CN108358866B

CN108358866B - Preparation method of febuxostat intermediate and application of febuxostat intermediate in preparation of febuxostat

Info

Publication number: CN108358866B
Application number: CN201810025214.2A
Authority: CN
Inventors: 周立勇; 黄伟平; 曾维霖; 徐烘材; 康禄; 冯玉杰; 林艳
Original assignee: JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
Current assignee: JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
Priority date: 2017-01-12
Filing date: 2018-01-11
Publication date: 2021-03-23
Anticipated expiration: 2038-01-11
Also published as: CN108358866A

Abstract

The invention provides a preparation method of a compound of a structural formula II, which comprises the following steps: 1) reacting the compound of the structural formula VII under the action of an alkylating agent and alkali to obtain a compound of a structural formula VI; 2) reacting the compound with the structural formula VI to obtain a compound with a structural formula V; 3) the compound with the structural formula V reacts with urotropine under an acidic condition without a solvent to obtain a compound with a structural formula IV; 4) reacting the compound shown in the structural formula IV with hydroxylamine hydrochloride in the presence of alkali, and dehydrating to obtain a compound shown in a structural formula III; 5) and carrying out ring closing reaction on the compound with the structural formula III and the compound with the structural formula VIII to obtain the compound with the structural formula II. The invention also provides application of the preparation method in synthesizing febuxostat. The method has the advantages of simple operation, high yield, less side reaction and no use of hypertoxic, is used as a novel method for preparing the febuxostat intermediate, and is suitable for industrial production.

Wherein R ═ C₁～C₄Alkyl group of (1).

Description

Preparation method of febuxostat intermediate and application of febuxostat intermediate in preparation of febuxostat

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a novel preparation method of a febuxostat intermediate and application of the febuxostat intermediate in preparation of febuxostat.

Background

Febuxostat (Febuxostat, also known as Febuxostat, CAS number 144060-53-7) chemical name: the structure of the 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-1, 3-thiazole-5-formic acid is shown in a formula I.

Febuxostat is a latest generation of drug inhibiting uric acid synthesis, was first developed by the japanese imperial (TAP) pharmaceutical company, was approved for marketing in the european union 5 months in 2008, and approved for marketing in the united states by FDA in 2 months in 2009, and is currently promoted globally. The febuxostat has a novel action mechanism, is a novel non-purine Xanthine Oxidase (XOR) inhibitor, has high selectivity on XOR, and has obvious inhibition effect on both oxidized and reduced XOR. Febuxostat has definite curative effect, most of adverse reactions are slight, and febuxostat has self-limitation effect. Currently, febuxostat is listed in ACR gout diagnosis and treatment guidelines in the United states and is used as a first choice drug for reducing uric acid.

The original pharmaceutical factory-Japanese emperor pharmaceutical several invention patents disclose several preparation routes of febuxostat. The synthetic route disclosed in the invention patent publication No. JP2725886(B2) (publication No. 3/11/1998) is:

the method comprises the steps of taking 3-nitro-4-hydroxybenzaldehyde with a structural formula 1 as an initial raw material, heating and reacting the initial raw material with hydroxylamine hydrochloride and sodium acetate in a formic acid solvent to obtain a compound with a structural formula 2, then reacting the compound with thioacetamide to obtain a compound with a structural formula 3, closing a ring with 2-chloroacetoacetic acid ethyl ester to construct a thiazole ring to obtain a compound with a structural formula 4, carrying out oxyalkylation on hydroxyl under the condition of potassium carbonate to obtain a compound with a structural formula 5, carrying out catalytic hydrogenation on nitro, then converting the amino into amino, diazotizing the amino, reacting the amino with cuprous cyanide and potassium cyanide to obtain a compound with a structural formula 6, and finally hydrolyzing and acidifying to obtain febuxostat. The reaction scheme is as follows:

although the route is the original research and synthesis route of febuxostat, dangerous reactions such as noble metal catalytic hydrogenation, diazo reaction and the like are used in the whole route, and virulent cuprous cyanide and potassium cyanide are used when a cyano group is introduced. Therefore, the whole process has high production cost and high operation risk, and is not suitable for industrial production.

The invention patent of Imperial pharmaceutical publication No. JP3169735B2 (on 28.5.2001) discloses a one-pot synthetic route for the preparation of intermediates of formula 6: 4-nitrobenzonitrile with a structural formula 7 as a starting material is reacted with thioacetamide or P₄S₁₀Reacting to generate 4-nitrothiophenylacetamide with a structural formula 8, performing ring closure with 2-chloroacetoacetic acid ethyl ester to obtain a compound with a structural formula 9, then performing one-pot method with potassium cyanide and bromoisobutane in DMSO to prepare an intermediate with a structural formula 6, and finally performing hydrolysis and acidification to prepare febuxostat. The reaction scheme is as follows:

the route has the advantages that the route is short, but the price of the starting material 4-nitrobenzonitrile is high, and the starting material cannot be purchased in a large amount in the market, which directly results in the overhigh production cost of febuxostat. In addition, the process uses high-boiling point DMSO, which brings a large amount of wastewater; the use of potassium cyanide, a highly toxic substance, increases the operational risk and is also not suitable for industrial scale-up production.

