FORM -2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)
PROCESS FOR THE PREPARATION OF A COSMETIC ACTIVE
HINDUSTAN LEVER LIMITED, a company incorporated under the Indian Companies Act, 1913 and having its registered office at. Hindustan Lever House,. 165/1.66, Backbay Reclamation
Mumbai -400 020, Maharashtra, India
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

TECHNICAL FIELD
The present invention relates to a novel process for the preparation of one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol starting from resorcinol as the raw material, particularly useful in cosmetic applications.
BACKGROUND AND PRIOR ART
Resorcinols 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 important application of resorcinol and its derivatives is in cosmetic products. Resorcinol has been used as antioxidants in some skin creams. Some compounds like 2 - 4, dihydroxyacetophenone have been used in sun-protective applications. Esters of resorcinol like resorcinol mono-acetate have been used in cosmetic preparation for stimulating the scalp. Resorcinol and resorcinol mono-acetate have been used in anti-acne preparations. 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.
There have been methods reported to prepare esters of resorcinol. JP61180738 (Nippon Zeon, 1986) describes a process to prepare 2,4- dihydroxyacetophenone from resorcinol by reacting it with a monocarboxylic acid halide such as acetyl chloride in the presence of Zinc Chloride as a catalyst.
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US5621146 (Kuraray, 1997) discloses a process to prepare 2,4-dihydroxyacetophenone comprising reacting resorcinol and acetic acid in a reaction medium containing a proton acid, catalyst and removing water as it is formed by the reaction of resorcinol with acetic acid.
Ketones produced by the esterification of resorcinol and its derivatives have been known to be reduced to the alkane group by Clemmenson's reduction using Zinc-Mercury amalgam as the catalyst. GB256225 (Hirzel, 1926) discloses the reduction of di-ethoxy-caprophenone to di-ethoxy-hexyl-benzene with zinc-amalgam in the presence of 10% hydrochloric acid.
The reduction reaction disclosed in GB256225 suffers from the drawback of having to use mercury compounds as catalyst. Mercury and its compounds have been increasingly indicated as an element of environmental pollution. It is desirable to carry out this reaction using more environmentally acceptable catalyst.
OBJECTS OF THE INVENTION
It is thus an object of the present invention to prepare one or more esters of 4-alkyl resorcinol with or without' 4-alkyl resorcinol using catalysts that are non-polluting and easy to handle.
It is-a further object of the present invention to prepare one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol in high yields.
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It is a yet another object of the present invention to prepare one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol in high yields by a process that is easily impterrrerrtable' on industrial scale.
It is also a further object of the present invention to selectively prepare 4-alkyl resorcinol diesters.
SUMMARY OF THE INVENTION
According to one aspect of the invention there is provided a process for preparation of one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol comprising the steps of
(i) reacting resorcinol with at least one of an organic acid, anhydride or chloride
(ii) reducing the products from step (i) under substantially neutral conditions in the presence of a catalyst.
According to a preferred aspect of the present invention, there is provided a process for preparation of one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol comprising the steps of
(i) reacting resorcinol with at feast one of an organic acid anhydride or ""chloride
having a maximum carbon chain length of 18, at a temperature of 10 to 250 °C,
preferably in the presence of an acid catalyst
(ii) reducing the products from step (i) at a pH of 6.5 to 7.5 in the presence of a
catalyst in an alcoholic medium.
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According to a further preferred aspect of the present invention, there is provided a process for preparation of one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinolcomprising the steps of
(i) reacting resorcinol with at least one of an organic acid, anhydride or chloride
having a maximum carbon chain length of 9, at a temperature of 20 to 150 °C,
preferably in the presence of an acid catalyst
(ii) cooling the products from step (i) to less than 50 °C
(iii) reducing the products from step (ii) at a pH close to 7 in the presence of a
catalyst in an alcoholic medium.
