Resorcinol and its derivatives have a wide variety of applications. The largest consumption of resorcinol is in the tyre industry, where the preferred hardening resins are based on resorcinol. Another value-added application of resorcinol and its derivatives is in cosmetic products.

Some compounds like 2-4, dihydroxyacetophenone have been used in sun-protective applications.

Alkyl resorcinols and aromatic resorcinols are reported to possess valuable therapeutic and antiseptic properties. In particular, 4-alkyl resorcinol is reported to have skin- beautifying effect and low toxicity and irritation when applied on to human skin. 4-Alkyl resorcinol has also been reported to be used to inhibit browning of foods and beverages. Alkyl resorcinols like 4-n-butyl resorcinol have been used in skin creams and lotions which are claimed to have good bleaching and anti-microbial effect. 2-alkyl resorcinol (where the alkyl group is linear) has been reported to have skin depigmentation properties.

There have been many methods reported to prepare alkyl resorcinols. As far back as the 1920's, Sharp and Dohme

Inc. has applied for a series of patents (US 1,697, 168, US 1,697, 667 and US 1,649, 668) disclosing methods to prepare alkyl resorcinols and iso-alkyl resorcinols. N-alkyl or isoalkyl resorcinols were prepared from the corresponding n- acyl or iso-acyl resorcinols, which were first prepared by reacting resorcinol with n-fatty acids or iso-fatty acid in the presence of a condensing agent like zinc chloride at elevated temperature. This was followed by reduction of the corresponding n-acyl or iso-acyl resorcinol in the presence of zinc amalgam and hydrochloric acid. These processes are now considered to be environmentally unacceptable due to the use of amalgams (which are mercury alloys). Mercury compounds are increasingly being indicated as a major cause of water pollution.

US 2,006, 039 (Redro Laboratories, 1932) describes a process to prepare unsymmetrical di-substituted alkyl resorcinols of , ... the general formula C6H2 (OH) 2R R wherein R and R represent different alkyls, one of which contains three or more carbons atoms. The process consists of starting with mono- ketone derivative of resorcinols prepared by the well known process of reacting resorcinol with a acid, acid chloride or acid anhydride in the presence of a condensing agent like zinc chloride. The mono-ketone derivative is then reacted with an acid, acid chloride or anhydride containing a radical different from the substituting radical already present in the mono-ketone, in the presence of condensing agent like zinc chloride to form the diketone. The diketone is then reduced in the presence of zinc amalgam and acid to produce the corresponding di-alkyl resorcinol. This process

is a multi-step synthesis, suffers form low yields, and makes use of mercury compounds.

US 470587 (Koppers, 1987) describes a process to prepare long-chain alkyl resorcinol phosphites which consists of a first step of preparing long-chain alkyl resorcinol, where the alkyl group has 8 to 18 carbon atoms consisting of at least 75% secondary, preferably 90% secondary alkyl group.

The secondary alkyl group is preferably attached to the second carbon in the benzene ring and the alkyl is preferably attached to the 2,4, or 6 positions. This process consists of the steps of reacting resorcinol with alpha-olefins in the presence of a catalyst such as clay aluminosilicates or high silica zeolites, preferably in an inert atmosphere. This process suffers from low yields, and does not disclose methods to selectively prepare iso 4-alkyl and iso 4-6 dialkyl resorcinols.

GB 1,581, 428 (Conoco, 1980) describes a method of alkylating phenolic compounds including resorcinols to prepare n-alkyl resorcinol by the reaction of the phenolic compound with the n-alkanol in the presence of an alumina catalyst derived from aluminium alkoxide hydrolysis at high pressures up to 20 atmospheres, and high temperatures of 200 to 400 °C. It is desirable to develop processes that work at atmospheric pressures, and are selective to iso-alkyls.

