Description: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 DIFLUORO PROPIONIC ACID AND ITS ESTER DERIVATIVES
This patent application is a modification of the invention filed in Indian patent application No. 201811018180, granted as Indian Patent No. 398135.

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

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

FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and process for preparation of difluoropropionic acid and its ester derivatives.

BACKGROUND OF THE INVENTION
Difluoropropionic acid and its ester derivatives are valuable intermediates in the field of medicine and agricultural chemicals. Furthermore, the difluoropropionic acid and its ester derivatives are used for preparing cyclized product having difluoro group.
Indian Patent No. 398135 (granted to the same applicant) provides a process for preparation of difluoropropionic acid and its ester derivatives using difluoroacetone as a key raw material, which is prepared in moderate yield by the reaction of difluoroacetoester with sulfuric acid. The applicant explored the scope of improving the process for preparation of difluoroacetone to scale up the commercial production of difluoropropionic acid and its ester derivatives.
Bulletin de la Classe des Sciences, Academie Royale de Belgique, Volume15, Pages966-82, Journal 1929, discloses a process for preparation of trifluoroacetone by reacting sodium derivative of trifluoroethyl acetoacetate with 20% sulfuric acid.
Zhurnal Obshchei Khimii, 28, 2288-91; 1958, Syntheses of vinyl monomers. IV. Fluoro acrylates, discloses a process for preparation of difluoroacetone from dichloroacetone using potassium fluoride in diethylene glycol.
Indian Patent No. 335000 discloses a process for preparation of haloketones from keto esters in presence of phosphoric acid. The phosphoric acid is pyrophoric in nature and therefore difficult to handle as well as dispose during commercial scale ups.
Indian Patent No. 398135 granted to the same applicant discloses a process for preparation of difluoroacetone in moderate yields by reacting ethyldifluoroacetoacetate with sulfuric acid. The applicant tried to explore a further improvement in the yield and came up with a modification using a resin that provided better yield and purity of difluoroacetone thereby giving significant cost advantage during commercial scale ups.

OBJECT OF THE INVENTION
The main object of the present invention is to provide simple, cost effective and industrially applicable processes for preparation of difluoroacetone.

SUMMARY OF THE INVENTION
A first aspect of the present invention provides a process for preparation of difluoroacetone by decomposing alkyl difluoroacetoacetate in presence of a resin.
A second aspect of the present invention provides a process for preparation of compound of formula I,

Formula I
wherein R represents alkyl group having 1 to 6 carbon atoms
comprising the step of:
ii) halogenating difluroacetone, to give a compound of formula IV,

Formula IV
wherein X represents halogen independently selected from Cl, Br or I
ii) converting the compound of formula IV to a compound of formula V,

Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms,
iii) reducing the compound of formula V to compound of formula I, wherein the improvement lies in the preparation of difluoroacetone by decomposition of alkyl difluoroacetoacetate in presence of a resin.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “acid” refers to an inorganic acid or an organic acid selected from the group consisting of sulfuric acid (H2SO4), phosphoric acid (H3PO4), hydrochloric acid, methane sulfonic acid (CH3SO3H), p-toluenesulfonic acid, trifluoroacetic acid and the like or mixture thereof.
As used herein, the term “alkyl difluoroacetoacetate” refers to methyl difluoroacetoacetate, ethyl difluoroacetoacetate and isopropyl difluoroacetoacetate, or the like.
In an embodiment of the present invention, the resin is preferably an acidic resin selected from a group consisting of DIAION acidic series such as DIAION PK2201, PK28, RCP145H; DOWEX UPCORE series such as Mono C-600, MC-575, DOWEX 50W; DOWEX MARATHON series such as C, C-10, MSC, Amberlyte IR120, Amberlyte IR100; Acidic amberlyst series such as Amberlyst 15 dry, Amberlyst 35 dry, Amberlyst 17 dry, Amberlyst 45, 46, 19, and salts sulphate thereof.
In another embodiment of the present invention, the step of decomposition of ethyl difluoroaceto acetate is carried out at a temperature of 70 to 110°C.
The acid resin used as catalyst are strongly acidic, cation exchanger and have various advantages such as it can be recycled multiple times without any reprocessing which makes the process more economically viable. The effluent discharge of acidic resin is minimum in the environment due to its high recyclability.
The use of acidic resins eliminates the necessary step of pH adjustment, extraction, removal of inorganic by products and aqueous waste which are essential in conventional means of acidic and basic hydrolysis and decarboxylation.
The halogenating agent selected from chlorine, bromine and iodine and the step of halogenation is performed at a temperature range of 20 to 100°C, preferably at a temperature range of 30 to 70°C and more preferably at a temperature range of 40 to 50°C.
The step of halogenation is carried out in the presence of an acid and solvent selected from water, carbontetrachloride, dichloromethane, toluene, tetrahydrofuran, and the like or mixtures thereof.
The conversion of the compound of formula IV to the compound of formula V is carried out via the steps of hydrolysis and optionally the step of esterification.
The step of hydrolysis is carried out in the presence of a base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or the like at a temperature range of 0 to 50°C.
The step of hydrolysis is preferably carried out at a temperature range of 10 to 20°C.
The step of esterification is carried out using an alcohol in the presence of an acid in a polar solvent selected from water, methanol, ethanol, isopropanol, tertiary butanol, pentanol, acetonitrile, tetrahydrofuran, or the like.
The step of esterification is carried out at a temperature range of 40°C to 100°C, preferably at a temperature range of 50°C to 80°C.
As used herein, the term “reduction” refers to a reaction with a reducing agent selected from triphenylphosphine or chlorodiphenylphosphine in presence of an additive, optionally in presence of a base, in a solvent at a temperature range of 20 to 60°C. The additive is selected from iodine, carbontetraiodide, triiodoimidazole or the like.
The base is an organic base selected from trimethylamine, trimethylamine, tributylamine, pyridine, imidazole, pyrazole, piperidine, or the like.
The solvent for the step of reduction is selected from dichloromethane, toluene, acetonitrile, tetrahydrofuran, or the like.
The step of reduction is preferably carried out at a temperature range of 40 to 50°C.
In another embodiment, the present invention provides a process for preparation of haloketones of formula R1COCH3, wherein R1 is selected from haloalkyl, by decomposing ketoesters of formula R1COCH2COOR2, in presence of a resin, R1 is C1-C3-haloalkyl selected from chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and 1,1,1-trifluoroprop-2-yl; and R2 is C1-C12-alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl, n-pentyl, n-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n-heptyl, n-nonyl, n-decyl, n-undecyl or n-dodecyl and benzyl.
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

