KR20200008127A - Process for preparing substituted phenylacetic acid derivative - Google Patents

Abstract

The present invention belongs to the field of synthesis of drugs, and relates to a method for preparing substituted phenylacetic acid derivatives, and more particularly, to a method for preparing 2- (4-((2-oxocyclopentyl) methyl) phenyl) propanoic acid. . The present invention includes Friedel-Crafts reaction, exchange cyclization and binding reaction, and reduction reaction. This method of manufacture has not been taught or inspired by the prior art. This manufacturing method is suitable for commercial scale production. At the same time the present invention provides another technical method for the industrial production of roxofene sodium.

Description

Process for preparing substituted phenylacetic acid derivative

This application claims the priority of application No. 201710438332.1, filed with the Chinese Patent Office on June 13, 2017, and a Chinese patent application entitled “Method for preparing substituted phenylacetic acid derivatives”. The contents of this patent are all incorporated herein by reference.

The present invention belongs to the field of synthesis of drugs, and relates to a method for preparing substituted phenylacetic acid derivatives, and more particularly, to a method for preparing 2- (4-((2-oxocyclopentyl) methyl) phenyl) propanoic acid. .

Substituted phenylacetic acid derivatives are disclosed in US patents, such as US Pat. No. 4,161,538, wherein the formula is:

.

.

In patent US 4161538 it is also reported that the derivative has a very good effect on the activity of anti-inflammatory, analgesic and antipyretic agents.

If A is oxygen in the above formula, the value of n is 1 and R ¹ is methyl. This is a very representative substituted phenylacetic acid derivative of roxofene, with the specific structural formula:

.

.

Roxopropene is a drug of propionic acid derivatives for nonsteroidal anti-inflammatory drugs. These propionic acid derivatives also include ibuprofen and naproxen. Roxopropene is sold by Sankyo in the form of sodium salts in Brazil, Mexico and Japan. In Japan, Argentina and India, the trade names for roxofene sodium are Loxonin, Oxeno and Loxomac. Roxopropene sodium is used for oral administration in these countries, and the injection dosage form was approved for sale in Japan in January 2006.

Patent US 4161538 discloses the synthetic route of oxopropene shown below, wherein the value of n is 1 and R ¹ is methyl.

.

.

In Chinese journal Medical chemistry 20 (1), 25-28, 2010, Compound I was provided via reduction with sodium borohydride using 4-methylacetophenone as starting material. Compound I is directly chlorinated without purification to give Compound II. Compound II is chlorinated in the presence of a phase transfer catalyst to provide compound III. Compound III is then hydrolyzed and acidified under alkaline heating conditions to yield Compound IV. Compound IV is brominated with benzoyl peroxide as initiator to give compound V. Compound V is esterified with methanol to give compound VI, followed by condensation with 2-ethoxycarbonyl cyclopentanone under alkaline conditions to give compound VII. Compound VII is then hydrolyzed and decarboxylated with heating in 48% HBr and acetic acid system to give roxofene sodium. The synthetic route is as shown below.

While there is a good medical prospect of roxofene sodium, the route is not suitable for industrial production, and there is a need to develop novel roxofene penetrate pathways that can be synthesized industrially.

The present invention provides an economical route to prepare substituted phenylacetic acid derivatives or pharmaceutically acceptable non-toxic salt forms thereof, in particular a method for preparing roxofene, which differs from conventional methods. This method of manufacture cannot be taught or inspired by the prior art. This process takes a relatively inexpensive starting material, which is suitable for commercial scale production.

The present invention provides a compound of formula F,

또는

이고; G는 CN 또는 COOR²이고, G₁은 O, NR₆, S 또는 C이고; n은 1 내지 3의 정수이고; R₅는 COOR₃, CN, OTf, OTs, OMs, 할로겐, OH, CHO, 탄소-탄소 이중 결합 또는 탄소-탄소 삼중 결합이며; R₁, R², R₃ 및 R₆은 각각 독립적으로 수소 또는 저 치환된 알킬기이다.Where the general formula F is

or

ego; G is CN or COOR ² and G ₁ is O, NR ₆ , S or C; n is an integer from 1 to 3; R ₅ is COOR ₃ , CN, OTf, OTs, OMs, halogen, OH, CHO, carbon-carbon double bond or carbon-carbon triple bond; R ₁ , R ² , R ₃ and R ₆ are each independently hydrogen or a low substituted alkyl group.

