DESC:
FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“A PROCESS FOR PREPARATION OF HALO SUSTITUTED BENZYL ALCOHOL AND INTERMEDIATE THEREOF”

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a process for preparation of halosubstituted benzyl alcohol of formula I and intermediate thereof.

Formula I
wherein X represent halogen, n represents an integer from 1-5.
BACKGROUND OF THE INVENTION
The halosubstituted benzyl alcohol compounds are very useful intermediates in preparation of pharmaceuticals and agrochemicals.
The various processes are known in the literature for the preparation of halosubstituted benzyl alcohol and intermediate thereof.
JP2015214503 discloses a process for the preparation of 2,6-dihalobenzaldehyde by reacting 2,6-difluorobenzonitrile with methanol, sulfuric acid, and rhodium carbon at 70°C. The process involves use of expensive metal catalysts that increase the cost of production during commercial scaleups.
EP1101752 discloses a process for preparation of 2,6-difluorobenzyl alcohol from 2,6-dihalobenzaldehyde by reacting it with Pd/C at 25-30°C. The said process involves formation of byproducts and gives low yield.
The present invention provides a simple, safe and environment friendly process for the preparation of halosubstituted benzyl alcohol with minimum impurity formation.
OBJECT OF THE INVENTION
The main object of present invention is to provide a simple and an industrial applicable process for the preparation of halosubstituted benzyl alcohol and intermediate thereof having high yield and purity.

SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein X represents halogen, n represents an integer from 1-5,
comprising the steps of,
a) hydrogenating a compound of formula III,

Formula III
wherein X and n' represented as above,
using hydrogen in presence of nickel-aluminum alloy and an acid to obtain a compound of formula II; and

Formula II
wherein X and n represented as above,
b) hydrogenating the compound of formula II, using hydrogen in presence of Raney nickel in a solvent to obtain the compound of formula I.
In second aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein X represents halogen, n represents an integer from 1-5,
comprising a step of hydrogenating a compound of formula II,

Formula II
wherein X and n represented as above,
using hydrogen in presence of Raney nickel in a solvent to obtain the compound of formula I.
In a third aspect, the present invention provides a process for preparation of a compound of formula II,

Formula II
wherein X and n represented as above,
comprising the step of hydrogenating a compound of formula III,

