FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION (SECTION 10 and Rule 13)


"AN IMPROVED METHOD FOR PREPARATION OF LAFUTIDINE
INTERMEDIATE"
Emcure Pharmaceuticals Limited., an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED


FIELD OF INVENTION
The present invention relates to a method for the deprotection of the amino group, more particularly the invention relates to a removal of the phthalimido group from a Lafutidine intermediate utilizing a combination of bases to provide the resulting amino intermediate of high purity and free from associated impurities.
BACKGROUND OF THE INVENTION
Ulcer formation in stomach and duodenum is primarily due to excess secretion of gastric acid, which is due to the presence of Histamine H2 receptors at the affected site. Administration of a drug having histamine H2 receptor antagonizing activity inhibits secretion of gastric acid and is useful for treatment of ulcer. Certain substituted Pyridyloxy derivatives have been suggested as drug having histamine H2 receptor antagonizing activity as disclosed in European Patent Publication Nos. 87274, 89153, 105702, 172968 and 177016.
Lafutidine of formula (I) chemically known as (±)-2-(Furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl)oxy-(Z)-2-butenyl]acetamide is a pyridyloxy derivative having anti-ulcer properties due to its histamine H2 receptor antagonistic and mucosal protective activity.

(I) One of the key steps in the preparation of Lafutidine of formula (I) is the
hydrolysis of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide
of formula (II) to 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-]-2-butenamine of
formula (III). Prior art discloses the utilization of hydrazine hydrate for such a
functional group transformation.


Scheme-I: Prior art method for the preparation of 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-]-2-butenamine of formula (III)
US 4,912,101 and US 4,977,267 disclose a method for hydrolysis of the phthalimide group of a Lafutidine derivative of formula (VI) by hydrolysis of the corresponding phthalimide compound of formula (V) with hydrazine hydrate.

The present inventors have replicated the experiment disclosed in example 27 of US 4,912,101 using hydrazine hydrate for preparation of Lafutidine intermediate of formula (III). However, such a transformation resulted in formation of an impurity of formula (VII) in the range of 4-5%.


The compound of formula (III) thus obtained required repeated purification to remove the impurity (VII), which resulted in low yield, thereby making the transformation quite costly and unviable on a commercial scale.
JP 5059045 also discloses the use of hydrazine hydrate for deprotection of the amino group; however the method resorts to removal of the associated impurity by purification of Lafutidine intermediate of formula (III) through preparation of its acid addition salts, which in turn also reduces the yield.
It is pertinent to mention that if the impurity of formula (VII) is not removed at the intermediate stage, further reaction with compound of formula (IV) to give Lafutidine (I) results in an additional impurity of formula (VIM).

Removal of these impurities requires repeated purifications, which further reduces the yield and increases the cost of manufacturing on a commercial scale.
Regulatory authorities all over the world are becoming very stringent about the level of impurities in an approved drug. Pharmacopoeia! specification requires that the impurities such as the impurity of formula (VII), impurity of formula (Vlll) should be below 0.2%.
Needless to mention, most of the prior art methods do not give product conforming to the above mentioned criteria.

Thus, in view of the above shortcomings, there was a long felt need to develop an improved method, which would give Lafutidine of formula (I) of high purity and free from associated impurities of formula VII and formula VIII and also be cost-effective and give good yields for commercial viability.
OBJECT OF THE INVENTION
An object of the present invention is to provide a novel improved process for preparation of Lafutidine (I) of high purity free from associated impurities.
Another object of the present invention is to provide a process for Lafutidine (I) which is simple, cost-effective, environmentally safe and commercially viable.
Yet another object of the present invention is to provide a process which yields Lafutidine (I) having high purity and conforming to regulatory specifications, without any additional step of purification.
SUMMARY OF THE INVENTION
The inventors in their quest for preparing Lafutidine (I) of high purity, have developed an improved process for deprotection of the amino group by treating N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) with a combination of bases in a selective manner to obtain 4-[(4-piperidinomethyl)pyridin-2-yl) oxy-]-2-butenamine of formula (III) with high purity, free of associated impurities.
According to the main aspect of the invention, there is provided an improved process for the preparation of 4-[(4-piperidinomethyl)pyridin-2-yl)oxy-]-2-butenamine of formula (III) with high purity comprising reaction of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) with an organic base followed by an inorganic base in a solvent and obtaining compound of formula (III).

