Title of Invention

A PROCESS FOR THE PREPARATION OF N-(2-CHLORO-5-PYRIDYLMETHYL)-2-CYANOIMINOTHIAZOLIDINE(THIACLOPRID)

Abstract The invention disclosed in this application relates to an improved process for the preparation of insecticides of formula-I Which comprises (i) Condensing dipotassium salt of N-cyanodithioiminocarbonate of the formula (II) with benzyl chloride of the formula (III) in the presence of a solvent. (ii) converting the resultant compound from the above step of formula (Iv) into 2-cyanoiminothiazoiidine of the formula (VI) by the reaction with cysteamine hydrochloride of formula (v) in the presence of a base. (i i i) Condensing the 2-cyanoiminothiazolidine of formula vI with 2-chloro-5-chloromethylpyridine of the formula VII in presence of base to give N- (2-chloro-5-pyridyl methyl)-2-cyanoiminothiazolidine of formula I.
Full Text FORM 2
THE PATENTS ACT, 1970
COMPLETE SPECIFICATION [SEE SECTION 10]
A PROCESS FOR THE PREPARATION OF N-(2-CHLORO-5-PYRIDYLMETHYL)-2-CYANOIMINOTHIAZOLIDINE (THIACLOPRID)
RALLIS INDIA LIMITED, 21 D.S.MARG, FORT,
MUMBAI-400 001. MAHARASHTRA NATIONALITY - INDIAN
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.


ORIGINAL

GRANTED
7-1-2005

Field of Invention:
The present invention relates to an improved process for the preparation of N-(2-Chloro-5-pyridylmethyl)-2-cyano imino thiazolidine having the formula I given below

I are useful as a broad spectrum and systemic insecticides, for the control of
sucking insects, aphids, thrips, hoppers, whiteflies, scales and mealy bugs.
This invention also relates to the derivatives of the above formula I where S group can be substituted by NH group which are ideal for controlling certain insect pests, which are of economic importance from the point of crop losses for example aphids, thrips, leaf hoppers, plant hoppers, whiteflies, from the order of homoptera on various crops.
Prior Art
The process of preparation of N - (2-Chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine of formula I involves the condensation of two important intermediates namely N- Cyano imino thiazolidine of formula VI and 2-Chloro-5-Chloro methyl pyridine of formula VII.
The condensation reaction between N- Cyano imino thiazolidine of formula VI
and 2-Chloro-5-Chloro methyl pyridine of formula VII as reported in US Patent
No: 6211379. involves the condensation of 2-Chloro-5-Chloro methyl pyridine
with N- Cyano imino thiazolidine in the presence of n-Butanol as solvent at 80°C
in presence of bases like sodium, potassium or calcium hydroxides or sodium or
potassium carbonates

Method of preparing 2- cyanoiminothiazolidine of formula VI is described in US Patent No: 5591589, which comprises the reaction of 2- Amino ethane thiol with a dialkyl N- Cyano imidocarbonate in ethanol or water as solvent and at a temperature ranging from -10°C to 40 deg C and at a pH value of 7 - 12
The above-mentioned process involves the liberation of obnoxious gases like ethane thiol, which are not easy to scrub, recover and reuse. Due to environmental considerations this process cannot be applied industrially
Considering the importance of 2-chloro-5-chloromethyl pyridine)-2-cyano imino thiazolidine as an insecticide a need was felt to develop an improved process for its preparation which can be applied for its commercial production which will be environmentally safe.
Objectives of the invention:
The main objective of the present invention is to provide a simple and convenient process for the preparation of N-(2chloro-5-pyridylmethyl)-2-cyano imino thiazolidine.
Another objective of the present invention is to provide an industrially applicable process for the preparation of N-(2chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine.
Yet another objective of the present invention is to provide an efficient process for the recovery and recycle of benzylthiol by converting it to benzyl chloride in the process.