Formula III
wherein X and n represented as above,
using hydrogen in presence of nickel-aluminum alloy and an acid to obtain a compound of formula II.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, X represents halogens and may be selected from a group consisting of fluoro, chloro and bromo and most preferred X for present invention is fluorine and chloro. “n” represents an integer from 1-5. The halogen may be present at any position in the phenyl ring, wherein preferred position are ortho and para of phenyl ring.
In an embodiment of the present invention, the compound of formula I includes 2,6-
difluorobenzyl alcohol; 2,6-dichlorobenzyl alcohol; 2-chloro-6-fluorobenzyl alcohol; 2,6-dibromobenzyl alcohol; 2-bromo-6-chlorobenzyl alcohol; 2-bromo-6-fluorobenzyl alcohol; 2-chloro-4-fluorobenzyl alcohol; 4-chloro-2-fluorobenzyl alcohol; 2-chlorobenzyl alcohol, 4-chlorobenzyl alcohol; 2-fluorobenzyl alcohol, 4-fluorobenzyl alcohol; 2,4,6-trifluorobenzyl alcohol; 2,4,6-trichlorobenzyl alcohol; 2,6-dichloro-4-fluorobenzyl alcohol; 2,6-difluoro-4-chlorobenzyl alcohol; 2,4-dichloro-6-fluorobenzyl alcohol; 2-fluoro-4,6-dichlorobenzyl alcohol; 2-chloro-4,6-difluorobenzyl alcohol or like.
In another embodiment of the present invention, the compound of formula II includes 2,6-difluorobenzaldehyde; 2,6-dichlorobenzaldehyde; 2-chloro-6-fluorobenzaldehyde; 2,6-dibromobenzaldehyde; 2-bromo-6-chlorobenzaldehyde; 2-bromo-6-fluorobenzaldehyde; 2-chloro-4-fluoroenzaldehyde; 4-chloro-2-fluoroenzaldehyde; 2-chloroenzaldehyde; 4-chloroenzaldehyde; 2-fluoroenzaldehyde; 4-fluoroenzaldehyde; 2,4,6-trifluoroenzaldehyde; 2,4,6-trichloroenzaldehyde; 2,6-dichloro-4-fluoroenzaldehyde; 2,6-difluoro-4-chloroenzaldehyde; 2,4-dichloro-6-fluoroenzaldehyde; 2-fluoro-4,6-dichloroenzaldehyde; 2-chloro-4,6-difluoroenzaldehyde or like.
In another embodiment of the present invention, the compound of formula III includes 2,6-difluorobenzonitrile; 2,6-dichlorobenzonitrile; 2-chloro-6-fluorobenzonitrile; 2,6-dibromobenzonitrile; 2-bromo-6-chlorobenzonitrile; 2-bromo-6-fluorobenzonitrile; 2-chloro-4-fluorobenzonitrile; 4-chloro-2-fluorobenzonitrile; 2-chlorobenzonitrile; 4-chlorobenzonitrile; 2-fluorobenzonitrile; 4-fluorobenzonitrile; 2,4,6-trifluorobenzonitrile; 2,4,6-trichlorobenzonitrile; 2,6-dichloro-4-fluorobenzonitrile; 2,6-difluoro-4-chlorobenzonitrile; 2,4-dichloro-6-fluorobenzonitrile; 2-fluoro-4,6-dichlorobenzonitrile; 2-chloro-4,6-difluorobenzonitrile or like.
In an embodiment, the step of hydrogenating a compound of formula III using hydrogen is carried out in presence of nickel-aluminum alloy and an acid.
The weight percentage of nickel-aluminum alloy to compound of formula III is in 10-30%.
The acid is selected from a group consisting of formic acid, acetic acid, propanoic acid, butanoic acid, p-toluene sulfonic acid, methane sulfonic acid, 2-methylsulfonyl acetic acid, benzoic acid, oxalic acid, trichloroacetic acid, sulfurous acid, methanoic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, or the like.
In another embodiment, the hydrogenation of the compound of formula III using hydrogen in presence of nickel-aluminum alloy is carried out at a temperature selected from in the range from 40 to 70°C, preferably at 50 to 60°C.
In an embodiment, the step of hydrogenating a compound of formula III using hydrogen is carried out in presence of nickel-aluminum alloy and an acid is carried out in a reaction time of 2 to 7 hours.
In an embodiment, the hydrogenation of the compound of formula III using hydrogen in presence of nickel-aluminum alloy is carried out in a solvent.
The solvent is selected from a group consisting of water, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, tert-butanol, and ethers such as tetrahydrofuran or the like and mixture thereof.
The nickel-aluminum alloy catalyst is used for step-a is obtained commercially.
In an embodiment, the step of hydrogenating a compound of formula III using hydrogen in presence of nickel-aluminum alloy and acid and isolated a compound of formula II.
In another embodiment, the step of hydrogenating a compound of formula III using hydrogen in presence of nickel-aluminum alloy is carried out in presence of acid and directly used for preparation of compound of formula I, without isolation of compound of formula II.
In an embodiment, the compound of formula II, prepared from compound of formula III, is used in-situ for preparation of a compound of formula I.
In an embodiment of present invention, a process for preparation of 2,6-difluorobenzaldehyde comprising the step of hydrogenating 2,6-difluorobenzonitrile using hydrogen in presence of nickel-aluminium alloy and formic acid in water solvent.
In an embodiment of present invention, a process for preparation of 2,6-difluorobenzaldehyde comprising the step of hydrogenating 2,6-difluorobenzonitrile using hydrogen in presence of nickel-aluminum alloy and formic acid in methanol solvent.
In an embodiment of present invention, a process for preparation of 2-chloro-6-fluorobenzaldehyde comprising the step of hydrogenating 2-chloro-6-fluorobenzonitrile using hydrogen in presence of nickel-aluminium alloy and formic acid in water solvent.
In an embodiment of present invention, a process for preparation of 2,6-dichlorobenzaldehyde comprising the step of hydrogenating 2,6-dichlorobenzonitrile with hydrogen in presence of nickel-aluminum alloy and formic acid in methanol solvent.
In a first aspect, the present invention provides a process for preparation of a compound of formula I, comprising the steps of,
a) hydrogenating a compound of formula III using hydrogen in presence of nickel-aluminum alloy and acid to obtain a compound of formula II; and
b) hydrogenating the compound of formula II, using hydrogen in presence of Raney nickel in presence of a solvent to obtain the compound of formula I, wherein compound of formula II is not isolated or used in-situ.
In an embodiment, the step of hydrogenating a compound of formula II with hydrogen in presence of Raney nickel is carried out in a solvent.
The solvent is selected from a group consisting of pentane, hexane, heptane, xylene, ethylbenzene, and toluene or the like.
The weight percentage of nickel-aluminum alloy to compound of formula II is in 1-30%, preferably 5-20%.
In an embodiment, the step of hydrogenating a compound of formula II using hydrogen in presence of Raney nickel is carried out in a solvent at a temperature selected from 60 to 90°C.
In an embodiment, the step of hydrogenating a compound of formula II using hydrogen in presence of Raney nickel is carried out in a solvent is carried out in a reaction hour of 2 to 7 hours.
In an embodiment of the present invention, the isolation is conducted by means of filtration followed by fractional distillation using packed column.
In an embodiment, the compound of formula I obtained in present invention has yield in the range of 80 to 95% and purity in the range of 98 to 99.9%.
In another embodiment, the compound of formula I is isolated with impurity content in the range of 0-0.01% of impurity of monohalo benzyl alcohol.
In an embodiment of present invention, a process for preparation of 2,6-difluorobenzyl alcohol, comprising the step of reacting 2,6-difluorobenzaldehyde with hydrogen in presence of Raney nickel in toluene at 70 to 80°C.
In an embodiment of present invention, a process for preparation of 2-chloro-6-fluorobenzyl alcohol, comprising the step of hydrogenating 2-chloro-6-fluorobenzaldehyde using hydrogen in presence of Raney nickel in xylene at 70 to 80°C.
In an embodiment of present invention, a process for preparation of 2-chloro-6-fluorobenzyl alcohol, comprising the step of hydrogenating 2-chloro-6-fluorobenzaldehyde using hydrogen in presence of Raney nickel in toluene at 70 to 80°C.
In an embodiment of present invention, a process for preparation of 2,6-dichlorobenzyl alcohol, comprising the step of hydrogenating 2,6-dichlorobenzaldehyde using hydrogen in presence of Raney nickel in toluene at 70 to 80°C.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The reagents or reactants used in the present invention can be prepared by any method known in the art or may be obtained commercially.
The completion of the reaction may 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.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES:
EXAMPLE 1: Preparation of 2,6-difluorobenzaldehyde.
2,6-Difluorobenzonitrile (14.5g), water (92g) and formic acid (29g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The nickel-aluminum alloy (3.5g) was added in the reaction mixture and reaction was heated to 50°C and stirred for 7 hours while maintaining the reaction pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated and fractional distillated to get pure 2,6-difluorobenzaldehyde.
Yield: 75%; Purity: 99%

