DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
TITLE OF THE INVENTION
“DEUTERATED TRIHEXYPHENIDYL COMOUND AND PROCESS FOR MAKING THE SAME”
APPLICANT (S)
NAME NATIONALITY ADDRESS
CLEARSYNTH LABS LIMITED
INDIAN 17th Floor, Lotus Nilkamal Business Park, New Link Road, Andheri [West], Mumbai 400053, Maharashtra, India.
PREAMBLE TO THE DESCRIPTION

COMPLETE SPECIFICATION
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 compound of formula I. Most particularly, it relates to deuterated compound of formula I and process for making the same. The compound of formula I shows improved efficacy, reduced side effects, enhanced bioavailability, prolonged duration of action, less susceptible to certain types of drug interactions.

BACKGROUND OF THE INVENTION
Trihexyphenidyl (THP, benzhexol, trihex, marketed as Artane) is an antispasmodic drug used to treat stiffness, tremors, spasms, and poor muscle control. It is an agent of the antimuscarinic class and is often used in management of Parkinson's disease. It was approved by the FDA for the treatment of Parkinson's in the US in 2003.
It is on the World Health Organization's List of Essential Medicines.
Artane shows side effects including such as but are not limited to brain feeling drowsiness, dizziness, and headache are common, especially with high doses, feeling anxious, restless, confused, or even euphoric can happen in high doses; sleep patterns might change, and seizures might be more likely. Furthermore, dry mouth, constipation, nausea, and sweating problems are common; heart might beat faster, some side effects, like anxiety and heart rate changes, could be withdrawal symptoms, especially for people with mental health conditions. Eyes pupils widen and become sensitive to light, Glaucoma attacks or blurred vision might occur ("Trihexyphenidyl". Web MD. First Databank Inc.)
Overall, the body needs more medicine over time to get the same effect. Thus, improved pharmacological properties of Trihexyphenidyl may be needed.
Deuterium (2H) is a nonradioactive isotope of hydrogen that contains a neutron in addition to hydrogen’s proton and electron. Deuterium can covalently bind to other atoms in the same manner as hydrogen. a deuterated compound and its hydrogen-containing counterpart may bind similarly to a biological target, such as a protein relevant to treating disease.
However, deuterium is heavier than hydrogen and can form stronger bonds with carbon. These differences can give rise to differences in pharmacological properties. Whether deuteration has any meaningful beneficial effect, however, depends on the compound and its use. For example, reduction of one metabolic pathway may lead to a compensatory increase in metabolism at a different site.
To overcome above mentioned side effects there is a need to develop or design of deuterated Trihexyphenidyl and its synthesis to improve efficacy, reduce side effects, enhance bioavailability, prolong duration of action.
Thus, the present invention provides deuterated trihexyphenidyl compound of formula I with improved efficacy, reduced side effects, enhanced bioavailability, prolonged duration of action, less susceptible to certain types of drug interactions.

OBJECTS OF THE INVENTION
One of the objects of the present invention is to provide a compound of formula I.
Another object of the present invention is to provide deuterated compound of formula I, specifically deuterated trihexyphenidyl (D11).
Another object of the present invention is to provide a process for making deuterated compound of formula I.
Another object of the present invention is to study the biological activity of the deuterated compound of formula I.
Another object of the present invention is to provide pharmaceutical compositions comprising a therapeutically effective amount of at least one of the deuterated compounds of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
Another object of the present invention is to provide the mechanism of action of deuterated trihexyphenidyl (D11).
Another object of the present invention is to provide deuterated trihexyphenidyl (D11) with improved efficacy, reduced side effects, enhanced bioavailability, prolonged duration of action, less susceptible to certain types of drug interactions.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides a compound of formula I represented by

Wherein R1 to R22 are independently selected from hydrogen (H), deuterium (D), C1-C5 alkyl, aryl group.
Another aspect of the present invention provides a process for making compound of formula I, the process comprising:
refluxing a compound of formula 1 with a compound of formula 2 and a compound of formula 3 in presence of an acid in a solvent for a time period in the range of 5 hrs to 20 hrs to obtain a compound of formula 4;
reacting the compound of formula 4 with a compound of formula 5 in presence of metal catalyst and an initiator in a solvent at a temperature in the range of 0oC to 70oC for a time period in the range of 15min to 12 hrs to obtain a compound of formula I with yield in the range of about 50% to about 99% and purity about 80% to about 99%.

BRIEF DESCRIPTION OF FIGURES
Figure 1 shows Intrinsic Clearance Determination-Human Liver Microsomes for Trihexyphenidyl-HCl (compound of formula I)
Figure 2 depicts Intrinsic Clearance Determination-Human Liver Microsomes for Trihexyphenidyl-D11-HCl (compound of formula I)

DETAILED DESCRIPTION OF THE INVENTION
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art.
The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described.
Detailed embodiments of the present invention are disclosed herein; however, it is to be understood that the disclosed embodiments are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific functional and structural details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present invention in virtually any appropriately detailed structure.
In the specification different terms are used for describing the invention. The definitions of the terms are provided below.
The term ‘compound’ or ‘deuterated Trihexyphenidyl (D11) or ‘compound of formula I’ used herein, is also intended to include any salts, solvates, or hydrates thereof. Thus, it is to be understood that when any compound is referred to herein by name and structure, salts, solvates, and hydrates thereof are included.
The terms ‘compound’, ‘deuterated Trihexyphenidyl, ‘compound of formula I’ can be used interchangeably in the specification.
‘D’ and ‘d’ both used herein refer to deuterium. ‘D’ and ‘d’ can be used interchangeably in the specification.
The term ‘solvent’ used herein refers to a substance that can dissolve another substance, or in which another substance is dissolved, forming a solution. The solvent used in the present invention can be polar or nonpolar solvent. The said solvent may be used in anhydrous form. The solvent includes such as but not limit to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
The term ‘C1-C5 alkyl’ group used in the compound of formula I includes straight chain or branch chain carbon atoms. The ‘C1-C5 alkyl’ group may include such as but is not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, n-butyl and n-pentyl group.
One of the embodiments of the present invention provides a compound of formula I represented by

Wherein R1 to R22 are independently selected from hydrogen (H), deuterium (D), C1-C5 alkyl, aryl group.
Another embodiment of the present invention provides a compound of formula I, wherein R1, R2, R3, R4, R5 and R17, R18, R19, R20, R21, R22 are deuterium (D), and R6 to R16 are hydrogen (H); and wherein R1 to R5 and R17 to R22 are hydrogen (H); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are deuterium (D).
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I is selected from

In another embodiment of the present invention there is provided a process for making compound of formula I, the process comprising:
refluxing a compound of formula 1

with a compound of formula 2

and a compound of formula 3

in presence of an acid in a solvent for a time period in the range of 5 hrs to 20 hrs to obtain a compound of formula 4

reacting the compound of formula 4 with a compound of formula 5

in presence of metal catalyst and an initiator in a solvent at a temperature in the range of 0oC to 70oC for a time period in the range of 15min to 12 hrs to obtain a compound of formula I with yield in the range of about 50% to about 99% and purity about 80% to about 99%;
Wherein in the compound of formula 1, R19, R20, R21, & R22 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (- Cl), bromine (-Br) and iodine (-I);
Wherein in the compound of formula 2, R1 to R5 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 3, R17 to R18 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 4, R1 to R5; R17 to R22 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (- Cl), bromine (-Br) and iodine (-I).
Wherein in the compound of formula 5, R6 to R16 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
In another embodiment of the present invention, there is provided a process for making compound of formula I, wherein in the compound of formula 1, R19, R20, R21, & R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are deuterium (D); wherein in the compound of formula 3, R17 to R18 are deuterium (D); wherein in the compound of formula 4, R1 to R5; R17 to R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are hydrogen (H) and X is chlorine (-Cl).
In another embodiment of the present invention, there is provided a process for making compound of formula I, wherein in the compound of formula 1, R19, R20, R21, & R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are hydrogen (H); Wherein in the compound of formula 3, R17 to R18 are hydrogen (H); wherein in the compound of formula 4, R1 to R5; R17 to R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are deuterium (D) and X is chlorine (-Cl).
Another embodiment of the present invention provides a process for making compound of formula I, wherein the compound of formula 1 is

Wherein R19, R20, R21, & R22 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Another embodiment of the present invention provides a process for making compound of formula I, wherein the compound of formula 2 is

Wherein R1 to R5 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group.
Another embodiment of the present invention provides a process for making compound of formula I, wherein the compound of formula 3 is