It is particularly preferred that the esteritication reaction is carried out with an anhydride. A highly preferred catalyst in the reduction reaction is Raney Nickel.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for a novel process to prepare one or more esters of 4-alkyl resorcinol with or without 4-alkyl resorcinol. The process essentially comprises two important steps: a) the esteritication reaction and b) the reduction reaction.
The Esterification reaction:
The esteritication reaction involves reaction of resorcinol with an organic acid, anhydride or chloride. 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.
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Although the esterifying agent could be an organic acid, anhydride or chloride the preferred reactant is an anhydride. The carbon chain length of the esterifying agent could be up to 18, but the preferred chain length is a maximum of 9 and the most preferred agent is one with a carbon chain length of one or two. Thus, when the desired product is an acetate, the preferred reagent is acetic anhydride. The concentration of the esterifying agent can be from 0.1 to 20 moles per mole of resorcinol reacted, preferably from 1 to 10 moles per mole of resorcinol reacted.
Although the reaction can be carried out without the use of an acid, it is preferred that the reaction is carried out in the presence of an acid. The preferred acids are 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). One or more of the acids can be used in the reaction. The concentration of the acids can be from 0 to 10 times the weight of resorcinol, preferably from 0.1 to 100% of the weight of resorcinol added.
The esterification reaction can be carried out from 10 to 250 °C, preferably from 20 to 150 °C. A highly preferred temperature range for carrying out the reaction is from 50 to 150 °Cr I tist also preferred that the reaction mass after this reaction is cooled to less than 50 °C, more preferably in the range of 20 to 40 °C before the reduction reaction is carried out.
Reduction reaction:
The products from the esterification reaction are reduced to 4-alkyl resorcinol and its
esters at substantially neutral conditions in the presence of a catalyst.
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The reaction is carried out preferably in the pH range of 6.5 to 7.5, and a highly preferred pH value is close to 7.
It is preferred that the reaction is carried out in an alcoholic medium. Preferred alcohols are ethanol, methonol, propyl alcohol, butanol and iso-propyl alcohol. Highly preferred alcohols are ethanol, methanol and iso-propyl alcohol. The alcohols may be mixed with water to prepare the medium for carrying out the reaction. Water and alcohol could be mixed in any ratio but the preferred percentage of water in the medium is from 0 to 80%. The reaction requires the presence of a catalyst chosen from the group consisting of Nickel supported on noble metals, metal hydrides/hydrozones, sodium borohydride in trifluoroacetic acid, palladium supported on carbon (with or without use of promotors e.g. diisopropoxyaluminiumtrifluoroacetate). Preferred catalysts include various nickel catalysts either with support or otherwise or supported noble metal catalysts. A highly preferred catalyst is Raney Nickel. The amount of catalyst to be used can vary from 0.1 to 20 moles per mole of the reactant.
The reduction reaction can be carried out in the temperature range of 10 °C to 240 °C. A preferred temperature range is from 20 to 150 °C.
It is possible to produce more than one ester by this reaction, e.g. when acetic anhydride is used in the esterification reaction, it is possible to produce both 4-alkyl resorcinol mono-acetate and 4-alkyl resorcinol di-acetate depending on the concentration of the reactants and the reactant conditions.
The invention will now be illustrated with the help of the following non-limiting examples:
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EXAMPLES:
Example 1
1. Esterification of resorcinol in the absence of an acid catalyst
110 grams of resorcinol was mixed with 255 grams of acetic anhydride at 25°C temperature. The mixture was then heated to 50 °C and maintained at that temperature for one hour with stirring. The reaction mixture was then heated to 150°C and maintained at that temperature for up to 1 hr with constant stirring.
The reaction mixture was analyzed through Gas chromatography/mass spectroscopy (GC-MS), revealing that the product contained resorcinol monoacetate, resorcinol diacetate, 2, 4-dihydroxy acetophenone and 2,4-dihydroxy acetophenone mono-acetate and 2,4-dihydroxy acetophenone diacetate.
2. Esterification of resorcinol in the presence of an acid catalyst:
11 grams of resorcinol and 25.5 grams of acetic anhydride were mixed at 25°C. and a catalytic amount of sulphuric acid was added. The mixture was heated to 50°C and maintained for 30 minutes with stirring. The reaction mixture was then heated to 120°C and maintained at that temperature for 45 minutes.
To this mixture was added 64 grams of distilled water and 0.5 grams of sulphuric acid and the reaction mixture was refluxed for 5-10 hrs. The reaction was cooled to 25 °C and the products were isolated. The product was analysed by Gas chromatography/Mass spectroscopy to be a mixture of 2, 4-dihydroxy acetophenone mono acetate, 2,4-dihydroxy acetophenone and 2,4-dihydroxy acetophenone diacetate.
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The 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.
Example 2
Reduction of the compounds obtained in Example 1:
10 g of the mixture as produced in Example 1 was dissolved in a 50% ethanol in water at
25 °C. 20 gram of Raney Nickel was added and the reaction was refluxed for 5 hrs. A
mixture of 4-ethyl resorcinol; 4-ethyl resorcinol mono-acetate; 4-ethyl resorcinol
diacetate were isolated in > 95% yield. The products were separated on a silica column
and individually characterized using NMR, Mass spectroscopy and Infra- Red
Spectroscopy.
10 g of the mixture of ethyl resorcinol, and ethyl resorcinol mono acetate and ethyl resorcinol diacetate was taken in a clean, dry round bottomed flask. The flask was cooled to 25 °C before adding 100 g of anhydrous triethylamine. The mixture was stirred until it became homogeneous. 50 g of acetic anhydride was added to the reaction mixture dropwise. The reaction was stirred at room temperature for 12 hrs. Excess triethylamine and acetic anhydride was removed under reduced pressure^ on a rotaevaporator at a temperature range of 30 to 40°C. The product was dissolved in diethyl ether before extracting three times with water and once with saturated sodium chloride solution. The ether layer is isolated, dried over magnesium sulfate, filtered and concentrated under high vacuum to give a dark rust colored liquid (90% crude yield). The crude product was distilled under vacuum and distillate was collected at 83-85°C at 0.05 mm Hg to give a clear, colorless liquid. Gas chromatography analysis indicated a
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product 4 ethyl resorcinol diacetate with 99% purity. The product was analyzed by IR, 1H NMR, 13C NMR, GC and GC-MS and gave the following characterisation of the product.
The procedures followed for Gas chromatography, Infrared and Proton magnetic resonance are as follows.
Gas chromatography (GC) 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 urn coating of cross-linked methyl silicone . The parameters were as follows:
Inj. temp.= 250°C , det. temp.= 250°C, initial oven temp.= 70°C, initial time = 2 min., rate
= 25°C/min., final oven temp.= 250°C and final time = 11 min. Samples were derivatized with Sil-Prep to ensure no unreacted starting material was present.
Infrared(IR): IR spectra were recorded on a Nicolet Impact model 410 spectrometer using a NaCI cell. Data was processed using OMNIC software. Peak positions are listed in cm"1 as vs (very strong), s (strong), m (medium), w (weak) or br (broad).
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.
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All solvents were reagent grade and were used as received. All reagents were purchased from- the Aid rich or Sigma Chemical Companies and were used as received unless otherwise noted.
IR(neat): 1770 cm-1 (s)
1H NMR (200 MHz, CdCI3): 7.2 (d, 1H) , 6.95 (m, 1H), 6.8 (d, 1H), 2.5 (q, 2H), 2.3 (s,
3H), 2.2 (s, 3H),1.15(t,3 H) (Figure 1).
