LT3546B - Process for the preparation of ketones and salts thereof - Google Patents

Abstract

The invention is an improved method for extracting large amounts of compounds of formula (I):<IMAGE>(I)where R-hydrogen or hydroxyl, R<2>- hydrogen or hydroxyl,R<3> or R<4>-hydrogen or alkoxy group with 1-6-C atoms.

Description

(57) Report:

The present invention relates to an improved process for the preparation of large amounts of compounds of formula (I):

(I).

wherein R is hydrogen or hydroxyl,

R ² is hydrogen or hydroxyl,

R ³ and R ⁴ are hydrogen or alkoxy having 1-6 C atoms for the preparation.

i

The present invention relates to an improved process for the administration of large amounts of ketones of formula (I):

(I) wherein R is hydrogen or hydroxyl,

R ² is hydrogen or hydroxyl,

R ³ and R ⁴ are hydrogen or alkoxy having 1-6

C-atoms.

It is known that ketones of formula (I) can be used as intermediates for isoflavone and its derivatives (Hungarian Patent No. 163,515), as well as metabolites that act on it.

Methods of preparation employing resorcinol as starting material, i.e. the desired product can be obtained by the Houben-Hoesch reaction, in which resorcinol is reacted in anhydrous medium with benzyl cyanide in the presence of dry HCl gas and anhydrous tin chloride (see J. Chem. Soc. 1923, 404 and J. Amer. Chem. Soc. 48, 791 (1926)). The yield of the product is 50% and the disadvantage of the method is that the hydrolysis of the ketimine intermediate of the intermediate product causes strong corrosion.

Similarly, 2-hydroxy-4-n-butoxyphenyl-benzylketone or 4-hydroxy-2-n-butoxyphenyl-benzylketone can be obtained by reacting resorcinol mono-n-butyl ether with phenylacetyl chloride in the presence of pyridine followed by removal of pyridine by distillation. The residue was dissolved in ether, the solution was extracted several times with HCl, the ether was distilled off and the resulting 1-phenylacetyloxy-4-n-butoxyphenol was treated with aluminum chloride in nitrobenzene and the resulting mixture was steam distilled (Example 7 of Hungarian Patent No. 168,744). The starting product of the first step, resorcinyl mono-n-butyl ether, can be obtained, for example, by reacting resorcinol with n-butyl bromide in dimethylformamide. The reaction may give rise to resorcinol diethyl derivatives and the monoethers must be purified prior to the second reaction step in order to obtain a good quality product.

An analogous phenolic compound may also be prepared by the known reaction of Buvol (Bouveault) by reacting 2 moles of anhydrous aluminum chloride with phenol. The first step of this reaction produces phenoxyaluminum dichloride and liberates the HCl gas. In a second step, said phenoxyaluminum dichloride is reacted with acid chloro anhydride derivatives in the presence of another mole of aluminum chloride. (Olah, Gy: Friedel Crafts and Related Reactions, Vol. I, page 97, 1963).

The disadvantages of these known methods are as follows:

- the methodology of the reaction as well as the technology are complex,

- high content (2 moles) of aluminum chloride is required,

- Hydrogen chloride liberates corrosion.

The present invention includes an improved ketone of formula (I):

wherein R, R ² , R ³ are salts,

R ⁴ , R ⁶ are the heights given and are the phenols of formula (II):

R

R ^{2 is} treated with chloro anhydrides of formula (IV):

(IV) in the presence of an inert anhydrous solvent and anhydrous aluminum chloride, followed by separation of the mixture thus obtained with an aqueous acid solution and separation of the layers obtained; Reaction of the above phenolic derivative with 1 mol of aluminum chloride (based on the phenolic derivative) at 0-40 ° C in the presence of an alkyl halide, preferably dichlorotane, followed by the preparation of the following compound of formula (III):

© (III) is treated with acid chloro anhydride of formula (IV):

(IV)

R 'is preferably carried out in the above solvent at 10-60 ° C, a solution of aqueous acid is added to the resulting mixture, the layers are separated and the required ketone derivative is isolated from the organic layer.

