Field of invention
The present invention relates to a synthetic process for preparing the side-chain precursor l-(mercaptomethyl)cyclopropaneacetic acid, which is useful in the synthesis of leukotriene receptor antagonist such as Montelukast and salts thereof.
This invention describes an improved and industrially scalable process for the preparation of l-(rnercaptomethyl)cyclopropaneacetic acid, one of key intermediates of anti asthamatic drug, Motelukast, using an inexpensive and commercially available chemical, Dibromoneopentylglycol.
Background of the Invention:
Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti¬asthmatic, anti-allergic, anti-inflammatoryand cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis. Chemically Montelukast sodium is described as a [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(l-hydroxy-methylethyl)phenyl]propyl]thio]methyl] cyclopropaneacetic acid, monosodium salt having an empirical formula C35H35ClNNa03S, and molecular weight 608.18 and is represented by the structural Formula I below:

According to US patent US 5,270,324 A and US-5,565,473 A, the patent describes process for the preparation of l-(mercaptomethyl)eyclopropaneacetic acid is described in following methods:

Method 1:

Method 2:

Method 3: --

Method 4:


Due to the strong disagreeable odour used, the manipulation of these reagents and the corresponding synthetic intermediates is technically demanding. Further, essentially all the key intermediates in known syntheses are liquids or oils, which require either vacuum distillation or column chromatography in order to obtain the products with the desired purity.
According to US patent US 5,614,632 A the process comprises converting the starting
material 1,1-cyclopropanedimethanol into the corresponding cyclicsulfite by using
thionyl chloride and in the presence of a base such as diisopropylethylamine. The
cyclic sulfite is treated with catalytic amount of sodium iodide and sodium cyanide to
obtain the compound l-(hydroxymethyl)cyclopropaneacetonitrile, which is converted
into the corresponding mesylate l-(methanesulfonyloxymethyl)-
cyclopropaneacetonitrile, by using methanesulfonyl chloride in the presence of a base. The obtained compound is treated with potassium thioacetate or thioacetic acid in the presence of a base to yield the " compound l-(acetylthiomethyl)-cyclopropaneacetonitrile.the obtained compound is converted into 1 -(mercaptomethyl)cyclopropaneacetic acid by reacting in a biphasic solvent system comprising toluene and aqueous NaOH for 16-18 hours.

The intermediate l-(mercaptomethyl)cyclopropaneacetic acid is not stable and is being prone to oxidation like many other thiols, This is evident from example 4 of the "'632 patent, Which tackles the instability problem of l{mercaptomethyl)cyclopropaneacetic acid by carrying out the reaction under intert atmosphere. In addition, the use ofthioacetic acid or it's alkali metal salt is imfavorable on industrial scale because of high toxicity or pungent odor.

According to US patent US 5,523,477 A, the process for l-(mercaptomethyl) cyclopropaneacetic acid comprises contacting 151 -cyclopropanedimethanol with dialkylsulfite in the presence of a base or acid; followed by sodium cyanide and sodium iodide to provide the l-(hydroxymethyl)cyclopropaneacetonitrile, which is protected with methanesulfonyl (mesyl) group and reacted with thioacetic acid and followed by hydrolysis in a biphasic solvent containing base.

However, the process involving thioacetic acid and due to'its strong disagreeable odour, the manipulation of these reagents and the corresponding synthetic intermediates is technically demanding. In addition, the final step of each of these syntheses involves a hot basic hydrolysis in which the temperature may range from 90°C for 9-12 hours to aqueous reflux. Since l-(mercaptomethyl)-cyclopropaneacetic acid is sensitive to oxidation, the use of such harsh reaction conditions may lead to reduced yields and/or product of unacceptable purity.
According to US Patent US 5,534,651 A, the process for preparing 1-(mercaptomethyl) cyclopropaneacetic acid comprises the treating 5-oxaspiro[2.4]heptan-6-one with potassium thioacetate in the presence of hydroquinone and N,N-dimethylacetamide and followed by basic hydrolysis.