W094/15986 (Indspec) describes preparation of 4-isopropyl resorcinol and 2-4-diisopropyl resorcinol by reaction of resorcinol and iso-propyl alcohol in the presence of sulphuric acid. This process produces a large number of

undesirable by-products like isopropyl ether, 2-isopropyl resorcinol, 2,6-di-isopropyl resorcinol and 2,4, 6, tri- isopropyl resorcinol. It is desirable to develop a process to selectively prepare 4 isopropyl resorcinol and 4,6 di- isopropyl resorcinols in high yield and purity, as these are especially useful in skin applications. Any presence of undesirable by-products in skin creams or lotions can be harmful or at least cause skin irritations. Processes to produce the desired compounds by downstream purification will render the products expensive.

It is thus an object of the invention to be able to prepare compound of the formula 1, wherein R1 is hydrogen or iso-alkyl and R2 is an iso-alkyl group, in high yields and purity.

It is a further object of the present invention to be able to prepare compounds of formula 1 in high yields and purity that uses chemicals which are environmentally acceptable.

It is yet another object of the present invention to be able to prepare compounds of formula 1 in high yields and purity, which can be carried out at atmospheric pressure and does not require expensive equipment.

It is a further object of the present invention to be able to prepare compounds of formula 1 in high yields and purity in a single step reaction, thus requiring a single reaction vessel.

It is a further object of the present invention to be able to prepare 4,6-diisoalkyl resorcinol in high yields and purity using environmentally acceptable chemicals, at atmospheric pressure using inexpensive equipment, in a single step reaction, thus requiring a single reaction vessel.

According to one aspect of the invention, there is provided a process for preparation of compound of the formula 1, wherein R1 is hydrogen or iso-alkyl and R2 is an iso-alkyl group, comprising the step of reacting resorcinol with at least one secondary alcohol in the presence of a proton acid catalyst, wherein the reaction is carried out in a water removing system.

According to a preferred aspect of the invention, there is provided a process for the preparation of a compound of formula 1 comprising the step of reacting resorcinol with at least one secondary alcohol in the presence of a proton acid catalyst, wherein the reaction is carried out in a solvent

media where the solvent is capable of forming an azeotrope with water.

According to a further preferred aspect of the invention, there is provided a process for the preparation of a compound of formula 1 comprising the step of reacting resorcinol with at least one secondary alcohol in the presence of a proton acid catalyst at a temperature range of 50 to 175 °C, wherein the reaction is carried out in a solvent media where the solvent is capable of forming an azeotrope with water.

It is particularly preferred that the solvent used is cyclohexane or toluene.

The present invention provides for a novel process to prepare 4,6-di-isoalkyl resorcinol, or a combination of 4,6- di-isoalkyl resorcinol and 4-isoalkyl resorcinol. The novel process can also be used to prepare exclusively 4,6-di- isoalkyl resorcinol. The process is a single step reaction which involves reacting resorcinol with a secondary alcohol in the presence of a proton donor acid wherein a system is provided that enables removal of the water as it is formed by the reaction. In the formula 1, when Rl is hydrogen and R2 is an iso-alkyl group, then the product is 4 isoalkyl resorcinol. When R1 is an isoalkyl group and R2 is the same or another iso-alkyl group, then the product is 4,6, di- isoalkyl resorcinol.

Although the raw material as per this invention is resorcinol, the process could also be carried out starting with precursors of resorcinol, from which reactions well known in the art could be employed to first prepare resorcinol, following which the process of the invention could be carried out.

Suitable types secondary alcohols used as a reactant as per the process of the invention could be chosen from one or more of linear alkyl alcohol, cyclic alkyl alcohol, or heterocyclic alcohol. The carbon chain length of the secondary alcohol could be 1 up to 18, but the preferred chain length is a maximum of 8. Highly preferred alcohols to be used for preparing alkyl and dialkyl resocinols for skin application have carbon chain lengths up to a maximum of six. Thus, when the desired product is an 4,6 diiso- propyl resorcinol, the preferred reagent is isopropyl alcohol. The concentration of the secondary alcohols can range from 0.1 to 20 moles per mole of resorcinol reacted, preferably from 0.1 to 10 moles per mole of resorcinol reacted.

The reaction has to be carried out in the presence of a proton donor acid. Suitable examples of acids that can be used to carry out the reaction as per the invention include

methane sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, p-toluene sulfonic acid, and acidic ion- exchange resins such as Amberlyst (available from Rohm & Hass), and Dowex (from Dow chemicals). The acid can also be a metal catalyst such as alumina. An example is Houdry 100S manufactured by Houdry Process and Chemical Company. The acid donor can also be acidic clays, alumina silicates and the like. One or more of the acids can be used in the reaction. The concentration of the acids can be from 0.001 % to 10 times the weight of resorcinol, preferably from 0.001 % to 5 % of the weight of resorcinol added. A highly preferred acid as per this invention is sulphuric acid.

The alkylation reaction can be carried out from 50 to 175°C, preferably from 50 to 150°C. A highly preferred temperature range for carrying out the reaction is from 50 to 135 °C.

An essential feature of the invention is a system that removes the water as it is formed by the reaction. Although water could be removed either by physical or chemical means, physical means of removal of water are preferred. The water could be removed batch wise as the reaction progresses, or in a continuous fashion. Methods well known in the art could be employed for effective removal of water, viz. using adsorption, distillation, partitioning with solvents, use of dehydrating clays, use of membranes, use of solid, liquid or solubilized chemcials that have a high affinity for water.

A combination of one or more of the above methods could also be used. One way to achieve removal of water is to distill off the secondary alcohol along with the water during the

course of the reaction, pass the distillate through a drying agent to remove the water, and recycle the secondary alcohol substantially free of water back to the reaction vessel.

Preferred methods for removal of water include use of solvents that form azeotropes with water, and the use of drying agents. Highly preferred solvents that can be used to partition water are toluene, xylene, cyclohexane and methyl tert-butyl ether, and the like. Suitable drying agents include aluminium oxides, calcium oxides, magnesium oxides, sodium sulfate, magnesium sulfate, zeolites, calcium chloride, molecular sieves, sodium oxides and sodium- potassium alloys. Highly preferred solvents that can be used to remove water are cyclohexane or toluene.

Examples The invention will now be illustrated with the help of the following non-limiting examples.

The products formed by the processes where there is no water removing system, and the present invention where the water removing system is a key feature was compared.

1. Comparative Example without water removing system A three necked flask equipped with a Dean-Stark trap, additional funnel and a condensor was taken. To this flask was added a mixture of 275 grams (2.5 moles) of resorcinol, 2.5 ml of sulphuric acid and 60 grams (1 mole) of isopropyl alcohol. The flask was heated to reflux. The pot temperature reached 140 °C. Isopropyl alcohol was added as

needed. A total of 260 grams (4.3 moles) of isopropyl alcohol was added. The reaction was maintained between 135 to 155°C for 12 hours. The reaction mixture was monitored by gas chromatography, GC-MS and NMR, which are described below.

The chemical composition of the product was found to be 30 % unreacted resorcinol, 30 % of a mixture of 2-isopropyl resorcinol, 2,6-diisopropyl resorcinol and 2,4, 6- triisopropyl resorcinol and 40% of a mixture of 4-isopropyl resorcinol and 4,6-diisopropyl resorcinol.

Gas chromatography/mass spectrometry (GC-MS): GC-MS was performed on an Agilent 6890 Series Plus gas chromatograph in conjunction with an Agilent 5973 Network Mass Selective Detector. An Agilent HP-1 column used was.

Gas chromatography (GC): GC analysis was performed using a Hewlett-Packard 5890 Series II Plus gas chromatograph with an HP 7673 injector controlled by Hewlett-Packard ChemStation software. The Hewlett-Packard HP-1 column used was 25 M x 0.22 mm with a 0. 33 um coating of cross-linked methyl silicone.

Proton magnetic resonance (NMR): NMR spectra were recorded on a Bruker 200 mHz spectrophotometer. Chemical shifts are reported in parts per million from tetramethylsilane as an internal standard. Spin multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). The deuterated NMR solvents contain 99.0-99. 8% deuterium in the indicated position.

All solvents were reagent grade and were used as received.

All reagents were purchased from the Aldrich or Sigma Chemical Companies and were used as received unless otherwise noted.

2. Processes according to the invention: Example 1 A three-necked flask equipped with a Dean-Stark trap, additional funnel and a condensor was taken. To this flask was added a mixture of 275 grams (2.5 moles) of resorcinol, 2.5 ml of sulphuric acid, 60 grams (1 mole) of isopropyl alcohol and 250 ml of toluene. The flask was heated to reflux. The pot temperature reached 120 °C. A total of 260 grams (4.3 moles) of isopropyl alcohol was added. The reaction was maintained between 110 and 120°C for 12 hours.

Toluene/water mixture was removed periodically, and additional toluene was added as needed until such time most of the water (that can theoretically be formed) was removed.

The reaction mixture was monitored by gas chromatography, GC-MS and NMR.

The chemical composition of the product was found to be 5 % unreacted resorcinol, 10 % of a mixture of 2-isopropyl resorcinol, 2,6-di-isopropyl resorcinol and 2,4, 6-tri- isopropyl resorcinol and 85 % of a mixture of 4-isopropyl resorcinol and 4,6-di-isopropyl resorcinol.

Example 2

275 grams of resorcinol was taken in a flask as per Example 1 and heated to 115 °C. To this flask was added dropwise 2.5 ml of sulphuric acid, 260 grams (1 mole) of isopropyl alcohol and 250 ml of toluene while maintaining the temperature at 115 °C. The flask was heated to reflux. The pot temperature reached 120 °C. The reaction was maintained between 110 and 120 °C for 12 hours. Toluene/water mixture was removed periodically and additional toluene was added as needed until such time most of the water (that can theoretically be formed) was removed. The reaction mixture was monitored by gas chromatography, GC-MS and NMR.

The chemical composition of the product was found to be 3 % unreacted resorcinol, 5 % of a mixture of 2-isopropyl resorcinol, 2,6-di-isopropyl resorcinol and 2,4, 6-tri- isopropyl resorcinol and 92 % of a mixture of 4-isopropyl resorcinol and 4,6-di-isopropyl resorcinol.

Example 3 An experiment as per Example 2 was carried out except that cyclohexane was used instead of toluene, and the addition of the reactants was carried out at a pot temperature of 110°C.

The reaction mixture was monitored by gas chromatography, GC-MS and NMR.

The chemical composition of the product was found to be 2 % unreacted resorcinol, 5 % of a mixture of 2-isopropyl resorcinol, 2,6-di-isopropyl resorcinol and 2,4, 6-tri- isopropyl resorcinol and 93 % of a mixture of 4-isopropyl resorcinol and 4,6-di-isopropyl resorcinol.

Example 4 An experiment as per Example 3 was carried out except that 660 grams of isopropyl alcohol (11 moles) and 1.0 ml of sulphuric acid were used. The reaction mixture was monitored by gas chromatography, GC-MS and NMR.

The chemical composition of the product was found to be 2 % unreacted resorcinol, 2 % of a mixture of 2-isopropyl resorcinol, 2,6-di-isopropyl resorcinol and 2,4, 6-tri- isopropyl resorcinol and 96% of 4,6-di-isopropyl resorcinol.

The examples indicate that the experiments as per the invention (Examples 1 to 4) produce 4,6-dialkyl resorcinol or a combination of 4,6-dialkyl resorcinol and 4-alkyl resorcinol in very high yield and purity as compared to the known processes existing in the prior art. The unreacted resorcinol in the process according to the invention is only upto 5 % in comparison to that in the known process where it is about 30 %.