Description of the invention:
Accordingly the present invention provides a process for the preparation of insecticides of formula-I

Which comprises the following steps
Step I Condensing dipotassium salt of N-cyanodithioiminocarbonate of the formula (II) with benzyl chloride of the formula (III) in the presence of an aqueous solvent or an aqueous solvent mixture.
Step II
Converting the resultant compound from the above step of the formula (IV) into
2-cyanoiminothiazolidine of the formula (VI) by the reaction with cysteamine
hydrochloride of the formula (V) in the presence of a base,
Step III
Condensing the 2-cyanoiminothiazolidine of formula VI with 2-chloro-5-
chloromethylpyridine of the formula VII in presence of base to give N-(2-chloro-5-
pyridylmethyl)-2-cyanoiminothiazolidine of formula I.
The above reactions are shown in the scheme given below


The first step of the process namely the reaction between 0.1 mole of di potassium /sodium salt of N-cyanodithioiminocarbonate and 0.22 moles of benzyl chloride may be carried out in the presence of an aqueous solvent mixture of methanol and water, water and acetone, ethanol and water, acetonitrile and water etc. More preferably methanol and water mixture or acetone and water mixture. The amount of solvent, which may be employed, may be in the range of 10-15 times molar equivalents of dipotassium salt of N-cyano dithio imino carbonate.
The first step of the process may be carried out at a temperature in the range of -10°C to 30°C by using ice salt mixture bath.

The second step of the process involves the condensation reaction between 0.1 mole of dibenzyl N-cyano dithioimino carbonate of the formula (IV) and cysteamine hydrochloride is carried out in the presence of bases such as hydroxides, carbonates, bicarbonates taken in equal mole ratios of starting material in presence of an aqueous solvent like water. The reaction is carried out on a cool water bath in the temperature range of 0-25°C initially for 3 hours and then heated to 30 - 60 °C for 2 - 4 hours.
The benzyl thiol liberated in the second step of the process can be recovered by trapping it in water, which is cooled in an ice bath and then extracted in a suitable organic solvent like ethyl acetate. After the reaction the solvent is evaporated to get benzyl thiol. The benzylthiol thus obtained is refluxed with thionyl chloride to get benzyl chloride, which can be used, in the subsequent reactions after fractional distillation.
The third step of the process involves the reaction between 0.1 mole of 2-cyanoiminothiazolidine and 0.1 mole of 2-chloro-5-chloromethylpyridine, which is carried out in presence of bases like hydroxides, carbonates or bicarbonates in presence of solvents like acetone, acetonitrile, n-butanol, ethanol, N, N-Dimethyl formamide or DMSO, more preferably N,N-Dimethyl formamide or DMSO or n-butanol at temperatures ranging from 0-80°C, more preferably 0-40°C on a water bath.
The following examples illustrate the manner in which the invention has to be carried out and not construed to limit the scope of the invention.

Example 1 Step -1
(a) Process for the preparation of Dibenzyl-N-cyanodithioiminocarbonate of
formula IV.
19.4g (0.1 mole) dipotassium salt of N-cyanodithioiminocarbonate is reacted with
27.83g benzyl chloride (0.22 mole) in acetone water mixture (50ml + 50ml) at 0-
10 °C for 3hrs. After 3hrs organic layer is separated, dissolved in methylene
chloride.dried over anhydrous sodium sulphate. Solvent is distilled off to get this
pure product of purity 95%.
Yield = 25g (83% of theory)
(b) Process for the preparation of Dibenzyl-N-cyanodithioiminocarbonte
19.4g (0.1 mole) dipotassium salt of N-cyanodithioiminocarbonate is reacted with 27.83g benzyl chloride (0.22 mole) in methanol -water mixture (50ml + 50ml) at 0-10°C for 3hrs. After 3hrs, the organic layer is separated, extracted in methylene chloride, dried over anhydrous sodium sulphate. Solvent is distilled off to get the pure product of purity 95%.
Yield = 20g(67%of theory)

