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

PROCESS FOR THE PREPARATION OF PYRIDINE CARBOXALDEHYDES AND INTERMEDIATES THEREOF

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

The following specification describes the invention.

FIELD OF THE INVENTION
The present invention provides a process for preparation of pyridine carboxaldehydes and intermediates thereof.

BACKGROUND OF THE INVENTION
The present invention provides a process for preparation of pyridine carboxaldehydes and intermediates thereof.
Pyridine carboxaldehydes such as 5-halo-3-pyridinecarboxaldehyde are important intermediates used in synthesis of various pharmaceuticals and agrochemicals.
There are several methods known in the art for preparation of pyridine carboxaldehydes and intermediates thereof.
European Patent No. 210782 discloses a process for preparation of pyridinecarboxaldehyde using hydrazine monohydrate, p-toluenesulfonyl chloride in presence of pyridine followed by treatment with sodium carbonate at 160°C.
The above process is very tedious and uses expensive raw material like nicotinate, hydrazine monohydrate and pyridine. Also, hydrazine monohydrate and pyridine are toxic in nature.
PCT Publication No. 2004009552 discloses a process for preparation of pyridinecarboxaldehyde using Diisobutylaluminium hydride in presence of toluene at -78°C to obtain crude product. The crude product is purified by eluting with 20%-35% ethyl acetate in hexanes.
It uses expensive raw materials and reagents like nicotinate and Diisobutylaluminium hydride. The process is using hazardous reagents like Diisobutylaluminium hydride and hexane. Diisobutylaluminium hydride need special attention of handling and react violently with water and air. Hexane is highly flammable. The temperature condition of -78? is harsh too. The process is not industrially feasible.
U.S. Patent No. 3637714 discloses a process for preparation of pyridinecarboxaldehyde using lead tetraacetate. The use of toxic reagent i.e., lead tetraacetate is not recommended at commercial scale.
J. Org. Chem. 1988,53, 3513-3521 discloses a process for preparation of pyridinecarboxaldehyde by oxidation of corresponding pyridinemethanol.
Thus, there is a need to develop an alternate process to produce halo substituted pyridinecarboxaldehyde and its intermediate to overcome the drawbacks of the processes known in the art.
Surprisingly, the inventors of present invention found that halo substituted pyridinecarboxaldehyde can be prepared using novel compounds i.e., halo substituted dihalomethyl pyridines.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a simple, safe, and commercially viable process for preparation of halo substituted pyridinecarboxaldehyde and intermediate thereof in good yield and purity.

SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for preparation of a compound of formula I, comprising the step of:

Formula I
wherein X1 is halogen or hydrogen,
hydrolyzing a compound of formula II to obtain the compound of formula I.

Formula II
wherein X1 is halogen or hydrogen; X2, X3 and X4 are independently selected from hydrogen and halogen, provided that at least two of X2, X3 and X4 are halogen.
In another aspect, the present invention provides a compound of formula IIa,

Formula IIa
wherein X1 is halogen; X2, X3 and X4 are independently selected from hydrogen and halogen, provided that at least two of X2, X3 and X4 are halogen.

