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 AMINO CROTONATES”

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 invention relates to a process for the preparation of amino crotonates, particularly halogenated amino crotonates.

BACKGROUND OF THE INVENTION
Amino crotonates are useful as intermediates for agricultural chemicals, particularly herbicides. These compounds are also of interest since they find use as intermediates for the synthesis of calcium channel blockers such as nisoldipine, benidipine, nicardipine, in purification of various metals and as a catalyst for polymerization. Several methods are known in the art for the preparation of these compounds.
Japanese Patent Publication No. 06321877 discloses a process for preparation of 3-amino-4,4,4-trifluorocrotonates by reacting alkyl 4,4,4-trifluoroacetoacetate with an amine in a solvent in the presence of a fatty acid.
European Patent Publication No. 0808826 discloses a process for preparation of 3-amino-4,4,4-trifluorocrotonates by refluxing a mixture of ethyl 4,4,4-trifluoroacetoacetate in ethanol with ammonium acetate for about 10 hours.
The conventional processes are tedious, time consuming and involve the use of solvent resulting in effluent generation that adds to the cost of running the process at commercial scale.
European Patent Publication No. 2702035 provides a continuous process for preparation of beta amino crotonate by reacting ketonic ester with a base optionally in presence of an organic solvent and an acid catalyst at a temperature range of 20-60?.
There is no prior art disclosing a continuous flow synthesis process of halogenated amino crotonates, that provides high yield and overcomes cited challenges.
The present invention overcomes the challenges of prior art and provides a yield selective, commercially feasible and a continuous process for preparation of halogenated amino crotonates.

OBJECT OF THE INVENTION
The object of the present invention is to provide a continuous process for the preparation of halogenated amino crotonates. The present invention process is continuous, commercially feasible, cost-effective and provides good yields.

SUMMARY OF THE INVENTION
The present invention provides a continuous process for preparation of halogenated amino crotonates, comprising the step of reacting a halogenated acetoacetate with a base in the presence of an acid.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “halogenated amino crotonates” particularly refers to “halogenated beta amino crotonate’ substituted with amino at beta-position and halogen in the carbon chain. The “amino” group substituted at beta position may be substituted with alkyl, cycloalkyl or aryl optionally substituted with halogen, hetero atom or alkyl group. The amino crotonate refers to an ester form and ester is formed using alkyl group.
As used herein, “alkyl” group refers to any carbon chain from C1-C6, “cycloalkyl” of C1-C6 carbon chain such as cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, or “aryl” group such as phenyl, pyridyl or the like and “halogen” such as chloro, fluoro, and bromo or the like.
The “halogenated beta amino crotonates” are selected from a group comprising ethyl 3-amino-4,4,4-trifluorocrotonate, ethyl 3-amino-4,4-difluorocrotonate, ethyl 3-amino-4-fluorocrotonate, methyl 3-amino-4,4,4-trifluorocrotonate, methyl 3-amino-4,4-difluorocrotonate, methyl 3-amino-4-fluorocrotonate, ethyl 3-amino-4,4,4-trichlorocrotonate, ethyl 3-amino-4,4-dichlorocrotonate, ethyl 3-amino-4-chlorocrotonate, methyl 3-amino-4,4,4-trichlorocrotonate, methyl 3-amino-4,4-dichlorocrotonate, methyl 3-amino-4-chlorocrotonate, propyl 3-amino-4,4,4-trifluorocrotonate, propyl 3-amino-4,4-difluorocrotonate, propyl 3-amino-4-fluorocrotonate, propyl 3-amino-4,4,4-trichlorocrotonate, propyl 3-amino-4,4-dichlorocrotonate, propyl 3-amino-4-chlorocrotonate, methyl 3-amino-4,4,4-chlorodifluorocrotonate, ethyl 3-amino-4,4,4-chlorodifluorocrotonate, methyl 3-amino-4,4,4-dichlorofluorocrotonate, ethyl 3-amino-4,4,4-dichlorofluorocrotonate, methyl 3-amino-4,4-chlorofluorocrotonate, ethyl 3-amino-4,4-chlorofluorocrotonate, methyl 3-(methylamino)-4,4,4-trifluorocrotonate, ethyl 3-(methylamino)-4,4,4-trifluorocrotonate, methyl 3-(ethylamino)-4,4,4-trifluorocrotonate, ethyl 3-(ethylamino)-4,4,4-trifluorocrotonate, ethyl 3-(4-anilino)-4-chlorocrotonate, ethyl 3-(cyclopropylamino)-4,4,4-trifluorocrotonate, ethyl 3-(cyclopropylamino)-4,4,4-dichlorofluorocrotonate, and ethyl 3-(4-fluorophenyl)amino-4,4,4-fluoroacetoacetate or the like.
In an embodiment, the “halogenated acetoacetate” refers to acetoacetate substituted with halogen and halogen is selected from chloro, fluoro, and bromo. The “halogenated acetoacetate” also refers to “ester of halogenated acetoacetate”.
The “ester of halogenated acetoacetate or halogenated acetoacetate” are selected from a group comprising ethyl 4,4,4-trifluoroacetoacetate, ethyl 4,4-difluoroacetoacetate, ethyl 4-fluoroacetoacetate, methyl 4,4,4-trifluoroacetoacetate, methyl 4,4-difluoroacetoacetate, methyl 4-fluoroacetoacetate, ethyl 4,4,4-trichloroacetoacetate, ethyl 4,4-dichloroacetoacetate, ethyl 4-chloroacetoacetate, methyl 4,4,4-trichloroacetoacetate, methyl 4,4-dichloroacetoacetate, methyl 4-chloroacetoacetate, propyl 4,4,4-trifluoroacetoacetate, propyl 4,4-difluoroacetoacetate, propyl 4-fluoroacetoacetate, propyl 4,4,4-trichloroacetoacetate, propyl 4,4-dichloroacetoacetate, propyl 4-chloroacetoacetate, methyl 4,4,4-chlorodifluoroacetoacetate, ethyl 4,4,4-chlorodifluoroacetoacetate, methyl 4,4,4-dichlorofluoroacetoacetate, ethyl 4,4,4-dichlorofluoroacetoacetate, methyl 4,4-chlorofluoroacetoacetate, and ethyl 4,4-chlorofluoroacetoacetate, or the like.
In an embodiment, the present invention provides a continuous process for preparation of halogenated amino crotonates, comprising the step of reacting a halogenated acetoacetate with a base in the presence of an acid.
In an embodiment, the present invention provides a continuous process for preparation of halogenated beta amino crotonates, comprising the step of reacting an acetoacetate with a base in the presence of an acid.
In an embodiment, the present invention provides a continuous process for preparation of halogenated amino crotonates, comprising the step of reacting a halogenated acetoacetate with a salt.
In an embodiment, “salt” may be prepared by reacting a base with an acid. The salt can be prepared in-situ in the reaction or can be made separately.
In another embodiment, the present invention provides a continuous process for preparation of halogenated beta amino crotonate by reacting halogenated acetoacetate with a salt, wherein salt is prepared by reacting a base and acid in a separate continuous reactor.
The base is selected a group comprising of ammonia, amines, particularly, primary and secondary amine selected from alkyl amine such as methylamine, ethylamine, tertiary butylamine, butyl amine, propyl amine, dimethylamine, diethylamine, ethylmethylamine, cyclic amine such as cyclopropyl amine, cyclohexyl amine, and cyclopentyl amine or the like, aniline, substituted anilines such as alkylated or halopgenated aniline such as 4-fluoroaniline, 4-chloroaniline, and 4-methylaniline or the like.
The base may be used in aqueous solution, organic solution or pure form thereof.
In an embodiment, the present invention is using base is in pure form.
In an embodiment, the molar ratio of base w.r.t halogenated acetoacetate is selected from the range 1-3.
In an embodiment, acid used in the present invention is selected from a group comprising formic acid, acetic acid, n-propanoic acid, iso-propanoic acid, and butanoic acid or the like.
In an embodiment, the molar ratio of acid w.r.t halogenated acetoacetate is selected from the range 0.2 to 0.8.
In an embodiment, the halogenated acetoacetate is used in the form of solution, wherein solution is made in the acid. The concentration of acid in the solution is in the range from 5-25%.
In an embodiment, the acid used in the present invention is recycled and generate no effluent in the process.
In an embodiment, the acid used in the present invention is recycled and pumped in reaction reactor.
In another embodiment, the step of reaction of halogenated acetoacetate with a base in the presence of an acid is carried out at a temperature range from 60-150°C.
In preferred embodiment, the step of reaction of halogenated acetoacetate with base is carried out in presence of acid and in absence of any solvent.
In another embodiment, the step of reaction of acetoacetate with a base is carried out in the presence of an acid in a solvent, wherein solvent is acid.
In another embodiment, the step of reaction of halogenated acetoacetate with salt is carried out in presence of solvent. The solvent is selected from a group consisting of alcohol such as methanol, ethanol, propanol, 2-propanol, hydrocarbon like cyclohexane, toluene, ethers like diethyl ether, methyl ether, and tetrahydrofuran or the like.
In another embodiment, the step of reaction of ester of halogenated acetoacetate with base in the presence of acid is carried out with residence time of 1 minutes to 5 hours.