Comparative example for Process for preparation of difluoroacetone as provided in Indian Patent Application No. 201811018180
Ethyldifluoroacetoacetate (95 %, 250 g) was added to a mixture of sulfuric acid (98 5%, 53g), and water (105 g) at a temperature of 80 °C. After the addition of ethyldifluoroacetoacetate, the reaction temperature was slowly increased to 90 °C. Mixture of ethanol and product was collected from the top of condenser. When collection of product was stopped, the reaction mass was cooled to 0 °C and concentrated sulphuric acid (98%) was added to reaction mass. The titled compound (93 g, 64%) was isolated by distillation.

EXAMPLE 1 (Improvement using resin): Process for preparation of difluoroacetone
Ethyl difluoroacetoacetate (50 g) was added using dosing pump with 0.7-0.8 g/min to a resin (30 g Amberlyst® 15 resin) and water (10 g) mixture heated at a temperature of 95°C. The reaction proceeded along with evolution of carbon dioxide. After the addition of EDFAA, distillation was continued till the vapour temperature reaches more than 75 °C. Difluoroacetone (88-93%) was collected as a distillate along with 11% ethanol (73% yield).
EXAMPLE 1A (Improvement using resin): Process for preparation of difluoroacetone
Ethyl difluoroacetoacetate (100 g) was added using dosing pump with 0.7-0.8 g/min to a resin (30 g DOWEX 50W resin) and water (10 g) mixture heated at a temperature of 95°C. The reaction proceeded along with evolution of carbon dioxide. After the addition of EDFAA, distillation was continued till the vapour temperature reaches more than 75 °C. Difluoroacetone (88-93%) was collected as a distillate along with 11% ethanol (78% yield).
EXAMPLE 2: Process for preparation of dibromodifluoro acetone
Difluoroacetone (70.5 g) was added to concentrated sulfuric acid (96%, 250g) at a temperature of -10 °C. The temperature of the reaction mixture was raised to 0 °C and bromine (119g) was added. After addition, the reaction mixture was heated at a temperature of 35 °C and was maintained at the same temperature for three hours. Again bromine (25 g) was added, and the reaction mass was further heated to a temperature of 40 °C for 5 hours. The reaction mixture was allowed to settle, and the layers were separated. Dichloromethane (70mL) was added to the product layer and sodium thiosulphate was added to neutralize unreacted bromine. Organic layer was concentrated to get titled compound (158 g; 84 %). The sulphuric acid was recovered and reused in the reaction.
EXAMPLE 3: Process for preparation of difluorolactic acid
A solution of sodium hydroxide (35%) and dibromodifluoro acetone (198g) was added to the reactor at 0 °C to obtain a reaction mixture. The reaction mixture was heated to a temperature of 60 °C for 2 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 1 using an aqueous solution of hydrochloric acid (35%). The reaction mixture was heated at 70-80˚C and concentrated under reduced pressure to distill out water to obtain a residue. Ethanol (350ml) was added to the residue. The resulting mixture was filtered, and filtrate was carried forward for next step.
EXAMPLE 4: Process for preparation of ethyl difluorolactate
Sulphuric acid (98%; 44g) was slowly added to mixture of difluorolactic acid (example 3) in ethanol (500ml) at a temperature of about 0˚C. The reaction mixture was heated to a temperature of 80˚C for 2 hours. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mixture was allowed to cool to room temperature. Dichloromethane (200ml) and water (200ml) was added the reaction mixture. The reaction mixture was allowed to settle, and the layers were separated. The aqueous layer was washed with dichloromethane (50ml). The organic layers were combined and concentrated at a temperature of 50-60˚C to get the titled product (51g; 42%).
EXAMPLE 5: Process for preparation of ethyl difluoropropionate
A solution of iodine (5%; 37g) in dichloromethane (700ml) was slowly added to a solution of ethyl difluorolactate (22.8g), triphenyl phosphine (50.1g) and imidazole (15g) in dichloromethane (150ml) at a temperature of about -30˚C. The reaction mixture was stirred for one hour at the same temperature. The progress of the reaction was monitored by gas chromatography. After completion of the reaction the mixture was concentrated at 50-60˚C to recover about 80% of dichloromethane. Hexane (400ml) was added to the residue to precipitate out the titled compound. The mixture was filtered and washed with hexane (100ml) to get the titled product (51g; 42%). The filtrate was also concentrated, washed and filtered to get the titled product.