Patent applications for preparing febuxostat or an intermediate thereof, such as chinese invention patent application with publication number CN102120733A (publication No. 2011, 7/13), also appear in the prior art successively, and the disclosed synthetic route is: 2, 4-dibromophenol of a structural formula 10 is used as an initial raw material, and is alkylated with isopropyl bromide to obtain a compound of a structural formula 11, bromine at 2, 4-position of the compound reacts with cuprous cyanide under the catalysis of CuI to be converted into cyano to obtain a compound of a structural formula 12, the compound of the structural formula 12 is selectively subjected to cyano-thiocarboxamide reaction under the action of thioacetamide to obtain a compound of a structural formula 13, the compound is subjected to ring closure with 2-chloroacetoacetic acid ethyl ester to obtain an intermediate of a structural formula 6, and finally, febuxostat is obtained through hydrolysis and acidification.

The route uses the highly toxic cuprous cyanide. In addition, the compound of formula 12 has two cyano groups, and the cyano group at the 4' position can also be converted to produce a by-product during selective thiomethylation, which has a structure similar to that of the product, thereby causing difficulty in separation and purification.

Chinese patent application publication No. CN102229581A (published 2011/11/2/h) discloses that 3-methyl-4-hydroxybenzaldehyde of structural formula 14 is used as an initiator to obtain febuxostat key intermediate through cyanation, ether formation, carbonylation, thioamidation and cyclization: ethyl 2- (3-formyl-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate (compound of structural formula 19). The reaction route is as follows:

in the above preparation method, the compound of formula 16 is subjected to N-bromosuccinimide (NBS) and dibenzoyl peroxide ((PhCO) in carbon tetrachloride₂)₂) Catalytic reaction, namely, firstly generating dibromide from methyl on a benzene ring, and then hydrolyzing and converting the dibromide into aldehyde group; in the meantime, monobromide is generated, and the hydrolysis generates byproducts which have similar structures to the compound of the structural formula 17 and are difficult to separate and purify. The monobromide formation and hydrolysis reaction is as follows:

in addition, before the thiazole ring is constructed, unstable aldehyde group is introduced, so that the aldehyde group is easily oxidized and discolored under the subsequent high-temperature reflux condition, and the subsequent purification difficulty and cost are increased. And the solvent carbon tetrachloride used in the reaction has high toxicity.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a novel preparation method of a febuxostat key intermediate. The preparation method has the advantages that the raw materials are cheap and easy to obtain, and dangerous operations such as noble metal catalytic hydrogenation, diazotization, hypertoxic drugs and the like are avoided; and the reaction selectivity is high, the side reaction is less, and the post-treatment is simple. The method is applied to the preparation of febuxostat, and the final product (febuxostat) has high purity and high yield.

In order to achieve the purpose, the invention adopts the following technical scheme:

a process for the preparation of a compound of formula II,

wherein R ═ C₁～C₄Alkyl groups of (a);

the preparation method comprises the following steps:

1) reacting parahydroxybenzonitrile with a structural formula VII under the action of an alkylating agent and alkali to obtain a compound with a structural formula VI;

2) converting the cyano group of the compound of formula VI to a thiocarboxamide to give the compound of formula V;

3) the compound with the structural formula V reacts with urotropine under an acidic condition without a solvent to obtain a compound with a structural formula IV;

4) reacting the compound shown in the structural formula IV with hydroxylamine hydrochloride in the presence of alkali, and dehydrating to obtain a compound shown in a structural formula III;

5) carrying out a ring closing reaction on the compound with the structural formula III and a 2-halogenated acetoacetate compound with the structural formula VIII to obtain a compound with a structural formula II;

wherein, X ═ Cl, Br, I, R ═ C₁～C₄Alkyl group of (1).

The synthetic route for the compounds of structural formula II above is:

preferably, R is methyl, ethyl or tert-butyl.

Preferably, in the step 1), the alkylating agent is 1-bromoisobutane or 1-iodoisobutane, and more preferably 1-bromoisobutane.

Preferably, in the step 1), the molar ratio of the alkylating agent to the p-hydroxybenzonitrile of the structural formula VII is: 1 to 5:1, preferably 1.2 to 2: 1.

Preferably, in the step 1), the base is an organic base or an inorganic base; the organic base is selected from one of 1, 8-diazabicycloundecen-7-ene (DBU), Lithium Diisopropylamide (LDA), morpholine, 4-Dimethylaminopyridine (DMAP), n-butyllithium (n-BuLi), potassium hexamethyldisilazide (KHMDS), sodium hexamethyldisilazide (NaHMDS) and lithium hexamethyldisilazide (LiHMDS); the inorganic base is selected from NaH, KOH, NaOH and Na₂CO₃、 K₂CO₃t-BuOK and t-BuONa.

More preferably, in the step 1), the base is an inorganic base, and most preferably, K is₂CO₃。

Preferably, in the step 1), the molar ratio of the alkali to the p-hydroxybenzonitrile is 1-10: 1, and more preferably 1.5-2.5: 1.

In the step 1), the solvent used is an organic solvent which does not affect the reaction, such as esters, and can be selected from ethyl acetate, methyl acetate, tert-butyl acetate, isopropyl acetate and the like; such as ethers, which may be selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, etc.; such as amides, and may be selected from N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMAC), and the like; dimethyl sulfoxide (DMSO), acetone, etc.; preferably, the solvent used in step 1) is N, N-Dimethylformamide (DMF).

Preferably, in the step 1), the reaction temperature is 50 ℃ to 120 ℃, and more preferably 60 ℃ to 100 ℃.

In the step 1), potassium iodide may or may not be added as a reaction catalyst.

Preferably, in step 2), the cyano group of the compound of formula VI is converted to a thiocarboxamide under conditions selected from any one of the following to give the compound of formula V:

A. reacting a compound of formula VI with thioacetamide under acidic conditions; the acid is selected from glacial acetic acid, polyphosphoric acid, HCl gas or HBr gas and the like, and HCl gas is preferred; the acid is gas, the using amount of the acid is the saturated amount of the solvent, and the solvent is selected from N, N-Dimethylformamide (DMF), DMSO, N-methylpyrrolidone (NMP) and the like, preferably DMF; the acid is liquid and is directly used as a solvent; or

B. Under alkaline conditions, reacting a compound of structural formula VI with ammonium sulfide; the base is selected from pyridine, triethylamine, 1, 8-diazabicycloundec-7-ene (DBU), Lithium Diisopropylamide (LDA), morpholine, 4-Dimethylaminopyridine (DMAP) or N, N-Diisopropylethylamine (DIEA), more preferably triethylamine; the molar ratio of the alkali to the compound of the structural formula VI is 1.5-10: 1, and more preferably 2-3: 1; or

C. Reacting a compound of formula VI with sodium hydrosulfide in the presence of a Lewis acid; the Lewis acid is selected from magnesium chloride, zinc bromide, aluminum trichloride, titanium tetrachloride or zinc chloride, and is preferably zinc chloride; the molar ratio of the Lewis acid to the compound of the structural formula VI is 0.5-5: 1, preferably 0.5-2: 1; or

D. A compound of formula VI and O, O-di (1-methylethyl) dithiophosphate or P₄S₁₀And (4) reacting.

Preferably, in the step 2), the thioacetamide, sodium hydrosulfide, ammonium sulfide, dithiophosphoric acid-O, O-di (1-methylethyl) ester or P₄S₁₀And the compound of the structural formula VI is in a molar ratio of 1-10: 1, more preferably 1.5-2.5: 1.

More preferably, in said step 2), the compound of formula VI is reacted under said condition a to obtain the compound of formula V.

Preferably, in the step 2), the reaction temperature is 0 ℃ to 120 ℃, and more preferably 20 ℃ to 80 ℃.

Preferably, in the step 3), the molar ratio of the urotropin to the compound of the structural formula V is 1-10: 1, and 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 polyphosphoric acid, and is more preferably methanesulfonic acid; the volume ratio of the acid to the compound of the structural formula V is 1-20: 1, preferably 5-8: 1.

As an alternative, in step 3), the compound of formula V is reacted with 1, 1-dichloroethyl ether, DMF/pyrophosphoryl chloride and acetone cyanohydrin in the presence of a lewis acid to give the compound of formula IV; wherein the Lewis acid is selected from zinc chloride, zinc bromide, titanium tetrachloride, magnesium chloride or aluminum trichloride, and is preferably aluminum trichloride; the molar ratio of the Lewis acid to the compound of the structural formula V is 1-10: 1, preferably 2-3: 1.

Preferably, in the step 3), the reaction temperature is 0 ℃ to 120 ℃, and more preferably 0 ℃ to 80 ℃.

Preferably, in the step 4), the molar ratio of the hydroxylamine hydrochloride to the compound of the structural formula IV is 1-10: 1, and more preferably 1.2-2.5: 1.

Preferably, in the step 4), the base is selected from sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, and more preferably sodium acetate; the molar ratio of the base to the compound of the structural formula IV is 1-10: 1, and more preferably 1.5-3: 1.

As an alternative scheme, in the step 4), the compound with the structural formula IV reacts with O-arylamine formyl hydroxylamine p-toluenesulfonate, and the compound with the structural formula III is obtained after dehydration; wherein the O-arylamine formyl hydroxylamine p-toluenesulfonate is selected from O-carboxanilido hydroxylamine p-toluenesulfonate, O-2-methoxybenzoyl hydroxylamine p-toluenesulfonate, O-3-methoxybenzoyl hydroxylamine p-toluenesulfonate, O-4-methoxybenzoyl hydroxylamine p-toluenesulfonate or O-2-nitrobenzoyl hydroxylamine p-toluenesulfonate; the molar ratio of the O-arylamino formyl hydroxylamine p-toluenesulfonate to the compound with the structural formula IV is 1-3: 1, and more preferably 1-1.5: 1.

Preferably, in the step 4), the dehydration reaction is performed in formic acid or acetic anhydride.

Preferably, in the step 4), the reaction temperature is 40 ℃ to 120 ℃, and more preferably 60 ℃ to 80 ℃.

Preferably, in the step 5), the molar ratio of the 2-haloacetoacetic ester compound of the structural formula VIII to the compound of the structural formula III is 1-10: 1, and more preferably 1.2-3: 1.

Preferably, in the step 5), X ═ Cl or Br.

Preferably, in the step 5), the reaction temperature is-20 ℃ to 120 ℃, and more preferably-10 ℃ to 100 ℃.

The invention also aims to provide the application of the preparation method of the compound with the structural formula II in the synthesis of febuxostat; specifically, the compound with the structural formula II is prepared by the preparation method, and febuxostat is obtained by hydrolysis.

Preferably, when R is methyl or ethyl, the compound of formula II is hydrolyzed in corresponding methanol or mixed solvent of ethanol and water under the action of sodium hydroxide, and then the obtained product is acidified to obtain a crude febuxostat product; when R is tert-butyl, the compound with the structural formula II is hydrolyzed in dichloromethane by trifluoroacetic acid to obtain the crude febuxostat.

Recrystallizing the febuxostat crude product to obtain refined febuxostat; the purity of the refined febuxostat is more than 99.5%, and the single impurity is less than 0.1%.

