DESC:Field of the Invention:
The invention relates to a process for the preparation of chiral ionic liquids.

Background of the Invention:
Ionic liquids have emerged as an environmentally friendly alternative to the volatile organic solvents. Being designer solvents, they can be modulated to suit the reaction conditions, therefore earning the name “task specific ionic liquids.” Though primarily used as solvents, they are now finding applications in various fields like catalysis, electrochemistry, spectroscopy, and material science to mention a few. The present application is aimed at preparing the ionic liquids.

One of the principles of green chemistry is that the use of auxiliary substances such as solvents and separation agents should be made unnecessary and if used should be innocuous. The toxic and hazardous properties of many solvents particularly chlorinated hydrocarbons pose crucial environmental concerns such as atmospheric emissions and contamination of water effluents. It is recognized that employing the use of nonconventional solvents as alternatives for environmentally unfriendly traditional solvents can reduce waste solvent production and hence reduce the negative impact on environment to a great extent. The most prevalent of these new solvents includes ionic liquids.
Ionic liquid is defined as a salt with melting point below the boiling point of water. Ionic liquids are known by several different names like neoteric solvents, designer solvents, ionic fluids, and molten salts. Most of the ionic liquids are composed of organic cation and inorganic anions. In order to be liquid at room temperature, the cation should preferably be unsymmetrical; that is, the alkyl groups should be different. Polarity and hydrophilicity/hydrophobicity of ionic liquids can be tuned by suitable combination of cation and anion. It is this property of ionic liquids which has earned them the accolade “designer solvents.”
As solvents, ionic liquids have found applications in a number of reactions. Dupont et al. extensively reviewed the application of ionic liquids as catalytic phase in various organometallic reactions.
Summary of the Invention:
The present invention relates to:
i) a process for preparation of chiral ionic liquids using tartaric acid (1);
ii) a process for the preparation of chiral ionic liquids using proline (6).

Detailed description of the invention:
In the preferred embodiment, the present invention is related to a novel process for the preparation of chiral ionic liquids using readily available tartaric acid as described in scheme -I.

Scheme-I

L-Tartaric acid is reacted with 2-chloroethanol in the presence of solvent and a catalyst to provide bis (2-chloroethyl)2,3-dihydroxysuccinate (2).

The solvents used for the reaction are selected from the group comprising of ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone etc; the most preferred solvent is toluene.

The catalysts used in the reaction are selected from the group comprising of methane sulphonic acid, sulfuric acid, para toluene sulphonic acid (PTSA). The most preferred catalyst is PTSA.

In another embodiment of the present invention bis (2-chloroethyl) 2,3-dihydroxysuccinate (2) is treated with heterocyclic compounds such as N-methyl imidazole, N-methyl morpholine and N-methyl pyrrolidine in the presence of solvent to yield respective ionic liquids (3), (4) and (5).

The solvents used for the reaction are selected from the group comprising of alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone etc; the most preferred solvent is dimethyl sulfoxide.

The reaction is carried out at a temperature range of 0-200°C, preferably 100-150°C.

Yet another embodiment of the present invention is related to a novel process for the preparation of chiral ionic liquids using readily available proline as depicted in Scheme (II).

Scheme-II
L-Proline (6) is treated with thionyl chloride in presence of suitable solvent like methanol and the resultant mixture is reduced using lithium aluminum hydride in the presence of tetrahydrofuran to yield pyrrolidin-2-yl methanol (7). The obtained pyrrolidin-2-yl methanol is treated with tert-butoxycarbonyl anhydride in a suitable solvent like ethyl acetate to yield 2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8) which is further treated with a leaving group like mesyl chloride to yield (S)-1-(tert-butoxycarbonyl)pyrrolidin-3-ol (9). The (S)-1-(tert-butoxycarbonyl) pyrrolidin-3-ol (9) is further treated with mercapto imidazole in tetrahydrofuran and a base to give (10) which is treated with alkyl halide in a suitable solvent to give ionic liquid (11).
The alkyl halides used for the aforementioned reaction are selected from a group comprising of bromo butane, bromo propane, bromo ethane, bromo hexane, chloro butane, chloro propane etc. The most preferred alkyl halide is bromo butane.
The aforementioned processes for the preparation of ionic liquids have the following advantages:
i) Use of less toxic reagents,
ii) Simple reaction conditions and
iii) Reduced time cycle.

