KR820000690B1 - Process for preparation of trifluoromethyl phenols - Google Patents

Abstract

Title compds. (I; R,R1 = C1-3 alkyl, methoxy or nitro; n,m = 0 or 1) useful as hypochondria were prepd. by reacting sodiumbenzylate(II) with trifluoromethylhalobenzene, followed by hydrogenolysis of the resulting trifluoromethylphenyl benzylether(III). Thus, 4-F3CC6H4OCH2Ph was prepd. in 66.5% yield by the reaction of 4-F3CC6H4Cl with NaOCH2Ph. Hydrogenolysis of 4-F3CC6H4OCH2Ph over Pd/C gave 84.5% 4-F3CC6H4OH. The 2- and 3-ixomers of 4-F3CC6H4OCH2Ph and 4-F3CC6H4OH were prepd. similarly.

Description

Method for producing methyl phenols of tripulouro

The present invention relates to a method for producing trifluuromethyl phenols of general formula (II), which is an intermediate for the preparation of psychotropic agent 3- (trifuluromethylphenoxy) -3-phenylpropylamines effective for treating depression. .

Phenols with many substitutions are difficult to synthesize. One common reaction is the substitution of a base with a halogen atom in substituted chlorobenzene. "It is very difficult to remove halogen atoms from the benzene ring without meta-oriented groups in the ortho and / or para positions for the halogen atoms," he says. (See Billman and Cleland, Methods of Synthesis in Organic Chemistry, Edwards Brothers, Inc., Ann Arbor, Mich. 1954). In other words, misplaced chlorine atoms, such as picryl chloride, can be easily replaced with hydroxyl groups by the action of aqueous sodium hydroxide to obtain the corresponding phenol, picric acid. However, the conversion of chlorobenzene to phenols without misdirected metadirectional groups requires the most stringent reaction conditions. For example, a reaction temperature of 300 ° C., high pressure and flaky sodium hydroxide or other alkali conditions are required. Another reaction to prepare phenols is to melt with sulfonic acid alkali or sodium sulfonate under vigorous reaction conditions. In the case of the production of highly substituted phenols, especially trifluoromethyl phenols, trifluoromethyl groups tend to react under such violent conditions. Therefore, it is not suitable for the reaction conditions requiring such intense temperatures, pressures and strong alkalis. It is obvious.

The second method of preparing phenols is to hydrolyze the substituted phenyldiazonium salts. This synthesis method is a prerequisite to prepare a properly substituted nitrobenzene, phenol is produced by reducing the initro group to aniline and diazotizing the amine group to decompose the diazonium salt. The reaction is not suitable for the preparation of ortho or paratrifluorofluoromethyl phenols, since the desired trinitro compound can not be prepared by directly replacing the starting material since it is a trifluorofluoro group. Tripulomethyl groups can of course be prepared from the corresponding carboxylic acids. However, carboxylic acid groups are likewise meta-groups, making it difficult to produce 0- or P-nitrobenzoic acid.

Another method of preparing P-tripulomethyl methylphenol is to prepare P-trichloromethylphenol by chlorinating P-cresol. Chlorine atoms can be replaced with fluorine atoms by reacting with antimony pentafluoride, but this method is not suitable for commercial production because it is an experimental scale. (See R.G.Joues, J.Am.Soc., 69, 2346 (1947).

Alternatively the acid-reacted with the carboxylic acid group of (O-hydroxybenzoic acid) with SF ₄ and HF method is substituted with a methyl group in a tree pool Luo is suitable yulmyeon the number of 0-hydroxy compound but to deal with SF ₄ The problem is difficult and therefore difficult in commercial production. However, the yield is poor in using P-hydroxy benzoic acid and this acid itself is more difficult to prepare than salicylic acid.

An indirect method can be used as part of solving the problem in preparing phenols that are difficult to synthesize. In this method chlorobenzene is nitrated in the auto position relative to the chloro group. Therefore, it may be easily substituted by hydrolysis. The nitro group is removed by reduction, the diazotization of the resulting aniline and the reaction of substituting azido groups with hydrogen.

