CN103183604A - Preparation method of vedaprofen - Google Patents

Abstract

The invention relates to a preparation method of vidaprofen. The method provided by the invention has only four steps of reaction, the required raw materials are all conventional raw materials, and the method is easy to operate, and all steps can be carried out by "one-pot method", which is convenient for industrial production.

Description

The preparation method of vidaprofen

technical field

The invention relates to a preparation method of vidaprofen.

Background technique

Vidaprofen (vedaprofen) shown in the following structural formula 1 is the generic drug name of the compound 2-(4-cyclohexylnaphthyl)propionic acid.

Vidaprofen belongs to 2-arylpropionic acid compounds and is a non-steroidal anti-inflammatory drug used for antipyretic and analgesic. It is mainly used in gout, endocrine and metabolic diseases. The compound has a chiral center and therefore has a pair of enantiomers, S(+) and R(-). Modern pharmacological studies have proved that the S(+) and R(-) configurations of vidaprofen are completely the same in the inhibitory effect on prostaglandins (PGF _2α ), so these two configurations are superior and different. Construct. The racemic mixture of vidaprofen has been developed into equine and canine veterinary drugs, and has been approved for the treatment of dogs and horses in Europe and America. Therefore, there is no need for asymmetric synthesis or chiral resolution to synthesize vidaprofen, only the racemate can be obtained.

Through literature search, the main synthetic routes and methods reported in the literature or patents are as follows:

For example, U.S. Patent US4218473 discloses a kind of preparation method of vidaprofen, and reaction formula is as follows:

Taking 1-cyclohexylnaphthalene (which can be prepared with reference to the document Journal of the American Chemical Society, 2004, 126 (12), 3686-3687) as a starting material, firstly carry out chloromethylation reaction with formaldehyde and concentrated hydrochloric acid to obtain 1 -Chloromethyl-4-cyclohexylnaphthalene; The obtained chloromethylated intermediate is cyanated with sodium cyanide, and then the cyano group is hydrolyzed to obtain the intermediate 4-cyclohexyl-1-naphthalene acetic acid; The acid intermediate obtained is used Methanol is esterified to the corresponding methyl ester, and methylated at the α position with methyl iodide to obtain methyl 2-(4-cyclohexylnaphthyl) propionate; the methyl ester is hydrolyzed under alkaline conditions and acidified with hydrochloric acid to obtain Vidaprofen .

This route requires the use of highly toxic controlled products such as sodium cyanide and methyl iodide, which greatly threaten the personal health and safety of operators in large-scale production. In addition, this method has a long route and many steps, including 6-step reactions, and the production cost is relatively high.

According to the literature [Journal of medicinal chemistry, 2007, 50 (12), 2787-2798 and Tetrahedron, 1995, 51 (46), 12583-12590], a preparation method of vidaprofen can also be obtained, and the reaction formula is as follows:

Using 1-cyclohexylnaphthalene as the starting material, firstly carry out chloroacetylation reaction with acetyl chloride to obtain 1-acetyl-4-cyclohexylnaphthalene; the obtained acetylated intermediate is reduced to alcohol, hydroxyl chloride and The cyano group of sodium cyanide is substituted to obtain 2-(4-cyclohexylnaphthyl) propanecyanide; the intermediate of propanecyanide is hydrolyzed to obtain vidaprofen.

The disadvantage of this route is still the need to use highly toxic control products such as sodium cyanide, high reaction risk, difficult operation, and 5-step reaction.

Contents of the invention

For the problems referred to above, the purpose of this invention is to provide a kind of new preparation method for preparing compound 2-(4-cyclohexylnaphthyl) propionic acid. The method has only four reaction steps, and the steps are relatively short, and the required raw materials are conventional raw materials, thereby avoiding the use of highly toxic sodium cyanide or potassium cyanide. Moreover, all steps of this route can be carried out by "one pot method", and the product quality is stable, which is convenient for industrial production. Therefore, the process is easy to operate and convenient for industrial production.

In order to achieve the above object, the present invention adopts the following technical solutions to achieve.

The preparation method of Vidaprofen of the present invention may further comprise the steps:

A) 1-cyclohexylnaphthalene (i.e. compound 2) and 2-halopropionylating reagents carry out Friedel-Crafts acylation reaction to obtain compound 3, and its reaction formula is as follows:

B) Compound 3 is protected by ketalization with a dihydric alcohol to obtain compound 4, the reaction formula of which is as follows:

C) Compound 4 undergoes aryl migration rearrangement under Lewis acid catalysis to obtain compound 5, the reaction formula of which is as follows:

D) compound 5 is hydrolyzed to obtain vidaprofen (i.e. compound 1), and its reaction formula is as follows:

Wherein, X is fluorine, chlorine, bromine or iodine,

each R is independently hydrogen, methyl or ethyl,

n is 0, 1 or 2;

Preferably,

X is chlorine or bromine,

each R is independently hydrogen or methyl,

n is 0 or 1.

Describe the preparation method of the present invention in more detail below:

In said step A):

The 2-halopropionylating reagent can be 2-chloropropionyl chloride, 2-chloropropionic anhydride, 2-bromopropionyl chloride or 2-bromopropionic anhydride, etc.; general 2-halogenating propionylating reagent and compound 2 The molar ratio is 1.5:1 to 1:1, and preferably 1.1:1.

The reaction uses a Lewis acid as a catalyst, and the Lewis acid can be one or more selected from AlCl ₃ , ZnCl ₂ , BF ₃ and TiCl ₄ , and the molar ratio of Lewis acid to compound 2 is 2:1 to 1: 1, and preferably 1.2:1. The reaction mechanism is: Lewis acid is combined with acid chloride or acid anhydride, and the carbonyl cation formed can combine with the carbanion on the aromatic ring to form a carbon-carbon bond structure.

The solvent used in this reaction can be dichloromethane, chloroform, 1,2-dichloroethane or chlorobenzene and the like.

A suitable temperature range for this reaction is -78°C to 30°C, and preferably -10°C to 0°C.

After the reaction is completed, quench the reaction with a quencher, then extract with an organic solvent, and then concentrate the extracted organic phase under reduced pressure to obtain a crude compound 3, which can be directly used in the next step without purification. Wherein, the quenching agent can be selected from one or more of water, hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid and citric acid; the organic solvent used for extraction is ethyl acetate, Toluene, dichloromethane or methyl tert-butyl ether, etc.

In said step B):

Carry out ketalization protection to the carbonyl on compound 3 with dibasic alcohol, described dibasic alcohol can be ethylene glycol, 1,3 propanediol, neopentyl glycol etc.; The molar ratio of general dibasic alcohol reagent and compound 3 is 3:1 to 1:1, and preferably 1.5:1.

The catalyst used in the ketalization reaction is one or more selected from sulfuric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid; and the molar ratio of the general acid catalyst to compound 3 is 0:1～1: 1, and preferably 0.1:1.

The solvent used in this reaction can be benzene, toluene, xylene or chlorobenzene and the like. During the reaction, it is necessary to use a water separator or other water removal devices or water removal reagents to separate and remove the water generated by the reaction in time.

After the reaction was completed, the reaction solution was quenched with water as a quencher; the organic phase was washed with water and brine and then concentrated under reduced pressure to obtain a crude compound 4, which could be directly used in the next step without purification.

In said step C):

The catalyst used in the aryl transfer rearrangement reaction of compound 4 is one or more selected from ZnO, ZnCl ₂ and Zn(OAc) ₂ , and the molar ratio of catalyst to compound 4 is 0:1～3:1, And preferably 0.2:1. The reaction mechanism is: under the catalysis of the zinc reagent, the aryl group migrates from the ketal carbon to the carbon of the adjacent halogen atom, and at the same time the halogen atom combines with the zinc reagent to form the ester group structure of compound 5.