Unexpectedly, for example, the reaction of resorcinol with 1 mol of anhydrous aluminum chloride, without the formation of hydrogen chloride, produces hydroaluminium trichloro-3-hydroxyphenolate (hereinafter complex), which is dissolved in the medium used. This complex is very active and can react with acid chloro-anhydride without the addition of additional aluminum chloride.

The proposed process is based on the above discovery and also on the use of phenolic derivatives of formula (II) as starting material.

In the process of the invention, the alkyl halides, preferably dichloroethane, are used as a solvent and are present in amounts of 3 to 10 times higher. The reaction temperature depends on the starting material used; in the case of resorcinol and dichloroethane, the reaction is best carried out at 10-25 ° C.

The reaction of the complex with the chloro-anhydride is carried out by adding the aromatic acid chloro-anhydride or its solution to the complex solution or suspension, or atLT 3546 B, the complex-solution or suspension is added to the chloro-anhydride or its solution.

It is best to prepare the complex and to carry out the subsequent steps in the same solvent, preferably alkyl halides.

The process of the invention allows the isolation of a clean end product. The ketones of formula (I) were obtained from resorcinol derivatives of formula (V):

R ⁶

OH wherein R ⁶ is hydrogen or hydroxyl may be substituted.

cry with potassium carbonate to form double salts coms whose formula (VI): KO & R ³ (VI), R ⁶ 'c-ch ₂ - <O ^khc ° 3

wherein R ³ , R ⁴ and R ⁶ are as defined above. These salts are insoluble in aprotic solvents. Thus, according to a preferred embodiment of the process of the invention, the product is isolated (i.e., isolated by filtration) in the form of this salt and can thus be selectively isolated from by-products or other by-products present or formed in the reaction mixture. The ketone of formula (I) can be obtained from the double salt of formula (VI),

By dissolving it in water and acidifying the solution to pH 3.5 - 4.5.

The above step is particularly suitable if the starting materials, resorcinol or acid anhydride, are not sufficiently pure. When using pure starting materials, ketones of suitable quality can be obtained either by evaporation of the organic layer solvent or by recrystallization of the resulting residue, preferably from toluene.

The method of the present invention has the following advantages:

i

- the synthesis can be carried out without isolation of the intermediate pro 15 without resorcinol mcno-n-butyl ether and the use of nitromethane, nitrobenzene or ether as solvents,

- the amount of aluminum chloride is doubled compared to the known method,

- significant corrosion of the Houben-Hoesch method is eliminated,

- yields in the range 82-85% which are significantly higher than the yields of any of the known methods,

- the product quality is very good.

The invention is further illustrated by the following examples.

example

55 g (0.5 mol) of resorcinol are suspended in 250 ml of dichloroethane and 67 g (0.502 mol) of anhydrous aluminum chloride are added at 20 ° C. To the resulting homogeneous dark solution containing hydroaluminium trichloro-3-hydroxyphenolate was added 77.2 g (0.5 mol) of phenylacetyl chloride in 100 ml of dichloroethane over a period of one hour at a temperature of 35-40 ° C. The reaction mixture is stirred for one hour, the resulting solution is poured into aqueous hydrochloric acid solution, the layers are separated, the organic layer is washed with water to neutral pH, the solvent is evaporated and the residue is recrystallized from toluene if necessary. 96.9 g of 2,4-dihyd10-hydroxyphenylbenzyl ketone, m.p. temp. 112-114 ° C, yield 85%. Recrystallization from toluene, m.p. temp. mp 113-114 ° C.

Elemental analysis for C ₁₄ H ₁₂ O ₃ (mol. Wt. 228):

Found: C, 73.68; H, 5.26

Found: C, 73.6; H, 5.3

NMR spectrum (Bruker WP 80 spectrometer, solvent DMSO-D ₆ , internal standard - TMS):

6th C-H 7, 90 m.d. (d), ³ J = 9 Hz, 5 C-H 6.37 m.d. (dd), 3 C-H 6, 25 m.d. (d), ⁴ J = 2 Hz. ¹³ C: 4- C, 165.1 m .d.

example

The reaction is carried out according to the procedure described in Example 1. After separation of the two layers, the organic layer is washed with water until the water becomes neutral, the dichloroethane layer is separated and 69 g (0.5 mol) of anhydrous potassium carbonate are added. The potassium potassium bicarbonate double salt (C ₁₄ H ₁₁ O ₃ K. KHCO ₃ ) (166 g) was precipitated by filtration, dissolved in methanol: water (1: 3) and the solution was acidified (pH = 4) with 33% acetic acid. After precipitation, the product is filtered off, dried to give 96.2 g of 2,4-dihydroxyphenylbenzyl ketone, m.p. temp. mp 113-114 ° C. The quality of the product thus obtained is analogous to that of the product obtained in Example 1 after recrystallization. The mixture of these products (1: 1) was not depressed by temperature.

