Title of Invention

AN IMPROVED PROCESS FOR CONVERSION OF TRANS-N-METHYL-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPHTHALENEAMINE TO ITS CIS-N-METHYL-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHALENEAMINE (AN INTERMEDIATE OF SERTRALINE HYDROCHLORIDE)

Abstract The present invention relates to an improved process for converting trans isomer of N methyl-4-(3,4-dich!orophenyl)-l ,2,3,4-tetrahydro-l-naphthalencamine to corresponding cis isomeric product. The cis isomer serves as valuable intermediate in the production of Cis (lS)(4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3.4-tetrahydro-l-naphthaleneamine, which is a potent anti-depressant agent. The improved method of preparation is safe, cost effective and industrially scalable.
Full Text An Improved Process for Conversion of trans-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine to its cis- N-methyl-4- (3,4-diclilorophenyl)-l,2,3,4-tetrahydro-1-naphthaleneamine (An intermediate of Sertraline hydrochloride)
Field of Invention
The present invention relates to a process for converting trans isomer of N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine to corresponding cis isomeric product. The cis isomer serves as a valuable intermediate in the production of cis (lS)(4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphlhaIcncaminc hydrochloride (Scrtraline hydrochloride), which is a potent anti-depressant agent. Background of Invention
US Pat. No. 5,082,970 describes a process for converting trans isomer of N-methyl-4(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine (in absence or presence of up to an equal part by weight of cis isomer) to the related cis isomeric product. The conversion is conducted in the presence of a basic equilibrium agent as an alkali metal alkoxide in an inert polar solvent.
The synthetic procedure as disclosed is aforementioned US Pat No. 5,082,970, for conversion of trans-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalen-eamine to desired cis-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalene-amine involves the use of expensive and water incompatible alkali metal alkoxide, as potassium tertiary butoxide. The reaction is conducted in solvent, like tetrahydrofuran, which is not well suited for commercial scale up. Distillation of tetrahydrofuran at industrial scale, may lead as hazards as explosion.

The patent also embodies elaborate workup process. For instance, upon completion of reaction, tetrahydrofuran is distilled under reduced pressure and the residue obtained is dissolved in halogenated solvent. This is accompanied by water washing and drying of organic layer. Redistillation of organic layer is again followed by redissolution of oil in tetrahydrofuran. Anhydrous hydrogen chloride gas is then passed after which cis isomer precipitates out as a crystalline hydrochloride salt.
The multistep workup coupled with use of expensive reagents and solvents like potassium tertiary butoxide and tetrahydrofuran together with an additional step for generation of hydrogen chloride gas makes the process hazardous, expensive and less commercially viable. Summary of invention
In accordance with the present invention there is now provided a new, simple and improved process for conversion of trans isomer of N-methyl-4-(3,4-dichlorophenyl-1,2,3,4-tetrahydro-1-naphthaleneamine to corresponding cis isomeric product.
This conversion of trans isomer to cis isomer is affected in an aromatic non-polar solvent containing lower metal alkoxide and tertiary butanol.
In a more preferred embodiment of the present invention the conversion of trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphtheleneamine to cis isomer is achieved in the presence of alkali metal hydroxide and tertiary butanol in aromatic non-polar organic solvent.
The present invention describes the preferable usage of cheap and commercially available alkali metal hydroxide over lower metal alkoxide, which is described in US Pat. 5, 082, 970. The present invention also incorporates use of inexpensive non-polar solvents like toluene and xylene, which are recovered and reused making the process inexpensive and environment