An example of such an indirect method is a method of synthesizing P-trifuluromethyl phenol by Labagni labor, which was the best method until the present invention. [Reference: Laragnino et al., Org. Prop Proced. Int. 9,96 (1977)].

In recent years, 3- (trifuluro methylphenol-C) -3-phenylfurophyllamines, including primary amines, secondary N-methylamines, and tertiary N, N-dimethylamines, have been serotonin by Moloy and Schmiegel. It has been shown to be effective as a psychotropic drug useful in the treatment of depression by specifically inhibiting the absorption. (See US Patent No. 4,018,895). The compound is prepared by the following general method. The keto group of β-diethylaminofulopiophenol is reacted with diborane to reduce to secondary alcohol.

This hydroxy group is substituted with chlorine using HCl and the chloro compound is reacted with the sodium salt of a specific tripulomethyl methyl phenol to obtain the target compound. The corresponding N-methyl compound is made by removing methyl groups from the N, N-dimethyl derivative using cyanide bromide. Corresponding primary amines are prepared by the reaction of the desired tri-fuluromethylphenol sodium salt with 3-chloro-1-bromo furopropylbenzene. By the same scheme, N-methyl-secondary amine is prepared by reacting 3-chloro-1- (trifuluromethylphenoloxy) furophyllbenzene with methylamine instead of N _a N ₃ .

In each of the above reactions, a specific tripulomethyl methyl phenol is required. OBJECT OF THE INVENTION The object of the present invention relates to a novel useful method of preparing three trifluuromethylphenols which are very suitable for commercial use. In particular, the present invention provides a process for the preparation of P-trifuluromethylphenol from P-trifuluromethylchloro benzene, a relatively inexpensive production intermediate.

The present invention relates to a process for the preparation of trifluuromethylphenol, characterized by reacting trifluuromethylhalobenzene with sodium benzylate or appropriately substituted sodium benzylate. The resulting trifluuromethylphenol benzyl ether is hydrogenated in the presence of a heavy metal catalyst to remove the benzyl group (as toluene or substituted toluene) to obtain the desired trifluuromethyl in high yield.

The present invention relates to a process for preparing trifluuromethyl phenol and trifluuromethyl phenylbenzyl ether, which method comprises the steps of: a) trifluuromethyl halobenzene in sodium inert solvent of general formula (I) And trifluorofluoromethylphenyl benzyl ether of general formula (II), and b) hydrolyzing benzyl ether at low hydrogen pressure in the presence of a heavy metal catalyst to produce the desired trifluorofluoromethylphenol. It is done.

Wherein R and R ¹ are each an alkyl, methoxy or nitro group having 1 to 3 carbon atoms, and adjacent carbons of R, R ¹ and phenyl ring together form a methylene dioxy group, and m and n are each 0 or 1.

The term "halo" in halobenzenes includes chloro, urethra, bromo and pullouro. However, in the first step of the present invention, it is preferable to use trifluorofluoromethylchlorobenzene or trifluorofluoromethylbromo benzene.

In the novel synthetic reaction of the present invention, it is preferable to use benzyl alcohol and sodium benzylate, but a benzyl alcohol substituted mainly in an economic sense may also be used. The substituents should of course be inert to sodium hydride and benzylate ions. Such inert substituents include alkyl groups of 1 to 3 carbohydrates, such as methyl groups, nitro, methoxy or methylene deoxy groups. Useful benzyl alcohols are represented by the following general formula.

Wherein R and R ¹ are each an alkyl group having 1 to 3 carbon atoms, nitro, or methoxy, and adjacent carbons of R, R ¹ and a benzene ring together form methylene dioxy, and n and m are each 0 or 1.

The term alkyl having 1 to 3 carbon atoms includes methyl, ethyl, n-propofyl and isofurophyll groups. Benzyl alcohols useful for the production of reactant sodium benzylates include the following compounds:

The choice of appropriate benzyl alcohols for use in the process of the invention should take into account the independent and opposing chemical aspects of the two reaction steps.

On the other hand, when one or more substituents are attracted to the ortho or para position with respect to the benzyl group, sodium salt formation and benzylate ion activity are increased. If there is a substituent providing an electron, the opposite will of course appear. On the other hand, in the presence of a substituent that attracts electrons, the activity of the benzylate ion for the hydrogenation reaction is reduced because of the property of strengthening the carbon-oxygen bond of the group that attracts electrons. The electron donating group has the opposite effect. 0- or P-nitrobenzyl alcohols are interestingly characterized by negative electrode substituents that promote the formation of benzylate or benzylether ions. However, during hydrogenation, the nitro group is first reduced to an electron donating amino group, which tends to facilitate the hydrogenolysis of phenylbenzene ether.

Considering the above, it is possible to easily compensate for the relatively lack of activity by adjusting the reaction conditions. Therefore, in most cases, it is most important to consider economics, so it is preferable to use inexpensive and easy to purchase benzyl alcohol.

Scheme I illustrates the present invention. In the scheme, the synthesis of P-trifuluro methylphenol is shown as an example only, and this synthesis can be applied to the synthesis of m-trifuluro methylphenol and 0-trifuluromethyleneol. Benzyl alcohol was also used for illustrative purposes only.

In accordance with the above scheme, the sodium salt of benzyl alcohol is, for example, sodium hydride, sodium amide and similar compounds, and suitable non-reactive solvents such as N, N-dimethyl acetamide (DMA), diglyme, DMF or similar compounds. It is prepared using. After the reaction between sodium hydride and benzyl alcohol has been completed to some degree to produce sodium benzylate, a solution of trifluomethyl chlorobenzene in the same solvent is added, and the reaction mixture is left for a day or two until the ether formation is almost complete. Heat. The reaction is carried out under a stream of nitrogen. The reaction mixture is diluted with water to separate trifluuromethyl phenyl benzyl ether, the product of this reaction. Once the ether has crystallized it is isolated by filtration. The amorphous ether is extracted with a solvent incompatible with water, the organic layer is separated separately, the solvent is removed in vacuo and the ether residue is separated by distillation. Hydrolysis of the ether, the second stage of the reaction, uses heavy metal catalysts such as 5% palladium on carbon, platinum oxide, and palladium on calcium sulfate. The hydrogenation reaction is carried out in a closed vessel under relatively low pressure hydrogen of 50 to 100 psi. Trifuluromethylphenol is first isolated by filtration of the catalyst and concentration of the filtrate. Phenol is easily purified by distillation. Suitable solvents for the hydrogenation reaction include lower alcohols such as ethanol. The invention is illustrated by the following specific examples.

Example 1

Method for preparing 4-trifluorofluoromethylphenol benzyl ether

110 g sodium hydrophobide in the form of 50% oil dispersion is washed with hexane under nitrogen pressure (to remove oil). 500 ml of DMA was added and 251 benzyl alcohol dissolved in 1 liter of DMA was added little by little. The reaction is exothermic. After the addition, the reaction mixture is stirred at 80 to 90 ° C. for 1 hour to complete sodium benzylate production. To 1 L of DMA is then added 420 g of 4-tripulolu methylchloro benzene. The reaction solution was refluxed for about 18 hours under a nitrogen stream and then cooled. 2 liters of water is added to this cooled solution. 4-trifuluromethylphenyl benzyl ether produced in the above reaction forms a crystal upon cooling, and the crystal is collected by filtration. Recrystallization with methanol yields 390 g of ether with a melting point of 77-79 ° C. in 66.5% yield. NMR (CDCl ₃ ) δ 5.08 (S, Z, -CH ₂ -6.88 to 7.69 (Mq, ArH) index spectra M ⁺ = 252,

Base peak m / e91

Analytical Theory: C 66.67; H 4.40

Found: C 66.57; H 4.27.

According to the method described above, 2-trifuluromethyl phenol benzyl ether was obtained in 68% yield using 2-trifulo methyl methyl benzene in place of 4-trifulomethyl methyl benzene. The boiling point of this ether is from 127 ° C to 128 ° C at 5 Torr. NMR (CDCl ₃ ) δ 5.20 (s, 2, CH _2- ) 6.80 to 7.75 (M, 9, ArH), mass spectrum M ⁺ = 252,

Base peak m / e91

Analytical Theory: C 66.67; H 4.40

Found: C 66.77; H 4.45,

According to the method described above, 3-trifluorofluoromethyl phenolbenzyl ether was obtained in 68% yield instead of 4-trifluorofluoromethylchlorobenzene. Ether boiling point is 112 ° to 116 ° C at 5 Torr. When the distillate is dried, the melting point is 56 ° to 58 ° C. NMR (CDCl ₃ ) δ 5.02 (S, 2, -CH _2- ) 6.85 to 7.63 (M, 9, ArH) mass spectrum M ⁺ = 252,

Base picky m / e 91.

Analytical Theory: C 66.67; H 4.40

Found: C 66.75; H 4.62.

Example 2

Method for preparing 4-trifluorofluorophenol

A solution of 390 g of 4-trifuluromethyl phenyl benzyl ether in 3580 ml of ethanol is placed in a low pressure hydrogenation vessel with 30 5% palladium on carbon. The initial hydrogen pressure is 60 psi and hydrogenated at room temperature until the theoretical amount of hydrogen has been consumed over about 2 hours. The filtrate was concentrated and distilled at 51 ° to 54 ° C. under 6 Torr to afford 4-tripulouromethylphenol.

Yield = 212 g (84.5%) mass spectrum M ⁺ = 162

According to the above method, butylated 2-tripulouromethylphenol benzyl ether to obtain 2-tripulomethyl methylphenol having a boiling point of 147 ° to 148 ° at 1 atm in 75% yield.

NMR (CDCl ₃ ) δ5.74 (S, 1, OH exchange with D ₂ O) 6.60 to 7.75 (M, 4,4ArH) mass spectrum M ⁺ = 142

According to the method described above, using 3-tripulouromethylphenyl ether yields 3-tripulomethyl methylphenol having a boiling point of 57 ° to 60 ° C. at 9 Torr in a yield of 79%.

NMR (CDCl ₃ ) δ 6.10 (S, 1, OH exchanged with D ₂ O) 6.70 to 7.71 (M, 4, ArH), mass spectrum M ⁺ = 162

The preparation method of the present invention is particularly suitable for commercially preparing 4-tripulomethyl methylphenol. The starting material, 4-trifluorofluoromethyl-methylchlorobenzene, is prepared by fluorination of 4-chlorobenzoic acid and can be easily obtained from many commercial raw materials like other 4-trifluorofluorohalobenzene. Chlorobenzoic acid itself is prepared by oxidizing 4-chlorotoluene prepared by chlorination of toluene and then separation of the resulting isomers.

Other methods of preparing 4-trifuluromethylphenol are not so desirable commercially. For example, the hydrolysis of trifluuromethyl groups occurs without exception for the hydroxide substitution of chlorine in 4-trifluuromethylchloro benzene in the presence of a base. Diazoization is not so good either.

First, trifluoromethylbenzene cannot nitrate in the para position because the trifluoromethyl group has an inactivating action or is a meta-oriented group. For the same reason, benzoic acid cannot occur nitration in the para position. Thus, toluene itself is obtained by nitro separation of the isomers produced. This production method involves oxidation of the methyl group of toluene, reduction of the nitro group, diazoated diazo of the amino group, substitution of the group with hydroxyl, and finally fluorination of the carboxylic acid group. This method is very difficult and expensive compared to the synthesis method of the present invention.

Claims (1)

Characterized by reacting sodium benzylate of formula (I) with trifluomethylmethyl halobenzene to produce trifluuromethylphenyl benzyl ether of formula (II), and then hydrolyzing the benzyl ether. A method for producing trifluuromethylphenol of formula (II).

Wherein R and R ¹ are each an alkyl, methoxy or nitro group having 1 to 3 carbon atoms, and adjacent carbons of R, R ¹ and phenyl ring together form a methylene dioxy group and n and m are each 0 or 1.