WO2015054960A1

WO2015054960A1 - Gout drug lesinurad preparation method, and lesinurad intermediate

Info

Publication number: WO2015054960A1
Application number: PCT/CN2013/090399
Authority: WO
Inventors: 王鹏; 李丕旭; 谷向永
Original assignee: 苏州鹏旭医药科技有限公司
Priority date: 2013-10-15
Filing date: 2013-12-25
Publication date: 2015-04-23
Also published as: CN103524440A; CN103524440B

Abstract

Provided are a novel Lesinurad intermediate, providing a synthetic process more economical, more efficient, safer, more environmentally friendly, and suitable for large-scale industrial production for the preparation of Lesinurad. Also provided is a method for preparing the known Lesinurad intermediate and Lesinurad via the provided novel Lesinurad intermediate. Using the novel Lesinurad intermediate of the present invention to synthesize Lesinurad has the following advantages of using cheap and easily available required raw materials, avoiding the use of heavy metals and solvents harmful to the environment, easily separating and purifying the intermediate and the product with a simple operation, avoiding the use of the thiophosgene having high toxicity and difficulty of operation, and enabling the total yield of the reaction to reach a level equal to or higher than the prior art.

Description

Gout treatment drug Lesmurad preparation method and Lesinurad intermediate

Technical field

The invention relates to a preparation method of a gout therapeutic drug Lesmurad and a key intermediate thereof.

Background technique

Gout is a crystal-associated joint disease caused by the deposition of sputum urate (MSU), which is directly related to hyperuricemia caused by a disorder of sputum metabolism and/or a decrease in uric acid excretion. More than 20 million patients worldwide have gout. Lesimirad (1«^^594) is an oral uric acid cistern that inhibits renal proximal uric acid transporter URAT. Exploratory studies in previous gout patients have shown that allopurinol (ALLO), combined with iesimirad treatment, is more effective in reducing serum uric acid (SUA) than ALLO alone. A study of more than 500 ^ healthy people and gout patients found that Lesirmrad reduced blood uric acid in a dose-dependent manner and that Febuxostat was well tolerated. It is also a xanthine oxidase inhibitor approved for high uric acid treatment of gout > Lesinurad combined with Febuxostat is well tolerated and can significantly reduce uric acid.

Originally, this compound was developed from Compound 5 (RDEA806) synthesized by Vaieaiit in 2006 and reported in the form of a patent (Patent: WO2006026356A2), and its synthetic route is as follows.

4 5

Soon after, Ardea Bio discovered Lesimirad, which has a better effect on treating gout. Now Lesinurad's patent rights [! Genus Astrazenecao

So far, there have been few reports on the synthesis of Lesinurad. The synthesis of Lesinurad (Compound 8), which is similar to RDEA806, is reported, for example, in the patents WO2009070740A2, US2010056464AK WO2011085009A2 and related patents.

Chinese patent CN102040546A starts from 4-cyclopropyl-1-naphthaldehyde and, after three steps, synthesizes an intermediate isothionitrite to avoid the use of sulfur phosgene.

10 1 1 Comprehensive analysis of the existing Lesinurad preparation method shows that the bromine on the Lesmurad structure is converted by amino groups (from compounds 6 to 7). This step is complicated in operation and expensive in raw materials, which is not conducive to cost reduction. In addition, the existing Lesinurad preparation method mostly uses sulphur phosgene, which is inconvenient to operate and has poor safety. Although the Chinese patent CN102040546A adopts a method of avoiding the use of sulphur phosgene, the method greatly prolongs the synthetic route of Lesimirad and makes the process More complicated and costly.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art, to provide a new type of Lesmumd intermediate, and to provide a more economical, more efficient, safer, more environmentally friendly, and suitable for large-scale industrial production of the preparation of Lesinurad. Process.

The present invention also provides a method of preparing a known Lesinurad intermediate and Lesmurad using the novel Lesmurad intermediate provided.

In order to solve the above technical problems, a technical solution adopted by the present invention is as follows:

A Lesinurad intermediate, the Lesinurad intermediate is a compound represented by Formula I,

In formula I:

R represents H or COCH _{3 ;} or R represents CH ₂ R ^f , wherein R ¹ represents an ester group; CN; CH ₂ OH; unsubstituted or selected from one of C _r , . C ₆ alkyl, or a plurality of substituted phenyl groups;

R ² represents a cyclopropyl group; halogen; OTf.

According to a specific aspect, in the formula I, R represents H, and R ² represents a cyclopropane group, and the structural formula is as shown in Formula 13 -

The present invention also provides a Lesmurad intermediate which is a compound represented by the general formula II.

In formula II, R ² represents a cyclopropyl group; halogen; OTf.

According to a specific aspect: In the formula II, R ² represents a cyclopropenyl group, and the structural formula of the Lesinurad intermediate is as shown in the formula 12:

12 Another technical solution of the present invention is: a method for preparing a Lesinurad intermediate represented by the formula ίίΐ,

It includes the step of reacting a compound of formula to form a compound of formula ra.