The compound of formula F may be a compound of formula F-1, F-2, F-3 or F-4.

Wherein G is CN or COOR ² and n is an integer from 1 to 3; R ₁ , R ² , R ₃ , and R ₆ are each independently hydrogen or a low substituted alkyl group.

Preferably, the compound is formula II-2, formula II-2 ', formula I-2 or formula I-2'.

Here, R ₁ , R ² and R ₃ are each independently hydrogen or a low substituted alkyl group, and n is an integer of 1 to 3.

The present invention further provides a process for preparing a compound of formula (I) from a compound of formula (II) by a cyclization reaction, which reaction is shown in reaction 1 as follows:

Reaction 1

이고, R₁, R², R₃은 각각 독립적으로 수소 또는 저 치환 알킬기이고; n은 1 내지 3의 정수이고; X는 할로겐, OTf, OTs, OMs, 실릴, 티오알킬 또는 암모니아 알킬이고, 보다 바람직하게는, X는 브로모이다.Where R is X or

R ₁ , R ² , and R ₃ are each independently hydrogen or a low substituted alkyl group; n is an integer from 1 to 3; X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl, more preferably X is bromo.

In the present invention, R ₅ is prepared from a compound of formula F which represents the compound in the group of OH, CHO, OTf, OTs, Oms, halogen, carbon-carbon double bond or carbon-carbon triple bond. The raw material can be converted to the compound of formula II according to existing techniques, followed by subsequent reactions.

As shown in reaction 1, the general formula I compound was obtained from the general formula II compound by cyclization reaction.

Reagents of the cyclization reaction may be bases commonly used in the art. Reagents include, but are not limited to, conventional inorganic base or alkaline earth metal hydroxides, alkali metal salts of weak acids, or various alkali metal alkoxides, or hydrides, amides and the like, such as sodium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, potassium phosphate, Sodium ethoxide, potassium t-butoxide, sodium hydride, calcium hydride, sodium amide and the like. At the same time, the reagents are, but are not limited to, conventional organic bases, or amines, or pyridine, or imidazole, or piperidine, or pyrrole.

If R is X, the reaction is as shown below:

X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl, more preferably X is bromo; R ₃ is an alkyl group or hydrogen.

이면, 반응은 다음에 나타낸 바와 같다:R is

If so, the reaction is as shown below:

The definitions of R ₁ , R ² and R ₃ are the same as above.

The present invention further provides a process for preparing a compound of formula I-2 'from a compound of formula II-2' by a cyclization reaction at a base.

R ₁ and R ² are each independently hydrogen or a low substituted alkyl group; n is an integer of 1-3.

In the present invention, the compounds of the formulas (II-2) and (I-2) can be obtained from the compounds of the formulas (II-1) and (I-1), each of which reacts with the compound of the formula (a) by a coupling reaction, and the reaction is as follows. :

The definitions of R ₁ , R ² , R ₃ , X and n are the same as above.

The compound of formula F can be obtained from the compound of formula F 'by a coupling reaction, and the reaction is as follows:

또는

이고; G₁은 O, NR₆, S또는 C이고; n은 1 내지 3의 정수이고; R₅는 COOR₃, CN, OTf, OTs, OMs, 할로겐, OH, CHO, 탄소-탄소 이중 결합 또는 탄소-탄소 삼중 결합이고; R₁, R², R₃, R₆은 각각 독립적으로 수소 또는 저 치환된 알킬기이다. X의 정의는 위와 동일하다.The E part of formula F, F '

or

ego; G ₁ is O, NR ₆ , S or C; n is an integer from 1 to 3; R ₅ is COOR ₃ , CN, OTf, OTs, OMs, halogen, OH, CHO, carbon-carbon double bond or carbon-carbon triple bond; R ₁ , R ² , R ₃ and R ₆ are each independently hydrogen or a low substituted alkyl group. The definition of X is the same as above.

The coupling reaction is carried out in the presence of a catalyst. The catalyst is a compound of nickel, palladium or a mixture of these compounds and ligands. The nickel compound may be a compound of Ni having various valences, preferably nickel bromide and nickel acetylacetonate. The palladium compound may be a compound of Pd having various valences, preferably palladium dichloride and tetrakis triphenylphosphine palladium. These ligands are 2-2'-bipyridine, terpyridine, phenanthroline or derivatives thereof, preferably 2-2'-bipyridine; The metal is Cu, Zn, Fe, Mn, Mg, salts thereof, and the like, more preferably Mn and salts thereof.

The present invention further provides another method for preparing compound II-2 from the compound of substituted phenylacetic acid reacted with acyl chloride by Friedel-Craft acylation reaction.

The definitions of these R ₁ , R ² , R ₃ , X and n are the same as above.

Further, substituted phenylacetic acid and adipic anhydride (n = 1) are reacted, followed by reaction with alcohol by esterification to give compound II-2.

The definitions of these R ₁ , R ² , R ₃ , X and n are the same as above.

Alcohols are methanol, ethanol and the like commonly used in the art.

Another method for preparing compound II-2 is obtained from a compound of substituted phenylacetic acid which reacts with the corresponding carboxylic acid.

The definitions of these R ₁ , R ² , R ₃ , X and n are the same as above.

In the present invention, the compound of formula II-1 is obtained from a compound of benzene halide which reacts with adipic anhydride (n = 1) and then with alcohol by esterification reaction.

X is halogen, more preferably, X is bromo. The definition of R ₃ is the same as above.

Alcohols are methanol, ethanol and the like commonly used in the art.

Alternatively, the compound of formula (II-1) is obtained from benzene halides which react with acyl halides by acyl chloride reactions.

X is halogen, more preferably, X is bromo. The definition of R ₃ is the same as above.

Compounds of formula (II-1) are obtained from benzene halides which react with carboxylic acids or carboxylic esters.

X is halogen, more preferably, X is bromo. The definition of R ₃ is the same as above.

The present invention further provides a process for preparing a compound of substituted phenylacetic acid from a compound of formula (I-2) by reduction of a carbonyl group.

R ₁ and R ² are independently hydrogen or a low substituted alkyl group, and n is an integer of 1 to 3.

According to another aspect of the present invention, the present invention provides a method for preparing a substituted phenylacetic acid compound from a compound of formula I-2 'by reacting with an acid or a base by a hydrolysis reaction and then by reduction of a carbonyl group. do.

R ₁ and R ² are independently hydrogen or a low substituted alkyl group. n is an integer of 1-3.

The reducing agent is a reducing agent commonly used in the art, such as palladium carbon / hydrogen, raney-nickel, boron reducing agent, aluminum reducing agent, metal iron powder, zinc powder, Zn-Hg or hydrazine hydrate.

If n is 1, R ₁ is methyl, R ² is hydrogen, and the substituted phenylacetic acid compound is loxopropene. Roxopropene sodium is available to those skilled in the art using known methods, such as roxofene, which reacts with sodium hydroxide.

The reaction associated with the present invention can be represented by the equation diagram as follows.

Wherein X is halogen; R ₁ , R ² , R ₃ are hydrogen or a low substituted alkyl group; n is an integer form, such as 0, 1, 2, 3. More preferably, n is 1, R ₁ is methyl, R ² is hydrogen and X is bromine.

The manufacturing method provided by the present invention has the following advantageous effects. First, the present invention provides an alternative method for preparing substituted phenylacetic acid derivatives. Second, the manufacturing method of the present invention has not been taught by the prior art. Third, when benzene propanoic acid, adipic anhydride and adipic acid are used in the reaction as starting materials, the price is low and easy to obtain. Fourth, the manufacturing method provided by the present invention is suitable for large scale industrial production, and has certain economic advantages.

Dichloromethane (1.1 kg, 7 w) and anhydrous aluminum trichloride (333.4 g, 2.5 moles) were added to a 3 L reaction vessel and heated and refluxed. Next, adipic anhydride (140.8 g dissolved in 470 g of dichloromethane) was added dropwise to the reaction mixture. Adipic anhydride was produced by dehydration of adipic acid, and the dropwise addition was terminated while maintaining the temperature for 2-3 hours. Bromine benzene (157 g, 1 mole) was added dropwise to the reaction mixture at reflux, and samples were taken 3-5 hours after addition, and raw materials were detected by less than 0.5% HPLC. Methanol (160 g, 5 moles) was added dropwise while maintaining the temperature for 3-4 hours and then detected by HPLC until the reaction was complete. Cool to room temperature and add the reaction mixture to crushed ice (1.78 kg, 10 w) with sufficient stirring to give an organic phase, extract the aqueous phase with dichloromethane (178 g × 2), and combine the organic phases with 5% sodium bicarbonate ( 356 g, 2W) solution. It was then concentrated to thicken with n-heptane (356 g, 2W) to give a yellow solid A-5, followed by suction filtration and dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, white solid II-1 (253.0 g) was obtained with 84.6% (HPLC purity 98.1%).