Wherein R17 to R18 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group.
Another embodiment of the present invention provides a process for making compound of formula I, wherein the compound of formula 4 is

Wherein R1 to R5; R17 to R22 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Another embodiment of the present invention provides a process for making compound of formula I, wherein the compound of formula 5 is

Wherein R6 to R16 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I is

Wherein R1 to R5 are deuterium (D), R6 to R16 are hydrogen (H), R17 to R22 are deuterium (D).
Another embodiment of the present invention provides a compound of formula I, wherein the compound of formula I is

Wherein R1 to R5 are hydrogen (H), R6 to R16 are deuterium (D), R17 to R22 are hydrogen (H).
In most preferred embodiment of the present invention, the compound of formula I is

In another most preferred embodiment, the compound of formula I is

Another embodiment of the present invention provides a process for making compound of formula I, wherein the acid is organic acid or inorganic acid.
In yet another embodiment of the present invention there is provided a process for making compound of formula I, wherein inorganic acid may include such as but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
In another embodiment of the present invention there is provided a process for making compound of formula I, wherein organic acid include such as but is not limited to acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3 -(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethyl acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.
In another embodiment of the present invention there is provided a process for making compound of formula I, wherein the base used in the reaction is an organic base or an inorganic base.
Another embodiment of the present invention provides a process for making compound of formula I, wherein the reaction is carried out in presence of a solvent. The solvents that can be used, include such as but is not limited to water, ketone solvent such as acetone, methyl ethyl ketone, methylisobutylketone (MIBK) or the like; halogenated hydrocarbon solvent such as dichloromethane, ethylene dichloride, chloroform, or the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile or the like; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, or the like; alcohols such as methanol, ethanol, 2-propanol, 2-butanol and mixtures thereof.
Another embodiment of the present invention provides a process for making compound of formula I, wherein the solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, tert-butyl methyl ether, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, 2-butanol and mixtures thereof.
Another embodiment of the present invention provides a process for making compound of formula I, wherein organic solvent includes such as but is not limited to water, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol and mixture(s) thereof.
Another embodiment of the present invention provides a process for making compound of formula I, wherein metal catalyst include such as but is not limited to Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na.
In an embodiment, the metal catalyst is Mg.
Another embodiment of the present invention provides a process for making compound of formula I, wherein initiator include such as but is not limited to fluorine (F2), chlorine (Cl2), bromine (Br2) and iodine (I2).
In an embodiment, the initiator is iodine (I2).
Another embodiment of the present invention provides a process for making compound of formula I, wherein compound of formula 4 is purified by using known conventional techniques such as but is not limited to crystallisation, chromatography, precipitation etc.
Another embodiment of the present invention provides a process for making compound of formula I, wherein compound of formula 4 is purified by using polar and non-polar solvents.
Another embodiment of the present invention provides a process for making compound of formula I, wherein synthesis of compound 1 is carried out as per following scheme.
Scheme:

Another embodiment of the present invention provides a process for making compound of formula I, wherein said process is carried out as per the scheme provided below.
Scheme 1:

Scheme 2:

In another embodiment of the present invention there is provided a process for making compound of formula I, wherein formula I is optionally converted into its pharmaceutically acceptable salt at a desired reaction condition.
In another embodiment of the present invention there is provided compound of formula I or its pharmaceutically acceptable salts, wherein said salts can be prepared from acids or bases including inorganic or organic acids and inorganic or organic bases by conventional chemical methods using a compound of formula I.
In one embodiment of the present invention, the compound of formula I can be used in combinations of another Active pharmaceutical ingredient or other drug.
In another embodiment of the present invention there is provided a pharmaceutical composition, wherein the said composition comprises of
compound of formula I or its pharmaceutically acceptable salt; and
one or more carrier or pharmaceutically acceptable excipient.
Another embodiment of the present invention provides a compound of formula I, wherein the present invention provides specific properties and advantages of deuterated trihexyphenidyl compared to non-deuterated trihexyphenidyl. This may comprise:
Improved efficacy
Reduced side effects
Enhanced bioavailability
Prolonged duration of action
Improve yield and purity.
less susceptible to certain types of drug interactions
The examples provided in the definitions present in this application are non-inclusive unless otherwise stated. They include but are not limited to the recited examples.

