Field of invention

The present invention provides a process for the preparation of substantially pure 2-cyanoimino-l,3-thiazolidine of Formula -I,

by cyclisation of dimethyl N-cyanoiminodithiocarbonate ester and 2-aminoethanethiol or salts thereof in presence of an alkali metal alkoxide.

Background and prior art

The methods for preparation of 2-cyanoimino-l, 3-thiazolidine from the reaction between dimethyl N-cyanoiminodithiocarbonate ester and 2-aminoethanethiol, are those described in Arch, pharm. (weiheim, Ger.), 305(10), P731 (1972), Japanese unexamined patent publication (Kokai) No. 48-91064, Gazz.Chim.ltal., 110 (5-6), P345, and W092-17462 (1992). This reaction is considered to follow the following scheme:

J. Heterocyclic. Chem., 24(1), P275 (1987) describes a method for preparing 2-cyanoimino-1, 3-thiazolidine from the reaction between diphenyl N-cyanoiminodithiocarbonate and 2-aminoethanethiol. The drawback of this process is using the relatively expensive diphenyl N-cyanoiminodithiocarbonate compound. This reaction is depicted in the following scheme.


Org. Prep. Procedure Int. 23, (6), 721-728 (1991) describes a method for preparing cyanoimino-l,3-thiazolidine in 48% yield which comprises stirring dimethyl N-cyanoimidocarbonate for a prolonged period at a pH of 10-11 with cysteamine in aqueous sodium hydroxide solution. The melting point of the product thus obtained (m.p. 168°-170°C), however, differs considerably from that of pure 2-cyanoimino-l,3-thiazolidine (m.p. 154°-156°C), since the former is probably contaminated by secondary products. Therefore, further purification would reduce still further the yield from the reported 48%, so that this process is unsuitable for industrial production.

US 5574165 discloses a two-step process for preparing 2-cyanoimino-1, 3-thiazolidine, said process comprising; reacting 2-aminoethanethiol or salt thereof and dialkyl N-cyanoimidocarbonate in a diluent, in the presence of a base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium methylate, potassium methylate, sodium ethylate or potassium ethylate, in the presence of a protective-gas atmosphere to obtain an intermediate which is subsequently cyclized at a pH of from 8 to 9.5 to obtain 2-cyanoimino-1, 3-thiazolidine. In this process the purity of the product is only 95.8%. This reaction is depicted in the following scheme:

Step 1

Step 2
US 5591859 discloses a process for preparation of 2-cyanoimino-l, 3-thiazolidine (CITD), said process comprising; reacting 2-aminoethanethiol or salt thereof (wherein 2-aminoethanethiol is released by addition of a base) and dialkyl N-cyanoimidocarbonate in water and/or an organic solvent in a pH range from 7 to 12, in the presence of a protective-gas atmosphere and completing the cyclization at a pH of > 8 by addition of a base such as alkali hydroxides, alkali carbonates and strongly basic amines in aqueous solution such as diethylamine and diethylamine to obtain 2-cyanoimino-l, 3-thiazolidine.

US 6858737 B2 discloses a process for the preparation of 2-cyanoimino-l,3-thiazolidine comprising the cyclization reaction of dimethyl N-cyanoiminodithiocarbonate with 2-aminoethanethiol or the salt thereof in the presence of an alkali metal hydroxide. This process is limited to the scope of using alkali metal hydroxide as a base and water as the solvent.

Summary of the invention

The present invention provides a process for the preparation of substantially pure 2-cyanoimino-1, 3-thiazolidine of Formula-1,

said process comprising: dissolving alkali metal alkoxide in an organic solvent to obtain a solution of alkali metal alkoxide; adding 2-aminoethanethiol or salt thereof of Formula-II


and dimethyl N-cyanoiminodithiocarbonate ester of Formula-Ill

to said solution of alkali metal alkoxide in inert atmosphere to obtain a reaction mixture; and adjusting pH of said reaction mixture with a mineral acid such as hydrochloric acid, followed by heating to obtain substantially pure 2-cyanoimino-l, 3-thiazolidine of Formula-I.

These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This Summary is provided to introduce a selection of concepts in a simplified form. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

Detailed description of the invention

Accordingly, the present invention provides a process for the preparation of substantially pure 2-cyanoimino-l, 3-thiazolidine of Formula-I,


said process comprising:

a) dissolving alkali metal alkoxide in an organic solvent to obtain a solution of alkali metal alkoxide;

b) adding 2-aminoethanethiol or salt thereof of Formula-II

and dimethyl N-cyanoiminodithiocarbonate ester of Formula-Ill

to said solution of alkali metal alkoxide in inert atmosphere to obtain a reaction mixture; and

c) adjusting pH of said reaction mixture with a mineral acid followed by heating to
obtain substantially pure 2-cyanoimino-l, 3-thiazolidine of Formula-I.

The reaction of the present invention is depicted in the form of the following scheme

According to the present discloser, at the time of reaction, the dimethyl N-cyanoiminodithiocarbonate is gradually added so that the temperature of the reaction mixture does not rise above S^C. After the completion of the addition of the dimethyl N-cyanoiminothiocarbonate ester, the cyclisation reaction is preferably performed at 0°C to 5°C.

The reaction ratio of the dimethyl N-cyanoiminothiocarbonate and acid salt of 2-aminoethanethiol, by molar ratio is, preferably 1: 0.95 to 1.15, more preferably 1: 0.99 to 1.1. If the amount of the 2-aminoethanethiol is too large, an undesirable polymerization reaction occurs resulting in lower yield.

The reaction time of the cyclisation reaction is not particularly limited, but for example is 10 minutes to 5 hours, preferably 1 to 3 hours. If the cyclisation reaction time is too short, the cyclisation reaction does not proceed sufficiently, while if too long, the reaction will not proceed further, and therefore this is not wise economically.

After the end of the reaction, the temperature of the reaction mixture is raised to 10 to 30° C, preferably to about 20°C then the system is adjusted to a pH of 3 to 10 by a suitable acid, preferably 3 to 6. After the adjustment of the pH, an operation is performed to gradually raise the temperature in the system to about 40°C and remove the byproduct that is methyl mercaptan, from the system. It is to be noted that, when removing the methyl mercaptan from the system, the rapid temperature rise becomes a cause of violent bubbling etc., and therefore, this is not preferred. Further, the temperature is not particularly limited, but after the operation for removing the methyl mercaptan from the system is over, the system is cooled to approximately room temperature, the operation of this procedure at a high temperature is not preferable in view of the process time. A temperature of about 35° C to about 45°C is preferable.

Also, the above-mentioned stirring time is not particularly limited, but the treatment is preferably completed for preferably 1 to 5 hours, more preferably 2 to 3 hours. By removing the byproduct methyl mercaptan from the system in vacuo during the stirring, it is possible to reduce the odor of the product and the surrounding environment.

According to the present discloser, next, the resultant reaction mixture containing the 2-cyanoimino-],3-thiazolidine obtained is again cooled to about 0°C to about 5°C, preferably about 0°C, then the resultant 2-cyanoimino-l,3-thiazolidine is filtered and then washed. This washing can be performed with water or another solvent (for example, methanol, ethanol, etc.), but from the viewpoints of economy and environment, the washing with water is preferred.

The drying conditions of the 2-cyanoimino-l,3-thiazolidine thus produced are also not particularly limited and also differ depending on the type of the dryer, but when using a box type dryer, the drying is preferably carried out at a drying temperature of 60 to 120° C, more preferably 80 to 100° C for a drying time of preferably 30 minutes to 24 hours, more preferably 3 to 6 hours, and a degree of vacuum of preferably 25 mmHg or less.

As specific examples of mineral acids used for controlling the pH of the reaction mixture, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc. may be mentioned, but from an economical viewpoint, the use of hydrochloric acid or sulfuric acid is preferred.

An embodiment of the present discloser the alkali metal alkoxide is first dissolved in an organic solvent. Specific examples of the alkali metal alkoxides used in the present invention are sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium butoxide, sodium isobutoxide, potassium butoxide, or the like, preferably sodium methoxide is used. These alkali metal alkoxides are used in amounts of preferably 1 to 1.5 moles based upon 1 mole of acid salt of 2-aminoethanethiol.

Another embodiment of the present discloser the organic solvent is a lower straight or branched chain alcohol consisting of C1 -C4 carbon atoms, tetrahydrofuran or toluene or a mixture thereof.. The lower straight or branched chain alcohol consisting of C1-C4 carbon atoms is methanol, ethanol, propanol, isopropanol, and the like.

Yet another embodiment of the present discloser the acid salt of 2-aminoethanethiol is selected from the group of hydrochloride, sulfate, nitrate, carbonate, acetate or the like. Any salt alone or any combination thereof may be used, but the use of a mineral acid salt is preferable from the viewpoint of the reactivity, while a hydrochloride is more preferable from the viewpoint of solubility, and economy. The acid salt of 2-aminoethanethiol is added to an alkali metal alkoxide preferably in such an amount that the molar ratio with the alkali metal alkoxide comes in the above range, and then the mixture is cooled to 0 to 5°C, preferably to 0C.

In an embodiment of the present discloser the molar ratio of alkali metal alkoxide to acid salt of 2 aminoethanediol is from 1:1 to 1.5:1

Although the subject matter has been described in considerable detail with reference to certain preferred embodiments thereof, other embodiments are possible. As such, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiment contained therein.

EXAMPLE:

The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure.

EXAMPLE 1

Preparation of 2-Cyanoimino-l, 3-Thiazolidine

A 100 ml four-necked flask provided with a thermometer and a stirrer is charged with 8 g of methanol (0.25 moles) and 2.5 g of sodium methoxide (0.046 mole, 1.36 moles based upon 1.1 mole of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in the methanol. Then, 4.2 g of 2-aminoethane thiol hydrochloride (0.037 moles) was added thereto and dissolved therein, and the reaction mixture is cooled to 0°C. To this reaction mixture, 5g of dimethyl N-cyanoiminodithiocarbonate (0.034 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5° C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40° C and stirred for 2 hours. After stirring, the reaction mixture was cooled to 0° C and the crystals were suction filtered and washed with 15ml of water to obtain 3.8 g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals were dried in vacuo at 80° C under reduced pressure for 5 hours to obtain 3.5 g of 2-cyanoimino-l,3-thiazolidine (yield 80%) with 99.9% HPLC purity.

EXAMPLE 2

Preparation of 2-Cyanoimino-l, 3-Thiazolidine

A 100 ml four-necked flask provided with a thermometer and a stirrer is charged with 4 g of methanol and 6,5ml of 30% sodium methoxide solution (0.0342 mole, 1 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in methanol, then 4.2 g of 2-aminoethane thiol hydrochloride (0.037 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0°C and 5g of dimethyl N-cyanoiminodithiocarbonate (0.034 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5°C for 2 hours. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36%) w/w) and further heated to 40°C and stirred for 2 hours. After stirring, the reaction mixture was cooled to 0°C and the crystals are suction filtered and washed with 15ml of water to obtain 3.8 g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80° C under reduced pressure for 5 hours to obtain 3.5 g of 2-cyanoimino-l, 3-thiazolidine (yield 80%) with >99% HPLC purity.

EXAMPLE 3

Preparation of 2-Cyanoimino-l, 3-Thiazolidine

A 1 litre four-necked flask provided with a thermometer and stirrer is charged with 90g of methanol (2.815 moles) and 36g of sodium methoxide (0.667 moles, 1.3 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in methanol, then 63.5g of 2-aminoethane thiol hydrochloride (0.564 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0° C and 75g of dimethyl N-cyanoiminodithiocarbonate (0.514 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5° C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40° C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0° C and the crystals are suction filtered and the slurry thus obtained is washed with 225ml of chilled water to obtain 66g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80° C under reduced pressure for 5 hours to obtain 58g of 2-cyanoimino-l, 3-thiazolidine (yield 85.8%) with 99.9% HPLC purity.

EXAMPLE 4

Preparation of 2-Cyanoiniino-l, 3-Thiazolidine

A l litre four-necked flask provided with a thermometer and stirrer is charged with 60g of ethanol (1.304 moles) and 30.2g of sodium ethoxide (0.444 moles, 1.3 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in ethanol and then 42.3g of 2-aminoethane thiol hydrochloride (0.376 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0°C and 50g of dimethyl N-cyanoiminodithiocarbonate (0.342 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5° C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40° C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0° C and the crystals are suction filtered and the slurry thus obtained is washed with 150ml of chilled water to obtain 44g of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80°C under reduced pressure for 5 hours to obtain 36g of 2-cyanoimino-l, 3-thiazolidine (yield 83%) with 99.5% HPLC purity.

EXAMPLE 5

Preparation of 2-Cyanoimino-l, 3-Thiazolidine

A 100ml four-necked flask provided with a thermometer and stirrer is charged with 7g of toluene (0.076 moles) and 1g of sodium methoxide (0.0185 moles, 1.36 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under nitrogen. The mixture is cooled and stirred to dissolve in toluene, then 1.73g of 2-aminoethane thiol hydrochloride (0.016 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0° C and 2g of dimethyl N-cyanoiminodithiocarbonate (0.0136 moles) is added keeping the inside temperature at 5° C or less. After the end of addition, the mixture is allowed to react at 0 to 5° C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20° C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40°C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0°C and the crystals are suction filtered and the slurry thus obtained is washed with 6ml of chilled water to obtain l.lg of 2-cyanoimino-l, 3-thiazolidine. The wet crystals are dried in vacuo at 80°C under reduced pressure for 5 hours to obtain 0.9g of 2-cyanoimino-1, 3-thiazolidine (yield 52%) with >99% HPLC purity.

EXAMPLE 6

Preparation of 2-Cyanoimino-l, 3-Thiazolidine

A 100ml four-necked flask provided with a thermometer and stirrer is charged with 6.2g of tetrahydrofuran (0.0861 moles) and 1g of sodium methoxide (0.0185 moles, 1.36 mole equivalent based upon 1.1 mole equivalent of 2-aminoethane thiol hydrochloride) under
nitrogen. The mixture is cooled and stirred to dissolve in the tetrahydrofuran (THF) and then 1.73g of 2-aminoethane thiol hydrochloride (0.016 moles) is added thereto and dissolved therein. The reaction mixture is cooled to 0°C and 2g of dimethyl N-cyanoiminodithiocarbonate (0.0136 moles) is added keeping the inside temperature at 5°C or less. After the end of addition, the mixture is allowed to react at 0 to 5°C for 2 hours under nitrogen. Thereafter, the reaction mixture is heated to 20°C and pH is adjusted to 4 with aqueous hydrochloric acid solution (36% w/w), then further heated to 40°C and stirred for 2 hours. After stirring, the reaction mixture is cooled to 0°C and the crystals are suction filtered and the slurry thus obtained is washed with 6ml of chilled water to obtain 1.3g of 2-cyanoimino-1, 3-thiazolidine. The wet crystals were dried in vacuo at 80°C under reduced pressure for 5 hours to obtain l.lg of 2-cyanoimino-l, 3-thiazolidine (yield 63%) with >99%» HPLC purity.

Advantage of the present invention

The previously described versions of the subject matter and its equivalent thereof have many advantages, including those which are described below

a) The process of the present invention uses reduced volumes of solvent to achieve good yields of substantially pure 2-cyanoimino-l, 3-thiazolidine.

We claim:

1. A process for the preparation of 2-cyanoimino -1,3- thiazolidine said process
comprising dissolving alkali metal alkoxide in an organic solvent , adding 2-
aminoethanethiol of formula II or salts thereof

and dimethyl N cyanoiminodithiocarbonate ester of formula III

in inert atmosphere to obtain a reaction mixture, adjusting the pH of the reaction mixture with a mineral acid and then heating to obtain substantially pure 2-cyanoimino -1,3- thiazolidine, wherein the molar ratio of alkali metal alkoxide to acid salt of 2 aminoethanediol is from 1:1 to 1.5:1 and the molar ratio of dimethyl N cyanoiminothiocarbonate to acid salt of 2 aminoethanethiol is from 1:0.95 to 1:1.15.

2. A process as claimed in claim 1 wherein the alkali metal alkoxide is selected from sodium ethoxide, sodium ethoxide , potassium ethoxide ,potassium ethoxide ,sodium but oxide, sodium isobutoxide, potassium but oxide.

3. A process as claimed in claim 1 wherein the organic solvent is a lower straight or branched chain alcohol of C1-C4 carbon atom ,tetrahydrofuran or toluene or a mixture thereof.

4. A process as claimed in claim 1 wherein the salt of the compound of formula II
is selected from the group of hydrochloride, sulfate, nitrate, carbonate or acetate.

5. A process as claimed in claim I wherein the mineral acid is selected from
hydrochloric acid, sulfuric acid ,nitric acid, carbonic acid or phosphoric acid.

6. A process as claimed in claim 1 wherein time of reaction is 10 min to 5 hrs.

7. A process as claimed in claim1 wherein the pH of the reaction mixture is 3-10.