FORM2 THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2003COMPLETE SPECIFICATION(See section 10; rule 13)
1. Title of the invention. - AN IMPROVED PROCESS FOR THE PREPARATION OF 3-ISOPROPYL-4- METHOXYPHENOL
2. Applicant(s)(a) NAME :(b) NATIONALITY(c) ADDRESS : ALEMBIC LIMITEDAn Indian Company.Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of the invention:
The present invention relates to an improved process for preparation of 3-isopropyl-4-methoxyphenol represented by a structural formula (I) as given below.

Background of the invention:
The molecular formula of 3-isopropyl-4-methoxyphenol is C10H14O2 and molecular weight is 166.21. CAS registry No. of 3-isopropyl-4-methoxyphenol is [13523-62-1].
3-isopropyl-4-methoxyphenol is used as an intermediate in the various synthetic preparation like in preparation of thyroid receptor ligands such as N-[3,5-dibromo-4-[4-hydroxy-3-( 1 -methylethyl)-phenoxy]phenyl ]-1 -earbamylcyclobutane-1 -carboxylic acid. Thyroid hormone receptor agonists that interact selectively with the fi-form of the thyroid hormone receptor.
WO2004066929 discloses a process for preparation of 3-isopropyl-4-methoxyphenol in example I. The synthetic reaction scheme for the preparation is as given below in the scheme.
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P-toluene sulfonic acid used in above process is hygroscopic and difficult to handle at industrial scale. The purity of 3-isopropyl-4-methoxyphenol obtained by this process is 93%. The main reason for such low purity is the generation of impurities at the final step reaction. One major impurity formed in this process which is difficult to remove even after repeated crystallization. Moreover, this patent does not provide any purification method for 3-isopropyl-4-methoxyphenoI. For using this intermediate in the preparation of other drugs, the purity of this compound is required to be around 98 to 99%. Therefore, the claimed purity level is not acceptable for synthesis of other compounds.
WO03/094845 discloses a process for preparation of 3-isopropyl-4-methoxyphenol which is as given below in the scheme.


The above process requires chromatographic purification which is difficult at industrial scale.
WO00/73265 discloses a process for preparation of 3-isopropyl-4-methoxyphenol in example 1 j which is as given below in the scheme.

Purification of crude 3-isopropyl-4-methoxyphenol is given by treating it with alkali followed by extraction into ethylacetate. However. the purity obtained after the purification has not mentioned.
Hence, there is a need to develop a process which not only overcomes disadvantages of the prior art but also provide a process which is economical, operationally simple and industrially applicable.
The present inventors have directed their research work towards developing a process which increases purity and reduces the formation of impurities. They found that the impurity forms at minimal level when the hydroxyl-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V) is substantially anhydrous. However, the drying of compound (V) is difficult and time consuming because the compound (V) does not tend to leave moisture easily. The present inventors have tried various methods including replacement of reagent p-toluene sulfonic acid which is also a moisture sensitive reagent with mineral acid. Surprisingly they found that when compound (V) is reacted with cone, sulfuric acid in the presence of hydrogen peroxide to give the final product, the level of impurity formation is below 0.5%. Moreover, this improved process also does not require vigorous drying of compound (V). The present inventors also isolated the impurity and identified it to be 5,5'-dimethoxy-4,4'-bis(l-methylethyl)biphenyl-2,2'-diol (VI).
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Object of the invention:
The primary object of the present invention is to provide an improved process for the preparation of 3-isopropyl-4-methoxyphenol (I)
Another object of the present invention is to provide an improved process for the preparation of 3-isopropyl-4-methoxyphenol having purity of at least 99%.
A further object of the present invention is to provide a process which is easy to handle at an industrial scale.
Yet another object of the present invention the preparation of 5,5'-dimethoxy-4,4'-bis(l-methylethyl)biphenyl-2,2'-diol (VI) which is a possible impurity generated in the reaction.
Summary of the invention:

comprising steps of:
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Accordingly, the present invention provides a process for preparation of 3-isopropyI-4-methoxyphenol (I)