In another embodiment, the reaction of halogenated acetoacetate with a salt is carried out at a temperature of 60-150°C.
In yet another embodiment of the present invention, ratio of salt to said ester is 1-2 and preferably 0.2 to 0.8.
In another embodiment, the present invention also provides a continuous process for preparation of halogenated beta amino crotonates, comprising the step of reacting an halogenated acetoacetate with a base in the presence of an acid, wherein process is carried out in absence of solvent.
In an embodiment, the present invention continuous process is carried out in a continuous stirred tank reactor (CSTR), tubular reactor, flow reactor or combination thereof.
In an embodiment, the present invention is preparing halogenated amino crotonate, wherein multiple reactors or their combination thereof are used.
In an embodiment, the present invention is preparing halogenated amino crotonate, using a series of continuous stirred reactor.
In an embodiment, the present invention is preparing halogenated amino crotonate, using a series of continuous stirred reactor and flow reactor.
In an embodiment, the present invention is preparing halogenated amino crotonate, using a series of flow reactors.
In an embodiment, the present invention provides a continuous process for preparation of halogenated amino crotonates, comprising the step of reacting a halogenated acetoacetate with a salt, wherein salt is prepared by reacting a base and acid in a separate reactor.
In another embodiment, the present invention provides a continuous process for preparation of halogenated amino crotonate comprising a reaction of halogenated acetoacetate with a base in the presence of an acid at 60-150?.
In another embodiment, the present invention provides a continuous process for preparation of halogenated amino crotonate comprising a reaction halogenated acetoacetate with a base in the presence of acid at 60-150?.
In another embodiment, after the completion of the reaction, the reaction mass is separated to obtain layers. The product layer obtained is distilled to isolate product and another layer, comprising acid and water is recycled to CSTR.
The recycled layer comprising acid and water, do not contain more than one mole of water. After first reaction cycle, the another layer comprising acid and water, is puried, so that recycled layer do not have more than one molar ratio of water before using in further process.
In an embodiment, the product layer is distilled to obtain product and another layer containing acetic acid and water is purified to remove water and recycled back in process.
In preferred embodiment, the present invention provides a continuous process for preparation of ethyl 3-amino-4,4,4-trifluorocrotonate by reacting ethyl 4,4,4-trifluoroacetoacetate and ammonia in presence of acetic acid.
In preferred embodiment, the present invention provides a continuous process for preparation of ethyl 3-amino-4,4,4-trifluorocrotonate by reacting ethyl 4,4,4-trifluoroacetoacetate and ammonia in presence of formic acid.
In another preferred embodiment, the present invention provides a continuous process for preparation of ethyl 3-amino-4,4,4-trichlorocrotonate by reacting ethyl 4,4,4-trichloroacetoacetate and ammonia in presence of propanoic acid.
In another preferred embodiment, the present invention provides a continuous process for preparation of ethyl 3-amino-4,4,4-dichlorofluorocrotonate by reacting ethyl 4,4,4-dichlorofluoroacetoacetate and ammonia in presence of acetic acid.
In another preferred embodiment, the present invention provides a preparation of ethyl 3-amino-4,4,4-trifluorocrotonate by reacting ethyl 4,4,4-trifluoroacetoacetate, with ammonium formate, wherein ammonium formate is obtained by reacting ammonia and formic acid in a separate reactor.
In another preferred embodiment, the present invention provides a preparation of ethyl 3-methylamino-4,4,4-trifluorocrotonate by reacting ethyl 4,4,4-trifluoroacetoacetate with methylamine in presence of acetic acid.
In another preferred embodiment, the present invention provides a continuous process for preparation of ethyl 3-ethylamino-4,4,4-trifluorocrotonate by reacting ethyl 4,4,4-trifluoroacetoacetate and ethylamine in the presence of acetic acid.
In an embodiment, halogenated amino crotonate is obtained with a purity greater than 95%, or in the range from 95-100%.
In another embodiment, halogenated amino crotonate is obtained with a yield greater than 90%, or in the range from 91-100%.
The isolation is carried out using any of the process consisting of extraction, distillation, filtration, decantation, washing, drying or a combination thereof in continuous mode.
The completion of the reaction may be monitored by gas chromatography and high pressure liquid chromatography (HPLC).
The reactant and reagents are used herein in the reaction can be prepared by any of the methods known in the art or can be obtained commercially.
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 ethyl 3-amino-4,4,4-trifluorocrotonate.
A mixture of acetic acid and ethyl 4,4,4-trifluoroacetoacetate (10% w/w acetic acid concentration) was pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 80?. The reaction mass was transferred by overflow line to next two CSTR’s. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising acetic acid and water was recycled to remove water.
Purity: 99%, Yield 96%.
Example 2: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate.
A stream of acetic acid and ethyl 4,4,4-trifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 75?. The reaction mass was transferred by overflow line to next two CSTR’s. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising acetic acid and water was recycled to remove water.
Purity: 99.99%, Yield 96.5%.
Example 3: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate.
A stream of propanoic acid and ethyl 4,4,4-trifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 85?. The reaction mass was transferred by overflow line to next two CSTR’s. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising propanoic acid and water was recycled.
Purity: 99%, Yield 97.1%.

Example 4: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate.
A stream of formic acid and ethyl 4,4,4-trifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 85?. The reaction mass was transferred by overflow line to next two CSTR in 1 hours. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising propanoic acid and water was recycled.
Purity: 99.1%, Yield 97%.
Example 5: Preparation of ethyl 3-amino-4,4,4-chlorodifluorocrotonate
A stream of propanoic acid and ethyl 4,4,4-chlorodifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 85?. The reaction mass was transferred by overflow line to next two CSTR’s. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising propanoic acid and water was recycled.
Purity: 99.1%, Yield 97%.
Example 6: Preparation of methyl 3-amino-4,4,4-chlorodifluorocrotonate
A stream of propanoic acid and methyl 4,4,4-chlorodifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with gaseous ammonia purging, while maintaining the temperature 85?. The reaction mass was transferred by overflow line to next two CSTR’s. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising propanoic acid and water was recycled.
Purity: 99.3%, Yield 96%.
Example 7: Preparation of ethyl 3-phenylamino-4,4,4-trifluorocrotonate
A stream of acetic acid and ethyl 4,4,4-trifluoroacetoacetate were pumped in a continuous stirred tank reactor (CSTR), along with an aniline stream, while maintaining the temperature 85?. The reaction mass was transferred by overflow line to next two CSTR in 30 minutes. The product was collected at the outlet of last CSTR, and the product layer was taken for product recovery through distillation and other layer comprising acetic acid and water was recycled.
Purity: 99.3%, Yield 96%.
Example 8: Preparation of ethyl 3-amino-4,4,4-trifluorocrotonate.
ethyl 4,4,4-trifluoroacetoacetate was charged in flow reactor-1 at 85?. Then, mass from reactor-1 is mixed with acetic acid stream in next flow reactor-2, maintaining 85?. The reaction mass from reactor-2 was mixed with ammonia stream in flow reactor-3 maintained at 85?. The outlet from reactor-3 was separated into layer and product layer was taken for product recovery through distillation and other layer comprising acetic acid and water was recycled.
Purity: 98.9%, Yield 96.5%.
,CLAIMS:WE CLAIM:
1. A continuous process for preparation of halogenated amino crotonate, comprising the step of reacting a halogenated acetoacetate with a base in the presence of an acid.
2. The process as claimed in claim 1, wherein the continuous process for preparation of halogenated amino crotonate, comprising the step of reacting an acetoacetate with a base in the presence of an acid.
3. The process as claimed in claim 1, wherein the continuous process for preparation of halogenated beta amino crotonate involves the reaction of halogenated acetoacetate with a salt, wherein salt is prepared by reacting a base and acid in a separate continuous reactor.
4. The process as claimed in claim 3, wherein the base is selected a group consisting of ammonia; amine selected from methylamine, ethylamine, tertiary butylamine, butyl amine, propyl amine, dimethylamine, diethylamine, ethylmethylamine; cyclic amine selected from cyclopropyl amine, cyclohexyl amine, and cyclopentyl amine; aniline; substituted aniline selected from 4-fluoroaniline, 4-chloroaniline, and 4-methylaniline.
5. The process as claimed in claim 1, wherein the molar ratio of base w.r.t halogenated acetoacetate is selected in the range of 1-3.
6. The process as claimed in claim 1, wherein the acid used is selected from a group consisting of formic acid, acetic acid, n-propanoic acid, iso-propanoic acid, and butanoic acid.
7. The process as claimed in claim 1, wherein the molar ratio of acid w.r.t halogenated acetoacetate is selected in the range of 0.2 to 0.8.
8. The process as claimed in claim 1, wherein the acid used is recycled and pumped in reaction reactor.
9. The process as claimed in claim 1, wherein the step of reaction of halogenated acetoacetate with a base in the presence of an acid is carried out at a temperature range from 60-150°C.
10. The process as claimed in claim 1, for preparing halogenated amino crotonate, wherein multiple reactors or combination thereof are used.

Dated this 1st day of March 2024.