DETAILED DESCRIPTION OF THE INVENTION
As disclosed herein, the compound of formula I refers to halosubstituted or unsubstituted pyridine carboxaldehyde selected from a group consisting of 5-fluoro-3-pyridinecarboxaldehyde, 5-chloro-3-pyridinecarboxaldehyde, 5-bromo-3-pyridinecarboxaldehyde and 5-iodo-3-pyridinecarboxaldehyde, pyridinecarboxaldehyde.
As disclosed herein, the compound of formula II refers to 3-fluoro-5-difluoromethyl pyridine, 3-fluoro-5-dichloromethyl pyridine, 3-fluoro-5-dibromomethyl pyridine, 3-fluoro-5-diiodomethyl pyridine, 3-bromo-5-dichloromethyl pyridine, 3-bromo-5-dibromomethyl pyridine, 3-bromo-5-diiodomethyl pyridine, 3-bromo-5-difluoromethyl pyridine, 3-chloro-5-dichloromethyl pyridine, 3-chloro-5-dibromomethyl pyridine, 3-chloro-5-diiodomethyl pyridine, 3-chloro-5-difluoromethyl pyridine, 3-iodo-5-dichloromethyl pyridine, 3-iodo-5-dibromomethyl pyridine, 3-iodo-5-diiodomethyl pyridine, 3-iodo-5-difluoromethyl pyridine, 3-difluoromethyl pyridine, 3-dichloromethyl pyridine, 3-dibromomethyl pyridine.
As disclosed herein, the compound of formula II also refers to 4-fluoro-5-difluoromethyl pyridine, 4-fluoro-5-dichloromethyl pyridine, 4-fluoro-5-dibromomethyl pyridine, 4-fluoro-5-diiodomethyl pyridine, 4-bromo-5-dichloromethyl pyridine, 4-bromo-5-dibromomethyl pyridine, 4-bromo-5-diiodomethyl pyridine, 4-bromo-5-difluoromethyl pyridine, 4-chloro-5-dichloromethyl pyridine, 4-chloro-5-dibromomethyl pyridine, 4-chloro-5-diiodomethyl pyridine, 4-chloro-5-difluoromethyl pyridine, 4-iodo-5-dichloromethyl pyridine, 4-iodo-5-dibromomethyl pyridine, 4-iodo-5-diiodomethyl pyridine, 4-iodo-5-difluoromethyl pyridine.
As disclosed herein, the compound of formula II also includes the respective compounds of formula IIa, IIb and IIc. The compound of formula III, IV and V also includes the respective compounds of formula IIIc, IVc and Vc.
As used herein, the halo group refers to Cl, Br, I and F.
In an aspect, the present invention provides a process for preparation of a compound of formula I by hydrolyzing a compound of formula II.
In an embodiment, the hydrolysis is carried out using an acid selected from a group consisting of hydrochloric acid, acetic acid, nitric acid, phosphoric acid, trifluoro acetic acid, concentrated sulfuric acid and a mixture thereof at a temperature selected in the range of 90-140?. During hydrolysis, hydrogen halide gas was liberated which was scrubbed using caustic solution.
In a specific embodiment, the present invention provides a process for preparation of 5-fluoro-3-pyridinecarboxaldehyde by hydrolysis of 3-fluoro-5-dichloromethyl pyridine.
In an embodiment, the compound of formula I is obtained with a yield of more than 90%, preferably more than 92% and a purity (by liquid chromatography) of more than 99%.
In an embodiment, the present invention provides a process for preparation of a compound of formula II, comprising the step of:

Formula II
halogenating a compound of formula III to obtain the compound of formula II,

Formula III
wherein X1 is halogen or hydrogen.
In an embodiment, the compound of formula III is treated with a halogenating agent in presence of a solvent and a catalyst.
In an embodiment, the halogenating agent is selected from a group consisting of chlorine, trichloroisocyanuric acid, mixture of hydrochloric acid and hydrogen peroxide, N-chlorosuccinimide.
In another embodiment, the solvent for halogenation is selected from the group consisting of benzotrifluoride, monochlorobenzene and dichlorobenzene.
In another embodiment, the halogenation can be carried out without using any solvent.
In another embodiment, the catalyst for chlorination is selected from the group consisting of 2,2'-azobis(isobutyronitrile), benzamide, azobisdimethylvaleronitrile, benzoyl peroxide and hydrogen peroxide.
In an embodiment, the halogenation using halogenating agent is performed by illuminating a reaction mixture comprising a compound of formula III using 70-125W UV light, tungsten lamp at a temperature selected in the range of 100-150?.
In another aspect, the present invention provides a compound of formula IIb,

Formula IIb
wherein X1 is halogen.
In another aspect, the present invention provides a compound of formula IIc,

Formula IIc
wherein X1 is halogen.
In another specific embodiment, the present invention provides 5-fluoro-3-dichloromethyl pyridine.
In another specific embodiment, the present invention provides 4-fluoro-3-dichloromethyl pyridine.
In a specific embodiment, the present invention provides a process for preparation of 3-fluoro-5-dichloromethyl pyridine by chlorination of 3-fluoro-5-methyl pyridine.
In an embodiment, the present invention provides a process for preparation of compound of formula IIIc, comprising the step of:

Formula IIIc
wherein X1 is halogen;
treating a compound of formula IVc

Formula IVc
with hydrogen halide and a nitrite or nitrosyl sulfuric acid.
In another embodiment, the present invention provides a process for preparation of formula IIIc by reaction of compound of formula IVc with a mixture of hydrogen halide and a compound selected from a group consisting of sodium nitrite, potassium nitrite, n-butyl nitrite, tertbutyl nitrite and amyl nitrite; mixture of nitrosyl sulfuric acid and hydrogen halide.
In a specific embodiment, the present invention provides a process for preparation of 3-fluoro-5-methyl pyridine by reaction of 3-amino-5-methyl pyridine with a mixture of hydrofluoric acid and sodium nitrite.
In an embodiment, the mole equivalents of anhydrous hydrohalic acid are used in the range from 5 to 15, preferably 8-10 w.r.t. 3-amino-5-methyl pyridine.
The anhydrous hydrohalic acid are hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, wherein hydrogen fluoride, hydrogen chloride, hydrogen bromide are used in gaseous form and hydrogen iodide is used as liquid.
In an embodiment, the 3-amino-5-methyl pyridine is first treated with hydrohalic acid at 0-5? followed by sodium nitrite addition and mixture was heated to 20-30°C to produce 3-halo-5-methyl pyridine.
In a specific embodiment, the 3-amino-5-methyl pyridine is first treated with hydrofluoric acid at -5 to 15? and followed by addition of sodium nitrite and then heated to 20-50? for the decomposition.
In an embodiment, the present invention provides a process for preparation of compound of formula IVc by reduction of compound of formula Vc using a catalyst selected from a group consisting of Raney-Ni, Aluminum-Nickel alloy, iron-nickel, and nickel supported with silica or alumina.

Formula Vc
In another embodiment, the present invention provides a process for preparation of 3-amino-5-methyl pyridine by reduction of 3-methyl-5-nitro pyridine using a catalyst in presence of an alcohol solvent such as methanol, ethanol, propanol, isopropyl alcohol, butanol and tert-butanol or the like, an ester such as methyl acetate, methyl propionate, ethyl acetate, ethyl propionate, isopropyl acetate, n-propyl acetate, n-butyl acetate, propyl formate, tetrahydrofuran, 1,4-dioxane and cyclohexane or a mixture thereof.
In an embodiment, the reduction is carried out at a temperature selected in the range of 20-65? and at a pressure selected in the range of 0.1 to 10 bar.
In an embodiment, the present invention provides a process for preparation of a compound of formula Ia, comprising the step of:

Formula Ia
wherein X1 is halogen;
hydrolyzing a compound of formula IIa to obtain the compound of formula Ia.

Formula IIa
wherein X1 is halogen or hydrogen; X2, X3 and X4 are independently selected from hydrogen and halogen, provided that at least two of X2, X3 and X4 are halogen.
In another aspect, the present invention provides a process for preparation of a compound of formula IIa, comprising the step of:

Formula IIa
halogenating a compound of formula IIIa to obtain the compound of formula IIa,

Formula IIIa
wherein X1 is halogen or hydrogen.
In another aspect, the present invention provides a process for preparation of 3-halo-5-methyl pyridine compound of formula IIIa, comprising the step of:

Formula IIIa
wherein X1 is halogen or hydrogen;
treating 3-amino-5-methyl pyridine using hydrogen halide and sodium nitrite.
The present invention for preparation of the compounds of formulae I, II, III and IV has following advantages over the known methods:
The present invention uses relatively inexpensive raw materials and reagent, using minimum no. of solvents in the process, relatively safer process and simpler procedure to meet the need of scale-up.
In another embodiment, the solvent used in the reaction are recovered, recycled and reused.
As used herein, the starting material 3-methylpyridine may be prepared by any method known in the art or may be obtained commercially.
In an embodiment, the conversion of compound of formula V to compound of formula I is carried out in-situ without isolating any intermediate (compound of formula IV, III and II) in-between.
In another embodiment, the compounds of formula I, II and III are isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
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: Hydrolysis of 3-Fluoro-5-(dichloromethyl) pyridine to produce 5-fluoro-3-pyridinecarboxaldehyde using sulphuric acid.
To a one litre four-necked flask equipped with a stirrer and a thermometer, concentrated sulfuric acid (50g) was charged followed by slow addition of 3-fluoro-5-dichloromethyl pyridine (10g) into the flask and the temperature was slowly raised to 90-110°C. When the temperature reached to 90°C, hydrogen chloride gas began to release, which was introduced into the caustic scrubber solution. The reaction progress was checked after quenching the reaction mixture in ice-cold water and was extracted with dichloromethane, the bottom organic phase was checked on gas chromatography till 3-Fluoro-5-(dichloromethyl) pyridine was less than 0.5%. The reaction solution was cooled to 30°C and was slowly added to ice water. The product was precipitated, filtered, washed with water and dried at 50°C under reduced pressure to obtain desired product (5.4g).
Purity (liquid chromatography): 99.0%; Yield: 92%.
Example 2: Hydrolysis of 3-fluoro-5-(dichloromethyl) pyridine to produce 5-fluoro-3-pyridinecarboxaldehyde using conc. hydrochloric acid
To a one litre four-necked flask equipped with a stirrer and a thermometer, concentrated hydrochloric acid (35g) was charged followed by slow addition of 3-fluoro-5-dichloromethyl pyridine (5g) into the flask and the temperature was slowly raised to 90-95°C. The reaction progress was checked after quenching the reaction mixture in ice-cold water and was extracted with dichloromethane, the bottom organic phase was checked on gas chromatography till 3-fluoro-5-(dichloromethyl) pyridine was less than 1%. The reaction solution was cooled to 30°C and was slowly added to ice water. The product was precipitated, filtered, washed with water and crystallized from dichloromethane, filtered, dried at 50°C under reduced pressure to obtain desired product (2.88g).
Purity (liquid chromatography): 98.2%; Yield: 83%.
Example 3: Chlorination of 3-fluoro-5-methyl pyridine to produce 3-Fluoro-5-(dichloromethyl) pyridine
To a 100ml glass reactor, 3-fluoro-5-methyl pyridine (10g, 0.09mol) and benzotrifluoride (53g) were charged and the mixture was heated to 105°C followed by addition of 2,2'-azobis(isobutyronitrile) catalyst (0.14g). The reaction mixture was illuminated using a tungsten light and chlorine gas was bubbled slowly into the mixture for 7-8 hours at 105°C. The reaction progress was checked by gas chromatography till 3-fluoro-5-methyl pyridine was less than 0.5%. The reaction mixture was taken for complete removal of benzotrifluoride to leave bottom product i.e., 3-Fluoro-5-(dichloromethyl) pyridine with purity 91.8%.
Yield: 88%
Example 4: Chlorination of 4-fluoro-5-methyl pyridine to produce 4-Fluoro-5-(dichloromethyl) pyridine
To a 100ml glass reactor, 4-fluoro-5-methyl pyridine (10g, 0.09mol) and benzotrifluoride (51g) were charged and the mixture was heated to 106°C followed by addition of 2,2'-azobis(isobutyronitrile) catalyst (0.15g). The reaction mixture was illuminated using a tungsten light and chlorine gas was bubbled slowly into the mixture for 7-9 hours at 105°C. The reaction progress was checked by gas chromatography till 4-fluoro-5-methyl pyridine was less than 0.4%. The reaction mixture was taken for complete removal of benzotrifluoride to leave bottom product i.e., 4-Fluoro-5-(dichloromethyl) pyridine with purity 94.2%.
Yield: 90%
Example 5: Chlorination of 3-fluoro-5-methyl pyridine to produce 3-Fluoro-5-(trichloromethyl) pyridine
To a 100ml UV reactor, 3-fluoro-5-methyl pyridine (10g, 0.09mol) and benzotrifluoride (53g) were charged and the mixture was heated to 105°C followed by addition of 2,2'-azobis(isobutyronitrile) catalyst (0.07g). The reaction mixture was illuminated using a 125W UV light and chlorine gas was bubbled slowly into the mixture for 10-12 hours at 105°C. The reaction progress was checked by gas chromatography till 3-fluoro-5-methyl pyridine was less than 0.5%. The reaction mixture was taken for complete removal of benzotrifluoride to leave bottom product i.e., 3-Fluoro-5-(trichloromethyl) pyridine.
Yield: 89%, Purity: 94%
Example 6: Diazotization and fluorination of 3-Amino-5-methyl pyridine to produce 3-Fluoro-5-methyl pyridine
To a 250ml pressure reactor, anhydrous hydrofluoric acid (44g, 2.2mol) was charged followed by slow addition of 3-Amino-5-methyl pyridine (21g, 0.19mol) at 0-5°C and stirred for 30minutes at 0-5°C followed by addition of sodium nitrite (15g, 0.22mol) at 0-5°C in 1.0 hour and the mixture was maintained for 1 hour at 0-5°C. The mixture was slowly heated to 20-35°C over a range of 1 hour. The mixture was added slowly into cold water (200g) followed by neutralization and the mixture was extracted using dichloromethane twice. The organic phase was taken for complete solvent removal at 50°C to get crude 3-fluoro-5-methyl pyridine (20.38g)
Yield: 85%; Purity 90%
Example 7: Reduction of 3-methyl-5-nitro pyridine to produce 3-amino-5-methyl pyridine using methanol solvent.
3-methyl-5-nitropyridine (40g, 0.287 mole), Raney-Ni catalyst (2.55g, 0.04 mole) and methanol (360g, 9.20 mole) were taken sequentially in a pressure reactor at 20-30°C. The reaction mass was flushed with nitrogen pressure followed by hydrogen pressure and then reaction mixture was heated to 50°C, and pressurized with 5 bar hydrogen gas pressure for 2-3 hours. The reaction progress was monitored by gas chromatography. On getting 3-methyl-5-nitropyridine less than 0.5%, the reactor was depressurized and flushed with nitrogen. The reaction mass was filtered through hyflo bed and the residue was washed with methanol-water mixture and the combined mother liquor was concentrated to dryness at 55°C under vacuum to get 3-amino-5-methyl pyridine (29.7g).
Purity: 98.5%; Yield: 95%
Example 8: Reduction of 3-methyl-5-nitro pyridine to produce 3-amino-5-methyl pyridine in ethyl acetate solvent
3-methyl-5-nitropyridine (10g, 0.072 mole), Raney-Ni catalyst (0.637g, 0.01 mole) and ethyl acetate (100g, 1.12 mole) were taken sequentially in a pressure reactor at 20-30°C. The reaction mass was flushed with nitrogen pressure followed by hydrogen pressure and then reaction mixture was heated to 50°C, and pressurized with 5 bar hydrogen gas pressure for 3 hours. The reaction progress was monitored by gas chromatography. On getting 3-methyl-5-nitropyridine less than 0.5%, the reactor was depressurized and flushed with nitrogen. The reaction mass was filtered through hyflo bed and the residue was washed with ethyl acetate followed by water and the combined mother liquor was concentrated to dryness at 55°C under vacuum to get 3-amino-5-methyl pyridine (7.2g).
Purity: 98.1%; Yield: 92%
Example 9: Nitration of 3-methylpyridine to produce 3-methyl-5-nitro pyridine
In a 500ml round bottom flask, Trifluoroacetic anhydride (172g, 0.806 mol) was charged and cooled to 5°C followed by slow addition of 3-methyl pyridine (30g, 0.32 mol) at 0-5°C. After complete addition of 3-methyl pyridine, the mixture was stirred for 45-60 minute followed by the dropwise addition of concentrated nitric acid (52g, 0.70mol) at 0-5°C. After stirring for 2-3 hours., the solution was added slowly into cooled aqueous solution of sodium metabisulfite (0.32 mol). After 2 h, the pH of the mixture was adjusted to 6–7 by slowly adding 48% NaOH solution. The mixture was filtered to get wet solid and aqueous mother liquor. The wet cake was washed with water. The wet cake was dried at 50-60°C and pressure was reduced to get dried 3-methyl-5-nitro pyridine (27g).
Purity: 99%, yield: 60%

ABSTRACT
PROCESS FOR THE PREPARATION OF PYRIDINE CARBOXALDEHYDES AND INTERMEDIATES THEREOF
The present invention provides a process for preparation of pyridine carboxaldehydes using novel compounds and intermediates thereof. Pyridine carboxaldehydes and their intermediates are important precursors in the field of pharmaceuticals and agrochemicals.

,CLAIMS:
WE CLAIM:
1. A process for preparation of a compound of formula I, comprising the step of:

Formula I
wherein X1 is halogen or hydrogen;
hydrolyzing a compound of formula II to obtain the compound of formula I.

Formula II
wherein X1 is halogen or hydrogen; X2, X3 and X4 are independently selected from hydrogen and halogen, provided that at least two of X2, X3 and X4 are halogen.
2. The process as claimed in claim 1, wherein the compound of formula II is prepared by a process comprising the step of:

Formula II
halogenating a compound of formula III to obtain the compound of formula II,

Formula III
wherein X1 is halogen or hydrogen.
3. The process as claimed in claim 1, wherein the hydrolysis is carried out using an acid selected from a group consisting of hydrochloric acid, acetic acid, nitric acid, phosphoric acid, trifluoro acetic acid, concentrated sulfuric acid and a mixture thereof.
4. The process as claimed in claim 2, wherein the halogenating agent is selected from a group consisting of chlorine, trichloroisocyanuric acid, mixture of hydrochloric acid and hydrogen peroxide, N-chlorosuccinimide.
5. The process as claimed in claim 2, wherein the catalyst for halogenation is selected from the group consisting of 2,2'-azobis(isobutyronitrile), benzamide, azobisdimethylvaleronitrile, benzoyl peroxide and hydrogen peroxide.
6. The process as claimed in claim 2, wherein the halogenation using halogenating agent is performed by illuminating a reaction mixture comprising a compound of formula III using 70-125W UV light, tungsten lamp.
7. The process as claimed in claim 2, wherein the compound of formula III is prepared by a process comprising the step of:

Formula IIIc
wherein X1 is halogen;
treating a compound of formula IVc

Formula IVc
with hydrogen halide and a nitrite or nitrosyl sulfuric acid.
8. The process as claimed in claim 7, wherein the reaction is carried out using hydrogen halide and a compound selected from a group consisting of sodium nitrite, potassium nitrite, n-butyl nitrite, tertbutyl nitrite and amyl nitrite, nitrosyl sulfuric acid.
9. The process as claimed in claim 7, wherein the hydrogen halide is selected from a group consisting of hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide.
10. A compound of formula II,

Formula II
wherein X1 is halogen; X2, X3 and X4 are independently selected from hydrogen and halogen, provided that at least two of X2, X3 and X4 are halogen.

Dated this 23rd day of Sep 2024.