friendly. Moreover this invention discloses usage of concentrated hydrochloric acid, over
anhydrous hydrogen chloride gas (usage of which described in US Pat. No. 5,082,97) during
workup.
As Sertraline hydrochloride is a useful anti-depressant agent it is very important to have a cost
effective, commercially viable and environment friendly process for its preparation.
Therefore, the main objective of the present invention is to utilize unwanted trans isomer co
produced during synthesis of Sertraline hydrochloride, convert it into valuable, cis isomer by
cost effective, industrially scaleable and environment friendly process.
Detailed Description of the invention
Accordingly the present invention, describes a new and improved process for converting trans
isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine or its
hydrochloride salt to the corresponding is isomeric product which comprises:
a. contacting trans isomer of N-methyl-4-(3,4-dichlorophenyI)-1,2,3,4-tetrahydro-1 -
naphthaleneamine or its hydrochloride salt in alkali metal hydroxide selected from
potassium hydroxide or sodium hydroxide in tertiary butanol and aromatic non-polar
solvent, selected from toluene or xylene;
b. heating the reaction solution to reflux at a temperature ranging from 80 tol 10°C for a
period of 15 to 60 hours till the reaction is substantially complete;
c. cooling the reaction mass to 50-60°C and diluting with water;
d. subsequently stirring the reaction mass for 30 minutes at 30-35°C after which the
organic layer is separated from biphasic system, water washed and cooled to 5-15°C;

e. acidifying the organic layer obtained in step (d) with conc, hydrochloric acid to precipitate the desired cis isomer as hydrochloride salt, together with trans isomeric impurity;
f stirring the precipitated salt for 30 minutes at 20°C accompanied by filtration;
g. stirring the wet cake in alcohol at reflux temperature for a period of 1 to 5 hours and then cooling to 0-5°C and maintaining for 30 minutes at the same temperature;
h. filtering the suspension and washing with/without chilled alcohol rendering desired cis isomer. According to another embodiment of the present invention the conversion of trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphlhalcneamine or its hydrochloride salt to the corresponding cis isomeric product comprises:
a. contacting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-
naphthaleneamine or its hydrochloride salt with an alkali metal alkoxide selected from
sodium butoxide or potassium tertiary butoxide, in presence of tertiary butanol and
aromatic non-polar solvent selected from toluene or xylene,
b. refluxing the reaction solution at a temperature ranging from 80 to 110 °C for a period
of 15 to 60 hours until the desired conversion is substantially complete,
c. cooling the reaction mixture to room temperature and further cooling to 0 to 10°C
followed by dilution with water,
d. separating the organic layer from the resultant biphasic system, and distilling the
solvent to half of the volume under reduced pressure, washing with water and cooling
to 5-10°C,

e. acidifying the suspension obtained in step (d) with hydrochloric acid to precipitate the
desired, cis isomer as hydrochloride salt containing trans isomer as impurity, f purifying the obtained isomer by recrystallisation in alcohol which comprises, i. dissolving the isomer in alcohol the amount of isomer to alcohol being 1:5-30
times, ii. heating the suspension to reflux at 60-65°C, iii. subsequently subjecting the solution to carbon treatment accompanied by filtration. The
filtrate on evaporation to half of its volume followed by cooling to 5-10°C, iv. subjecting the resultant suspension to filtration and washing with without methanol
where after pure cis isomer isolated while the corresponding trans isomer remains in
solution.
The present invention, hence, provides a simple, novel process for conversion of trans isomeric N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydronaphthaleneamine or its hydrochloride salt to the corresponding cis isomeric product, which involves:
i. replacement of water incompatible metal alkoxide with cheap, safe and
commercially available, alkali hydroxide
ii. substitution of hazardous tetrahydrofuran with inexpensive aromatic non polar
solvent which is recovered and reused iii. replacing anhydrous hydrogen chloride gas with cheap and commercially available
hydrochloric acid and iv. Overall providing a simple work-up procedure.

Keeping in view, the above mentioned facts, the present invcntion hence, delivers a simple, improved cost effective, industrially scaleable and environment friendly process for converting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthaleneamine to corresponding cis isomeric product.
It is noteworthy to mention the trans isomeric N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro naphthaleneamine is obtained as per procedure described in US 4, 536, 518.
Examples The present invention is described in detail in the examples, which are provided by way of illustration and does not limit the scope of the invention.
Example 1
Trans isomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthaleneamine (50.0 g, 0.163 moles) was dissolved in toluene (230 ml) containing potassium hydroxide (13.7 g, 0.244 moles) and tertiary butasnol (36.0 ml). The mixture was heated to reflux and stirred for 30 hours. Upon completion of this step, the reaction mass was cooled to 50-60°C and diluted with water (200.0 ml) and further cooled to 30~35°C and stirred for 30 minutes. The organic layer was separated from the resultant biphasic system and washed with water. The organic layer was then cooled to 5-15°C and acidified with cone, hydrochloric acid to precipitate the hydrochloride salt, which was stirred for another 30 minutes at 10-13°C and filtered. The wet compound obtained, was suspended in methanol (225.0 ml) and refluxed for a period of 2.30 hours and then cooled to 5°C and maintained at the same temperature for 30 minutes. Thereafter, it was filtered and washed with chilled methanol (50.0 ml) rendering cis isomer. (Yie^ 28 g, 50%) MP: 286-290°C. Reported MP: 289-290°C. (EP Pat. No. 30081, example 1, sub example F)

Example 2
A mixture consisting of trans isomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthaleneamine (50 g, 0.163 moles) dissolved in toluene (600.0 ml), which also contained potassium tertiary butoxide (37.0 g, 0.330 moles) and tertiary butanol (31.0 ml) was heated to reflux for a period of 30 hours. Upon completion of this step, the reaction mixture was cooled to room temperature and further cooled to 4°C where after it was diluted with water (200 ml). Of the resultant biphasic system, the organic layer was separated, washed with water and subjected to distillation under reduced pressure to half of its volume. Thereafter it was cooled to 5°C and acidified with cone, hydrochloric acid. The precipitated hydrochloride salt was stirred at 4-ll°C for a period of 30 minutes accompanied by filtration. The wet hydrochloride salt was then subjected to recrystallisation by dissolving in methanol (950.0 ml) and heating to reflux followed by carbon treatment and filtration. The filtrate was concentrated to half of its volume by evaporation under reduced pressure, cooled to 5-lO°C and subjected to filtration and washing by methanol to yield desired cis isomer. (Yield 23 g, 42%). MP: 290-294°C. Reported MP: 289-290°C. (EP Pat. No. 30081, example 1, sub example le



We claim:
1. An improved process for converting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthaleneamine or its hydrochloride salt to the corresponding cis isomer, which comprises of:
a. contacting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine or its hydrochloride salt with a suspension of base containing alcohol in an aromatic non-polar solvent.

b. heating the reaction mass to reflux temperature till the reaction is complete,
c. cooling the reaction mixture and diluting with water,
d. separating the organic layer from biphasic system, water washed and cooled, to 5-
15°C,
e. acidifying the organic layer with acid to precipitate the acid salt,
£ stirring the precipitated salt accompanied by filtration;
g. stirring the wet cake in alcohol at reflux temperature, then cooling to 0-5^C and stirring
at the same temperature, h. filtering the suspension and washing with/without chilled alcohol rendering desired cis
isomer.
2. A process as claimed in claim 1 in which the alcohol is methanol, n-propanol, isopropanol,
sec-butanol, n-butanol or tert. Butanol or a mixture thereof.
3. A process as claimed in claim 1 in which the non-polar aromatic solvent is toluene or
xylene or a mixture thereof
4. A process as claimed in claim 1 in which the base is sodium hydroxide or potassium hydroxide.
5. A process as claimed in claim 4 in which the mole ratio of base to the trans isomer in the ratio of 1: 2 to 1: 5.
6. A process as claimed in claim 1 in which the reflux temperature is in the range o f80-110^C
7. A process as claimed in claim 1 in which the reaction mixture is stirred for a period of 15 to 60 hours at reflux temperature.

8. A process as claimed in claim 1 in which the acidification of the organic layer with mineral acid such as hydrochloric acid or sulphuric acid to precipitate acid salt, preferably hydrochloric acid.
9. A process as claimed in claim 1 in which the stirring the wet cake in an alcohol such as methanol, ethanol or isopropanol or a mixture thereof.