EXAMPLE 6: Process for preparation of methyl difluorolactate
Sulphuric acid (98%; 311g) was slowly added to mixture of difluorolactic acid (example 3) in methanol (1292 ml) at a temperature of about 20-25˚C. The reaction mixture was heated to a temperature of 80˚C for 7-8 hours. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mixture was allowed to cool to room temperature and half quantity of methanol (575ml) was distilled off. Dichloromethane (200ml) and water (200ml) was added the reaction mixture. The reaction mixture was allowed to settle and the layers were separated. The organic layers were combined and concentrated at a temperature of 50-60˚C to get the crude product. Pure product was isolated by fractional distillation on 1 feet column (GC purity:>99%, Yield: 50-55%).
EXAMPLE 7: Process for preparation of methyl difluoropyruvate
A solution of sodium hypochlorite (11%, 552g) was added to a mixture of methyl fluoroacetate (100g) and tetra n-butyl ammonium hydrogen sulphate(15g) in ethylacetate (300g) at a temperature of 0-5˚C. Reaction mixture was stirred for 2 hours at 0-5˚C. Reaction mixture was quenched using aqueous sodium thiosulphate solution at 0-5˚C and allowed to settle layers. The organic layer was concentrated to get the crude product. Pure product was isolated by fractional distillation of in the presence of phosphorous pentoxide. (Yield: 40-50%, Purity: >98%).
EXAMPLE 8: Process for preparation of Methyl difluoropropionate
Methyl difluorolactate (40g) was added to a mixture of iodine (80g) ,triphenyl phosphine(188g) and dichloromethane (266g) at a temperature of 10 ˚C. The reaction mixture was heated to 50 ˚C for 3 hours. After completion of reaction, the reaction mixture was concentrated to recover dichloromethane at 50-60 ˚C, followed by distillation at 110 ˚C to get the titled product (Yield: 90%, Purity:>99%). , C , Claims:WE CLAIM:
1. A process for preparation of compound of formula I,

Formula I
wherein R represents alkyl group having 1 to 6 carbon atoms
comprising the step of:
i) halogenating difluoroacetone to give a compound of formula IV;

Formula IV
wherein X represents halogen independently selected from Cl, Br, or I
ii) converting the compound of formula IV to a compound of formula V,

Formula V
wherein R represents hydrogen; alkyl group having 1 to 6 carbon atoms
iii) reducing the compound of formula V to compound of formula I, wherein the improvement lies in the preparation of difluoroacetone by decomposition of alkyl difluoroacetoacetate in presence of a resin.
2. A process for preparation of difluoroacetone, comprising a step of decomposition of alkyl difluoroacetoacetate in presence of a resin.
3. The process as claimed in claim 1, wherein the resin is an acidic resin selected from a group consisting of DIAION acidic series such as DIAION PK2201, PK28, RCP145H; DOWEX UPCORE series such as Mono C-600, MC-575; DOWEX MARATHON series such as C, C-10, MSC, Amberlyte IR120, Amberlyte IR100; Acidic amberlyst series such as Amberlyst 15 dry, Amberlyst 35 dry, Amberlyst 17 dry, Amberlyst 45, 46, 19, and salts sulphate thereof.
4. The process as claimed in claim 1, wherein the step of decomposition of alkyl difluoroacetoacetate is carried out at a temperature of 70 to 110°C.
5. The process as claimed in claim 1, wherein halogenation is carried out using bromine in the presence of sulfuric acid.
6. The process as claimed in claim 1, wherein conversion of the compound of formula IV to the compound of formula V comprises a step of hydrolysis.
7. The process as claimed in claim 1, wherein reduction is carried out using a reducing agent, selected from triphenylphosphine or chlorodiphenylphosphine.

8. The process as claimed in claim 1, reduction is carried out in presence of an additive, selected from a group consisting of iodine, carbon tetraiodide or, triiodo imidazole.

Dated this 24th day of July, 2023.