Field of Invention

The present invention provides a process for preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I. The compounds of formula I are useful as intermediates of medicaments.

The process of the present invention results in very high quality of the product after fractional distillation, with an overall yield of greater than 50%.

Background

The strong electron donating properties of 1, 2-di-alkoxy-3-fluoro benzene has been utilized for the development of Ziegler-Natta catalyst; used as monomer for electrolytic polymerization, moreover this intermediate is known for the synthesis of medicament (see WO 02/085855, WO 2004/078721, WO 2006/018955). The synthesis of such compounds is disclosed in patents US 5968865, US 6124507, US 6399837 and patent application WO 02/085855. In such description 2-alkoxy phenol compounds are utilized and further alkylated under strong alkaline condition. Since the starting materials are costly and the process offers lower yield these processes are not commercially feasible.

One of the approaches could be to oxidize 3-fluoro salisaldehyde to phenol and subsequent alkylation. In general there are no of methods available in the literature for the formylation of substituted phenols e.g., Duff, Gattermann, Reimer-Tiemann, Vilsmeier etc.(Chem rev. 1987, 87,671), but most of these reactions give very poor yield making the process not feasible commercially.

Some recent method developed for ortho selective formylation involves use of paraformaldehyde and aryl magnesium salts derived by deprotonation of phenol by alkyl Grignard reagent (Synth. Commun. 1994, 24, 1757); Mg (OEt) (J. Chem. Soc. Perkin Trans I, 1994, 1823) or MgCl/EtN (Acta Chem Scand 1999, 53, 528). However poor yields are obtained with electron withdrawing group such as 2-fluoro phenol gave 5% yield with Mg (OEt) conditions.

Recently the synthesis of 3-fluorosalisaldehyde was described (Synthesis, 2006, 1575-1577) based on regioselective formylation through carbamate. The synthesis involve the directed ortho lithiation of in-situ generated N-silylated -O-aryl-N-isopropylcarbamates in two steps. Use of costly reagent, cryogenic reaction condition and 6-7 steps from 2-fluorophenol makes this process uneconomical.

The patent JP 2005/314322 discloses the synthesis of 1, 2-dialkoxy 3-fluoro benzene by lithiation at 2-position of 3-fluorophenol in presence of a diamine, boronation with trialkyl borate, hydrolysis to boronic acid, oxidation to phenol and final dialkylation. Use of nBu Li in production scale is anticipated to be hazardous and hence the process has its limitation.

EP 2055692 discloses the synthesis of 1, 2-diethoxy -3-fluoro phenol starting from 2-fluorophenol. The synthesis involved protection of 4- position by sulfonation, halogenation at 6 position, removal of sulfonic acid group, alkylation of hydroxyl group, hydrolysis of halogen (for iodo group) or hydroxylation reaction using Grignard reagent followed by treatment with tert-butyl perbenzoate, removal of tert butyl group and alkylation of 2-ethoxy-3-fluoro phenol. The synthesis involves seven steps with low overall yield thus making the process commercially not very attractive.

There is a scope to improve the process by an innovative approach. Therefore the object of the invention is to produce 1, 2-dialkoxy-3-fluoro benzene in minimum number of steps to minimize unit operation and result in high process yield with low production cost and high safety..

SUMMARY
The present invention provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I

PICTURE

wherein:
R3 and R1 are each independently a linear or a branched C1-C20 alkyl, a C3-C8 cycloalkyl, a C7-C15 alkylaryl or a C4-C7 cycloalkyl alkyl; said process comprising: halogenating 2-fluoro phenol at 6-position with a halogenating agent to obtain 2-fluoro-6-halophenol, wherein said halogenating agent is not a fluorinating agent;

alkylating 2-fluoro-6-halophenol with an alkylating agent in presence of a base to obtain l-alkoxy-2-fluoro-6-halobenzene;

reacting said 1 -alkoxy-2-fiuoro-6-halobenzene with magnesium metal and iodine in presence of a solvent and further treating with a boronating reagent to obtain boronate esters;

optionally hydrolyzing said boronate esters in presence of an acid to obtain boronic acids;
oxidizing said boronate ester or said boronic acids to obtain 1-alkoxy-2-fluoro-6-hydroxy benzene; and

alkylating said l-alkoxy-2-fluoro-6-hydroxy benzene with an alkylating agent to obtain l,2-dialkoxy-3-fluorobenzene. These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

DETAILED DESCRIPTION

The present invention now will be described more fully hereinafter. Indeed, the invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a", "an", "the", include plural referents unless the context clearly dictates otherwise.

