FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Process for the industrial preparation of pure lafutidine
2. APPLICANT (S)
(a) NAME : ELDER PHARMACEUTICALS LTD.
(b) NATIONALITY : INDIAN
(c) ADDRESS : Elder House, Plot No. C/9, Dalia Indl. Estate,
Off. New Link Road, Andheri (W),
Mumbai-400 058, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to an industrially viable process for the preparation of pure lafutidine by deprotecting the phthaloyl group of aminoolefin and /or its acid addition salts and condensing the deprotected aminoolefin with furfurylsulfinylacetic ester compound.
BACKGROUND OF THE INVENTION:
An ulcer occurs when the acidic digestive juices, which are secreted by the stomach cells, corrode the lining of the stomach, duodenum or esophagus.
Various antiulcer agents with different action mechanisms are used to treat peptic ulcer or irritation of the gastrointestinal tract. These agents neutralize gastric acid and these compounds, have anti-cholinergic activity. These drugs have side effects and poor duration of effect.
Histamine plays a central role in the physiologic control of gastric acid secretion. Histamine H2 receptor stimulates the secretion of gastric acid. The histamine H2- receptor antagonists are useful in the treatment of peptic ulcer as these compounds exhibit a gastric acid secretion suppressing action by antagonizing the histamine H2-receptor of the gastric mucosal parietal cell.
In EP105702, EP172968, EP89153 substituted pyridyloxy derivatives are suggested as drugs that have histamine H2 receptor antagonizing activity.
The present invention relates to a process of preparing lafutidine of formula (I) which is a histamine H2-receptor antagonist having the gastro protective activities. In the year 2000, this drug was first marketed in Japan. Lafutidine inhibits acid secretion and strengthens the mucus barrier of the human gastric mucosa.


Several processes describing the preparation of lafutidine were published earlier. Lafutidine has been first disclosed in EP282077. The process involves dehydrocondensation reaction of amine compound with carboxylic acid compound in presence of condensation agent such as l-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride in dichloromethane at room temperature for 18 hours. Yield is 67%.
In EP282077 patent, deprotection of phthaloyl group of pyridine protected-amino olefin is carried out in the presence of an inorganic base such as hydrazine, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, or an organic base such as methylamine and ethylamine. The patent is silent on use of substituted hydrazines or ethylene diamine.
In journal reference, Chemical and pharmaceutical bulletin (1998), 46(4). 616-22 hydrazine is used for the deprotection of phthaloyl group from pyridine-protected aminoolefins.
JP05059045 discloses a process to prepare lafutidine by the deprotection of phthalimide protecting group from aminobutene derivative with hydrazine hydrate in ethanol at 78°C in 2 hours and reported 75% yield with 99.6% purity.
JP07010816 patent describes a process to prepare lafutidine by the deprotection of phthaloyl group from aminoolefins compounds with hydrazine in nitrogen atmosphere at 80°C to 90°C in 2hrs 20mins. Solvents like 1,4-butanediol, toluene, and ethanol are used for deprotection step. Reaction uses toxic solvents such as benzene, and xylene.
JP07010817 patent disclose deprotection of phthaloyl group at 80°C to 90°C in 2hrs 20mins from aminoolefin compound with hydrazine in the presence of compounds having double bond, which are more reducible. Such compounds are 1-hexene, 1-heptene, 1-octene, 1-nonene, 1-decene, cis-2-butene-1, 4-diol and

trans-2-butene-l, 4-diol. Although these compounds are highly expensive, highly inflammable and hazardous, these are used in large quantities. Solvents like toluene, ethanol are used for deprotection step.
In the prior art hydrazine hydrate is used for deprotection of phthaloyl group. which is highly toxic, unstable, explosive.
Lafutidine which is produced by the prior art processes is contaminated with different byproducts, for e.g. 4-(4-{piperidin-l-ylmethyl)pyridin-2-yloxy)butan-l-amine of formula (II). N-[4-(4-]-piperidylmethyl-pyridyl-2-oxy)-butyl]-2-(2-furfuryl) sulfinylacetamide of formula (III), out of which N-[4-(4-l-piperidylmethyl-pyridyl-2-oxy)-butyl]-2-(2-furfuryl) sulfinylacetamide is the main impurity. This impurity is very difficult to separate from the final product as it has similar physical properties as that of product.

Process disclosed by JP05059045 uses a toxic, hazardous and explosive input namely hydrazine. The patent disclosure is silent on the aspects of impurity profile and level. About 2 hours are required for the process and temperatures in the process are at times upto 80°C to 90°C. The product is often contaminated.