10. A process as claimed in claim 1 in which the stirring the wet cake in an alcohol at reflux temperature for a period of 1 to 5 hours
11. An improved process for converting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine or its hydrochloride salt to the corresponding cis isomer, which comprises of:
a. contacting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-
naphthaleneamine or its hydrochloride salt with a suspension of base containing
alcohol in an aromatic non-polar solvent.
b. heating the reaction mass to reflux temperature till the reaction is complete,
c. cooling the reaction mixture and diluting with water,
d. separating the organic layer from biphasic system, water washed and cooled, to 5-
15°C,
e. acidifying the organic layer with acid to precipitate the acid salt,
f. stirring the precipitated salt accompanied by filtration;
g. dissolving the wet cake in alcohol at reflux temperature accompanied by carbon
treatment,
h. Concentrating the filtrate, then cooling to 0-5°C and stirring at the same temperature,

i. filtering the precipitated solid and washing with/without/chilled alcohol rendering desired cis isomer.
12. A process as claimed in claim 11 in which the alcohol is methanol, n-propanol,
isopropanol, sec-butanol, n-butanol or tert. Butanol or a mixture thereof.
13. A process as claimed in claim 11 in which the non-polar aromatic solvent is toluene or
xylene or a mixture thereof.
14. A process as claimed in claim 11 in which the base is sodium tertiary butoxide or
potassium tertiary butoxide.
15. A process as claimed in claim 14 in which the mole ratio of base to the trans isomer in the ratio of 1: 2 to 1: 5.
16. A process as claimed in claim 11 in which the reflux temperature is in the range of 80-llO°C
17. A process as claimed in claim 11 in which the reaction mixture is stirred for a period of 15 to 60 hours at reflux temperature.
18. A process as claimed in claim 11 in which the acidification of the organic layer with mineral acid such as hydrochloric acid or sulphuric acid to precipitate acid salt, preferably hydrochloric acid.
19. A process as claimed in claim 11 in which the dissolving or stirring the wet cake in an alcohol such as methanol, ethanol or isopropanol or a mixture thereof at reflux temperature,
20. A process as claimed in claim 11 in which the concentrating the filtrate to half of the volume to precipitate the desired product.

21. A process for converting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-
tctrahydro-1-naphthalencamine or its hydrochloride salt to the corresponding cis isomeric
product as described herein with reference to example 1.
22. A process for converting trans isomer of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-
tetrahydro-1-naphthaleneamine or its hydrochloride salt to the corresponding cis isomeric
product as described herein with reference to example2.


Documents:

819-mas-2000-abstract.pdf

819-mas-2000-claims filed.pdf

819-mas-2000-claims grand.pdf

819-mas-2000-correspondnece-others.pdf

819-mas-2000-correspondnece-po.pdf

819-mas-2000-description(complete) filed.pdf

819-mas-2000-description(complete) grand.pdf

819-mas-2000-form 1.pdf

819-mas-2000-form 6.pdf

819-mas-2000-other documents.pdf


Patent Number 192259
Indian Patent Application Number 819/MAS/2000
PG Journal Number 20/2006
Publication Date 19-May-2006
Grant Date 25-Jan-2006
Date of Filing 29-Sep-2000
Name of Patentee DR. REDDY'S LABORATORIES LIMITED
Applicant Address 7-1-27, AMEERPET HYDERABAD, A.P., 500 016
Inventors:
# Inventor's Name Inventor's Address
1 REGURI BUCHI REDDY DR. REDDYS, RESEARCH FOUNDATION 7-1-27, AMEERPET HYDERABAD, A.P., 500 016
2 KADABOINA RAKASEKHAR DR. REDDYS, RESEARCH FOUNDATION 7-1-27, AMEERPET HYDERABAD, A.P., 500 016
3 THATIPALLI POORNA CHANDER DR. REDDYS, RESEARCH FOUNDATION 7-1-27, AMEERPET HYDERABAD, A.P., 500 016
PCT International Classification Number C07B35/08
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA