WO2021014395A1

WO2021014395A1 - Process for the synthesis of deuterated capsaicin, capsaicinoids and synthetic capsaicin analogs

Info

Publication number: WO2021014395A1
Application number: PCT/IB2020/056938
Authority: WO
Inventors: Srinivas ORUGANTI; Sravanth Kumar AMRUTAPU; Magesh SAMPATH; Saikat Sen
Original assignee: Dr. Reddy’S Institute Of Life Sciences
Priority date: 2019-07-24
Filing date: 2020-07-23
Publication date: 2021-01-28

Abstract

The present application provides novel processes for the synthesis of deuterated intermediates of capsaicinoids, particularly II, III, IV and V of capsaicinoids, relating to pharmaceutical applications. The invention also provides novel intermediates of compounds of formula IX, XIV, XV, XVI, XVII, XVIII, XX and XXI utilized in the process of making deuterated capsaicin II, III, IV and V.

Description

Process for the Synthesis of deuterated Capsaicin, Capsaicinoids and synthetic Capsaicin analogs

RELATED APPLICATION

This application is related to and takes priority from the Indian Provisional 201941029972 filed on 24th July 2019 and is incorporated herein in its entirety.

FIELD OF THE INVENTION

The present application relates to novel processes for the synthesis of deuterated intermediates of capsaicinoids, relating to pharmaceutical applications. In particular the invention provides synthesis of deuterated intermediates of capsaicinoids, particularly, compounds II, III, IV and V and also provides novel intermediates of compounds of formula IX, XIV, XV, XVI, XVII, XVIII, XX and XXI utilized in the process of making deuterated capsaicin II, III, IV and V.

BACKGROUND OF THE INVENTION

Capsaicinoids are produced as the secondary metabolites by plants belonging to genus capsaicin: red chili peppers, jalapenos and habaneros. Among the various capsaicinoids, the main active component is capsaicin (I). The chemical name of capsaicin is trans -8-methyl-N-vanillyl-6- nonenamideand is represented by structure of formula I.

Capsaicin (I) produces a burning sensation when comes in contact with mucous membrane. It is used in food as a spicing agent. Also, capsaicin containing creams have been in clinical use since many years as analgesics. Recently, there have been reports on the application of capsaicin as an anti-oxidant, anti-carcinogen, anti-inflammatory agent and as an anti-obesity agents etc.

Structure activity relationship (SAR) studies on capsaicin (I) have shown that the substituents present on the aromatic ring, in particular, play an important role in imparting the agonist activity. For example, presence of the phenolic group at the fourth position on the aromatic ring is necessary for hydrogen bond donor-acceptor interactions with the receptor. Hence we were interested in manipulating the methyloxy substituent at the third position. It is believed that the incorporation of deuterium improves pharmacokinetic properties by slowing down the rate of drug metabolism, thereby allowing less frequent dosing.

The present application provides a process for the synthesis of various deuterated analogues particularly II, III, IV and V of capsaicinoids.

There have been reports on the preparation of various capsaicin analogues. However, only one process was reported for preparation of deuterated capsaicin II in J. Label compd. Radiopharm. 2009, 52, 563-565 and no publication thus far provides the process for preparation of deuterated analogues III, IV and V.

The process for the preparation of II described in J. Label compd. Radiopharm. 2009, 52, 563-565, commences with the preparation of 4-hydroxy-3-methoxy-d₃- benzaldehydeviabromination of 4-hydroxybenzaldehyde with bromine in CD₃OD, followed by refluxing the mixture obtained with NaOCD₃ and CuBrinCD₃OD. The prior art process utilizes bromination as the first step which forms unwanted polybrominated compounds. The second step is carried out at a very high temperature of 120°C.Inaddition deuterated methanol is used as a solvent which renders the process very expensive.

The present invention provides novel processes for the preparation of II, III, IV and V which are efficient, practical, cost-effective and avoids formation of side -products.

SUMMARY OF THE INVENTION The present application presents processes for the synthesis of various deuterated analogues of capsaicinoids particularly II, III, IV and V.

Firstly, the present application provides a process for preparation of compound of formula II, comprising:

(a) reacting3,4-dihydroxybenzaldehyde(compound of formula VI) with a benzyl halide in presence of a base to form a compound of formula VII.

(b) converting a compound of formula VII to get a compound of formula VIII.

(c) reacting a compound of formula VIII with hydroxylamine to get compound of formula IX.

(d) reacting a compound of formula IX with hydrogen to get compound of formula X.

(e) reacting a compound of formula X with a compound of formula XI to get compound of formula II.

Secondly, the present application provides a process for preparation of III, comprising:

(a) reacting isovanillin (a compound of formula XII) with p-toluenesulfonyl chloride to get a compound of formula XIII.

(b) reacting a compound of formula XIII with a demethylating agent to get compound of

formula XIV.

(c) reacting a compound of formula XIV with hydroxylamine to get compound of formula XV.

(d) reacting a compound of formula XV with hydrogento get compound of formula XVI.

(e) reacting a compound of formula XVI with a compound of Formula XI to get compound of formula XVII.

Thirdly, the present application provides a process for the preparation of compound of formula IV, comprising:

a) reacting3,4-dihydroxybenzaldehyde (compound of formula VI) with CD₃OD under Mitsunobu conditions to form a compound of formula XIX.

b) reacting the compound of formula XIX with hydroxylamine to get a compound of formula

XX.

(c) reacting a compound of formula XX with hydrogen to get a compound of formula XXI.

(d) reacting a compound of formula XXI with a compound of formula XI to get acompound of formula IV.

In a fourth aspect of the invention, the present application provides a process for the preparation of compound of formula V, comprising:

(a) reacting a compound of formula X with oleic acid to get a compound of formula V.

In a fifth aspect of the invention, the present application provides novel intermediates of the compounds of formula IX, XIV, XV, XVI, XVII, XVIII, XX and XXI.

In a sixth aspect, the invention provides compositions of Formula (A), (B) and (C)

In a sixth aspect of the invention, the present application provides use of the compounds of formula VIII and IX in the synthesis of the deuterated capsaicinoid II; compounds of formula XIII, XIV, XV, XVI, XVII and XVIII in the synthesis of the deuterated capsaicinoid III;

compounds of formula XIX, XX and XXI in the synthesis of the deuterated capsaicinoid IV and compounds of formula X in the synthesis of the deuterated capsaicinoid V.

DETAILED DESCRITPION OF THE INVENTION

In first embodiment, the present application provides a process for preparation of compound of formula II, with steps comprising: (a) reacting 3,4-dihydroxybenzaldehyde (compound of formula VI) with a benzyl halide in presence of a base to form a compound of formula VII.

(b) converting the compound of formula VII to get a compound of formula VIII.

(e) reacting a compound of formula X with a compound of formula XI to get compound

of formula II.

Step (a) of the process involves reaction of the compound of formula VI with a suitable benzyl halide using a suitable base and solvent to form compound of formula VII. Compound of formula VI is obtained by any process described in the art. Benzyl halides which can be employed in the reaction of step a) include, but are not limited tobenzyl chloride, benzyl bromide, benzyl iodide, 4-methoxybenzyl bromide, 3,4-dimethoxybenzyl bromide, and the likes thereof. Preferably, the benzyl halide may be benzyl bromide.

The reaction of step a) is carried out in the presence of a suitable base and an inert solvent. The base that is used, includes, but is not limited to organic bases such as triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole and the likes thereof, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and the likes thereof. Specifically, the base may be an inorganic base. More specifically, the inorganic base may be potassium carbonate.

The solvent that is used, includes, but is not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and so on; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the likes thereof; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichlorome thane, chloroform and the likes thereof; water; any mixtures of two or more thereof. Specifically, the solvent may be a nitrile solvent. More specifically, the nitrile solvent may be acetonitrile.

The reaction is carried out at a temperature not lower than 0°C to about boiling point of the solvent. The reaction is carried out preferably at 60°C.

Step (b) of the process involves converting the compound of formula VII under suitable reagents and conditions to form a compound of formula VIII.

The reaction of step b), may be carried out in the presence of a suitable combination of Mitsunobu reagent including but not limited to Diisopropylazodicarboxylate/PPh₃; Diethyl azodicarboxylate/PPh₃; Di-tert-butyl azodicarboxylate/PPh₃; 1,1'- (Azodicarbonyl)dipiperidine/PPh₃ and the likes thereof. Specifically, the reagent is

Diisopropylazodicarboxylate /PPh_3. The reaction is carried out at a temperature of about -20 °C to about 35°C. Specifically, the reaction is carried out at a temperature about 0°C to 35°C.

