Field of the invention
The present invention relates to an improved process for preparation of trifluoromethyl ether derivatives.
Background of the invention
Trifluoromethyl ether derivatives are used as important intermediates in agrochemical and pharmaceutical industry.
United States Patent Nos. 5,932,571 and 6,211,199 disclose a process for preparation of 2-hydroxyethy trifluoromethyl ether comprising the reaction of 2-(benzyloxy)ethanol with carbon disulphide in the presence of sodium hydride to obtain 0-(2-benxyloxyethyl)-S-methyl dithiocarbonate. 0-(2-Benxyloxyethyl)-S-methyl dithiocarbonate upon successive bromination and fluorination gives 2-(4-bromobenzyloxy)ethyl trifluoromethyl ether which upon reaction with thioanisole, trifluoroacetic acid and finally with base gives 2-hydroxyethy trifluoromethyl ether.
The method discussed above is lengthy, necessitate the step of bromination, use of trifluoroacetic acid, chromatography purification of intermediate and purification of the product with molecular sieve.
There is therefore a need to overcome the deficiencies of the known processes and to develop an industrially viable process for preparation of 2-hydroxyethyl trifluoromethyl ether.
Object of the invention
The present invention provides a simple, cost effective, industrially safe, and viable process for preparation of 2-hydroxyethyl trifluoromethyl ether.
Summary of the invention
A first aspect of the present invention provides a process for preparation of compound of formula I,
Formula I

comprising the steps of:
a) sulfonating compound of formula II,
Formula II to give compound of formula III,
Formula III wherein R is selected from the group comprises ofalkyl or aryl,
b) trifluoromethylating the compound of formula III to give compound of formula IV, and
Formula IV c) reducing the compound of formula IV to the compound of formula I. A second aspect of the present invention provides a process for preparation of compound of formula 1, comprising the steps of: a) trifluoromethylating compound of formula III
Formula III wherein R is selected from the group comprises ofalkyl or aryl, to obtain compound of formula IV, and

Formula IV b) reducing the compound of formula IV to the compound of formula I.
A third aspect of the present invention provides a process for preparation of compound of formula 1, comprising the step of converting compound of formula IV

V^
Formula IV to the compound of formula I.
A fourth aspect of the present invention provides a process for preparation of compound of formula IV, comprising: a) sulfonating compound of formula II,
„OH
^
Formula II
to give compound of formula III,
o
\y
.0' ^O
Formula III wherein R is selected from the group comprises ofalkyl or aryl
b) trifluoromethylating the compound of formula III to obtain compound of formula IV, and

V^
Formula IV c) reducing the compound of formula IV to obtain compound of formula I.
A fifth aspect of the present invention provides a compound of formula IV

Formula IV A sixth aspect of the present invention provides use of the compound of formula IV for preparing compound of formula I.

Formula IV A seventh aspect of the present invention provides a compound of formula I,


HO

Formula I having purity greater than 98% or preferably greater than 99% and yield greater than 80%) or preferably greater than 85%.
Detailed description of the invention
The term "alkyl" in the present invention refers to straight chain or branched chain alkyl group selected from methyl, ethyl, isopropyl, n-butyl, iso-butyl, tert-butyl, or the like.
The term "aryl" in the present invention refers to aromatic or substituted aromatic compounds selected from benzene or substituted benzene or the like.
The step of "sulfonation" in the present invention refers to the step of introducing sulfonate group on the alcohol. The sulfonation of compound of formula II gives compound of formula III.
The compound of formula II may be prepared on an industrial scale by any methods known in the art or prepared by benzylation of ethylene glycol with benzyl chloride in basic medium.
The reagents used in the step of sulfonation are selected from methanesulfonyl chloride, trifluoromethane sulfonyl chloride, benzene sulfonyl chloride, p-toluenesulfonyl chloride, or the like.