However, the process suffers from use of less stable cyclic ester and thioester and use of expensive hydroquinone and toxic potassium thioacetate.
According to US Patent US 6,512,140 Bl the process comprises reacting 1
(hydroxymethyl)cyclopropaneacetonitrilewith an acid, to thus obtain the
corresponding mixture of cyclic imino ether and halo-amide, which when reacted with
thiourea provides the corresponding amide-isothiuronium salt . Hydrolysis of the
amide-isothiuronium salt followed by an in-situ oxidation affords the intermediate 1-
(mercaptomethyl)cyclopropaneacetic acid disulfide, which affords the finalproduct
upon treatment with a solution containing ammonium hydroxide and metal Zinc for
3.5 hours followed by treatment with .citric acid, thus, the oxidation problem of the
corresponding amide was solved by dimerizing the thiolamide, which may yield the
requested product by reduction. —

However, it is lengthy and contains laborious procedures, this production process industrially required anhydrous conditions in the reaction of anhydrous boric acid is difficult to apply to the manufacturing process, is long and the overall yield is generally low and industrially in order to suppress the by-product produced is much improved in terms of efficiency is required.

According to US Patent US7,271,268 B2 describes the process for for preparing 1-(mercaptomethyl) cyclopropaneacetic acid as the schematical representation given below:

US '268 that it is lengthy and contains laborious procedures. Further, conversion of 1
(hydroxymethyl)cyclopropaneacetonitrile to (1 -
(bromomethyl)cyclopropyl)acetonitrile involves use of PBr3. and there are some difficulties in separation and purification of each step.
According to US patent US7,572,930 B2, the process treating of 1 (hydroxymethyl)cyclopropaneacetonitrile with Ph3P/Br2 and followed treating the obtained (1 -(bromomethyl)cyclopropyl)acetonitrile with thiourea followed by hydrolysis.

According to PCT application WO 2013/105688 Al, the specification describes a alternate process for the preparation of disulfide compound using sodium disulfide.

According to WO 2013/149364 Al the process comprises acetylating tribromo-neopentyl alcohol in an acetylating agent, so as to obtain a tribromo-neopentyl acetate; reducing the tribromo-neopentyl acetate in the presence of zinc powder and a catalyst to obtain methyl l-(bromomethyl) cyclopropyl acetate; substituting the methyl I-(bromomethyl) cyclopropyl acetate with a cyanide in an organic solvent; and then performing ester hydrolysis under basic conditions to obtain the 1-hydroxymethyl cyclopropyl acetonitrile.

According to CN101880270 A, the process for preparing 1,1-cyclopropanedimethyl cyclicsulfite comprises reacting dibromoneopentyl glycol with thionyl chloride in a first reaction solvent to fonn cyclicsulfite serving as a solid intermediate; and the

cyclicsulfite is reacted with zinc powder in a second reaction solvent to form a 1,1-cyclopropanedimethyl cyclicsulfite.

Although this method less reaction steps, process route is short, low raw material prices, but the method is not only the intermediate cyclic sulfite extracted before the next reaction, cyclization reaction temperature is high, the lower the yield of the final product, and direct filtration, low product quality, is not conducive to industrial production.
According to CN102206201 A the process comprising esterifying dibromoneopentyl glycol with thionyl chloride, and followed by cyclizing using zinc powder in the presence of amide solvent such as DMF and DMAc and involves the use of a complexing agent complexation to give cyclopropylmethylenesulfonate.

However, use of amide solvents in the reaction suffers toxic effect of the solvent.
According to CN 102757311 A the process for the preparation of 1,1-cyclopropane dimethanol involves ring-closure reaction of organic dihalide and a reducing agent in an alcohol solvent under a certain condition to obtain a solution of 1, 1-cyclopropane dimethanol and halide salt, introducing ammonia under certain conditions so as to conduct solid-liquid separation, filter and rectify to obtain 1,1 -cyclopropane dimethanol.
^


According to CN 104860845 A, the process for the preparation of 1-(hydroxymethyl) cyclopropaneacetonitrile comprises the reaction of cyclopropylmethylenesulfonate with sodium cyanide and sodium iodide, tetrabutylammonium bromide.

According to CN 103539714 A an alternate process for preparation of 1-(mercaptomethyl) cycroproparieacetic acid is described as'depicted in the'scheme given below which also suffer from use of toxic thioacetate and reaction selectivity and low yield.

According to CN 103288695 Aa alternate process for preparing the 1-mercaptomethylcyclopropyl acetic acid with 1,4-butanediol as a starting raw material which is cheap, low in toxicity and easy to obtain as a starting raw material through reactions such as etherification or esterification, oxidization, corey-chaykovsky or simmons-smith, reduction, substitution, deprotection and the like, However, the process is lengthy and reduced overall yield.