Example 2 Step - 2
(a) Process for the preparation of 2-cyanoimino thiazolidine.
11.6g of 2-aminoethanethiol hydrochloride is dissolved in 5 ml of water under nitrogen atmosphere and 16.0g (0.1 mole) of a 25% (w/w) sodium hydroxide solution is added, Then 19.4g (0.1 mole) of dibenzyl-N-cyano dithio imino carbonate obtained in step 1 is added portion wise. The temperature is maintained at 20°C for 2.5 hours after which the temperature is increased to 50°C and the reaction mass is stirred for 3 hours at this temperature. The pH is adjusted to 6 by adding hydrochloric acid and subsequently cooled to 10°C. The colorless solid is filtered and washed well with water, and then dried in vacuum. Yield: 9.9 g (78% of theory) Purity: 99%
(b) Recovery and recycle of Benzyl thiol
The benzyl thiol liberated in this step is trapped in water and is present in the mother liquor of the reaction mixture, which is collected from the filtrate, after recovering the solvent. The benzyl thiol is extracted from the aqueous filtrate by using ethyl acetate and the ethyl acetate is distilled off to get benzyl thiol. The benzyl thiol thus obtained is refluxed with 28.56 g (0.24 moles) of thionyl chloride to get benzyl chloride, which is purified by fractional distillation.

Example 3 Step 3
(a) Process for the preparation of N- (2-chloro-5-pyridyl methyl)-2-cyano imino thiazolidine
12.7 g (0.1 mole) of 2-cyanoiminothiazolidine obtained in step 2 is reacted with
16.2 g of 2-chloro-5-chloromethyl pyridine (0.1 mole) in N, N - Dimethyl
Formamide (90ml), in presence of potassium hydroxide 5.88 g (0.1 mole) at
40°C for 6 hours. Once the starting materials have been converted the solvent is
distilled off under vacuum and the product is crystallized from ethanol.
Yield: 17.6 g (70% of theory)
Purity: 99%
(b) Preparation of N-(2-chloro-5-pyridyl methyl)-2-cyano imino thiazolidine
12.7 g of 2-cyanoiminothiazolidine and 16.2 g of 2-chloro-5-chloromethyl pyridine
are dissolved in 80 g of n-Butanol and the solution is heated to 80°C. At this
temperature 0.12 mole (7.02g) of potassium carbonate is added and stirred at
80°C for 2 more hours.
After cooling the reaction mixture to 65°C water is added and the layers are
separated the organic phase is stirred at 50°C for 3 hours and subsequently
cooled to 3°C. The precipitated product is filtered and dried.
Yield: 16.3 g (65% of theory)
Purity: 98 %

Advantages of the invention
1. The process is simple and convenient for the preparation of N-(2chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine.
2. The process can be industrially applied for the preparation of N-(2-chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine.
3. The process is efficient for the recovery and recycle of benzylthiol by converting it to benzyl chloride in the process.

We Claim
1. A process for the preparation of N-(2-Chloro-5-Pyridylmethyl)-2-cyanoimino thiazolidine of formula-1 as given below


The reaction of dipotassium salt of N-cyanodithioiminocarbonate of the formula (II) as given above with benzyl chloride of the formula (III) as given above in the presence of an aqueous solvent or an aqueous solvent mixture to give the dibenzyl salt of N- Cyanodithioiminocarbonate of formula (IV)

Reaction of di benzyl salt of N - Cyano dithioiminocarbonate of formula (IV) as
given above, with cysteamine hydrochloride of formula V as given above, to give
2-cyanoiminothiazolidine of the formula (VI) as given above, in the presence
of a base,


Condensing the 2-cyanoiminothiazolidine of formula VI as given above, with 2-chloro-5-chloromethylpyridine of the formula VII as given above, in presence of base to give N-(2-chloro-5-pyridylmethyl)-2-cyanoiminothiazolidine of formula I as given above.
2. A process as claimed in claim 1 wherein the Step I reaction between the dipotassium/sodium salt of N-cyanodithioiminocarbonate and benzyl chloride is effected in the presence of an aqueous solvent mixtures of methanol and water, water and acetone, ethanol and water, acetonitrile and water etc.
3. A process as claimed in claim 2 wherein the aqueous solvent mixture employed used is methanol and water or acetone and water.
4. A process as claimed in claims 2 & 3 wherein the amount of solvent present in the mixture ranges from 10-15 times molar equivalents of dipotassium salt of N-cyano dithio imino carbonate.
5. A process as claimed in claims 1 to 4 wherein the process is carried out at a temperature in the range of-10°C to 30°C preferably in the range of-10°C to 20°C on an ice salt mixture bath.
6. A process as claimed in claim 1 wherein the bases used are hydroxides, carbonates, and bicarbonates taken in equal mole ratios as that of starting material