The sulfonation is carried out in the presence of base. The base is selected from amines. The amines are selected from the group comprises primary amine, secondary amine, tertiary amine, cyclic amine and aromatic amines or the like. The amines are selected from methylamine, dimethylamine, trimethylamine, ethylamine, diisopropylethylamine, pyridine or mixture thereof or the like.
The sulfonation may be carried out in the presence of solvent. The solvent is selected from the group comprising ester, ether, ketone, chlorinated solvent, nitrile solvent. The ester solvent is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate or isopropyl acetate; the ether solvent selected from tetrahydrofuran, methyl tert-butyl ether or diisopropyl ether; the ketone solvent is selected from acetone, methylethylketone or methylisobutylketone; the chlorinated solvent is selected from dichloromethane, chloroform, carbontertrachloride; the nitrile solvent is acetonitrile, or mixture thereof or the like.
The sulfonation reaction is carried out at a temperature in the range of -10°C to 50°C or preferably in the range of-5°C to 40°C.
The step of "trifluoromethylation" in the present invention refers to the step of introducing trifluoromethyl group on the sulfonate (-O-SO2R) group.
Trifluoromethylation of compound of formula III gives compound of formula IV.
The reagents used in the step of trifluoromethylation are selected from trifluoromethyltrimethylsilane (TMSCF3)/ silver triflate; 1-trifluoromethyl-1,2-benziodoxol-3(lH)-one)/ zinc bis(trifluoromethylsulfonyl)imide [Zn(NTf2)2J; trifluoromethyltriflate; or the like.
The trifluoromethylation may be carried out in the presence of metal halide. The metal halide can be selected from sodium fluoride, potassium fluoride, silver fluoride, or the like.
The trifluoromethylation may be carried out in the presence of solvent. The solvent can be selected from the group comprising dimethylformamide, diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-

dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone and acetonitrile or mixture thereof or the like .
The trifluoromethylation may be carried out at a temperature in the range of -5°C to 95°C or preferably in the range of 0°C to 85°C.
The compound of formula IV having purity greater than 95% or preferably greater than 97%.
The step of "reduction" of compound of formula IV results compound of formula I. The reduction is carried out using either catalytic hydrogen or reducing agent. The catalytic hydrogenation may be carried out in the presence of hydrogen using Palladium-on-carbon, Raney nickel, Rhodium on carbon, Ruthenium on carbon, Nickel on carbon and platinum on carbon or the like. The concentration of the catalyst may vary from 1% to 10% loading on carbon.
The step of reduction can be carried out in the presence of solvent can be selected from the group comprising alcohol, ester, ether, ketone or the like and mixture thereof. The alcoholic solvent is selected from methanol, ethanol, isopropanol, n-propanol or butanol; the ester solvent is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate or isopropyl acetate; the ether solvent selected from tetrahydrofuran, methyl tert-butyl ether or diisopropyl ether; the ketone solvent is selected from acetone, methylethylketone and methylisobutylketone.
The compound of formula I or its intermediates can be isolated by the
techniques known in the art such as extraction, filtration and evaporation of solvent.
In general, the isolation of compound of formula I and intermediates can be
done with extraction, comprises the steps separation of organic layer followed by
distillation or concentration of organic layer to obtain compound of formula I.
In an embodiment of the present invention, the step of sulfonation is carried out using methanesulfonyl chloride in the presence of trimethylamine in the chlorinated solvent.
In another embodiment of the present invention, the step of trifluoromethylation is carried out using trifluoromethyltriflate using metal halide in the presence of solvent. The metal halide can be selected from sodium fluoride,

potassium fluoride, silver fluoride, or the like. The solvent can be selected from the group comprising of dimethylformamide, diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone, acetonitrile or mixture thereof or the like .
In another embodiment of the present invention, the step of reduction is carried by hydrogenation using palladium on carbon.
In a specific embodiment 2-(benzyloxy)ethanol is reacted with methanesulfonyl chloride in dichloromethane in presence of trimethylamine to give 2-(benzyloxy)ethyl methanesulfonate. 2-(Benzyloxy)ethyl methanesulfonate is treated with trifluoromethyltriflate in presence of potassium fluoride to give 2-(benzyloxy)ethyl trifluoromethyl ether which upon hydrogenation over palladium carbon give 2-(trifluoromethoxy) ethanol in good purity and yield.
The compound of formula I, namely 2-(trifluoromethoxy) ethanol, obtained by the present invention have purity greater than 98% or preferably greater than 99%) and having yield greater than 80%> or preferably greater than 85%>.
The completion of the reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
Purity of the compound of formula I and its intermediates may be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, distillation, slurry wash, acid or base treatment, solvent-anti solvent system, crystallization, recrystallization or combination of these procedures.
The compound of formula I, prepared by the process of the present invention, may be used as a key intermediate for preparing agrochemical and pharmaceutical products.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES:
Example 1: Process for preparation of 2-(benzyloxy)ethyl methanesulfonate Methanesulfonyl chloride (180.54g) was slowly added to a mixture 2-(benzyloxy)ethanol (200g), triethylamine (199.54g) in dichloromethane (2535g) at 0°C. After complete addition, the temperature of the mixture was allowed to raise to 30°C. The reaction was monitored by gas chromatography (GC). After completion of the reaction, the reaction mixture was quenched with ice cooled water(500g). The layers were seperated, the organic layer was washed with an aqueous solution of hydrochloric acid (500g, 5%). The organic layer was then washed with an aqueous solution of sodium bicarbonate (500g,9%). The organic layer was concentrated under reduced pressure of 50°C to obtain 2-(benzyloxy)ethyl methanesulfonate (95%) having purity 97% by GC. Example 2: Process for the preparation of 2-(benzyloxy)ethyl trifluoromethyl ether Step-1: Generation of trifluoromethyl triflate
Triflic acid (500g) was added slowly phosphorous pentoxide (142g) at room temperature in an hour. The reactor was connected to the column followed by the condenser. The reaction mixture was slowly heated to a temperature of 130°C. The exit gas was passed through potassium hydroxide scrubber and collected into the cooled traps maintained at a temperature of about -60 to -70°C. After no more gas was observed at the exit, the reaction was terminated. The collected trifluoromethyltrifiate(188g) was transferred to stainless steel pressure vessel and stored for further use. Step 2: Process for the preparation of 2-(benzyloxy)ethyl trifluoromethyl ether

Trifluoromethyltriflate (95g) was slowly purged to a mixture of 2-(benzyloxy)ethyl methanesulfonate (50g) and potassium fluoride (25.2g), dimethyl acetamide (lOOOg) in a reactor. After complete addditon, the reaction mixture was additionally stirred at 0°C for two hours and heated to 85°C for 36 hours. The progress of the reaction was monitored by GC. After completion of the reaction, the reaction mixture was quenched with ice cooled water (lOOOg ,20°C) and extracted with n-pentane (600g). The orgainc layer was concentrated to obtain a crude mixture. The crude mixture was distilled under reduced pressure to obtain 2-(benzyloxy)ethyl trifluoromethyl ether (65%) having purity 97% by GC. Example 3: Process for preparation of 2-(trifluoromethoxy) ethanol Hydrogen gas was passed through a mixture of 2-(benzyloxy)ethyl trifluoromethyl ether (85g) and 10% palladium carbon catalyst (9g) in methanol. The reaction was pressurised to 12 Kg/cm2 with hydrogen and heated to a temperature of 75°C. The progress of the reaction was monitored by GC. After completion of the reaction, the reaction mixture was cooled to a temperature of about 30°C and filtered. Tetrahydrofuran (amount) was added to the filtrate and reulting mixture was distilled to get the titled compound (85%) having purity 99.5% by GC.

We claim:
1. A process for preparation of a compound of formula I,

HO

F F

Formula I comprising the steps of:
a) sulfonating a compound of formula II,

O'

,OH

\^
Formula II
to give a compound of formula III,

vO"

O
\\ R
O' ^O

Formula III wherein R is selected from the group comprises of alkyl or aryl,
b) trifluoromethylating the compound of formula III to give a compound of formula IV, and

O

,O F
F F

Formula IV c) reducing the compound of formula IV to obtain the compound of formula I. 2. A process for preparation of a compound of formula IV, comprising the steps of: a) sulfonating a compound of formula II,

^O'

„OH

\^
Formula II
to give a compound of formula III,
11

Formula III wherein R is selected from the group comprises ofalkyl or aryl
b) trifluoromethylating the compound of formula III to obtain a compound of formula IV.
Formula IV 3. A process for preparation of a compound of formula I, comprising the steps of: a) trifluoromethylating a compound of formula III
Formula III wherein R is selected from the group comprises ofalkyl or aryl, to obtain a compound of formula IV, and
Formula IV b) reducing the compound of formula IV to obtain the compound of formula I. 4. The process as claimed in claim 1 and claim 2, wherein, sulfonating agent is selected from a group consisting of methanesulfonyl chloride, trifluoromethane sulfonyl chloride, benzene sulfonyl chloride and p-toluenesulfonyl chloride.

5. The process as claimed in claims 1-3, wherein, trifluoromethylating agent is selected from a group consisting of trifluoromethyltrimethylsilane (TMSCF3)/ silver triflate; l-trifluoromethyl-l,2-benziodoxol-3(lH)-one)/ zinc bis(trifluoromethylsulfonyl) imide [Zn(NTf2)2J; and trifluoromethyltriflate.
6. The process as claimed in claim 1 and claim 3, wherein, reduction is carried out using catalytic hydrogenation in presence of hydrogen using Palladium-on-carbon, Raney nickel, Rhodium on carbon, Ruthenium on carbon, Nickel on carbon and platinum on carbon.
7. A process for preparation of compound of formula I, comprising the step of converting compound of formula IV
Formula IV to the compound of formula I. 8. A compound of formula IV,
Formula IV 9. A process for preparation of a compound of formula I,
Formula I using a compound of formula IV.
Formula IV

10. A compound of formula I,
Formula I having purity greater than 98%.