JP2020520974A - Method for preparing substituted phenylacetic acid derivative - Google Patents

Abstract

The present invention belongs to the field of drug synthesis, and relates to a method for preparing a substituted phenylacetic acid derivative, and particularly to a method for preparing 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid. The invention includes the Friedel-Crafts reaction, the cyclization reaction and the coupling reaction interchangeably in their order, as well as the reduction reaction. The method of preparation has not been taught or inspired by the prior art. This method of preparation is suitable for commercial scale production, while at the same time providing another technical method for the industrial production of loxolonephen sodium.

Description

Detailed Description of the Invention

[Reference of related application]
This application claims the priority of a Chinese patent application filed on Jun. 13, 2017 to the Chinese Patent Office with application number 2017104438332.1. The title of the invention is "Preparation Method of Substituted Phenylacetic Acid Derivatives". All of its contents are incorporated herein by reference.

[Field of the Invention]
The present invention belongs to the field of drug synthesis, and relates to a method for preparing a substituted phenylacetic acid derivative, and particularly to a method for preparing 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid.

[Background of the Invention]
Substituted phenylacetic acid derivatives are disclosed in US patents such as US Pat. No. 4,161,538, and the structural formulas are as follows.

In US Pat. No. 4,161,538, they are also reported to have very good effects on anti-inflammatory, analgesic and antipyretic properties.

In the structure of the above general formula, when A is oxygen, the value of n is 1, and R ¹ is methyl, it is a very typical substituted phenylacetic acid derivative of loxoprofen. Is as follows.

Loxoprofen is a propionic acid derivative drug for non-steroidal anti-inflammatory drugs. These propionic acid derivatives also include ibuprofen and naproxen. Loxoprofen is marketed in the sodium salt form by Sankyo in Brazil, Mexico and Japan. The trade names for loxoprofen sodium in Japan, Argentina and India are loxonin, oxono and loxomac. In these countries, loxoprofen sodium is used for oral administration, and in January 2006, marketing of injections in Japan was approved.

U.S. Pat. No. 4,161,538 discloses the following illustrated route for the synthesis of loxoprofen, where the value of n is 1 and R ¹ is methyl.

In Chinese journal of medicinal chemistry 20(1), 25-28, 2010, 4-methylacetophenone is used as a starting material and compound I is obtained by reduction with sodium borohydride. Direct chlorination of compound I without purification gives compound II. Compound II is cyanated in the presence of a phase transfer catalyst to give compound III. Next, compound III is hydrolyzed and acidified under alkaline heating conditions to obtain compound IV. Bromination with compound IV as an initiator with benzoyl peroxide gives compound V. Compound V is esterified with methanol to give compound VI and then condensed with 2-ethoxycarbonylcyclopentanone under alkaline conditions to give compound VII. Compound VII is then hydrolyzed and decarboxylated with heating in a system of 48% HBr and acetic acid to give loxoprofen sodium. The synthetic route is shown as follows.

Due to the good medical prospects of loxoprofen sodium, the above routes are not suitable for industrial production, so there is a need to develop new routes for loxoprofen that can be industrially synthesized.

[Outline of Invention]
The present invention provides an economical route for preparing a substituted phenylacetic acid derivative or a non-toxic pharmaceutically acceptable salt form thereof, in particular a method for preparing loxoprofen, which is different from the prior art methods. different. This method of preparation is not taught or inspired by the prior art. This preparation method uses relatively inexpensive starting materials, which are suitable for commercial scale production.

The present invention provides compounds represented by general formula F.

E part in the general formula F is

And
G is CN or COOR ² and G ₁ is O, NR ₆ , S or C;
n is an integer of 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 general formula F can be a compound of formula F-1, formula F-2, formula F-3 or formula F-4.

Wherein G is CN or COOR ² ;
n is an integer of 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 of formula II-2, formula II-2', formula I-2 or formula I-2'.

