FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - "NOVEL AMIDE DERIVATIVES OF
LINAGLIPTIN AND PROCESS FOR THE PREPARATION THEREOF"
2. Applicant(s)
(a) NAME: Zenvision Pharma LLP
(b) NATIONALITY : An Indian Company
(c) ADDRESS : First Floor, K.K. Chambers, SIR P.T. Road
Fort, Mumbai, Maharashtra, India 400001
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

"NOVEL AMIDE DERIVATIVES OF LINAGLIPTIN AND PROCESS
FOR THE PREPARATION THEREOF"
FIELD OF THE INVENTION
The present invention relates to novel amide derivatives of Linagliptin and process of preparation thereof.
BACKGROUND OF THE INVENTION
Linagliptin is a hypoglycemic agent belonging to the chemical class of purine and
quinazoline derivative. It is a dipeptidyl peptidase-4 (DPP-4) inhibitor. The
Chemical name is lH-Purine-2,6-dione, 8-[(3R)-3-amino-l-piperidinyl]-7-(2-
butyn-1 -yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-. The
empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. Linagliptin is represented by compound of structural formula II:

Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca. 1 mg/mL).
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic

polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent maimer and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta-cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in a reduction in hepatic glucose output.
The Linagliptin tablet of Boehringer Ingelheim has been approved in USA as on May 2, 2011 under the trade name TRADJENTA ® and is available in the strength 5mg (Light-red). The product is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
The Linagliptin in combination with Empagliflozin is in the form of film coated tablet and with Metformin hydrochloride in the form of film coated tablet and extended release tablet of Boehringer Ingelheim Pharmaceuticals Inc has been approved in USA under the trade name GLYXAMBI®, JENTADUETO® and JENTADUETO XR® respectively. The products are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
The U.S. Patent No. 8,865,729 discloses acid addition salt of Linagliptin with an acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, D-ascorbic acid, L-ascorbic acid, D-aspartic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (-)-camphoric acid, (+)-camphor-10-sulfonic, (-)-camphor-lO-sulfonic, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,

fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, L-glucoheptonic acid, D-gluconic acid, L-gluconic acid; D-glucuronic acid, L-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, D-lactic acid, L-lactic acid, lactobionic acid, lauric acid, maleic acid, D-malic acid, L-malic acid, malonic acid, D-mandelic acid, L-mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), propionic acid, D-pyroglutamic acid, L-pyroglutamic acid, salicyclic acid, 4-aminosalicyclic acid, sebacic acid, stearic acid, succinic acid, D-tartaric acid, L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid, in the form of an organic solvate, hydrate, or mixed hydrate/organic solvate thereof and process for preparing a salt. However, the said patent does not disclose or teaches novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
The Chinese Patent Publication No. 103936739B generically discloses substituted amide derivatives of Linagliptin and their process for preparation threof. However, the said patent application does not disclose or teaches novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
The Chinese Patent Publication No. 104387315B discloses a method for preparation optically active 3-amino-piperidine and its hydrochloride form. The said patent application further discloses method of preparation of Linagliptin by using 3-amino-piperidine and its hydrochloride form as an intermediate. However, the said patent application does not disclose or teaches novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.

The European Patent No. 1953162B1 genetically discloses Linagliptin and its substituted amide derivatives. However, the said patent does not disclose or teaches novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
Currently, the commercially marketed product of Linagliptin is available in the form of tablet and extended release tablet and also along with other antidiabetic agents such as Empagliflozin and Metformin hydrochloride. The commercially available tablet and extended release tablet products contains Linagliptin base.
The physicochemical properties of commercially available salts and derivatives of linagliptin as well as product known in the prior art for linagliptin impacts stability and efficacy of the product in the treatment of diabetes mellitus.
Therefore, there is need in art to develop hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin and process of preparation thereof.
Accordingly, applicant of the present invention invented novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin and process of preparation thereof. The novel amide derivatives with superior physicochemical properties provide better patient compliance and efficacy in the treatment of diabetes mellitus.
OBJECT OF THE INVENTION
It is another object of the present invention to provide novel hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin; preferably Linagliptin palmitamide.