(i) reacting 2-isopropyl phenol with methyl iodide in the presence of potassium hydroxide and tetrabutylammonium hydrogen sulfate and dichloromethane to give l-isopropyl-2-methoxybenzene (III);

(ii) reacting l-isopropyl-2-methoxybenzene (III) obtained in step (i) with phosphorous oxychloride and dimethylformamide to give 3-isopropyl-4-methoxybenzaldehyde (IV);
u r rw

(iii) reacting 3-isopropyl-4-methoxybenzaIdehyde (IV) obtained in step (ii) with sodium bisulfite in the presence of solvent to give hydroxyl-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V);

(iv) reacting hydroxyl-(3-isopropyl-4-methoxy-phcnyl) methane sulfonic acid sodium salt (V) obtained in step (iii) with cone. H2SO4 and hydrogen peroxide to give 3-isopropyl-4-methoxyphenol (I).
In another aspect, the present invention provides a process for purification of 3-isopropyl-4-methoxyphenol (I) comprising steps of:
(a) treating 3-isopropyl-4-methoxyphenol (I) with aq. sodium hydroxide in methanol
(b) washing the reaction mixture of (a) with 20 % toluene in hexane;
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(c) separating the aqueous layer;
(d) treating the aqueous layer of (c) with cone. HCI and isolating the product
(e) triturating the product obtained in (d) with hexane and filtering it
to give the 3-isopropyl-4-methoxyphenol (I) having purity of at least 99%.
In another aspect the present invention provides a process for purification of 3-isopropyl-4-methoxyphenol (I) comprising steps of:
(x) treating 3-isopropyl-4-methoxyphenol (I) with aq. sodium hydroxide in
methanol
(y) isolating the product;
(z) triturating the product obtained in (d) with hexane and filtering it
to give the 3-isopropyl-4-methoxyphenol (1) having purity of at least 99%.
In further aspect, the present invention provides a compound 5.5'-dimethoxy-4.4'-bis(l-methylethyl)biphenyl-2.2'-diol (VI) which is a possible impurity generated in the reaction.

