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

PROCESS FOR PREPARATION OF SUBSTITUTED IMINES

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

The following specification describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention provides an improved process for preparation of substituted imine compounds.

BACKGROUND OF THE INVENTION
Substituted imine compounds are widely used as raw material for pharmaceutical compounds and agrochemicals. These are widely used as intermediate in the synthesis of DPP-IV inhibitors and so can be used as a diabetes therapeutic agent. Various methods are known in the art for preparation of substituted imine compounds and intermediates thereof.
Canadian Journal of Chemistry (1961), 39, 761-4 discloses synthesis of haloacetamidines by the reaction of halogenated acetonitriles with corresponding organic amines or its solution with water or an organic solvent such as methanol, benzene, acetonitrile. The preferred haloacetamidines are selected from N-butyl-trifluoroacetamidine, N-benzyl-trifluoroacetamidine, N-phenyl-trifluoroacetamidine N,N-dimethyl-trifluoroacetamidine N-methyl-a,a-dichloroacetamidine; N,N-pentamethylene-a,a-dichloroacetamidine; N-phenyl-a,a-dichloroacetamidine; N-(5-methyl-2-pyridyl)-a,a,a-trichloroacetamidine; N-(2-thiazolyl)-a,a,a-trichloroacetamidine.
Synthesis 2018, 50, 4133–4139 also discloses synthesis of trifluoroacetamidine by reaction of trifluoroacetonitrile with ammonia at –78 °C. Such a low temperature conditions are not suitable at commercial scale.
Inorg. Chem. 2011, 50, 5123–5136 also discloses synthesis of amidines such as CH3OC6H4C(NH)NH2 by contacting 4-Methoxybenzonitrile with Et2O3 LiN(SiMe3)2 in presence of distilled diethyl ether with 22% yield only. Similarly, it discloses synthesis of other amidines like CH3C6H4C(NH)NH2, ClC6H4C(NH)NH2, CF3C6H4C(NH)NH2.

Canadian Journal of Chemistry (1958), 36, 771-4 disclose synthesis of trichloroacetamidines by the addition of primary or secondary amines to chlorinated acetonitriles without any catalyst. The preferred trichloroacetamidines includes Cl3CC(=NH)NRR’ selected from Cl3CC(=NH)NHMe, Cl3CC(=NH)NMe2, Cl3CC(=NH)NHBu, Cl3CC(=NH)NHPh. The R & R’ are further selected from groups like picrate, piperidino, picrate, morpholino, iso-propyl, benzyl, p-ethoxy benzene4, p-tolyl, m-tolyl and o-tolyl.
Science of Synthesis (2005), 22, 361-366 also discloses synthesis of thioimidates by reaction of trifluoroacetonitrile with thiol.
PCT Pat. Pub. No. 2019075259 also discloses synthesis of trifluoroacetamidoates in which, a solution of 2,2,2-trifluoroacetamide in pyridine was added to trifluoroacetic anhydride. The generated gas was bubbled into the sodium methoxide solution cooled to -70°C to obtain trifluoroacetamidoates with 3.2% yield.
EP Pat App. 1138668 also discloses synthesis of aromatic amidine by reaction of difluoroacetic acid with 2,6-dichloro-4-trifluoromethylaniline in presence of triethyl amine and triphenyl phosphine using a solvent like carbon tetrachloride. The product was isolated using column chromatography.
Thus, most of the prior arts uses acetonitrile derivative for preparing corresponding imine compounds. These acetonitrile derivatives are highly expensive and involves tedious synthetic processes.
Thus, there is an urgent need to develop an economic, high yielding, safe and robust alternative process for preparation of substituted imine compounds.
The inventors of present invention found that the synthesis of substituted imine compounds is possible from corresponding acids using simple reaction conditions.

OBJECT OF THE INVENTION
The present invention provides an improved process for preparation of substituted imines from corresponding acids.

SUMMARY OF THE INVENTION
The present invention provides a process for preparation of a compound of formula I. comprising the step of:

Formula I
wherein, X1, X2, X3 are independently selected from hydrogen, halogen, provided at least one of X1, X2, X3 is halogen, C2-3 alkyl or haloalkyl; A is hetero atom selected from O, S and N; R1, R2 is independently selected from hydrogen, alkyl, cycloalkyl, substituted or unsubstituted aryl, heteroaryl or together form a substituted or unsubstituted 5-6 membered hetero aryl ring; n is 0-1.
a) passing a preheated stream of a compound of formula II and anhydrous ammonia through a catalyst bed provided in a reactor to obtain a reaction mixture; and

Formula II
b) contacting the reaction mixture of step a) with a compound of formula III,

Formula III
wherein A, R1, R2 are as defined above, n is 0-1.
to obtain the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the compound of formula III preferably selected from an alkanol, thiol, ammonia, primary and secondary amine. The amines can be further substituted with alkyl, aryl or heteroaryl.
In an embodiment, when the compound of formula III is alkanol or thiol, it contains 1-5% metal alkoxides preferably sodium or potassium alkoxide or Sodium or Potassium salt of thiols respectively.
The catalyst bed comprising a catalyst selected form vanadium adsorbed on silica or alumina, molybdenum adsorbed on silica or alumina, vanadium (V) oxide, antimony (III) oxide, titanium dioxide, molybdenum trioxide adsorbed on silica or alumina.
In an embodiment, the catalyst used in the present invention is recovered and reused.
In an embodiment, when the compound of formula III is ammonia, primary or secondary amine, it is used as such, or in aqueous solution form or with an organic solvent.
In an embodiment, the temperature at which, the compound of formula II is preheated is selected in the range of 180 to 500? preferably in the range of 250 to 320?.
In an embodiment, the compound of formula II is converted to the compound of formula I in vapour phase at a temperature selected in the range of 180 to 500? preferably in the range of 250 to 320? and at a pressure range of 0 to 10bar.
In an embodiment, the conversion of compound of formula II to the compound of formula I is carried out without isolating any intermediate in-between.
In an embodiment, the compound of formula II is supplied at a flow rate of 0.5 to 5ml/min.
In an embodiment anhydrous ammonia is supplied along with the compound of formula II. The molar ratio of ammonia w.r.to the compound of formula II is 1: 3-30.
In an embodiment, the compound of formula II is reacted with gaseous ammonia with a residence time of 1-25 sec. In a preferred embodiment, the residence time is in the range of 3-10 second.
In an embodiment nitrogen is optionally supplied along with the compound of formula II at a flow rate of 100 to 500 ml/minute.
In an embodiment, the conversion of compound of formula II to compound of formula I is carried out in a single tubular reactor comprising a catalyst bed.
In an embodiment, the synthesis of compound of formula I is carried out in continuous mode or continuous flow mode where the compound of formula II is contacted with compound of formula III at a specific flow rate.
In another embodiment, the unreacted compound of formula II is recycled back to reactor.
In a specific embodiment, the present invention provides a process for preparation of CF3C=NHOEt, comprising the steps of:
a) contacting a preheated stream of CF3COOH and anhydrous ammonia with a catalyst bed provided in a reactor to obtain a reaction mixture; and
b) contacting the reaction mixture of step a) with 1% sodium ethoxide in ethanol to obtain the CF3C=NHOEt.
In another specific embodiment, the present invention provides a process for preparation of CF3C=NHNH2, comprising the steps of:
a) contacting a preheated stream of CF3COOH and anhydrous ammonia with a catalyst bed provided in a reactor to obtain a reaction mixture; and
b) contacting the reaction mixture of step a) with ammonia to obtain CF3C=NHNH2.
The purity of compound of formula I is greater than 85%. The yield of compound of formula I is greater than 40%.
The compound of formula I is 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 or formation of compound may be detected by NMR spectroscopy or any 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. The reagents and raw materials used in the present invention may be prepared or 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: Preheated trichloroacetic acid was fed at a flow rate of 1 ml/min along with anhydrous ammonia (flow rate: 50 ml/minute) into tubular reactor, packed with vanadium catalyst adsorbed on alumina at 300 °C. The reactor outlet gaseous stream was purged into aqueous ammonia to get trichloroacetamidine in water confirmed by NMR quantification.
Example 2: Preheated difluorochloroacetic acid was fed at a flow rate of 1 ml/min along with anhydrous ammonia (flow rate: 50 ml/minute) into tubular reactor, packed with vanadium catalyst adsorbed on alumina at 300 °C. The reactor outlet gaseous stream was purged into aqueous N,N-dimethylamine to get N,N-dimethyl-difluorochloroacetamidine in water confirmed by NMR quantification.
Example 3: Preheated trifluoroacetic acid was fed at a flow rate of 1 ml/min along with anhydrous ammonia (flow rate: 50 ml/minute) into tubular reactor, packed with molybdenum catalyst adsorbed on silica at 250-320 °C. The reactor outlet gaseous stream was purged into ethanol containing 1% sodium ethoxide to get ethyl trifluoroacetimidate solution in ethanol confirmed by NMR quantification.
Example 4: Preheated trifluoroacetic acid was fed at a flow rate of 1 ml/min along with anhydrous ammonia (flow rate: 40 ml/minute) into tubular reactor, packed with molybdenum catalyst adsorbed on alumina at 250-320 °C. The reactor outlet gaseous stream was purged into aqueous ammonia to get trifluoroacetamidine in water confirmed by NMR quantification.
Example 5: Preheated difluorochloroacetic acid was fed at a flow rate of 1 ml/min along with anhydrous ammonia (flow rate: 50 ml/minute) into tubular reactor, packed with molybdenum catalyst adsorbed on silica at 250-320 °C. The reactor outlet gaseous stream was purged into ethanol containing 1% sodium ethoxide to get ethyl difluorochloroacetimidate solution in ethanol confirmed by NMR quantification.

ABSTRACT
PROCESS FOR PREPARATION OF SUBSTITUTED IMINES
Substituted Imine compounds are widely used as raw material for pharmaceutical compounds and agrochemicals. The present invention provides a one pot process for the synthesis of substituted imine compounds.

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

Formula I
wherein, X1, X2, X3 are independently selected from hydrogen, halogen, provided at least one of X1, X2, X3 is halogen, C2-3 alkyl or haloalkyl; A is hetero atom selected from O, S and N; R1, R2 is independently selected from hydrogen, alkyl, cycloalkyl, substituted or unsubstituted aryl, heteroaryl or together form a substituted or unsubstituted 5-6 membered hetero aryl ring; n is 0-1.
a) passing a preheated stream of a compound of formula II and anhydrous ammonia through a catalyst bed provided in a reactor to obtain a reaction mixture; and

Formula II
b) contacting the reaction mixture of step a) with a compound of formula III,

Formula III
wherein A, R1, R2 are as defined above, n is 0-1.
to obtain the compound of formula I.
2.The process as claimed in claim 1, wherein the compound of formula II is reacted with anhydrous ammonia with a residence time of 1-25 sec.
3. The process as claimed in claim 1, wherein the catalyst bed comprising a catalyst selected from vanadium adsorbed on silica or alumina, molybdenum adsorbed on silica or alumina, vanadium (V) oxide, antimony (III) oxide, titanium dioxide, molybdenum trioxide adsorbed on silica or alumina.
4. The process as claimed in claim 1, wherein the synthesis of compound of formula I is carried out in continuous mode or continuous flow mode where the compound of formula II is contacted with compound of formula III at a specific flow rate.
5. The process as claimed in claim 1, wherein the compound of formula II is supplied at a flow rate of 0.5 to 5ml/min.
6. The process as claimed in claim 1, wherein the compound of formula II is converted to the compound of formula I in vapour phase at a temperature selected in the range of 180 to 500?.
7. The process as claimed in claim 1, wherein the conversion of compound of formula II to the compound of formula I is carried out without isolating any intermediate in between.
8. The process as claimed in claim 1, wherein the catalyst and unreacted compound of formula II are recycled back to reactor.

Dated this 24th day of December 2024