According to the method provided by the invention, the p-hydroxybenzonitrile serving as the starting material is cheap and easy to obtain, and the febuxostat key intermediate with the structural formula II can be prepared only by 5 steps of reaction. The method of the invention firstly performs oxygen alkylation on the starting raw material, can avoid the increase of oxygen alkylation difficulty caused by intramolecular hydrogen bonds of naked hydroxyl and subsequently introduced adjacent aldehyde groups, reduces the dosage of alkylating agent and lowers the production cost. In addition, the preparation method can also avoid the problem that the two cyano groups are generated simultaneously to increase the difficulty of subsequent selective reaction in the patent application with the publication number of CN102120733A, thereby reducing the generation of byproducts with similar structures, being beneficial to preparing the high-purity febuxostat key intermediate II and finally preparing the high-purity febuxostat.

In the step 2), cyano of the compound of formula VI is converted into thiocarboxamide (to obtain the compound of formula V), and then aldehyde group is introduced (to obtain the compound of formula IV), so that an unstable aldehyde group is introduced prematurely on a benzene ring in the patent application of patent publication No. CN102229581A, adverse factors that the aldehyde group cannot tolerate under subsequent high-temperature conditions are avoided, and the subsequent purification difficulty is reduced. With respect to the prior art of publication No. CN102229581A, if the prematurely introduced aldehyde group is to be protected and converted to a cyano group, the presence of two cyano groups in the molecular structure is detrimental to the subsequent selective conversion of the cyano group to the thiocarboxamide.

In addition, in the step 3) of directly introducing the aldehyde group on the benzene ring of the structural formula V by using acid as a solvent, not only is an additional solvent (such as carbon tetrachloride which is a solvent of CN 102229581A) not required to be added, but also the defect that monobromide byproduct is brought when methyl is converted into the aldehyde group in the prior art with the publication number of CN102229581A is overcome, so that the purity of the final product febuxostat can be better ensured.

In a word, the method disclosed by the invention is simple to operate, high in yield, less in side reaction, free of using highly toxic substances, environment-friendly, and suitable for industrial production as a novel febuxostat intermediate preparation method.

Drawings

The invention will be further explained with reference to the drawings.

FIG. 1 shows an HPLC chromatogram of the compound of formula II (febuxostat ethyl ester) prepared in example 14, wherein a chromatographic peak with a retention time of 18.5min is an absorption peak of the compound.

FIG. 2 shows an HPLC chromatogram of the compound of formula II (febuxostat methyl ester) prepared in example 15, wherein the chromatographic peak with retention time of 20min is the absorption peak of the compound.

FIG. 3 shows an HPLC chromatogram of febuxostat prepared in example 17, wherein a chromatographic peak with a retention time of 7.5min is an absorption peak of the compound.

FIG. 4 shows an HPLC chromatogram of febuxostat prepared in example 18, wherein a chromatographic peak with a retention time of 7.5min is an absorption peak of the compound.

Detailed Description

The invention provides a preparation method of a compound of a structural formula II, which comprises the following reaction route:

wherein R ═ C₁～C₄The alkyl group of (1) is preferably a methyl group, an ethyl group or a tert-butyl group.

The preparation method is preferably realized by the following reaction steps:

1) p-hydroxybenzonitrile with a structural formula VII reacts at 60-100 ℃ under the action of an alkylating agent (1-bromoisobutane or 1-iodoisobutane) and alkali to obtain a compound with a structural formula VI; the molar ratio of the alkylating agent to the p-hydroxybenzonitrile is 1.2-2: 1; the above-mentionedThe alkylating agent is preferably 1-bromoisobutane; the molar ratio of the alkali to the p-hydroxybenzonitrile is 1.5-2.5: 1, the alkali is inorganic alkali, and preferably K₂CO₃(ii) a The reaction solvent is N, N-Dimethylformamide (DMF);

2) under the acidic condition, the compound with the structural formula VI and thioacetamide react in N, N-Dimethylformamide (DMF) dissolved with saturated HCl gas at the temperature of 20-80 ℃ to obtain a compound with a structural formula V; the molar ratio of thioacetamide to the compound of the structural formula VI is 1.5-2.5: 1;

3) reacting the compound with the structural formula V and urotropine at 0-80 ℃ in the presence of methanesulfonic acid without a solvent to obtain a compound with a structural formula IV; the volume ratio of the methanesulfonic acid to the compound of the structural formula V is 5-8: 1;

or,

the compound with the structural formula V reacts with 1, 1-dichloroethyl ether, DMF/pyrophosphoryl chloride and acetone cyanohydrin together without solvent under the condition of the existence of aluminum trichloride at 0-80 ℃ to obtain the compound with the structural formula IV; the molar ratio of the aluminum trichloride to the compound of the structural formula V is 2-3: 1;

4) reacting the compound with the structural formula IV with hydroxylamine hydrochloride in the presence of sodium acetate at the temperature of between 60 and 80 ℃; dehydrating the product in formic acid or acetic anhydride to obtain a compound with a structural formula III; the molar ratio of the sodium acetate to the compound with the structural formula IV is 1.5-3: 1; or,

reacting the compound with the structural formula IV and O-arylamine formyl hydroxylamine p-toluenesulfonate at 60-80 ℃ to obtain a compound with a structural formula III; the molar ratio of the O-arylamino formyl hydroxylamine p-toluenesulfonate to the compound with the structural formula IV is 1-1.5: 1;

5) carrying out a ring closing reaction on the compound with the structural formula III and a 2-halogenated acetoacetate compound with the structural formula VIII to obtain a compound with a structural formula II; the molar ratio of the 2-halogenated acetoacetic ester compound with the structural formula VIII to the compound with the structural formula III is 1.2-3: 1; the 2-halogenated acetoacetate ester compound is selected from one of 2-chloroacetoacetic acid methyl ester, 2-chloroacetoacetic acid ethyl ester, 2-chloroacetoacetic acid tert-butyl ester, 2-bromoacetoacetate methyl ester, 2-bromoacetoacetate ethyl ester and 2-bromoacetoacetate tert-butyl ester.

