MXPA96003877A - Procedure for developing monoacetals dehydroquin - Google Patents

Abstract

The present invention relates to a process for preparing hydroquinone monoacetals characterized in that it comprises the steps of: a) reacting monoether of hydroquinone with enol ether in the presence of an acid catalyst to produce the hydroquinone monoacetal intermediate which is protected by a protecting group and b) reacting said intermediate with a non-acid hydrogen transfer source selected from the group consisting of hydrazine, ammonium formate, trialkylammonium formats, and mixtures thereof, in a molar ratio of hydrogen transfer source to intermediate from about 6: 1 to about 1: 1, in the presence of a metal catalyst such that the dethreel protecting group is selectively cleaved to give the hydroquinone monoacetal desired

Description

PROCEDURE FOR DEVELOPING MONOACETALS OF HYDROQUINONE FIELD OF THE INVENTION The present invention is for a process for preparing monoquinones of hydroquinone, wherein said process produces high yields of higher purity than the reactions previously used. IÜ BACKGROUND OF THE INVENTION The process for making monoquinones of hydroquinone are described in the patent application United States of America Co-operative serial number 08/206, 573, filed on March 4, 1994; Incoporated here by reference. Said process involves the equimolar reaction of amounts of hydroquinone with enol ethers in the presence of an acid catalyst: (i) each R is, independently, selected from the group consisting of hydrogen, C ^ -C ^ alkyl, benzyl, aryl and benzyl or substituted aryl. (ii) each R 'is, independently, selected from the group consisting of C, -C 10 alkyl, benzyl, aryl, and benzyl or substituted aryl. (iii) n is an integer from 0 to 3. However, said reaction has several limitations. For equimolar concentrations of hydroquinone and enol ethers, said reaction also results in the formation of hydroquinone biacetals which are reduced relief compounds for the skin. The removal of the inefficient biacetal compounds, together with the unreacted hydroquinone, requires large scale, expensive chromatographic purification, such that the isolated yield of said monoacetal, typically 30-40%, is poor. Attempts to improve the yield and total cost of the process via conversion / recycling of biacetals to desired monoacetals is problematic due to the similar reactivity of the two compounds, although changing the stoichiometry of the reaction to minimize the formation of biacetals, the amount of hydroquinone that finally needs to be chromatographically removed.

BRIEF DESCRIPTION OF THE INVENTION The present invention is a process for preparing hydroquinone monoacetals comprising the steps of: a) reacting monoethers of hydroquinone with an enol ether in the presence of an acid catalyst to produce the protected monoacetal of hydroquinone as an intermediary; and b) reacting said intermediate with a source of hydrogen transfer in the presence of a metal catalyst, such that the protecting group is selectively opened to give the desired hydroquinone monoacetal. These reactions produce pure hydroquinone monoacetals of high yield, without the need for chromatographic purification.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for making hydroquinone monoacetals comprising a series of steps where hydroquinone monoethers are used to improve the purity and yield of the desired final product when compared to the previously described process . The reaction of said hydroquinone monoether with an enol ether produces an intermediate product which is protected from the catalyzed acid which couples with a second enol ether equivalent, without consideration to the stoichiometry of the monoether compound and the enol ether. The use of protecting groups to eliminate the production of undesirable byproducts of synthesis reactions is well known in the art. In the present invention, it is desirable to eliminate or at least minimize the production of hydroquinone bisacetal compounds, which if present at the time of the second step of the process of the present invention, produces undesirable end products. In the subsequent hydrogenolysis of said intermediate product, the selective partition of the ether protecting group provides the desired final product in higher yields with higher purity. The hydroquinone protecting groups useful in the present invention are ethers susceptible to selective hydrogenolysis under mild conditions. Said ethers used as protecting groups in the present invention are selected from the group consisting of arylmethyl ethers, diarylmethyl, triarylmethyl, trimethylsilyl and mixtures thereof, preferably arylmethyl ethers. The preferred arylmethyl ether protecting groups of the present invention are selected from the group consisting of benzyl, aliphatic benzyl ethers and mixtures thereof, preferably aliphatic benzyl ether, more preferably monobenzyl ether. The monobenzyl ether of hydroquinone can be purchased as monobenzone or 4- (benzyloxy) phenol directly from commercial sources such as Adrich Chemical Company and Hoechst Celanese Corporation. Monobenzone can also be produced by routine chemical reactions well known in the art; see Schiff and Pellizzari. Justus Liebig's Annalen Der Chimie. vol. 221, pp 370 (18T3), incorporated herein by reference. This hydroquinone monoether is reacted with acyclic or cyclic enol ethers to produce the protected intermediate, preferably the hydroquinone monoacetal protected in the benzyl moiety, as illustrated below: wherein: (i) each R is independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, benzyl, aryl and benzyl or substituted aryl; (ii) each R 'is, independently, selected from the group consisting of C 1 -C 4 alkyl, benzyl, aryl, and benzyl or substituted aryl; (iii) n is an integer from 0 to 3; (iv) Bn is a benzyl group. This intermediate product is then subjected to a subsequent hydrogenolysis reaction in order to split said benzyl protecting group from the above intermediate to provide the final desired product. The selective removal of the hydroxyl protecting groups including ortho-benzyl groups is known. Bieg and Szeja, Removal of O-Benyl Protective Groups by Catalytic Transfer Hydroaenation. Synthesis, January 1985, discloses the partition of benzyl ethers of monosaccharides using ammonium format as a hydrogen donor and 10% palladium in a carbon catalyst. It is further disclosed therein that said method can be used for the selective removal of ortho-benzyl ethers in the presence of other types or ortho-protective groups. Bieg and Zseja, Cleavage of 2-Phenyl-l, 3-dioxolanes and Benzyl Ethers by Catalytic Transfer Hydroaenation. Synthesis, April 1986, discloses the partition of protective groups of 2-phenyl-1,3-dioxolane by the hydrogenation of catalytic transfer which avoids the disadvantages of the simultaneous partition of a 2-phenyl-1, 3-dioxane group. present in the molecule. Hydrazine hydrate is used as the source of hydrogen and 10% palladium in carbon as the catalyst. Said reaction can be used for the preparation of a wide range of partially protected sugars. In the present invention, the hydrogenolysis step is as illustrated below: The partition of the benzyl group is carried out in virtually quantitative production with non-acid hydrogen transfer sources such as hydrazine hydrate and ammonium formate, in combination with a supported metal catalyst. The acetal portion of the intermediate molecule is unaffected by these conditions, elminating the simultaneous formation of hydroquinone and / or monobenzone regeneration. Hence, there is no need for any chromatographic separation and the desired compounds can be isolated by simple purification techniques. The total yield for the two-stage process is significantly greater than the single-stage process previously described.

REACTION METHOD A. STAGE ONE As described above, the first stage of the procedure is to produce the protected intermediate product. In the case of the benzyl protecting group, 4- (benzyloxy) phenol is combined with a cyclic or acyclic enol ether and a catalytic amount of an acid under an inert atmosphere. In general, the estequeometric ratio of enol ether and 4- (benzyloxy) phenol is from 1: 1 to 2: 1. A variety of acid sources can be used, preferably those selected from the group consisting of hydrochloric acid, sulfuric acid, para-toluenesulfonic acid and mixtures thereof, where the catalyst dose does not exceed 0.02 equivalents based on the weight of the 4- (benzyloxy) phenol. A typical dose is 0.005-0.015 equivalents of acid. More preferred sources of acid is hydrochloric acid.