The solvent used in this reaction can be toluene, xylene or chlorobenzene and the like.

A suitable temperature range for this reaction is 80°C to 160°C, and preferably 110°C to 130°C.

After the reaction was completed, the reaction was quenched with a quencher, the organic phase of the reaction was washed with water and brine, and then concentrated under reduced pressure to obtain a crude compound 5, which could be directly used in the next reaction without purification. Wherein, the quenching agent may be one or more selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid and citric acid.

In said step D):

The hydrolysis of compound 5 can be under basic or acidic conditions. The base used for hydrolyzing compound 5 can be KOH, NaOH, LiOH, K ₂ CO ₃ , Cs ₂ CO ₃ or Na ₂ CO ₃ etc.; generally the molar ratio of base to compound 5 is 5:1 to 1:1, and preferably 3 : 1. The acid used for the hydrolysis of compound 5 can be sulfuric acid, hydrochloric acid or p-toluenesulfonic acid and the like.

The preparation method of the present invention has a total of four steps, and the synthesis route is short; the required raw materials are all conventional raw materials, and the use of highly toxic cyanide is avoided. Each step in this route is a conventional reaction, and the post-treatment is simple and easy to operate; and after the reaction, the crude product obtained from the reaction solution after post-treatment can be directly used in the next step without purification, realizing the "one-pot method" of the whole route "Carry out, be convenient to industrialized production.

Detailed ways

The following examples further illustrate the technical solutions, features and advantages of the present invention, but the present invention is not limited to the following examples.

1. Synthesis of compound 3

Example 1

Synthesis of 1-(2-chloropropionyl)-4cyclohexylnaphthalene

Under the protection of N ₂ , AlCl ₃ (22.8 g, 0.17 mol) and dichloromethane (250 mL) were added into a 500 ml three-necked flask and cooled to -10°C to 0°C. Under stirring, a dichloromethane (50 mL) solution of a mixture of 2-chloropropionyl chloride (19.8 g, 0.157 mol) and 1-cyclohexylnaphthalene (2, 30.0 g, 0.143 mol) was added dropwise, and the reaction temperature was kept at -10 ℃～0℃. After the addition, continue to keep at -10°C to 0°C for 2 hours until the reaction is complete. The reaction solution was poured into 300mL of dilute hydrochloric acid (2N) to quench the reaction, the layers were stirred and the organic layer was separated, and the organic layer was washed with 200mL of water and 200mL of saturated brine respectively, and the solvent was evaporated under reduced pressure to obtain a crude product. Brown oily. Crude yield: Quantitative.

The crude product was directly used in the next reaction without further purification.

MS (ESI, m/z): [M+] ⁺ 301.2.

¹ H-NMR (400MHz, CDCl ₃ ): δ8.52(m, 1H); 8.03(d, 1H, J=8.8Hz); 7.65～7.92(m, 2H); 7.42～7.60(m, 2H); 5.42(m, 1H); 2.70(m, 1H); 1.84-2.05(m, 4H); 1.80(d, 3H, J=3.6Hz); 1.78(m, 1H); 1.29-1.59(m, 4H) ; 1.31 (m, 1H).

Example 2

Under the protection of N ₂ , TiCl ₄ (32.2 g, 0.17 mol) and chlorobenzene (250 mL) were added into a 500 ml three-necked flask and cooled to -10°C to 0°C. Under stirring, a chlorobenzene (50mL) solution of a mixture of 2-bromopropionic anhydride (45.2g, 0.157mol) and 1-cyclohexylnaphthalene (30.0g, 0.143mol) was added dropwise, and the reaction temperature was kept at -10°C to 0°C. After the addition, continue to keep at 10°C to 0°C for 2 hours until the reaction is complete. Pour the reaction solution into 300mL citric acid aqueous solution (2N) to quench the reaction, stir and separate the layers and separate the organic layer. After the organic layer is washed with 200mL water and 200mL saturated brine, the solvent is evaporated under reduced pressure to obtain a crude product, brown Oily. Crude product yield: Quantitative.

The crude product was directly used in the next reaction without further purification.

2. Synthesis of compound 4

Example 3

Synthesis of 2-(1-chloroethyl)-2-(4-cyclohexylnaphthyl)-5,5-dimethyl-1,3-dioxane

Under the protection of N ₂ gas, 1-(2-chloropropionyl)-4cyclohexylnaphthalene (3, 42.9g, 0.143mol) and toluene (430mL) were added into a 500ml three-necked flask at room temperature. Under stirring, neopentyl glycol (22.3 g, 0.214 mol) and p-toluenesulfonic acid (2.7 g, 0.014 mol) were added to the reaction liquid. After the addition is complete, install a water separator on the reaction bottle, then heat to reflux and maintain reflux for 20 hours until the reaction is complete. Cool the reaction solution to room temperature, add 200 mL of water to quench the reaction, stir and separate the organic phase. The organic phase was washed twice with water (200 mL×2) and once with saturated brine (200 mL), and the solvent was evaporated under reduced pressure to obtain a crude product as a brown oil. Crude product yield: Quantitative.

The crude product was directly used in the next reaction without further purification.

MS (ESI, m/z): [M+] ⁺ 387.2.

¹ H-NMR (400MHz, CDCl ₃ ): δ7.81～7.88(m, 2H); 7.38～7.51(m, 3H); 7.16(m, 1H); 4.14(m, 1H); 3.52(m, 4H ); 2.70 (m, 1H); 1.81-1.98 (m, 4H); 1.46-1.59 (m, 4H); 1.25-1.44 (m, 7H).

Example 4

Under the protection of N ₂ gas, 1-(2-chloropropionyl)-4cyclohexylnaphthalene (3, 42.9g, 0.143mol) and xylene (430mL) were added into a 500ml three-necked flask at room temperature. Under stirring, ethylene glycol (13.3 g, 0.214 mol) and concentrated sulfuric acid (1.4 g, 0.014 mol) were added to the reaction liquid. After the addition is complete, install a water separator on the reaction bottle, then heat to reflux and maintain reflux for 20 hours until the reaction is complete. Cool the reaction solution to room temperature, add 200 mL of water to quench the reaction, stir and separate the organic phase. The organic phase was washed twice with water (200 mL×2) and once with saturated brine (200 mL), and then the solvent was evaporated under reduced pressure to obtain a crude product as a brown oil. Crude yield: Quantitative.

The crude product was directly used in the next reaction without further purification.

MS (ESI, m/z): [M+] ⁺ 345.1.

3. Synthesis of Compound 5

Example 5

Synthesis of 3-chloro-2,2-dimethylpropyl 2-(4-cyclohexylnaphthyl)propionate

Under _N protection, 2-(1-chloroethyl)-2-(4-cyclohexylnaphthyl)-5,5-dimethyl-1,3-dioxane ( 4, 55.2 g, 0.143 mol), zinc oxide (2.4 g, 0.029 mol) and toluene (200 mL). The reaction solution was heated to 110°C-130°C and kept at this temperature and stirred for more than 16 hours until the reaction was complete. Cool the reaction solution to room temperature, add 100 mL of dilute sulfuric acid (2N) to quench the reaction, stir and separate the organic phase. The organic phase was washed twice with water (150 mL×2) and once with saturated brine (150 mL), and then the solvent was evaporated under reduced pressure to obtain a crude product as a brown oil. Crude yield: 90%.

The crude product was directly used in the next reaction without further purification.

MS (ESI, m/z): [M+] ⁺ 387.2.

¹ H-NMR (400MHz, CDCl ₃ ): δ7.60～7.80(m, 4H); 7.40(m, 2H); 3.89(m, 3H); 3.12(m, 2H); 2.65(m, 1H); 1.90-1.98(m, 4H); 1.87(m, 1H); 1.77(d, 3H, J=7.2Hz); 1.25-1.51(m, 4H); 1.26(m, 1H); 0.81(m, 6H) .

Example 6

Under _N protection, 2-(1-chloroethyl)-2-(4-cyclohexylnaphthyl)-5,5-dimethyl-1,3-dioxane ( 55.2 g, 0.143 mol), zinc oxide (2.4 g, 0.029 mol), zinc chloride (3.9 g, 0.029 mol) and xylene (200 mL). The reaction liquid was heated to 110° C. to 130° C. and kept at this temperature and stirred for more than 4 hours until the reaction was complete. Cool the reaction solution to room temperature, add 100 mL of dilute hydrochloric acid (2N) to quench the reaction, and stir to separate the organic phase. The organic phase was washed twice with water (150 mL×2) and once with saturated brine (150 mL), and then the solvent was evaporated under reduced pressure to obtain a crude product as a brown oil. Crude yield: 90%.

The crude product was directly used in the next reaction without further purification.

Example 7

Under _N protection, 2-(1-chloroethyl)-2-(4-cyclohexylnaphthyl)-5,5-dimethyl-1,3-dioxane ( 55.2 g, 0.143 mol), zinc acetate (5.4 g, 0.029 mol) and xylene (200 mL). The reaction solution was heated to 110° C. to 130° C. and kept at this temperature and stirred for more than 6 hours until the reaction was complete. Cool the reaction solution to room temperature, add 100 mL of dilute hydrochloric acid (2N) to quench the reaction, and stir to separate the organic phase. The organic phase was washed twice with water (150 mL×2) and once with saturated brine (150 mL), and then the solvent was evaporated under reduced pressure to obtain a crude product as a brown oil. Crude yield: 85%.

4. Synthesis of Compound 1 [Vidaprofen]

Example 8

To a 500mL three-neck reaction flask at room temperature, add 3-chloro-2,2-dimethylpropyl 2-(4-cyclohexylnaphthyl)propionate (5, 50.0g, 0.13mol), tetrahydrofuran (150mL) and methanol (150 mL); after stirring for 5 minutes until the solid dissolved, 52 mL of aqueous sodium hydroxide solution (23%) was added to the reaction solution. The obtained reaction mixture was heated to 60° C. to 70° C. for 2 hours until the reaction was complete. The reaction solution was cooled to room temperature, and the organic solvent was distilled off under reduced pressure. The resulting brown suspension was diluted with 100 mL of water, and then extracted with 200 mL of ethyl acetate. The organic layer was separated, and the organic phase was stirred at room temperature for 1 hour, then cooled to 0°C-10°C and stirred for 1 hour. After filtering, the filter cake was washed with ethyl acetate (40 mL×2) to obtain a white solid which was the sodium salt of vidaprofen. The obtained white solid was put into 100 mL of dilute hydrochloric acid (2N), stirred for 30 minutes, filtered, and the filter cake was washed twice with water (40 mL×2) to obtain a white solid, which was dried at 50°C under vacuum for about 16 hours to obtain a white solid , vidaprofen. Yield: ~30%, purity 99.7%.

MS (ESI, m/z): [M+] ⁺ 283.4.

¹ H-NMR (400MHz, DMSO-d ₆ ): δ7.73 (d, 2H, J = 8.0Hz); 7.65 (d, 2H, J = 17.6Hz); 6.84 (dd, 2H, J ₁ = 8.0Hz , J ₂ =18.8Hz); 3.69(m, 1H); 2.64(m, 1H); 1.80-1.90(m, 4H); 1.73(m, 1H); 1.35-1.55(m, 4H); , 3H, J=7.2Hz); 1.27(m, 1H).

Example 9

Add 3-chloro-2,2-dimethylpropyl 2-(4-cyclohexylnaphthyl)propionate (50.0g, 0.13mol) and acetone (300mL) to a 500mL three-necked reaction flask at room temperature; stir After 5 minutes until the solid dissolved, 150 mL of potassium carbonate aqueous solution (30%) was added to the reaction liquid. The obtained reaction mixture was heated to 60° C. to 70° C. for 2 hours until the reaction was complete. The reaction solution was cooled to room temperature, and the organic solvent was distilled off under reduced pressure. The obtained brown suspension was diluted with 100 mL of water, and then extracted by adding 200 mL of methyl tert-butyl ether. The organic layer was separated, and the organic phase was stirred at room temperature for 1 hour, then cooled to 0°C-10°C and stirred for 1 hour. After filtering, the filter cake was washed with methyl tert-butyl ether (40 mL×2) to obtain a white solid which was the sodium salt of vidaprofen. The obtained white solid was put into 100 mL of dilute hydrochloric acid (2N), stirred for 30 minutes, filtered, and the filter cake was washed twice with water (40 mL×2) to obtain a white solid, which was dried at 50°C under vacuum for about 16 hours to obtain a white solid , vidaprofen. Yield: ~30%, purity 99.7%.

The foregoing describes and illustrates the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited by the above examples, and that the above examples and implementations described in the specification are only used to illustrate the principle of the present invention, and without departing from the spirit and scope of the present invention, the present invention The invention also has various changes and improvements, and these changes and improvements all fall within the scope of the claimed invention. The protection scope of the present invention is defined by the appended claims.

Claims (8)

1. A method for synthesizing Vidaprofen, comprising the following steps: A) The Friedel-Crafts acylation reaction of compound 2 with a 2-halopropionylating reagent yields compound 3, whose reaction formula is as follows: B) Compound 3 is protected by ketalization with a dihydric alcohol to obtain compound 4, the reaction formula of which is as follows:

C) Compound 4 undergoes aryl migration rearrangement under Lewis acid catalysis to obtain compound 5, the reaction formula of which is as follows:

D) compound 5 is hydrolyzed to obtain vidaprofen 1, and its reaction formula is as follows:

Wherein, X is fluorine, chlorine, bromine or iodine, each R is independently hydrogen, methyl or ethyl, n is 0, 1 or 2. 2. The method according to claim 1, wherein, in the step A), the 2-halopropionylating reagent is 2-chloropropionyl chloride, 2-chloropropionic anhydride, 2-bromopropionyl chloride or 2-bromopropionic anhydride; the molar ratio of the 2-halopropionylating reagent to compound 2 is 1.5:1˜1:1. 3. The method according to claim 1, wherein, in the step A), a Lewis acid is used as a catalyst, and the Lewis acid is selected from AlCl ₃ , ZnCl ₂ , BF ₃ , TiCl ₄ or Various. 4. The method according to claim 1, wherein, in the step A), the solvent used in the reaction is methylene chloride, chloroform, ethylene dichloride or chlorobenzene; the reaction temperature range is -78°C to 30°C . 5. method according to claim 1, wherein, in described step B) in, described dibasic alcohol is ethylene glycol, 1,3 propylene glycol or neopentyl glycol; Described dibasic alcohol and compound 3 The molar ratio is 3:1 to 1:1. 6. The method according to claim 1, wherein, in the step B), the catalyst used in the ketalization reaction is selected from sulfuric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid One or more; the molar ratio of the catalyst to the compound 3 is 0:1˜1:1. 7. method according to claim 1, wherein, in described step C) in, the catalyst that rearrangement reaction adopts is selected from ZnO, ZnCl ₂ and Zn(OAc) ₂ in one or more, and the The molar ratio of the catalyst to the compound 4 is 0:1-3:1. 8. The method according to claim 1, wherein, in the step C), the solvent used is toluene, xylene or chlorobenzene; the reaction temperature ranges from 80°C to 160°C.