The compound with the structural formula II is prepared by the preparation method, and a febuxostat crude product is obtained by hydrolysis; and recrystallizing the febuxostat crude product to obtain the refined febuxostat.

The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.

In the following examples, room temperature means 20 ℃ to 35 ℃ unless otherwise specified. "purity" is the purity of a compound as determined by liquid chromatography peak area normalization.

Example 1Preparation of Compounds of formula VI

P-hydroxybenzonitrile 12g (1eq), K₂CO₃A reaction system of 21g (1.5eq), 18g (1.3eq) of 1-bromoisobutane, 1.7g (0.1 eq) of KI and 120ml of DMF was heated to 60 ℃ to react for 10 hours, 100ml of each of water and ethyl acetate was added, liquid separation was performed, the aqueous phase was continuously extracted with ethyl acetate, the organic phases were combined, dried, and spin-dried under reduced pressure to obtain 17.7g of the title compound with a yield of about 100% and a purity of 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).

Example 2Preparation of Compounds of formula VI

The reaction system of 12g (1eq) of p-hydroxybenzonitrile, 22g (2.5eq) of morpholine, 25g (1.8eq) of 1-bromoisobutane, 1.7g (0.1 eq) of KI and 200ml of ethyl acetate is heated to 60 ℃ for reaction for 12 hours, 100ml of each of water and ethyl acetate are added for liquid separation, the aqueous phase is continuously extracted by ethyl acetate, the organic phases are combined, dried and dried under reduced pressure to obtain 16g of the title compound, the yield is about 90 percent, and the purity is 93 percent.

¹H-NMR(CDCI₃)δ：1.04(d，6H)，2.32(m，1H)，3.97(d，2H)，6.99(d， 2H)，7.50(d，2H).

Example 3Preparation of Compounds of formula VI

The reaction system of 12g (1eq) of p-hydroxybenzonitrile, 36g (1.8eq) of hexamethyldisilazane, 25g (1.8eq) of 1-bromoisobutane, and 200ml of DMF was heated to 80 ℃ to react for 15 hours, 100ml of each of water and ethyl acetate were added to separate the liquids, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried, and dried under reduced pressure to obtain 15.6g of the title compound with a yield of about 88% and a purity of 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).

Example 4Preparation of Compounds of formula V

17.7g (1eq) of the compound of formula VI prepared in example 1 and 12g (1.6eq) of thioacetamide were dissolved in 200ml of DMF saturated with hydrogen chloride gas and heated to 80 ℃ for 4 hours. After the reaction was completed, 5% sodium hydroxide solution was added to adjust the pH to 8-9, and the resulting solid was collected by filtration, recrystallized from ethanol and dried to obtain 18g of the title compound. The yield is about 85 percent, and the purity is 99 percent.

¹H-NMR(CDCI₃)δ：1.08(d，6H)，2.36(m，1H)，3.97(d，2H)，6.82(d， 2H)，7.17(d，2H).

Example 5Preparation of Compounds of formula V

17.7g (1eq) of the compound of formula VI prepared as described in example 2 was dissolved in 170mL pyridine followed by addition of 7.6g (1.1eq) triethylamine and 37.4g (1.1eq) 20% aqueous ammonium sulfide and heating to 50 ℃ for 6 hours. After completion, 5% sodium hydroxide solution was added to adjust the pH to 8-9, the resulting solid was collected by filtration, recrystallized from ethanol and dried to yield 17g of the title compound. The yield is about 80 percent, and the purity is 95 percent.

¹H-NMR(CDCI₃)δ：1.02(d，6H)，2.33(m，1H)，3.90(d，2H)，6.75(d， 2H)，7.13(d，2H).

Example 6Conversion of formula VPreparation of the Compounds

17.7g (1eq) of compound of formula VI prepared as described in example 3 were added to 100mL of DMF solution containing 11g (2eq) of sodium hydrosulfide and 20.3g (1.0eq) of magnesium chloride hexahydrate and reacted at room temperature for 1.5 hours. After the reaction was completed, 5% sodium hydroxide solution was added to adjust the pH to 8-9, and the resulting solid was collected by filtration, recrystallized from ethanol and dried to obtain 17g of the title compound. The yield is about 80%, and the purity is 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).

EXAMPLE 7 preparation of Compound of formula V

17.7g (1eq) of the compound of formula VI prepared as described in example 1, 21.5g (1eq) of the dithiophosphoric acid-O, O-bis (1-methylethyl) ester are dissolved in 100mL of DMSO and reacted at 40 ℃ for 10 hours. After the reaction was complete, 500mL of water were added, the mixture was extracted three times with 100mL of ethyl acetate, and the organic phase was washed with saturated NaHCO3 solution (200 mL). The organic phase was concentrated under reduced pressure, and the resulting solid was recrystallized from ethanol and dried to give 16.4g of the title compound. The yield is about 78%, and the purity is 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).

Example 8Preparation of Compounds of formula IV

Urotropin 31g (2.5eq) was slowly added to a solution of 18g (1eq) of compound of formula V prepared as described in example 4 in methanesulfonic acid 50g (6eq) and heated to 75 ℃ with stirring for 10 hours. After the reaction was completed, the reaction mixture was cooled to 30 ℃ and 200ml of water was added thereto, the temperature was lowered to 0 ℃ again and the mixture was stirred for 1 hour, and the precipitated solid was collected by filtration, washed with water and dried to obtain 16.3g of the titled compound. The yield is 80 percent, and the purity is 99.4 percent.