Detailed description of the invention:
The present invention provides a process for preparation of 3-isopropyl-4-melhoxyphenol (1). It also provides process for purification of 3-isopropyl-4-methoxyphenol (1). The synthetic reaction scheme of the present invention is as shown below.
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In one embodiment, the process for preparation of 3-isopropyl-4-methox\phenol (I) is given. 2-isopropylphenol (II) is reacted at ambient temperature with methyl iodide in the presence of phase transfer catalyst such as tetrabutylammonium hydrogen sulfate, base such as KOH or NaOH. water and solvent such as dichloromethane. After completion of the reaction, layers are separated. Triethylamine is added to the organic phase and stirred. The solvent is distilled out hexane is added and stirred it for 15 min. The mixture is filtered and solid is washed with hexane. The hexane solution is washed with dilute 2N HCI and brine. Hexane is removed by distillation to give l-isopropyl 2-methox\benzene as light yellow oil.
l-isopropyl 2-methoxybenzene in dimethylformamide is heated at about 80°C. Phosphorus oxychloride is added at about 80°C to about 90°C over 3 hr. The reaction mixture is maintained at 80°C for 19 hr. The progress of the reaction is monitored on TI.C. The reaction mixture is quenched by slow addition to ice water from about 0 to about 5°C. Ethyl acetate is added to the reaction mixture and stirred it. The layers are separated and extracted the aqueous layer with ethyl acetate. Combined organic layer is washed with saturated sodium bicarbonate solution and brine. Ethyl acetate is removed by distillation to give 3-isopropyl-4-methoxybenzaldehyde.
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3-isopropyl-4-methoxybenzaldehyde is reacted with aqueous solution of sodium bisulfite in the presence of solvent tetrahydrofuran and hexane at room temperature. The reaction mixture is stirred for overnight at room temperature. The product is filtered and slurry washed with Ti IF: Hexane mixture in the ratio 1:3. this slurry washing is repeated. The product is filtered and dried overnight in air followed by vacuum drying for 8 to 10 hr at about 30° to about 40°C to give dry salt hydroxyl-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V)
A mixture of Hydroxyl-(3-isopropyl-4-methoxy-phcnyl) methane sulfonic acid sodium salt (V). Cone. IfS04 and methanol is cooled at about 0° to about 5°C. 30% aq. hydrogen peroxide was added to the reaction mixture at about 0° to about 5°C for 3 hr. The reaction mixture is stirred for overnight at room temperature. The reaction mixture is cooled to about 0° to about 5°C and sodium dithionite in water is added drop wise to it. The reaction mixture is stirred for 1.5 to 2 hr at about 25°C. The reaction mixture is filtered and white solids are washed with ethyl acetate. Ethyl acetate and aqueous filtrate are combined stirred for 10 min and allowed to separate, hexane is added to facilitate the separation and collect organic layer. Again the aqueous layer is extracted with ethyl acetate:hexane mixture (3:1) and separated. Combined organic layers are washed with saturated sodium bicarbonate solution and brine. Solvent is removed by distillation to give crude 3-isopropyl-4-methoxyphenol
In another embodiment, the purification of 3-isopropyl-4-methoxyphenol (1) is given. Crude 3-isopropyl-4-methoxyphenol is purified by giving it alkali treatment. Aqueous KOI 1 solution is added to the crude 3-isopropyl-4-methoxyphenol and stirred it for 1 hr. The aqueous layer is washed with 20 % toluene in hexane. The aq. layer is separated and acidified with cone. HO at about 0° to about 5°C. The product is extracted from aqueous layer with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate solution and brine. Solvent is removed from organic layer by distillation. Hexane is added to the residue at room temperature and cooled the mixture at about 0° to about 5°C with stirring for I hr. The solid precipitates out which is filtered and washed with chilled
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hexane and dried under vacuum to give 3-isopropyl-4-methoxyphenol. The purity obtained is greater than 99% by HPLC having individual impurity less than 2.0% The present invention also provides another method for purification of 3-isopropyl-4-methoxyphenol (I). The crude 3-isopropyl-4-methoxyphenol (I) is dissolved in methanol and cooled to about 5 to about I5°C. IN sodium hydroxide solution is added drop wise to it. The aqueous layer is washed with 20 % toluene in hexane. The aq. Layer is separated and acidified with cone. IICI at about 0° to about 5°C. The product is extracted from aqueous layer with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate solution and brine. Solvent is removed from organic layer by distillation to give residue. Hexane was added to the residue at room temperature and cooled the mixture at about 0° to about 5°C with stirring for I hr. The product is filtered and washed with chilled hexane (150ml) and dried under vacuum to give 3-isopropyi-4-methoxyphenol (40.Og)
The purity obtained is greater than 99% by 11 PLC having individual impurity less than 2.0%.
In another method of purification, the crude 3-isopropyl-4-methoxyphenol (I) is dissolved in methanol and cooled at about 5° to about 15°C in an ice bath. IN sodium hydroxide solution is added drop wise to it. The mixture is stirred for 3 hr at room temperature. Ethyl acetate is added to the reaction mixture and extracted. The layers are separated. The aq. layer is extracted with ethyl acetate. Combined org. layer was washed with IN NaOH solution, water and brine. The organic layer is dried over sodium sulfate and concentrated under reduce pressure to give 3-isopropyl-4-methoxyphenol. To this residue hexane was added at room temperature and cooled the mixture at about 0° to about 5°C with stirring for 1 hr. The product was filtered and washed with chilled hexane and dried under vacuum to give 3-isopropyl-4-methoxyphenol
The purity obtained is greater than 99% by HPLC having individual impurity less than 2.0%.
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In further embodiment, the present invention provides compound 5.5'-dimethoxy-4,4'-bis(l-methylethyl)biphenyl-2,2'-diol (VI) as possible impurity generated in the reaction. It also provides process for isolating it. Preparative High pressure liquid chromatography (HPLC) is carried out for the crude 3-isopropyl-4-methoxyphenol obtained after the reaction and before alkali purification treatment. The impurity is separated and identified it to be 5.5'-dimethoxy-4.4'-bis(l-methylethyl)biphenyl-2.2'-diol (VI) by LC-mass spectra. M-l peak at 329.6 is observed confirming the structure to be