It is another object of the present invention to provide novel hydroxy1 substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin; preferably Linagliptin 16-hydroxyhexadecanamide.
It is another object of the present invention to provide novel halogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
It is another object of the present invention to provide novel halogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin; preferably Linagliptin 16-chlorohexadecanamide or Linagliptin 16-bromohexadecanamide.
It is another object of the present invention to provide novel and commercially viable process with ease of operations for the preparation of hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin by use of one or more intermediate; preferably process of preparation of Linagliptin palmitamide.
It is another object of the present invention to provide novel and commercially viable process with ease of operations for the preparation of hydroxyl substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin by use of one or more intermediate; preferably process of preparation of Linagliptin 16-hydroxyhexadecanamide.
It is another object of the present invention to provide novel and commercially viable process with ease of operations for the preparation of halogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin by use of one
TV
or more intermediate; preferably process of preparation of Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide.
It is another object of the present invention to provide method of treating type 2 diabetes mellitus by administrating the composition comprising novel hydroxyl or

halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
It is another object of the present invention to provide method of treating type 2 diabetes mellitus by administrating the composition comprising Linagliptin palmitamide or Linagliptin 16-hydroxyhexadecanamide or Linagliptin 16-chlorohexadecanamide or Linagliptin 16-bromohexadecanamide.
SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin compound of formula I.

Wherein, Ri is a hydrogen or halogen atom or hydroxyl group substituted at any
position from C2 to C16 Carbon atom Formula I
In another aspect of the present invention is to provide novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide.

In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin by use of one or more intermediate.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide by use of one or more intermediate.
In another aspect of the present invention provides a novel Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin compound (Formula I) comprises the step of reacting Linagliptin (Formula II) with substituted Palmitoyl halide or Palmitic Acid (Formula III). (Reaction is represented as per Scheme-I).


Wherein, X is a halogen atom or hydroxyl group or any leaving group; Ri is a hydrogen or halogen atom or hydroxyl group substituted at any position
from C2 to C16 Carbon atom.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin compound (Formula I) comprises the step of reacting Linagliptin (Formula II) with substituted Palmitoyl halide or Palmitic acid (Formula III) in the presence of one or more solvent or reagents.
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin compound (Formula I) comprises the step of reacting Linagliptin (Formula II) with substituted Palmitic anhydride (Hexadecanoic acid, 1,1'-anhydride) or Palmitic thioanhydride (Hexadecanethioic acid, 1,r-anhydrosulfide) (Formula IV). (Reaction is represented as per Scheme-
II).


Wherein, A is oxygen or sulfur atom; R1 is a hydrogen or halogen atom or hydroxyl group substituted at any position from C2 to C16 Carbon atom
In another aspect of the present invention is to provide process for preparation of novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin compound (Formula I) comprises the step of reacting Linagliptin (Formula II) with substituted Palmitic anhydride (Hexadecanoic acid, 1,r-anhydride) or Palmitic thioanhydride (Hexadecanethioic acid, l,l'-anhydrosulfide) (Formula IV) in the presence of one or more solvent or reagents.
In another aspect of the present invention provides process for preparation of novel Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide.

In another aspect of the present invention provides process for preparation of novel Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide by use of one or more intermediate.
In another aspect of the present invention provides a process for preparing novel Linagliptin palmitamide compound of formula III comprising the step of reacting Linagliptin with Palmitoyl chloride.
In another aspect of the present invention provides a process for preparing novel Linagliptin palmitamide comprises the step of reacting Linagliptin with Palmitoyl chloride in the presence of one or more solvent or reagent.
In another aspect of the present invention provides a process for preparing novel Linagliptin 16-hydroxyhexadecanamide comprises the step of reacting Linagliptin with 16-Hydroxyhexadecanoicacid.
In another aspect of the present invention provides a process for preparing novel Linagliptin 16-hydroxyhexadecanamide comprises the step of reacting Linagliptin with 16-Hydroxyhexadecanoic acid in the presence of one or more solvent or reagent.
In another aspect of the present invention provides a process for preparing novel Linagliptin 16-chlorohexadecanamide or Linagliptin 16-bromohexadecanamide comprises the step of reacting Linagliptin with 16-Chlorohexadecanoyl chloride or 16-Bromohexadecanoyl chloride respectively.
In another aspect of the present invention provides a process for preparing novel Linagliptin 16-chlorohexadecanamide or Linagliptin 16-bromohexadecanamide comprises the step of reacting Linagliptin with 16-Chlorohexadecanoyl chloride

