WO2012073249A1

WO2012073249A1 - A novel process for the preparation of 3-(benzyloxy)- benzenethiol, a key intermediate for the preparation of pharmaceutical drugs.

Info

Publication number: WO2012073249A1
Application number: PCT/IN2011/000025
Authority: WO
Inventors: Ganesh Gurpur Pai; Satish Wasudeo Mahajan; Yashwant Vasudeo Dharap; Arun Tulsiram Barhate; Deepak Hanumant Ranjane
Original assignee: Arch Pharmalabs Ltd
Current assignee: Arch Pharmalabs Ltd
Priority date: 2010-12-01
Filing date: 2011-01-14
Publication date: 2012-06-07
Anticipated expiration: 2013-06-01

Abstract

Disclosed herein is an efficient and economical process for the preparation of 3-Benzyloxybenzenethiol of formula-I which is a key intermediate for the preparation of pharmaceutical drugs. R' is hydrogen, halogen, trihalomethyl, lower alkoxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like. R" is hydrogen, halogen, trihalomethyl, lower alkoxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like.

Description

TITLE: A novel process for the preparation of 3-(benzyloxy)- benzenethiol, a key intermediate for the preparation of pharmaceutical drugs.

TECHNICAL FIELD OF THE INVENTION:

Disclosed herein is an efficient and economical process for the preparation of compound of formula-I which is a key intermediate for the preparation of

Formula I

Wherein R' is hydrogen, halogen, trihalomethyl, lower alkoxy having 1- 4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or unsubstituted arylloxy and the like.

R" is hydrogen, halogen, trihalomethyl, lower alkoxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or unsubtituted arylloxy and the like.

BACKGROUND OF THE INVENTION:

Yashushi Kohno disclose in US6960692 (hereinafter referred as '692) substituted diaryl derivatives of formula II as potent immune depressant

Formula II '692 particularly discloses a compound of formula I wherein R' and R" are independently hydrogen as an intermediate for the preparation of 2- amino-2-[2-[4-(3-bezyloxyphenylthio)-2-chlorophenyl]-ethyl]-l,3- propanediol hydrochloride of formula- III which is an effective immune suppressant that has

Formula III

Example 46 of '692 describes a process for the preparation of compound of formula III but does not describe a process for the preparation of compound of formula I (wherein R' and R" are independently hydrogen) which is a key intermediate for the preparation of compound of formula ΠΙ.

EP1806338 (hereinafter referred as '338) discloses a process for the preparation of compound of formula I (wherein R' and R" are independently hydrogen) which is used as an intermediate to prepare a compound of formula III. The process disclosed in '338 is given below in scheme-I.

Scheme-I

3-{benzyloxy)phenol Dimeth thiocarbamoyl chloride 0¾3-(benzyloxy)phenyl) dimethylcarbamoftioate S-(3-(benzyloxy)phenyl) dtmethylcarbamofluoate

3-(benzyloxyjbenzenethiol

First drawback of the process of '338 comprises use of sodium hydride (NaH) which is unsafe for use on industrial scale for the preparation of O-3-(benzyloxy)-phenyl dimethylcarbamothioate. Second drawback of the process is rearrangement reaction in second step to prepare S-3- (benzyloxy)-phenyl dimethylcarbamothioate for which, the reaction is carried out at high temperature 285 °C and pressure. Thermal transformation of O-3-(benzyloxy)-phenyl dimethylcarbamothioate to S- 3-(benzyloxy) - phenyl dimethylcarbamothioate at high temperature and pressure makes the process uneconomical and unsafe.

WO2005087731 (hereinafter referred as '731) discloses novel compounds which have HCV protease inhibitor activity. '731 discloses compound of formula formula I as a moiety.

Formula IV

'731(page No 134) discloses a process for the preparation of compound of . formula I which is used as an intermediate for the preparation of compound of formula IV. The process disclosed comprises reaction of 3-benzyloxy aniline with potassium-O-ethylxanthate to obtain S-3- (benzyloxy) phenyl O-ethyl carbonodithioate in the presence of sodium nitrite and hydrochloric acid. This dithioate compound is then reduced using lithium aluminium hydride as a reducing agent. Lithium aluminium hydride which being pyrophoric and dusting nature is unsafe for use on industrial scale, and also being expensive, chromatographic purification at both the stages makes the process uneconomical. Moreover the yield in first step for the preparation of S-3- (benzyloxy)phenyl O-ethyl carbonodithioate is only 47%. The process disclosed for the preparation of compound of formula I in '731 is given herein below in scheme-2.

