Claims:We claim:

1. An environment-friendly process for selective acylation of a dicarboxylic acid comprising the step of reacting a dicarboxylic acid solution and a ketene in the presence of a catalyst.

2. The process as claimed in claim 1, wherein the weight ratio between the ketene and the dicarboxylic acid is in the range of 0.1:1.0 to 5.0:1.0.

3. The process as claimed in claim 1 or claim 2, wherein the dicarboxylic acid is malonic acid.

4. The process as claimed in claim 1, wherein the dicarboxylic acid solution comprises the dicarboxylic acid and a ketone.

5. The process as claimed in claim 4, wherein the weight ratio between the ketone and the dicarboxylic acid 0.1:1.0 to 2.0:1.0.

6. The process as claimed in claim 4 or 5, wherein the ketone is acetone.

7. The process as claimed in claim 1, wherein the ketene is represented as:

wherein R1 and R2, independent of each other, are selected from H, an alkyl group having 1 to 6 carbon atoms, and a cyclic alkyl group having 3 to 6 carbon atoms.

8. The process as claimed in claim 1, wherein the catalyst is selected from phosphorous based Lewis acids, sulfur based Lewis acids, silicon based Lewis acids, boron based Lewis acids and salts of transition and alkaline earth metals.

9. The process as claimed in claim 1, wherein the reaction step is carried out by:
(A) preparing a reaction mixture comprising the dicarboxylic acid solution, ketene, and the catalyst at a temperature ranging between 0°C to 30°C in a reactor, and
(B) maintaining the temperature of the reactor to less than 30°C to obtain a reaction mass comprising an acylation product of the dicarboxylic acid.

10. The process as claimed in claim 9, wherein the amount of the catalyst is in between 0.01 wt.% to 15.0 wt.% based on the total weight of the reaction mixture.

11. The process as claimed in claim 9 or 10 further comprising the step of:
(C) adding an anti-solvent to the reaction mass,
(D) filtering the reaction mass of step (C) to obtain a mixture comprising a mother liquor and a wet cake of the acylation product of the dicarboxylic acid,
(E) optionally repeating the steps (A) to (D) with the mother liquor, and
(F) drying the wet cake of the acylation product of the dicarboxylic acid.

12. The process as claimed in claim 11, wherein the weight ratio of the anti-solvent to the dicarboxylic acid is in the range of 0.001:1.0 to 1.0:1.0.

13. The process as claimed in claim 11 or 12, wherein the anti-solvent is selected from one or more of the following:
(v) linear or branched or cyclic, substituted or unsubstituted aliphatic hydrocarbons having 4 to 10 carbon atoms,
(vi) substituted or unsubstituted aromatic hydrocarbons having 6 to 12 carbon atoms,
(vii) cyclic ethers selected from tetrahydrofuran (THF), alkyl substituted THF, and dioxane, and
(viii) ethereal solvents having the general formula R-O-R', wherein R and R', independent of each other, can be selected from linear or branched or cyclic, substituted or unsubstituted aliphatic hydrocarbon having 1 to 7 carbon atoms.

14. The process as claimed in one or more of claims 10 to 13 further comprising the step of:
(G) processing the mother liquor of step (D) or optionally step (E).

15. The process as claimed in one or more of claims 1 to 14, wherein the selective acylation of the dicarboxylic acid is the selective acylation of malonic acid to obtain Meldrum’s acid.

Dated this 30th Day of July 2021
LAXMI ORGANIC INDUSTRIES LIMITED
By their Agent & Attorney

(Nisha Austine)
of Khaitan & Co
Reg No IN-PA- 1390 , Description:FIELD OF THE INVENTION
[001] The present invention relates to an environment-friendly process for selective acylation of dicarboxylic acid. In particular, the present invention relates to an environment-friendly process for selective acylation of malonic acid to obtain Meldrum’s acid.

BACKGROUND OF THE INVENTION
[002] Selective acylation of dicarboxylic acid is usually carried out using a suitable combination of acylation reagents and catalysts. The most common acylation product of malonic acid is 2,2-Dimethyl-1,3-dioxane-4,6-dione. 2,2-Dimethyl-1,3-dioxane-4,6-dione is popularly known as Meldrum’s acid.

[003] The state-of-the-art or commercially used processes for Meldrum’s acid synthesis use various acylation reagents. Acetic anhydride is one such widely used acylation reagent. Other similar reagents used in the art include, such as but not limited to, acetic acid and azo compounds. These reagents have several limitations of their own – one of the major limitations being the explosive nature of the reagents and strict regulation on their usage in several countries. For instance, acetic anhydride is a hazardous substance and being used in narcotics and therefore, regulated in countries like US and India. Another major limitation is the generation of acetic acid as by product, which is a troublesome effluent. Particularly, the generation of acetic acid is generally in equimolar amounts and gets diluted in water, thereby increasing the cost incurred in recovering the same. Furthermore, this process is relatively complex requiring a fair number of reaction and purification steps.