or 16-Bromohexadecanoyl chloride respectively in the presence of one or more solvent or reagent.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin along with one or more pharmaceutically acceptable excipient.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide along with one or more pharmaceutically acceptable excipient.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide along with one or more pharmaceutically acceptable excipient.

In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin for the treatment of type 2 diabetes mellitus.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide for the treatment of type 2 diabetes mellitus.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide for the treatment of type 2 diabetes mellitus.
BRIEF DESCRIPTION OF ACCOMPANYING FIGURES
FIG. 1: Illustrates the 1H NMR Spectrum of Linagliptin palmitamide. FIG. 2: Illustrates the 1H NMR Spectrum of Linagliptin 16-hydroxyhexadecanamide.
FIG. 3: Illustrates the 1H NMR Spectrum of Linagliptin 16-chlorohexadecanamide.
FIG. 4: Illustrates the 1H NMR Spectrum of Linagliptin 16-bromohexadecanamide.
FIG. 5: Illustrates the Mass Spectra of Linagliptin palmitamide. FIG. 6: Illustrates the Mass Spectra of Linagliptin 16-hydroxyhexadecanamide. FIG. 7: Illustrates the Mass Spectra of Linagliptin 16-chlorohexadecanamide. FIG. 8: Illustrates the Mass Spectra of Linagliptin 16-bromohexadecanamide.

DETAIL DESCRIPTION OF THE INVENTION
The present invention provides novel amide derivatives of Linagliptin and process of preparation thereof.
The novel derivatives of Linagliptin according to present invention are hydroxyl or halogen or hydrogen substituted derivatives of Palmitic acid or Palmitoyl halide amide of Linagliptin of Formula-I.

The halogen atoms according to present invention may be the Cl, Br, F or I.
The novel hydroxyl or halogen or hydrogen substituted derivatives of palmitic acid or Palmitoyl halide amide of Linagliptin; wherein hydroxyl or halogen or hydrogen group is preferably substituted at C16 of Palmitic acid or Palmitoyl halide amide. Therefore, according to present invention said compound can be termed as Linagliptin palmitamide of Formula-V, Linagliptin 16-hydroxyhexadecanamide of Formula-VI, Linagliptin 16-chlorohexadecanamide of Formula-VII and Linagliptin 16-bromohexadecanamide of Formula-VIII.


(R)-N-( 1 -(7-(but-2-yn-1 -yl)-3-methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)palmitamide (Linagliptin palmitamide): (M.Wt: 710.95)

(R)-N-(l-(7-(but-2-yn-l-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)piperidin-3-yl)-16-hydroxyhexadecanamide (Linagliptin-16-hydroxyhexadecanamide) (M.Wt: 726.95)

(R)-N-(l-(7-(but-2-yn-l-yl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3 -yl)-16-chlorohexadecanamide (Linagliptin-16-chlorohexadecanamide) (M.Wt: 745.40)
Formula-VII


(R)-16-bromo-N-( 1 -(7-(but-2-yn-1 -yl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)piperidin-3-yl)hexadecanamide(Linagliptin-16-bromohexadecanamide) (M.Wt: 789.85)
Formula-VIII
In another aspect of the present invention is to provide novel process for preparation of hydroxy 1 or halogen or hydrogen substituted derivatives of palmitic acid or Palmitoyl halide amide of Linagliptin of Formula-I.
In another aspect of the present invention is to provide novel process for preparation of hydroxy 1 or halogen or hydrogen substituted derivatives of palmitic acid or Palmitoyl halide amide of Linagliptin; wherein, hydroxyl or halogen or hydrogen group can be substituted at any position from C2 to C16 Carbon atom of Palmitic acid or Palmitoyl halide.
The process of preparation of novel compounds according to present invention involves use of one or more solvents and reagents.
The one or more solvents according to present invention may be selected from but not limited to dichloromethane, methanol, acetone, ethanol, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl

tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate, acetonitrile or propionitrile, Dimethylformamide, Thionyl chloride.
The one or more reagents according to present invention may be selected from but not limited to potassium carbonate, 4-dimethylaminopyridine, sodium carbonate, sodium sulphate, potassium sulphate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, triethylamine, diisopropylamine or pyridine, N,N'-Dicyclohexylcarbodiimide (DCC).
The novel process for preparation of hydroxyl substituted derivatives of palmitic acid or Palmitoyl halide amide of Linagliptin; preferably Linagliptin palmitamide of Formula-V involves use of one or more intermediates.
The one or more intermediates for the preparation of Linagliptin palmitamide may include but not limited to Palmitoyl chloride.
The process of preparation Linagliptin palmitamide according to present invention involves step of reacting Linagliptin of Formula-II with Palmitoyl chloride in presence of dichloromethane and Potassium carbonate and 4-dimethylaminopyridine, which results in the formation of Linagliptin palmitamide of formula-V.



(R)-N-( 1-(7-(but-2-y n-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-2,6-
dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)palmitamide(Linagliptin palmitamide): (M.Wt: 710.95)
Formula-V
The process of preparation Linagliptin 16-hydroxyhexadecanamide according to present invention involves step of reacting Linagliptin of Formula-II with 16-Hydroxyhexadecanoic acid in presence of N,N'-Dicyclohexylcarbodiimide (DCC) & Tetrahydrofuran (THF),which results in the formation of Linagliptin 16-hydroxyhexadecanamide of formula -VI.


R)-N-( 1 -(7-(but-2-yn-1 -yl)-3 -methyl-1 -((4-methylquinazolin-2-yl)methy l)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)piperidin-3-yl)-16-hydroxyhexadecanamide (Linagliptin-16-hydroxyhexadecanamide) (M.Wt: 726.95)
Formula-VI
The process of preparation Linagliptin 16-chlorohexadecanamide according to present invention involves step of reacting Linagliptin of Formula-II with 16-Chlorohexadecanoyl chloride in presence of dichloromethane and Potassium carbonate and 4-dimethylaminopyridine,which results in the formation of Linagliptin-16-chlorohexadecanamide of formula -VII.



(R)-N-(l-(7-(but-2-yn-l-yl)-3-methyM
dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-3-yl)-16-chlorohexadecanamide (Linagliptin-16-chlorohexadecanamide) (M.Wt: 745.40)
Formula -VII
The process of preparation Linagliptin 16-bromohexadecanamide according to present invention involves step of reacting Linagliptin of Formula-II with 16-Bromohexadecanoyl chloride in presence of dichloromethane and Potassium carbonate and 4-dimethylaminopyridine,which results in the formation of 16-bromohexadecanamide of Linagliptin of formula -VIII.


(R)-16-bromo-N-( 1 -(7-(but-2-yn-1 -y l)-3 -methyl-1 -((4-methy lquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-yl)piperidin-3-yl) hexadecanamide(Linagliptin-16-bromohexadecanamide) (M.Wt: 789.85)
Formula -VIII
The novel compounds according to present invention i.e. Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide were evaluated for physical appearance, color, odor, melting point, boiling point, purity, NMR spectra, Mass spectra and found to comply with the specifications.

