Field of the Invention

The present invention provides an improved, less expensive, simpler, safer and easily scaled-up manufacturing process with less number of steps and much shorter time cycle for producing halo-dialkoxybenzene, such as l -fluoro-2,3-dialkoxybenzene and 2-fluoro- l ,4- dialkoxybenzene, from 2-fluorophenol from 2-halophenol and an allyl halide.

Background

Alkoxy derivatives of 3-fluorocatechol are potential precursor in the synthesis of a wide range of pharmaceuticals such as adrenergic catecholamines and the recent 2- iminopyrrolidine derivatives as thrombin receptor antagonists.

In the Applicant's patent publication IN 2006CH00825, a process for producing 1 - fluoro-2,3-dialkoxybenzene along with 2-fluoro-l ,4-dialkoxybenzene is provided. However the process includes seven steps and longer time cycle.

The present invention is directed towards cost reduction of the overall procedure, besides a much shorter time cycle, better yield and is therefore more cost effective.

Summary

The present invention provides an improved process for the preparation of halo dialkoxybenzene compounds of formula I

Formula I wherein R _\ and R ₂ are each independently a straight or a branched chain Ci to C ₄ alkyl group, C3-C7 cycloalkyl, C3-C7 cycloalkyl alkyl, C ₅ -Ci ₀ arylalkyl groups;

X is selected from F, CI or Br; said process comprising reacting 2-halo phenol with an allyl halide in the presence of a base and solvent N-methyl pyrrolidone to reaction completion, followed by filtration to obtain a filtrate; heating the filtrate to obtain a reaction mass followed by alkylating the reaction mixture with an alkylating agent and a suitable base to obtain an alkylated product; heating the alkylated product in the presence of a metallic hydroxide to obtain isomeric mixtures of allyl products; separating the isomers by fractional distillation; oxidizing the isomers to obtain the corresponding benzaldehydes using oxidants in presence of a halo hydrocarbon solvent; further oxidizing the benzaldehydes with an organic or an inorganic peroxide in a halo hydrocarbon solvent to obtain the corresponding phenols; and alkylating the phenols thus obtained with an alkylating agent in presence of a base, and an organic solvent to obtain the compounds of formula I.

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 relates to an improved process for the preparation of halo dialkoxybenzene compounds of formula I

Formula I wherein R _\ and R ₂ are each independently a straight or a branched chain Ci to C ₄ alkyl group, C ₃ -C ₇ cycloalkyl, C ₃ -C ₇ cycloalkyl alkyl, C5-C ₁₀ arylalkyl groups;

X is selected from F, CI or Br; said process comprising:

(i) reacting 2-halo phenol with an allyl halide in the presence of a base and solvent N-methyl pyrrolidone to reaction completion, followed by filtration to obtain a filtrate; (ii) heating the filtrate to obtain a reaction mass followed by alkylating the reaction mixture with an alkylating agent and a suitable base to obtain an alkylated product;

(iii) heating the alkylated product in the presence of a metallic hydroxide to obtain isomeric mixtures of allyl products;

(iv) separating the isomers by fractional distillation;

(v) oxidizing the isomers to obtain the corresponding benzaldehydes using oxidants in presence of a halo hydrocarbon solvent;

(vi) further oxidizing the benzaldehydes with an organic or an inorganic peroxide in a halo hydrocarbon solvent to obtain the corresponding phenols; and

(vii) alkylating the phenols thus obtained with an alkylating agent in presence of a base, and an organic solvent to obtain the compounds of formula I.

In an embodiment of the present invention the preparation of halo dialkoxybenzene compound is for the compound of formula I (a)

Formula I (a) wherein:

Ri and R ₂ are each independently a straight or a branched chain Q to C ₄ alkyl group; said process comprising:

(i) reacting 2-fluoro phenol with an allyl halide in the presence of a base and solvent N-methyl pyrrolidone to reaction completion, followed by filtration to obtain a filtrate;

(ii) heating the filtrate to obtain a reaction mass followed by alkylating the reaction mixture with an alkylating agent and a suitable base to obtain an alkylated product; (iii) heating the alkylated product in the presence of a metallic hydroxide to obtain ortho and para- isomeric mixtures of allyl products;

(iv) separating the isomers by fractional distillation;

(v) oxidizing the isomers to obtain the corresponding benzaldehydes using oxidants in presence of a halo hydrocarbon solvent;

(vi) further oxidizing the benzaldehydes with an organic or an inorganic peroxide in a halo hydrocarbon solvent to obtain the corresponding phenols; and

(vii) alkylating the phenols thus obtained with an alkylating agent in presence of a base, and an organic solvent to obtain the compounds of formula I (a).

In an embodiment of the present invention, the allyl halide is selected from allyl chloride, allyl bromide or allyl iodide, preferably allyl chloride. The base used with allyl halide is selected from sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate and cesium carbonate, preferably potassium carbonate.

In another embodiment, the alkylating agent is selected from dimethyl sulphate, diethyl sulphate, methyl iodide, ethyl bromide, isopropyl bromide and ethyl iodide, preferably diethyl sulphate. Further, the suitable base used with the alkylating agent is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, magnesium carbonate, cesium carbonate, preferably potassium carbonate or magnesium hydroxide, preferably potassium hydroxide.

In another embodiment, the metallic hydroxide is selected from sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide, preferably potassium hydroxide. This metallic hydroxide is used in an amount 2.5 to 3moles based on the weight of starting 2-substituted phenol.

The oxidant in the present invention is selected from potassium permanganate, sodium periodate, potassium periodate, osmium tetroxide, preferably potassium permanganate, which is another embodiment of the invention.

In another embodiment, the halo hydrocarbon solvent is selected from dichloromethane, chloroform, carbon tetrachloride, and dichloroethane, preferably dichloromethane. The organic peroxide used is selected from per benzoic acid, per acetic acid, meta chloroperbenzoic acid and per formic acid, preferably meta chloroperbenzoic acid. Preferably, hydrogen peroxide is the preferred inorganic peroxide.

In the process of the present invention, the 2-halo phenol and solvent NMP are in the ratio of l :2(w/v).

In another embodiment, the alkylation and isomerisation is using potassium hydroxide in amount 2.5 to 3 moles based on the weight of 2- halo phenol.

In another embodiment of the present invention, the desired products are obtained at a higher yield without any worked-up steps in the process, and consuming lesser time.

In the present invention, first four steps were carried out using NMP solvent, without any workup except one filtration and after stage 4, purification of compound 5 is carried out by fractional distillation. Remaining three steps were carried out following procedure described in the Applicant's publication(IN 2006CH00825) with little modification in amount of catalyst used in KMn04 oxidation step.

Scheme

W ithout worku S eparated by fractio na l d istillation

ea

2-Fluorophenol( 1 ) was heated with a base in presence of NMP solvent under stirring and allyl halide was added in to the reaction vessel over a period of time with a preferred temperature range of about 60o to 80 oC. Allyl halide used may be allyl chloride, allyl bromide, allyl iodide, and preferred halide quantity is 1-1.2 mole %. The basic material includes a basic metal carbonate; potassium carbonate is the usual preferred reagent. NMP as organic solvent is used two volumes per unit weight of phenol compound. Addition time of allyl halide into a reaction flask is about 2 hours. Progress of reaction may be monitored by TLC, GC or HPLC methods. After completion of the reaction (time is about 5-6 hr), the solid material is filtered and washed with 0.5 times by volume NMP. The filtrate is heated to 180-225°C for 6-7 hour in an atmosphere of nitrogen. The reaction may be followed by TLC, GC or HPLC methods. After completion of rearrangement reaction, the reaction mass is alkylated with suitable alkylating agent, without any workup. The alkylating agents comprise methyl and ethyl esters of sulphuric acid, suitable alkyl halides such as ethyl bromide, isopropyl bromide etc., in an amount of about 1 mole % based on the starting 2-fluorophenol. The basic material includes a basic metal hydroxide; potassium hydroxide is the preferred reagent. Preferred temperature range is about 70o to 80°C. The reaction may be followed by TLC, GC or HPLC methods. After the completion of reaction, the mass may be heated to about 100- l lOoC and metallic hydroxides preferably potassium hydroxide is added in 4 equal lots. The reaction is maintained at 100- 1 lOoC for 3-4hour. Reaction may be followed by either GC or HPLC methods.

In this stage, the crude mixture of oi ho (5, 70-73%) and para (5a, 12-14 %) isomeric allyl products are separated almost completely by a fractional distillation technique.

After these consecutive four steps, remaining three steps follows the process described in our earlier filed patent (ΓΝ 2006CH00825) with little modification in amount of catalyst used in MnC<4 oxidation step. This pure propenyl compound (5 and 5a), is oxidized to benzaldehydes (6 and 6a) using potassium permanganate (amount of catalyst used is reduced to 0.69 equivalent from 1.4 equivalent) followed by reaction with organic peroxides like meta chloroperbenzoic acid or per formic acid etc to obtain the corresponding alkoxyphenols(7 and 7a). Thereafter these phenolic compounds thus obtained may be alkylated to obtain the targeted products (8 and 8a) in good yields with high purity.

It is obvious that the synthesis can be extended to compounds 8 and 8a where Rl and R2 can be also cycloalkyl, cycloalkyl alkyl, arylalkyl etc. Further, compounds 7 and 7a can be dealkylated to the catechols. Finally the fluorine atom in 1 can be other halogens like chlorine, bromine etc.

Some compounds that are prepared by the process of the present invention are represented by the following structural formula (8A to 8F).

8 D 8 E 8 F

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.

EXAMPLE

The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure.

EXAMPLE 1

Production of l-fluoro-2,3-diethoxybenzene along with 2-fluoro-l,4-diethoxybenzene (8A and 8A')

A). Preparation of crude 6-fluoro-2-propenylethylphenylether (5 and 5a, R=F,

2-Fluorophenol (500 g, 4.464 m) and NMP (1 Lt) were charged in a clean and dry 3 lit

4 neck round bottomed flask fitted with mechanical stirrer, condenser and thermometer pocket under nitrogen dry condition at room temperature (RT) and stirred for 10 min. K ₂ C0 ₃ (677.6 g, 4.91 m) was added while the reaction temperature was slowly raised to 30-50°C. It was then stirred for 45 minutes and reaction temperature was increased to 60-70°C. Allyl chloride (409 g, 5.357 m) was added drop wise for 2 h maintaining the temp at 60-70°C. The temp was raised to 75-80o C and maintained for 6-7hour. The completion of the reaction was monitored by TLC. If starting material was present, the reaction mixture was further heated at 75-80° C for another lhour to ensure completion. The reaction mixture was cooled to RT; the solid was filtered and washed with NMP (0.25 Lt). The above NMP solution (0.25 Lt) was charged to a clean dry 3 lit 4 neck RBF fitted mechanical stirrer, condenser and thermometer pocket under nitrogen atmosphere. The temp was slowly raised to 180- 195°C and remaining NMP solution (about 2 lt) was added drop wise (addition time 2 hour) and the temp maintained at 205-210°C for 6-7hour.

The completion of the reaction was monitored by TLC study. If starting material is present, the reaction mixture was further heated at 205-210°C for another lhour to ensure completion.

The reaction mixture was cooled to 60°C. Solid KOH (275 g, 4.91 m) was added in two lots (total time 30 min) at 60oC (internal temp raised to 70-80°C) and stirred for 40 minutes in order to get a clear solution. Diethyl sulphate (686.9g, 4.46 m) was added drop wise for 2 hour maintaining the temp at 6O-8O0C. Then the reaction mixture was stirred at 70- 8O0C for 45 min. TLC study was done to check the completion of the reaction.

The reaction mixture was heated to 100-1 lOoC. Solid KOH (400 g, 7.14 m) was added in four lots (total time 1.5 h) and stirred at 95-100°C for 3-4hour. The completion of the reaction was studied by GC which showed 70-73 % o-isomer along with 12-14 % p-isomer. Water (6 L) was added to this reaction mixture at lOOoC and steam distilled. The organic layer in the distillate was collected and careful fractional distillation afforded 610 g of compound 5 with 81.84% GC purity (p-isomer 8.1%; nonpolar impurity 2.7 %) along with 80 g of compound 5a with 79 % GC purity (o-isomer 7 %).

B). Preparation of crude 2-ethoxy-3-fluorobenzaldehyde (6, R=F, Rl=C ₂ Hs)

To a mixture of 6-fluoro-2-propenylethylphenylether (5, R=F, Rl=C ₂ Hs, 576 g, 2.72 mole), benzyltriethylammonium chloride(428.5 g, 1.88 moles) in MDC(4.5 L) at 0°C, was added freshly ground potassium permanganate (645 g, 4.08 moles) portion wise over a period of 1 hour. The reaction mass was stirred at 0°C for 1 hour and monitored by TLC. After completion of the reaction, concentrated sulphuric acid (60 g, in 6.2 L water) was added during 1 to 2 hour. After cooling the mixture to RT, the slurry was filtered through hyflo, and washed the bed with dichloromethane (600 ml). The organic layer was separated, washed with saturated solution of sodium bicarbonate (2 x 1 L), washed with water (500 ml), and dried over anhydrous magnesium sulphate. Solvent was removed to obtain 500 g of the desired aldehyde product with purity by G.C 92 %.

C). Preparation of crude 2-ethoxy-3-fluorophenol (7, R=F, R1=C ₂ H ₅ )

To a stirred solution of formic acid (98%, 2,472 g, 53.7 moles) and hydrogen peroxide

(30 %, 1,328 g, 39 moles) was added 2-ethoxy-3-fluorobenzaldehyde (6, R=F, R1=C ₂ H ₅ , 496 g, 2.68 moles) in MDC (1.49 L) at RT. The reaction mass was heated to 35o to 40°C for 24 hour. Reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to RT, and the layers were allowed to separate. The dichloromethane layer was separated and concentrated. To the resulting residue was added methanol (1 L) and 10 % KOH (2 L) at about 10°C, and stirred at RT for 1 hour. The alkali solution was concentrated to remove methanol and neutralized with dilute hydrochloric acid (400 ml) to pH 2-4. The product was extracted from the aqueous layer with dichloromethane (1.5 L), washed with saturated solution of sodium bicarbonate (500 ml), dried over anhydrous magnesium chloride and distilled to obtain 315 g of the desired phenol product with G.C purity 98 %.

D). Preparation of l-fluoro-2, 3-diethoxy benzene (8A)

To a stirred mixture of anhydrous potassium carbonate (269 g, 1.94 moles) in dimethylformamide (900 ml) at RT, was added 2-ethoxy-3-fluorophenol (7, R=F, R1=C2H5, 315 g, 1.948 moles) under stirring. The reaction mixture was heated to 65o to 70oC and to this hot slurry was added diethyl sulphate (451 g, 2.93 moles) over a period of 1.5 to 2 hour. The reaction was monitored by TLC. After completion, the reaction mass was concentrated and quenched with water (1.5 L). The organic layer was separated, washed with water (500 ml), concentrated and dried over anhydrous sodium sulphate to obtain 275 g of the desired product.

1H NMR (CDC13, 300 MHz): 8 6.96-6.86 (m, 1H), 6.74-6.63 (m, 2H), 4.13 (q, 2H), 4.07 (q, 2H), 1.43 (t, 3H), 1.37 (t, 3H).

HPLC purity: 99.5 % Preparation of 2-fluoro-l, 4-diethoxy benzene (8Α')

Following the above exact procedure for compound 8A, starting from 2-fluoro-4- propenylethylphenylether (5a, R=F, R|=C ₂ H ₅ ), 2-fluoro-l , 4-diethoxybenzene (8Α', R=F, Ri=R ₂ =C ₂ H5) was synthesized.

IH NMR (CDC13, 300 MHz): δ 6.88 (t, IH), 6.66 (dd, IH), 6.6-6.53 (m, IH), 4.04 (q, 2H), 3.95 (q, 2H), 1.45-1.35 (m, 6H).

GC purity: 88 %

The following examples were prepared from 2-fluorophenol following the above exact procedure for compound 8A

EXAMPLE 2

l-Fluoro-2-ethoxy-3-isopropoxy-benzene (8B):

IH NMR (CDCI3, 300 MHz): d 6.95-6.85 (m, IH), 6.75-6.65 (m, 2H), 4.45-4.6 (m, IH), 4.15 (q, 2H), 1.3-1.4 (m, 9H).

GC purity: 99.2 %

EXAMPLE 3

l-Fluoro-3-isopropoxy-2-methoxy-benzene (8C):

IH NMR (CDCI3, 300 MHz): d 6.95-6.85 (m, IH), 6.75-6.64 (m, 2H), 4.48-4.62 (m, IH), 3.9 (s, 3H), 1.35 (d, 6H).

GC purity: 98.24 %

EXAMPLE 4

l-Fluoro-3-ethoxy-2-methoxy-benzene (8D):

IH NMR (CDCI3, 300 MHz): d 7.0-6.85 (m, IH), 6.75-6.6 (m, 2H), 4.05 (q, 2H), 3.9 (s, 3H),

1.45 (t, 3H).

GC purity: 98.34 % EXAMPLE 5

l-Fluoro-2, 3-diniethoxy-benzene (8E):

I H NMR (CDCI3, 300 MHz): 0 7.0-6.9 (m, I H), 6.75-6.65 (m, 2H), 3.95 (s, 3H), 3.85 (s, 3H) GC purity: 98.18 %

EXAMPLE 6

l-Fluoro-3-methoxy-2-ethoxy benzene (8F):

I H NMR (CDCI3, 300 MHz): B 7.0-6.9 (m, I H), 6.75-6.65 (m, 2H), 4. 15 (q, 2H), 3.85 (s 3H), 1.35 (t, 3H).

GC purity: 99.62 %

Following table shows the area of improvement in the process of the present invention compared to the earlier process of IN 2006CH00825 which predict overall more than 20 % cost reduction in the whole process.