One aspect of the invention is the utilization of a combination of bases in a sequential manner and in definite proportions and at ambient temperature to obtain compound of formula (111) in high yield and purity.
Another aspect of the invention relates to a process wherein the ratio of the organic base to the inorganic base is between 2.0:0.5 and 2.0:1.5.
Yet another aspect of the invention relates to a process wherein the mole equivalent of organic base and inorganic base respectively utilized per mole of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) is between 9.0:5.0 and 15.0:10.0
A further aspect of the invention is to provide a method for manufacture of 4-[(4-piperidinomethyl)pyridin-2-yl) oxy-]-2-butenamine of formula (III) by treating N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) with an organic base at 20-40°C for 2-6 hours followed by treatment with an inorganic base at 20-40°C for 2-6 hours and obtaining compound of formula III with high purity.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a process for the preparation of 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-]-2-butenamine of formula (III). The present inventors have found that use of a combination of bases in a sequential and definite ratio for the hydrolysis or deprotection of N-{4-[4-(piperidinomethyl)pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) to provide the amine compound of formula (111) in high yield 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-] 2-butenamine of formula (III) as shown in Scheme-ll.


(III)
Scheme-ll: Method of the present invention for preparation of 4-[(4-pi peri dinom ethyl) pyridin-2-yl) oxy-]-2-bu ten amine of formula (III).
N-{4-[4-(piperidinornethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula-ll was prepared according to the process disclosed in US 4,912,101, US 4,977,267 or JP 5059045.
The present inventors in pursuit of the desired quality have tried out several experiments using several bases in different combinations for deprotection of the amino group.
The bases were selected from the group comprising of organic and inorganic bases.
The organic bases were selected from the group comprising of triethyl amine, monomethylamine, isopropyl amine, diisopropyl amine, dimethyl amine etc.
The preferred organic base is monomethyl amine.
The inorganic bases were selected from the group comprising of alkali carbonates and alkali metal hydroxides and were selected from the group

comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
The preferred inorganic bases are sodium hydroxide and potassium hydroxide.
A comparative study of these bases when utilized slone was carried out and it was revealed that utilization of a single base invariably gave rise to impurities of formula (VII), (VIII), (IX) or (X).

The impurities formed were in the range of 7% to about 90%, therefore, the utilization of these bases without combination with another base was not found suitable for commercial scale as further repeated purification would be required, which in turn would result in loss of yield.
On the other hand when a combination of bases i.e. an organic base followed by an inorganic base was tried out the level of impurity formation was reduced to only about 0.02%. Subsequently, the yield was also found to increase, since the steps of repeated purification were not required for obtaining compound of formula (III) having desired purity.
If the organic and inorganic bases were added together then various impurities amounting to 36.87% was formed.
Further it was also found that the organic and inorganic bases were to be used in a specific ratio and in a specific sequence for obtaining the desired purity.
Also, there was pattern in which the organic bases were to be added, an inorganic base followed by an organic base invariably gave rise to an increased

level of impurity whereas interchange in the sequence was found to decrease the associated impurities considerably.
It was also found that the ratio of organic base: inorganic base also played a significant part on impurity formation.
A 1:1 ratio of the bases was found to give about 15% impurity, but it was found that the ratio of the organic base to the inorganic base between 2.0:0.5 and 2.0:1.5.was found to give the desired results.
Further, the mole equivalent of both the organic bases as well as inorganic bases
that were to be used should be atleast more than 5.0 moles per mole of N-[4-[4-
(piperidinomethyl)pyridyl-2-oxy]-cis-2-butene}phthalimide of formula-ll,
otherwise, either the reaction does not go to completion or there is a high degree of impurity formation.
In a specific embodiment, N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide Maleic acid of formula-li was added to an alcohol as solvent.
The alcoholic solvent was selected from a straight chain or branched C1-6 alcohols. Examples of such alcoholic solvents include methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, n-pentyl alcohol, neopentyl alcohol, tert-pentyl alcohol and n-hexyl alcohol.
The preferred alcohol was methanol.
An organic base like monomethyl amine was added to the mixture of compound of formula (II) in methanol.
The resulting reaction mixture was stirred at a temperature of 15 to 35°C, preferably between 20°C and 30°C for 3-5 hours.

An inorganic base such as sodium hydroxide as an aqueous solution was then added to the mixture and stirred at a temperature of 15 to 35°C, preferably between 20°C and 30°C for 3-5 hours.
Typically, the ratio of organic base: inorganic base employed for deprotection of phthalimide reaction was preferably in the range of 2.0:0.5 to 2.0:1.5 and the mole equivalent of organic base: inorganic base per mole equivalent of the compound of formula (II) was in the range between 9.0:5.0 and 15:10.0.
The preferred ratio was 2.0:1.0 (Organic: Inorganic) and 10.0:5.0 (mole equivalent of Organic: Inorganic respectively per mole equivalent of the compound of formula (II).
The reaction was stirred between 15°C to 35°C, preferably between a temperature range of 20°C and 30°C.
The reaction mixture was monitored by HPLC and on completion of reaction methanol was evaporated under reduced pressure to give 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-]-2-butenamine of formula-Ill with a yield of 96% and purity of
99.25%.
It is worth mentioning that the compound of formula (III) thus obtained did not require any further purification since the level of individual impurities was below detectable limits.
4-[(4-Piperidinomethyl)pyridin-2-yl)oxy-]-2-butenamine of formula (III) thus obtained was converted to Lafutidine of formula (I) by conventional methods with yield of above 84% and a purity of 99.9%.
Although, the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the

illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above. All patent and non-patent publications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.
EXAMPLES
Example-1
Preparation of 4-[(4-piperidinomethyl) pyridin-2-yl) oxy-] 2-butenamine (III). N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide maleic acid salt (50gms, 0.09 moles) was charged into methanol (500 ml) under stirring, Monomethylamine solution (40%) (77ml, 0.98 moles) was charged in the reaction mixture at 25°C to 30°C and reaction mass was stirred for 3 to 5 hours. Sodium Hydroxide solution (19.72gms, 0.49 moles) in water was charged under stirring at 25°C to 30°C and again reaction mass was stirred for 3 to 5 hours. After completion of the reaction, methanol was evaporated under vacuum at 45°C to 50°C. Product was isolated from dichloromethane after stirring for 1 hour at room temperature %Yield: 96% Purity: 99.25%.
Example-2
Preparation of 4-[(4-piperidinomethyl)pyridin-2-yi)oxy-]-2-butenamine (III). N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide (5gms, 0.01 moles) was charged into methanol (50 ml) under stirring, Monomethylamine solution (40%) (8 ml, 0.10moles) was charged in the reaction mixture at 25°C to 30°C and reaction mass was stirred for 3 to 5 hours. Potassium Hydroxide solution (2.75 g, 0.06 moles) in water was charged under stirring at 25°C to 30°C and reaction mass was stirred for 3 to 5 hours. After completion of the reaction,

methanol was evaporated under vacuum at 45°C to 50°C. Product was isolated from dichloromethane after stirring for 1 hour at room temperature Yield: 3.0 g. Purity: 99.78%
Example 3
Preparation of Lafutidine (Formula-I).
4-[(4-piperidinomethyl)pyridin-2-yi)oxy-]-2-butenamine (25 g, 0.09 mol) obtained in Example-1 or 2 was added to dichloromethane (250 ml) in a reaction vessel at room temperature. p-Nitrophenyl-2-[(Furanylmethyl) sulfinyl] acetic acid (29.59 g, 0.09 moles) was added drop wise at 25°C to 30°C and reaction mass was stirred for 4 to 6 hours. After completion of the reaction, reaction mass was washed with sodium hydroxide solution (500ml) and water (200ml) wash. Dichloromethane was evaporated under vacuum at 35°C to 40°C. Lafutidine product was isolated from Methyl isobutyl ketone (MIBK) after stirring for 1 hour at0°Cto10°C. %Yield: 84.42% Purity: 99.9%.

We Claim,
1. A process for preparation of 4-[(4-piperidinomethyl) pyridin-2-yl)oxy-] 2-butenamine of formula (III) with high purity comprising reaction of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) with an organic base followed by an inorganic base in a solvent and obtaining compound of formula (III).
2. A process according to claim 1, wherein the organic base is selected from the group comprising of triethyl amine, monomethylamine, isopropyl amine, diisopropyl amine and dimethyl amine.
3. A process according to claim 2, wherein the organic base is preferably monomethyl amine.
4. A process according to claim 1, wherein the inorganic base is selected from the group comprising of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
5. A process according to claim 4, wherein the inorganic base is preferably sodium hydroxide and potassium hydroxide.
6. A process according to claim 1, wherein the ratio of the organic base to inorganic base is between 2.0:0.5 and 2.0:1.5.
7. A process according to claim 1 wherein the mole equivalent of the organic base and inorganic base utilized per mole equivalent of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) is between 9.0:5.0 and 15:10.0.
8. A process according to claim 1 wherein the reaction is carried out between 20°C and 30°C.
9. A process for preparation of Lafutidine of formula (I) having high purity comprising reaction of N-{4-[4-(piperidinomethyl) pyridyl-2-oxy]-cis-2-butene} phthalimide of formula (II) with an organic base followed by an inorganic base in a solvent and obtaining 4-[(4-piperidinomethyl) pyridin-2-yl)oxy-] 2-butenamine of formula (III), further reacting with p-Nitro phenyl-2-[(furanylmethyl) sulfinyl] acetic acid of formula (IV) to yield Lafutidine of formula (I).

10. A process according to claim 1 and 9, wherein the associated impurities are less than 0.2%.
Dated this twenty fifth (25th) day of March, 2009.

(Signed)
Dr. Mukund. K. Gurjar Chief Scientific Officer Emcure Pharmaceuticals Ltd.