All the prior art process suffers the use of toxic compounds or solvent, low yield.There is need to provide an improved process for the preparation l-(mercaptomethyl) cyclopropaneacetic acid. Considering the importance of, there is need for a simple, economical and industrially viable and odorless process for the preparation ofl-(mercaptomethyl) cyclopropaneacetic acid, with a view to find a simple process applicant diligently worked and identified a simple, robust and economical process for the preparation of l-(mercaptomethyl) cyclopropaneacetic acid
Object of the Invention:
The primary object of the invention is to provide a process for the preparation of 1-
(bromomethyl) cyclopropaneacetonitrile.. starting .„,. from 1-
(hydroxymethyl)cyclopropaneacetonitrile.
Another object of the present invention is to provide a process for the preparation of l-(bromomethyl) cyclopropane-acetonitrile starting from 2,25-dibromoneopentyl glycol.
Another object of the invention is to provide a process for the preparation of 1-
(mercaptomethyl)cyclopropaneacetic acid starting from 1 -
(hydroxymethyl)cyclopropane acetonitrile.
Another object of the invention is to provide a process for the preparation of 1-(mercaptomethyl)cyclopropaneacetic acid starting from 2,2'-dibromoneopentyl glycol.
Another object of the present invention is to provide a process for the preparationl-(hydroxymethyl)cyclopropaneacetonitrile starting from 1,1-cyclopropanedimethanol cyclicsulfate using of less toxic solvent DMSO avoiding other additional components such as catalyst or reagents.

Summary of the Invention:
The present invention relates to a process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of Formula III:
which comprises the steps:
a) treating the l-(hydroxymethyl)cyclopropaneacetonitrile of Formula V:

with a compound of having formula R-SO2CI; wherein R is alkyl or aryl. Preferably methyl or tolyl.
b) treating the obtained compound of Formula IV:

with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst.
Yet another embodiment of the present invention is to provide a process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of Formula III:

which comprises the steps:
a) esterifying the compound of formula VIII:


whereinX is leaving group such as chloro, bromo, iodo, mesyl and tosyl and like.; with thionyl chloride in a suitable solvent;
b) the obtained compound of Formula VII:

wherein X is as defined above; is treated with Zinc powder in the presence of water, alcohol or mixture thereof;
c) treating the obtained compound of Formula VI
o
M
o o
V
Formula VI
with sodium cyanide in the presence of DMSO;
d) treating the compound of l-(hydroxymethyl) cyclopropaneacetonitrile of Formula
V:

with a compound of having formula R-SO2CI; wherein R is alkyl or aryl. Preferably methyl or tolyl.
e) treating the obtained compound of Formula IV:


with a metal bromide of Formula M+Br"; wherein M is. Monovalent atom such as H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst to provide compound of Formula III.
Yet another embodiment of the present invention is to provide a process for the preparation of l-(mercaptomethyl)cyclopropaneacetic acid Formula I:
which comprises the steps:
a) esterifying the compound of formula VIII:

wherein X is leaving group such as chloro, bromo, iodo, mesyl and tosyl and like.; with thionyl chloride in a suitable solvent;
b) the obtained compound of Formula VII:

wherein X is as defined above; is treated with Zinc powder in the presence of water, alcohol or mixture thereof;
c) treating the obtained compound of Formula VI

with sodium-cyanide in the presence of DMSO;

d) treating the obtained compound of l-(hydroxymethyl) cyclopropaneacetonitrile of
Formula V:

with a compound of having formula R-S02C1; wherein R is alkyl or aryl. Preferably methyl or tolyl.
e) treating the obtained compound of Formula IV:

with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst to provide compound of Formula III.
f) treating the compound of formula III with thiourea in the presence of acetone to
give compound of Formula II:

g) hydrolyzing the compound of Formula II using base to provide compound of
Formula I.

Detailed Description of the Invention:
The present invention relates to a process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of Formula III:

which comprises the steps:
a) treating the l-(hydroxymethyl) cyclopropaneacetonitrile of Formula V:

with a compound of having formula R-S02C1; wherein R is alkyl or aryl. Preferably methyl or tolyl.in the presence of suitable solvent and a base;
b) treating the obtained compound of Formula IV:
2 o y( CN
with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst.
As used herein, the term "alkyl55 means a saturated, straight chain or branched, non-cyclic hydrocarbon having from 1 to 5 carbon atoms.Preferably methyl, ethyl, propyl, isopropyl, butyl and isobutyl and like.;
As used herein, the term "aryl" means is phenyl or substituted phenyl such tolyl, halophenyl and like.;
In an embodiment of the present invention the suitable solvent used is a non-polar aprotic solvent. Preferably the suitable solvent is methanol, ethanol, Isopropyl alcohol, N-N- dimethylformamide, dichloromethane, toluene and dimethylsulfoxide.