JP07010816 necessitates use of nitrogen atmosphere along with toxic solvents, and does not produce pure lafutidine.
JP070I0817 describes a process where several undesirable toxic compounds are used as either catalysts or inputs that are likely to remain in trace amounts in final product.
Deprotection of phthaloyl group using hydrazine and like substances in presence of base and subsequent condensation as described in the prior art has produced lafutidine having higher impurities of the formula (II) and (III).
Although prior art discloses some processes for the preparation of lafutidine, these processes have several drawbacks namely:
a) very poor yields
b) use of special conditions such as nitrogen atmosphere
c) output of the product is often contaminated with undesirable impurities
d) undesirable byproducts are present
e) processes use toxic, hazardous and explosive inputs, reactants and catalysts
Prior art does not report a process for the preparation of lafutidine that has better yield, or produces a product that is free from impurities and byproducts and does not use toxic, hazardous or explosive inputs, reactants or catalysts.
There is need to provide a process for the preparation of lafutidine that has better yield, free from impurities and byproducts and does not use toxic, hazardous and explosive inputs, reactants or catalysts.
There is a need to provide a process for the preparation of aminoolefin that is free from impurities of formula (II).
The present invention provides a process to prepare lafutidine that has better yields, that produces lafutidine that is free from impurities and byproducts and does not use toxic, hazardous and explosive inputs, reactants or catalysts.

Prior art does not disclose a process for the preparation of lafutidine using ethylene diamine as a base for deprotecting the phthaloyl group of protected aminoolefin and/or its acid addition salts.
There is a need to provide a process that is environment friendly and can be carried out at lower temperatures in shorter period. Inventive step of the invention resides in use of ethylene diamine as a base that results in substantial reduction in reaction temperature, reaction time and yet produces excellent yield with excellent purity, free of impurities.
OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide a process to prepare pure
lafutidine and to provide pure lafutidine.
Another object of the invention is to provide a process for the preparation of
lafutidine that has better and higher yields.
Yet another object of the invention is to provide a process to prepare substantially
pure aminoolefin.
Yet another object of the invention is to provide a process to prepare pure
lafutidine and substantially pure aminoolefin using ethylene diamine as base.
SUMMARY OF THE INVENTION:
Accordingly, this invention discloses a process for the preparation of pure lafutidine by deprotecting the phthaloyl group of protected aminoolefin and /or its acid addition salts by using ethylene diamine as base to form substantially pure aminoolefin and condensing the deprotected substantially pure aminoolefin with furfurylsulfinylacetic ester compound.
DETAILED DESCRIPTION OF THE INVENTION:
This invention discloses a process for the preparation of pure lafutidine by deprotecting the phthaloyl group of protected aminoolefin and/or its acid addition salts by using ethylene diamine as base to form substantially pure aminoolefin

and condensing the deprotected substantially pure aminoolefin with furfurylsulfinylacetic ester compound.
The process for the preparation of Iafutidine of formula (I) comprising of
a) deprotecting the phthaloyl group of protected aminoolefin of formula (IV) and/or its acid addition salts in presence of base ifl an appropriate solvent at a temperature in the range of 10°C to 50oC, preferably from 20°C to 40°C and most preferably from 25°C to 35°C to produce substantially pure aminoolefin of formula (V);
b) condensation of the substantially pure aminoolefin of formula (V) obtained in step a) with furfurylsulfinylacetic ester compound of formula (VI) to form crude lafutidine product at a temperature in the range of 60°C to 70°C in an appropriate solvent; and
c) isolating and crystallizing the product from step b) in an appropriate solvent to give pure Iafutidine.


Furfurylsulfinylacetic ester compound is represented by the formula (VI)

Wherein R represents o or p-nitrophenyl group or 2,4-dinitrophenyl group
Noveity of the invention resides in use of novel bases for deprotection of phthaloyl group. It was surprisingly found that this process produces good yield and product is free from 4-(4-(piperidin-l-ylmethyl) pyridin-2-yloxy) butan-I-amine of formula (II). N-[4-(4-]-piperidylrnethyl-pyridy]-2-oxy)-butyl]-2-(2-furfuryl) sulfinylacetamide of formula (III) impurities.
There are available several types of bases. There are present organic bases, inorganic bases, strong bases, weak bases. Sometimes organometallic complexes act as bases. A substance, which may act as base in one reaction, may not act as base in another reaction. At times presence of other substances and their properties may decide whether a given substance would be basic or not in presence of those other substances. Deprotection of phthaloyl group i.e. step a) is carried out in the presence of an base such as aliphatic polyamine like ethylene diamine, propylene diamine, substituted hydrazine like methyl hydrazine, preferably in presence of amines and most preferably in ethylene diamine. When ethylene diamine is used as base, there is substantial reduction in reaction temperature. It was also surprisingly noticed that reaction time is reduced as well. The condensation is complete in much shorter time than described by the prior art.
There is no specific limitation on solvents for the deprotection step as long as the solvent does not participate in the reaction. Examples of the solvents include alcohols such as methanol, ethanol, propanol, n-butanol, ether such as ethyl ether,

tetrahydrofuran, dimethoxyethane, ketone such as acetone, methyl ethyl ketone, methylisobutylketone, ester such as ethyl acetate, amides such as N, N-dimethylformamide, and aromatic hydrocarbons such as toluene, xylene and nitriles such as acetonitrile. Alcohols are preferred for use in the practice of the present invention.
In step a), the temperature is in the range of 10°C to 50°C, preferably from 20°C to 40°C and most preferably from 25°C to 35°C.
In step b), the temperature is in the range of 60°C to 70°C.
Solvent used for the condensation step is also not specific as long as the solvent does not participate in the reaction. Examples of the solvents include alcohols such as methanol, ethanol, propanol, n-butanol, ether such as ethyl ether, tetrahydrofuran, dimethoxyethane, ketone such as acetone, methyl ethyl ketone, methylisobutylketone, ester such as ethyl acetate, amides such as N, N-dimethylformamide, and aromatic hydrocarbons such as toluene, xylene and nitriles such as acetonitrile. Aromatic hydrocarbons are preferred.
Solvents used for the isolation and purification includes ketone such as methylisobutylketone, ether such as petroleum ether, diisopropyl ether, ethyl ether, isopropyl ether, ketone such as acetone, ester such as ethyl acetate, aliphatic hydrocarbons such as hexane, heptane, aromatic hydrocarbons such as toluene, xylene, alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol and mixtures thereof. Heptane, propanols are preferred.
Pure lafutidine as described in the present invention is lafutidine that is free from 4-(4-(piperidin-l-ylmethyl) pyridin-2-yloxy) butan-1-amine (II) and impurity of N-[4-(4-1 -piperidylmethyl-pyridyl-2-oxy)-butyl]-2-(2-furfuryl) sulfinylacetamide (III) is not more than 0.08%; and purity of active content well above 99.8%. Better and higher yield as described in the present invention is atleast 85 %.

Substantially pure aminoolefin is aminoolefin of formula (V) having impurity of formula (II) not more than 0.08%.
The following non-limiting specific examples presented to illustrate the best mode of carrying out the process of the present invention.
EXAMPLES:
Example - ]: Preparation of lafutidine
To a solution of 5 gm of 2-[4-[[4-(l-piperidinylmethyI)-2-pyridinyl] oxy]-2-butenyl]-lH-Isoindole-l,3(2H)-dione maleate in 50ml methanol at a temperature in the range of 25°C to 35°C, charged 25.8gm ethylene diamine and maintained till reaction is completed. After completion of reaction charged 50m! toluene and IN sodium hydroxide solution and separated layers. Organic layer washed with water and dried over sodium sulphate. To the organic layer, charged 3gm furfuryl sulfiny[acetic acid p-nitrophenyl ester and maintained at a temperature in the range of 60°C to 70°C until reaction is completed. Filtered the reaction mixture. Washed the filtrate with IN sodium hydroxide solution and then with water. Distilled toluene under vacuum. To the oily mass, charged diisopropyl ether and heated to 60°C to 70°C. Cooled to 35°C to 25°C and filtered. Yield (86%); Purity 99.93%; Total impurity 0.07%.
Example - 2 : Preparation of lafutidine
To a solution of 5 gm of 2-[4-[[4-(l-piperidinylmethyl)-2-pyridinyl] oxy]-2-butenyl]-lH-(soindo!e-],3(2H)-dione maleate in 50ml methanol at a temperature in the range of 25°C to 35°C, charged 8.88gm ethylene diamine and maintained till reaction is completed. Distilled methanol under vacuum, after completion of reaction. Cooled the reaction mass to 20 to 25°C. Charged 50ml toluene and IN sodium hydroxide solution and separated layers. Organic layer washed with water and dried over sodium sulphate. To the organic layer, charged 3gm furfuryl sulfinylacetic acid p-nitrophenyl ester and maintained at a temperature in the range of 60°C to 70°C until reaction is completed, Filtered the reaction mixture.

Washed the toluene layer with 1N sodium hydroxide solution and then with water. Distilled toluene under vacuum. To the oily mass, charged heptane and isopropyl alcohol mixture heated to 80°C to 90°C. Cooled to 35°C to 25°C and filtered and then dried. Yield (85%); Purity 99.96%; Total impurity 0.04%.
Example - 3: Preparation of lafutidine
To a solution of 3 gm of 2-[4-[[4-(l-piperidinylmethyl)-2-pyridinyl] oxy]-2-butenyl]-1H-Lsoindole-l,3(2H)-dione maleate in 30ml methanol at a temperature in the range of 25°C to 35°C, charged 10.65gm ethylene diamine and maintained till reaction is completed. After completion of reaction distilled out methanol under vacuum and cool the reaction mass to 20°C to 25°C charged 30ml toluene and IN sodium hydroxide solution and separated layers. Organic layer washed with water and dried over sodium sulphate. To the organic layer, charged 1.8gm furfuryl sulfinylacetic acid p-nitrophenyl ester and maintained at a temperature in the range of 60°C to 70°C until reaction is completed. Filtered the reaction mixture. Washed the toluene layer with 1N sodium hydroxide solution and then with water. Distilled toluene under vacuum. To the oily mass, charged diisopropylether and heated to 60°C to 70°C. Cooled to 35°C to 25°C, filtered and dried. Yield 85%; Purity 99.81%; Total impurity 0.19%.
Example-4: Preparation of lafutidine
To a solution of 3 gm of 2-[4-[[4-(]-piperidinylmethyl)-2-pyridinyl] oxy]-2-butenyl]-lH-Isoindole-l,3(2H)-dione maleate in 30ml methanol at a temperature in the range of 25°C to 35°C, charged 12,43gm ethylene diamine and maintained till reaction is completed. After completion of reaction distilled out methanol under vacuum and cool the reaction mass to 20°C to 25°C charged 30ml toluene and 1N sodium hydroxide solution and separated layers. Organic layer washed with water and dried over sodium sulphate. To the organic layer, charged 1.8gm furfuryl sulfinylacetic acid p-nitrophenyl ester and maintained at a temperature in the range of 60°C to 700C until reaction is completed. Filtered the reaction mixture. Washed the toluene layer with 1N sodium hydroxide solution and then

with water. Distilled toluene under vacuum. To the oily mass, charged diisopropylether, heated to 60°C to 70°C. Cooled to 25°C to 35°C, filtered and dried. Yield 85%; Purity 99.94%; Total impurity 0 06%.

We claim:
1. A process to prepare pure lafutidine, comprising the steps of:
a) deprotecting the phthaloyl group of protected aminoolefin of formula (IV) and/or its acid addition salts in presence of a base in an organic solvent at a temperature in the range of 10°C to 50°C to produce substantially pure aminoolefin of formula (V);
b) condensation of the substantially pure aminoolefin obtained in step a) with furfurylsulfinylacetic ester compound of formula (VI) wherein R represents o or p-nitrophenyl group or 2, 4-dinitrophenyl group at a temperature in the range of 60°C to 70°C in an organic solvent to form crude lafutidine product; and
c) isolating and crystallizing the product from step b) in an organic solvent to give pure lafutidine.



2. The process as claimed in claim la), wherein the base is one of the aliphatic polyamine such as ethylene diamine or propylene diamine, and substituted hydrazine such as methyl hydrazine or a combination thereof.
3. The process as claimed in claimed la), wherein the base is ethylenediamine.
4. The process as claimed in claim 1 a), wherein the deprotection step takes place at a temperature ranging from 10°C to 50°C, preferably from 20°C to 40°C and most preferably from 25°C to 35°C.
5. The process as claimed in claim 1c), wherein the organic solvent is selected from ether such as petroleum ether, diisopropyl ether, ethyl ether, isopropyl ether, ketone such as acetone, ester such as ethyl acetate, aliphatic hydrocarbons such as hexane, heptane, aromatic hydrocarbons such as toluene, xylene, alcohol such as methanol, ethanol, propanol, n-butanol, and mixtures thereof.
6. The process of preparing lafutidine as herein described and exemplified by the examples.