[004] In the conventional arts, preparation of Meldrum’s acid from the corresponding azo compound is economically unfeasible owing to high cost and explosive nature of azo compounds which would significantly increase the cost of preparation of Meldrum’s acid.

[005] Another method of preparation of Meldrum’s acid cited in the conventional arts is by Grignard reaction, followed by isolation using aqueous method. This process generates aqueous effluent along with large amount of byproducts, which are not environmentally friendly. Moreover, Grignard reaction requires special care due to its hazardous properties.

[006] EP0637581 A1 and EP0496362 A2 disclose a process of producing Meldrum’s acid organic compounds, using hazardous ingredients like diketene, acetaldehyde, ozone, tin chloride, etc. In addition, cryogenic temperature conditions in the range of -60°C to -65 °C are required. Meldrum’s acid is obtained with a maximum yield of approx. 70% along with high aqueous effluent load generation.

[007] Thus, there is a need for an environment-friendly, less complex, and economical process for selective acylation of a dicarboxylic acid to produce an acylation product, such as Meldrum’s acid, with higher yield and purity, while at the same time minimizing and eliminating the generation of hazardous substances and troublesome effluents.

SUMMARY OF THE INVENTION
[008] In one aspect, the present invention provides an environment-friendly process for selective acylation of dicarboxylic acid comprising the step of reacting a dicarboxylic acid solution and a ketene in presence of a catalyst.

DESCRIPTION OF THE INVENTION
[009] The present invention provides an environment-friendly process for selective acylation of dicarboxylic acid comprising the step of reacting a dicarboxylic acid solution and a ketene in presence of a catalyst.

[010] In the present context, “environment-friendly” refers to the process being capable of substantially reducing the requirement of recovering the hazardous and troublesome effluents in comparison with the state-of-the-art or commercially used processes. In particular, the requirement of recovering the hazardous and troublesome effluents, such as but not limited to acetic acid, acetic anhydride, etc, is significantly low. Said otherwise, in the state-of-the-art or commercially used processes, acetic acid generated during the first batch (after acylation reaction using acetic anhydride) is in the range of 65% wt./wt. to 75% wt./wt., which causes the loss of yield of Meldrum’s acid and therefore requires immediate recovery of the acetic acid. On the contrary, the amount of acetic acid generated in the present invention is as low as one tenth of that of the state-of-the-art or commercially used processes. Hence, significantly lesser number of recovery steps are required, thereby resulting in an increase in the yield and selectivity of the final product.

[011] The present invention is also advantageous in that impurities are also reduced after every recycling, as described hereinbelow.

[012] In an embodiment, the dicarboxylic acid is preferably malonic acid.

[013] In another embodiment, ketene is used as an acylation reagent in the present invention. Ketene is represented as:

[014] wherein R1 and R2, independent of each other, are selected from H, an alkyl group having 1 to 6 carbon atoms, and a cyclic alkyl group having 3 to 6 carbon atoms.

[015] In one embodiment, ethenone is used as the suitable ketene, i.e., both R1 and R2 are H. For an acylation reaction, the weight ratio between the ketene and the dicarboxylic acid is in between 0.1:1.0 to 5.0:1.0. Preferably, the weight ratio between the ketene and the dicarboxylic acid is in between 0.2:1.0 to 3.0:1.0, or in between 0.3:1.0 to 1.0:1.0, or in between 0.3:1.0 to 0.6:1.0.

[016] The weight ratio between ketone and dicarboxylic acid is between 0.1:1.0 to 2.0:1.0. Preferably, the weight ratio between ketone and dicarboxylic acid is in between 0.2:1.0 to 2.0:1.0, or in between 0.4:1.0 to 1.0:1.0, or in between 0.5:1.0 to 0.8:1.0.

[017] In an embodiment, the reaction step is carried out by:
(A) preparing a reaction mixture comprising the dicarboxylic acid solution and ketene in presence of the catalyst at a temperature ranging between 0°C to 30°C in a reactor, and
(B) maintaining the temperature of the reactor to less than 30°C to obtain a reaction mass comprising an acylation product of the dicarboxylic acid.

[018] In another embodiment, the reaction step further comprises the steps of:
(C) adding an anti-solvent to the reaction mass,
(D) filtering the reaction mass of step (C) to obtain a mixture comprising a mother liquor and a wet cake of the acylation product of the dicarboxylic acid,
(E) optionally repeating the steps (A) to (D) with the mother liquor, and
(F) drying the wet cake of the acylation product of the dicarboxylic acid.