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

The present invention further provides a method of preparing a compound of general formula I from a compound of general formula II by a cyclization reaction, said reaction being shown in reaction 1 below:

Where R is X or

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

In the present invention, R ₅ is prepared from a compound of formula F which regenerates a compound having a group of OH, CHO, OTf, OTs, Oms, halogen, carbon-carbon double bond or carbon-carbon triple bond. The starting materials are those which can be converted into compounds of formula II according to existing techniques and then the subsequent reactions can be carried out.

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

The reagent for the cyclization reaction can be a base commonly used in the art. Reagents are common inorganic such as sodium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, potassium phosphate, sodium ethoxide, potassium t-butoxide, sodium hydride, calcium hydride, sodium amide, etc. It is not limited to bases or alkaline earth metal hydroxides, alkali metal salts of weak acids, or various alkali metal alkoxides, hydrides, amides and the like. At the same time, the reagents are not limited to their common organic bases, or amines, or pyridines, or imidazoles, or piperidines, or pyrroles.

When R is X, the reaction is shown as follows:

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

R is

, The reaction is shown as follows:

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

The invention further provides a method for preparing a compound of formula I-2' from a compound of formula II-2' by a cyclization reaction in the presence of a base.

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

In the present invention, the compounds of the formulas II-2 and I-2 can be obtained by reacting the compounds of the formulas II-1 and I-1 with the compound of the formula a by a coupling reaction. As shown.

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, the reaction is shown below.

The E moiety of general formulas F and F′ is

And
G ₁ is O, NR ₆ , S or C;
n is an integer of 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 thereof with a ligand. The nickel compound can be a compound of Ni with different valences, preferably nickel bromide and nickel acetylacetonate. The palladium compound may be a compound of Pd having various valences, preferably palladium dichloride and tetrakistriphenylphosphine palladium. These ligands are 2-2'-bipyridine, terpyridine, phenanthroline, or their derivatives, preferably 2-2'-bipyridine, the metal being Cu, Zn, Fe, Mn, Mg and salts etc., More preferred are Mn and salts thereof.

The present invention further provides another method of preparing compound II-2 from a substituted phenylacetic acid compound that reacts with an acyl chloride by Friedel-Crafts acylation reaction.

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

In addition, compound II-2 is obtained from a substituted phenylacetic acid compound that reacts with adipic anhydride (n=1) and then with an alcohol by an esterification reaction.

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

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

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

These definitions of 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 halogenated benzene which reacts with adipic anhydride (n=1) and then with an alcohol by an esterification reaction.

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

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

Alternatively, the compound of formula II-1 is obtained from a benzene halide that reacts with an acyl halide by an acyl chloride reaction.

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

The compounds of formula II-1 are obtained from halogenated benzene which reacts with carboxylic acids or carboxylic acid esters.

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

The present invention further provides a method for preparing substituted phenylacetic acid compounds from compounds of formula I-2 by reduction of the 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 invention, there is provided a process for the preparation of substituted phenylacetic acid compounds from compounds of formula I-2' which reacts with acids or bases by a hydrolysis reaction followed by reduction of the carbonyl group.

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

The reducing agent may be a reducing agent commonly used in the art, such as palladium carbon/hydrogen, Raney-nickel, boron reducing agent, aluminum reducing agent, metallic iron powder, zinc powder, Zn-Hg or hydrazine hydrate. Is.

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

The reactions involved in the present invention can be shown in the scheme as follows:

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

The preparation method provided by the present invention has the following beneficial effects. First, the present invention provides an alternative method for the preparation of substituted phenylacetic acid derivatives. Second, the method of preparation of the present invention is not taught in the prior art. Thirdly, when benzenepropanoic acid, adipic acid anhydride, and adipic acid are used as starting materials in the reaction, they are inexpensive and easily available. Fourth, the preparation method provided by the present invention is suitable for industrial large-scale production and has certain economic advantages.

[Detailed description]
Example 1:

Dichloromethane (1.1 kg, 7 w) and anhydrous aluminum trichloride (333.4 g, 2.5 mol) were added to a 3 L reaction kettle, heated and refluxed. Then adipic anhydride (140.8 g dissolved in 470 g dichloromethane) was added dropwise into the reaction mixture. Adipic acid anhydride was prepared by dehydration of adipic acid, and the temperature was maintained for 2 to 3 hours after the completion of dropping. Benzene bromide (157 g, 1 mol) was added dropwise to the reaction mixture at reflux and a sample was taken 3-5 hours after addition and the raw material was detected by HPLC <0.5%. Methanol (160 g, 5 mol) was added dropwise while maintaining the temperature for 3-4 hours, then detected by HPLC until the reaction was complete. After cooling to room temperature, the reaction mixture was stirred well and crushed ice (1.78 kg, 10 w) was added to obtain an organic layer, the aqueous phase was extracted with dichloromethane (178 g×2), then the organic layers were combined and 5%. It was washed with an aqueous solution of sodium hydrogen carbonate (356 g, 2 W). It was then concentrated to give a yellow solid A-5, pulped with n-heptane (356g, 2W), suction filtered and dried in a vacuum oven at 40-45°C for 10-16 hours. .. Finally, white solid II-1 (253.0 g) was obtained in a yield of 84.6% (HPLC purity 98.1%).

Example 2:

Dichloromethane (1.1 kg, 7 w) and anhydrous aluminum trichloride (333.4 g, 2.5 mol) were added to a 3 L reaction kettle, heated and refluxed. Then adipic anhydride (140.8 g dissolved in 470 g dichloromethane) was added dropwise into the reaction mixture. Adipic acid anhydride was prepared by dehydration of adipic acid, and the temperature was maintained for 2 to 3 hours after the completion of dropping. 2-Phenylethylpropionate (178 g, 1 mol) was added dropwise to the reaction mixture at reflux and a sample was taken 3-5 hours after the addition and the raw material was detected by HPLC <0.5%. Methanol (160 g, 5 mol) was added dropwise while maintaining the temperature for 3-5 hours, then detected by HPLC until the reaction was complete. After cooling to room temperature, the reaction mixture was stirred well and crushed ice (1.78 kg, 10 w) was added to obtain an organic layer, the aqueous phase was extracted with dichloromethane (178 g×2), then the organic layers were combined and 5%. It was washed with an aqueous solution of sodium hydrogen carbonate (356 g, 2 W). It was then concentrated to give a yellow solid A-5, pulped with n-heptane (356g, 2W), suction filtered and dried in a vacuum oven at 40-45°C for 10-16 hours. Finally, a white solid II-2 (271.3 g) was obtained with a yield of 84.8% (HPLC purity 98.4%).

Example 3:

Adipic acid monomethyl ester (16.00 kg) was added to a 30 L dry reaction kettle, thionyl chloride (11.30 kg, 0.95 equivalent) was added dropwise while controlling the temperature at 10 to 25° C., and after about 5 hours, added dropwise. Was completed and then stirred at room temperature for 2 hours while detecting ethanol derivatization. After completion of the reaction, the mixture was concentrated at 25 to 30°C using a rotary evaporator water bath. Then, an oily substance was obtained and dried with dichloromethane (5 kg) to obtain compound A-4 (16.02 kg, yield 90.0%, GC 92.8%).

Example 4:

Dichloromethane (8.8 kg) and anhydrous aluminum chloride (3.0 kg) were added to the 30 L reactor at a temperature of 20-40°C. Then, after the dropping was completed, the compound A-4 (2.35 kg) was dropped into the reaction mixture while maintaining the temperature for 2 hours. Benzene bromide (1.76 kg) was added dropwise to the reaction mixture, the reaction was completed after 0.5 hour, and anhydrous aluminum chloride (3.0 kg) was added for 10 to 14 hours while maintaining the temperature at 20 to 25°C, and the reaction was completed Until it was detected by HPLC. The reaction mixture was added to crushed ice (20 kg) while controlling the temperature to <30° C. by adding crushed ice. An organic layer was obtained, the aqueous phase was extracted with dichloromethane (1 kg x 2), then the organic layers were combined, washed with 5% sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Then it was concentrated to give a crude product (3.1 kg), pulped with n-heptane (3.5 kg) at 20-40° C. for 1 h, suction filtered and n-heptane (2 kg). It was washed with 0.0 kg×2). The resulting solid 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 with a yield of 88% (97.6% HPLC purity).

Example 5:

Dichloromethane (800 g) and anhydrous aluminum chloride (200 g) were added to a 2 L reaction kettle at a temperature of 20-40°C. Then, after the dropping was completed, the compound A-4 (195.8 g) was added dropwise to the reaction mixture while maintaining the temperature for 2 hours. 2-Phenylethylpropionate (178 g) was added dropwise to the reaction mixture, the addition was completed after 0.5 hours, and anhydrous aluminum chloride (60 g) was added while maintaining the temperature at 20 to 25° C. for 10 to 14 hours to complete the reaction. Until it was detected by HPLC. The reaction mixture was added to crushed ice (500 g), controlling the temperature to <30° C. by adding crushed ice. An organic layer was obtained, the aqueous phase was extracted with dichloromethane (100 g x 2), then the organic layers were combined, washed with 5% sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Then, it was concentrated to obtain a crude product (310 g), pulped with n-heptane (200 g) at 20 to 40° C. for 1 hour, suction-filtered, and washed with n-heptane (100 g×2). The resulting solid was dried in a vacuum oven at 40-45°C for 10-16 hours. Finally, the compound of formula II-2 (283.5 g) was obtained with a yield of 88.6% (HPLC purity>97.8%).

Example 6:

Toluene (100 g), compound II-1 (29.9 g) and sodium amide (3.9 g) were added to a 1 L reaction kettle and the raw material was subjected to HPLC while heating to reflux temperature and maintaining the temperature for 3 to 4 hours. Detected by <0.2%. The mixture was cooled to room temperature, filtered to obtain a filtrate, adjusted to pH=6 by adding acetic acid, and washed with a 5% sodium hydrogen carbonate solution (50 g×3). It was then concentrated to give a crude product (310 g), pulped with n-heptane, suction filtered and washed with n-heptane. The resulting solid 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%).

Example 7:

N-N'-dimethylformamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g), and trifluoroacetic acid (0.034 g) were added. , 250 ml reaction kettle and heated to a temperature of 80-85°C. Then, Compound I-1 (29.9 g was dissolved in 2-chloropropionic acid ethyl ester 13.66 g) was added dropwise to the reaction solution while maintaining the temperature for 30 minutes after completion of the addition, and the raw material was analyzed by HPLC<0.2. Detected in %. After cooling to room temperature and adjusting the pH to 6 by adding 1N hydrochloric acid, the mixture was extracted with EA (100 g×2), and the organic layers were combined and washed with 5% sodium hydrogen carbonate solution (30 g). Then, the reaction mixture was concentrated to obtain a crude product, which was subjected to high vacuum distillation to obtain 26.33 g of compound II-2 in a yield of 82.3% (HPLC purity>99.2%).

Example 8:

Toluene (960 g, 3 w), compound II-2 (320.4 g, 1 mol) and sodium amide (39 g, 1.0 mol) were added to a 3 L reaction kettle and a large amount of gas (ammonia) was released. The temperature was raised to reflux and maintained at that temperature for 2 hours. After that, the system became viscous and after reacting the reaction mixture continuously for 2 hours, the system gradually became thinner. After 4 hours reaction, raw material was detected by HPLC <0.5%. Cooled to room temperature, adjusted to pH=6 by adding acetic acid, then filtered, the filtrate was washed with 5% sodium hydrogen carbonate solution (320 g×3), and the organic layer was concentrated to obtain a crude product, It was then pulped with n-heptane (640 g, 2w) and suction filtered. The resulting solid was dried in a vacuum oven at 40-45°C for 10-16 hours. Finally, white solid I-2 (267.0 g) was obtained with a yield of 92.6% (HPLC purity> 98.2%).

Example 9:

N-N'-dimethylformamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g), and trifluoroacetic acid (0.034 g) were added. It was added to a 250 ml reaction kettle and heated to a temperature of 80-85°C. Then, compound I-1 (29.9 g was dissolved in 2-chloropropionic acid ethyl ester 13.66 g) was added dropwise to the reaction solution while maintaining the temperature for 30 minutes after completion of the addition, and the raw material was analyzed by HPLC<0.2. Detected in %. After cooling to room temperature and adjusting the pH to 6 by adding 1N hydrochloric acid, the mixture was extracted with EA (100 g×2), the organic layers were combined and washed with 5% sodium hydrogen carbonate solution (30 g). Then, the reaction mixture was concentrated to obtain a crude product, which was subjected to high vacuum distillation to obtain 26.33 g of compound II-2 in a yield of 82.3% (HPLC purity>99.2%).

Example 10:

Isopropanol (1.5 kg), compound I-2 (576.7 g, 2 mol) and palladium carbon (28.8 g) were added to a 3 L autoclave in an H ₂ atmosphere, 1.2-1.4 mPa, 100-. Bubbling at 110° C. for 2 hours, raw material was detected by HPLC<0.5%. Cooled to room temperature, the reaction mixture was filtered and washed with isopropanol (200g). Next, this was concentrated to obtain a crude product of oil compound I-3 (539.9 g) in a yield of 98.4% (HPLC purity: 98.1%).

Example 11:

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 reactor and heated while maintaining the temperature for 3 hours, Refluxed. After the reaction was completed, it was cooled to room temperature, filtered, 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 a yield of 98.6% (HPLC purity 98. 0.7%).

Example 12:

10% Hydrochloric acid (1 kg) and compound I-2′ (283.2 g) were added to a 3 L reaction kettle, heated to 50 to 55° C., and the temperature was maintained for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, extracted with ethyl acetate (300 g), and the aqueous phase was extracted once with ethyl acetate. The organic layers were combined, dried and concentrated to give compound I-2 (266.1 g) in 98.4% yield (HPLC purity 98.7%).

Isopropanol (1.5 kg), compound I-2 (266.1 g), and palladium carbon (28.8 g) were added to a 3 L autoclave in an H ₂ atmosphere, 1.2 to 1.4 mPa, 100 to 110°C. Bubbling in for 2 hours, raw material was detected by HPLC <0.5%. Cooled to room temperature, the reaction mixture was filtered and washed with isopropanol (200g). Next, this was concentrated to obtain a crude product of oil compound I-3 (248.1 g) in a yield of 98% (HPLC purity: 98.3%).

N-N'-dimethylformamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g), and trifluoroacetic acid (0.034 g) were added. , 250 ml reaction kettle and heated to a temperature of 80-85°C. Then, compound II-1 (29.9 g was dissolved in 2-chloropropionic acid ethyl ester 13.66 g) was added dropwise to the reaction solution while maintaining the temperature for 30 minutes after the completion of the addition, and the raw material was subjected to HPLC<0.2. Detected in %. After cooling to room temperature and adjusting the pH to 6 by adding 1N hydrochloric acid, the mixture was extracted with EA (100 g×2), and the organic layers were combined and washed with 5% sodium hydrogen carbonate solution (30 g). Then, the reaction mixture was concentrated to obtain a crude product, which was subjected to high vacuum distillation to obtain 26.33 g of compound II-2 in a yield of 82.3% (HPLC purity>99.2%).

N-N'-dimethylformamide (100 g), nickel bromide (1.53 g), 2-2'-bipyridyl (1.09 g), manganese powder (6.05 g), and trifluoroacetic acid (0.034 g) were added. It was added to a 250 ml reaction kettle and heated to a temperature of 80-85°C. Then, compound I-1 (29.9 g was dissolved in 2-chloropropionic acid ethyl ester 13.66 g) was added dropwise to the reaction solution while maintaining the temperature for 30 minutes after completion of the addition, and the raw material was analyzed by HPLC<0.2. Detected in %. After cooling to room temperature and adjusting the pH to 6 by adding 1N hydrochloric acid, the mixture was extracted with EA (100 g×2), the organic layers were combined and washed with 5% sodium hydrogen carbonate solution (30 g). Then, the mixture was concentrated to obtain a crude product, which was subjected to high vacuum distillation to obtain 26.33 g of Compound I-2 in a yield of 82.3% (HPLC purity>99.2%).

In the present invention, R ₅ is prepared from a compound of formula F, which represents a compound having a group of COOR ₃ , CN, OH, CHO, OTf, OTs, Oms, halogen, carbon-carbon double bond or carbon-carbon triple bond. To be done. The starting materials are those which can be converted into compounds of formula II according to existing techniques and then the subsequent reactions can be carried out.

Claims (11)

Compounds of general formula F having the structure shown below:
E part in the general formula F is
And
G is CN or COOR ² and G ₁ is O, NR ₆ , S or C;
n is an integer of 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. A compound according to claim 1 which is a compound of formula F-1, formula F-2, formula F-3 or formula F-4:
Wherein G is CN or COOR ² ;
n is an integer of 1 to 3;
R ₁ , R ² , R ₃ and R ₆ are independently hydrogen or a low-substituted alkyl group. A compound according to claim 1 which 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;
n is an integer of 1 to 3. Methods for preparing compounds of formula I, obtained by cyclization reaction from compounds of formula II:
In the formula, R is X or
And
R ₁ , R ² and R ₃ are independently hydrogen or a low-substituted alkyl group;
n is an integer of 1 to 3;
X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. Process for the preparation of compounds of formula I-2' according to claim 3, obtained from compounds of formula II-2' by cyclization reaction in the presence of a base:
In the formula, R ₁ and R ² are independently a hydrogen atom or a low-substituted alkyl group;
n is an integer of 1 to 3. A process for the preparation of a compound of formula F according to claim 1, obtained by a coupling reaction from a compound of formula F'and formula a:
Formula F′ and the E portion of Formula F are
And
G ₁ is O, NR ₆ , S or C;
n is an integer of 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,
X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. A method for preparing a compound of formula II-2 or formula II-1 according to claim 3, obtained by the Faucoult reaction, which is the reaction shown below:
Wherein R ₁ , R ² and R ₃ are each independently hydrogen or a low-substituted alkyl group;
n is an integer of 1 to 3;
X is halogen, OTf, OTs, OMs, silyl, thioalkyl or ammonia alkyl. A method for preparing a substituted phenylacetic acid, which is obtained from the compound of formula I-2 according to claim 3 by a carbonyl reduction reaction or is obtained by a carbonyl reduction reaction after a hydrolysis reaction of the compound of formula I-2′:
Wherein R ₁ and R ² are each hydrogen or a low-substituted alkyl group;
n is an integer of 1 to 3. The cyclization reaction is carried out in the presence of a base,
The preparation method according to claim 4 or 5, wherein the base is an organic base, an inorganic base, or a weak alkaline rare earth acid salt, an alkali metal alcoholate, a hydride or an ammonide. The coupling reaction is carried out in the presence of a catalyst, a metal or a metal salt,
The catalyst is a nickel compound, a palladium compound or a mixture thereof with a ligand,
The preparation method according to claim 6, wherein the metal or metal salt is Cu, Zn, Fe, Mg or Mn and a salt thereof. The carbonyl reduction reaction is carried out in the presence of a reducing agent,
The reducing agent is palladium carbon/hydrogen, Raney nickel, boron reducing agent, aluminum reducing agent, metallic iron powder, zinc powder, Zn-Hg or hydrazine hydrate,
The preparation method according to claim 8, wherein the hydrolysis reagent for the hydrolysis reaction is an acid or a base.