FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
A novel process for preparation of heterocyclic N-substituted
alkylamines
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner m which it is performed.

FIELD OF INVENTION
The present invention relates to a novel process for the preparation of heterocyclic N-substituted alkylamines. The present invention also relates to a novel one pot process for the preparation of heterocyclic N-substituted alkylamines.
BACKGROUND OF INVENTION
Heterocyclic N-substituted alkylamines have many applications in pharmaceuticals, photographic and agricultural areas. These N-substituted alkylamines have been prepared by direct aminoethylation of appropriately substituted amines using either azirides or 2-substituted ethylamines. However these methods suffer from limited scope and necessitate the use of toxic and otherwise noxious materials.
Cancer 1959, 12, 446-450, discloses process for preparation of 1,2-ethane diamines. The starting material used here is aryl N-nitroso-N-(2-chloro-ethyl) carbamate. The process involves synthesis of nitroso compound.
The reaction scheme of the process proceeds as follows


The above process is not feasible since it involves multisteps with the use of nitroso compound.
Synthesis 1981, 541-543, describes a process for the preparation of 1,2-ethane diamines from 2-ethyl-4,5-dihydro-l,3-oxazole which function as aziridine equivalent. Following is the reaction scheme provided in this publication.


The above sequence involves treatment of 2-ethyl-4,5-dihydro-l,3-oxazole with anhydrous hydrogen chloride to afford the N-(2-chloroethyl)-carboxamide which after reaction with appropriately substituted amine, gives the N-(2-aminoethyl) carboxamide. Subsequent hydrolysis affords the desired diamine.
This process suffers from a drawback in terms of low yield as well as tedious preparation of 2-ethyl-4,5-dihydro-l,3-oxazole.
J. Am chem. Soc. 1957, 79, 4457-62 reports the method for preparation of pyrrolidine ethyl amine by reacting dry pyrrolidine to bromoethylamine hydrobromide at temperature below 10°C.
This process also suffers drawbacks. The process requires the temperature to be maintained below 10°C for the addition of bromoethylamine hydrobromide. Thus, the said addition required to be carried out very slowly, makes the process longer. Excess of pyrrolidine is used which has to be removed by distillation which makes the process tedious.
The prior art mentioned herein thus suffers from several drawbacks. Hence there is a need to develop a robust and environment friendly process for preparation of heterocyclic N-substituted alkylamines.
The inventors of the present invention surprisingly found out a simple, economical and environmental friendly process for the preparation of heterocyclic N-substituted alkylamines. The process provides the said compounds in high yield and purity.

OBJECT OF INVENTION
An object of the present invention is to provide a novel process for the preparation of heterocyclic N-substituted alkylamines.
It is another object of the present invention to provide a novel one pot process for the preparation of heterocyclic N-substituted alkylamines.
It is another object of the present invention to provide processes for the preparation of heterocyclic N-substituted alkylamines with a high yield and purity.
It is yet another object of the present invention to provide simple and economically viable processes for the preparation of heterocyclic N-substituted alkylamines.
It is yet another object of the present invention to provide environmentally safe processes for the preparation of heterocyclic N-substituted alkylamines.
SUMMARY OF INVENTION
According to an aspect of the invention, there is provided a novel process for the preparation of heterocyclic N-substituted alkylamines of formula I, by reacting appropriate amine with protected halo-substituted alkyl amine salt in the presence of catalyst and water as a solvent.


wherein, R1 and R2 are identical or different, represents C1-C4 alkyl group which along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom.
A represents formula (CR4R5)n
wherein, R4 and R5 are hydrogen or alkyl group and n is 2 to 3.
R3 is hydrogen or optionally substituted C1-C3 alkyl group, which may be linear or branched.
comprising the steps of,
1. protecting amino group of halo-substituted alkyl amine salt of formula II

wherein X is halogen.
A represents formula (CR4R5)n
wherein, R4 and R5 are hydrogen or alkyl group and n is 2 to 3
R3 is hydrogen or optionally substituted C1-C3 alkyl group, which may be linear or
branched.
by reacting it with a suitable protecting agent in presence of a base and water as a solvent to obtain compound of formula III.


wherein X, A and R3 are as defined above Z represents protecting group
2. reacting compound of formula III with an amine of formula IV

wherein, R1 and R2 are identical or different, represents C1-C4 alkyl group which along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom.
in presence of a base, water as a solvent and a catalyst at 70-90 °C to obtain compound of formula V


wherein R1,R2 , R3, A and Z are as defined above.
3. de-protecting compound of formula V in organic solvent with an acid followed by separation of aqueous layer and treatment with a base such as alkali metal hydroxide at 0-5 °C to obtain the desired heterocyclic N-substituted alkylamines of formula I.
In yet another aspect of the present invention there is provided a novel one-pot process for the preparation of heterocyclic N-substituted alkylamines of formula I, comprising the steps of,
(a) protecting the amino group of halo-substituted alkylamine salt of formula II by reacting it with suitable protecting agent in presence of a base and water at 25- 40°C for 1 to 5 hours;
(b) separating the organic layer and the aqueous layer;
(c) adding a base, water and a catalyst to the organic layer obtained in step (b)
followed by addition of an amine of formula IV at 70-90°C and maintaining
the reaction mixture at 70-90°C for 7 to 9 hours;
(d) separating the organic layer and the aqueous layer at room temperature,
adding organic solvent to organic layer and treating it with an acid at
temperature 0-5°C;
(e) separating the aqueous layer at room temperature and adding base such as
alkali metal hydroxide to the aqueous layer at temperature below 5°C and
isolating the desired heterocyclic N-substituted alkylamines of formula I.
DETAILED DESCRIPTION OF INVENTION
The present invention relates to a novel and simple process for the preparation of heterocyclic N-substituted alkylamines of formula I with high purity and yield. The

present invention also relates to a novel one pot process for the preparation of heterocyclic N-substituted alkylamines of formula I.

wherein, R1 and R2 are identical or different, represents C1-C4 alkyl group which along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom.
A represents formula (CR4R5)n
wherein, R4 and R5 are hydrogen or alkyl group and n is 2 to 3.
R3 is hydrogen or optionally substituted C1-C3 alkyl group, which may be linear or branched.
In an aspect of the present invention there is provided a novel process for the preparation of heterocyclic N-substituted alkylamines of formula I, comprising the steps of,
1. protecting the amino group of halo-substituted alkyl amine salt of formula II


wherein, X is halogen A and R3 are as defined above.
by reacting it with suitable protecting agent in presence of a base and water as a solvent to afford compound of formula III.

wherein, X, A and R3 are as defined above Z represents protecting group
2) reacting compound of formula III with an amine of formula IV

wherein, R1 or R2 are as defined above.
in presence of a base, a catalyst and water as a solvent at 70-90°C to obtain compound of formula V


Formula V wherein, R1,R2, R3, A and Z are as defined above.
3) de-protecting compound of formula V in organic solvent with an acid followed by separation of aqueous layer and treatment with base such as alkali metal hydroxide at 0-5 °C to obtain the desired heterocyclic N-substituted alkylamines of formula I.
In another aspect of the present invention there is provided a novel one pot process for the preparation of heterocyclic N-substituted alkylamines of formula I, comprising the steps of,
(a) protecting the amino group of halo-substituted alkylamine salt of formula II by reacting it with suitable protecting agent in presence of a base and water at 25- 40°C for 1 to 5 hours;
(b) separating the organic layer and the aqueous layer;
(c) adding a base, water and a catalyst to the organic layer from step (b) followed by addition of an amine of formula IV at 70-90°C and maintaining the reaction mixture at 70-90°C for 7 to 9 hours;
(d) separating the organic layer and the aqueous layer at room temperature, adding organic solvent to organic layer and treating it with an acid at temperature 0-5°C;

