DESC:FORM 2

THE PATENT ACT, 1970
(39 of 1970)

COMPELETE SPECIFICATION
(See section 10; rule 13)

“AN IMPROVED PROCESS FOR PREPARATION OF PROHEXADIONE AND ITS CALCIUM SALT”

HIKAL LIMITED, an Indian Company, of 3A & 3B, International Biotech Park, Hinjewadi, Pune – 411057, Maharashtra, 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 relates to an improved and efficient process for the preparation of Prohexadione and its calcium salt of formula (I). The present invention further relates to one step process for preparation of ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate a key intermediate of 3,5-dioxo-4-propionylcyclohexanecarboxylic acid by avoiding an O-alkylation reaction.

BACKGROUND OF THE INVENTION

Prohexadione, 3,5-dioxo-4-propionyl-cyclohexanecarboxylic acid is a plant growth regulator, it is used (commonly as the corresponding calcium salt, known as Prohexadione-calcium) as an anti-lodging agent in small-grain cereals. It has a role as an agrochemical, a plant growth regulator and a gibberellin biosynthesis inhibitor.

Prohexadione was first disclosed in US patent 4,678,496 (hereinafter US‘496) and corresponding patent publications, as a cyclohexane derivative. The references predominantly disclose the synthesis of ethyl 3,5-dioxo-4-propionyl cyclohexane carboxylate a key intermediate of Prohexadione in multiple operational steps: (i) reacting ethyl 3,5-dioxocyclohexane carboxylate with propionyl chloride; (ii) obtaining O-alkylated intermediate by treating with sodium bicarbonate, separating organic layer, drying and concentrating; (iii) Fries rearrangementto obtain C-alkylated compound; (iv) isolation by column chromatography with low yield 46.5%.
The reaction scheme is as shown in Scheme-1.

Scheme-1:

The patent application CN 101774906 disclose the process for the preparation of Prohexadione calcium which comprises steps; (i) hydrogenation; (ii) O-alkylation; (iii) rearrangement of O-alkylation to C-alkylation; (iv) hydrolysis; and (v) salt preparation.

The patent CN 107162907B disclose the preparation of Prohexadione calcium by using multiple reaction sequence: (i) Michael addition reaction; (ii) condensation; (iii) esterification and O-alkylation; (iv) rearrangement of O-alkylation to C-alkylation; (v) hydrolysis; and (vii) salt preparation.

The existing processes are suffered with one or more disadvantages for example: (i) O-alkylation step; (ii) more number of steps; (iii) use of multiple solvents; (iv) tedious column chromatography for purification; (v) long cycle time; (vi) more effluent generation. The process further requires multiple operations for reduction or removal of impurities, which reduces overall yield, increase production cost and generate more hazardous waste for disposal.

Thus, there is a need for an improved process particularly for a preparation of key intermediate ethyl 3,5-dioxo-4-propionyl cyclohexane carboxylate by avoiding O-alkylation, directly resulting a C-alkylated compound in one step, avoiding purification, and further conversion into 3, 5-dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt. To overcome the limitations of the existing process an inventor has come-up with an improved process to obtain ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate an intermediate compound in single step without formation of O-alkylated compound and further conversion into Prohexadione calcium salt.

SUMMARY OF THE INVENTION

In one aspect, the invention provides an improved process of 3,5-Dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I)in high yield.

In another aspect, the invention provides a direct C-alkylation of ethyl 3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate for a preparation of ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate by avoiding O-alkylation.

In another aspect, the present invention provides a cost-effective process by avoiding multiple operations(s) with an environment friendly and commercially viable manner.

In another aspect, the present invention relates to a process for the preparation of 3,5-dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) which comprises the steps of:

a) reacting the compound of formula (II)where R is C1-C10alkyl, with propionyl chloride in presence of a base(s) and a solvent to obtain compound of formula (III);

b) reacting compound of formula (III) where R is C1-C10 alkyl in presence of a base, phase transfer catalyst (PTC), solvent(s), an acid; and further reacting with calcium hydroxide in solvent(s).

DETAILED DESCRIPTION OF THE INVENTION

The present invention is described more in details hereinafter. The invention is embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

In one embodiment, the instant invention provides the preparation of Prohexadione calcium salt which involve only two steps starting from ethyl 3-hydroxy-5-oxocyclohex-3-ene-1-carboxylate, thus the process is economically viable.

In another embodiment, the process for preparation of Prohexadione calcium salt does not involve purification step and generates less effluent, thus process is environment friendly and thereby commercially viable.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In an embodiment, the present invention provides a process for the preparation of 3,5-Dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) is illustrated in the following synthetic scheme.

Scheme 2:

In another embodiment, the present invention provides a process for the preparation of 3,5-dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) with purity greater than 90%, preferably greater than 96%.

In another embodiment, the present invention provides a process for the preparation of 3,5-dioxo-4-propionyl-cyclohexanecarboxylic acid calcium salt of formula (I) with overall yield greater than 65%.

In another embodiment, the present invention provides a C-alkylation process in one step for the preparation of ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate by avoiding O-alkylation.

In another embodiment of the present invention, wherein the base(s) in step (a) is base selected from triethyl amine (TEA), ammonia, diisopropylethylamine, diethylamine, dipropylamine, diisopropylamine, pyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, histidine and guanidine, 4-dimethylaminopyridine (DMAP), and 4-aminopyridines.

In another embodiment of the present invention, wherein the base(s) in step (a) is used simultaneously and in any combination of TEA and DMAP.

In another embodiment of present invention, wherein solvent in step (a) is selected from dichloromethane (DCM), ethylene dichloride (EDC), chloroform (CHCl3), carbon tetrachloride (CCl4), toluene, cyclohexane, monohalobenzenes such as monochlorobenzene, dihalobenzenes such as dichlorobenzene, dialkyl (C1-C12) ethers, and the like.

In another embodiment of the present invention, wherein the step (a) is carried out at a temperature between 20°C to 120°C, preferably 20°C to 45°C.

In another embodiment of the present invention, wherein the base in step (b) is selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs2CO3), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), ammonia (NH3), ammonium hydroxide (NH4OH), magnesium tertiary butoxide [(t-BuO)2Mg], potassium tertiary butoxide (t-BuOK), and sodium tertiary butoxide (t-BuONa).

In another embodiment of the present invention, wherein the phase transfer catalyst in step (b) is selected from tetra alkyl ammonium halide such as tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium chloride (TBACl), tetrabutylammonium fluoride (TBAF), benzyltriethylammonium chloride; methyl tri alkyl ammonium halides such as methyltricaprylammonium chloride, methyltributylammonium chloride, methyl trioctylammonium chloride, tetra butyl ammonium hydrogen sulphate (TBAHS), Aliquat 336; and potassium iodide (KI).

In another embodiment of the present invention, wherein the solvent in step (b) is selected from water, tetrahydrofuran (THF), toluene, inert organic solvents such as aliphatic, alicyclic and aromatic hydrocarbons solvent selected from cyclohexane, methylcyclohexane, xylene, benzene, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dimethoxyethane, dimethoxymethane, 1,3-dioxane, 1,4-dioxane, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, polyethylene glycol dimethyl ether, cyclic, acyclic ethers, alcoholic solvent such as methanol, ethanol, isopropanol, n-butenol and the like.

In another embodiment of the present invention, wherein the an acid in step (b) is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid, trifluoroacetic acid (TFA), formic acid (HCOOH), phosphoric acid (H3PO4), sodium hydrogen sulfate (NaHSO4), p-toluenesulfonic acid (p-TSA), and acetic acid (AcOH).

In another embodiment of the present invention, wherein the step (b) is carried out at a temperature between 20°C to 90°C, preferably 80°C to 90°C.

In another embodiment of the present invention, wherein the step (b) is carried out by using base in presence or absence of phase transfer catalyst.

The preparation of the starting material used in the present invention is well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL

1) Preparation of compound (III)

To a solution of compound (II) (10 g) in MDC (130ml), a 4-dimethylaminopyridine (1.99g), and trimethylamine (11g) was added at rt. A solution of propionyl chloride (6.03g) in MDC (65ml) was added dropwise for 30 min. The reaction mixture was heated to reflux temperature for 4-6 h. The reaction completion was ensured by HPLC. The reaction mixture was quenched by water and solvent was removed by distillation to obtain compound (III) (11.67g, 78% yield, HPLC purity 88.41%)
1H NMR (CDCl3) ? = 1.114 (t, J = 7.2 Hz, 3H), 1.251 (t, J = 7.2 Hz, 3H), 2.60-3.00 (m, 4H), 3.048 (q, J = 7.2 Hz, 2H), 4.167 (q, J = 7.2 Hz, 2H);13C NMR (CDCl3) ? = 8.13, 14.03, 34.13, 34.89, 36.37, 40.50, 61.37, 112.36, 172.12, 192.50, 196.0, 206.69 ppm; Mass for C12H16O5 241.26 (M+H), found 241.0.

2) Preparation of compound (I)

To a solution containing compound (III) (10g) in toluene (50ml) and water (30ml), a TBAB (0.067g) and caustic lye (4.86 g) was added at rt. The reaction mixture was heated to 80°C to 90°C for 2 h. The reaction completion was ensured by HPLC. The reaction mixture was cooled to rt and layer separated. The aqueous layer was acidified with aq. HCl till pH 1-2 and extracted with MDC. The solvent from organic layer was removed by distillation to obtain Prohexadione free acid (8.83g, 96.2% purity). The Prohexadione free acid was added into water (80ml), ethanol (80ml). To the reaction mixture a calcium hydroxide (3.08g) was added and heated to 80°C to 90°C for 8-10 h. The solid was filtered and washed with water and dried to obtain compound of formula (I) (8.33 g, 80% yield, 96% HPLC purity)

Two step prior art process for preparation of Compound (III)

3) Preparation of compound (III) from compound (II) by formation of an O-alkyl intermediate.