3-(benzyloxy)aniline Potassium O-ethylxanthate i-(3-(benzyloxy)p enyl) O-ethyl carbonodithioate 3-(benzyloxy)benzenetiiiol

Yield 47 %

Tanaka, Muneaki discloses in JP2010018531 (hereinafter referred as '531) a process for the preparation of 3-Benzyloxybenzenethiol comprising treating bis- (3-hydroxy phenyl) disulfide with benzyl chloride to obtain bis- (3-benzyloxy phenyl) disulfide which is reduced to obtain 3-Benzyloxybenzenethiol. The process disclosed in '531 is described in scheme- 3 given herein below.

Scheme-3 jf> Ph-CH Cl i^ l^ _*- (I ) bis- (3-hydroxy phenyl) disulfide bis- (3-benzyloxy phenyl) disulfide 3-Benzyloxybenzenethiol

Example- 1 of '531 describes the process for the preparation of bis- (3- hydroxy phenyl) disulfide which uses 3-mercapto phenol as a starting material, the said patent also discloses the use of zinc metal for the reduction of disulphide to convert into thiol. It is uncomfortable and unhygienic to use 3-mercapto phenol on industrial scale.

WO2008078563 (hereinafter referred as '563) discloses a process for the preparation of 3-Benzyloxybenzenethiol comprising reacting 3- Benzyloxy phenyl chloride with magnesium to prepare a Grignard reagent which is reacted with sulphur to obtain 3-Bezyloxybenzenethiol. The process disclosed in '563 has been described in scheme-4 given herein below.

Scheme -4

Process disclosed in '563 comprises the preparation of Grignard reagent which is very difficult to handle at industrial scale.

WO201051031 (hereinafter referred as '031) discloses compounds of formula V for prevention or treatment of a pathological condition or symptom in a mammal, where the pathological condition is neuropathic pain, autoimmune disease, altering lymphocyte trafficking provides prolonged allograft survival, where the allograft is for transplantation. The autoimmune disease is uveitis, type I diabetes, rheumatoid arthritis, inflammatory bowel diseases, lupus, asthma, psoriasis, or multiple sclerosis.

Formula V

'031 discloses a compound wherein -W-Cy moiety is also represented by a compound of formula-I. However '031 does not disclose the process for the preparation of compound of formula-I.

The processes disclosed hereinabove and hereinbefore in the prior art for the preparation of compound of formula-I (wherein R' and R" are independently hydrogen) comprises use of hazardous sodium hydride, lithium aluminium hydride and high temperature conditions and pressure, chromatographic purification methods, Grignard reaction which makes the process unsafe ,unhygienic and uneconomical for industrial scale production. Therefore, there is a dire need to develop a safe and economical process devoiding the drawback of the prior art for the preparation of compound of formula-I preferably wherein R' and R" are independently hydrogen which is used as a key raw material for the preparation of pharmaceutical drugs and a few of them are described below.

1. As a key raw material for the preparation of pharmaceutically active compounds represented by the formula given below which are used as immunosuppressant. Pharmaceutically acceptable salts of the said compound include acid salts such as hydrochloride, hydrobromide, actate, trifluoroacetate, methane sulfonate, citrate and tartarate and the like.

Wherein R₂ is hydrogen, halogen, trihalomethyl, lower alkoxy having 1- 4 carbon atoms, lower alkyl having 1-7 carbon atoms,or benzyloxy.

R₃ is hydrogen, halogen, lower alkyl having 1-7 carbon atoms, lower alkoxy having 1-4 carbon atoms or, trihalomethyl(trifluoromethyl).

R₄ is hydrogen, halogen, lower alkyl having 1-7 carbon atoms, lower alkoxy having 1-4 carbon atoms or trifluoromethyl.