5,5'-dimethoxy-4.4'-bis(l-methylethyl)biphenyl-2.2'-dioI (VI) can be used as reference marker in the determination of purity of 3-isopropyl-4-methoxyphenol (I) in the analytical methods known in the art such as HPLC.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
Examplc-1
Preparation of l-isopropyl-2-tnethoxybenzene (HI)
To the dried 20.OL. three-necked round-bottomed flask equipped with a mechanical stirrer, condenser and guard tube, was charged potassium hydroxide (978.Og), DM water (4.8L) and tetrabutylammonium hydrogen sulfate (I I8.64g). The mixture was cooled to 20 to 25°C. Dichloromcthane (4.8L) and isopropyl phenol (500.Og) were added and stirred the mixture for 30 min. lodomelhane (628.Og) was added in the reaction mass for 10 min and stirred the reaction mixture for overnight at room temperature. The reaction was monitored by HPLC. Stirring was discontinued and separated the layers. Triethylamine (I 14.13g) was added to the organic phase with stirring at least for 15 min. Distilled out the solvent and added hexane (4.8L) and stirred it for 15 min. The mixture
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was filtered it and washed with hexane. The hexane solution was washed with 2N HCI
(6.4L), brine (2.4L). Hexane was removed by distillation to afford l-isopropyl 2-
methoxybenzene as light yellow oil (518g).
Yield: 92 %
Purity: 99 % by HPLC.
Example-2
Preparation of 3-isopropyl-4-methoxybenzaldehyde (IV)
To the stirred solution of l-isopropyl 2-methoxybenzene (5l8g) in dimethylformainide (897.7g) at 80°C phosphorus oxychloride (1622g) was added at 80°C to 90°C over 3 hr. The reaction mixture was maintained for 80°C for 19 hr. The progress of the reaction was monitored on TLC. The reaction mixture was quenched by slow addition to ice water between 0 to 5°C. Ethyl acetate (7.251.) was added to the reaction mixture and stirred it. Separated the layers and again extracted the aqueous layer with ethyl acetate (2.5L). Combined organic layers and washed with saturated sodium bicarbonate solution (4.5L) and brine (4.5L). Ethyl acetate was removed by distillation to give 3-isopropyl-4-methoxybenzaldehycle (557g). Yield: 89.8 % Purity: 95.9 % by HPLC
Example-3
Preparation of hydroxyl-(3-isopropyl-4-inethoxy-phenyl) methane sulfonic acid
sodium salt (V)
To the dried 10.0L, three-necked round-bottomed flask equipped with a mechanical stirrer, condenser and guard tube was charged with 3--isopropyl-4-methoxybenzaldehyde (550.Og). tetrahydrofuran (2.901.), hexane (2.341.) at room temperature. To this mixture was added, an aqueous solution of sodium bisulfite (8l8.8g in 2.4771. water) at room temperature. The reaction mixture was stirred for overnight at room temperature. The product was filtered and slurry washed with THF: Hexane (1:3, 4Lx2) for 20 min. Slurry washed again repeated with same solvent (21-). The product was filtered and dried
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overnight in air followed by vacuum drying for 8 hr at 35°C to give dry salt the title product. Yield: 91 %.
Example-4
Preparation of 3-isopropyl-4-methoxyphcnol (I)
To the dried 5.0 lit. three-necked round-bottomed flask equipped with a mechanical stirrer, condenser and guard tube was charged hydroxyl-(3-isopropyl-4-methoxy-phenyT) methane sulfonic acid sodium salt (V) (200g). Cone. ELS04 (68.32g. 37.3ml) and methanol (1.54L). The mixture was cooled 0° to 5°C. 30% aq. hydrogen peroxide (260ml) was added to the reaction mixture at 0° to 5°C for 3 hr. The reaction mixture was stirred for overnight at room temperature. The reaction was monitored on TLC. The reaction mixture was cooled to 0° to 5°C. Sodium dithionite (286g) in water (1.01.) was added drop wise at 0° to 5°C to it. The reaction mixture was stirred for 1.5 hr at 25°C. The reaction mixture was filtered and white solids were washed with ethyl acetate (1.4L). Ethyl acetate and aqueous filtrate were combined stirred for 10 min and allowed to separate, hexane (800ml) was added to facilitate the separation and collect organic layer. Again extracted the aqueous layer with ethyl acetate:hexane mixture (600:200) and separate it. Combined organic layers were washed with saturated sodium bicarbonate solution (2.0L) and brine (2.0L). Solvent was removed by distillation to give crude 3-isopropyI-4-methoxyphenol (75.0 g) Yield: 50% Purity: 72.55% by HPLC