In an embodiment of the present invention the base used is a inorganic or organic base; wherein organic base is selected from dimethylamine, diethylamine or triethylamine and inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. Preferably triethylamine.
A preferred embodiment of the present invention provides a process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of Formula III: which comprises:treating the l-(hydroxymethyl) cyclopropaneacetonitrile with methanesulfonyl chloride in the presence of triethylamine and dichloromethane to getl -(Methanosulfonyloxymethyl)cyclopropaneacetonitrile which on treating with potassium bromide and N-N- dimethylformamide optionally in the presence of TBAB to providel-(bromomethyl) cyclopropane acetonitrile
Yet another embodiment of the present invention is to provide a process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of Formula III:

which comprises the steps:
a) esterifying the compound of formula VIII:

wherein X is leaving group such as chloro, bromo, iodo, mesyl and tosyl and like.; with thionyl chloride in a suitable solvent;
b) the obtained compound of Formula VII:


wherein X is as defined above; is treated with Zinc powder in the presence of water, alcohol or mixture thereof;
c) treating the obtained compound of Formula VI

'* ... - . •..
with sodium cyanide in the presence of DMSO;
d) treating the compound of r-(hydroxymethyl) cyclopropaneacetonitrile of Formula
V:

with a compound of having formula R-SO2CI; wherein R is alkyl or aryl. Preferably methyl or tolyl.
e) treating the obtained compound of Formula JV:

with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as
H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst to provide compound of Formula III.
A preferred embodiment of the present invention provides a process for the preparation of l-(bromomethyF) cyclopropane acetonitrile of Formula III which comprises: treating 2,25-Dibromoneopentyl glycol with thionyh chloride, followed by

treating the obtained 2,2?-Bis(Bromomethyl)-l,3-propanediol cyclic sulfite with zii dust in the presence of solvent mixture of Water and alcohol to provide 1, Cyclopropanedimethanol cyclicsulfate. Treating the obtained 1,'. Cyclopropanedimethanol cyclicsulfate with sodium cyanide in DMSO to provide \ (Hydroxymethyl)cyclopropaneacetonitrile3l-(Hydroxymethyl)cyclopropane acetonitrile is treated with methanesulfonyl chloride in the presence of triethylamir and dichloromethane to getl-(Methanosulfonyloxymethyl)cyclopropaneacetonitrr which on treating with potassium bromide and N-N- dimethylformamide optionally i the presence of TBAB to provide l-(bromomethyl) cyclopropane acetonitrile
Yet another embodiment of the present invention is to provide a process for tt preparation of l-(mercaptomethyl)cyclopropaneacetic acid Formula I:
which comprises the steps:
a) esterifying the compound of formula VIII:

wherein X is leaving group such as chloro, bromo, iodo, mesyl and tosyl and like.; with thionyl chloride in a suitable solvent;
b) the obtained compound of Formula VII:

wherein X is as defined above; is treated with Zinc powder in the presence of water, alcohol or mixture thereof;
c) treating the obtained compound of Formula VI


with sodium cyanide in the presence of DMSO;
d) treating the obtained compound of l-(hydroxymethyl) cyclopropaneacetonitrile of
Formula V:

with a compound of having formula R-S02C1; wherein R is alkyl or aryl. Preferably methyl or tolyl.
e) treating the obtained compound of Formula IV:
R02S.o/^cN
with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as
H3 Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst to provide compound of Formula III.
f) treating the compound of formula III with thiourea in the presence of acetone to
give compound of Formula II:

g) hydrolyzing the compound of Formula II using base to provide compound of
Formula I.
A preferred embodiment of the present invention provides a process for the preparation of l-(mercaptomethyl)cyclopropaneacetic acidwhich comprises: treating 2.25-Dibromoneopentyl glycol with thionyl chloride, followed by treating the obtained

2,2'-Bis(Bromomethyl)-l,3-propanediol cyclic sulfite with zinc dust in the presence of solvent mixture of Water and alcohol to provide 1,1-Cyclopropanedimethanol cyclicsulfate. Treating the obtained 1,1-Cyclopropanedimethanol cyclicsulfate with sodium cyanide in DMSO to provide l-(Hydroxymethyl)cyclopropaneacetonitrile. 1-(Hydroxymethyl)cyclopropane acetonitrile is treated with methanesulfonyl chloride in the presence of triethylamine and dichloromethane to getl-(Methanosulfonyloxymethyl)cyclopropaneacetonitrile which on treating with potassium bromide and N-N- dimethylformamide optionally in the presence of TBAB to provide l-(bromomethyl) cyclopropane acetonitrile. The bromo compound is treated withthiourea in acetone to provide l-(isothiuroniummethyl) cyclopropane-acetonitrile hydrobromide which on hydrolysis with base such as KOH or NaOH provide 1-(mercaptomethyl)cyclopropaneacetic acid
Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.
Examples:
Example 1: Preparation of 2,2'-Bis(Bromomethyl)-l?3-propanediol cyclic sulfite:
2,2'-Dibromoneopentyl glycol (230g, 0.877mol) is taken in to a dry one liter 4-necked round bottom flask and the flask was cooled to the -30°C to -60°. To this added thionyl chloride (7000g,)as a solvent, taken in dropping funnel, added drop wise over a period of 30mints. After completion of addition the reaction is maintained for 30 mi-ns at 0-10° C. The reaction gently heated to reflux, the reaction mass concentrated under vacuum to remove the excess, thionyl chloride. To the residue was dissolved in

DCM(2500ml) added water (460ml) and stirred. The organic layer is separated. To the organic layer washed with sat.NaHC03 and separate the layer and concentrated. The obtained solid is then dried at till a constant weight of 260g (96% yield) of the cyclic sulfite, as white solid ,a purity of 97-98% .
Example 2: Preparation of 1,1-Cyclopropanedimethanol cyclicsulfate:
The above cyclic sulfite (260g, 0.844moles) obtained from example 1, was suspended in a mixture of water (1300ml), and isopropanol (1300ml) under stirring at RT and continued the stirring. Zinc dust (220 g, 3.26 moles) was added and gently heated the contents to 90 0C and continued the stirring for 10 hrs. The reaction progress is monitored by TLC till the disappearance of the starting material. The reaction mass was cooled to RT and diluted with Heptane (750ml) and brought to RT and stirred at that temperature for 30 minutes and filtered. The Two layers were separated, and the* aqueous layer was extracted with Heptane (2 x 250ml). The combined the organic layers was washed with water (3><300ml) and separated. The organic layer was concentrated to dryness under vacuum to give 1, 1 -cyclopropane dimethanol cyclicsulfate 55 grms as a white solid.
Example 3: Preparation of l-(Hydroxymethyl)cyclopropaneacetonitrile:
The above cyclic sulfate (HOg, 0.743moles), was dissolved in dry DMSO (1100ml) under stirring at RT and continued the stirring. Powdered Sodiumcyanide (145.6, 2-9-72 moles) was added and gently heated the contents to 150°C and continued the stirring for 12hrs.. The reaction mass was cooled to 20-25°C and diluted with water (2000ml) and acidified with dilute HO (85ml). The mass was diluted with ethylacetate (500ml) and stirred at RT for 30 minutes. The two layers were separated and . The extraction was repeated with fresh quantity of ethylacetate (1x 300ml). The combined the organic layers was washed with sat.NaHCC>3 soln (lxl 50ml),. The total organic layer was concentrated to dryness under vacuum to afford the crude product which was subjected to HVD 81.5-g (98.7%) yield ,as red color liquid with a purity of 92% .

Example 4: Preparation of l-(Methanosulfonyloxymethyl) yclopropane acetonitrile:
The above cyclopropane acetonitrile derivative obtained in Ex-3.3 (81.5g, 0.7342moles)3 was dissolved in dry MDC (1500ml) under stirring at RT and continued the stirring. Triethylamine (151.6g, 1.5moles) was added and cooled to the -5 to 10 OC. To this was added Methanesulfonylchloride (100.8g, O.881mol), taken in dropping funnel, drop wise over a period of 4 hrs under continuous stirring and maintained at that temperature for 6 hrs. The reaction mass was diluted with water (150ml) and stirred for 15mints and the layers were separated. The aqueous layer was extracted with MDC (1x500ml). The combined the organic layers was washed with sat.NaHC03 solution (l*120ml)).The total organic was concentrated under vacuum to dryness to furnish the mesylate derivative 125g (90%) yield 3as red color liquid .
Example 5: Preparation of l-(bromomethyl) cyclopropaneacetonitrile:
The above mesylate (125-g, 0.661moles) dissolved in Acetone (1500ml) under stirring at RT. TBAB (42.5g, 0.1322mol)3 potassium bromide (196.3g3 1.65moles) were added and the contents were gently heated to 65-70°C and continued the stirring for 3hrs. Then another portion of TBAB (21.5g3 0.0661mol) was added and continued stirring at that temperature 3 hrs.. The reaction mass was concentrated to its dryness and the residue diluted with water (650ml) and Ethylacetate (600ml) and stir for 30mints. The organic layer was separated. The aqueous layer was extracted with Ethylacetate(2x300ml). The combined the organic layers evaporated under vacuum at to dryness to provide crude product which was subjected to HVD to get 1-(bromomethyl) Cyclopropane-acetonitrile 86.3g (75%yield)3as pale brown liquid. A purity of 90%.

Example 6: Preparation of l-(isothiuroniummethyl) cyclopropane-acetonitrile hydrobromide:
The above broniocornpound (86.3g, 0.495moles), was dissolved in dry Acetone (430ml) under stirring at RT and continued the stirring. Thiourea (75.3g, 0.99moles) was added gently heated the contents to 65-70°C. After 30-45mints clear solution slowly turned to turbid mass and after another 30 minutes a precipitate formation observed. The stirring was continued the stirring for 16hrs. The reaction mass was cool to 0-5°C and stir for 4hr and filtered. The obtained white solid was dried under vacuum to get a constant weight of 103g (83% yield)..
Example 7: Preparation of l-(mercaptomethyl) cyclopropaneaceticacid:
A 4 necked RB flash (1 lit) was charged with l-(isothiuroniummethyl) cyclopropane-acetonitrilehydrobromide (103g, 0.412moles) and 460ml of 50% potassium hydroxide solution degassed with Nitrogen. The mixture was stirred and heated to reflux on an oil bath for about 48 hrs under continuous nitrogen purging, The RM was cooled to 25-30°C. The aqueous was acidified with degassed 98%formicacid until a pH value of 2.0 to 2.25 was obtained (pH meter). The reaction mass was diluted with degassed Hepatane (2400ml) and stirred for 30 mints and separated the layers, the organic layer concentrated to dryness under vacuum at to get crude product which was subjected to HVD to get final product 54g (90%yield )as a off- white crystalline solid, a purity of 98%.

We Claim- "I™ I" llllllllllllll
we Claim. 700145362
1. A process for the preparation of l-(bromomethyl) cyclopropane acetonitrile of
Formula III:

which comprises the steps:
c) treating the l-(hydroxymethyl)cyclopropaneacetonitrile of Formula V:

with a compound of having formula R-SO2CI; wherein R is alkyl or aryl.
Preferably methyl or tolyl, ,.. . .
d) treating the obtained compound of Formula IV:

with a metal bromide of Formula M+Br"; wherein M is Monovalent atom such as H, Na or K; in the presence of a suitable solvent optionally in the presence of phase transfer catalyst.
2. The process as claimed in claim 1 wherein preparation of l-(bromomethyl)
cyclopropane acetonitrile of Formula III:
which comprises the steps:
f) esterifying the compound of formula VIII:


wherein X is leaving group such as chloro, bromo, iodo, mesyl and tosyl and like.; with thionyl chloride in a suitable solvent; g) the obtained compound of Formula VII:

wherein X is as defined above; is treated with Zinc powder in the presence of water,
alcohol or mixture thereof;
h) treating the obtained compound of Formula VI
o
n
o o
Formula VI
with sodium cyanide in the presence of DMSO to obtain l-(hydroxymethyl) cyclopropaneacetonitrile of Formula V:

3. The process as claimed in claim 1 wherein the suitable solvent used is a non-polar aprotic solvent. Preferably the suitable solvent is methanol, ethanol, Isopropyl alcohol, N-N- dimethylformamide, dichloromethane, toluene and dimethylsulfoxide.
4. The process as claimed in claim 1 the process is carried in the presence of a base wherein the base used is a inorganic or organic base wherein organic base

is selected from dimethylamine, diethylamine or triethylamine
and inorganic base is selected from ammonia, sodium carbonate, potassium
carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or
potassium hydroxide.
5. The process as claimed in claim 1 base used is triethylamine.
6. The process as claimed in claim 1, further comprises preparation of of 1-(mercaptomethyl)cyclopropaneacetic acid Formula I:

a) treating the compound of formula III with thiourea in the presence of acetone
to give compound of Formula 11:^

b) hydrolyzing the compound of Formula II using base to provide compound of
Formula I.
7. A process for the preparation of compound of formula III according to the
examples as described herein.