13C NMR (50 MHz, CdCI3): 168.9, 168.8, 148.8, 133.1, 129.4, 119.0, 115.6,22.6,20.8,
20.6, 13.8, 12.9 GC (R,): 7.5 minutes
m/z (GC/MS): 222
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We claim:
1. A process for preparation of one or more esters of 4-alkyl resorcinol with or
without 4-alkyl resorcinol comprising the steps of
(i) reacting resorcinol with selective organic acid, anhydride or
chloride; and
(ii) reducing the products from step (i) under substantially neutral
conditions in the presence of a catalyst.
2. A process as claimed in claim 1 wherein the step of reacting resorcinol with selective organic acid, anhydride or chloride and mixtures thereof is carried out in the presence of an acid.
3. A process as claimed in claim 2 wherein the acid selected from methane sulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, p-toulene sulfonic acid, or acidic ion-exchange resins and mixtures thereof.
4. A process as claimed in claims 2 or 3 wherein the acid is present in an amount of up to 10 times the weight of resorcinol.
5. A process as claimed in claim 4 wherein the acid is present in an amount of 0.1 to 100% by weight of resorcinol.
6. A process as claimed in anyone of claims 1 to 5 wherein the carbon chain length of the organic acid, anhydride or chloride is from 1 to 18.
7. A process as claimed in claim 6 wherein the carbon chain length of the organic acid, anhydride or chloride is from 1 to 9.
8. A process as claimed in claim 7 wherein the carbon chain length of the organic acid, anhydride or chloride is 1 or 2.
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9. A process as claimed in anyone of claims 1 to 8 wherein resorcinol is reacted with an organic anhydride.
10. A process as claimed in anyone of claims 1 to 9 wherein the organic acid, anhydride or chloride is present in a range of 0.1 to 20 moles per mole of resorcinol.
11. A process as claimed in claim 10 wherein the organic acid, anhydride or chloride is present in a range of 1 to 10 moles per mole of resorcinol
12. A process as claimed in anyone of claims 1 to 11 wherein the step of reacting resorcinol with selective organic acid, anhydride or chloride and mixtures thereof is carried out at a temperature in the range of 10 to 250°C.
13. A process as claimed in claim 12 wherein the step of reacting resorcinol with selective organic acid, anhydride or chloride and mixtures thereof is carried out at a temperature in the range of 20 to 150 °C.
14. A process as claimed in claim 13 wherein the step of reacting resorcinol with at least one of an organic acid, anhydride or chloride is carried out at a temperature in the range of 50 to 150°C.
15. A process as claimed in anyone of claims 1 to 14 wherein the reaction mixture
x
is cooled to less than 50°C prior to starting the reduction step.
16. A process as claimed in claim 15 wherein the reaction mixture is cooled to temperature in the range of 20 - 40°C prior to starting the reduction step.
17. A process as claimed in anyone of claims 1 to 16 wherein the reduction step is carried out in the pH range of 6.5 to 7.5.
18. A process as claimed in anyone of claims 1 to 17 wherein the reduction step is carried out in an alcoholic medium.
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19. A process as claimed i 1 claim 18 wherein the alcohol selected from methanol,
ethanol or iso-propyl alcohol and mixtures thereof.

20. A process as claimed in anyone of claims 1 to 19 wherein the reduction step is carried out in a medium comprising a mixture of water and alcohol.
21. A process as claimed in claim 20 wherein water is present in an amount of 0 to 80% by weight of alcohol.
22. A process as claimed in anyone of claims 'l to 21 wherein the reduction step is carried out in the presence of catalyst chosen from Nickel supported on noble metals.
23. A process as claimed in claim 22 wherein the Nickel catalyst is Raney Nickel.
24. A process as claimed in anyone of claims 1 to 23 wherein the catalyst is present in an amount of 0.1 to 20 moles per mole of resorcinol.
25. A process as claimed in anyone of claims 1 to 24 wherein the reduction step is carried out in the temperature range of 10 to 240°C.
26. A process as claimed in claim 25 wherein the reduction step is carried out in the temperature range of 20 to 150 °C.
27. A process substantially as herein described and illustrated with reference to the accompanying examples.

Dated this 8th day of December 2003

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