The same as Formula I ₅ I and III R, the same as R ^2, wherein;

: R_ represents H or COCH _{3 ;} or R represents CHsR ¹ , wherein: R ¹ represents an ester group; CN: C3⁄4OH; unsubstituted or substituted by one or more selected from the group consisting of C^C ₆ fluorenyl, halogen Phenyl-R ² represents cyclopropenyl; halogen; OTf.

Preferably, compounds of formula I and III wherein: R is COCH ₃ or C¾R ϋ R ^¾ represents an ester group; CN; CH ₂ OH; is selected from unsubstituted or C _r, ₆ alkyl, one or more one halogen Substituted phenyl; R ² represents a cyclopropane group.

According to the present invention, the bromine source used in the bromination reaction may be liquid bromine, bromine water, N-bromosuccinimide or dibromohydantoin. According to a specific aspect: the bromination reaction can be carried out as follows: A bromination reaction occurs in the presence of an acid-binding agent with a compound of the formula I and a source of bromine in a solvent.

4-(4-cyclopropylnaphthalene 3-thioacetate-1,2,4-azole, structural formula: 5

15 .

In addition, the preparation method of the Lewissrad intermediate represented by the formula III preferably further comprises the compound 13 RX in a solvent, a step-substituted compound of formula I reaction occurs in the presence of an acid-binding agent, wherein R is as defined above, in particular, R may be COC¾ or CHbR ^1, i Rj represents an ester group; CN; C¾OH; not a phenyl group substituted or substituted with one or more selected from the group consisting of CC ₆ fluorenyl, halogen; R ² represents a cyclopropyl group; X represents a leaving group,

Preferably, X is chlorine, bromine, iodine or OTf.

Further, the method for preparing a Lesinurad intermediate represented by the formula HI preferably further comprises the step of reacting the compound 12 with a dimercapyl acetal in a solvent to form the compound 13,

The hydrazine, hydrazine-dimethylformamide dialkyl acetal may be N-dimethylformamide dimethyl acetal or hydrazine, hydrazine-dimethylformamide diethyl acetal.

Further, the method for preparing the Lesimirad intermediate represented by the formula III further preferably comprises first reacting 4-cyclopropyl-1 naphthylamine, carbon disulfide with a base to form N-(4-cyclopropyl 1-naphthalene in a solvent. a salt of dithiocarbamic acid, followed by a step of reacting a salt of N-(4-cyclopropylphthalaphthalene)dithiocarbamic acid with hydrazine hydrate to form compound 12. Wherein, the base may be, for example, sodium hydroxide or potassium hydroxide or the like or a combination thereof.

A further technical solution adopted by the present invention is: a method for preparing Lesmnrad, which comprises the steps of Lesi Lesinurad represented by the formula: Π:

m

In formula III: R represents H or COCH _{3 ;} or R represents CH ₂ R wherein R ^3⁄4 represents an ester group; CN; CH ₂ OH _; unsubstituted or substituted by one or more selected from the group consisting of Ci~C ₆ alkyl, halogen Phenyl group;

R ² represents a cyclopropane group; halogen; OTft

In particular: the method further comprises the step _{t of} preparing the Lesmurad intermediate represented by Formula III by the above-described method of the present invention _!

Due to the implementation of the above technical solutions, the present invention has the following advantages over the prior art:

The present invention provides a novel Lesimirad intermediate which provides a new synthetic route for the preparation of Lesinurad.

The novel Lesimirad intermediate provided by the present invention is used to synthesize Lesmurad, which has the advantage of T -

(1) The required raw materials are inexpensive and readily available;

(2) It is possible not to use heavy metals and solvents harmful to the environment;

(3), intermediates and products are easy to separate and purify, and the operation is simple;

(4) It can avoid the use of sulfur phosgene which is very toxic and difficult to operate;

(5) The total reaction yield can reach a level comparable to or higher than the prior art.

detailed description

This invention relates to novel Lesiixurad intermediates and methods for preparing Lesimirad using these Lesiixurad intermediates. In a specific embodiment of the invention; the preparation method of Lesmimid can be expressed by the reaction equation as follows:

12 13

N V

In the above formula, R may be any alkyl group, such as methyl or ethyl.

!1 is preferably COCH ₃ or Ci-Wl ¹ , wherein: 1 ⁵ represents an ester group; CN; CH ₂ OH _; is substituted or selected from one or more of: ₆ alkyl, halogen Substituted phenyl (preferably phenyl). As a more preferred embodiment of the invention, R is CH2R ¹ ' wherein R ¹ is an ester group. Most preferably, R is C3⁄4R, wherein R ¹ is an ethyl ester group. The present invention will be further described below in conjunction with specific embodiments, but

Example 1 Preparation of Compound 12 from Compound 1

In a single-mouth bottle, add 4-cyclopropyl-1-naphthylamine (Compound 1, LOeq), add DMF (8,2 Vbl) to dissolve it, add NaOH (:L2eq) and CS ₂ (i.2 eq), room temperature Under the stirring reaction ih, adding hydrated cake (3.0 eq), transferred to a 70 ° C oil bath and stirred under reflux for 4 h, LC confirmed the reaction was completed, stop heating and stirring, after cooling, add 10 mL of water per lg of raw materials, suction filtration, filter cake 95% ethanol was recrystallized, suction filtered, and the solid was dried to give compound 12 in a yield of 50% to 70%.