Elemental analysis, C ₁₄ H ₁₁ O ₃ K. KHCO ₃ (mol. Wt. 366):

10th Excluded: c % 49.18, H% 3.27 Found: c %: 49.6 H F 3, 32 i j NMR Spectrum: ^Χ Η: 6 CH 7.63 m.d. (d), ³ J = 9 Hz, 5 C-H 6.00 m.d. (dd), 15th 3 C-H 5.78 m.d. (d), ⁴ J = 2 Hz. (Potassium 2,4-dihi drool .phenylbenzylketone in double salt

in position 4).

Example 3

Dissolve 64.25 g (0.5 mol) of 2-chlorophenol in 200 ml of dichloroethane and add 67 g (0.5 mol) of anhydrous aluminum chloride. Thereafter, 77.2 g (0.5 mol) of phenylacetyl chloride in 100 ml of dichloroethane are added with stirring until the reaction temperature rises from 15-20 ° C to 35-40 ° C. After stirring for an additional hour, the reaction mixture was added with aqueous HCl solution, the layers were separated, and the organic layer was washed with water until the water became neutral and the solvent was evaporated. 106.1 g of 2-hydroxy-3-chlorophenylbenzyl ketone are obtained, m.p. temp. mp 62-64 ° C. Recrystallization from a mixture of water and isopropanol (1: 2), m.p. temp. mp 63-67 ° C.

Elementary analysis, C ₁₄ H ₁₁ ClO ₂ (m.p. 246, 5): Excluded: C, 68.15; H, 4.46; Cl, 14.40 Found: C, 68.55; H, 4.70; Cl, 14.00.

Example 1 Dissolve g (0.2 mol) of hydroquinone in 60 ml of dichloroethane and add 26.8 g (0.2 mol) of anhydrous aluminum chloride. 30.8 g (0.2 mol) of phenylacetyl chloride in 30 ml of dichloroethane are added to the resulting complex. The following operations are described in Example 1. 10.1 g of 2,5-dihydroxyphenylbenzyl ketone are obtained, m.p. temp. mp 118-120 ° C.

Elementary analysis, C ₁₄ H ₁₂ O ₃ {mol. SV. 228): Excluded: C % 73, 68, H C.. to. 5.26 Found: C %: 73, 62, H g, · to · 5, 58.

example

Dissolve 24.7 g (0.196 mol) of phloroglucinol in 70 ml of dichloroethane and add 26.6 g (0.2 mol) of anhydrous aluminum chloride. To the resulting complex was added 30.1 g (0.196 mol) of phenylacetyl chloride in 30 ml of dichloroethane. The following operations are described in Example 1. 15 g of 2,4,6-trihydroxyphenylbenzyl ketone are obtained, m.p. temp. mp 117-120 ° C.

Elementary analysis, Οχ ₄ Η ₃₂ θ4 {mol. sv 244): Excluded: C, 68.85; H %: 4.92 Found: C, 69.05; H %: 4.67.

example

120 kg (1.09 kmol) of resorcinol are suspended in 660 l of dichloroethane and 150 kg (1.12 kmOLT 3546 B lio) of anhydrous aluminum chloride is added to the suspension; the temperature rises from 15 ° C to 25 ° C. The resulting complex dissolves in the reaction medium. Phenylacetyl chloride (171 kg, 1.10 kmol) was added over one hour at 3540 ° C. The mixture is stirred for one hour, diluted hydrochloric acid (600 L) is added and the operations described in the previous examples are carried out. The solvent was removed by distillation, the residue was recrystallized from toluene, the product was centrifuged and dried at 45-50 ° C. 205-210 kg are obtained

2.4- dihydroxyphenylbenzyl ketone in 82-84% yield.

j Calculated quantity: 248.5 kg. Physical data identical to Example 1.

Example 7

27.5 g (0.25 mol) of resorcinol are suspended in 150 ml of dichloroethane and 33.5 g (0.25 mol) of anhydrous aluminum chloride are added. To a solution containing the complex is added 42.9 g (0.2 mol) unclean

3.4-Dimethylphenylacetyl chloride in 50 ml of dichloroethane and stir for 4 hours. The resulting complex is cleaved by adding aqueous hydrochloric acid (1: 1), the dichloroethane layer containing the desired product is washed with water, the solvent is evaporated and the residue is recrystallized from toluene. 45.9 g of product are obtained, m.p. temp. mp 171-173 ° C, yield 79.8%. Withheld. amount 57.6 g.

30th Elementary analysis, ^ 16 ^ 16 ^ 5 {inol. sv 288): Excluded: c %: 66.66, H O. Ό · 4.17 Found: C Oh, o. 66, 45, H O. O · 4.10.

NMR spectrum gave the desired compound.

Thin layer chromatogram:

Eluent: toluene / n-butyl acetate / acetic acid = 8/2/1.

Adsorbent

Closure:

Silica gel 60 F ₂₅₄ (Merck).

0.2 g / 10 mL dimethylformamide - 100 µg.

Front: To 6 cm.

UV light at 254 nm.

R _f = 0.6.

example

27.5 g (0.25 mol) of resorcinol are suspended in 150 ml of dichloroethane and 33.5 g (0.25 mol) of anhydrous aluminum chloride are added. To the resulting solution of the complex was added 48.5 g (0.2 mol) of 3,4-diethoxyphenylbenzylacetyl chloride in 50 ml of dichloroethane. Following are the operations described in Example 7. 53.7 g of 2,4-dihydroxy-3,4-diethoxyphenylbenzyl ketone are obtained with a melting point of 141143 ° C after recrystallization from toluene. Yield: 63.2 g. Yield 85%.

Elemental analysis, C ₁₈ H ₂₀ O ₅ :

Found: C, 68.55; H, 6.23

Found: C, 68.35; H, 6.29.

NMR spectrum gave the title compound.

Thin layer chromatogram: Method described in R _f ).

0.7 (according to example 7 3546 B

Claims (2)

DEFINITION OF INVENTION 1. Ketones of Formula (I): wherein R is hydrogen or hydroxyl, R ² is hydrogen or hydroxyl, R ³ and R ⁴ are hydrogen or alkoxy groups having from 1 to 6 C atoms and a process for preparing salts thereof, wherein the phenol derivative of formula (II): R R ² is reacted with an acid chloro anhydride of formula (IV): (IV) wherein R, above. R ² , R ³ and R ⁴ are inert as the solvent and anhydrous I to aluminum chloride, followed by decomposition of the reaction mixture with an aqueous acid solution and separation of the layers, characterized in that the phenol derivative of formula (II) wherein R and R are as defined above is reacted with 1 mol of anhydrous aluminum chloride phenol derivative) in the presence of alkyl halides, preferably dichloroethane, at a temperature in the range of 0-45 ° C, followed by the resulting compound of formula (III): (III) wherein R and R are as defined above, 20 is treated with an acid chloro anhydride of formula (IV) wherein R and R are as defined above, in the presence of the solvent used in the preceding step, at a temperature of 1060 ° C, adding aqueous acid solution to the reaction mixture, separating layers and 25 organic layers liberate the required ketone by evaporation of the organic layer solvent and the residue is recrystallized from toluene or, if the starting material is resorcinol of formula (V): OH (V), OH wherein R ^v is hydrogen or hydroxyl, said organic layer is acting on potassium carbonate and the resultant insoluble double salt of formula (VI): wherein R ³ , R ⁴ and R ⁶ are as defined above, are isolated best by filtration, dissolve preferably in aqueous alcoholic solution and, upon acidification of the solution to pH 3.5-4.5, precipitate the required ketone of formula (I). 2. A process according to claim 1, wherein the reaction of the complex of formula (III) wherein R and R ² are as defined above with phenylacetyl chloride is carried out at a temperature between 2 ° C and 50 ° C.