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).

Example 9Preparation of Compounds of formula IV

21g (1eq) of the compound of formula V prepared as described in example 5 was dissolved in anhydrous dichloromethane (210mL) and cooled to 0 ℃ under nitrogen. TiCl (titanium dioxide)₄41.8g (1eq) was slowly added dropwise. After stirring at 0 ℃ for 1 hour, 12.5g (1eq) of 1, 1-dichloroethyl ether was slowly added dropwise, and stirring was continued for 45 minutes. After adding 125mL of saturated aqueous ammonium chloride solution and stirring at room temperature for 2 hours, the mixture was separated, extracted 2 times with 100mL of water-saturated dichloromethane, the organic phases were combined, washed with 0.1N hydrochloric acid (100 mL. times.1) and 100 mL. times.1 of saturated saline solution, concentrated under reduced pressure and dried by spin-drying the organic phase, and then dried to obtain 14.3g of the titled compound. The yield is 60 percent, and the purity is 99 percent.

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).

Example 10Preparation of Compounds of formula IV

To a mixed solution of 21g (1eq) of the compound of formula V prepared as described in example 6 and 11g (1.5eq) of DMF at 0 ℃ was slowly added dropwise 37.5g (1.5eq) of pyrophosphate chloride, which was heated to 100 ℃ for 24 hours after completion of the addition. After the reaction, the reaction mixture was cooled to room temperature, slowly poured into 200mL of ice water, adjusted to pH 3-4 at 0 ℃ with 2N sodium hydroxide solution, and the precipitated solid was collected by filtration, washed with water, and dried to obtain 13g of the titled compound. The yield is 54.8 percent, and the purity is 99 percent.

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).

Example 11Preparation of Compounds of formula IV

21g (1eq) of the compound of formula V prepared as described in example 7 and 8.5g (1eq) of acetone cyanohydrin were dissolved in 100mL of 1, 2-dichloroethane, the temperature was lowered to 0 ℃ and 26.7g (2eq) of aluminum trichloride was added slowly with stirring. After the addition, the temperature was raised to room temperature and refluxed for 24 hours. 10mL of water was added and stirring was continued for 2 hours. After washing with water, the organic phase was dried under reduced pressure, and the title compound (10.6 g) was dried in 45% yield and 98% purity.

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).

Example 12Preparation of Compounds of formula III

16g (1eq) of the compound IV prepared as described in example 8, 5.6g (1.2eq) of hydroxylamine hydrochloride and 10.6g (1.5eq) of sodium acetate were refluxed in formic acid for 5 hours, cooled to room temperature, and then water was added to the mixture to crystallize, and the precipitated solid was collected by filtration to obtain 14.2g of the title compound in 90% yield and 99.2% purity.

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).

Example 13Preparation of Compounds of formula III

10g (1eq) of the compound IV prepared as described in example 9 was dissolved in 100mL of ethanol, followed by addition of 13.7g (1eq) of O-anilinocarbonylhydroxylamine p-toluenesulfonate and stirring at room temperature for 2 hours. 100mL of water was slowly added, and the precipitated solid was collected by filtration to give 6.9g of the title compound in 70% yield and 99.0% purity.

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).

Example 14Preparation of compound of structural formula II (febuxostat ethyl ester)

Wherein R is ethyl.

14g (1eq) of the compound of formula III prepared as described in example 12 are dissolved in 200ml of ethanol, 28.7g (3eq) of ethyl 2-chloroacetoacetate are added and the mixture is stirred for 2 hours at 100 ℃. Cooling to-10 deg.C, precipitating a large amount of solid, filtering, and oven drying the filter cake to obtain the title compound 16.7g, white solid with yield of 85% and purity of 99.6%, and HPLC chromatogram 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).

Example 15Preparation of Compounds of formula II

Wherein R ═ methyl.

14g (1eq) of the compound of formula III prepared as described in example 13 are dissolved in 200ml of ethanol, 34.6g (3eq) of methyl 2-bromoacetoacetate are added, the temperature is raised to 100 ℃ and stirring is carried out for 2 hours. Cooling to-10 deg.C, precipitating a large amount of solid, filtering, and oven drying the filter cake to obtain the title compound 17.2g, white solid with yield 87% and purity 99.5%, and HPLC chromatogram 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).

Example 16Preparation of Compounds of formula II

Wherein R is tert-butyl.

14g (1eq) of the compound of formula III prepared as described in example 12 are dissolved in 200ml of ethanol, 27g (3eq) of tert-butyl 2-chloroacetoacetate are added and the mixture is stirred for 2 hours at 100 ℃. Cooling to-10 deg.C, precipitating a large amount of solid, filtering, and oven drying the filter cake to obtain title compound 18.9g, white solid with yield of 85% and purity of 99.3% (HPLC chromatogram is omitted).

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).

Example 17Preparation of febuxostat

17g (1eq) of the compound of formula II prepared as described in example 16 was dissolved in DCM (200mL), trifluoroacetic acid (200mL) was added and stirred at room temperature for 2 hours, after the reaction was finished, 200mL of water was added, the layers were separated and the aqueous layer was further extracted with dichloromethane. Mixing the extractive phases, adding activated carbon, filtering, and washing the filter cake with dichloromethane. The combined filtrates were concentrated under reduced pressure, and after concentration, the combined filtrates were dissolved in a mixed solvent of DCM and MeOH (vol/vol) 1:2.5, cooled to 0 ℃, and then crystallized under heat for 1 hour. The resulting solid was collected by filtration and washed with a pre-cooled mixture of DCM: MeOH ═ 1:2.5 (volume ratio). Decompression drying to obtain 8.8g febuxostat. Yield 90%, purity 99.7%, HPLC profile is 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).