Dichloromethane (1.1 kg, 7 w) and anhydrous aluminum trichloride (333.4 g, 2.5 moles) were added to a 3 L reaction vessel and heated and refluxed. Next, adipic anhydride (140.8 g dissolved in 470 g of dichloromethane) was added dropwise to the reaction mixture. Adipic anhydride was produced by dehydration of adipic acid, and the dropwise addition was terminated while maintaining the temperature for 2-3 hours. 2-phenyl ethyl propionate (178 g, 1 mole) was added dropwise to the reaction mixture at reflux, and samples were taken 3-5 hours after addition, and raw materials were detected by less than 0.5% HPLC. Methanol (160 g, 5 moles) was added dropwise while maintaining the temperature for 3-5 hours and then detected by HPLC until the reaction was complete. Cool to room temperature and add the reaction mixture to crushed ice (1.78 kg, 10 w) with sufficient stirring to give an organic phase, extract the aqueous phase with dichloromethane (178 g × 2), and combine the organic phases with 5% sodium bicarbonate ( 356 g, 2W) solution. It was then concentrated to thicken with n-heptane (356 g, 2W) to give a yellow solid A-5, followed by suction filtration and dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, white solid II-2 (271.3 g) was obtained with a yield of 84.8% (HPLC purity 98.4%).

Adipic acid monomethyl ester (16.00 kg) was added to a 30 L dry reaction vessel, thionyl chloride was added dropwise (11.30 kg, 0.95 equiv) while controlling the temperature at 10-25 ° C., and the dropwise addition was terminated after about 5 hours. It was then stirred for 2 hours at room temperature while detecting ethanol derivatization. After the reaction was completed, the reaction mixture was concentrated in a 25-30 ° C. rotary evaporator bath. An oil was then obtained, dried over dichloromethane (5 kg) to afford compound A-4 (16.02 kg, yield 90.0%, GC 92.8%).

Dichloromethane (8.8 kg) and anhydrous aluminum chloride (3.0 kg) were added to a 30 L reaction vessel at a temperature of 20-40 ° C. Next, after completion of the dropwise addition, Compound A-4 (2.35 kg) was added dropwise to the reaction mixture while maintaining the temperature for 2 hours. Bromine benzene (1.76 kg) was added dropwise to the reaction mixture and terminated after 0.5 hours, then anhydrous aluminum chloride (3.0 kg) was added while maintaining the temperature at 20-25 ° C. for 10-14 hours, and then the reaction was completed. This was detected by HPLC. The reaction mixture was added to crushed ice (20 kg) while adding crushed ice to control the temperature below 30 ° C. The organic phase was obtained and the aqueous phase was extracted with dichloromethane (1Kg × 2), then the combined organic phases were washed with 5% sodium bicarbonate solution and dried over anhydrous sodium sulfate. Then it was concentrated to give crude product (3.1 Kg), thickened with n-heptane (3.5 Kg) for 1 hour at 20-40 ° C. and filtered by suction, then n-heptane (2.0 Kg × 2) Washed. The solid obtained was dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, the compound of formula II-1 (2.95 Kg) was obtained in 88% yield (HPLC purity 97.6%).

Dichloromethane (800 g) and anhydrous aluminum chloride (200 g) were added to a 2 L reaction vessel at a temperature of 20-40 ° C. Next, after completion of the dropwise addition, Compound A-4 (195.8 g) was added dropwise to the reaction mixture while maintaining the temperature for 2 hours. 2-phenyl ethyl propionate (178 g) was added dropwise to the reaction mixture and terminated after 0.5 hour, then anhydrous aluminum chloride (60 g) was added while maintaining the temperature at 20-25 ° C. for 10-14 hours, and then the reaction was completed. HPLC was detected until The reaction mixture was added to the crushed ice (500 g) while adding crushed ice to adjust the temperature to below 30 ° C. An organic phase was obtained and the aqueous phase was extracted with dichloromethane (100 g × 2), then the combined organic phases were washed with 5% sodium bicarbonate solution and dried over anhydrous sodium sulfate. Then it was concentrated to give crude product (310 g), thickened with n-heptane (200 g) at 20-40 ° C. for 1 hour, subjected to suction filtration, and then with n-heptane (100 g × 2) Washed. The solid obtained was dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, compound (283.5 g) of formula II-2 was obtained in a yield of 88.6% (HPLC purity> 97.8%).