[019] Suitable catalyst for the present invention includes an acid catalyst (0.1 – 10% w/w). For instance, the acid catalyst includes a Lewis acid catalyst, and can be selected from a phosphorous based Lewis acids (phosphoric acids and derivatives, such as, ortho phosphoric acid, polyphosphoric acid, alkyl phosphates, etc.,), a sulfur based Lewis acids (sulfuric acid (90-100%), sulphurous acid, sulfinic acid, chlorosulfuric acid, oleum-SO3 (1- 100%), Acetyl sulfuric acid, etc.,), a silicon based Lewis acids (such as Halo tri methyl silanes (R3SiX) [X= Cl / Br /I, OTf, NTf2, C(C6F5) Tf-2, etc.] and (R3SiX+MLn)), boron based Lewis acids, and a metal salts, particularly salts of transition and alkaline earth metals. Suitable examples of metal salts include salts of Tin, Zinc, Aluminium, Iron, Lithium, Cerium and Boron. In the present context, the salts include halides (such as chlorides, bromides, iodides, fluorides, etc.), etherates, acetates, nitrates, sulphates, and the like and mixtures thereof.

[020] In the present context, the reaction mixture includes the dicarboxylic acid, ketone, catalyst, and ketene. Accordingly, in an embodiment, the amount of the catalyst is in between 0.01 wt.% to 15.0 wt.%, or in between 0.1 wt.% to 5.0 wt.% based on the total weight of the reaction mixture.

[021] For the acylation reaction between the dicarboxylic acid solution and ketene to occur, the reaction mixture is first obtained as outlined in step (A) above. This is achieved using the dicarboxylic acid, ketone, and ketene, as described herein.

[022] Preferably, the step (A) comprises the sub step of adding the catalyst to a precooled solution of dicarboxylic acid and ketone in the reactor at a temperature ranging between 5°C to 20°C to obtain the reaction mass.

[023] Preferably, the step (B) comprises the following sub steps:
(B1) mixing ketene with the dicarboxylic acid solution of step (A) over a duration of 0.5 h to 5 h and at a temperature ranging below 25°C to obtain the reaction mass, and
(B2) stirring the reaction mass below 25°C for 4h to 20h to obtain the acylation product of the dicarboxylic acid.

[024] The term “mixing” as used herein, refers to the conventional process of agitating using suitable mixing means known to a person skilled in the art. Such mixing means may be, such as but not limited to, a stirrer. Preferred temperature range in step (B1) is in between 0°C to 25°C for obtaining the reaction mass wherein ketene is mixed with the dicarboxylic acid solution over a duration of 0.5 h to 12 h and at temperature below 30°C to obtain the reaction mass. Preferably, the duration ranges between 8 h to 12 h and the temperature ranges between 0°C to 25°C.

[025] In the next step, i.e., step (C), the reaction mass is cooled to 0°C to 15°C and the anti-solvent is gradually added to the reaction mass. Suitable anti-solvents are selected from one or more of the following:
(i) linear or branched or cyclic, substituted or unsubstituted aliphatic hydrocarbons having 4 to 10 carbon atoms,
(ii) substituted or unsubstituted aromatic hydrocarbons having 6 to 12 carbon atoms,
(iii) cyclic ethers selected from tetrahydrofuran (THF), alkyl substituted THF, and dioxane, and
(iv) ethereal solvents having the general formula R-O-R', wherein R and R', independent of each other, can be selected from linear or branched or cyclic, substituted or unsubstituted aliphatic hydrocarbon having 1 to 7 carbon atoms.

[026] Suitable examples of linear or branched or cyclic, substituted or unsubstituted aliphatic hydrocarbons having 4 to 10 carbon atoms include pentane, hexane, cyclohexane.

[027] Suitable examples of substituted or unsubstituted aromatic hydrocarbons having 6 to 12 carbon atoms include benzene, toluene, xylene, tri-methylbenzene, cumene, and isomers and mixtures thereof.

[028] Ethereal solvents include dialkyl ethers having the general formula R-O-R', wherein (1) R = R' = linear or branched or cyclic aliphatic alkyl having 1 to 7 carbon atoms such as diethyl ether, di-isopropyl ether, dipropyl ether, dipentyl ether di-tert butyl ether, dicyclohexyl ether, dicyclopentyl ether, and the likes, or (2) R and R' can exist in combinations of linear or branched or cyclic aliphatic alkyl having 1 to 7 carbon atoms.

[029] The reaction mass is then stirred over the duration of 0.5 h to 5 h, or in between 1.5 h to 2 h, and at temperature below 10°C.

[030] In the next step, i.e., step (D), a slurry of the reaction mass is filtered under vacuum at the temperature range of 0°C to 10°C. Filtration of the slurry of the reaction mass results in a wet cake. The acylation product of the dicarboxylic acid, preferably Meldrum’s acid, as the wet cake is a white colour precipitate.