The present invention relates to a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula 1

wherein:

R3 and R4 are each independently a linear or a branched C1-C20 alkyl, a C3-C8 cycloalkyl, a C7-C15 alkylaryl or a C4-C7 cycloalkyl alkyl; said process comprising: halogenating 2-fluoro phenol at 6-position with a halogenating agent to obtain 2-fluoro-6-halophenol, wherein said halogenating agent is not a fluorinating agent;

alkylating 2-fluoro-6-halophenol with an alkylating agent in presence of a base to obtain l-alkoxy-2-fluoro-6-halobenzene;

reacting said l-alkoxy-2-fluro-halobenzene with magnesium metal and iodine in presence of a solvent and further treating with a boronating reagent to obtain boronate esters;
optionally hydrolyzing said boronate esters in presence of an acid to obtain boronic acids;
oxidizing said boronate ester or said boronic acids to obtain 1-alkoxy-2-fluoro-6-hydroxy benzene; and

alkylating said l-alkoxy-2-fluoro-6-hydroxy benzene with an alkylating agent to obtain 1,2-dialkoxy-3-fluorobenzene. An embodiment of the present invention provides a process for the preparation of 1,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, the halogenating agent employed is N-haloamine.

Another embodiment of the present invention provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, the solvent used in reacting the l-alkoxy-2-fluoro-6-halobenzene with magnesium metal and iodine, is selected from a group consisting of ether, THF, methanol and dioxane or mixtures thereof.

Another embodiment of the present invention provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, the boronating agent is trialkyl borate.

In yet another embodiment, it provides a process for the preparation of 1,2-dialkoxy-3-fluorobenzene compounds of formula I, the base used in alkylating 2-fluoro-6-halophenol with an alkylating agent, is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate and cesium carbonate.

Still another embodiment of the present invention provides a process for the preparation of 1,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, the acid for hydrolyzing the boronate esters is selected from a group consisting of hydrochloric acid, sulfuric acid and phosphoric acid.

In another embodiment of the present invention it provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, R3 and R4 are each independently a linear or a branched C1-C5 alkyl or C3-C6 cycloalkyl.

In yet another embodiment of the present invention, it provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I, wherein, R3 and R4

are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclopentyl or cyclohexyl.

An embodiment of the present invention further provides a process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of formula I, comprising:

brominating 2-fluoro phenol at 6-position with N-bromoamine to obtain 2-fluoro-6-bromophenol in a solvent and optionally a co-solvent;

ethylating 2-fluoro-6-bromophenol with an ethylating agent in presence of a base to obtain l-ethoxy-2-fluoro-6-halobenzene;

reacting said l-ethoxy-2-fluoro-6-halobenzene with magnesium metal and iodine in presence of dry solvents selected from ether, THF, methanol-THF or dioxane, and further treating with a trialkyl borate to obtain boronate esters;

optionally hydrolyzing said boronate esters in presence of an acid to obtain boronic acids;
oxidizing said boronate ester or said boronic acids to obtain 1-ethoxy-2-fluoro-6-hydroxy benzene; and

ethylating said l-ethoxy-2-fluoro-6-hydroxy benzene with an ethylating agent to obtain l,2-diethoxy-3-fluorobenzene.

The process steps of the present invention are described in the embodiments.

Selected embodiments have been described by way of examples. They are only illustrative in nature and should not be construed as limiting the scope of the invention in any manner.

It is obvious for a person skilled in the art that changes can be made without deviating from

the scope of the invention as defined in the claims.

The process for preparing 1, 2-dialkoxy-3-fluoro benzene using 2-fluorophenol as the starting material according to the following synthetic steps:

■ Preparation of halogenating agent was carried out by the reaction of hypohalous acid with primary or secondary amine to generate N-halo amine.

■ Selective halogination of 2-fluorophenol was carried out with the haloginating agent at 6- position.

■ An alkylation step was carried out on 2-fluoro-6-halophenol using suitable alkylating agent where in the alkyl chain consist of C-1 to C-20 carbon atom, most preferably methyl, ethyl or propyl group and specifically preferably ethyl group, in presence of suitable base.

■ A Grignard reaction was carried out on l-alkoxy-2-fluoro-6-halo benzene.

The Grignard reagent prepared in-situ was converted to boronic acid and its derivatives by using suitable boronating agent such as tri-alkyl borate. The resulting boronate ester or its corresponding acid with or preferably without isolation was oxidized with a suitable oxidizing agent in suitable solvent to afford l-ethoxy-2-fluoro-6-hydroxy benzene. This material can be isolated or the solution containing the compound preferably be used for the next step.

■ An alkylation step was carried out on l-alkoxy-3-fluoro-6-hydroxy using suitable alkylating agent where in the alkyl chain independent to each other consist of C-l to C-20 carbon atom, most preferably methyl, ethyl or propyl cyclopropyl group and specifically preferably ethyl group, in presence of suitable base.

The compounds involved in the present invention are represented by:

In the structural formula described, Ri and R2 independent to each other represent H, C1-C10 linear or branched alky, C3-C8 cycloalkyl, C7-C15 alkylaryl or phenyl; alternatively R1 and R2 together may form 3-7 membered cyclic structures; R1| and R2 preferably represent without limiting to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl cyclopentyl, cyclohexyl, phenyl, naphthyl and the like. The most preferred alkyl group among R1 and R2 represent H, tert butyl, cyclohexyl and the like.

R3 and R4 are each independently a linear or a branched C1-C20 alkyl, a C3-C8 cycloalkyl, a C7-C15 alkylaryl or a C4-C7 cycloalkyl alkyl; said process comprising:

R3 and R4 preferably represent, without limiting to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl cyclopentyl, cyclohexyl and the like. The more preferred alkyl groups are methyl, ethyl, propyl, isopropyl, tert butyl cyclohexyl and the like, while the most preferred represent ethyl group.

Example 1: Reaction of 2-fluorophenol [A] with a selective halogenating agent, wherein the halogenating agent is not a fluoronating agent, to produce [C].

The halogenating reagent is prepared by reacting amine of general structure [B] with a halogen source and an alkali; in case of the halogen being a bromine, the bromine source include not limiting to bromine, bromantin, N-bromo succimide alkali and alkaline metal hypo bromide and the like. The most preferred brominating agent is bromine in alkali or alkali and alkaline earth metal hypo bromide. The reaction can be carried out at -50°C to 30°C. The preferred temperature of the reaction is -30°C to 25°C; more preferred reaction temperature is -25°C to 25°C and most preferred temperature being -15°C to 5°C. The term "alkali" includes without limiting to NaOH, KOH, and LiOH. CsOH, Ca(OH)2, Ba(OH)2 and the like; The term "hypo bromide" include without limiting to NaOBr, KOBr, LiOBr , Ca(OBr)2 and the like. The reaction is carried out in solvents such as water, MeOH, EtOH, DMF, DMSO and the like, the most suitable solvent is water.

After the halogenating reagent is formed, it was added to compound [A] in presence of the amine [B] with 0.5-2.0 molar ratio, more preferably 0.8-1.5 molar ratio based on [A] and most preferably is 1.0 molar ratio based on [A]; in a solvent chosen from among Benzene, Toluene, Xylene, Hexane, Heptane, kerosene, MTBE, MIBK, Chloroform, Dichloromethane and the like; more preferred solvents are Benzene, Toluene, Xylene, Hexane, Heptane, while the most preferred solvent is Toluene. The reaction is preferably carried out in presence of a polar co-solvent chosen from among DMF, DMSO, NMP, EtOH, MeOH, IPA and the like, the most preferred being NMP. The amount of co-solvent may vary from 0.5-30% v/v; preferably 0.5-15% v/v and most preferred is 0.5-5%. The temperature maintained during addition is preferred in the range of-50°C to 15°C; more preferred being -30°C to 10°C and most preferred is -15°C to 0°C.
Example 2: Alkylation of compound [C] to produce compound [D].

Compound [C] obtained in example 1 was treated with a suitable alkylating agent wherein the alkyl group is attached with a suitable leaving group; a suitable leaving group include without limiting to, F, C1, Br, I, OTs, OMes, corresponding alkyl sulphate ester and

the like; in presence of a base selected from without limiting to NaOH, KOH, LiOH, CsOH, Ca(OH)2, Ba(OH)2, NaHCO2, K2CO3, Na2CO3, Cs2CO3, TEA, Pyridine, and any other proton abstracting agent easily understood by those skilled in the art of organic synthesis. The most preferred base is chosen as K2CO3 or Na2CO3. The reaction is carried out at 25°C to 150°C, more preferable at 50°C-150°C and most preferably at the 100°C -110°C. The reaction can be carried in solvents chosen from DMF, Dioxane, THF, MeTHF, Toluene, Xylene, Chlorobenzene, Dichlorobenzene, MTBE, MIBK, Acetone and the like or preferably can be carried out without distilling the solvent. The product could be used as such or preferably could be isolated by distillation.

Example 3: Successive synthesis of [E-l], [E-2] and [F] by the reactions on [D].
Compound [D] was subjected to a reaction for preparation of Grignard reagent using Mg metal and catalytic amount of iodine in dry solvents selected from Ether, THF, Me¬THF, Dioxane and the like; most preferably in dry THF. The reaction is carried out for 2-4 rs at 10-60°C, most preferably at 25°C -35°C.

The Grignard thus obtained is reacted with trialkyl borate at -10-25°C; more preferably at 0-15°C and most preferably at 5-15°C for 2-4 hours followed by 3 hours at 25-30°C. The trialkyl borate can be selected from trimethyl borate, triethyl borate, tri-n-butyl botate, propyl borate, tri-isopropyl borate and other mixed borates derived from geminal diol and any other alcohol and phenol can also be useful, known to those skilled in the art. The most preferred alkyl borate is tri isopropyl borate.

The reaction mixture was treated with acid chosen from HC1, H2SO4, phosphoric acid and the like to hydrolyze boronate ester. The most preferred acid is HC1. Thus a mixture of compounds [E-l], [E-2] and F are formed. After usual work-up, the mixture can be extracted in an organic solvent and can be used directly for subsequent oxidation. The organic solvent for extraction can be chosen from any that is water immiscible. From the process advantage Toluene is the most preferred one.

The intermediates can optionally be purified by column chromatography. Optionally the boronate ester can directly be oxidized without hydrolyzing with acid. In the further sequence of events the compound mixture in the toluene layer was oxidized to get compound [F], The oxidation is carried out by any known oxidizing agent for this purpose known to those skilled in the art; most preferred oxidizing agent used is hydrogen peroxide. The reaction is carried out in presence of an alkali and PTC (<0.1 molar equivalent). The alkali is chosen from NaOH, KOH, LiOH, K2CO3, Na2CO3 and the like; the most preferred alkali is NaOH; the PTC is selected from quaternary ammonium salts such Alliquat 336, TBAB, benzyltrimethyl ammonium chloride, CTAB, tetrabutyl ammonium fluoroborate and the like; the most preferred PTC is TBAB. The reaction temperature is maintained at -10 to 30°C; more preferably at -5 to 25°C; most preferably at 5 tol5°C. The product formed is extracted in an organic solvent after acidification. Any water immiscible solvent can be used for the extraction known for those skilled in the art; for process advantage toluene is most preferred. The Toluene layer optionally can be used as such for final step.

Example 4: Alkylation of compound [F] to produce compound [G].

Compound [F] obtained in example 3 was treated with a suitable alkylating agent wherein the alkyl group is attached with a suitable leaving group; a suitable leaving group include without limiting to F, C1, Br,I, OTs, OMes, corresponding alkyl sulphate ester and the like; in presence of a base selected from without limiting to NaOH, KOH, LiOH, CsOH, Ca(OH)2, Ba(OH)2, NaHCO2, K2CO3, Na2CO3, Cs2CO3, TEA, Pyridine, and any other proton abstracting agent easily understood by those skilled in the art of organic synthesis. The most preferred base is chosen as K2CO3 or Na2C03. The reaction is carried out at 25 °C to 150°C, more preferable at 50°C to 150°C and most preferably at the 100°C to 110°C. The reaction can be carried in solvents chosen from DMF, Dioxane, THF, MeTHF, Toluene, Xylene, Chlorobenzene, dichlorobenzene, MTBE, MIBK, Acetone and the like, or preferably can be carried out without distilling the solvent. The product could be optionally isolated by distillation.
Example 5: Synthesis of 2-bromo-6-fluoro-phenol:
A 2 liter four neck RB flask was fitted with overhead stirrer, condenser and thermometer pocket. 50 % caustic lie (126.4 ml, 192.76 g, and 2.7 eqv.) was charged at 25 °C into the flask. It was diluted to 25% by adding water (192.76 g, 1.927 volumes) at 25°C. The solution was cooled to - 5°C to 2°C and liquid bromine (47.1 ml, 146.90 g, 1.03 eqv) was added drop wise over 30 min at - 5°C to 2°C. The reaction mixture was stirred at - 5eC to 2°C for 2.0 hours. To the resulting solution tert-butylamine (122.0 ml, 84.92 g, 1.3 eqv) was added drop wise over 40 min at - 5°C to 2°C.

The mixture was vigorously stirred at the same temperature (- 5°C to 2°C) for 2.0 h. During addition time, yellow precipitate was generated which got dissolved after ~ 60 % of the addition was completed, and solution turned yellow. The reaction mixture was extracted with toluene (400.0 ml). The aqueous layer was further extracted with Toluene (2 x 200.0ml). All the toluene layers were combined and the solution was stirred at -15°C to 2°C for l0 min.

Another 3-litre four neck RB flask was fitted with overhead stirrer, condenser and thermometer pocket. A solution of 2-fluorophenol (79.62 ml, 100.0 g, 1.0 eqv.) in toluene (900.0 ml) and N-Methylpyrrolidone (20.0 ml) and tert-butylamine (65.24 g, 93.8 ml, 1.0 eqv.) were added maintaining the temperature below 30°C. The temperature of the final solution was stirred at -15°C to 0°C for 10 min. The chilled toluene layer of N-bromo-tert-butylamine (prepared above) was added to the solution of 2-fluorophenol at temperature below -15°C to 0°C. The reaction mass was stirred and allowed to warm up to 10°C for 1.0 h. A solution of 15% HC1 (541.2 ml) was added maintaining the temperature belowl0°C. The resulting solution was stirred for an additional 30 min. The lower acidic aqueous layer containing tert-butylamine was separated for recovery. The organic layer was washed with water (200.0 ml). The toluene solution (1850 ml) was used as such for next step.

'H NMR (CDC13): 8 values, 5.56 (s, 1H), 6.75-6.80 (m, 1H), 7.03-7.08 (m, 1H), 7.22-7.43 (m, 1H).

A 3 litre four neck RB flask was fitted with overhead stirrer, condenser and thermometer pocket. The toluene layer (1850.0 ml) from 6.14 was transferred and heated the solution to 60°C to 80°C followed by the addition of potassium carbonate (135.6 g, 1.1 eqv.) lot wise while controlling frothing. The mixture was heated at reflux temperature of toluene (110°C) for 20 minutes and added diethyl sulphate (128.5 ml; 1.1 eqv.) drop wise at 110°C. During addition of diethyl sulphate, a heavy precipitate was seen. It was stirred at the same temperature for additional 3 h. Water (300 ml) was added and heated at reflux temperature for additional 1.0 h. The reaction mixture was brought to room temperature. The layers were then separated. The toluene layer was washed with water (400.0 ml). The toluene was distilled at atmospheric pressure. (Recovery of toluene was 90 % with GC purity >99 %). Crude product (245.0 g) with traces of toluene was distilled under vacuum and the residue was distilled using fractionating column as the main fraction. The yield was 180,0 g (84.7 - 85.7 %). The GC purity was 92-93 %.'H NMR (CDC13): 8 values, 1.43 (t, 3H), 4.17 (q, 2H), 6.88-6.93 (m, 1H), 7.02-7.07 (m, 1H), 7.26-7.33 (m, 1H).

To a 2 litre four neck RB flask with overhead stirrer, condenser and thermometer pocket was charged magnesium metal turnings (1.3 g) and heated the flask at 130°C for 30 min under N2 atmosphere. The flask was cooled below 40°C under N2 atmosphere and charged dry THF (20.0 ml) and compound [D] (0.5 g, 0.05 eqv.) and iodine (0.2 g). The

reaction mass was stirred vigorously where reaction mass changed the color from dark brown to colorless within 10 minute. As soon as color change was observed, remaining solution of Compound [D] (9.5 g, 0.95 eqv.) in dry THF (23.0 ml) was added drop wise over 30 min at 30°C. The stirring was continued for an additional 3h. The reaction mass was cooled to 10°C. Another 3-L RB flask was fitted with overhead stirrer, condenser and thermometer pocket. Freshly distilled triisopropylborate (6.6 g, 0.7 eqv) and dry THF (20.0 ml) was charged and cooled to 10°C. The solution of Grignard reagent in THF prepared above was added to the triisopropylborate solution slowly by maintaining temperature below 10°C. White granules were precipitated out. The mixture was allowed to attain room temperature and subsequently stirred for 3.0 h. To the reaction mixture 10% HC1 solution (3.0 g) was added by maintaining the temperature below 30°C. The mixture of THF and IPA was distilled and the last traces of THF were removed by nitrogen flushing. The reaction mass was cooled below 60°C and MTBE (100.0 ml) was added. Stirred the mixture for 30 min at 50°C to 60°C and separated aqueous layer. The aqueous layer was extracted with MTBE (50.0 ml).The organic layer was washed with water (50 ml) and brine (20 ml) and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by column chromatography over silica gel with 0-2% ethyl acetate in hexane to give [E-l], 1.4 g and[E-2],3.1g.

[E-l]: 'H NMR (DMSO-D6): 8 values, 1.26 (t, 3H), 4.06 (q, 2H), 7.02-7.09 (m, 1H), 7.19-7.26 (m, 2H), 8.07 (s, 2H).

[E-2]: 'H NMR (DMSO-D6): 5 values, 0.96 (t, 6H), 3.82 (q, 4H), 7.02-7,09 (m, 2H), 7.19-7.28 (m,4H), 10.28 (s,lH).

To a 2 litre four neck RB flask with overhead stirrer, condenser and thermometer pocket was charged magnesium metal turnings (1.3 g, 1.1 eqv.) and heated the flask at 130 °C for 30 min under N2 atmosphere. The flask was cooled below 40°C under N2 atmosphere and charged dry THF (20.0 ml) and compound [D] product (0.5 g, 0.05 eqv.) and iodine (0.2 g). The reaction mass was stirred vigorously where reaction mass changed the color from dark brown to colorless within 10 minute. As soon as color change was observed, remaining solution of compound [D] (9.5 g, 0.95 eqv.) in dry THF (23.0 ml) was added drop wise over 30 min at 30°C. The stirring was continued for additional 3 h. The reaction mass was cooled to 10°C. Another 3-L RB flask was fitted with overhead stirrer, condenser and thermometer pocket. Freshly distilled triisopropylborate (6.6 g, 0.7 eqv) and dry THF (20.0 ml) was charged and cooled to 10°C. The solution of Grignard reagent in THF

prepared above was added to the triisopropylborate solution slowly by maintaining temperature below 10 ˚ C. White granules were precipitated out. The mixture was allowed to attain room temperature and subsequently stirred for 2.0 h. To the reaction mixture 10% HC1 solution (306.0 g, 1.1 eqv.) was added by maintaining the temperature below 30°. The mixture of THF and IPA was distilled and the last traces of THF were removed by nitrogen flushing. The reaction mass was cooled below 60°C and toluene (684.0 ml) was added. Stirred the mixture for 30 min at 50°C to 60°C and separated aqueous layer. The aqueous layer was extracted with toluene (342.0 ml).
To the combined toluene layers, water (618 ml) and caustic lie (68.93 g, 1.1 eqv) were added at 5°C to 15°C followed by tetrabutyammonium bromide (7.6 g, 0.03 eqv). To this solution was added 30% H2O2 solution (105 ml, 1.3 eqv.) drop wise and stirred the mixture for additional 2 h at ambient temperature. Sodium metabisulphite (44.5 g, 0.30 eqv.) was added by maintaining temperature below 30°C to quench the excess H2O2. The reaction mass was heated at 50°C to 60°C for 20 min. The lower aqueous layer was separated. The organic layer was washed with water (280 ml) and caustic lie (20.5 ml) followed by water (280 ml). All the aqueous layers were combined and washed with toluene (340 ml). The basic aqueous layer was acidified by 30% HC1 solution (213 ml) to pH 1 - 2. The acidified aqueous layer was extracted twice with toluene (684 ml) and (342 ml) respectively. The organic layer was used as such for the next step. 'H NMR (CDCb): 8 values, 1.40 (t, 3H), 4.23 (q, 2H), 5.80 (s, 1H), 6.60-6.65 (m, 1H), 6.72-6.75 (m, 1H), 6.85-6.91 (m, 1H).

A 3 litre four neck RB flask was equipped with overhead stirrer, condenser and thermometer pocket and charged the toluene solution (-1150 ml) obtained above. The reaction mass was heated to 75°C to 85°C and potassium carbonate (108 g, 1.0 eqv.) was charged in small lots. The mixture was heated to reflux for 20 - 30 min. To the refluxing solution diethyl sulphate (103 ml, 1.0 eqv.) was added drop wise under stirring and maintained the reflux for additional 3.0 h. Water (513.0 ml) was added and heated the mixture for additional 1.0 h. The mixture was cooled to room temperature and separated lower aqueous layer. The aqueous layer was extracted with toluene (342 ml). The combined toluene layer was distilled at atmospheric pressure. This leaves behind 150-160 g of the oily residue. The crude product was distilled under vacuum with glass bead packed column and micro-liquid divider. The main fractions were collected at vapor temperature range of 121 -

123 ˚ C/ 10 mbar. The product isolated was a colorless liquid with LC purity of >99.5 %. Yield was 82 - 85 g (59 - 61 %) based on the crude product.

'H NMR (CDC13): 8 values, 1.37, 1.44 (2xt, 6H), 4.07, 4.13 (2xq, 4H), 6.66-6.72 (m, 2H), 6.90-6.95 (m, 1H).

1, 2-dialkoxy-3-fluoro benzene prepared by the present invention and specifically 1, 2-diethoxy-3-fluoro benzene is useful as intermediates of medicament (see WO02/085855, WO2004/078721 and WO2006/018955).

Advantages: The previously described versions of the subject matter and its equivalent thereof have many advantages, including those which are described below.

The process of the present invention involves easily available 2-fluoro phenol as a starting material. The salient feature involve the regioselective halogination most preferably bromination of 2-fluoro phenol using halogenating agent N-halo amine, generated by the reaction of primary or secondary amine with halogen in presence of organic or inorganic peroxide. The halogenated product without isolation was alkylated in presence of a suitable base to get the alkylated product effectively in one pot. The halo compound is purified by distillation. The Halo compound was subjected to Grignard reaction with Mg in a suitable non protic solvent followed by boronation with tralkyl borate to give the mixture of boronic acid (s) and was oxidized in situ to give the corresponding phenol. The phenol was alkylated without isolation to produce the final compound. The process is designed in such a manner that at two different alkylation steps different alkyl group can be introduced. The sequence of synthetic steps resulted very high quality of the product after fractional distillation with overall yield of >50%. The process involves five formal synthetic steps however there are only two isolation steps. All the synthetic steps are very easy to practice except for the step that involves dry solvent. Moreover the process does not require any hazardous reagent and does not require very low temperature as required in lithiation chemistry. Considering the simplicity in the operation this is highly suitable for industrial production.

Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the

preferred embodiment contained therein.

List of abbreviation:

CTAB: Cetyltrimethyl ammonium bromide
DMF: Dimethyl formamide
DMSO: Dimethyl sulfoxide
GC: Gas chromatography
IPA: Ulsopropyl alcohol
Mes: Methane sulfonyl
MeTHF: 2-Methyl tetrahydrofuran
MIBK: Methyl isobutyl ketone
MTBE: Methyl-tert-butylether
NMP: N-methylpyrrolidone
PTC: Phase transfer catalyst
RB: Round bottomed
TBAB: Tetrabutyl ammonium bromide
TEA: Triethylamine
THF: Tetrahydrofuran
Ts: 4-methyl benzene sulfonyl

We claim:

1. A process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of
formula I
PICTURE

wherein:
R3 and R4 are each independently a linear or a branched C1-C20 alkyl, a C3-C8 cycloalkyl, a C7-C15 alkylaryl or a C4-C7 cycloalkyl alkyl; said process comprising:

halogenating 2-fluoro phenol at 6-position with a halogenating agent to obtain 2-fluoro-6-halophenol, wherein said halogenating agent is not a fluorinating agent;

alkylating 2-fluoro-6-halophenol with an alkylating agent in presence of a base to obtain l-alkoxy-2-fluoro-6-halobenzene;

reacting said l-alkoxy-2-fiuoro-6-halobenzene with magnesium metal and iodine in presence of a solvent and further treating with a boronating reagent to obtain boronate esters;

optionally hydrolyzing said boronate esters in presence of an acid to obtain boronic acids;
oxidizing said boronate ester or said boronic acids to obtain 1-alkoxy-2-fluoro-6-hydroxy benzene; and

alkylating said l-alkoxy-2-fluoro-6-hydroxy benzene with an alkylating agent to obtain 1,2-dialkoxy-3-fluorobenzene.

2. The process as claimed in claim 1 wherein, said halogenating agent is N-haloamine.

3. The process as claimed in claim 1 wherein, said solvent is selected from a group consisting of ether, THF, methanol and dioxane or mixtures thereof.

4. The process as claimed in claim 1 wherein, said boronating agent is trialkyl borate.

5. The process as claimed in claim 1 wherein, said base is selected from a group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, barium hydroxide, sodium bicarbonate, potassium carbonate, sodium carbonate and cesium carbonate.

6. The process as claimed in claim 1 wherein, said acid is selected from a group consisting of hydrochloric acid, sulphuric acid and phosphoric acid.

7. The process as claimed in claim 1 wherein, R3 and R4 are each independently a linear or a branched C1-C5 alkyl or C3-C6 cycloalkyl.

8. The process as claimed in claim 1 wherein, R3 and R4 are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, cyclopropyl, cyclopentyl or cyclohexyl.

9. The process as claimed in claim 1 wherein, said process comprises:
brominating 2-fluoro phenol at 6-position with N-bromoamine to obtain 2-fluoro-6-bromophenol in a solvent and optionally a co-solvent;

ethylating 2-fluoro-6-bromophenol with an ethylating agent in presence of a base to obtain l-ethoxy-2-fluoro-6-halobenzene;

reacting said l-ethoxy-2-fluoro-6-halobenzene with magnesium metal and iodine in presence of dry solvents selected from ether, THF, methanol-THF or dioxane, and further treating with a trialkyl borate to obtain boronate esters;

optionally hydrolyzing said boronate esters in presence of an acid to obtain boronic acids;
oxidizing said boronate ester or said boronic acids to obtain 1-ethoxy-2-fluoro-6-hydroxy benzene; and

ethylating said l-ethoxy-2-fluoro-6-hydroxy benzene with an ethylating agent to obtain l,2-diethoxy-3-fluorobenzene.

10. A process for the preparation of l,2-dialkoxy-3-fluorobenzene compounds of
formula I substantially as herein described in the specification.