Examplc-5
Purification of 3-isopropyl-4-methoxyphenol (I)
Charge KOI I solution (80.Og in 200ml water) in above crude material obtained in example 3 and stirred it for 1 hr. The aqueous layer was washed with 20 % toluene in hexane (4.0L). The aq. Layer was separated and acidified with cone. 1ICI at 0° to 5°C. The product was extracted from aqueous layer with ethyl acetate (400ml). The organic layer was washed with saturated sodium bicarbonate solution (400ml) and brine (400ml). Solvent was removed from organic layer by distillation to give residue (60g). Hexane
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(600ml) was added to the residue at room temperature and cooled the mixture at 0° to 5°C with proper stirring for I hr. The product was filtered and washed with chilled hexane (150ml) and dried under vacuum to give 3-isopropyl-4-methoxyphenol (40.Og) Purity: 99.45 % by HPLC; Individual impurity: 0.06 % by HPLC
Example-6
Purification of 3-isopropyl-4-methoxyphcnol (I)
The crude product (80g) was dissolved in methanol (430ml) and stirred. The solution was
cooled at 5-15°C in an ice bath. I N sodium hydroxide solution (430ml) was added drop
wise to it. The ice bath was removed and the reaction is allowed to warm to room
temperature and stirred for 3 hr. Ethyl acetate (600ml) was added to the reaction mixture
and extracted. The layers were separated. The aq. layer was extracted with ethyl acetate
(300ml). Combined org. layer was washed with IN NaOH solution (150ml x 2). water
(920ml) and brine (1.2L). The organic layer was dried over sodium sulfate and
concentrated under reduce pressure to give 3-isopropyl-4-methoxyphenol (60g). To this
residue hexane (600ml) was added at room temperature and cooled the mixture at 0° to
5°C with stirring for I hr. The product was filtered and washed with chilled hexane
(150ml) and dried under vacuum to give 3-isopropyl-4-methoxyphenol (40g)
Purity: 99.73 % by HPLC:
Individual impurity: 0.05 % by HPLC
'UNMR (300MHz. CDCI3. 5): 6.715 (d. 1M, J - 2.8 Hz). 6.705 (d. 1H. J = 3.3 Hz). 6.595
(dd.1H. J =8.8 Hz. 3.3 Hz). 4.44(s. 111). 3.77 (s. 3H). 3.27 (septet. IH. 7 Hz). 1.175 (d.
6H. J - 7.2 Hz).
IR (KBr tablet in cm'1): 3273.8. 3003.7. 2959.8. 1594.9. 1500.2. 1286.8. 1209.2. 1029.7.
809.8.751.8,707.6.
13CNMR (300MHz, CDCb. 5): 23.116. 27.132. 56.865, 112.757. 113.046, 114.158,
139.286, 149.942, 151.408.
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Example-/
Preparation of 5,5'-dimethoxy-4,4'-bis(l-methylethyl)biphenyl-2,2'-diol (VI)
Preparative High pressure liquid chromatography (HPLC) is carried out for crude 3-
isopropyl-4-methoxyphenol obtained in example 4. The impurity which comes at Rt 17-
18min is separated and identified to be 5.5'-dimethoxy-4.4'-bis(l-methylethyl)biphenyl-
2.2'-diol (VI).
Mass spectra: 329.6 (M-l)
'HNMR (300MHZ. CDCI3. 5): 6.82 (s. 2H). 6.67 (s. 211). 5.34(s. 2H). 3.72 (s. 6H). 3.19-
3.28 (septet, 2H. 6.87 Hz). 1.14-1.16 (d. 12H. J = 6.89 Hz).
IR (KBr tablet in cm"1): 3421.4. 2961.2. 2927.2. 1648.0, 1406.3, 1204.9. 1064.1. 808.0.
784.4.
13CNMR (300MHz. CDCI3. 5): 23.039. 27.142. 56.571, 113.358. 115.268. 121.347.
139.604. 147.061, 151.894.
Purity: 99.77% by HPLC
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We claim:
1. A process for preparation of 3-isopropyl-4-methoxyphenol of formula (I)

comprising steps of: (i) reacting 2-isopropyl phenol with methyl iodide in the presence of potassium hydroxide and tetrabutylammonium hydrogen sulfate and dichloromethane to give l-isopropyl-2-methoxybenzene (III):

(ii) reacting l-isopropyI-2-methoxybenzene (III) obtained in step (i) with phosphorous oxychloride and dimethylformamide to give 3-isopropyl-4-methoxybenzaldehyde (IV);

(iii) reacting 3-isopropyl-4-methoxybenzaldehyde (IV) obtained in step (ii) with sodium bisulfite in the presence of solvent to give hydroxyl-(3-isoprop\i-4-methoxy-phenyl) methane sulfonic acid sodium salt (V);


(iv) reacting hydroxyl-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V) obtained in step (iii) with cone. H2SO4 and hydrogen peroxide to give 3-isopropyl-4-methoxyphenol (I).
2. A process for preparation of 3-isoprop\i-4-methoxyphenol of formula (I) having
purity of at least 99%

comprising steps of: (i) reacting 2-isopropyl phenol with methyl iodide in the presence of potassium hydroxide and tetrabutylammonium hydrogen sulfate and dichloromethane to give 1 -isopropy 1-2-methoxybenzene (III);

(ii) reacting 1-isopropyl-2-methoxybenzene (III) obtained in step (i) with phosphorous oxychloride and dimethylformamide to give 3-isopropyl-4-methoxybenzaldehyde (IV):

(iii) reacting 3-isopropyl-4-methoxybenzaldehyde (IV) obtained in step (ii) with sodium bisulfite in the presence of solvent to give hydroxy-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V);
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S03Na
(iv) reacting hydroxyl-(3-isopropyl-4-methoxy-phenyl) methane sulfonic acid sodium salt (V) obtained in step (iii) with cone. H1SO4 and hydrogen peroxide to give 3-isopropyl-4-methox\phenol (I).
3. A process for purification of 3-isopropyl-4-methoxyphenol (I) comprising steps
of:
(a) treating 3-isopropyl-4-methoxyphenol (1) with aq. sodium hydroxide in methanol
(b) washing the reaction mixture of (a) with 20 % toluene in hexane;
(c) separating the aqueous layer:
(d) treating the aqueous layer of (c) with cone. MCI and isolating the product;
(e) triturating the product obtained in (d) with hexane and filtering it
to give the 3-isopropyl-4-methoxyphenol (I) having purity of at least 99%
4. A process for purification of 3-isopropyl-4-methoxyphenol (I) comprising steps
of:
(x) treating 3-isopropyl-4-methoxyphenol (I) with aq. sodium hydroxide in
methanol
(y) isolating the product:
(z) triturating the product obtained in (d) with hexane and filtering it
to give the 3-isopropyl-4-methoxyphenol (I) having purity of at least 99%
5. A compound 5,5'-dimethoxy-4,4'-bis(l-methylethyl)biphenyl-2,2'-diol (VI).

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6. 3-isopropyl-4-methoxyphenol (I) having the content of 5,5'-dimethoxy-4,4'-bis(l
methylethyl)biphenyl-2,2'-diol (VI) less than about 0.5%
Dated this 27th day of September 2007
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Title: AN IMPROVED PROCESS FOR THE PREPARATION OF 3-ISOPROPYL-4-METHOXYPHENOL
ABSTRACT
The present invention relates to an improved process for preparation of 3-isopropyl-4-methoxyphenol represented by a structural formula (I) as given below.