[031] Preferably, the wet cake of the acylation product of the dicarboxylic acid obtained in the filtration step (D) is obtained by the following sub-steps:
(D1) filtering the slurry of the reaction mass of step (C) at a temperature ranging between 0°C to 10°C under vacuum to obtain the wet cake of the acylation product of the dicarboxylic acid and the mother liquor,
(D2) washing the wet cake of step (D1) with the anti-solvent, and
(D3) subjecting the mother liquor of step (D1) to flash distillation to obtain a residue comprising unreacted ingredients of the reaction mixture.

[032] The mother liquor, thus obtained, is optionally recycled to the step (A) and thereafter, to the step (B) followed by step (C) and step (D). This is step (E), also referred as recycling step.

[033] It has been observed that the recycling step (E) advantageously increases the yield and purity of the selective acylation product of dicarboxylic acid by ensuring that the amount of the impurities is minimized. The recycling step makes the wet cake is saturated with selective acylation product of dicarboxylic acid, thereby increasing its yield.

[034] The mother liquor in step (D1) can be subjected to recycling to step (A) and subsequently to step (B) followed by step (C) for more than once. For example, the mother liquor is recycled for multiple time, for e.g., 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10 times to step (A).

[035] The wet cake after washing with the anti-solvent in step (D2) can be further subjected to step (F), also referred as the drying step, wherein the wet cake is suck dried to obtain selective acylation product of dicarboxylic acid in dry state.

[036] Drying is preferably carried under vacuum conditions. Vacuum drying further increases the purity of the selective acylation product of dicarboxylic acid. The vacuum drying is carried out at suitable conditions of pressure and temperature. Preferably, the temperature ranges between 0°C to 30°C.

[037] The mother liquor obtained in step (D3) or optionally step (E), can be further subjected to step (G), also referred as the recovery step, wherein the mother liquor is processed using suitable means known to the person skilled in the art, such as distillation. Herein, byproducts and solvent are recovered as distillate. The distillate and byproducts obtained are recycled back in the process to the step (A).

[038] The byproducts obtained in step (G) can be further subjected to suitable techniques known to the person skilled in the art to recover solvent and byproducts which are then recycled back in the process step (A) to enhance the overall yield of the acylation product of dicarboxylic acid.

[039] For increasing the yield and purity of the acylation product of dicarboxylic acid, all the process steps described herein are to be performed. In the present context, the recycling step can be performed more than once, such as 2, or 3, or 4, or 5, or 6 times.

[040] Preferably, the selective acylation of dicarboxylic acid, as described herein, is the selective acylation of malonic acid. Accordingly, the selective acylation product of malonic acid is 2,2-Dimethyl-1,3-dioxane-4,6-dione or Meldrum’s acid.

[041] Advantageously, the process of the present invention is clean and environment-friendly, resulting in high purity and yield for Meldrum’s acid. Additionally, the process is less complex, economical with minimum generation of impurities, as described herein. The impurities generated in the present invention process are quite on much lower concentration as compared to other commercial processes. Ketene being an environmentally friendly acylation reagent, imparts faster rate of reaction resulting in almost quantitative conversions and effective reduction of unwanted byproducts which are otherwise difficult to recover or destroy.

[042] Moreover, the overall process steps inclusive of recycling of byproducts and mother liquor, results in better control on the impurities which are soluble in the reaction mass, thereby imparting improved product yield and purity.

EXAMPLES
[043] Preparation of 2,2-Dimethyl-1,3-dioxane-4,6-dione or Meldrum’s acid

[044] To the precooled solution of Malonic acid (100gm) in acetone (65 gm) in a reactor at temperature 5°C to 10°C was added Lewis acid poly phosphoric acid (99% pure) (5 gm). The reaction mass was then purged with ketene (50 gm) with slow rate over a period of 1h to 2h maintaining temperature below 15°C. Reaction mass was subsequently stirred at temperature below 15°C for 8-12 h until necessary conversion is obtained on HPLC (High Performance Liquid Chromatography) analysis.

[045] The reaction mass was then cooled to 0°C to 10°C, and the anti-solvent diethyl ether (1 vol) was added gradually. The reaction mass was stirred and filtered at 0°C to 10°C under vacuum to obtain the mixture comprising the mother liquor and the wet cake of Meldrum acid. The wet cake of Meldrum acid was washed with the anti-solvent and subsequently dried to obtain the product yield of ~88-92 %.

[046] Subsequently, the mother liquor obtained was processed and the solvent and byproducts recycled back, thereby enhancing the overall yield to ~ 93-97%.

[047] The foregoing description of the invention has been set merely to illustrate the invention and is not intended to be limiting. Since the modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to the person skilled in the art, the invention should be construed to include everything within the scope of the disclosure.