The novel compounds according to present invention i.e. Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide of Linagliptin was characterized by 1H NMR Spectrum as depicted in Fig.l, Fig 2 Fig. 3 and Fig 4.
The novel compounds according to present invention i.e. Linagliptin palmitamide, Linagliptin 16-hydroxyhexadecanamide, Linagliptin 16-chlorohexadecanamide, Linagliptin 16-bromohexadecanamide were characterized by Mass Spectrum as depicted in Fig.5, Fig 6 Fig. 7 and Fig 8.
The pharmaceutical composition comprising compound selected from the Linagliptin palmitamide or Linagliptin 16-hydroxyhexadecanamide or Linagliptin 16-chlorohcxadecanamide or Linagliptin 16-bromohexadecanamide along with one or more pharmaceutically acceptable excipient.
The pharmaceutical composition according to present invention contains suitable amount of Linagliptin palmitamide or Linagliptin 16-hydroxyhexadecanamide or Linagliptin 16-chlorohexadecanamide or Linagliptin 16-bromohexadecanamide as active ingredients. The pharmaceutical composition contains in the range of 0.05mg to 50mg, preferably 0.5mg to 20mg of active ingredient.
The pharmaceutical composition according to present invention may be in the form of tablet, capsule, pill, solution, liquids, suspension, emulsion, syrup, ointment, cream, gel, lotions, pastes, spray, injection, inhalers, powder, sachet, granules, beads, suppositories, pessaries, liniments, elixirs, transdermal patches, foam, stick or drops.
The one or more pharmaceutically acceptable excipient present in the composition according to present invention may be selected from the group consisting of diluents, disintegrant, binders, lubricant, release modifier, plasticizers, solubilizing

agent or emulsifying agent, surfactant, stabilizing agent, acidic agent, basic agent, sweeteners, flavour, pH regulating agent, osmotic or tonicity adjusting agents, chelating agents, buffers, bases, antioxidants/sequestrant, preservatives, solvents/ co-solvents, thickeners/suspending agents, flocculating agents, complexing agents, colorants, gelling agents, humectant, adsorbents, permeation enhancer, opacifying agent and vehicles.
In another aspect of the present invention is to provide pharmaceutical composition comprising novel Linagliptin palmitamide or Linagliptin 16-chloropalmitamide or Linagliptin 16-bromopalmitamide or Linagliptin 16-hydropalmitamide for the treatment of type 2 diabetes mellitus.
EXAMPLES:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1:
Preparation of Linagliptin palmitamide ((R)-N-(l-(7-(but-2-yn-l-yl)-3-methyl-
l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahydro-lH-purin-8-
yl)piperidin-3-yl)palmitamide. (M.Wt: 710.95):
To a stirred solution of Linagliptin (1.2 g, 2.54 mmol) in DCM (10 ml) at 0-5°C was added potassium carbonate (0.8 g, 5.5 mmol) and 4-dimethylaminopyridine (0.1 g, 1.02 mmol) and palmitoyl chloride (0.8 g, 2.8 mmol). The reaction mixture was stirred at RT for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20 ml) and layers were separated. The aq, layer was washed with DCM (20 ml). The combine organic layer was washed with 10% sodium bicarbonate solution (50 ml). The

organic layer was dried over sodium sulphate and evaporated under vacuum. The
crude product was purified by column chromatography (mobile phase: DCM:
methanol) to get Linagliptin palmitamide, Yield: 1.05 g (70%).
1H NMR (500MHz? CDC13): δ 0.87 (triplet, 3H), 1.20-1.36 (m, 24H), 1.54-1.78 (m, 4H), 1.79 (triplet, 3H), 1.82-1.90 (m, 2H), 2.19 (triplet, 2H), 2.89 (s, 3H), 3.30-3.55 (m, 4H), 3.56 (s, 3H), 4.19 (brs, 1H), 4.83-4.97 (m, 2H), 5.56 (s, 2H), 6.57 (d, 1H), 7.50-7.54 (m, 1H), 7.74-7.78 (m, 1H), 7.87 (d, 1H), 8.02 (d, 1H). [Depicted in FIG. 1] MS: ES+ 711.84 [Depicted in FIG. 5]
Example 2:
Preparation of Linagliptin 16-hydroxyhexadecanamide ((R)-N-(l-(7-(but-2-
yn-l-yl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-
tetrahydro-lH-purin-8-yl)piperidin-3-yl)-16-hydroxyhexadecanamide) (M.Wt:
726.95))
To a stirred solution of Linagliptin (L89 g, 4.0 mmol) in THF (10 ml) at 0-5°C
was added 16-hydroxyhexadecanoic acid (1.0 g, 3.7 mmol) and DCC (0.83 g, 4.0
mmol). The reaction mixture was stirred at RT for 5 h. The progress of the
reaction was monitored by TLC. After completion, the reaction mixture was
evaporated under vacuum. The residue was dissolved in DCM (20 ml) and water
(20 ml) and layers were separated. The aq. Layer was washed with DCM (20 ml).
The combine organic layer was dried over sodium sulphate and evaporated under
vacuum. The crude product was purified by column chromatography (mobile
phase: MDC: Methanol) to get Linagliptin 16-hydroxyhexadecanamide, Yield:
2.0g (75%).

1H NMR (500MHz, CDC13): δ 1.20-1.40 (m, 26H), 1.52-1.68 (m, 3H), 1.80
(triplet, 3H), 1.82-1.90 (m, 2H), 2.19 (triplet, 2H), 2.89 (s, 3H), 3.30-3.56 (m,
4H), 3.56 (s, 3H), 3.63 (triplet, 2H), 4.19 (brs, 1H), 4.81-5.0(m, 211), 5.56 (s, 211),
6.59 (d, 1H), 7.50-7.55 (m, 1H), 7.74-7.78 (m, 1H), 7.87 (d, 1H), 8.01 (d, 1H).
[Depicted in FIG. 2]
MS: ES+727.89,
MS: ES- 725.54 [Depicted in FIG. 6]
Example 3:
Preparation of Linagliptin 16-chlorohexadecanamide ((R)-N-(l-(7-(but-2-yn-
l-yl)-3-methyl-l-((4-methylquinazolin-2-yl)methyl)-2,6-dioxo-2,3,6,7-tetrahyd
1 H-purin-8-yl)piperidin-3-yl)-16-chlorohexadecanamide. (M.Wt: 745.40)
To a stirred solution of Linagliptin (0.7 g, 1.5 mmol) in DCM (15 ml) at 0-5°C was added potassium carbonate (0.45 g, 3.3 mmol), 4-dimethylaminopyridine (70 mg, 0.6 mmol) and 16-chlorohexadecanoyl chloride (0.47 g, 1.6 mmol). The reaction mixture was stirred at RT for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20 ml) and layers were separated. The aq. layer was washed with DCM (20 ml). The combine organic layer was washed with 10% sodium bicarbonate solution (25 ml). The organic layer was dried over sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography (mobile phase: DCM: methanol) to get Linagliptin 16-chlorohexadecanamide, Yield: 1.1 g (70%).
1H NMR (500MHz, CDC13): δ 1.20-1.35 (m, 26H), 1.58-1.78 (m, 2H), 1.79 (triplet, 3H), 1.82-1.90 (m, 2H), 2.19 (triplet, 2H), 2.89 (s, 3H), 3.28-3.50 (m, 4H), 3,53 (triplet, 2H), 3.56 (s, 3H), 4.18 (brs, 1H), 4.82-5.00 (m, 2H), 5.56 (s, 2H), 6.58 (d, 1H), 7.50-7.60 (m, 1H), 7.76-7.80 (m, 1H), 7.86 (d, 1H), 8.02 (d, 1H). [Depicted in FIG. 3] MS: ES+ 745.79 747.04 (3:1) [Depicted in FIG. 7]

Example 4:
Preparation of Linagliptin 16-bromohexadecanamide ((R)-16-bromo-N-(l-(7-
(but-2-yn-1-yl)3-methyl-1-((4-methylquinazolin-2-y
tetrahydro-lH-purin-8-yl)piperidin-3-yl)hexadecanamide. (M.Wt: 789.85).
To a stirred solution of Linagliptin (2.0 g, 4.23 mmol) in DCM (15 ml) at 0-5°C was added potassium carbonate (1.28 g, 9.52 mmol), 4-dimethylaminopyridine (0.2 g, 1.7 mmol) and 16-bromohexadecanoyl chloride (1.64 g, 4.6 mmol). The reaction mixture was stirred at RT for 6 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with water (20ml) and layers were separated. The aq. layer was washed with DCM (20 ml). The combine organic layer was washed with 10% sodium bicarbonate solution (20 ml). The organic layer was dried over sodium sulphate and evaporated under vacuum. The crude product was purified by column chromatography (mobile phase: DCM: methanol) to get Linagliptin 16-bromohexadecanamide . Yield: 1.8 g (54%).
1H NMR (500MHz, CDC13): δ 1.20-1.35 (m, 24H), 1.56-1.70 (m, 2H), 1.70-1.78 (m, 2H) 1.80 (triplet, 3H), 1.84-1.90 (m, 2H), 2.19 (triplet, 2H), 2.89 (s, 3H), 3.20-3.36 (m, 2H), 3.40 (triplet, 2H), 3.44-3.55 (m, 2H), 3.56 (s, 3H), 4.18 (brs, 1H), 4.82-5.00 (m, 2H), 5.56 (s, 2H), 6.62 (d, 1H), 7.50-7.58 (m, 1H), 7.72-7.80 (m, 1H), 7.87 (d, 1H), 8.02 (d, 1H). [Depicted in FIG. 4] MS: ES+ 789.89, 791.79 [Depicted in FIG. 8]

We Claim:
1. A compound of Formula I:

Wherein, Ri is a hydrogen or halogen atom or hydroxyl group substituted at any position from C2 to C16 Carbon atom.
(Formula I)
2. The compound according to claim 1 having formula :

Wherein, R1 = hydrogen substituted at C16 carbon atom
3. The compound according to claim 1 having formula :

Wherein, Rl = hydroxyl substituted at C16 carbon atom.
4. The compound according to claim 1 having formula :


Wherein, R1 = halogen substituted at C16 carbon atom
5. The compound according to claim 4 wherein halogen substitution in Rl is selected from the group consisting of Cl, Br, F and I.
6. A process of preparing compound of formula (I), wherein the process comprises the step of reacting Linagliptin with one or more intermediates; optionally along with one or more solvents and/or reagents.

Wherein, R1 is a hydrogen or halogen atom or hydroxyl group substituted at any position from C2 to C16 Carbon atom.
(Formula I)
7. The process according to claim 7, wherein one or more intermediates is selected from compound of formula:

Wherein, X is a halogen atom or hydroxyl group or any leaving group, Rl is a hydrogen or halogen atom or hydroxyl group substituted at any position from C2 to C16 Carbon atom.

8. The process according to claim 7, wherein one or more intermediates is
preferably selected from Palmitoyl chloride, 16-Hydroxyhexadecanoic
acid, 16-Chlorohexadecanoyl chloride, 16-Bromohexadecanoyl chloride.
9. The process according to claim 6, wherein one or more solvents is
selected from dichloromethane, methanol, acetone, ethanol, methyl ethyl
ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl
ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone,
methyl isopropyl ketone, ethyl isopropyl ketone, propanol, isopropanol,
butanol, isobutanol, t-butanol, pentanol, dichloroethane, chloroform,
carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl
ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl
isobutyl ether, ethyl acetate, propyl acetate, isopropyl acetate, butyl
acetate, tertiary butyl acetate, pentyl acetate, acetonitrile or propionitrile,
Dimethylformamide, Thionyl chloride or mixture thereof.
10. The process according to claim 6, wherein one or more reagents is selected
from potassium carbonate, 4-dimethylaminopyridine, sodium carbonate,
sodium sulphate, potassium sulphate, potassium carbonate, sodium
hydroxide, potassium hydroxide, sodium bicarbonate, potassium
bicarbonate, lithium hydroxide, lithium carbonate, triethylamine,
diisopropylamine or pyridine, N,N'-Dicyclohexylcarbodiimide (DCC).