Examples

Example 1: Preparation of bis (2-chloroethyl) 2,3-dihydroxysuccinate (2)

L-Tartaric acid (20 g) was added to 2-chloroethanol (44 ml) and was refluxed in toluene (200 ml) in the presence of pTSA (12 g). After the completion of the reaction toluene was evaporated and dichloromethane was added to the reaction mixture. 5% aqueous sodium carbonate was added. Dichloromethane was evaporated completely.
Yield: 35 g.
1H NMR: 2.46 (2H), 3.74 (4H), 4.45 (4H), 4.53 (2H)

Example 2: Preparation of ionic liquid (3) using N-methyl imidazole:

Bis(2-chloroethyl)2,3-dihydroxysuccinate (10g) was treated with N-methyl imidazole at 100-110°C. After the completion of the reaction water (50 ml) was added to the mixture along with dichloromethane (50 ml x 3). The aqueous layer was separated and concentrated to give oil.
Yield: 13g
1H NMR: 3.67 (4H), 3.84 (6H), 4.29 (4H), 4,46 (2H), 5.37 (2H), 7.69 (4H), 9.16 (2H)

Example 3: Preparation of ionic liquid (4) using N-methyl morpholine:

Bis(2-chloroethyl)2,3-dihydroxysuccinate (10g) was treated with N-methyl morpholine and dimethyl sulfoxide at 100-110°C. After the completion of the reaction, ethyl acetate (50 ml x 3) was added and decanted. Water (50 ml) was added to the mixture along with dichloromethane (50 ml x 3). The aqueous layer was separated and concentrated to give oil.
Yield : 15g
1H NMR (DMSO-D6): 2.177 (S, 6H), 2.308-2.508 (t, 8H), 3.567-3.590 (t, 8H), 3.824-3.849 (m, 4H), 4.304-3.413 (m, 4H), 4.484 (s, 2H), 5.287 (s, 2H)

Example 4: Preparation of ionic liquid (5) using N-methyl pyrrolidine:

Bis(2-chloroethyl)2,3-dihydroxysuccinate (10g) was treated with N-methyl pyrrolidine and dimethyl sulfoxide at 100-110°C. After the completion of the reaction, ethyl acetate (50 ml x 3) was added and decanted. Water (50 ml) was added to the mixture along with dichloromethane (50 ml x 3). The aqueous layer was separated and concentrated to give oil.
Yield: 12g
NMR (DMSO-D6): 1.686-1.719 (m, 8H), 2.277(s, 6H), 2.408-2.442 (m, 8H), 3.825-3.849 (m, 4H), 4.300-4.401 (m, 4H), 4.479 (s, 2H), 5.497 (s, 2H)

Example 5: Preparation of pyrrolidin-2-yl methanol (7):

To a solution of L-proline (6) (10 g) in methanol (150 ml) was added thionyl chloride. The reaction mixture was stirred at room temperature and concentrated to give solid. The solid was dissolved in tetrahydrofuran (170 ml). To the mixture lithium aluminum hydride (13 g) was added. The mixture was heated at 60°C. The excess lithium aluminum hydride was quenched with potassium hydroxide. The reaction mixture was filtered and the solid was washed with methanol (100 ml). The combined organic layers were dried and concentrated to give pyrrolidin-2-yl methanol (7).

Example 6: Preparation of 2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8):

A solution of pyrrolidin-2-yl methanol (7) (5g) in ethyl acetate (25 ml) was cooled to 0°C. Triethylamine (10 g) was added to the reaction mixture. A solution of tert-butoxy carbonyl anhydride (12 g) in ethyl acetate (10 ml) was added drop wise to the reaction mixture with stirring. The reaction mixture was then quenched with 1M aqueous H3PO4 (30 ml). The organic layer was separated and washed with H3PO4 (3x 30 ml) followed by saturated aqueous NaHCO3 (3 x 20 ml). The organic layer was concentrated to give an oily product.
Yield: 9g.
1H NMR (CDCl3): ? 1.47 (s, 9H, 3-CH3), 1.85-2.04 (m, 4H, CH2, CH2), 3.27-3.60 (m, 4H, CH2, CH2) and 3.93 (m, 1H, CH)

Example 7: Preparation of (S)-1-(tert-butoxycarbonyl) pyrrolidin-3-yl methanesulfonate (9)

To a mixture of 2-(S)-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (8) (1 g) and triethyl amine (1.2 ml) in dichloromethane (15 ml) was added mesyl chloride (0.62 ml) drop wise at 0°C. The reaction mixture was stirred and then concentrated. The residue was diluted with water (35 ml) and extracted with ethyl acetate (25 ml x 3). The combined organic phases were washed with 1 M KHSO4 (20 ml) followed by water (20 ml), dried and concentrated to give yellow oil.
Yield: 1.4 g.
1H NMR (CDCl3): ? 1.44 (s, 9H, 3-CH3), 1.84-2.01 (m, 4H, 2 CH2), 3.99 (s, 3H, CH3), 3.33-3.34 (m, 2H, CH2) and 4.01 (m, 1H, CH), 4.09-4.28 (m, 2H, CH2)

Example 8: Preparation of (S)-tert-butyl 2-(((1-methyl-1H-imidazol-2-yl) thio)methyl)pyrrolidine-1-carboxylate (10)

To a mixture of 2-mercapto methyl imidazole (0.4g) in tetrahydrofuran (10ml) was added potassium tert butoxide (0.45g) at 5-10°C. The reaction mixture was stirred for 1hr at 5-10°C. A solution of (S)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl methane sulfonate (9) (1g) in tetrahydrofuran was added at 5-10°C. After completion of addition the reaction mixture was stirred at 25-30°C. The reaction mixture was concentrated under vacuum. Ethyl acetate (20ml) was added and washed with water (10ml x 2). The organic layer was concentrated to get the title compound (10).
Mass (M+1) = 298.
Example 9: Preparation of chiral ionic liquids (11)

To a solution of (S)-tert-butyl 2-(((1-methyl-1H-imidazol-yl) thio) methyl) pyrrolidine- 1-carboxylate (10) (1g) in acetonitrile was added 1-bromobutane (1ml). The reaction mixture was refluxed for 24-30 hrs. After completion of reaction concentrated hydrochloric acid (0.6ml) was added and the reaction mixture was heated to 60-70°C. After completion of reaction, the reaction mixture was concentrated. Water (20 ml) was added to the residue and was washed with ethyl acetate (10 ml x 2). The aqueous layer was concentrated to get the residue.
,CLAIMS:1) The ionic compounds of formula (3), (4) and (5)

2) The process for the preparation of compounds of claim 1, comprising the steps of:
a) reaction of L-tartaric acid with 2-chloro ethanol in the presence of solvent and a catalyst to give bis (2-chloroethyl) 2,3-dihydroxysuccinate;
b) reaction of bis (2-chloroethyl) 2,3-dihydroxysuccinate with heterocyclic compounds in the presence of suitable solvents.
3) The process according to claim 2(step a) wherein, the catalysts are selected from the group comprising of methane sulfonic acid, sulfuric acid, para toluene sulfonic acid.
4) The process according to claim 3, wherein the most preferred catalyst is para toluene sulfonic acid.
5) The process according to claim 2(step a) wherein the solvent is selected from the group comprising of ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone.
6) The process according to claim 5, wherein the most preferred solvent is toluene.
7) The process according to claim 2(step b) wherein the heterocyclic compound is selected from the group consisting of N-methyl imidazole, N-methyl morpholine and N-methyl pyrrolidine.
8) The process according to claim 2(step b) wherein the solvent is selected from the group comprising of alcohols such as methanol, ethanol, isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane, hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as dimethylformamide, dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone.
9) The process of claim 8 wherein the most preferred solvent is dimethyl sulfoxide.
10) The process according to claim 2(step b), wherein the reaction is carried at a temperature of 0-200°C.
11) The process according to claim 10, wherein the reaction is preferably carried at 100-150°C.