The nuclear magnetic data of the product are as follows: ⁱ H NMR (400 MHz, DM SO) δ 9.16 (s, IH), 8.43 (d, J- 7.8 Hz, IH), 7.98 ― 7.89 (m, IH), 7.66-7.48 (m, 3H), 7.26 (d, J- 7.6 Hz, IH), 5,54― 4.50 (m, IH), 2.46-2,34 (m, IH), 1.12 - 1.02 (m, 2H), 0.80 - 0.69 ( m, 2H).

Example 2 From Compound 12 Compound 13

Compound 12 (U) eq) was added to a vial, 1,4-dioxane (7,5 Vol) was added to dissolve it, and hydrazine, hydrazine-dimethylformamide dimethyl acetal (1.0 eq) was added. After stirring at 100'Ό, the mixture was stirred for 1.5-2 h. After confirming the completion of LC, the reaction mixture was cooled to room temperature, then water was added to the g material, iOmL water was added, and the solid was separated by suction filtration. The filter cake was washed twice with ethanol, and the solid was dried. Compound 13 [Lesinurad Intermediate, Chemical Name: 4-(4-Cyclopropylnaphthalene)-3-indolyl-1,2,4-triazole). The yield is 70% - 80%.

The nuclear magnetic data of the product are as follows: 1H NMR (400 MHz, DMSO) δ 8.69 (s, IH), 8,57 (d, J --- --- 8.4 Hz, I H), 7.72

(t, J- 7.3 Hz, IH), 7.64 (t, J - 7,4 Hz, IH), 7.54 (d, J- 7,6 Hz,]H), 7.44― 7.37 (m, 2H), 2 , 56.2.50 (m, IH), 1.19-1 .09 fm, 2H), 0.90 . 0.75 (m, 2H).

Example 3 Preparation of Compound IS from Compound 13

13 15 The product nuclear magnetic data is as follows: Compound 13 (4 g, leq) was added to a single-necked flask, dissolved in solvent DMF (67 mL, 16.8 voi), stirred at room temperature, and added to K ₂ C0 ₃ (2.272 g, l.leq). Compound 14 (1.74 mL, 1.05 eq) was added dropwise, and the dropping rate was controlled at 0.5 mL/min. After 2 hours at room temperature, the reaction was completed. The reaction solution was diluted with EA (ethyl acetate) and water, and extracted with EA three times. The saline solution was washed three times, and the anhydrous MgS0 _{4 was} dried. The organic phase is dried to give a white solid [ie compound 15, Lesirmrad intermediate, chemical name: 4-(4-cyclopropylnaphthalene)-3-thioethylacetate-1,2,4-:triazo] After drying, 5.13 g was obtained, and the yield was 97%.

The nuclear magnetic data of the product are as follows: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.54 (d, J --- --- 8.4 Hz, 1 H), 8.30 (s, 1 H),

7.70-7.62 (m, IH), 7.61-7.53 (m, IH), 7.36 (m, 3H), 4.22-4.15 (m, 2H), 4.14-4.05 (m, 2H), 2.47 - 2.36 (m, IH ), 1.25 (t, J = 7.1 Hz, 3H), 1.19-1.14 (m, 2H), 0.93-0.78 (m, 2.H).

Example 4 Preparation of Compound 16 from 15

15 16

Example 4-1 Preparation of a compound by bromination using liquid bromine as a bromine source] 6

Add solvent acetonitrile (5 mL), Pft3⁄4 (0.24 mL) to a single-necked flask containing compound 15. After the dissolution is complete, slowly add liquid bromine in acetonitrile (3 eq Br ₂ in 1 mL acetonitrile) and add dropwise. The reaction was completed at room temperature for 2 h. 30 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL).

The nuclear magnetic data of the product are as follows: MR (400 MHz, DMSO) δ 8.59 (d, J:: 8.4 Hz, IH), 7.77-7.70 (m, IH), 7.69 - 7.60 (m, 2H), 7.44 (d, J = 7.7 Hz, IH), 7.17 (d, J = 8.3 Hz, IH), 4.13 - 3.99 (m, 4H), 2.62 --- 2.52 (m, IH), 1.16 (t, J = 7.1 Hz, 3H, 0.87 (q, J = 5.4 Hz, 2H).

4-2 Preparation of compounds by bromination from N-bromosuccinimide as bromine source 16

Compound 15 was charged with 1 mmol, NBS was used in an amount of 6 mmol, and refluxed for 2 h in a 60 Ό oil bath. After completion of the reaction, the reaction mixture was extracted with EA, washed with saturated brine, dried over anhydrous EtOAc, and concentrated under reduced pressure. →:1 Elution was carried out by adding 1% TEA as an eluent to obtain 0.3496 g of a product, and the yield was 80.8%.

The nuclear magnetic data of the product is as follows: ^l H NMR (400 MHz, DMSO) δ 8.59 (d, J = 8.4 Hz, 1H), 7.77-7.70 (m,

IH), 7.69― 7.60 (m, 2H), 7,44 (d, J = 7,7 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 4,13― 3.99 (m,

4H), 2,62― 2.52 (m, I H), 1.16 (t, J - 7, 1 Hz, 3H, 0,87 (q, J - 5.4 Hz, 2H),

Example 4- 3 Preparation of a compound by bromination from dibromo海 as a source of bromine 16

Compound 15 was charged with 1 mmol, dibromohydantoin was used in an amount of 6 mmol, and refluxed in an oil bath at 60 ° C for 2 h. The liquid phase was found to have been depleted in the liquid phase. The reaction solution was extracted with EA, washed with saturated brine, and dried with anhydrous MgS0 ₄ After concentration under reduced pressure, the column was separated and purified, and eluted with PE:EA=3:1 plus 1% of '1 as the eluent to obtain 0.2328 g of the product, the yield was 53.9%.

The nuclear magnetic data of the product are as follows: 1H NMR (400 MHz, DMSO) δ 8,59 (d, J - 8, 4 Hz, IH), 7.77-7.70 (m, IH), 7.69 - 7.60 ( _m , 21-1;) , 7,44 (d, J :: 7.7 Hz, IH), 7.17 (d, J :: 8.3 Hz, IH), 4.13 - 3.99 (m, 4H), 2.62 - 2.52 (m, IH), 1.16 (t , j == 7, 1 Hz, 3H, 0.87 (q, J :: 5.4 Hz, 2H).

Example 4-4 Preparation of a compound by bromination using dichloromethane as a solvent

Add solvent dichloromethane (5 mL), pyridine (0.24 mL) to a single-mouth flask containing compound 15. After the dissolution is complete, slowly add liquid bromine in dichloromethane (3 eq Br ₂ dissolved in 1 mL two) Methyl chloride), after completion of the dropwise addition, the reaction was completed at room temperature for 2 h. 30 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate.

The reaction can be preferably carried out in a solvent such as THF, chloroform, carbon tetrachloride or 1,2-dichloroethane.

Example 5 Preparation of Compound 1⁄2 Les irad (Compound 8)

Add 95% ethanol (6.5 mL), THF (6.5 mL) to a jar containing compound 16 (ig), stir to 16 full solution, then cool the system to about -6 Torr, and add LiOH (1.5 eq). Aqueous solution (6,5 mL). After the addition was completed, the reaction was continued at 0 C until the reaction was completed.

After the reaction, the pH was adjusted to neutral with 0.5 hydrochloric acid, and the organic phase in the system was spun off, and the pH was adjusted to about 3 to 4 with a 0.5 N hydrochloric acid solution. The resulting suspension was extracted with CH ₂ Ci ₂ and the organic phase was stirred to give the desired product, that is, Lesinurad, yield 99%.

The product NMR data is as follows: ^! H NMR (400 MHz, DMSO) δ 12.98 (s, IH), 8.58 (d, J = 8.5 Hz, 1H), 7,74 (t, J - 7.3 Hz, IH), 7.69― 7,57 (ra, 2H), 7.44 (d, J - 7.6 Hz, IH), 7,17 (d, J 8.3 Hz, IH), 4.06-3.95 (m, 2H), 2.60-2.52 (m, 1H), 1.2.2 --- 1.10 (m, 2H), 0.87 (q, J = 5.3 Hz, 2H).

Example 6 Preparation of Lesimirad Intermediate (Compound 13)

Compound 12 (U) eq) was added to a vial, 1,4-dioxane (7,5 Vol) was added to dissolve it, and hydrazine, hydrazine-dimethylformamide diethyl acetal (1. After stirring at 1.5 °C for 1.5-2 h, the reaction was confirmed by LC. After the reaction mixture was cooled to room temperature, 10 g of water was added to the raw material, and the solid was filtered off with suction. The filter cake was washed twice with 95% ethanol and dried to give a compound. 13. The yield was 82%.

Example 7 Preparation of Lesimirad Intermediate (Compound 15)

13 17 15 Add compound 13 (lg, leq) to a single-mouth bottle, dissolve in solvent DMF (16.75m:L), stir #K ₂ C0 ₃ (569mg, l.leq) at room temperature, and add compound 17 dropwise. 0.42mL, l,05eq)), control the dropping rate after stirring at 0,5 room temperature for 2.5h, the reaction is complete, add EA (ethyl acetate) and dilute the reaction solution with water, EA 100mLx3 extraction saturated brine i00niLx3 wash, anhydrous The MgS04 was dried. The organic phase was obtained as a white solid (i.e., compound 15), i.33 g, yield >99%.

Example 8 Preparation of Les urad Intermediate (Compound 19)

The compound: B (lg, eq) was added to a single-necked flask, dissolved in a solvent DM:F (i6.75 mL), stirred at room temperature, 2C0 ₃ (569 mg, l.leq) was added, and then compound 18 (0.42 mL) was added dropwise. , l.OSeq), control the drip rate at 0,5m:L / mi stirring at room temperature for 2.5h, the reaction is complete, add EA (ethyl acetate) and water to dilute the reaction solution, EA 100mL _X 3 extraction, saturated brine 100K wash , anhydrous MgS0 _{4 is} dry. The organic phase was dried to give a white solid (i.e., compound 19).

The nuclear magnetic data of the product are as follows: NMR (400 MHz, CDC1 ₃ ) δ 8.54 (d, J 8.5 Hz, 1H), 8.30 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.57 (t, J = 7,6 Hz, H:), 7.43 - 7.30 (m, 3H), 4.09 (d, J = 6.3 Hz, 2H:), 3.72 (s, 3H), 2.49 - 2.35 (m, 1H), 1.17 (d , J = 8,4 Hz, 2H), 0.91 - 0.76 (m, 2H).

Example 9 Preparation of Lesimirad Intermediate (Compound 20)

Add solvent acetonitrile (5 mL), Pft3⁄4 (0.24 mL) to a single-necked flask containing compound 19. After the dissolution is complete, slowly add liquid bromine in acetonitrile (3 eqBr ₂ in i niL acetonitrile), add dropwise, room temperature The reaction was completed in 2 h. 30 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate.

The nuclear magnetic data of the product is as follows: NMR (400 MHz, CDC1 ₃ ) δ 8.43 (d, J - 8, 5 Hz, H), 7.53 (t, J - 7.3 Hz _: IH), 7.43 ft, J :: 7.4 Hz, 1H), 7.27 (dl J::: 17,2, 7.6 Hz, 2H), 7.15 (d, J== 8.3 Hz, IH), 3.57 (s, 3H), 2.38 - 2,24 (m, IH) , 1.10-1.08(m, 2.H:), 0.79-0.69 (m, 2H).

Example 10 Preparation of Lesis rad Intermediate (Compound 22)

Compound 13 (1 g) was added to a vial, dissolved in solvent DM:F (16.8 vol), stirred at room temperature, K ₂ CO ₃ (l.leq) was added, and compound 21 (1,05 eq) was added dropwise. controlling the drip rate in 0,5mL / mi stirred at room temperature 2h, the reaction was complete, EA (ethyl acetate) and the reaction solution was diluted with water, extracted with EA ≡ times, washed three times with saturated brine, dried over anhydrous MgS0 _4. The organic phase was obtained as a white solid (i.e., compound 22), dried to yield 0.99 g, yield 87%. The nuclear magnetic data of the product are as follows: ⁱ H NMR (400 MHz, DM SO) δ 9.01 (s, IH), 8.58 (d, J- 8, 4 Hz, IH), 7.80 - 7.71 (m, 1H), 7.69 - 7,58 (m, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.27 (s _: 2.H ), 2.53 (m, 1H), 1.14 (d, J = 8.5 Hz, 2H), 0.83 (m, 2H).

Example 11 Preparation of Lesis rad Intermediate (Compound 23)

Add solvent acetonitrile (5 mL) to pyridine (0,24 mL) to dissolve in a single-necked flask containing compound 22.

Acetonitrile was added liquid bromine (3 eq Br ₂ was dissolved in I mL of acetonitrile), completion of the dropwise addition, the reaction 20 is H at room temperature, 60 ° C oil bath was added the reaction 3H _£ 30mL water and 30mL ethyl acetate added to the reaction solution with ethyl acetate 30mL The ester was extracted 3 times, the phase was washed with saturated brine to wash the magnesium sulfate, and the product was obtained by spin-drying through a silica gel column (Compound 23) 0.63 g, yield 50% „

The nuclear magnetic data of the product is as follows: 'Ή NMR (400 MHz, CDC1 ₃ ) δ 8.56 (d, J :: 8.4 Hz, IH), 7.73-7.64 (m, l H)

7.63 - 7.55 (m, IH:), 7,38 (s, 2H), 7,23 - 7.16 (m, IH), 4.01 (d, J= 1.9 Hz, 2H), 2.50 - 2.40 (m

IH), 1.21 --- 1.14 (m, 2H), 0.92-0.84 (m, 2H).

Compound 23 can be obtained by a conventional hydrolysis reaction to obtain LesinuracL.

Example 12 Preparation of Lesi rad intermediate (combination 11 25)

Add compound 3 (leq) to a single-mouth bottle, add solvent DMF (16.8 voi) to dissolve, stir at room temperature, add K ₂ C0 ₃ (l. leq), then add compound 24 (l, 05 eq) one by one, control the drop After stirring at room temperature for 0.5 h at a flow rate of 0.5 mL/mi for 18 h, the reaction starting material was left, and 1.05 eq of the starting material was added to continue the reaction for 6 h, and the reaction was completed. Add EA (ethyl acetate) and the reaction solution was diluted with water, and extracted three times with EA, washed with water, brine, dried over anhydrous MgS0 ₄ was dry. The title product (Compound 25) was isolated over silica gel column (yield:

The nuclear magnetic data of the product is as follows: 1H M (400 MHz, DM SO) δ 8.87 (s, IH), 8.56 (d, J- 8.4 Hz, IH), 7.73 (t, J::: 7.4 Hz, IH), 7.64 ( t, J== 7,4 Hz, IH), 7.55 (d, J::: 7.6 Hz, IH), 7.40 (d, J::: 7.6 Hz, IH), 7.17 (d, J = 8.3 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 3.62 (q, J = 6.2 Hz, 2H:), 3, 21 (t, J = 6.5 Hz _: 2. H), 2.59-2.51 (m, 1H), 1.19-1.08 (m, 2H), 0.92 - 0.71 ( _m , 2H).

Example 13 Preparation of Lesimirad Intermediate (Compound 26)

28

Add solvent acetonitrile (5 mL), pyridine (0.24 mL) to a single-mouth flask containing compound 25. After the dissolution is complete, slowly add liquid bromine in acetonitrile (3 eq Br2 in 1 m: L acetonitrile), add dropwise After completion, the reaction was carried out at room temperature for 41 h, and the reaction was stopped. 30 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with 30 ml of ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. O.Bg, yield 18%,

The product nuclear magnetic data is as follows: NMR (400 MHz, D SO) 5 8.58 (d, J- 8, 5 Hz, 1H), 7.68-7.65 (m, IH), 7.68-7, (m, IH), 7, 63 (d, J- 7.6 Hz, 1H), 7,43 (d, J ::: 7.6 Hz, 1H), 7,13 (d, J - 8.2 Hz, 1H), 4.97 (s, IH), 3.61 (t, J == 6.5 Hz, 2H), 3.20 (i, J== 6.4 Hz, 2H), 2.60-2.52 (m, 】H), 1.16 - 1.12 (m, 3H), 0.89 --- 0.83 ( m, 2H).

Compound 26 is oxidized to an acid by a conventional oxidation reaction to obtain LesimiracL.

Example 14 Preparation of Lesimsrad Intermediate (Compound 28)

3 (leq) was added to a single-mouth bottle, dissolved in solvent DMF (20 vol), stirred at room temperature, added to Cs ₂ C0 ₃ (2 eq) _; compound 27 (leq) was added dropwise, and the drip rate was controlled at 0,5 mL/mm. after stirring at room temperature 2h, the reaction was complete, EA (ethyl acetate) and the reaction solution was diluted with water, extracted with EA - three times, saturated brine: three times, dried over anhydrous MgS0 ₄ was dry. The mixture was dried to give a white solid (Compound 28), yield 98%. The nuclear magnetic data of the product are as follows: ^f H NMR (400 MHz, CDC1 ₃ ) δ 8.50 (d, J = 8.5 Hz, 1H), 8.27 (s, 1H), 7.62 (t, J = 7.3 Hz, 1H), 7.49 (t , J= 7.6 Hz, 1 H), 730 - 7.12 (m, 8H), 4.45 (d, J = 3.7 Hz, 2H), 2.47 - 2.29 (m, IH), 1.19-1.07 (m, 2H), 0.91 -0.73 (m, 2H).

Example 15 Preparation of Lesimsrad Intermediate (Chemical Formula 1Γ29)

Add solvent acetonitrile (5 mL), pyridine (0.24 mL) to a single-necked flask containing compound 28. After the dissolution is complete, slowly add a solution of bromine in acetonitrile (3 eq Br ₂ in 1 mL of acetonitrile) and add dropwise. The reaction was carried out at room temperature for 20 h, and the oil bath was reacted at 60 ° C for 3 h to stop the reaction. 30 mL of water and 30 mL of ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with 30 mL of ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous magnesium sulfate. g, yield 73%.

The nuclear magnetic data of the product are as follows: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.47 (d, J 8,5 Hz, IH), 7.62 - 7.53 (m, IH), 7.43 ft, J == 7.3 Hz, IH), 7.28 - 7.22 (m, IH), 7.22 - 7.12 (m, 5H), 7.06 fm, 2H), 4.42 - 4.32 (m, 2H), 2.42 --- 2.27 (m, IH), 1.14 - 1.05 (m, 2H ), 0.82 - 0.75 (m, 2H).

Compound 29 is deprotected with thioether to obtain a thiol, and then a thioether derivative is prepared and hydrolyzed to obtain Lesinurac L. Example 16 Preparation of Lesi srad intermediate (Compound 31)

Compound 13 (EQ]) was added to a single-neck flask, the solvent was added acetic anhydride (Compound 30, _4.5vol)? Dissolved, stirring at room temperature, was added _{_{K 2 C () 3 (2e}} q), stirred at room temperature for 2h, EA (acetic acid ethyl ester) and the reaction solution was diluted with water, and extracted three times with EA, washed three times with saturated brine, dried over anhydrous MgS0 ₄ was dry. The organic phase was dried to give a white solid (Compound 31) 1.12 g, yield 97%.

The nuclear magnetic data of the product is as follows: 3⁄4 NMR (400 MHz, CDCI3) δ 8.54 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7,68 - 7.61 (ra, IH), 7,61 - 7.54 ( m, IH), 7.48-7.34 (m, 3H), 2,84 (s, 3H), 2.47― 2.34 (ra, IH), 1.19- (m, 2.H), 0.91 - 0.79 (m, 2H).

Compound 31 is subjected to bromination, deprotection of thioacetyl group, hydrolysis after preparation of thioether derivative, and Lesimirac L is obtained.

32 33

In a single-necked flask, compound 32 (1.0 eq) was added, and DMF (8.2 eq) was added to dissolve it. NaOH (L2eq) and CS ₂ (1.2 eq) were added, and the reaction was stirred at room temperature for 1 h, and hydrazine hydrate (3.0 eq) was added. Transfer to a 70 ° C oil bath and reflux for 4 h, LC confirmed the reaction was completed, stop heating and stirring, after cooling: ig raw material added iOmL water, sleeve filtration, filter cake with 4mL / (g raw material) 95% ethanol weight Crystallization, suction filtration, and solids were pulled with an oil pump to give Compound 33, yield 27%.

The nuclear magnetic data of the product are as follows: NMR NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 8.15 (d, J = 8.3 Hz, 1H), 7.96 (d, J --- 8,1 Hz, 1H), 7.88 (d, J - 8.0 Hz, IH), 7.75 - 7.61 (m, 2H), 7,57 (d, J - 7.7 Hz, 1H), 6,62 (br, 2H). MH

\ HS"

N-CH{O e) _;

/

Br

Add compound 33 (1.0 eq) to a 34-neck vial, add 1,4-dioxane (7.5 Voi) to dissolve, and add hydrazine, hydrazine-dimethylformamide diethyl acetal (: L0eq). The mixture was stirred and refluxed for 3 h. After the reaction was cooled to room temperature, water (1 mL) was added to the lg material, and the solid was filtered off with suction. The filter cake was washed twice with 95% ethanol and dried to give compound 34. The yield was 69%. The nuclear magnetic data of the product are as follows: ^l li NR (400 MHz, DMSO) δ 14,09 (s, 1Η), 8,72 (s, 1H), 8,29 (d, J::: 8.4 Hz, 1H), 8.09 (d, J::: 7.9 Hz, 1H), 7.81 ft, , /:::: 7.7 Hz, IH), 7.72 (t, J :: 7.6 Hz, 1H), 7.60 fd, J :: 7.9 Hz, IH), 7,44 (d, J::: 8.4 Hz, IH).

Add compound 34 (0.98 g, leq) to a single-mouth flask, dissolve in solvent DMF (16.5 mL), stir at room temperature, add K ₂ C0 ₃ (486 mg, l.leq), and add compound 19 (0.37 mL) dropwise. , L05eq), control the dropping rate at 0.5mL / min, stirring at room temperature for 3 h, the reaction is complete, add EA (ethyl acetate) and water to dilute the reaction solution, EA60mLx3 extraction, saturated brine 60mLx3 wash, anhydrous MgSC dry. The organic phase was obtained as a white solid (i.e., compound 35), dried, l, 36 g, yield >99%.

The nuclear magnetic data of the product is as follows: 'Η NMR (400 MHz, CDC1 ₃ ) δ 8.38 (d, J = 8.5 Hz, IH), 8.32 (s, IH), 7.92

(d, J= 7.8 Hz, 1H), 7,78― 7.69 (m, IH), 7.68― 7.59 (m, IH), 7.37 (m, 2H), 4.19 (q, J= 7,1 Hz, 2H ), 4,09 (d, J ::: 5.8 Hz 2H), 1,26 (t, J- 7.1 Hz, 3H.

To a single-mouth bottle containing compound 35 (0.78 g), a solvent of acetonitrile (4 ml-), pyridine (0.48 mL) was added. After the dissolution was completed, a solution of liquid bromine in acetonitrile (3 eq Br2 in 1 mL acetonitrile) was slowly added dropwise. After the addition is completed, the reaction at room temperature is h. stop. 30 mL of water and 30 μL of ethyl acetate were added to the reaction mixture, and the mixture was extracted three times with 30 mL of ethyl acetate. The organic phase was washed with brine and dried over anhydrous magnesium

The nuclear magnetic data of the product are as follows: 1H NMR (400 MHz, CDC1 ₃ ) δ 8.39 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.78-7, 70 (m, 1H), 7,65 (dd, J - 11.3, 4,0 Hz, 1H), 7,35 (d, J - 7,9 Hz, 1H), 7.26 (t, j 4,2 Hz, 1H), 4.19 (q , J - 7.1 Hz, 2H), 4,10 - 3.98 (m, 2H), 1.26 (t, J - 7,1 Hz, 3H).