(e) separating the aqueous layer at room temperature and adding base such as alkali metal hydroxide to the aqueous layer at temperature below 5°C and isolating the desired heterocyclic N-substituted alkylamines of formula I.
The processes of the present invention are as depicted in scheme 1 and scheme 2
below
Scheme 1: Three step process


Scheme 2: One pot process

In scheme 1 and 2, R1, R2, R3, A, X and Z are as defined above.
In an embodiment of the present invention, the halo-substituted alkyl amine salt of formula II is selected from 2-halo alkyl amine hydrochloride or 2-halo alkyl amine hydrobromide, more preferably the halogen group in alkyl amine is chlorine and the chloro substituted alkyl amine salt is 2-chloro alkyl amine hydrochloride or 2-chloro alkyl amine hydrobromide.
In another embodiment of the present invention, the protecting agent used is selected from (t-butyloxy)carbamate (Boc), (9-fluorenylmethyl) carbamate (Fmoc), (allyl)

carbamate (Alloc), (trichloroethyl) carbamate (Troc) or (benzylcarboxy) carbamate (Cbz), preferably (t-butyloxy)carbamate (Boc) is used.
The base used in step 1 and step (a) reaction is selected from inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium hydroxide.
The step 1 reaction is carried out at temperature 25-40°C for 1 to 5 hours, preferably for 2 to 4 hours.
In another embodiment of the present invention, the amine of formula IV is selected from cyclic amines, preferably heterocyclic amines, more preferably pyrrolidine.
The amount of compound of formula II and amine of formula IV used are at least in the mole ratio of 1:1.
In yet another embodiment of the present invention, the catalyst used in step 2 and step (c) reaction is ammonium salt, selected from Tetrabutyl ammonium bromide (TBAB), Tetrabutyl ammonium iodide (TBAI) or Triethyl benzyl ammonium chloride (TEBA), preferably Tetrabutyl ammonium bromide (TBAB) is used.
The base used in step 2 and step (c) reaction is inorganic base selected from potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate, preferably potassium carbonate is used.
In yet another embodiment of the present invention, step 2 and step (c) reaction is carried out at temperature 70-90°C, preferably at 80-85°C for 7 to 9 hours.

The acid used in step 3 and step (d) reaction is selected from HC1 or trifluoroacetic acid, preferably HC1 is used.
The base alkali metal hydroxide used in step 3 and step (e) reaction is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
The organic solvent used in step 3 and step (d) reaction is selected from ethyl acetate, dichloromethane, chloroform or toluene, preferably ethyl acetate.
The organic solvent used for extraction was selected from ethyl acetate, dichloromethane, chloroform or toluene, preferably dichloromethane.
The crude product of heterocyclic N-substituted alkylamines of formula I is purified by methods known in the art like crystallization, distillation, chromatography etc.
In yet another aspect of the present invention, the heterocyclic N-substituted alkylamines, preferably are selected from the group represented by formula IA,

wherein R1 and R2 along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom and n is 2 to 3 more preferably, compound of formula IA is pyrrolidine ethyl amine.

The details of the invention provided in the following examples are given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1:
Preparation of 2-(pyrrolidine -1-yl)ethyl amine
Step1:
To a solution of 2-chloroethylamine hydrochloride (2.31 kg) in water (2.3L) was added BOC anhydride (3.91 kg). The reaction mixture was cooled up to 25°C. To the reaction mixture was added 6 N NaOH solution (dissolving 1.99 kg NaOH to 8.1 L water) and then temperature was raised to 35°C and maintained for 3 hours. The resulting suspension was extracted with 6.492 liters of ethyl acetate. The organic phase was washed with water and dried over sodium sulfate and concentrated in vacuum at 40°C to yield the t-BOC derivative (3.2 kg).
Step 2:
To a solution of 2.48 kg of potassium carbonate and 9.65L of water was added tetra butyl ammonium bromide (79.8 gm) and t-BOC derivative (3.2 kg) obtained in step 1. The mixture was heated up to 80-85°C and pyrrolidine (1.4 kg) was added to it. The temperature was maintained at 80-85°C for 8 hours. After completion of reaction, 11.3 liters of ethyl acetate was added and organic layer was separated and washed with 10% brine solution. The organic layer was dried on sodium sulphate and concentrated in vacuum at 40°C to yield compound of Formula V (2.86 kg).

Step 3:
The solution of compound of Formula V (2.86 kg) obtained from step 2 and ethyl acetate (3.34L) was chilled up to 0-5°C and HC1 (6.65L liters) was added. The temperature of the reaction mixture was raised to room temperature and stirred for an hour. The aqueous layer was separated and cooled to 0-5°C and NaOH flakes were added to the solution (This addition is highly exothermic). The temperature of reaction mass was then raised to room temperature and extracted with 9 x 3.34L liters of Dichloromethane. The combined MDC layer was distilled and degassed under vacuum at 30 °C to provide 1.52 kg of crude 2-(pyrrolidine -l-yl)ethyl amine. The crude product obtained was further distilled under vacuum of 30mbar to get 1kg of 2-(pyrrolidin -l-yl)ethyl amine with GC purity of >98%. The product was confirmed by H proton NMR spectra and C NMR spectra.
Example 2:
One pot process for preparation of 2-(pyrrolidine -1-yl)ethyl amine
To stirred solution of 2.31 kg 2-chloroethyl amine hydrochloride in 2.3L water was added 8.51L of BOC anhydride at 25-30°C.1.99 kg NaOH solution in 8.1L of water was further added to the reaction mass at 25-30°C over a period of 1 to 1.5 hours (addition slightly exothermic). After the addition, the reaction mixture was warmed to 35-37°C and maintained for 2-4 hours. It was further cooled to 25-30°C and was allowed to settle for 0.5 to 1 hour. The lower aqueous layer was carefully removed and to the organic layer was added potassium carbonate, TBAB and water. The reaction mixture was heated to 80-85°C and pyrrolidine was added over a period of 1 hour. The reaction mass was stirred at 80-85°C and temperature was maintained for 7-9 hours.
The reaction mass was then cooled to room temperature and allowed to settle. The lower aqueous layer was removed and to the organic layer was added ethyl acetate

(3.34 L). The mixture was stirred and cooled to 0-5°C. To the cooled mixture HC1 (6.65L) was slowly added over a period of 1 hour. The temperature of mixture was raised to room temperature and stirred for an hour. The organic layer was separated from aqueous layer. The aqueous layer was washed with ethyl acetate (2 X 6.68L). The aqueous layer was then cooled to 0-5°C and NaOH solution (3.43 kg NaOH in 6.87L water) was added to it over a period of 1 hour. The temperature of mixture was raised to about 25 to 30°C and the mixture was extracted with dichloromethane (9 X 3.34 L). The dichloromethane layer was dried over sodium sulphate. The dichloromethane layer was then concentrated under vacuum (>20mbar) at 30-35°C to obtain 1.6 kg crude product. The crude product was further distilled to provide 1 kg of pure 2-(pyrrolidine -1-yl) ethyl amine.

We claim
1. A novel process for the preparation of heterocyclic N-substituted alkylamines of formula I, by reacting appropriate amine with protected halo-substituted alkyl amine salt in the presence of catalyst and water as a solvent

wherein, R1 and R2 are identical or different, represents C1-C4 alkyl group which along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom
A represents formula (CR4R5)n
wherein, R4 and R5 are hydrogen or alkyl group and n is 2 to 3
R3 is hydrogen or optionally substituted C1-C3 alkyl group, which may be linear or branched
comprising the steps of,
i) protecting amino group of halo-substituted alkyl amine salt of formula II


wherein X is halogen.
A represents formula (CR4R5)n
wherein, R4 and R5 are hydrogen or alkyl group and n is 2 to 3
R3 is hydrogen or optionally substituted C1-C3 alkyl group, which may be linear or
branched
by reacting it with a suitable protecting agent in presence of a base and water as a
solvent to obtain compound of formula III


wherein X, A and R3 are as defined above Z represents protecting group
Amine Formula IV
ii) reacting compound of formula III with an amine of formula IV


wherein, R1 and R2 are identical or different, represents C1-C4 alkyl group which along with nitrogen atom on which they are substituents, form a saturated or an unsaturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom
in presence of a base, water as a solvent and a catalyst at 70-90 °C to obtain compound of formula V

Formula V wherein R1,R2, R3, A and Z are as defined above
iii) de-protecting compound of formula V in an organic solvent with an acid followed by separation of aqueous layer and treatment with a base such as alkali metal hydroxide at 0-5 °C to obtain the desired heterocyclic N-substituted alkylamines of formula I
2. A novel one-pot process for the preparation of heterocyclic N-substituted alkylamines of formula I, comprising the steps of,
(a) protecting the amino group of halo-substituted alkylamine salt of formula II by reacting it with suitable protecting agent in presence of a base and water at 25- 40°C for 1 to 5 hours;
(b) separating the organic layer and the aqueous layer;

(c) adding a base, water and a catalyst to the organic layer obtained in step (b)
followed by addition of an amine of formula IV at 70-90°C and maintaining
the reaction mixture at 70-90°C for 7 to 9 hours;
(d) separating the organic layer and the aqueous layer at room temperature,
adding an organic solvent to organic layer and treating it with an acid at
temperature 0-5°C;
(e) separating the aqueous layer at room temperature and adding a base such as
alkali metal hydroxide to the aqueous layer at temperature below 5°C and
isolating the desired heterocyclic N-substituted alkylamines of formula I
3. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the halo-substituted alkyl amine salt of formula II is
selected from 2-halo alkyl amine hydrochloride or 2-halo alkyl amine
hydrobromide, more preferably the halogen group in alkyl amine is chlorine and
the chloro substituted alkyl amine salt is 2-chloro alkyl amine hydrochloride or 2-
chloro alkyl amine hydrobromide
4. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the protecting agent used is selected from (t-butyloxy)carbamate (Boc), (9-fluorenylmethyl) carbamate (Fmoc), (allyl) carbamate (Alloc), (trichloroethyl) carbamate (Troc) or (benzylcarboxy) carbamate (Cbz), preferably (t-butyloxy)carbamate (Boc) is used
5. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the base used in step i) and a) is selected from inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, preferably sodium hydroxide is used

6. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the amine of formula IV is selected from cyclic amines, preferably heterocyclic amines, more preferably pyrrolidine is used
7. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the catalyst used in step ii) and step c) reaction is ammonium salt, selected from Tetrabutyl ammonium bromide (TBAB), Tetrabutyl ammonium iodide (TBAI) or Triethyl benzyl ammonium chloride (TEBA), preferably Tetrabutyl ammonium bromide (TBAB) is used
8. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the base used in step ii) and step c) reaction is inorganic base selected from potassium carbonate, sodium carbonate, potassium bicarbonate, or sodium bicarbonate, preferably potassium carbonate is used
9. The process for preparation of heterocyclic N-substituted alkylamines as claimed
in claim 1 or 2, wherein the acid used in step iii) and step d) reaction is selected from hydrochloric acid or trifluoroacetic acid, preferably hydrochloric acid is used
10. The process for preparation of heterocyclic N-substituted alkylamines as claimed in claim 1 or 2, wherein the organic solvent used in step iii) and step d) reaction is selected from ethyl acetate, dichloromethane, chloroform or toluene
11. The process for preparation of heterocyclic N-substituted alkylamines as claimed in claim 1 or 2, wherein the heterocyclic N-substituted alkylamines, preferably are selected from the group represented by formula IA,


Formula IA
wherein R1 and R2 along with nitrogen atom on which they are substituents, form a saturated 5, 6 or 7 membered ring, optionally interrupted with at least one hetero atom such as nitrogen or oxygen atom and n is 2 to 3 more preferably, compound of formula IA is pyrrolidine ethyl amine.