Claims:We claim:
1. The process for the synthesis of 2-chloromalonaldehyde, comprises the steps of:
(i) reacting N,N-dimethylformamide and phosphorus oxychloride with chloroacetyl chloride at 0-5 ºC;
(ii) reacting thus formed complex with a basifying agent;
(iii) breaking of the alkali salt obtained in step (ii) with an acid;
(iv) extracting 2-chloromalonaldehyde obtained in step (iii) with an organic solvent; and
(v) granulating the product obtained in step (iv) in an organic solvent.

2. The process according to claim 1, wherein the basifying agent may be selected from alkali metal salts and earth alkaline metal salts, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, calcium carbonate and calcium bicarbonate.

3. The process according to claim 1, wherein the acid may be selected from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and sulfuric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and carboxylic acids such as acetic acid, propionic acid, butyric acid and iso-butyric acid.

4. The process according to claim 1, wherein the organic solvent employed for the extraction of 2-chloromalonaldehyde may be selected from ester and ether solvents, each optionally in admixture with a hydrocarbon solvent, such as butyl acetate, iso-butyl acetate, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, methyl acetate, butyl formate, iso-butyl formate, tert-butyl formate, propyl formate, iso-propyl formate, ethyl formate, methyl formate, diethyl ether or tert-butyl methyl ether, each optionally in admixture with hexane, cyclohexane, heptane, octane or petroleum ether.

5. The process according to claim 4, wherein the organic solvent is preferably ethyl acetate, methyl acetate, tert-butyl methyl ether, dioxane, THF, or mixtures thereof.

6. The process according to claim 1, wherein the organic solvent employed for the granulation may be selected from dichloromethane, butyl acetate, iso-butyl acetate, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, methyl acetate, butyl formate, iso-butyl formate, tert-butyl formate, propyl formate, iso-propyl formate, ethyl formate, methyl formate, diethyl ether, tert-butyl methyl ether, hexane, cyclohexane, heptane, octane, petroleum ether, and mixtures thereof. , Description:FIELD OF THE INVENTION

The present invention relates to a process for the synthesis of 2-chloromalonaldehyde, which is carried out as a single step process without the formation of intermediates. In particular, the present invention relates to a process for the synthesis of 2-chloromalonaldehyde in high purity.

BACKGROUND OF THE INVENTION

2-Chloromalonaldehyde is an intermediate for the synthesis of an anti-inflammatory drug – etoricoxib, which is a potent selective inhibitor of cyclooxygenase-2 with anti-inflammatory, antipyretic and analgesic properties and has been approved by regulatory administrations for the clinical use as a non-steroidal anti-inflammatory drug.

The preparation of 2-chloromalondialdehyde was first accomplished by W. Dieckmann and Ludwid Platz in 1904 (W. Dieckmann, L. Platz, Ber. Deut. Chem. Ges. 1904, 37, 4638). The method employed for the synthesis of 2-chloropropyl acid is based on bran acid as a starting material for the preparation of 2-chloropropyl dialdehyde and further processing. This process however, involves the use of aniline as the reagent which is toxic and strong, coupled with the use of high temperature and post-acidification with hydrochloric acid that are high risk factors, not conducive to production operations, involve lengthy reaction steps, and low yielding.

Collect. Czech. Chem. Commun. Vol 26, page 3051 (1961) discloses a method for the synthesis of 2-chloromalondialdehyde from chloroacetylchloride. Herein, a starting material oxyalyl chloride was added at 10 ºC to dimethyl formamide. Further, chloroacetylchloride was added and the reaction mixture was warmed to 75 ºC for 3 hours and the resultant reaction mixture was quenched using water. To the cooled solution, 50% NaOH solution was added. The reaction mixture was heated to reflux for 5 hours. On cooling, a precipitate formed, which was filtered and washed with water. The sodium salt of chloromalondialdehyde was obtained on drying. This method for the preparation of 2-chloromalonaldehyde is a multi-step process and involves isolation and handling of corrosive intermediates. Another disadvantage of this method is that high temperatures are required for the reaction to take place and the addition of oxyalyl chloride to dimethyl formamide is a highly exothermic reaction.

The synthesis and use of 2-chloromalonaldehyde was reviewed extensively in 1975 by Rechardt and Halbritter (Angew. Chem. Int. Ed (1975) 14, 86).

Organic syntheses (Vol 80, page 200 (2003)) discloses a method for the synthesis of 2-chloro-1,3-bis(dimethylamino) trimethinium hexafluorophosphate. Herein, a starting material chloroacetyl chloride was added to dimethyl formamide and the mixture was heated to 65-70 ºC. Further, phosphorus oxychloride was added to the reaction mixture. The reaction mixture was cooled down and sodium hexafluorophosphate was added to the reaction mixture. Subsequently, vinamidinium chloride solution and NaOH solution were added to the reaction mixture followed by aging, washing and filtration to obtain 2-chloro-1,3-bis(dimethylamino)trimethinium hexafluorophosphate. Hexafluorophosphoric acid used in this method is highly toxic and corrosive, and hence difficult to handle.

US5861419 and US2002042375A disclose the synthesis of 2-chloromalonaldehyde from 1,1,2,3,3-penta-chloropropane and mucochloric acid. Both 1,1,2,3,3-pentachloropropane and mucochloric acid that were reportedly used for the synthesis of 2-chloromalondialdehyde are expensive and not easily available on commercial scale.

US6127545A and US6040450A disclose the synthesis of 2-chloromalondialdehyde from mucochloric acid. Herein, a starting material mucochloric acid was added to aniline, and the reaction mixture was further heated at 90 ºC for 60 mins, cooled and filtered to obtain 3-anilido-2-chloro-acrolein, which on further addition of NaOH gave the sodium salt of 3-chloromalondialdehyde. Mucochloric acid used for the synthesis of 2-chloromalondialdehyde is expensive and not easily available on commercial scale.

Prior art processes are multi-step processes wherein intermediates are formed and expensive and/or corrosive materials that make handling the material difficult, are used. Such processes involving hazardous chemicals increase the risk in process control and cause potential risk to operators and environment.

This led to the development of the present invention that provides a process to obtain 2-chloromalonaldehyde in a single step eliminating the need for isolation of intermediate(s) and use of cheap and commercially available raw materials such as dimethylformamide, phosphorus oxychloride and chloroacetyl chloride. The method is convenient to carry out and provides 2-chloromalonaldehyde in moderate yield & high purity.

OBJECTIVE OF THE PRESENT INVENTION

The principal object of the present invention is to provide a process for the preparation of 2-chloromalonaldehyde in high purity.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of 2-chloromalonaldehyde from dimethylformamide, phosphorus oxychloride and chloroacetyl chloride. The advantages of the process of the present invention are that the process is a single-step process without the formation of intermediates, and provides 2-chloromalonaldehyde with high purity.

The process for the synthesis of 2-chloromalonaldehyde, comprises the steps of:
(i) reacting N,N-dimethylformamide and phosphorus oxychloride with chloroacetyl chloride at 0-5 ºC;
(ii) reacting the complex formed in step (i) with a basifying agent;
(iii) breaking of the alkali salt obtained in step (ii) with an acid;
(iv) extracting 2-chloromalonaldehyde obtained in step (iii) with an organic solvent; and
(v) granulating the product obtained in step (iv) in an organic solvent.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Fig. 1 shows the schematic representation of the process for the synthesis of 2-chloromalonaldehyde of the present invention.

DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of high purity 2-chloromalonaldehyde from N,N-dimethylformamide, phosphorus oxychloride, and chloroacetyl chloride.
According to an embodiment of the invention, the process for the synthesis of 2-chloromalonaldehyde, comprises the steps of:
(i) reacting N,N-dimethylformamide and phosphorus oxychloride with chloroacetyl chloride at 0-5 ºC;
(ii) reacting the complex formed in step (i) with a basifying agent;
(iii) breaking of the alkali salt obtained in step (ii) with an acid;
(iv) extracting 2-chloromalonaldehyde obtained in step (iii) with an organic solvent; and
(v) granulating the product obtained in step (iv) in an organic solvent.

The basifying agent may be any suitable agent selected from alkali metal salts and earth alkaline metal salts, such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, calcium carbonate and calcium bicarbonate.

The acid employed for the breaking of the alkali salt in step (iii) may be any suitable acid selected from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid and sulfuric acid, sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and carboxylic acids such as acetic acid, propionic acid, butyric acid and iso-butyric acid.

The organic solvent used for the extraction of 2-chloromalonaldehyde obtained in step (iv), may be selected from ester and ether solvents, each optionally in admixture with a hydrocarbon solvent, such as butyl acetate, iso-butyl acetate, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, methyl acetate, butyl formate, iso-butyl formate, tert-butyl formate, propyl formate, iso-propyl formate, ethyl formate, methyl formate, diethyl ether or tert-butyl methyl ether, each optionally in admixture with hexane, cyclohexane, heptane, octane or petroleum ether; preferably ethyl acetate, methyl acetate, tert-butyl methyl ether, dioxane, THF, and mixtures thereof.

The organic solvent employed for the granulation may be selected from dichloromethane, butyl acetate, iso-butyl acetate, tert-butyl acetate, propyl acetate, iso-propyl acetate, ethyl acetate, methyl acetate, butyl formate, iso-butyl formate, tert-butyl formate, propyl formate, iso-propyl formate, ethyl formate, methyl formate, diethyl ether, tert-butyl methyl ether, hexane, cyclohexane, heptane, octane, petroleum ether, and mixtures thereof.
According to a preferred embodiment of the present invention, the process for the synthesis of 2-chloromalonaldehyde, comprises the steps of:
(i) reacting N,N-dimethylformamide and phosphorus oxychloride with chloroacetyl chloride at 0-5 ºC;
(ii) reacting the complex formed in step (i) with sodium hydroxide;
(iii) breaking of the sodium salt obtained in step (ii) with hydrochloric acid;
(iv) extracting 2-chloromalonaldehyde obtained in step (iii) with ethyl acetate; and
(v) granulating the product obtained in step (iv) in dichloromethane.

The following examples and experimental studies are provided for illustrative purposes only and are not limiting to this disclosure in any way. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

EXPERIMENTAL STUDY

The preparation process of 2-chloromalonaldehyde disclosed in the present invention is a convenient, economical and non-hazardous process, in which many hazardous and dangerous chemicals used in the prior art processes are avoided.

The present invention is illustrated further by the following examples in which, the course of the reaction was tracked by thin layer chromatography (TLC) or High Pressure Liquid Chromatography (HPLC); and the structure and purity of the product was confirmed by at least one of the following techniques: TLC, HPLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; with the NMR spectrometry being determined at 300 MHz or 400 MHz using the indicated solvent.

The chemical symbols have their usual meaning and the following abbreviations, L (liter(s)), g (gram(s)) and ºC (degrees Celsius) have also been used.

EXAMPLES
Example 1
N,N-dimethyl formamide (650g) was charged in a round-bottomed flask and was cooled to 0-5 ºC. While maintaining the temperature at 0-5 ºC and stirring, phosphorus oxychloride (680g) was added to the dimethyl formamide. The addition was carried out for a duration of two hours and chloroacetyl chloride (500g) was then added over a duration of two hours. The reaction mixture was allowed to attain 25-30 ºC, and stirring was continued for a further duration of 3 hours. It was then heated to 70-75 ºC under stirring and the reaction was maintained at 70-75 ºC under stirring for 6 hours. It was then cooled down to 0-5 ºC. The reaction mixture was then quenched with water (2L), and 50% sodium hydroxide solution (2L) was added and stirred for 2 hours. The pH of the reaction mixture was then adjusted to 1 using concentrated HCl (about 2L). The organic layer was extracted using ethyl acetate (2L) and the extract was concentrated to a thick mass. To the thick concentrated mass, dichloromethane (1L) was added and the mixture was stirred to yield a crystalline material which was filtered and dried in an oven at 50ºC to obtain an yellowish to brown free-flowing powder of 2-chloromalonaldehyde with a melting point of 140 – 145 ºC. The yield was 165gm [35%]. The purity was assessed by High Pressure Liquid Chromatography (HPLC) and found to be 99.5%.

Example 2:
N,N-dimethyl formamide (650g) was charged in a round-bottomed flask and was cooled to 0-5 ºC. While maintaining the temperature at 0-5 ºC and stirring, phosphorus oxychloride (680g) was added to the dimethyl formamide. The addition was carried out for a duration of two hours and chloroacetyl chloride (500g) was then added over a duration of two hours. The reaction mixture was allowed to attain 25-30 ºC, and stirring was continued for a further duration of 3 hours. It was then heated to 70-75 ºC under stirring and the reaction was maintained at 70-75 ºC under stirring for 6 hours. It was then cooled down to 0-5 ºC. The reaction mixture was then quenched with water (2L), and 50% potassium hydroxide solution (2.2L) was added and stirred for 2 hours. The pH of the reaction mixture was then adjusted to 1 using sulfuric acid (about 0.7L). The organic layer was extracted using toluene (4.5L) and the extract was concentrated to a thick mass. To the thick concentrated mass, dichloromethane (1L) was added and the mixture was stirred to yield a crystalline material which was filtered and dried in an oven at 50ºC to obtain an yellowish to brown free-flowing powder of 2-chloromalonaldehyde with a melting point of 140 – 145 ºC. The yield was 118gm [25%]. The purity was assessed by High Pressure Liquid Chromatography (HPLC) and found to be 99.6%.

Example 3:
N,N-dimethyl formamide (650g) was charged in a round-bottomed flask and was cooled to 0-5 ºC. While maintaining the temperature at 0-5 ºC and stirring, phosphorus oxychloride (680g) was added to the dimethyl formamide. The addition was carried out for a period of two hours and chloroacetyl chloride (500g) was then added over a duration of two hours. The reaction mixture was allowed to attain 25-30 ºC, and stirring was continued for a further duration of 3 hours. It was then heated to 70-75 ºC under stirring and the reaction was maintained at 70-75 ºC under stirring for 6 hours. It was then cooled down to 0-5 ºC. The reaction mixture was then quenched with water (2L), and 30% potassium carbonate solution (2.6L) was added and stirred for 2 hours. The pH of the reaction mixture was then adjusted to 1 using hydrochloric acid (about 1.5L). The organic layer was extracted using toluene (4.5L) and the extract was concentrated to a thick mass. To the thick concentrated mass, methanol (0.5L) was added and the mixture was stirred to yield a crystalline material which was filtered and dried in an oven at 50ºC to obtain an yellowish to brown free-flowing powder of 2-chloromalonaldehyde with a melting point of 140 – 145 ºC. The yield was 110gm [23%]. The purity was assessed by High Pressure Liquid Chromatography (HPLC) and found to be 99.6%.

Example 4:
N,N-dimethyl formamide (650g) was charged in a round-bottomed flask and was cooled to 0-5 ºC. While maintaining the temperature at 0-5 ºC and stirring, phosphorus oxychloride (680g) was added to the dimethyl formamide. The addition was carried out for a period of two hours and chloroacetyl chloride (500g) was then added over a duration of two hours. The reaction mixture was allowed to attain 25-30 ºC, and stirring was continued for a further duration of 3 hours. It was then heated to 70-75 ºC under stirring and the reaction was maintained at 70-75 ºC under stirring for 6 hours. It was then cooled down to 0-5 ºC. The reaction mixture was then quenched with water (2L), and 50% sodium hydroxide solution (2L) was added and stirred for 2 hours. The pH of the reaction mixture was then adjusted to 1 using acetic acid (about 1.2L). The organic layer was extracted using tertiary butyl methyl ether [TBME] (3.5L) and the extract was concentrated to a thick mass. To the thick concentrated mass, tetrahydrofuran (1L) was added and the mixture was stirred to yield a crystalline material which was filtered and dried in an oven at 50ºC to obtain an yellowish to brown free-flowing powder of 2-chloromalonaldehyde with a melting point of 140 – 145 ºC. The yield was 160gm [34%]. The purity was assessed by High Pressure Liquid Chromatography (HPLC) and found to be 99.6%.

While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments as fall within the true scope of the invention.