Toluene (100 g), Compound II-1 (29.9 g) and sodium amide (3.9 g) were added to a 1 L reaction vessel while raising the temperature to reflux and maintaining the temperature for 3-4 hours, with less than 0.2% HPLC Raw material was detected. Cool to room temperature, filter to obtain filtrate, adjust to pH = 6 by adding acetic acid and wash with 5% sodium bicarbonate solution (50 g × 3). Then it was concentrated to give crude product (310 g), thickened with n-heptane and subjected to suction filtration, followed by washing with n-heptane. The solid obtained was dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, white solid I-1 (24.5 g) was obtained with a yield of 92.0% (HPLC purity 98.1%).

250 ml of N-N'-dimethyl formamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g) and trifluoro acetic acid (0.034 g) Was added to the reaction vessel of and heated to a temperature of 80-85 ° C. Next, Compound II-1 (29.9 g dissolved in 13.66 g of 2-chloropropionic acid ethyl ester) was added dropwise to the reaction mixture, and then the temperature was maintained for 30 minutes after completion of the dropwise addition, followed by HPLC of less than 0.2%. Was detected. Cooled to room temperature, adjusted to pH = 6 by adding 1N hydrochloric acid, extracted with EA (100 g × 2), and then combined the organic phases and washed with 5% sodium bicarbonate solution (30 g). This was then concentrated to give crude product, which was then subjected to high vacuum distillation to give 26.33 g of compound II-2 in 82.3% yield (HPLC purity> 99.2%).

Toluene (960 g, 3w), compound II-2 (320.4 g, 1 mole) and sodium amide (39 g, 1.0 mole) were added to reflux by raising the temperature to reflux and maintaining the temperature for 2 hours by a large amount of gas evolution (ammonia). It was added to 3 L of reaction vessel. The system then became viscous and after reacting the reaction mixture continuously at that temperature for 2 hours, the system gradually became thinner. After 4 hours reaction, the raw material was detected by less than 0.5% HPLC. Cool to room temperature, adjust acetic acid to pH = 6, filter, wash the filtrate with 5% sodium bicarbonate solution (320g × 3), concentrate the organic phase to give crude product, then n-heptane Suction filtration was performed at (640 g, 2 W). The solid obtained was dried in a vacuum oven at 40-45 ° C. for 10-16 hours. Finally, white solid I-2 (267.0 g) was obtained in a yield of 92.6% (HPLC purity> 98.2%).

250 ml of N-N'-dimethyl formamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g) and trifluoro acetic acid (0.034 g) Was added to the reaction vessel and heated to a temperature of 80-85 ° C. Next, Compound I-1 (29.9 g dissolved in 13.66 g of 2-chloropropionic acid ethyl ester) was added dropwise to the reaction mixture, after which the dropping was completed, the temperature was maintained for 30 minutes, and the raw material was less than 0.2% HPLC. Was detected. Cooled to room temperature, adjusted to pH = 6 by adding 1N hydrochloric acid, extracted with EA (100 g × 2), and then combined the organic phases and washed with 5% sodium bicarbonate solution (30 g). This was then concentrated to give crude product, which was then subjected to high vacuum distillation to give 26.33 g of compound I-2 in 82.3% yield (HPLC purity> 99.2%).

Isopropanol (1.5 kg), Compound I-2 (576.7 g, 2 mol) and palladium carbon (28.8 g) were added to a 3L autoclave in H ₂ atmosphere under ventilation for 2 hours at a temperature of 1.2-1.4 MPa and 100-110 ° C. The raw material was added and detected by less than 0.5% HPLC. After cooling to room temperature, the reaction mixture was filtered and washed with isopropanol (200 g). Then it was concentrated to give crude product (539.9 g) of oil compound I-3 in yield 98.4% (HPLC purity 98.1%).

Methanol (1 kg), Compound II-2 '(287.3 g, 1 mol) and sodium methoxide solid (81 g, 1.5 mol) were added to a 3 L reaction vessel and heated to reflux for 3 hours while maintaining the temperature. After the reaction was completed, it was cooled to room temperature and concentrated. The obtained residue was dissolved in ethyl acetate (300 g), washed with water (50 g), dried and concentrated to give compound I-2 '(283.2 g) in yield 98.6% (HPLC purity 98.7%).