7. A process as claimed in claims 1 & 7 wherein the Step II of the process is carried out at a temperature in the range of 0-25°C initially for 3 hours and then heated to 30 - 60 °C for 2 - 4 hours on a water bath.
8. A process as claimed in claim1 wherein the benzylthiol liberated in step II of the process is recovered and then extracted in ethyl acetate and then the ethyl acetate is evaporated to get benzyl thiol, which is refluxed, with thionyl chloride to get benzyl chloride, which is reused after fractional distillation.
9. A process as claimed in claiml wherein the Step III of the process, the reaction between 2-cyanoiminothiazolidine and 2-chloro-5-chloromethylpyridine is effected in presence of bases like hydroxides, carbonates and in presence of solvents like n-butanol, ethanol, N,N-Dimethyl formamide
10. A process as claimed in claim 10 wherein the reaction is effected at a temperature ranging from 0-80°C, preferably 0-40°C

Documents:

19-mum-2003-abstract(07-01-2005).pdf

19-mum-2003-abstract-(7-1-2005).doc

19-mum-2003-cancelled pages(07-01-2005).pdf

19-mum-2003-claims(granted)-(7-1-2005).doc

19-mum-2003-correspondence(ipo)-(19-05-2008).pdf

19-mum-2003-correspondence1(09-05-2008).pdf

19-mum-2003-correspondence2(07-01-2005).pdf

19-mum-2003-form 1(06-01-2003).pdf

19-mum-2003-form 1(28-02-2003).pdf

19-mum-2003-form 19(21-11-2003).pdf

19-mum-2003-form 2(granted)-(07-01-2005).pdf

19-mum-2003-form 2(granted)-(7-1-2005).doc

19-mum-2003-form 3(27-12-2004).pdf


Patent Number 207147
Indian Patent Application Number 19/MUM/2003
PG Journal Number 43/2008
Publication Date 24-Oct-2008
Grant Date 23-May-2007
Date of Filing 06-Jan-2003
Name of Patentee RALLIS INDIA LIMITED
Applicant Address "RALLI HOUSE" 21, D.S. MARG, FORT, MUMBAI 400 001, MAHARASHTRA, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 MOODALAMAKKI SATHYANARAYANA MITHYANTHA RALLIS RESEARCH CENTRE, #21 & 22, PEENYA INDUSTRIAL AREA, PHASE - II, BANGALORE - 560 058, KARNATAKA, INDIA.
2 KOTHAPALLI SUNDARARAJA RAO, RALLIS RESEARCH CENTRE, #21 & 22, PEENYA INDUSTRIAL AREA, PHASE - II, BANGALORE - 560 058, KARNATAKA, INDIA.
3 KANAKAMAJULU SHRIDHARA BHAT RALLIS RESEARCH CENTRE, #21 & 22, PEENYA INDUSTRIAL AREA, PHASE - II, BANGALORE - 560 058, KARNATAKA, INDIA.
4 ALILUGATTA SESHAGIRI RAO PANIRAJ RALLIS RESEARCH CENTRE, #21 & 22, PEENYA INDUSTRIAL AREA, PHASE - II, BANGALORE - 560 058, KARNATAKA INDIA.
5 NADOLI BHAVANA RALLIS RESEARCH CENTRE, #21 & 22, PEENYA INDUSTRIAL AREA, PHASE - II, BANGALORE - 560 058, KARNATAKA, INDIA.
PCT International Classification Number A01N 25/02
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA