriation is brilliant, and precipitation solid is collected by filtration, obtains
14.2g title compounds, yield 90%, purity 99.2%.
1H-NMR(CDCI3)δ：1.10 (d, 6H), 2.28 (m, 1H), 4.01 (d, 2H), 7.19 (d, 1H), 7.92 (dd,
1H), 8.03 (d, 1H)
Embodiment 13The preparation of the compound of formula II I
According to compound IV 10g (1eq) prepared by 9 the method for embodiment, it is dissolved in 100mL ethyl alcohol, O- is then added
Aniline carbonyl azanol tosilate 13.7g (1eq) is stirred 2 hours at room temperature.Slowly add water 100mL, precipitation is collected by filtration
Solid obtains 6.9g title compounds, yield 70%, purity 99.0%.
1H-NMR(CDCI3)δ：1.05 (d, 6H), 2.24 (m, 1H), 3.91 (d, 2H), 7.15 (d, 1H), 7.88 (dd,
1H), 7.98 (d, 1H)
Embodiment 14The preparation of the compound (Febustat ethyl ester) of formula II
Wherein, R=ethyls.
The compound 14g (1eq) of the formula II I prepared according to 12 the method for embodiment is dissolved in 200ml ethyl alcohol, is added
Enter 2- chloroacetyl acetacetic esters 28.7g (3eq), is warming up to 100 DEG C and stirs 2 hours.- 10 DEG C are down to, a large amount of solids, mistake is precipitated
Filter, filter cake dry to obtain title compound 16.7g, white solid, yield 85%, purity 99.6%, and HPLC collection of illustrative plates is shown in Fig. 1.
1H-NMR(CDCI3)δ：1.07 (d, 6H), 1.30 (t, 3H), 2.24 (m, 1H), 2.56 (s, 3H), 3.90 (d,
2H), 4.29 (q, 2H), 7.01 (d, 1H), 8.02 (dd, 1H), 8.12 (d, 1H)
Embodiment 15The preparation of the compound of formula II
Wherein, R=methyl.
The compound 14g (1eq) of the formula II I prepared according to the method described in embodiment 13 is dissolved in 200ml ethyl alcohol,
2- acetyl bromide methyl acetate 34.6g (3eq) are added, is warming up to 100 DEG C and stirs 2 hours.- 10 DEG C are down to, a large amount of solids, mistake is precipitated
Filter, filter cake drying, obtains title compound 17.2g, white solid, yield 87%, purity 99.5%, and HPLC collection of illustrative plates is shown in Fig. 2.
1H-NMR(CDCI3)δ：1.08 (d, 6H), 2.24 (m, 1H), 2.57 (s, 3H), 3.90 (d, 2H), 4.40 (s, 3H),
7.01 (d, 1H), 8.01 (dd, 1H), 8.08 (d, 1H)
Embodiment 16The preparation of the compound of formula II
Wherein, R=tertiary butyls.
The compound 14g (1eq) of the formula II I prepared according to the method described in embodiment 12 is dissolved in 200ml ethyl alcohol,
2- chloracetyl tert-butyl acetate 27g (3eq) are added, is warming up to 100 DEG C and stirs 2 hours.- 10 DEG C are down to, a large amount of solids, mistake is precipitated
Filter, filter cake drying, obtains title compound 18.9g, white solid, yield 85%, purity 99.3% (summary of HPLC collection of illustrative plates).
1H-NMR(CDCI3)δ：1.06 (d, 6H), 1.48 (m, 9H), 2.53 (s, 3H), 3.85 (d, 2H), 4.40 (s,
3H), 6.93 (d, 1H), 8.05 (dd, 1H), 8.15 (d, 1H)
Embodiment 17The preparation of Febustat
According to the compound 17g (1eq) of formula II prepared by 16 the method for embodiment, it is dissolved in DCM (200ml)
In, trifluoroacetic acid (200mL) is added, is stirred at room temperature 2 hours, after reaction, water 200mL, liquid separation is added, water phase continues with two
Chloromethanes extracts.Merge extraction phase, activated carbon, filtering, the washing of filter cake dichloromethane is added.Merging filtrate is concentrated under reduced pressure, concentration
Afterwards, DCM is used:MeOH=1:The mixed solvent of 2.5 (volume ratios) dissolves, and temperature is down to 0 DEG C and keeps the temperature 1 hour crystallization.Filtering is received
Collect obtained solid, the DCM pre-cooled is used in combination:MeOH=1:The mixed solvent of 2.5 (volume ratios) washs.Decompression drying get Fei Bu
Take charge of his 8.8g.Yield 90%, purity 99.7%, HPLC collection of illustrative plates are shown in Fig. 3.
1H-NMR(d-DMSO)δ：1.05 (d, 6H), 2.27 (m, 1H), 2.66 (s, 3H), 4.01 (d, 2H), 7.27 (d,
1H), 8.09 (dd, 1H), 8.18 (d, 1H), 12.85 (s, 1H)
Embodiment 18The preparation of Febustat
According to compound 17g (1eq) prepared by 15 the method for embodiment, it is dissolved in MeOH:H2O=3:1 (volume ratio)
200ml in the mixed solvents, be added 1mol/L sodium hydrate aqueous solution 170ml, be warming up to 60 DEG C react 1.5-2 hour, react
After temperature be down to 45 DEG C, be added ethyl acetate and water, temperature control uses 6N HCl to adjust system pH to 0.5- in 35 DEG C
0.8, liquid separation, water phase continues to be extracted with ethyl acetate.Merge extraction phase, activated carbon, filtering, the washing of filter cake ethyl acetate is added.
Merging filtrate is concentrated under reduced pressure, and after concentration, uses DCM:MeOH=1:The mixed solvent of 2.5 (volume ratios) dissolves, and temperature is down to 0 DEG C simultaneously
Keep the temperature 1 hour crystallization.Obtained solid is collected by filtration, the DCM pre-cooled is used in combination:MeOH=1:The mixing of 2.5 (volume ratios) is molten
Agent is washed.Decompression drying obtains Febustat 13.7g.Yield 88%, purity 99.8%, HPLC collection of illustrative plates are shown in Fig. 4.
1H-NMR(d-DMSO)δ：1.02 (d, 6H), 2.30 (m, 1H), 2.64 (s, 3H), 3.99 (d, 2H), 7.32 (d,
1H), 8.11 (dd, 1H), 8.23 (d, 1H), 12.87 (s, 1H).
Claims (12)
1. a kind of preparation method of the compound of formula II,
Wherein, R=C1~C4Alkyl；
The preparation method includes the following steps：
1) compound of structural formula VI is obtained by the reaction under the action of alkylating agent and alkali in the para hydroxybenzene nitrile of structural formula VII；
2) cyano of the compound of structural formula VI is changed into thioformamide, obtains the compound of structural formula V；
3) it is not necessarily to solvent, the compound of structural formula V is reacted with methenamine in acid condition, obtains the chemical combination of structural formula IV
Object；
4) compound of structural formula IV and hydroxylamine hydrochloride react in the presence of a base, and dehydration obtains the chemical combination of formula II I
Object；
5) the 2- haloacetyl acetate compounds of the compound of formula II I and structural formula VIII progress ring closure reaction obtain
The compound of formula II；
Wherein, X=Cl, Br, I, R=C1~C4Alkyl, preferably R=methyl, ethyl or tertiary butyl.
2. preparation method according to claim 1, which is characterized in that in the step 1), the alkylating agent is 1- bromos
Iso-butane or 1- iodo isobutanes, more preferably 1- isobutane bromides；
Preferably, in the step 1), the molar ratio of the para hydroxybenzene nitrile of the alkylating agent and structural formula VII is：1~5:1, it is excellent
It is selected as 1.2~2:1；
Preferably, in the step 1), the alkali is organic base or inorganic base；The organic base is selected from 1,8- diazabicylos ten
One carbon -7- alkene (DBU), lithium diisopropylamine (LDA), morpholine, 4-dimethylaminopyridine (DMAP), n-BuLi (n-
BuLi), potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS), two silicon methylamino lithium of hexamethyl
(LiHMDS) one kind in；The inorganic base selects NaH, KOH, NaOH, Na2CO3、K2CO3, in t-BuOK and t-BuONa one
Kind；
It is furthermore preferred that in the step 1), the alkali is inorganic base, most preferably K2CO3；
Preferably, in the step 1), the molar ratio of the alkali and para hydroxybenzene nitrile is 1~10:1, more preferably 1.5~2.5:
1；
Preferably, solvent for use is n,N-Dimethylformamide in step 1)；
Preferably, in the step 1), reaction temperature is 50 DEG C~120 DEG C, more preferable 60 DEG C~100 DEG C.
3. preparation method according to claim 1 or 2, which is characterized in that in the step 2), selected from following any
Under the conditions of, the cyano of the compound of structural formula VI is changed into thioformamide, obtains the compound of structural formula V：
A. in acid condition, the compound of structural formula VI reacts with thioacetamide；The acid is selected from glacial acetic acid, poly
Phosphoric acid, HCl gases or HBr gases etc., preferably HCl gases；The acid is gas, and sour dosage is the saturation capacity of solvent, institute
It states solvent and is selected from n,N-Dimethylformamide (DMF), DMSO, N-Methyl pyrrolidone (NMP) etc., preferably DMF；The acid is liquid
Body directly makees solvent with the acid；Or
B under alkaline condition, react by the compound and ammonium sulfide of structural formulas VI；The alkali is selected from pyridine, triethylamine, 1,8- bis-
11 carbon -7- alkene (DBU) of azabicyclic, lithium diisopropylamine (LDA), morpholine, 4-dimethylaminopyridine (DMAP) or N, N-
Diisopropylethylamine (DIEA), more preferably triethylamine；The molar ratio of the compound of the alkali and structural formula VI is 1.5~10:
1, more preferably 2~3:1；Or
C. under the conditions of existing for lewis acid, the compound and NaHS of structural formula VI are reacted；The lewis acid is selected from
Magnesium chloride, zinc bromide, alchlor, titanium tetrachloride or zinc chloride, preferably zinc chloride；The lewis acid and structural formula VI's
The molar ratio of compound is 0.5~5:1, preferably 0.5~2:1；Or
D. the compound of structural formula VI and (1- Methylethyls) ester of phosphordithiic acid-O, O- bis- or P4S10Reaction；
Preferably, in the step 2), the thioacetamide, NaHS, ammonium sulfide, bis- (1- first of phosphordithiic acid-O, O-
Base ethyl) ester or P4S10Molar ratio with the compound of structural formula VI is 1~10:1, more preferably 1.5~2.5:1；
Preferably, in the step 2), reaction temperature is 0 DEG C~120 DEG C, more preferable 20 DEG C~80 DEG C.
4. preparation method according to claim 3, which is characterized in that in acid condition, the compound of structural formula VI with
Thioacetamide reacts；The acid is selected from glacial acetic acid, polyphosphoric acids, HCl gases or HBr gases etc., preferably HCl gas
Body；It is described acid be gas, sour dosage be solvent saturation capacity, the solvent be selected from n,N-Dimethylformamide (DMF),
DMSO, N-Methyl pyrrolidone (NMP) etc., preferably DMF；The acid is liquid, directly makees solvent with the acid.
5. preparation method according to any one of claim 1 to 4, which is characterized in that in the step 3), the crow Lip river
The molar ratio of the compound of tropine and structural formula V is 1~10:1, more preferably 3~5:1；
Preferably, in the step 3), the acid is selected from glacial acetic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, formic acid, methanesulfonic acid or poly
Phosphoric acid, more preferably methanesulfonic acid；The volume ratio of the acid and the compound of structural formula V is 1~20:1, preferably 5~8:1.
6. preparation method according to any one of claim 1 to 4, which is characterized in that in the step 3), in Louis
Under the conditions of existing for sour, compound and 1,1- dichloroether, DMF/ pyrophosphoryl chlorides and the acetone cyanohydrin one of structural formula V react,
Obtain the compound of structural formula IV；Wherein, the lewis acid is selected from zinc chloride, zinc bromide, titanium tetrachloride, magnesium chloride or trichlorine
Change aluminium, preferably alchlor；The molar ratio of the lewis acid and the compound of structural formula V is 1~10:1, preferably 2~
3:1。
7. preparation method according to claim 5 or 6, which is characterized in that in the step 3), reaction temperature be 0 DEG C~
120 DEG C, more preferable 0 DEG C~80 DEG C.
8. preparation method according to any one of claim 1 to 7, which is characterized in that in the step 4), the hydrochloric acid
The molar ratio of the compound of azanol and structural formula IV is 1~10:1, more preferably 1.2~2.5:1；
Preferably, in the step 4), the alkali is selected from sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, more
Preferably sodium acetate；The molar ratio of the compound of the alkali and structural formula IV is 1~10:1, more preferably 1.5~3:1；
It is also preferred that in the step 4), the dehydration carries out in formic acid or acetic anhydride.
9. preparation method according to any one of claim 1 to 7, which is characterized in that in the step 4), structural formula IV
Compound and O- arylamine formyl hydroxylamine p-methyl benzenesulfonic acid reactant salts, obtain the compound of formula II I；Wherein, the O-
Arylamine formyl hydroxylamine tosilate is selected from O- aniline formyl hydroxylamines tosilate, O-2- methoxybenzoyl bases
Azanol tosilate, O-3- methoxybenzoyl base azanols tosilate, O-4- methoxybenzoyl base azanols pair
Toluene fulfonate or O-2- nitro benzoyl azanol tosilate；The O- arylamine formyl hydroxylamine tosilate
Molar ratio with the compound of structural formula IV is 1~3:1, more preferably 1~1.5:1.
10. preparation method according to claim 8 or claim 9, which is characterized in that in the step 4), reaction temperature is 40 DEG C
~120 DEG C, more preferable 60 DEG C~80 DEG C.
11. preparation method according to any one of claim 1 to 10, which is characterized in that in the step 5), structural formula
The molar ratio of the 2- haloacetyls acetate compounds of VIII and the compound of formula II I is 1~10:1, more preferably
1.2~3:1；
Preferably, in the step 5), X=Cl or Br；
Preferably, in the step 5), reaction temperature is -20 DEG C~120 DEG C, more preferably -10 DEG C~100 DEG C.
12. application of the preparation method in synthesizing Febustat described in any one of claim 1 to 11；Specifically, passing through
The compound of formula II is prepared in above-mentioned preparation method, through hydrolysis, obtains Febustat；
Preferably, when R=methyl or ethyl, the compound of formula II is in corresponding methanol or the mixed solvent of second alcohol and water
In, it is hydrolyzed under sodium hydroxide effect, it is acidified rear up to Febustat crude product；When R=tertiary butyls, the chemical combination of formula II
Object is in methylene chloride through trifluoroacetic acid hydrolysis, you can obtains Febustat crude product；The Febustat crude product is through recrystallizing smart
Febustat processed；The refined Febustat purity is 99.5% or more, and single contaminant is below 0.1%.
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