WO2008078350A2 - Process for the preparation of fluorophenylacetic acids and derivatives thereof - Google Patents

Process for the preparation of fluorophenylacetic acids and derivatives thereof Download PDF

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WO2008078350A2
WO2008078350A2 PCT/IT2007/000860 IT2007000860W WO2008078350A2 WO 2008078350 A2 WO2008078350 A2 WO 2008078350A2 IT 2007000860 W IT2007000860 W IT 2007000860W WO 2008078350 A2 WO2008078350 A2 WO 2008078350A2
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formula
process according
compound
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acid
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WO2008078350A3 (en
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Alessandro Falchi
Mariano Stivanello
Siro Serafini
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F.I.S. Fabbrica Italiana Sintetici S.P.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids

Definitions

  • Object of the present invention is a process for the preparation of fluorophenylacetic acids and derivatives thereof, Particularly 2,4, 5-trifluorophenylacetic acid.
  • Fluorophenylacetic acids are useful intermediates for the preparation of several pharmacologically active compounds.
  • trifluorophenylacetic acids are employed in the preparation of dipeptidyl peptidase-IV enzyme inhibitors. These drugs are useful in the treatment of diabetes, Particularly of type II diabetes (see, for example, WO 97/40832; WO 98/19998; US 5939560; Bioorg. Med. Chem. Lett., 6, 1163-1166 (1996); Bioorg. Med. Chem. Lett., 6, 2745-2748 (1996)).
  • US 5306833 claims a process for the preparation of phenyl acetic acids substituted in the aromatic ring with electron-giving groups by reduction of the relative mandelic acids.
  • the p-hydroxyphenylacetic acid is achieved from sodium p-hydroxymandelate
  • the p-methoxyphenylacetic acid is achieved from sodium p- methoxymandelate .
  • this method turns out to be applicable only to electron-rich substrates, and it does not work with substrates with electron-withdrawing substitutes such as fluorine.
  • X represents 0 to 4 groups selected from fluorine, chlorine, bromine, iodine, or trifluoromethyl
  • Z represents a COOH, COOR 1 , COCl, COBr, COI, CN, CONR 2 R 3 , COOCOR 1 group
  • R 1 represents C1-C4 alkyl, benzyl, phenyl or a group
  • R 2 and R 3 independently represent hydrogen, or C1-C4 alkyl , comprising the steps of : a) reacting the compound of Formula 2
  • X and Z have the above meaning
  • W represents chlorine, bromine, iodine, or -OSO 2 R 4
  • R 4 represents methyl, trifluoromethyl, or phenyl, optionally substituted with one or more groups selected from halogen, methyl, and nitro
  • the fluorine atom is preferably in the 4 th position;
  • X preferably represents 1 to 4 fluorine atoms, more preferably 2 fluorine atoms, still more preferably 2 fluorine atoms in the 2 nd and 5 th positions;
  • Z preferably represents COOH, COORi, COCl, or COBr, more preferably COOH.
  • R 1 preferably represents methyl, ethyl, isopropyl, t- butyl, or benzyl, more preferably methyl;
  • R 4 preferably represents methyl, trifluoromethyl, phenyl, 4-metilphenyl, 4-nitrophenyl, or 4-bromophenyl;
  • W preferably represents chlorine or -OSO 2 CH 3 .
  • Z represents a COORi group
  • the invention comprises the optional step of reacting the compound of Formula 2, in which Z represents a group selected from COOH, COCl, COBr, and COI, with an alcohol of Formula RiOH.
  • Such derivatizati ⁇ n is advantageous, since it allows transforming the carboxyl group, otherwise reactive with the halogenating or sulfonilating agents, in an ester - thus not reactive in the reaction conditions of step a) - group, thus allowing a suppression of the side-reactions and providing the further advantage of being able to work with a more concentrated solution.
  • This derivatization can be carried out according to the procedures well known in the synthetic organic chemistry.
  • the invention comprises the optional step of hydrolyzing the compound of Formula 1, in which Z 5 represents a COOR 1 group, to yield the compound of Formula 1 in which Z represents a COOH group, preferably in the presence of an acid or a base.
  • the hydrolysis can be carried out according to the procedures well known in the synthetic organic chemistry. io A particularly preferred embodiment of the invention is a process for the preparation of the 2,4,5- trifluorophenylacetic acid of Formula 4
  • Z represents a group selected from COOH, COCl, COBr, and COI, with a alcohol of Formula R x OH, in which R 1 has the meaning as before, to yield the ester of the 2,4,5-trifluoromandelic acid of Formula 6
  • a further aspect of the present invention is that in the compounds of Formula 9
  • W represents chlorine or -OSO 2 CH 3 ,
  • Z represents a COOH; COORi, COCl, COBr, COI, CN, CONR 2 R 3 ,
  • R 1 represents C1-C4 alkyl, benzyl, phenyl, or a group
  • R 2 and R 3 independently represent hydrogen or C1-C4 alkyl .
  • the halogenating agent is preferably selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous tribromide, phosphorous pentabromide, and hydrobromic acid, more preferably is thionyl chloride.
  • the halogenation reaction is preferably carried out in the absence of a solvent, or in a solvent selected from the group consisting of toluene, xylene, and methylene chloride, more preferably in the absence of a solvent, at a temperature ranging from 45 to 80° C, and in a period of time ranging from 6 to 24 hours.
  • the reaction is promoted by the presence of an excess of reagent which can be removed by distillation at the end of the reaction and by using high temperatures, which allow the progression and the removal of the by-products which form during the reaction by distillation.
  • the sulfonilating agent is preferably a compound of Formula Q-SO 2 IU, in which R 4 has the above meaning and Q represents chlorine, bromine, iodine, -OSO 2 R 4 .
  • the sulfonilation reaction is preferably carried out in a solvent selected from the group consisting of toluene, xylene, and methylene chloride, preferably in methylene chloride, at a temperature ranging from 20 to 60° C in a period of time ranging from 6 to 12 hours.
  • the reaction is preferably carried out in the presence of a base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, more preferably triethylamine.
  • the reducing agent is preferably selected from the group consisting of sodium dithionite, zinc, iron, tin, lithium aluminium hydride, sodium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, hydrogen, cyclohexadiene, ammonium formate, and formic acid, more preferably it is sodium dithionite.
  • the reaction is carried out in the presence of a catalyst, preferably palladium- or nickel-based.
  • a catalyst preferably palladium- or nickel-based.
  • formic acid the reaction is carried out in the presence of an amine, preferably triethylamine.
  • the reduction is preferably carried out in a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, water, acetone, methylethylketone, methylisobutylketone, dimethylformamide, and N-methylpyrrolidone, more preferably in methanol, at a temperature ranging from 20 to 80° C and in a period of time ranging from 2 to 18 hours .
  • a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, water, acetone, methylethylketone, methylisobutylketone, dimethylformamide, and N-methylpyrrolidone, more preferably in methanol, at a temperature ranging from 20 to 80° C and in a period of time ranging from 2 to 18 hours .
  • the 2, 4 , 5-trifluorophenylacetic acid ester can be hydrolyzed to the 2,4, 5-trifluorophenylacetic acid of Formula 4 in a yield above 90% and with purity above 99%. If needed, such product can be purified by crystallization, preferably from toluene and eptane, ethyl acetate and eptane, fc-butyl methyl ether and eptane, or isopropyl acetate and eptane in 90% yield and purity above 99% (HPLC) .
  • the compounds of Formula 2 and, particularly, the 2,4,5- trifluoromandelic acid, which are employed in the present invention can be prepared according to the teachings of EP 411252 in association with WO 2003/084914, or US 7019166.
  • a process for the preparation of compounds of Formula 2 has been employed, comprising the steps of: c) reacting a fluorobenzene of Formula 10
  • the catalyst for Friedel-Crafts acylations is preferably selected from aluminium trichloride, iron trichloride, aluminium tribromide, and iron tribromide.
  • the base in the step d) is preferably selected from the alkaline and earth-alkaline metal hydroxides and carbonates, more preferably it is sodium hydroxide or potassium hydroxide.
  • the present invention provides a simple preparation method for the compounds of Formula 1 having the following advantages: 1. it is applicable to the phenyl acetic acids substituted on the aromatic ring with electron- withdrawing groups; 2. it employs less expensive raw materials compared to those which are used in the known processes; 3. it is operatively simple and easily transferable to a productive plant;
  • 200 g aluminium trichloride in 100 g 1,2,4-trifluorobenzene is suspended, the mixture is heated to 60° C, and 167 g di-chloroacetyl chloride is added dropwise.
  • GC conversion is completed
  • the mixture is cooled to room temperature and it is taken up again with methylene chloride and water. The layers are separated and the organic layer is concentrated in vacuum.
  • the reaction raw-material is then added dropwise on a mixture of 900 mL water and 90 g sodium hydroxide at 60° C.
  • 1H-NMR 300 MHz, DMSO-d 6 ) : ⁇ (ppm) : 3.60 (s, 2H); 7.42- 7.53 (m, 2H); 12.5 (bs, IH).
  • the HPLC control indicates the creation of the 2,4,5- trifluoromandelic acid ethyl ester, but not of the 2,4, 5-trifluorophenylacetic acid or the ethyl ester thereof .

Abstract

The object of the present invention is a process for the preparation of fluorophenylacetic acids and derivatives thereof, particularly of 2,4, 5-trifluorophenylacetic acid, starting from the corresponding mandelic acids.

Description

DESCRIPTION
"Process for the preparation of fluorophenylacetic acids and derivatives thereof" Technical field of the invention Object of the present invention is a process for the preparation of fluorophenylacetic acids and derivatives thereof, Particularly 2,4, 5-trifluorophenylacetic acid. Background of the art Fluorophenylacetic acids are useful intermediates for the preparation of several pharmacologically active compounds. Particularly, trifluorophenylacetic acids are employed in the preparation of dipeptidyl peptidase-IV enzyme inhibitors. These drugs are useful in the treatment of diabetes, Particularly of type II diabetes (see, for example, WO 97/40832; WO 98/19998; US 5939560; Bioorg. Med. Chem. Lett., 6, 1163-1166 (1996); Bioorg. Med. Chem. Lett., 6, 2745-2748 (1996)).
US 20040068141 claims a process for the preparation of fluorophenylacetic acids from aryl halides according to the way described in the Scheme 1 (X is chlorine, bromine, or iodine) : Scheme 1
Figure imgf000003_0001
hydrolyzing agent
Figure imgf000003_0002
However, in the first step high amounts of copper salts should be used, with obvious problems of extraction and disposal of the heavy metal, and the aryl halide which is used often has a high cost.
US 5306833 claims a process for the preparation of phenyl acetic acids substituted in the aromatic ring with electron-giving groups by reduction of the relative mandelic acids. Particularly, the p-hydroxyphenylacetic acid is achieved from sodium p-hydroxymandelate, and the p-methoxyphenylacetic acid is achieved from sodium p- methoxymandelate . However, this method turns out to be applicable only to electron-rich substrates, and it does not work with substrates with electron-withdrawing substitutes such as fluorine. More recently, US 7012147 discloses the reduction of 2- hydroxy-2- (5-indolinyl) acetic acids to the corresponding 2-indolinylacetic acids by catalytic hydrogenation in the presence of palladium and a strong acid. As in the previous example, only one electron-rich aromatic ring is able to stabilize the carbocation intermediate at alpha to the carboxyl, thus promoting the removal of the OH group . Brief description of the invention The present invention relates to a process for the preparation of fluorophenylacetic acids and derivatives thereof, Particularly 2,4, 5-trifluorophenylacetic acid, starting from the corresponding mandelic acids. Detailed description of the invention It has been surprisingly found a process for the preparation of compounds of Formula 1
Figure imgf000004_0001
1 wherein X represents 0 to 4 groups selected from fluorine, chlorine, bromine, iodine, or trifluoromethyl, Z represents a COOH, COOR1, COCl, COBr, COI, CN, CONR2R3, COOCOR1 group, R1 represents C1-C4 alkyl, benzyl, phenyl or a
Figure imgf000005_0001
group,
R2 and R3 independently represent hydrogen, or C1-C4 alkyl , comprising the steps of : a) reacting the compound of Formula 2
Figure imgf000005_0002
2 in which X and Z have the above meaning, with a halogenating agent or a sulfonilating agent to yield the compound of Formula 3
Figure imgf000005_0003
3 wherein X and Z have the above meaning, W represents chlorine, bromine, iodine, or -OSO2R4, and R4 represents methyl, trifluoromethyl, or phenyl, optionally substituted with one or more groups selected from halogen, methyl, and nitro, b) reacting the compound of Formula 3 with a reducing agent . The fluorine atom is preferably in the 4th position; X preferably represents 1 to 4 fluorine atoms, more preferably 2 fluorine atoms, still more preferably 2 fluorine atoms in the 2nd and 5th positions; Z preferably represents COOH, COORi, COCl, or COBr, more preferably COOH.
R1 preferably represents methyl, ethyl, isopropyl, t- butyl, or benzyl, more preferably methyl; R4 preferably represents methyl, trifluoromethyl, phenyl, 4-metilphenyl, 4-nitrophenyl, or 4-bromophenyl; W preferably represents chlorine or -OSO2CH3. Where, in the compounds of Formula 2, Z represents a COORi group, the invention comprises the optional step of reacting the compound of Formula 2, in which Z represents a group selected from COOH, COCl, COBr, and COI, with an alcohol of Formula RiOH. Such derivatizatiσn is advantageous, since it allows transforming the carboxyl group, otherwise reactive with the halogenating or sulfonilating agents, in an ester - thus not reactive in the reaction conditions of step a) - group, thus allowing a suppression of the side-reactions and providing the further advantage of being able to work with a more concentrated solution. This derivatization can be carried out according to the procedures well known in the synthetic organic chemistry.
Where, in the compounds of Formula 1, Z represents a COOH group, the invention comprises the optional step of hydrolyzing the compound of Formula 1, in which Z 5 represents a COOR1 group, to yield the compound of Formula 1 in which Z represents a COOH group, preferably in the presence of an acid or a base. The hydrolysis can be carried out according to the procedures well known in the synthetic organic chemistry. io A particularly preferred embodiment of the invention is a process for the preparation of the 2,4,5- trifluorophenylacetic acid of Formula 4
Figure imgf000007_0001
4 comprising the steps of: B) reacting the compound of Formula 5
Figure imgf000007_0002
5 f) wherein Z represents a group selected from COOH, COCl, COBr, and COI, with a alcohol of Formula RxOH, in which R1 has the meaning as before, to yield the ester of the 2,4,5-trifluoromandelic acid of Formula 6
Figure imgf000008_0001
5 6 g) reacting the ester of the 2,4,5-trifluoromandelic acid of Formula 6 with a halogenating agent to give the compound of Formula 7, in which W represents chlorine, bromine, or iodine, or with a sulfonilating agent to io give the compound of Formula 7, in which W represents - OSO2R4 ,
Figure imgf000008_0002
h) reacting the compound of Formula 7 with a reducing agent to yield the compound of Formula 8,
Figure imgf000009_0001
8 hydrolizing the compound of Formula 8.
A further aspect of the present invention is that in the compounds of Formula 9
Figure imgf000009_0002
wherein W represents chlorine or -OSO2CH3,
Z represents a COOH; COORi, COCl, COBr, COI, CN, CONR2R3,
COOCORi group,
R1 represents C1-C4 alkyl, benzyl, phenyl, or a group
Figure imgf000009_0003
R2 and R3 independently represent hydrogen or C1-C4 alkyl .
The halogenating agent is preferably selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous tribromide, phosphorous pentabromide, and hydrobromic acid, more preferably is thionyl chloride. The halogenation reaction is preferably carried out in the absence of a solvent, or in a solvent selected from the group consisting of toluene, xylene, and methylene chloride, more preferably in the absence of a solvent, at a temperature ranging from 45 to 80° C, and in a period of time ranging from 6 to 24 hours. The reaction is promoted by the presence of an excess of reagent which can be removed by distillation at the end of the reaction and by using high temperatures, which allow the progression and the removal of the by-products which form during the reaction by distillation. The sulfonilating agent is preferably a compound of Formula Q-SO2IU, in which R4 has the above meaning and Q represents chlorine, bromine, iodine, -OSO2R4. The sulfonilation reaction is preferably carried out in a solvent selected from the group consisting of toluene, xylene, and methylene chloride, preferably in methylene chloride, at a temperature ranging from 20 to 60° C in a period of time ranging from 6 to 12 hours. The reaction is preferably carried out in the presence of a base, preferably selected from the group consisting of triethylamine, pyridine, dimethylaminopyridine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, more preferably triethylamine. The reducing agent is preferably selected from the group consisting of sodium dithionite, zinc, iron, tin, lithium aluminium hydride, sodium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, hydrogen, cyclohexadiene, ammonium formate, and formic acid, more preferably it is sodium dithionite. Where hydrogen, cyclohexadiene, ammonium formate, and formic acid are used, the reaction is carried out in the presence of a catalyst, preferably palladium- or nickel-based. Where formic acid is used, the reaction is carried out in the presence of an amine, preferably triethylamine. The use of sodium dithionite allows avoiding possible side-reactions of removal of fluorine or other halogens from the aromatic ring, which reactions may occur in the catalytic hydrogenations . The reduction is preferably carried out in a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, water, acetone, methylethylketone, methylisobutylketone, dimethylformamide, and N-methylpyrrolidone, more preferably in methanol, at a temperature ranging from 20 to 80° C and in a period of time ranging from 2 to 18 hours . The methyl ester of 2,4, 5-trifluorophenylacetic acid and analogues thereof of Formula 1, in which Z represents a COORi group, is preferably purified by distillation, allowing the effective removal of high-boiling impurities. The 2, 4 , 5-trifluorophenylacetic acid ester can be hydrolyzed to the 2,4, 5-trifluorophenylacetic acid of Formula 4 in a yield above 90% and with purity above 99%. If needed, such product can be purified by crystallization, preferably from toluene and eptane, ethyl acetate and eptane, fc-butyl methyl ether and eptane, or isopropyl acetate and eptane in 90% yield and purity above 99% (HPLC) .
The compounds of Formula 2 and, particularly, the 2,4,5- trifluoromandelic acid, which are employed in the present invention can be prepared according to the teachings of EP 411252 in association with WO 2003/084914, or US 7019166.
A process for the preparation of compounds of Formula 2 has been employed, comprising the steps of: c) reacting a fluorobenzene of Formula 10
Figure imgf000012_0001
10 wherein X has the above-described meaning, with di- chloroacetyl chloride or di-bromoacetyl bromide in the presence of a catalyst for Friedel-Crafts acylations to yield a compound of Formula 11
Figure imgf000013_0001
11 in which Y represents chlorine or bromine, and d) hydrolyzing the compound of Formula 10 in the presence of a base.
The catalyst for Friedel-Crafts acylations is preferably selected from aluminium trichloride, iron trichloride, aluminium tribromide, and iron tribromide. The base in the step d) is preferably selected from the alkaline and earth-alkaline metal hydroxides and carbonates, more preferably it is sodium hydroxide or potassium hydroxide.
The possibility of preparing in a simple manner and a high yield the compounds of Formula 2 from the fluorobenzenes of Formula 10 makes the process for the preparation of the compounds of Formula 1 more economically advantageous compared to other known processes (see US 20040068141) , which require as a raw material an aromatic compound already substituted with a leaving group (see Scheme 1) . For example, it is possible to prepare the 2, 4, 5-trifluoromandelic acid starting from 1,2,4-trifluorobenzene in 84% yield and 98% purity.
Finally, the present invention provides a simple preparation method for the compounds of Formula 1 having the following advantages: 1. it is applicable to the phenyl acetic acids substituted on the aromatic ring with electron- withdrawing groups; 2. it employs less expensive raw materials compared to those which are used in the known processes; 3. it is operatively simple and easily transferable to a productive plant;
Further features and advantages of the process of the invention will be appreciated from the description set forth herein below of preferred exemplary embodiments, which are given by way of non-limiting example only.
Examples
Example 1: 2, 4 , 5-Trifluoromandelic acid 5 (Z = COOH) Under inert atmosphere, 200 g aluminium trichloride in 100 g 1,2,4-trifluorobenzene is suspended, the mixture is heated to 60° C, and 167 g di-chloroacetyl chloride is added dropwise. Once the conversion is completed (GC) , the mixture is cooled to room temperature and it is taken up again with methylene chloride and water. The layers are separated and the organic layer is concentrated in vacuum. The reaction raw-material is then added dropwise on a mixture of 900 mL water and 90 g sodium hydroxide at 60° C. Once the conversion is completed, the mixture is cooled to room temperature, it is filtered and acidified with concentrated hydrochloric acid to pH = 1. The suspension is cooled to 0° C and it is filtered, isolating 130 g (84%) of product as a white solid with 98% HPLC purity (A%) . 1H-NMR (300 MHz, DMSO-d6) : δ (ppm) 3.92 (bs, IH); 4.85 (s, IH); 7.4-7.6 (m, 2H); 12.9 (bs, IH).
Example 2: Methyl 2,4, 5-trifluoro mandelate 6 (R1 = CH3) Under inert atmosphere, 50 g 2, 4, 5-trifluoromandelic acid is suspended in 135 mL methanol containing 3% HCl, and the mixture is heated to 60° C for 3 hours. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, it is concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution. The organic layer is concentrated in vacuum, yielding 50 g (94%) of product as a light- coloured oil with 99% HPLC purity (A%) .
1H-NMR (300 MHz, DMSO-d6) : δ (ppm) : 3.64 (s, 3H); 5.3 (d,
IH); 6.13 (S, IH); 7.45-7.6 (m, 2H).
Example 3: Methyl 2- (2,4, 5-trifiuorophenyl) -2- chloroacetate 7 (W = Cl, Ri = CH3)
Under inert atmosphere 50 g methyl 2, 4, 5-trifluoro mandelate prepared in the Example 2 is suspended in 150 mL thionyl chloride, and the mixture is heated to 80° C. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, it is concentrated in vacuum, taken up again with toluene, and washed with a aqueous sodium carbonate solution to a basic pH of the aqueous layer. The organic layer is concentrated in vacuum, yielding 57 g (105%) of product as an orange oil with 88% HPLC purity (A%) .
1H-NMR (300 MHz, DMSO-dβ) : δ (ppm): 3.7 (s, 3H); 6.13 (s, IH) ; 7.6-7.8 (m, 2H) .
Example 4: 2- (2, 4 , 5-Trifluorophenyl) -2-chloroacetic acid 7 (W = Cl, R1 = H)
Under inert atmosphere 10 g 2,4, 5-trifluoromandelic acid is suspended in 40 mL methylene chloride, 0.05 mL dimethylformamide is added and 23 g thionyl chloride is slowly added dropwise. The mixture is stirred at room temperature for 12 hours, and then it is refluxed for 12 hours. Once the conversion is completed (HPLC), it is cooled to room temperature, concentrated in vacuum, and taken up again with t-butyl methyl ether and an aqueous sodium carbonate solution. The layers are separated, the aqueous layer is acidified with concentrated hydrochloric acid to pH = 2, and it is extracted with t- butyl methyl ether. The organic layer is concentrated in vacuum, yielding 9.8 g (90%) of product as an orange oil with 90% HPLC purity (A%) .
1H-NMR (300 MHz, DMSO-d6) : δ (ppm) : 5.95 (s, IH); 7.6-7.7 (m, 2H) ; 12.5 (bs, IH) .
Example 5: Methyl 2- (2, 4 , 5-trifluorophenyl) -2- [ (methyl sulfonyl)oxy] acetate 7 (W = OSO2CH3, Rj. = CH3)
Under inert atmosphere 8.4 g methyl 2,4, 5-trifluoro mandelate is suspended in 56 rtiL methylene chloride and 4.9 mL methane sulfonyl chloride is added. 5 mL triethylamine is slowly added dropwise at 0° C, and the mixture is stirred at room temperature for 12 hours. 3 mL triethylamine is added, and the mixture is stirred for 2 hours. The organic layer is washed with water and concentrated in vacuum, yielding 10.7 g of product (94%) as a yellow oil with 85% HPLC purity (A%) . MS m/e: 298 (M+); 239; 203; 161; 144. Example 6: Methyl 2, 4, 5-trifluorophenylacetate 8 (Ri =
Under inert atmosphere the 57 g of methyl 2- (2,4,5- trifluorophenyl) -2-chloroacetate prepared in the example 3 is dissolved in 170 mL methanol, 67 g sodium dithionite is added, and the mixture is heated to 80° C. Once the conversion is completed, the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution and then with water. The organic layer is concentrated in vacuum. The reaction raw- material is distilled under reduced pressure, yielding 34 g of product (70%) with 97% HPLC purity (A%) . 1H-NMR (300 MHz, DMSOd6) : δ (ppm) : 3.36 (s, 3H); 3.70 (s, 2H); 7.44-7.55 (m, 2H).
Example 7: Methyl 2, 4 , 5-trifluorophenylacetate 8 (Rx =
Under inert atmosphere 5 g methyl 2- (2,4,5- trifluorophenyl) -2-chloroacetate is dissolved in 20 mL acid acetic and 2.34 g powdery iron is added. The mixture is heated to 60° C for 8 hours. Once the conversion is completed, the mixture is cooled to room temperature, taken up again with toluene, and washed with water and with an aqueous sodium bicarbonate solution. The organic layer is concentrated in vacuum, yielding 4 g (93%) of product as a yellow oil with 90% HPLC purity (A%) .
Example 8: 2, 4, 5-Trifluorophenylacetic acid 4 60 mL water and 4.7 g sodium hydroxide is added to the 34 g of methyl 2,4, 5-trifluorophenylacetate prepared in the example 6, and the mixture is stirred at 50° C. Once the conversion is completed, it is acidified with concentrated hydrochloric acid to pH = 1. The product is isolated by filtration as a white solid in a 30.2 g (95%) amount with 99% HPLC purity (A%) . 1H-NMR (300 MHz, DMSO-d6) : δ (ppm) : 3.60 (s, 2H); 7.42- 7.53 (m, 2H); 12.5 (bs, IH).
Example 9: 2, 4, 5-Trifluorophenylacetic acid 4
Under inert atmosphere 1 g 2- (2, 4, 5-trifluorophenyl) -2- chloroacetic acid is suspended in 20 mL water and 2.7 g triethylamine is added, 0.8 g formic acid, and 1 g 10% palladium supported on charcoal with 50% water, and the mixture is heated to 80° C. Once the conversion is completed, the mixture is cooled to room temperature, the catalyst is filtered, and the filtrate is acidified with concentrated hydrochloric acid. The product is isolated by filtration in a 0.7 g (83%) amount as a white solid with 95% HPLC titer (A%) .
Example 10 (comparative): reduction of the 2,4,5- trifluoromandelic acid 5 (Z = COOH) 7 g 2,4, 5-trifluoromandelic acid is dissolved in 125 itiL ethanol and 15 mL of an aqueous 32% hydrochloric acid solution; 1 g 5% palladium supported on charcoal is added, 4 bars of hydrogen is loaded, and the mixture is heated to 80° C with stirring for 4 hours. The HPLC control indicates the creation of the 2,4,5- trifluoromandelic acid ethyl ester, but not of the 2,4, 5-trifluorophenylacetic acid or the ethyl ester thereof . Example 11 (comparative): reduction of the 2,4,5- trifluoromandelic acid 5 (Z = COOH)
10 g 2,4, 5-trifluoromandelic acid is dissolved in 50 mL acid acetic and 10 mL sulphuric acid, 0.5 g 5% palladium supported on charcoal is added, 4 bars of hydrogen is loaded, and the mixture is heated to 80° C with stirring for 6 hours. The HPLC control indicates the creation of the 2- (2,4,5-trifluorophenyl) -2- (acetyloxy) acetic acid, but not of the 2,4, 5-trifluorophenylacetic acid. Example 12: Methyl 2- (2 , 4, 5-trifluorophenyl) -2- chloroacetate 7 (W = Cl, Ri = CH1) Under inert atmosphere 1 g 4-N-dimethylaminopyridine is suspended in 200 mL thionyl chloride and the mixture is heated to 80° C. In one hour period, 100 g methyl 2,4,5- trifluoro mandelate is added dropwise. Once the addition is completed, it is still stirred to reflux for 25 minutes . Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with a diluted aqueous sodium hydroxide solution to the basic pH of the aqueous layer. The organic layer is concentrated in vacuum, yielding 107 g (99%) of product as a yellow oil with 95% HPLC purity (A%) . Example 13: Methyl 2,3-difluoromandelate 2 (Z = COOCH3, F = 2-F, X = 3-F) Under inert atmosphere 1 g 2, 3-difluoromandelic acid is suspended in 20 mL methanol containing 10% HCl and the mixture is heated to 60° C for 8 hours. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution. The organic layer is concentrated in vacuum, yielding 0.8 g (75%) of product as a light- coloured oil with 99% purity GC (A%) . MS m/e: 202 (M+) . Example 14: Methyl 4-fluoromandelate 2 (Z = COOCHg, F = 4-F, X = H) Under inert atmosphere 1 g 4-fluoromandelic acid is suspended in 20 mL methanol containing 10% HCl, and the mixture is heated to 60° C for 8 hours. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution. The organic layer is concentrated in vacuum, yielding 0.8 g (74%) of product as a light- coloured oil with 99% purity GC (A%) . MS m/e: 184 (M+) .
Example 15>j Methyl 2- (2, 3-difluorophenyl) -2- chloroacetate 3 (W = Cl, Z = COOCH3, F = 2-F, X = 3-F) Under inert atmosphere 0.1 g 4-dimethylaminopyridine is suspended in 20 mL thionyl chloride, 0.4 g methyl 2,3- difluoromandelate is added, and the mixture is heated to 80° C. It is stirred to reflux for an hour. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with a diluted aqueous sodium carbonate solution to a basic pH of the aqueous layer. The organic layer is concentrated in vacuum, yielding 0.4 g (92%) of product as a yellow oil with 90% purity GC (A%) . MS m/e: 220 (M+) and 222 (M++2) . Example 16: Methyl 2- (4-fluorophenyl) -2-chloroacetate 3 (W = Cl, Z = COOCH3, F = 4-F, X = H)
Under inert atmosphere 0.1 g 4-dimethylaminopyridine is suspended in 20 mL thionyl chloride, 0.8 g methyl 2,3- difluoromandelate is added and the mixture is heated to 80° C. It is stirred to reflux for an hour. Once the conversion is completed (HPLC) , the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with a diluted aqueous sodium carbonate solution to a basic pH of the aqueous layer. The organic layer is concentrated in vacuum, yielding 0.6 g (68%) of product as a yellow oil with 95% purity GC (A%) . MS m/e: 202 (M+) and 204 (M++2) . Example 17: Methyl 2 , 3-difluorophenylacetate 1 (Z = COOCH3, F = 2-F, X = 3-F)
Under inert atmosphere 0.4 g methyl 2- (2, 3- difluorophenyl) -2-chloroacetate is dissolved in 20 mL methanol, 1 g sodium dithionite is added and the mixture is heated to 80° C. Once the conversion is completed, the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution and then with water. The organic layer is concentrated in vacuum, yielding 0.3 g of product (89%) with 90% purity GC (A%) . MS m/e: 186 (M+) .
Example 18: Methyl 4-fluorophenylacetate 1 (Z = COOCH3, F = 4-F, X = H)
Under inert atmosphere 0.6 g methyl 2- (2,35- difluorophenyl) -2-chloroacetate is dissolved in 20 mL methanol, 1 g sodium dithionite is added and the mixture is heated to 80° C. Once the conversion is completed, the mixture is cooled to room temperature, concentrated in vacuum, taken up again with toluene, and washed with an aqueous sodium carbonate solution and then with water. The organic layer is concentrated in vacuum, yielding 0.3 g of product (60%) with 90% purity GC (A%) . MS m/e: 168 (M+) . Example 19: 2, 3-Difluorophenylacetic acid 1 (Z = COOCH3, F = 2-F, X = 3-F)
10 mL water and 0.8 mL of a 30% sodium hydroxide solution is added to 0.3 g methyl 2,3- difluorophenylacetate and the mixture is stirred at 60° C for an hour. Once the conversion is completed, it is acidified with concentrated hydrochloric acid to pH = 1. The product is isolated by filtration as a white solid in a 0.2 g (72%) amount.
1H-NMR (300 MHz, CDCl3): δ (ppm) : 3.75 (s, 2H); 7.01-7.06 (m, 3H) ; 9.4 (bs, IH) . Example 20: 4-Fluorophenylacetic acid 1 (Z = COOCH3, F = 4-F, X = H)
10 mL water and 0.8 mL of a 30% sodium hydroxide solution is added to 0.3 g methyl 4-fluorophenylacetate and the mixture is stirred at 60° C for an hour. Once the conversion is completed, it is acidified with concentrated hydrochloric acid to pH = 1. The product is isolated by filtration as a white solid in a 0.15 g (55%) amount.
1H-NMR (300 MHz, CDCl3): δ (ppm) : 3.63 (s, 2H); 7.02 (t, 2H); 7.24 (t, 2H); 10.1 (bs, IH).

Claims

1. A process for the preparation of compounds of Formula 1
Figure imgf000026_0001
1 wherein X represents 0 to 4 groups selected from fluorine, chlorine, bromine, iodine, or trifluoromethyl, Z represents a COOH, COOR1, COCl, COBr, COI, CN, CONR2R3, COOCOR1 group,
R1 represents C1-C4 alkyl, benzyl, phenyl, or a group
Figure imgf000026_0002
R2 and R3 independently represent hydrogen or C1-C4 alkyl , comprising the steps of: a) reacting the compound of Formula 2
Figure imgf000026_0003
2 wherein X and Z have the above meaning, with a halogenating agent or a sulfonilating agent to yield the compound of Formula 3
Figure imgf000027_0001
3 in which X and Z have the meaning as above, W represents chlorine, bromine, iodine, or -OSO2R4, and R4 represents methyl, trifluoromethyl, or phenyl, optionally substituted with one or more groups selected from halogen, methyl, and nitro, b) reacting the compound of Formula 3 with a reducing agent .
2. The process according to claim 1, wherein the fluorine atom is in position 4.
3. The process according to claims 1-2, wherein X represents 1 to 4 fluorine atoms.
4. The process according to claims 1-3, wherein X represents 2 fluorine atoms.
5. The process according to claims 1-4, wherein X represents 2 fluorine atoms in positions 2 and 5.
6. The process according to the claims 1-5, wherein Z represents COOH, COOR1, COCl, or COBr.
7. The process according to claims 1-6, wherein R1 represents methyl, ethyl, isopropyl, t-butyl, or benzyl.
8. The process according to claims 1-7, wherein R1 represents methyl.
9. The process according to claims 1-8, wherein Z represents COOH.
10. The process according to claims 1-9, wherein R4 represents methyl, trifluoromethyl, phenyl, 4- methylphenyl , 4-nitrophenyl, or 4-bromophenyl.
11. The process according to claims 1-10, wherein W represents chlorine or -OSO2CH3.
12. The process according to claims 1-11, wherein, when in the compounds of Formula 2 Z represents a COORi group, the invention comprises the step of reacting the compound of Formula 2 , in which Z represents a group selected from COOH, COCl, COBr, and COI, with an alcohol of Formula RiOH.
13. The process according to claims 1-12, wherein, when in the compounds of Formula 1 Z represents a COOH group, the invention comprises the step of hydrolyzing the compound of Formula 1, in which Z represents a COORi group, to yield the compound of Formula 1, in which Z represents a COOH group.
14. The process according to claim 13, wherein the hydrolysis step is carried out in the presence of an acid or a base.
15. A process for the preparation of the 2,4,5- trifluorophenylacetic acid of Formula 4
Figure imgf000029_0001
comprising the steps of : B) reacting the compound of Formula 5
Figure imgf000029_0002
5 f) wherein Z represents a group selected from COOH,
COCl, COBr, and COI, with an alcohol of Formula RiOH, in which Rx has the meaning set forth in claim 1, to yield the ester of the 2,4, 5-trifluoromandelic acid of Formula
6
Figure imgf000029_0003
g) reacting the ester of the 2,4, 5-trifluoromandelic acid of Formula 6 with a halogenating agent to give the compound of Formula 7, in which W represents chlorine, bromine, or iodine, or with a sulfonilating agent, to give the compound of Formula 7, in which W represents OSO2R4 ,
Figure imgf000030_0001
h) reacting the compound of Formula 7 with a reducing agent to yield the compound of Formula 8,
Figure imgf000030_0002
8 i) hydrolizing the compound of Formula 8.
16. The process according to claims 1-15, wherein the halogenating agent is selected from thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, phosphorous tribromide, phosphorous pentabromide, and hydrobromic acid.
17. The process according to claims 1-16, wherein the halogenating agent is thionyl chloride.
18. The process according to claims 1-17, wherein the halogenation reaction is carried out in the absence of a solvent, or in a solvent selected from the group consisting of toluene, xylene, and methylene chloride.
19. The process according to claims 1-18, wherein the sulfonilating agent its a compound of Formula Q-SO2R4/ in which R4 has the meaning as before, and Q represents chlorine, bromine, iodine, -OSO2R4.
20. The process according to claims 1-19, wherein the sulfonilation reaction is carried out in a solvent selected from the group consisting of toluene, xylene, and methylene chloride.
21. The process according to claims 1-20, wherein the sulfonilation reaction is carried out in the presence of a base .
22. The process according to claims 1-21, wherein the reducing agent is preferably selected from the group consisting of sodium dithionite, zinc, iron, tin, lithium aluminium hydride, sodium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, hydrogen, cyclohexadiene, ammonium formate and formic acid, provided that, in the case of using hydrogen, cyclohexadiene, ammonium formate, and formic acid, the reaction is carried out in the presence of a catalyst, and in the case of using formic acid, the reaction is carried out in the presence of an amine.
23. The process according to claims 1-22, wherein the reducing agent is sodium dithionite.
24. The process according to claim 22 , wherein the catalyst is palladium- or nickel-based.
25. The process according to claims 1-24, wherein the reduction is preferably carried out in a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, water, acetone, methylethylketone, methylisobutylketone, dimethylformamide, and N-methylpyrrolidone.
26. The process according to claims 1-25, wherein the methyl ester of the 2,4, 5-trifluorophenylacetic acid and the analogues thereof of Formula 1, in which Z represents a COOR1 group are purified by distillation.
27. The process according to the claims 1-26 comprising the steps of: c) reacting a fluorobenzene of Formula 10
Figure imgf000032_0001
10 wherein X has the above-described meaning, with dichloroacetyl chloride or dibromoacetyl bromide in the presence of a catalyst for of Friedel-Crafts acylations to yield a compound of Formula 11
Figure imgf000033_0001
11 wherein Y represents chlorine or bromine, and d) hydrolyzing the compound of Formula 10 in the presence of a base to yield the compound of Formula 2.
28. The process according to claim 27, wherein the catalyst for Friedel-Crafts acylations is selected from aluminium trichloride, iron trichloride, aluminium tribromide, and iron tribromide.
29. The process according to claims 27-28, wherein the base in the step d) is selected from the alkaline and earth-alkaline metal hydroxides and carbonates.
30. Compound of Formula 9
Figure imgf000033_0002
wherein W represents chlorine or -OSO2CH3,
Z represents a COOH, COOR1, COCl, COBr, COI, CN, CONR2R3,
COOCOR1 group,
R1 represents C1-C4 alkyl, benzyl, phenyl, or a
Figure imgf000034_0001
group,
R2 and R3 independently represent hydrogen or C1-C4 alkyl .
31. The compound according to claim 30, wherein Z represents COOH, COORi, COCl, or COBr.
32. The compound according to claims 30-31, wherein R1 represents methyl, ethyl, isopropyl, t-butyl, or benzyl.
PCT/IT2007/000860 2006-12-27 2007-12-10 Process for the preparation of fluorophenylacetic acids and derivatives thereof WO2008078350A2 (en)

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WO2013135674A1 (en) * 2012-03-12 2013-09-19 Syngenta Participations Ag Insecticidal 2-aryl-acetamide compounds
CN103012111A (en) * 2012-09-12 2013-04-03 衢州学院 Preparation method 2,4,5-trifluorophenylacetic acid
CN103012111B (en) * 2012-09-12 2016-01-13 衢州学院 A kind of preparation method of 2,4,5-trifluoro benzene acetic acid
EP3424927A1 (en) 2017-07-04 2019-01-09 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid
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CN110831944A (en) * 2017-07-04 2020-02-21 意大利合成制造有限公司 Efficient process for the preparation of sitagliptin by very efficient preparation of intermediate 2,4, 5-trifluorophenylacetic acid
US10913747B2 (en) 2017-07-04 2021-02-09 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Efficient process for the preparation of sitagliptin through a very effective preparation of the intermediate 2,4,5-trifluorophenylacetic acid
CN110831944B (en) * 2017-07-04 2022-05-27 意大利合成制造有限公司 Method for preparing sitagliptin by preparing intermediate 2,4, 5-trifluoro-phenylacetic acid
CN107673951A (en) * 2017-08-18 2018-02-09 河南师范大学 A kind of high efficiency preparation method of 2,4,5 trifluoro benzene acetic acid
CN112457153A (en) * 2020-11-10 2021-03-09 杭州臻挚生物科技有限公司 Industrial preparation method of 2,4, 5-trifluoro-phenylacetic acid

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