Example 18Preparation of febuxostat

17g (1eq) of compound prepared according to the procedure described in example 15, dissolved in MeOH H₂Adding 170ml of 1mol/L aqueous solution of sodium hydroxide into 200ml of mixed solvent with O being 3:1 (volume ratio), heating to 60 ℃ for reaction for 1.5-2 hours, cooling to 45 ℃ after the reaction is finished, adding ethyl acetate and water, controlling the temperature to be within 35 ℃, adjusting the pH of the system to 0.5-0.8 by using 6N HCl, separating liquid, and continuously extracting the water phase by using ethyl acetate. Mixing the extractive phases, adding active carbon, filtering, and washing the filter cake with ethyl acetate. The combined filtrates were concentrated under reduced pressure, and after concentration, the combined filtrates were dissolved in a mixed solvent of DCM and MeOH (vol/vol) 1:2.5, cooled to 0 ℃, and then crystallized under heat for 1 hour. The resulting solid was collected by filtration and washed with a pre-cooled mixture of DCM: MeOH ═ 1:2.5 (volume ratio). Decompression drying to obtain 13.7g of febuxostat. The yield is 88%, the purity is 99.8%, and the HPLC chart is shown in figure 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

1. A process for the preparation of a compound of formula II,

wherein R ═ C₁～C₄Alkyl groups of (a);

the preparation method comprises the following steps:

3) the compound with the structural formula V reacts with urotropine under an acidic condition without a solvent to obtain a compound with a structural formula IV; the acid is methanesulfonic acid;

4) reacting the compound shown in the structural formula IV with hydroxylamine hydrochloride in the presence of alkali, and dehydrating to obtain a compound shown in a structural formula III; or

Reacting the compound with the structural formula IV and O-arylamine formyl hydroxylamine p-toluenesulfonate to obtain a compound with a structural formula III; wherein the O-arylamine formyl hydroxylamine p-toluenesulfonate is selected from O-carboxanilido hydroxylamine p-toluenesulfonate, O-2-methoxybenzoyl hydroxylamine p-toluenesulfonate, O-3-methoxybenzoyl hydroxylamine p-toluenesulfonate, O-4-methoxybenzoyl hydroxylamine p-toluenesulfonate or O-2-nitrobenzoyl hydroxylamine p-toluenesulfonate;

wherein, X ═ Cl, Br, I, R ═ C₁～C₄Alkyl group of (1).

2. The process according to claim 1, wherein R is methyl, ethyl or tert-butyl.

3. The method according to claim 1, wherein in the step 1), the alkylating agent is 1-bromoisobutane or 1-iodoisobutane.

4. The method according to claim 3, wherein the alkylating agent in the step 1) is 1-bromoisobutane.

5. The process according to claim 1,3 or 4, wherein in step 1), the molar ratio between the alkylating agent and the p-hydroxyphenylnitrile of formula VII is: 1-5: 1.

6. The method of claim 5, wherein the molar ratio of the alkylating agent to the p-hydroxyphenylnitrile of formula VII is 1.2-2: 1.

7. The production method according to claim 1, wherein in the step 1), the base is an organic base or an inorganic base; the organic base is selected from 1, 8-diazabicycloundecen-7-ene, lithium diisopropylamide, morpholine, 4-dimethylaminopyridineOne of pyridine, n-butyllithium, hexamethyldisilazane-based amino potassium, hexamethyldisilazane-based amino sodium and hexamethyldisilazane-based lithium; the inorganic base is selected from NaH, KOH, NaOH and Na₂CO₃、K₂CO₃t-BuOK and t-BuONa.

8. The method according to claim 7, wherein the base in the step 1) is an inorganic base.

9. The method according to claim 8, wherein the base is K₂CO₃。

10. The method according to claim 1, 7, 8 or 9, wherein the molar ratio of the base to the p-hydroxybenzonitrile in the step 1) is 1-10: 1.

11. The method according to claim 10, wherein the molar ratio of the base to the p-hydroxybenzonitrile in the step 1) is 1.5-2.5: 1.

12. The method according to claim 1, wherein the solvent used in step 1) is N, N-dimethylformamide.

13. The method according to claim 1, wherein the reaction temperature in the step 1) is 50 to 120 ℃.

14. The method according to claim 13, wherein the reaction temperature in the step 1) is 60 to 100 ℃.

15. The method of claim 1, wherein in step 2), the cyano group of the compound of formula VI is converted to the thiocarboxamide under any condition selected from the group consisting of:

A. reacting a compound of formula VI with thioacetamide under acidic conditions; the acid is selected from glacial acetic acid, polyphosphoric acid, HCl gas or HBr gas; when the acid is gas, the using amount of the acid is the saturated amount of the solvent, and the solvent is selected from N, N-dimethylformamide, DMSO and N-methylpyrrolidone; when the acid is liquid, the acid is directly used as a solvent; or

B, reacting the compound with the structural formula VI with ammonium sulfide under the alkaline condition; the base is selected from pyridine, triethylamine, 1, 8-diazabicycloundec-7-ene, lithium diisopropylamide, morpholine, 4-dimethylaminopyridine or N, N-diisopropylethylamine; the molar ratio of the alkali to the compound of the structural formula VI is 1.5-10: 1; or

C. Reacting a compound of formula VI with sodium hydrosulfide in the presence of a Lewis acid; the Lewis acid is selected from magnesium chloride, zinc bromide, aluminum trichloride, titanium tetrachloride or zinc chloride; the molar ratio of the Lewis acid to the compound of the structural formula VI is 0.5-5: 1; or

16. The method according to claim 15, wherein the acid in the step 2) is HCl gas under the condition a.

17. The method according to claim 15, wherein the solvent in the step 2) is N, N-dimethylformamide under the condition a.

18. The method according to claim 15, wherein the base in the step 2) is triethylamine under the condition B.

19. The method of claim 15 or 18, wherein the molar ratio of the base to the compound of formula VI under the condition B in the step 2) is 2-3: 1.

20. The method according to claim 15, wherein the lewis acid in the step 2) is zinc chloride under the condition C.

21. The method of claim 15 or 20, wherein the molar ratio of the lewis acid to the compound of formula VI under the condition C in the step 2) is 0.5-2: 1.

22. The method according to claim 15, wherein in the step 2), the thioacetamide, sodium hydrosulfide, ammonium sulfide, dithiophosphoric acid-O, O-bis (1-methylethyl) ester or P₄S₁₀And the molar ratio of the compound of the structural formula VI is 1-10: 1.

23. The method according to claim 22, wherein in the step 2), the thioacetamide, sodium hydrosulfide, ammonium sulfide, dithiophosphoric acid-O, O-bis (1-methylethyl) ester or P₄S₁₀And the molar ratio of the compound of the structural formula VI is 1.5-2.5: 1.

24. The production method according to claim 1 or 15, wherein the reaction temperature in the step 2) is 0 ℃ to 120 ℃.

25. The method according to claim 24, wherein the reaction temperature in the step 2) is 20 to 80 ℃.

26. The preparation method according to claim 1, wherein in the step 3), the molar ratio of the urotropin to the compound of the structural formula V is 1-10: 1.

27. The preparation method of claim 26, wherein in the step 3), the molar ratio of the urotropin to the compound of formula V is 3-5: 1.

28. The preparation method of claim 1, wherein in the step 3), the volume ratio of the acid to the compound of the structural formula V is 1-20: 1.

29. The method as claimed in claim 28, wherein the volume ratio of the acid to the compound of formula V in step 3) is 5-8: 1.

30. The method according to claim 1, wherein the reaction temperature in the step 3) is 0 ℃ to 120 ℃.

31. The method according to claim 30, wherein the reaction temperature in the step 3) is 0 to 80 ℃.

32. The preparation method according to claim 1, wherein in the step 4), the molar ratio of the hydroxylamine hydrochloride to the compound of formula IV is 1-10: 1.

33. The preparation method according to claim 32, wherein in the step 4), the molar ratio of the hydroxylamine hydrochloride to the compound of formula IV is 1.2 to 2.5: 1.

34. The method according to claim 1, wherein in the step 4), the base is selected from sodium acetate, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

35. The method according to claim 34, wherein the base in step 4) is sodium acetate.

36. The method of claim 1, 34 or 35, wherein in step 4), the molar ratio of the base to the compound of formula IV is 1-10: 1.

37. The preparation method of claim 36, wherein in the step 4), the molar ratio of the base to the compound of formula IV is 1.5-3: 1.

38. The method according to claim 1, wherein the dehydration reaction is carried out in formic acid or acetic anhydride in the step 4).

39. The preparation method of claim 1, wherein in the step 4), the molar ratio of the O-arylcarbamoyl hydroxylamine p-toluenesulfonate to the compound of the structural formula IV is 1-3: 1.

40. The preparation method of claim 39, wherein in the step 4), the molar ratio of the O-arylcarbamoyl hydroxylamine p-toluenesulfonate to the compound of the structural formula IV is 1-1.5: 1.

41. The method according to claim 1 or 40, wherein the reaction temperature in the step 4) is 40 to 120 ℃.

42. The method according to claim 41, wherein the reaction temperature in the step 4) is 60 to 80 ℃.

43. The preparation method of claim 1, wherein in the step 5), the molar ratio of the 2-haloacetoacetic ester compound of the structural formula VIII to the compound of the structural formula III is 1-10: 1.

44. The preparation method of claim 43, wherein in the step 5), the molar ratio of the 2-haloacetoacetic ester compound of the formula VIII to the compound of the formula III is 1.2-3: 1.

45. The method according to claim 1, wherein in step 5), X ═ Cl or Br.

46. The method according to claim 1, wherein the reaction temperature in the step 5) is-20 ℃ to 120 ℃.

47. The method according to claim 46, wherein the reaction temperature in the step 5) is-10 ℃ to 100 ℃.

48. Use of the preparation process of any one of claims 1 to 47 for the synthesis of febuxostat; the application refers to the preparation method of any one of claims 1 to 47 to obtain the compound with the structural formula II, and the compound is hydrolyzed to obtain febuxostat

。

49. The use of claim 48, wherein when R is methyl or ethyl, the compound of formula II is hydrolyzed in a corresponding mixed solvent of methanol or ethanol and water under the action of sodium hydroxide, and acidified to obtain a crude febuxostat product.

50. The use according to claim 48, wherein when R is tert-butyl, the compound of formula II is hydrolyzed with trifluoroacetic acid in dichloromethane to obtain crude febuxostat.

51. The use of claim 49 or 50, wherein the crude febuxostat product is recrystallized to obtain refined febuxostat; the purity of the refined febuxostat is more than 99.5%, and the single impurity is less than 0.1%.