2. As a key raw material for the preparation of 2-amino-2-[2-[4-(3- benzyloxyphenylthio)-2-chlorophenyl]ethyl]- 1 ,3-propandiol of formula III its pharmaceutically acceptable salts or hydrate and intermediates thereof

3. As a key raw material for the preparation of pharmaceutically active compounds represented by the structure given below and their pharmaceutically acceptable salts to be used as sphigosine-1 -phosphate (S IP) receptor modulators

Wherein R₂ is hydrogen, halogen, trihalomethyl, alkyl having 1-4 carbon atoms, lower alkoxy having 1-4 carbon atoms

m is 2-4, Y is CH:CH, CH₂OCH₂, (CH2)n, n is 0-2

R4 is hydrogen, (un) substituted alkyl having 1-4 carbon atoms, alkenyl having 1-4 carbon atoms, alkynyl having 1-4 carbon atoms, COOH, alkoxy carbonyl having 1-4 carbon atoms, benzyloxy carbonyl,

CH2OCH2COOH, CH2OCH2COOR6 (R6 is alkyl having 1-4 carbon atoms, benzyl.

4. A key raw material for the preparation of HCV inhibitor represented by the compound of fo

Formula IV Taking into consideration shortcomings in the in the processes for the synthesis of the 3-benzyloxy benzenethiol of formula I, wherein R' and R" are independently hydrogen which is a key raw material for various pharmaceutical compounds disclosed in the prior art, it was essential to invent an efficient, industrially safe, economical novel process for the preparation of compound of formula I which can overcome all the shortcomings of the processes disclosed therein in the prior art.

In the present invention inventors have proposed new route of synthesis for the preparation of compound of the formula I, wherein R' and R" are independently hydrogen using 3-amino benzene sulphonic acid of formula VI, wherein R' is hydrogen as starting material, which is never used in any of the processes known in the prior art.

Formula VI

R' is hydrogen, halogen, trihalomethyl, lower all oxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstitiited arylalkyl or substituted or arylloxy and the like.

when R' is H it is 3-aminbbenzenesulfonic acid

In the present process the compound of formula VI is diazotized followed by hydrolysis to prepare the compound of formula VII.

Formula VII

R' is hydrogen, halogen, trihalomethyl, lower alkoxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like.

when R' is hydrogen it is 3-hydroxybenzenesulfonic acid However, while working on the novel process for the preparation of compound of the formula I preferably wherein R' and R" are hydrogen, inventors observed that isolation of the hydroxy compound of formula VII affects the yield of corresponding alkali metal salt of 3-benzyloxy- benzenesulphonate remarkably which is an intermediate for the preparation of compound of formula I of the present invention wherein R' and R" are hydrogen. Therefore inventors have worked on both the modes i.e. with and without isolating the compound of unsubstituted formula VII and observed about six folds enhancement in the yield when insitu process is adopted for the preparation of corresponding alkali metal salt of 3-benzyloxy-benzenesulphonate of formula VIII and hence 3-benzyloxy benzenethiol of formula I wherein R' and R" are hydrogen, thereafter. Therefore, insitu process for the preparation of the compound , of formula VIII and its further conversion into compound of formula I not only increases the yield but also reduces the number of unit operations providing an economically better and technically advanced process.

Formula VTII

R" is hydrogen, halogen, trihalomethyl, lower alkoxy having 1-4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like.

When R' and R' are H and M is sodium it is sodium- 3-(benzyIoxy)-benzene sulphonate

Following tabular comparison clearly indicates the advantage of the insitu process for the preparation of compound of formula VIII over the isolated hydroxy compound of formula VII. Mode VI VII VIII Yield (w/w)

(wherein R' is H) (wherein R' is H) (R\R")

(isolated) are H

Insitu 200 g N.A. 142 71%

Isolated 200 g 60 g 25.2 12.6%

Therefore, it clearly indicates that insitu process shows 71% w/w yield against 12.6% w/w yield in case of process comprising isolation of phenolic (hydroxy) compound of formula VII.

OBJECTS OF THE INVENTION:

First aspect of the invention is to provide a novel process for the preparation of 3-(benzyloxy) benzenethiol of Formula-I using easily available raw materials, simple operations, easy handling of the raw materials and intermediates thereof.

Second aspect of the invention is to provide a novel process for the preparation of 3-(benzyloxy) - benzenethiol.

Third aspect of the invention is to provide an insitu process for the preparation of compound of formula VIII.

Fourth aspect of the invention is to provide an insitu process for the preparation of sodium 3- (benzyloxy)-benzenethiol and its conversion into 3-(benzyloxy) benzenethiol.

SUMMARY OF THE INVENTION:

Disclosed herein is an efficient, safe and economical process for the preparation of 3-(Benzyloxy)-benzenethiol of Formula-I comprising diazotization of substituted or unsubstituted 3-aminobenzenesulphonic acid using alkali metal nitrite and mineral acid followed by hydrolysis of diazonium salt to obtain substituted or unsubstituted 3- hydroxybenzenesulphonic acid which is optionally isolated, is then alkylated with substituted or unsubstituted benzyl halide in the presence of a alkali metal base to give alkali metal salt of substituted or unsubstituted 3-benzyloxy-benzenesulphonate which is treated with a halogenating agent to give substituted or unsubstituted 3-(benzyloxy) benzene- 1-sulfonyl chloride which is further reduced using metal and acid to give 3-(benzyloxy) benzenethiol of Formula-I wherein R' and R" are preferably hydrogen .

DETAILED DESCRIPTION:

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. In addition, and as will be appreciated by one of the skill in the art, the invention may be embodied as a method, system or process.

The present invention provides an efficient and economical process for the industrial scale production of 3-Benzyloxy-benzenethiol of Formula- I which is used as an intermediate for the preparation of a large number of pharmaceutical drugs.

The main embodiment of the invention describes a process schematically represented in scheme-5 given below: Scheme-5 alkali metal _

0 nitrite/ mineral x _nu » [ — £-R"

^H0 ¾ Rr' ^r ^ R' - ^{ag nt}

M is alkali metal ^¹¹

X is halogen

IX

R' and R" are same as defined hereinabove

In the first step of the main embodiment 3-aminobenzenesulphonic acid of formula VI is diazotized using alkali metal nitrite and mineral acid at low temperature resulting into corresponding diazonium salt followed by its optionally insitu hydrolysis to form 3-hydroxybenzenesulfonic acid of formula VII. This compound of formula VII with optional isolation is further reacted with benzyl halide in the presence of a alkali metal base in a suitable solvent to give alkali metal salt of 3-(benzyloxy)-benzene sulfonate of Formula- VIII.

Formula VI

R' is hydrogen, halogen, trihalomethyl, lower alkoxy having 1 -4 carbon atoms, lower alkyl having 1-7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like.

when R' is H it is 3-aminobenzenesulfonic acid

Formula VII

R' is hydrogen, halogen, trihalomethyl, lower alkoxy having 1 -4 carbon atoms, lower alkyl having 1 -7 carbon atoms, substituted or unsubstituted arylalkyl or substituted or arylloxy and the like.

when ' is hydrogen it is 3-hydroxybenzenesulfonic acid

Formula VIII

When R' and R' are H and M is sodium it is sodium- 3-(benzyloxy)-benzene sulphonate

First step of the main embodiment is depicted below:

vⁿ M is alkali metal ^vm

Mineral acid, used for the diazotization is selected from the group of sulphuric acid and hydrochloric acid and the like preferably hydrochloric acid.

Solvent used for the diazotization is selected from the group water; acetic acid and the like preferably water.

Substituted or unsubstituted benzyl halide used for the alkylation is selected from corresponding benzyl iodide, benzyl chloride and benzyl bromide and the like preferably benzyl bromide.

The base used for the conversion of 3-hydroxybenzenesulfonic of formula VI acid into alkali metal salt of 3-(benzyloxy)-benzenesulfonate of formula VIII is selected from alkali metal hydroxide, alkali metal alkoxide and the like. Preferably the base is alkali metal hydroxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide. More preferably the base is sodium hydroxide.

In second step of the main embodiment alkali metal salt of 3- (benzyloxy)-benzenesulfonate of formula VIII is converted into corresponding 3-(benzyloxy) benzene- 1-sulfonyl halide of formula IX by treating with a suitable halogenating agent optionally in the presence of a base and also optionally in an organic solvent

Second step of the main embodiment is depicted below:

R' and R" are same as defined hereinabove

The halogenating agent is selected from phosphorous halide, phosphorous oxyhalide, thionyl halide and the like. Preferably halogenating agent is selected from phosphorous pentachloride, phosphorous trichloride, and thionyl chloride. More preferably the halogenating agent is thionyl chloride.

Organic solvent is selected from halogenated solvents selected from the group comprising monochloro methane, dichloro ethane, chloroform, carbon tetrachloride and the like. Preferably halogenation is conducted without using any external solvent.

In third step of the main embodiment 3-(benzyloxy)-benzene- 1-sulfonyl halide of formula IX is converted into 3-Benzyloxy-benzenethiol of Formula-I comprising reacting 3-(benzyloxy)benzene-I-sulfonyl halide of formula IX with a suitable reducing agent. Preferably reducing agent is a metal and an acid in an appropriate solvent at a temp, about 0 C to about 80°C. Third step of the main embodiment is depicted below:

R' and R" are same as defined hereinabove

Metal is selected from the group of zinc, magnesium, aluminium and the like. Preferably metal is zinc.

Acid is selected from acetic acid hydrochloric acid, hydrobromic acid sulphuric acid and the like preferably acid is sulphuric acid.

Solvent used for the reduction is selected from straight chain or branched lower alkyl alcohols, water or mixture thereof and the like. Preferably solvent is water.

A specific embodiment of the present invention for the preparation of 3- (benzyloxy)-benzenethiol can be schematically represented in scheme-6 given below:

Scheme-6

3-aminobenzenesulfonic acid 3-hydroxybenzenesulfonic acid sodium-3-(benzyloxy)-benzene sulphonate

3-(benzyloxy)benzene-l-sulfonyl halide 3-(benzyloxy)benzenethiol

Different steps involved in the above process are described as follows: In first step of the invention for the preparation of 3-(benzyloxy)- benzenethiol, 3-aminobenzenesulphonic acid of formula VI when R' is hydrogen is diazotized using sodium nitrite and hydrochloric acid at low temperature resulting into corresponding diazonium chloride followed by its insitu hydrolysis to form 3-hydroxybenzenesulfonic acid of formula VII wherein R' is hydrogen. This compound of formula VII with optional isolation is further reacted with benzyl halide in the presence of a alkali metal base in a suitable solvent to give alkali metal salt of 3-(benzyloxy)-benzene sulfonate of Formula- VIII , wherein M is sodium, R'and R" are independently hydrogen as shown below.

Not isolated Not isolated

In second step, sodium salt of 3 -(benzyl oxy)-benzenesulfonate from first step is converted into corresponding 3-(benzyloxy)-benzene-l-sulfonyl chloride by treating with thionyl chloride and dimethyl formamide as shown below:

Formula VIII . Formula IX when M is Na, R' and R" are H when X is CI

In a third step 3-(benzyloxy)-benzene-l-sulfonyl chloride from second step is converted into 3-(Benzyloxy)-benzenethiol of Formula- 1 comprising reacting 3-(benzyloxy)-benzene-l-sulfonyl chloride with zinc, in an acidic solvent at temp, about 0 to about 80°C as shown below:

3-(benzyloxy)benzenesulphonyl chloride 3-(benzyloxy)benzenethiol

IX I

when X is CI, and R\ R" are H _{when R}, _R„ ^ _H The following non limiting examples are provided to illustrate further the present invention, It will be apparent to those skilled in the art that many modifications, variations and alterations to the present disclosure, both to materials, methods and reaction conditions, may be practiced. All such modifications, variations and alterations are intended to be within the spirit and scope of the present inventions.

Example 1:

Insitu preparation of sodium-3-(benzyloxy)-benzenesuIphonate:

200 g(1.15mol) of 3-aminobenzenesulphonic acid was added to the solution containing 2 L water and 51g ( 0.48mol) sodium carbonate at 25-27°C. Contents were heated to 40°C get a clear solution. This was followed by the addition of 355g (2.92mol) con HC1 at 25-27°C. The reaction mass was cooled to 7-9°C and solution of 81.6g (1.18mol) NaNO₂ dissolved 97.2 ml water was added maintaining the temperature at 7-9°C. Stirring was continued for 2 hrs at the same temperature. Contents were then gradually brought to 25-27 °C followed by the reflux and was maintained for 6-8 hrs till the completion of the reaction. Water was distilled of under the reduced pressure. Residue was added with isopropanol under stirring. Filter off the contents to remove the insolubles if any. Isopropanol was distilled off under reduced pressure at the temperature no exceeding 50°C. Residue so obtained was consumed as such without isolation for the next insitu reaction by dissolving it in 1.6 L water and was taken for cooling to 15-20°C. The contents were added with 440 mL of 5N sodium hydroxide till the pH was alkaline. The reaction was continued with addition of 152 g (0.89mol) benzyl bromide in about 45 minutes. Stirring at 25-27°C was continued till the completion of the reaction. The contents were cooled to 0-5°C and temp, was maintained for one hour. Product was filtered off and dried under vacuum at 50°C. Weight of product was 142 g.

Product was confirmed by its NMR

1H-NMR (DMSO d₆)-5: 5.1 (s, 2H), 6.9-7.46 (m, 9H) Example 2:

Preparation of 3-(benzyIoxy)-benzene sulphonyl chloride:

70 g (0.244mol) sodium-3-(benzyloxy)-benzenesulphonate was added to 658 g (5.5mol) thionyl chloride containing 5 mL dimethyl formamide keeping the temperature at 0-5 °C. Stirring was continued for another 15 minutes followed by heating the contents to reach first at 25-27 ^°C and then at 60-65 °C. Heating was continued till the completion of the reaction. Excessive thionyl chloride was distilled off under the reduced pressure at the temperature not exceeding 40° C. Reaction mass was quenched over 300 mL ice cold water under stirring. Product was extracted using dichloromethane as extractant (2 x 100 mL). Combined dichloromethane layer was dried over sodium sulphate and solvent was distilled off under the reduced pressure at temperature no exceeding 35 °C. Product was isolated by the addition of heptane and further cooling the reaction mass to 0-5°C. Product was dried under vacuum at 25-27°C till the constant weight. Weight of product: 43 g (Melting point range: 60-65 °C)

Product is further confirmed by its NMR

1H-NMR (CDC13)-5 in ppm: 5.14 (s, 2H), 7.25-7.62 (m, 9H)

Example 3:

Preparation of 3-(benzyloxy)-benzenethiol:

40 g (0.1414mol) 3-(benzyloxy)-benzene sulphonyl chloride was added in lots into a solution containing 104 g (1.04mol) con. H₂SO and 314 mL water at 0-5°C in 10-15 minutes. Contents were stirred at the same temperature for another 15 minutes. Powered Zinc 53 g (0.801mol) was the added in lot to the above contents at 0-5 °C and stirring was continued for half an hour. Contents were brought to 25-27^°C and maintained for one hour followed by hating to reach at 98-100°C and continued for 3 hrs till the completion of the reaction. Product was extracted at 25-27°C using dichloromethane as extractant (3 xlOOmL). Combined dichloromethane was dried over sodium sulphate. Solvent was distilled of under reduced pressure at temperature not exceeding 35°C. Product was isolated by the addition of heptane and further cooling the reaction mass to 10°C. Product was dried under vacuum at 25-27°C till the constant weight. Weight of product: 27 g. Product is further confirmed by its NMR

IH-NMR (CDC13)-5 in ppm: 3.4 (s, 1H), 5.02 (s, 2H), 6.74-7.41(m, 9H)

Claims

CLAIMS: We claim:

1. A process for the preparation of the compound of formula I

Formula I

wherein R'and R" are as hereinabove in the description

comprising: a) diazotising 3-amino benzenesulphonic acid of formula VI

Formula VI

wherein R' is as. described hereinabove in the description with alkali metal nitrite and a mineral acid at about 0°C to aboutl0°C and insitu hydrolyzing the diazonium product and optionally isolating the compound of the formula VII

Formula VII

wherein R' is as described hereinabove in the description

b) optionally insitu reacting the compound of the formula VII from the step a with benzyl halide in the presence of a base to prepare the compound of formula VIII

Formula VIII

wherein R'and R" are as described hereinabove in the description c) reacting the compound of the formula VIII from step b with a halogenating agent optionally using a solvent and optionally in the presence of base to prepare the compound of formula IX

X=C13r or I

Formula IX

wherein R'and R" are as described hereinabove in the description d) reducing the compound of the formula LX from step c using a metal in presence of acid to prepare the compound of formula I.

Formula I

wherein R'and R" are as described hereinabove in the description

2. Alkali metal nitrite as claimed in claim la is selected from the group of potassium nitrite, sodium nitrite and the like preferably sodium nitrite.

3. Mineral acid as claimed in claim la is selected from the group of sulphuric acid, hydrobromic acid, hydrochloric acid and the like preferably hydrochloric acid.

4. Benzyl halide as claimed in claim lb is selected from. the group of benzyl chloride, benzyl bromide and benzyl iodide preferably benzyl bromide.

5. The base as claimed in claim lb is selected from the group of alkali metal hydroxide, alkali metal carbonates, alkali metal bicarbonates or mixture thereof.

6. Alkali metal hydroxide as claimed in claim 5 is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide preferably sodium hydroxide.

7. Alkali metal carbonates as claimed in claim 5 is selected from the group of sodium carbonate, potassium carbonate, lithium carbonate preferably sodium carbonate and potassium carbonate more preferably sodium carbonate.

8. Alkali metal bicarbonates as claimed in claim 5 is selected from sodium bicarbonate, potassium bicarbonate, lithium bicarbonate preferably sodium bicarbonate and potassium bicarbonate more preferably sodium bicarbonate.

9. Halogenating agent as claimed in claim lc is selected from the group of thionyl chloride, phosphorous tri chloride, phosphorus pentachlonde and the like preferably thionyl chloride.

10. Solvent as claimed in claim lc is selected from group of halogenated solvents selected from dichloromethane, trichloromethane, carbontetrachloride, dichloroethane and like, aromatic hydrocarbons selected from toluene and xylenes preferably dichloroethane.

1 1. Base as claimed in claim lc is selected from alkyl amines selected from the dimethyl formamide, dimethyl amine, diethyl amine, triethyl amine and like.

12. Metal used for the reduction as claimed in claim Id is selected from Zn, Mg, Al, and like.

13. Metal used for the reduction as claimed in claim 12 is zinc.

14. Acid as claimed in claim Id is selected from the group containing acetic acid, hydrochloric acid, hydrobromic acid and sulphuric acid preferably sulphuric acid.

15. A process for the. preparation of compound of formula VIII in about 70% yield

Formula VIII

wherein R'and R" are as described hereinabove in the description comprising

reacting a compound of formula VI

Formula VI

wherein R' is as described hereinabove in the description a) with alkali metal nitrite and a mineral acid at about 0°C to about 10°C and insitu hydrolyzing the diazonium to obtain compound of formula

VII

Formula VII

wherein R' is as described hereinabove in the description b) insitu reacting the compound of the formula VII from the step a with benzyl halide in the presence of a base selected from alkali metal hydroxide,alkali metal alkoxide, alkali metal carbonate, alkali metal bicarbonate or mixture thereof to prepare the compound of formula VIII

Formula VIII

wherein R'and R" are as described hereinabove in the description

16. A novel process for the preparation of 3-(benzyloxy)-benzenethiol of formula I, wherein R' and R" are independently are hydrogen

Formula I,

wherein R', R" are hydrogen

comprising:

a) diazotising 3-amino benzenesulphonic acid of formula VI, wherein R' is hydrogen

R' is hydrogen

3-aminobenzenesulfonic acid

Formula VI with sodium nitrite and hydrochloric acid at about 0°C to about 10°C and insitu hydrolyzing the diazonium product and optionally isolating 3- hydroxybenzenesulfonic acid

when R' is hydrogen

3-hydroxybenzenesulfonic acid

Formula VII

b) insitu reacting the compound from the step a with benzyl bromide in the presence of a base selected from the group of alkali metal hydroxide, alkali metal carbonates, alkali metal bicarbonates or mixture thereof preferably sodium hydroxide to prepare the compound of formula VIII

M is Li, K, Na

R' and R" are hydrogen

Formula VIII c) reacting the compound from step b with a thionyl chloride optionally using a solvent and optionally in the presence of base selected from the group of alkyl amines selected from the, dimethyl amine, diethyl amine, triethyl amine preferably triethyl amine to prepare the compound of formula IV, wherein R' and R" are independently hydrogen

X=Cl,Br or I

R' and R" are hydrogen

Formula IX d) reducing the compound from step c using Zinc metal in presence of acid selected from the group of acetic acid, hydrochloric acid, hydrobromic acid , sulphuric acid preferably sulphuric acid to prepare 3- (benzyloxy) benzenethiol of formula I, wherein R' and R" are independently hydrogen.

' and R" are hydrogen