Compound 32-36 can be converted to a cyclopropyl group by a coupling reaction, and a target compound 8 can be obtained by a reaction similar to the route of the present application.

The invention has been described in detail above, and is intended to enable those skilled in the art to understand the invention and practice the invention, and is not intended to limit the scope of the present invention, which is in accordance with the spirit of the invention. Equivalent variations or modifications are intended to be included within the scope of the invention.

Claims

Rights request-

K A Lesinurad intermediate characterized by: said: Lesinurad intermediate is a compound of the formula:

式中中-

R represents deuterium or C()CH _{3 ;} or 11 represents CR^ wherein Ri represents an ester group; CN; C OH _; a phenyl group which is unsubstituted or substituted with one or more selected from the group consisting of a fluorenyl group and a halogen;

R ² represents a cyclopropane group; it is an OTf.

2. The Lesinurad intermediate according to claim 1, wherein: in the formula I, R represents H,

R ² represents a cyclopropane group, and the structural formula is as shown in Formula 13;

13

3. - 'A Lesir rad intermediate, characterized in that: the Lesinurad intermediate is a compound represented by the general formula II,

l\

In the formula H, R ² represents a cyclopropyl group; halogen; OTf.

4. The Leshmrad intermediate according to claim 3, wherein: in the formula II, R ² represents a cyclopropane group, and the structural formula is as shown in Formula 12 -

12

a method for preparing a Lesinurad intermediate represented by Formula III,

Characterized in that: a compound of formula I comprising reacting step occurs bromo compound of formula III is reacted substituent, of formula I and〗 1: R_ same, the same as R ^2,

I

Wherein R represents H or C()C3⁄4; or R represents CH ₂ :R wherein: ¹⁵ represents an ester group; CN; CH ₂ OH _: unsubstituted or selected from a Ci~C ₆ fluorenyl group, a halogen One or more substituted phenyl groups;

R ² represents a cyclopropyl group; halogen; OTf.

6. The method for preparing a Leshmrad intermediate represented by Formula III according to Claim 5, wherein: wherein R. is 0)() 3⁄4 or 0^, and R ¹ represents an ester group; CN: CH ₂ OH ; a phenyl group which is unsubstituted or substituted with one or more selected from the group consisting of Ci~C ₆ alkyl, 3⁄4; R ² represents a cyclopropenyl group.

7. The method for preparing a Leshmrad intermediate represented by the formula Γ Γ according to claim 6, wherein: the bromine source used in the bromination reaction is liquid bromine, bromine water, and N-bromosuccinimide. , dibromohydantoin.

8. The method for preparing a Lesinurad intermediate represented by Formula III according to Claim 7, wherein the bromination reaction is carried out as follows: a compound of the formula and the bromine source are present in a solvent, and an acid binding agent is present. The bromination reaction takes place. 9. A process for the preparation of a Lesmurad intermediate represented by formula III according to claim 6, wherein: the compound of formula I is 4 (4-cyclopropylnaphthalene)-3-thioacetate-1. 2,4-triazole, structural formula

15 _o

H) A method for preparing a Lesir rad intermediate represented by the formula according to any one of claims 6 to 9, characterized in that the method further comprises: compounding 13 and RX in a solvent, a step in which a substitution reaction occurs to form a compound of formula I,

13

Wherein R is as defined in claim 6, and X represents a leaving group.

A method for producing a Lesimirad intermediate represented by Formula III according to Claim 10, characterized in that X is chlorine, bromine, iodine or OTf.

12. A method of puncturing a Lesmurad intermediate represented by the formula I according to claim 1 (1), characterized in that the method further comprises: compound 12 and N,N-dimethylformamide difluorenyl The step of acetal forming the compound 13 in a solvent,

12

A method for producing a Lesinurad intermediate represented by Formula III according to claim 12, wherein: the N,N-dimethylformamide dimercaptoacetal is hydrazine, hydrazine-dimethyl Formamide dimethyl acetal or hydrazine, hydrazine dimethyl amide amide diethyl acetal.

14. A method of preparing a Lesinurad intermediate represented by the formula 根据 according to claim 12, The method further comprises: firstly reacting 4-cyclopropyl-1-naphthylamine, carbon disulfide with a base to form a salt of N 4-cyclopropyl-naphthalene)dithiocarbamic acid in a solvent, and then making N The reaction of a salt of 4-cyclopropyl-I-naphthalene)dithiocarbamic acid with hydrazine hydrate to form compound 12 is carried out.

The method for producing a Lesinurad intermediate represented by the formula 根据 according to claim 14, wherein the base is sodium hydroxide or potassium hydroxide or a combination of the two.

16. A method of preparing Lesiiiurad comprising the synthesis of a Lesinurad intermediate represented by Formula III,

In the formula III; R represents H or COCH _3; or R represents CH ₂ R ³ , wherein R ¹ represents an ester group; CN; C3⁄4OH; unsubstituted or selected from a C _S ' ₆ alkyl group, a halogen or a plurality of substituted phenyl groups;

R ² represents a cyclopropane group; halogen: hydrazine;

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