EXAMPLE 2: Preparation of 2,6-dichlorobenzaldehyde.
2,6-Dichlorobenzonitrile (17g), water (110g) and formic acid (33g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The nickel-aluminum alloy (3.4g) was added in the reaction mixture and reaction was heated to 50°C and stirred for 7 hours while maintaining the reaction pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated and fractional distillated to get pure 2,6-dichlorobenzaldehyde.
Yield: 77%; Purity: 99%

EXAMPLE 3: Preparation of 2-chloro-6-fluorobenzaldehyde.
2-chloro-6-fluorobenzonitrile (15g), water (95g) and formic acid (30g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The nickel-aluminum alloy (3.0g) was added in the reaction mixture and reaction was heated to 50°C and stirred for 7 hours while maintaining the reaction pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated and fractional distillated to get pure 2-chloro-6-fluorobenzaldehyde.
Yield: 76%; Purity: 99%

EXAMPLE 4: Preparation of 2,6-dichlorobenzyl alcohol
2,6-Dichlorobenzaldehyde (10g) and toluene (100g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The Raney nickel (1g) was added in the reaction mixture and reaction was heated to 80°C and stirred for 6 hours while maintained the pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to obtain product, fractionally distilled using packed column and isolated 2,6-dichlorobenzyl alcohol.
Yield: 90%; Purity: 99.5%

EXAMPLE 5: Preparation of 2,6-difluorobenzyl alcohol
2,6-Difluorobenzaldehyde (10g) and xylene (100g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The Raney nickel (0.8g) was added in the reaction mixture and reaction was heated to 80°C and stirred for 6 hours while maintained the pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to obtain product, fractionally distilled using packed column and isolated 2,6-difluorobenzyl alcohol. Yield: 91%; Purity: 99.1%.

EXAMPLE 6: Preparation of 2-chloro-6-fluorobenzyl alcohol
2-chloro-6-fluorobenzaldehyde (10g) and toluene (100g) were added into a 250 ml autoclave, which was flushed two times with hydrogen gas. The Raney nickel (1.2g) was added in the reaction mixture and reaction was heated to 80°C and stirred for 6 hours while maintained the pressure at 10 kg/cm2 using hydrogen gas. After reaction completion, the reaction mass was cooled, and the excess hydrogen gas was vented off. Thereafter, the reaction mass was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to obtain product, fractionally distilled using packed column and isolated 2-chloro-6-fluoro benzyl alcohol.
Yield: 90%; Purity: 99%.
The similar experiment as given in example 1 was carried out for preparation of 2-bromo-6-fluorobenzaldehyde using 2-bromo-6-fluorobenzonitrile. (Yield: 89%)
The similar experiment as given in example 1 was carried out for preparation of 2-bromo-6-chlorobenzaldehyde using 2-bromo-6-chlorobenzonitrile. (Yield: 87%)
The similar experiment as given in example 1 was carried for preparation of 2,6-difluoro-4-chlorobenzaldehyde using 2,6-difluoro-4-chlorobenzonitrile. (Yield: 90%)
The similar experiment as given in example 4 was carried for preparation of 2-bromo-6-fluorobenzyl alcohol using 2-bromo-6-fluorobenzaldehyde. (Yield: 91%).
The similar experiment as given in example 4 was carried for preparation of 2-bromo-6-chlorobenzyl alcohol using 2-bromo-6-chlorobenzaldehyde (Yield: 91.8%)
The similar experiment as given in example 4 was carried for preparation of 2,6-difluoro-4-chlorobenzyl alcohol using 2,6-difluoro-4-chlorobenzaldehyde. (Yield: 89%.

,CLAIMS:

WE CLAIM:
1. A process for preparation of a compound of formula I,

Formula I
wherein X represents halogen, n represents an integer from 1-5,
comprising the steps of,
a) hydrogenating a compound of formula III,

Formula III
wherein X and n' represented as above,
using hydrogen in presence of nickel-aluminum alloy and an acid to obtain a compound of formula II; and

Formula II
wherein X and n represented as above,
b) hydrogenating a compound of formula II, using hydrogen in presence of Raney nickel in a solvent to obtain the compound of formula I.
2. A process for preparation of a compound of formula I,

Formula I
wherein X represents halogen, n represents an integer from 1-5,
comprising a step of hydrogenating a compound of formula II,

Formula II
wherein X and n represented as above,
using hydrogen in presence of Raney nickel in a solvent to obtain the compound of formula I.
3. A process for preparation of a compound of formula II,

Formula II
wherein X and n represented as above,
comprising the step of hydrogenating a compound of formula III,

Formula III
wherein X and n represented as above,
using hydrogen in presence of nickel-aluminum alloy and an acid to obtain a compound of formula II.
4. The process as claimed in claim 1 and 3, wherein the acid is selected from formic acid, acetic acid, propanoic acid, butanoic acid, p-toluene sulfonic acid, methane sulfonic acid, 2-methylsulfonyl acetic acid, benzoic acid, oxalic acid, trichloroacetic acid, sulfurous acid, methanoic acid, benzene sulfonic acid, and trifluoromethane sulfonic acid.
5. The process as claimed in claim 1 and 3, wherein the hydrogenation of compound of formula III using hydrogen in presence of nickel-aluminum alloy is carried out in a solvent, selected from a group consisting of water, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, butanol, tert-butanol, and ethers such as tetrahydrofuran and mixture thereof.
6. The process as claimed in claim 1 and 2, wherein the hydrogenation of compound of formula II using hydrogen in presence of Raney nickel is carried in a solvent, selected from a group consisting of pentane, hexane, heptane, xylene, ethylbenzene, toluene, and mixture thereof.
7. The process as claimed in claim 1 and 2, wherein the step of hydrogenating a compound of formula II using hydrogen in presence of Raney nickel is carried out in a solvent at a temperature selected from 60 to 90°C.
8. The process as claimed in claim 1 and 3, wherein the compound of formula I isolated with a purity in the range of 98 to 99.9% and impurity in the range from 0-0.01%
9. The process as claimed in claim 1, wherein compound of formula I is selected from a group consisting of 2,6-difluorobenzyl alcohol; 2,6-dichlorobenzyl alcohol; 2-chloro-6-fluorobenzyl alcohol; 2,6-dibromobenzyl alcohol; 2-bromo-6-chlorobenzyl alcohol; and 2-bromo-6-fluorobenzyl alcohol.
10. The process as claimed in claim 1, wherein compound of formula II is selected from a group consisting of 2,6-difluorobenzaldehyde; 2,6-dichlorobenzaldehyde; 2-chloro-6-fluorobenzaldehyde; 2,6-dibromobenzaldehyde; 2-bromo-6-chlorobenzaldehyde; and 2-bromo-6-fluorobenzaldehyde.

Dated this 14th day of December 2022.