The formation of the intermediate product is conveniently carried out in a variety of polar organic solvents. Preferred polar solvents include those selected from the group consisting of methylene chloride, diethyl ether, tetrahydrofuran, dioxane, and mixtures thereof, with methylene chloride being more preferred. The typical total concentrations of reactants are within the weight range of 5 to 15%, although the complete solvation of 4- (benzyloxy) phenol is not crucial. Depending on the amount of starting materials, the formation reaction of the intermediate product takes from about 1 to about 16 hours at room temperature and atmospheric pressure. Changing the order of addition of starting materials has no effect on the formation of the intermediate product. In general, the reaction can be accelerated and forced to terminate by the addition of additional amounts of enol ether. After removal of the solvent, a series of rinses and triturations with non-polar solvents, typically hexanes, allows the purification of the intermediate product in high yields, usually greater than about 80%. In the present invention, a particular advantage of the use of 4- (benzyloxy) phenol is that large-scale chromatographic purification is not required, since any unreacted 4- (benzyloxy) phenol can be removed by washing with sodium hydroxide aqueous.

B. STEP TWO Following the formation of said intermediate product in step one, step two of the present process involves the selective hydrogenosis of the ortho-benzyl protecting group. Said hydrogenolysis is effected by the use of any number of hydrogen donors. In the present invention it is preferred that the hydrogen transfer source be non-acidic and is selected from the group consisting of hydrazine, ammonium formate, trialkylammonium formats, and mixtures thereof; all readily available from commercial sources or that can be prepared before the reaction. The hydrazine is typically supplied in the form of hydrate (55% by weight water / hydrazine) which can be used without further purification. The molar ratio of the source of hydrogen transfer to intermediate product is from about 6: 1 to about 1: 1, preferably 4: 1 to about 2: 1; most preferred of 3: 1. Said hydrogenolysis also requires a supported metal catalyst, preferably a carbon-supported metal selected from the group consisting of palladium, platinum, nickel and mixtures thereof. Palladium in carbon is very preferred. The weight percentage of the metal in the supported catalyst is about 2-20%, preferably 5-10%. The reaction is carried out in an organic solvent that completely dissolves the intermediate product upon reflux occurrence. The preferred organic solvent is a hydroxy solvent, more preferred are those selected from the group consisting of methanol, ethanol, isopropanol and mixtures thereof, preferably methanol and ethanol. The concentrations of the intermediate product are typically in the scale by weight of 5-15% relative to the solvent. Depending on the amount of starting materials, the complete removal of the benzyl group generally takes from about 0.5 to about 2.0 hours at reflux under an inert atmosphere. In the present invention, a particular advantage of the use of non-acidic hydrogen transfer sources is that large-scale chromatographic purification is not required, because essentially no by-products of hydroquinone or monobenzone are formed. The product is dried by removing the solvent / water and grinding with non-polar solvents or recrystallization from alcohol / water mixtures. With respect to this second step involving the reaction of the intermediate product with said hydrogen donor, it is preferred that said intermediate product be free of impurities, since these can negatively affect the reaction by, for example, modifying the surface of the preferred metal catalysts used herein.

EXAMPLE I 4- [(Tetrahydrofuran-2-yl) oxy] phenol was prepared as follows: Stage One; Combine 4- (benzyloxy) phenol (34.0 g, 0.17 mol, concentrated hydrochloric acid (0.20 ml, 37%) and 300 ml of methylene chloride, add a solution of 2,3-dihydrofuran (22.8 g) to the resulting suspension dropwise. g., 0.33 mol) and 100 ml of methylene chloride stir the mixture at room temperature under an inert atmosphere for 16 hours, at which time only trace amounts of 4- (benzyloxy) phenol remain by thin-layer chromatography analysis standard (Vogel's Textbook of Practical Organic Chemistry, 5th Edition, page 199) Wash the reaction mixture with approximately three aliquots of 1N sodium hydroxide, every 300 ml, and back off, extract said aqueous with approximately 200 ml. of methylene chloride Combine the organic layers, dry over sodium sulfate, and concentrate in vacuo to an oil.Crystallize the 2 [(4-benzyloxy) phenoxy] tetrahydrofuran from dich oil by careful trituration with a non-polar solvent such as hexanes, melting point 43-44 ° C.

Stage Doa Add 55% hydrazine hydrate (1.8 g, 30.0 mol) to a solution comprising 2 [(4-benzyloxy) - (phenoxy] tetrahydrofuran (2.7 g, 10.00 mmol), 5% Pd / C (0.4 g of 50% wet material) and 50 ml of absolute ethanol.The reaction mixture is heated at reflux under an inert atmosphere for approximately 30 minutes.Cool the reaction mixture and filter the catalyst.Concentrate the filtrate pale yellow, clear, Resulting, to an oil in the vacuum and codestilar in succession with two aliquots of ethanol (50 ml).

Triturate the resulting solid with about 25 ml of hexane and dry under vacuum at 40 ° C to constant weight. The composition and purity of the colored cream of 4- ([tetrahydrofuran-2-yl] oxy) phenol is confirmed by 1H and 13CNMR and elemental analysis; melting point 59-61 ° C.

EXAMPLE II 4- [(Tetrahydro-2H-pyran-2-yl) oxy] phenol is prepared as follows: Step One Slowly add, under an inert atmosphere, a methylene chloride solution of 3,4-dihydro-2H-pyran (37.3 g, 0.44 mo) to a solution comprising 4- (benzyloxy) phenol (88.8 g., 0.44 mol.), Concentrated hydrochloric acid (0.25ml, 37%) and 600 ml of methyl chlorine. This reaction mixture is stirred at room temperature for about 15 minutes, at which time a substantial amount of 4- (benzyloxy) phenol is present by thin layer chromatography. Consecutive portions of a solution comprising 3,4-dihydro-2H-pyran (7.5 g) and 25 ml are added to the reaction mixture. of methylene chloride. Stir the mixture for approximately 1 hour, where only trace amounts of the starting phenol remain. Wash the reaction mixture with approximately three aliquots of 4% aqueous sodium hydroxide, each 400 ml. Separate the aqueous layer and re-extract said layer with approximately 100 ml of methyl chloride. Combine the organic layers, dry over sodium sulfate, and concentrate in vacuo at about 40 ° C to a volume of about 200 ml. Remove the excess methylene chloride by co-distilling said concentrate with a sufficient amount of hexane to give the total volume of the distillate of approximately 250 ml. Dilute the resulting white suspension with hexane and cool said mixture to about room temperature. Collect the precipitated intermediate, 2- [(4-benzyloxy) -phenoxy] tetrahydropyran, on a filter and wash in-situ with aliquots of 100 ml of hexane. Dry said precipitate in vacuo at about 35 ° C until a constant weight is obtained; melting point 70-71 ° C.

Stage Two; Add 55% hydrazine hydrate (34.85 g, 0.6 mol) to a stirred suspension comprising 2- [(4-benzyloxy) -phenoxy] tetrahydropyran (56.4 g, 0.2 mol), 5% Pd / C (4.1 50% wet material) and approximately 450 ml. of absolute ethanol. Slowly heat the reaction mixture and reflux under an inert atmosphere until the thin-layer chromatography analysis indicates complete consumption of 2- [(4-benzyloxy) phenoxy] tetrahydropyran. Cool the reaction mixture to about 50 ° C, rinse said mixture by filtration, and concentrate to a solid under vacuum at 40 ° C. Suspend said solid in ethanol and slowly dilute said suspension with deionized water. Stir for approximately 30 minutes and collect the white solid in a filter. Wash said solid in-situ with water, then resuspend the solid in water. Recoloculate the solid, wash in-situ with water and dry under vacuum at 24 ° C at constant weight. Further purification of 4- [(tetrahydro-2H-2-yl) oxy] phenol, if necessary, is achieved by a second round of recrystallization of the aqueous ethanol. The composition and purity are confirmed by * H and 13CNMR and elemental analysis; melting point 86-87 ° C.

EXAMPLE III 4- [(1-Butoxyethyl) oxy] phenol is prepared as follows: Step One: In a manner similar to Examples I and II, a solution of methylene chloride of butyl vinyl ether (6.2 g, 0.06 mol) is slowly added to a solution comprising 4- (benzyloxy) phenol (12.4 g, 0.06 mol). ), hydrochloric acid (0.15 ml, 37%) and 100 ml of methylene chloride. Stir under an inert atmosphere for approximately two hours and analyze the reaction mixture for 4- (benzyloxy) phenol by thin layer chromatography. If 4- (benzyloxy) phenol is still present, add to this reaction mixture an additional portion of butyl vinyl ether (1.8 g, 0.02 mol) in 25 ml of methylene chloride and continue stirring until the phenol is consumed. Wash the reaction mixture with approximately three aliquots of 1N solium hydroxide, each of 250 ml., And re-extract said aqueous washes with approximately 100 ml. of methylene chloride. Combine the organic layers, dry over sodium sulfate, and concentrate the protected benzyl intermediate in vacuo to a pale yellow oil. The composition and purity are confirmed by 1H and 13CNMR.

Stage Two; 55% hydrazine hydrate (2.5 g, 0.078 mol) is added to a stirred suspension comprising the intermediate product from Step One (5.0 g, 0.017 mol), 5% Pd / C (3.8 gr.) And approximately 100 mi. of methanol. Heat the reaction mixture and keep it under reflux under an inert atmosphere for about two hours after which the thin layer chromatographic analysis indicates the complete consumption of the benzyl protected intermediate. The reaction mixture is cooled to room temperature and filtered by removing the catalyst. The pale, pale yellow filtrate is concentrated in an oil under vacuum, washed with hexanes and dried at constant weight in vacuo at 50 ° C. The composition and purity of isolated 4- [(1-butoxyethyl) oxy] phenol is confirmed by 'H and 13 CNMR.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. A process for preparing hydroquinone monoacetals comprising the steps of: a) reacting monoether of hydroquinone with an enol ether in the presence of an acid catalyst to produce the protected monoacetal of hydroquinone as an intermediate; and b) reacting said intermediate with a source of hydrogen transfer in the presence of a metal catalyst such that the protecting group is selectively cleaved to give the desired hydroquinone monoacetal.

2. The process for preparing hydroquinone monoacetals, according to claim 1, further characterized in that the ether protecting group is selected from the group consisting of arylmethyl, diarylmethyl, triarylmethyl, trimethylsilyl ethers and mixtures thereof, preferably a arylmethyl ether selected from the group consisting of benzyl, aliphatic benzyl ethers and mixtures thereof, preferably aliphatic benzyl ether, more preferably monobenzyl ether.

3. The process for preparing hydroquinone monoacetals, according to claim 1, further characterized in that the source of hydrogen transfer is non-acidic and is selected from the group consisting of hydrazine, ammonium formate, trialkylammonium formats, and mixtures of the same; in a molar ratio of the source of hydrogen transfer to intermediate is from 6: 1 to 1: 1, preferably hydrazine in a molar ratio of hydrazine to intermediate from 4: 1 to 2: 1.

4. The process for preparing hydroquinone monoacetals, according to claim 1, further characterized in that the formation of the intermediate is carried out in a polar solvent selected from the group consisting of methylene chloride, diethyl ether, tetrahydrofuran, dioxane and mixtures thereof. them, with methylene chloride being more preferred.

5. The process for preparing hydroquinone monoacetals, according to claim 1, further characterized in that the metal catalyst is a carbon-supported metal selected from the group consisting of palladium, platinum, nickel and mixtures thereof, whereby the percent by weight of the metal in the supported catalyst is 2-20%, preferably palladium on carbon.

6. The process for preparing hydroquinone monoacetals, according to claim 4, further characterized in that the reaction is carried out in a polar organic solvent, preferably a hydroxide solvent selected from the group consisting of methanol, ethanol, isopropanol, and mixtures thereof, more preferably methanol, ethanol and mixtures thereof. you 15 20 25 EXTRACT OF DISCLOSURE The present invention is for a process for preparing hydroquinone monoacetals, wherein said process is provided for high yields of higher purity. Said process employs a two-step reaction, wherein a protected hydroquinone is reacted with an enol ether to form a protected intermediate. Upon the hydrogenolysis of said intermediate, a final product, the monoacetal hydroquinone, is formed having a higher degree of purity and high yields than the yields attributed to reactions known in the art.