EXAMPLES
Step I: Synthesis of compound of formula 4:
a. Synthesis of compound of formula 4:
A mixture of acetophenone (20 mmol), paraformaldehyde and piperidine hydrochloride in 1:1.5:1 mol ratio was dissolved in ethanol. A few drops of HCl (37%) were added to the above mixture. The reaction content was refluxed for 9 hours. The solvent was removed under vacuum. The residue was crystallized from methanol-ether. The crystals formed were filtered and then washed the crystals with diethyl ether. The crystals were dried. Yield: 70%.
b. Synthesis of deuterated compound of formula 4:
A mixture of acetophenone (20 mmol), paraformaldehyde and deuterated piperidine hydrochloride (compound 1-D4) in 1:1.5:1 mol ratio was dissolved in ethanol. A few drops of HCl (37%) were added to the above mixture. The reaction content was refluxed for 9 hours. The solvent was removed under vacuum. The residue was crystallized from methanol-ether. The crystals formed were filtered and then washed the crystals with diethyl ether. The crystals were dried. Yield: 70%.
Step-2: Synthesis of compound of formula I:
40L methyl tert-butyl ether and 3.0kg chlorocyclohexane were pumped into the reaction tank under stirring. 7.64kg magnesium powder and 0.13kg iodine were added and sealed the can mouth, vent nitrogen. The sealed can was heated to about 55oC for initiation. 40kg chlorocyclohexane and 40L methyl tert-butyl ether were added dropwise. The mixed solution was added dropwise. Reaction was further stirred at 45 to 55oC for 2 hours. After the heat preservation was completed, reaction was cooled down to 0-10oC. 26.90 kg phenylketononepiperidine hydrochloride was added in 10 times and further incubated at 5-10oC for 2 hours. After the insulation was completed, dilute hydrochloric acid was added dropwise with stirring under controlled temperature. No more than 20°C, dripping was completed. The reaction solution was lowered to 0-5°C and stirred for 2 hours, and then incubated. The reaction mass was filtered and rinsed with water until the pH value 3-4 was achieved. 21.6Kg of crude trihexyphenidyl hydrochloride was obtained. Yield: 60.2%; Purity:90%.
Step-2: Synthesis of compound of formula I:
40L methyl tert-butyl ether and 3.0kg deuterated chlorocyclohexane (compound 5-D5) were pumped into the reaction tank under stirring. 7.64kg magnesium powder and 0.13kg iodine were added and sealed the can mouth, vent nitrogen. The sealed can was heated to about 55oC for initiation. 40kg deuterated chlorocyclohexane (compound 5-D5) and 40L methyl tert-butyl ether were added dropwise. The mixed solution was added dropwise. Reaction was further stirred at 45 to 55oC for 2 hours. After the heat preservation was completed, reaction was cooled down to 0-10oC. 26.90 kg phenylketononepiperidine hydrochloride was added in 10 times and further incubated at 5-10oC for 2 hours. After the insulation was completed, dilute hydrochloric acid was added dropwise with stirring under controlled temperature. No more than 20°C, dripping was completed. The reaction solution was lowered to 0-5°C and stirred for 2 hours, and then incubated. The reaction mass was filtered and rinsed with water until the pH value 3-4 was achieved. 21.6Kg of crude trihexyphenidyl hydrochloride was obtained. Yield: 60.2%; Purity:90%.

INTRINSIC CLEARANCE DETERMINATION-HUMAN LIVER MICROSOMES
Compound Name Name of the sample Drug Area IS Area Area Ratio %PCR Time Points min ln Slope Clint Average Clint

Trihexyphenidyl-HCl 0 Min-1 664883.9 81005 8.2079 100.00 0 4.605 0.024 47.32 49.41
5 Min-1 514244.5 71929 7.1494 87.10 5 4.467
10Min-1 410485.7 70071 5.8581 71.37 10 4.268
20 Min-1 326741 71159 4.5917 55.94 20 4.024
30 Min-1 260714.8 63492 4.1063 50.03 30 3.913
45 Min-1 215183.3 70296 3.0611 37.29 45 3.619
0 Min-1 613965.9 72770 8.4371 100.00 0 4.605 0.026 51.50
5 Min-1 512317.3 73309 6.9885 82.83 5 4.417
10Min-1 412808.3 71231 5.7954 68.69 10 4.230
20 Min-1 326168.5 71024 4.5924 54.43 20 3.997
30 Min-1 258866.9 67134 3.8560 45.70 30 3.822
45 Min-1 234505.7 76479 3.0663 36.34 45 3.593
45 Min (-NADPH)-1 545790.6 72385 7.5401 91.86 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min
(-NADPH)-2 549712.7 71587 7.6789 91.01 45

Trihexyphenidyl-D11-HCl 0 Min-1 224993 67160 3.3501 100.00 0 4.605 0.023 45.99 43.75

5 Min-1 200712.8 72896 2.7534 82.19 5 4.409
10Min-1 162552 65949 2.4648 73.57 10 4.298
20 Min-1 131872.3 68509 1.9249 57.46 20 4.051
30 Min-1 105437.3 63554 1.6590 49.52 30 3.902
45 Min-1 92893.5 68256 1.3610 40.63 45 3.704
0 Min-1 240743.3 72612 3.3155 100.00 0 4.605 0.021 41.51
5 Min-1 191986.3 65968 2.9103 87.78 5 4.475
10 Min-1
162510.3 65223 2.4916 75.15 10 4.319
20 Min-1 140905.6 69189 2.0365 61.42 20 4.118
30 Min-1 110433.3 61873 1.7849 53.84 30 3.986
45 Min-1 92292.4 68889 1.3397 40.41 45 3.699
45 Min (-NADPH)-1 225789.8 71598 3.1536 94.13 45 % Stability in microsomes at 45 mins (Without NADPH)
45 Min (-NADPH)-2 204456.2 65720 3.1110 93.83 45

Time ln %PCR

0 4.61
5 4.47
10 4.27
20 4.02
30 3.91
45 3.62
0 4.61
5 4.42
10 4.23
20 4.00
30 3.82
45 3.59
Time ln %PCR

0 4.61
5 4.41
10 4.30
20 4.05
30 3.90
45 3.70
0 4.61
5 4.47
10 4.32
20 4.12
30 3.99
45 3.70

Trihexyphenidyl-HCl
Trihexyphenidyl-D11-HCl

Liver Microsomal Intrinsic Clearance data Summary
Compound Name Intrinsic clearance (µL/min/mg protein)
Human Liver Microsomes
Trihexyphenidyl-HCl 49.41
Trihexyphenidyl-D11-HCl 43.75

We claim:
A compound of formula I represented by

Or its pharmaceutically acceptable salt;
Wherein R1 to R22 are interpedently selected from hydrogen (H), deuterium (D), C1-C5 alkyl, aryl group.
The compound as claimed in claim 1, wherein R1, R2, R3, R4, R5 and R17, R18, R19, R20, R21, R22 are deuterium (D), and R6 to R16 are hydrogen (H); and wherein R1 to R5 and R17 to R22 are hydrogen (H); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are deuterium (D).
The compound as claimed in claim 1, wherein the compound of formula I is selected from

A process for making compound of formula I, the process comprising:
refluxing a compound of formula 1

with a compound of formula 2

and a compound of formula 3

in presence of an acid in a solvent for a time period in the range of 5 hrs to 20 hrs to obtain a compound of formula 4

reacting the compound of formula 4 with a compound of formula 5

in presence of metal catalyst and an initiator in a solvent at a temperature in the range of 0oC to 70oC for a time period in the range of 15min to 12 hrs to obtain a compound of formula I with yield in the range of about 50% to about 99% and purity about 80% to about 99%;
Wherein in the compound of formula 1, R19, R20, R21, & R22 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (- F), chlorine (-Cl), bromine (-Br) and iodine (-I);
Wherein in the compound of formula 2, R1 to R5 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 3, R17 to R18 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 4, R1 to R5; R17 to R22 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Wherein in the compound of formula 5, R6 to R16 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (- F), chlorine (-Cl), bromine (-Br) and iodine (-I).
The process as claimed in claim 4, wherein in the compound of formula 1, R19, R20, R21, & R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are deuterium (D); wherein in the compound of formula 3, R17 to R18 are deuterium (D); wherein in the compound of formula 4, R1 to R5; R17 to R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are hydrogen (H) and X is chlorine (-Cl).
The process as claimed in claim 4, wherein in the compound of formula 1, R19, R20, R21, & R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are hydrogen (H); Wherein in the compound of formula 3, R17 to R18 are hydrogen (H); wherein in the compound of formula 4, R1 to R5; R17 to R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are deuterium (D) and X is chlorine (-Cl).
The process as claimed in claim 4, wherein the acid is organic acid or inorganic acid; wherein inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and combinations thereof.
The process as claimed in claim 4, wherein the solvent is selected from water, acetone, methylethylketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, tert-butyl methyl ether, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, 2-butanol and mixtures thereof.
The process as claimed in claim 4, wherein metal catalyst is selected from Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na.
The process as claimed in claim 4, wherein initiator is selected from fluorine (-F2), chlorine (Cl2), bromine (Br2) and iodine (I2) and combinations thereof.
Dated this: January 25, 2025

Vijaykumar Shivpuje
IN/PA-1096
Agent for the Applicant
To
The Controller of Patents
The Patent Office, Mumbai

ABSTRACT

“DEUTERATED TRIHEXYPHENIDYL COMOUND AND PROCESS FOR MAKING THE SAME”

The present invention relates to a compound of formula I or its pharmaceutically acceptable salt. Most particularly, it relates to deuterated compound of formula I and process for making the same. The compound of formula I is represented by:

Wherein R1 to R22 are interpedently selected from hydrogen (H), deuterium (D), C1-C5 alkyl, aryl group.

,CLAIMS:We claim:
1. A compound of formula I represented by

Or its pharmaceutically acceptable salt;
Wherein R1 to R22 are interpedently selected from hydrogen (H), deuterium (D), C1-C5 alkyl, aryl group.
2. The compound as claimed in claim 1, wherein R1, R2, R3, R4, R5 and R17, R18, R19, R20, R21, R22 are deuterium (D), and R6 to R16 are hydrogen (H); and wherein R1 to R5 and R17 to R22 are hydrogen (H); R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 are deuterium (D).
3. The compound as claimed in claim 1, wherein the compound of formula I is selected from

4. A process for making compound of formula I, the process comprising:
a) refluxing a compound of formula 1

with a compound of formula 2

and a compound of formula 3

in presence of an acid in a solvent for a time period in the range of 5 hrs to 20 hrs to obtain a compound of formula 4

b) reacting the compound of formula 4 with a compound of formula 5

in presence of metal catalyst and an initiator in a solvent at a temperature in the range of 0oC to 70oC for a time period in the range of 15min to 12 hrs to obtain a compound of formula I with yield in the range of about 50% to about 99% and purity about 80% to about 99%;
Wherein in the compound of formula 1, R19, R20, R21, & R22 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (- F), chlorine (-Cl), bromine (-Br) and iodine (-I);
Wherein in the compound of formula 2, R1 to R5 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 3, R17 to R18 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group;
Wherein in the compound of formula 4, R1 to R5; R17 to R22 are independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (-F), chlorine (-Cl), bromine (-Br) and iodine (-I).
Wherein in the compound of formula 5, R6 to R16 is independently selected from hydrogen (H), deuterium (D), C1 to C5 alkyl group; and X is halogen selected from fluorine (- F), chlorine (-Cl), bromine (-Br) and iodine (-I).
5. The process as claimed in claim 4, wherein in the compound of formula 1, R19, R20, R21, & R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are deuterium (D); wherein in the compound of formula 3, R17 to R18 are deuterium (D); wherein in the compound of formula 4, R1 to R5; R17 to R22 are deuterium (D) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are hydrogen (H) and X is chlorine (-Cl).
6. The process as claimed in claim 4, wherein in the compound of formula 1, R19, R20, R21, & R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 2, R1 to R5 are hydrogen (H); Wherein in the compound of formula 3, R17 to R18 are hydrogen (H); wherein in the compound of formula 4, R1 to R5; R17 to R22 are hydrogen (H) and X is chlorine (-Cl); wherein in the compound of formula 5, R6 to R16 are deuterium (D) and X is chlorine (-Cl).
7. The process as claimed in claim 4, wherein the acid is organic acid or inorganic acid; wherein inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and combinations thereof.
8. The process as claimed in claim 4, wherein the solvent is selected from water, acetone, methylethylketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, tert-butyl methyl ether, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, 2-butanol and mixtures thereof.
9. The process as claimed in claim 4, wherein metal catalyst is selected from Pd, Pt, Ni, Rh, Cu, Li, Mg, Al, Na.
10. The process as claimed in claim 4, wherein initiator is selected from fluorine (-F2), chlorine (Cl2), bromine (Br2) and iodine (I2) and combinations thereof.