Step-1: To a solution of 3-cyclohexene-1-carboxylic acid, 3-hydroxy-5-oxo-, ethyl ester 1 (17.0 g) in MDC (85 ml) triethylamine (14.01 g, 0.1385 mole, 1.5 eq.) was added at 20-30 °C. The c reaction mixture was cooled to 0°C to 5 °C. Propionyl chloride (0.1015 mole) was added to the reaction mixture over 30 min and allowed to stir the resulting mixture for 10-12 h. After completion of reaction, the mixture was washed with water and separated MDC layer from aqueous layers. The solvent was evaporated and crude residue was purified by column chromatography out under vacuum to afford crude 3-Cyclohexene-1-carboxylic acid, 5-oxo-3-(1-oxopropoxy)-, ethyl ester (IIa, 13.0 g, 58.63% yield, 90% purity) as brown colored liquid.

Step-2: A mixture of 3-Cyclohexene-1-carboxylic acid, 5-oxo-3-(1-oxopropoxy)-, ethyl ester IIa (7.5 g) and 4-dimethylamino pyridine (0.76 g) in toluene (110 ml) was heated to 80°C to 85 °C for 4-5 h. After completion of reaction, reaction mass was cooled to room temperature and washed with water and layer separated. Organic layer was concentrated under vacuum to obtain cyclohexane carboxylic acid, 3,5-dioxo-4-(1-oxopropyl)-, ethyl ester (III) (4.70 g, 63% yield, 75% purity) as light brown solid.
,CLAIMS:WE CLAIM:

1) A process for preparation of 3,5-dioxo-4-propionyl-cyclohexanecarboxylicacid calcium salt of formula (I)from ethyl 3,5-dioxo-4-propionyl-cyclohexanecarboxylate by avoiding an O-alkylation.

2) A process for preparation of 3,5-dioxo-4-propionyl-cyclohexanecarboxylicacid calcium salt of formula (I) as claimed in claim 1,comprising steps of:

a) reacting the compound of formula (II) where R is C1-C10 alkyl, with propionyl chloride in presence of a base(s) and a solventto obtain compound of formula (III);

b) reacting compound of formula (III) where R is C1-C10 alkyl in presence of a base, phase transfer catalyst (PTC), solvent(s), an acid; and further reacting with calcium hydroxide in solvent(s).

3) The process as claimed in claim 2, wherein the base used in step (a) is selected from triethyl amine (TEA), ammonia, diisopropylethylamine, diethylamine, dipropylamine, diisopropylamine, pyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, histidine and guanidine, 4-dimethylaminopyridine (DMAP), and 4-aminopyridines.

4) The process as claimed in claim 2, wherein the solvent used in step (a) is selected from dichloromethane (DCM), ethylene dichloride (EDC), chloroform (CHCl3), carbon tetrachloride (CCl4), toluene, cyclohexane, dichlorobenzene, and dialkyl (C1-C12) ethers.

5) The process as claimed in claim 2, wherein the base used in step (b) is selected from lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium carbonate (Cs2CO3), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), ammonia (NH3), ammonium hydroxide (NH4OH), magnesium tertiary butoxide [(t-BuO)2Mg], potassium tertiary butoxide (t-BuOK), and sodium tertiary butoxide (t-BuONa).

6) The process as claimed in claim 2 , wherein the phase transfer catalyst is selected from tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium chloride (TBACl), tetrabutylammonium fluoride (TBAF), benzyltriethylammonium chloride; methyl tri alkyl ammonium halides such as methyltricaprylammonium chloride, methyltributylammonium chloride, methyl trioctylammonium chloride, tetra butyl ammonium hydrogen sulphate (TBAHS), Aliquat 336and potassium iodide (KI).

7) The process as claimed in claim 2, wherein the solvent used in step (b) is selected from water, tetrahydrofuran (THF), toluene, cyclohexane, methylcyclohexane, xylene, benzene, 2-methyltetrahydrofuran, methyl tert-butyl ether, isopropyl ether, dimethoxyethane, dimethoxymethane, 1,3-dioxane, 1,4-dioxane, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, polyethylene glycol dimethyl ether, cyclic, acyclic ethers, methanol, ethanol, isopropanol, and n-butenol.

8) The process as claimed in claim 2, wherein the acid used is selected from hydrochloric acid (HCl), hydrobromic acid (HBr), sulfuric acid, trifluoroacetic acid (TFA), formic acid (HCOOH), phosphoric acid (H3PO4), sodium hydrogen sulfate (NaHSO4), p-toluenesulfonic acid (p-TSA), and acetic acid (AcOH).