10% hydrochloric acid (1Kg) and compound I-2 '(283.2g) were added to a 3L reaction vessel and heated to 50-55 ° C and the temperature was maintained for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, extracted with ethyl acetate (300 g), and the water phase was extracted once with ethyl acetate. The organic phases were combined, dried and concentrated to give compound I-2 (266.1 g) in yield 98.4% (HPLC purity 98.7%).

Isopropanol (1.5 kg), Compound I-2 (266.1 g) and palladium carbon (28.8 g) are added to a 3L autoclave in H ₂ atmosphere under ventilation at a temperature of 1.2-1.4 MPa and 100-110 ° C. for 2 hours, Raw material was detected by less than 0.5% HPLC. After cooling to room temperature, the reaction mixture was filtered and washed with isopropanol (200 g). Then it was concentrated to give crude product (248.1 g) of oil compound I-3 in yield 98% (HPLC purity 98.3%).

Claims (11)

A compound of formula F having the structure as shown below:

Here, the E part of general formula F

or

ego; G is CN or COOR ² and G ₁ is O, NR ₆ , S or C; n is an integer from 1 to 3; R ₅ is COOR ₃ , CN, OTf, OTs, OMs, halogen, OH, CHO, carbon-carbon double bond or carbon-carbon triple bond; R ₁ , R ² , R ₃ and R ₆ are each independently hydrogen or a low substituted alkyl group. The compound of claim 1, wherein the compound is a compound of Formula F-1, Formula F-2, Formula F-3, or Formula F-4:

Wherein G is CN or COOR ² and n is an integer from 1 to 3; R ₁ , R ² , R ₃ , and R ₆ are each independently hydrogen or a low substituted alkyl group. The compound of claim 1, wherein the compound is a compound of Formula II-2, Formula II-2 ′, Formula I-2 or Formula I-2 ′:

Wherein R ₁ , R ² and R ₃ are independently hydrogen or a low substituted alkyl group, and n is an integer from 1 to 3. Process for the preparation of compounds of formula (I), obtained via cyclization from compounds of formula (II):

Where R is X or

R ₁ , R ² and R ₃ are independently hydrogen or a low substituted alkyl group, n is an integer from 1 to 3; X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. Process for the preparation of the compound of formula I-2 'according to claim 3, obtained through a cyclization reaction in a base from the compound of formula II-2':

Here, R <_1> , R <^2> is a hydrogen atom or a low substituted alkyl group independently, n is an integer of 1-3. A process for preparing a compound of formula F according to claim 1, obtained through a coupling reaction with a compound of formula F ′ and a compound of formula a:

Here, the E portion of the general formula F, F '

or

ego; G ₁ is O, NR ₆ , S or C; n is an integer from 1 to 3; R ₅ is COOR ₃ , CN, OTf, OTs, OMs, halogen, OH, CHO, carbon-carbon double bond or carbon-carbon triple bond; R ₁ , R ² , R ₃ and R ₆ are each independently hydrogen or a low substituted alkyl group and X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. Obtained through a Friedel-Crafts reaction, the reaction is prepared by the process of the compounds of formulas II-2 and II-1 according to claim 3, as shown below:

Wherein R ₁ , R ² and R ₃ are each independently hydrogen or a low substituted alkyl group, n is an integer from 1 to 3; X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. A process for the preparation of substituted phenylacetic acid, obtained via carbonyl reduction from the compound of formula I-2 of claim 3 or through hydrolysis reaction from a compound of formula I-2 ', followed by carbonyl reduction.

Wherein R ₁ and R ² are each hydrogen or a low substituted alkyl group, and n is an integer of 1 to 3; The process according to claim 4 or 5, wherein the cyclization reaction is carried out in the presence of a base and the base is an alkaline earth metal salt, an alkali metal alcoholate, a hydride or an ammonia of an organic base, an inorganic base or a weak acid. The process of claim 6 wherein the bonding reaction is carried out in the presence of a catalyst, metal or metal salt, the catalyst is a mixture of a nickel compound, a palladium compound or a ligand and the metal or metal salt is Cu, Zn, Fe, Mg or Mn and Its salt. The method of claim 8, wherein the carbonyl reduction reaction is a reducing agent comprising palladium carbon / hydrogen, Raney nickel, boron reducing agent, aluminum reducing agent, metal iron powder, zinc powder, Zn-Hg and hydrazine hydrate, hydrolysis of the hydrolysis reaction The release is an acid or a base.