The amount of the CD₃OD used is a theoretical amount; but the use thereof in a large amount is not economical. Therefore the lower limit of the amount is generally not less than 1 time by mol, and the higher limit is generally not more than 5 times by mol, preferably not more than 3 times by mol, more preferably not more than 2 times by mol relative to the compound of the formula VII.

Optionally the reaction of step (b) of the process may be carried out with the agency of other suitable deuterated methylating reagents including but not limited to deuterated methanol, deuterated methoxy(diphenyl)phosphine, deuteratedtrimethoxyphosphine, deuterated trimethyl sulfoniumhydroxide, deuterated dimethylsulfate, deuterated dimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide, deuterated methyl 2,2,2-trichloroacetate and the likes thereof.

The solvent used includes but not is limited to polar aprotic solvent such as

dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and so on; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; any mixtures of two or more thereof. Specifically, the solvent may be ether solvent.More specifically, the ether solvent may be tetrahydrofuran.

Step (c) of the process involves reaction of the compound of formula VIII with hydroxylamine or a suitable source thereof to form compound of formula IX.

The reaction of step (c) is carried out by treating compound of formula VIII with hydroxylamine or a suitable source thereof including but not limited to hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate. The reaction may be carried out in presence of a suitable base which includes, but not limited to, organic bases such as pyridine, triethylamine, diisopropylethylamine and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.

Preferably the reaction of step (c) is carried out with hydroxylamine hydrochloride and sodium acetate.

The reaction is carried out in a suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof, water and any mixtures of two or more thereof. Specifically, the solvent may be a mixture of acetonitrile and water.

The reaction is carried out at a temperature from 20°C to about boiling point of the solvent. More preferably, the reaction is carried out at the boiling point of the solvent.

Step (d)of the process involves reacting a compound of formula IX with hydrogen to get compound of formula X.

The reaction of step (d) is carried out under the effect of hydrogen gas or ammonium formate and in the presence of a suitable metal catalyst selected from the group palladium, platinum and nickel. The amount of catalyst employed may be from 1 mol% to 50 mol%, preferably 10 mol%. The hydrogenation is carried out with a hydrogen pressure ranging of 20 to 100 psi, preferably 30 psi.

The reaction is carried out in a suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; water; any mixtures of two or more thereof. Specifically, the solvent may be an alcohol solvent. More specifically, the alcohol solvent may be ethanol.

Step (e) of the process involves reacting a compound of formula X with a suitably activated derivative of compound of formula XI to get compound of formula II.

Activation of the compound of formula XI and its reaction with compound of formula X can be carried out by a suitable acid-amine coupling reagent which includes but not limited to N,N'- Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI),N,N,N',N'-Tetramethyl-O-(1H-benzotriazol-1- yl)uroniumhexafluorophosphate (HBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b ]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)- 1,1,3,3-tetramethylaminium tetrafluoroborate(TBTU),Benzotriazol- 1 -yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic

anhydride(T3P) and 1,1'-Carbonyldiimidazole (CDI). Specifically, the acid-amine coupling reagent may be HATU.

Alternatively, the compound of formula XI can be converted into its corresponding acid chloride (such as by its reaction with oxalyl chloride or thionyl chloride), or an activated ester (such as by its reaction with N-hydroxysuccinimide, 1-Hydroxy-7-azabenzotriazole or

Hydroxybenzotriazole)or a mixed anhydride(such as by its reaction with ethyl chloroformate, isobutyl chloroformate or sec-butylchloroformate) prior to its reaction with compound of formula X.

The reaction of step (e) of the process is carried out in presence of a suitable base and solvent. The base that can be used includes, but is not limited to organic bases such as triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole and the likes thereof, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and the likes thereof. Specifically, the base may be an organic base. More specifically, the organic base may be diisopropylethylamine.

The solvent that can be used includes, but not limited to polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvents such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvents such as toluene, xylene and the like; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; or any mixtures of two or more thereof. Specifically, the solvent may be a polar aprotic solvent. More specifically, the solvent may be dimethylformamide.

The reaction is carried out at a temperature not lower than 0°C to about boiling point of the solvent. The reaction is carried out preferably at ambient temperature.

In second embodiment, the present application provides a process for preparation of compound of formula III, with steps comprising: (a) reacting isovanilin (a compound of formula XII) with p-toluenesulfonyl chloride to get a compound of formula XIII.

(b) reacting a compound of formula XIII with a demethylating agent to get compound of formula XIV.

(c) reacting a compound of formula XIV with hydroxylamine to get compound of formula

XV.

(d) reacting a compound of formula XV with hydrogen to get compound of formula XVI.

(f) converting a compound of formula XVII to a compound of formula XVIII.

(g) converting a compound of formula XVIII to a compound of formula III.

Step (a) of the process involves protecting the phenol group in compound of formula XII as a p- toluene sulfonate ester with p-toluene sulfonyl chloride to get compound of formula XIII.

Alternatively the phenol group in compound of formula XII may also be protected as a methanesulfonate or benzenesulfonate ester.

The reaction of step a) is carried out in the presence of a suitable base and solvent. The base that can be used, includes, but is not limited to organic bases such as triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole and the likes thereof, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and the likes thereof. Specifically, the base may be an organic base. More specifically, the organic base may be triethylamine.

The solvent that is used, includes, but is not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and so on; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the likes thereof; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichlorome thane, chloroform and the likes thereof; any mixtures of two or more thereof. Specifically, the solvent may be a chlorinated solvent. More specifically, the chlorinated solvent may be

dichloromethane. The reaction is carried out at a temperature not lower than 0°Cto about boiling point of the solvent. The reaction is carried out preferably at 30°C.

Step (b) of the process involves reacting a compound of formula XIII with a suitable demethylating agent to get a compound of formula XIV.

The demethylating agent that can be used includes, but not limited to boron tribromide, cerium chloride, aluminum iodide, aluminum chloride-thiourea, trimethylsilyl iodide, hydrobromic acid, hydroiodic acid, methanesulfonic acid-methionine, pyridinium-hydrochloride, alkaline thiolate, methylmagnesium iodide, lithium tri-sec-butylborohydride, trisiamylborohydride, lithium triethylborohydride and the likes thereof. Specifically, the demethylating reagent may be boron tribormide.

The reaction is carried out in a suitable inert solvent that includes, but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the likes thereof; alcoholic solvent such as methanol, isopropanol and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichlorome thane, chloroform and the likes thereof and mixtures thereof. Specifically, the solvent may be a chlorinated solvent. More specifically, the chlorinated solvent may be dichloromethane. The reaction may be carried out at a temperature of about -70°C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature of about 20°C to about 10°C.

Step (c) of the process involves reacting a compound of formula XIV with hydroxylamine to get compound of formula XV.

The reaction of step c) is carried out by treating compound of formula XIV with hydroxylamine or a suitable source thereof including but not limited to hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate. The reaction may be carried out in presence of a suitable base which includes, but not limited to, organic bases such as pyridine, triethylamine, diisopropylethylamine and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate. Preferably the reaction of step (c) is carried out with hydroxylamine hydrochloride and sodium acetate.

The reaction is carried out in a suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; alcoholic solvent such as methanol, isopropanol and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; water; any mixtures of two or more thereof. Specifically, the solvent may be a mixture of acetonitrile and water.

The reaction is carried out at a temperature from 20°C to about boiling point of the solvent. More preferably, the reaction is carried out between 60 to 80°C.

Step (d) of the process involvesreacting a compound of formula XV with hydrogen to get compound of formula XVI.

The reaction of step (d) is carried out under the effect of hydrogen gas or ammonium formate and in the presence of a suitable metal catalyst selected from the group palladium, platinum and nickel. The amount of catalyst employed may be from 1 mol% to 50 mol%, preferably 10 mol%. The hydrogenation is carried out with a hydrogen pressure ranging of 20 to 100 psi, preferably 25 psi.

Step (e) of the process involves reacting a compound of formula XVI with a suitably activated derivative of compound of formula XI to get compound of formula XVII. Activation of the compound of formula XI and its reaction with compound of formula XVI can be carried out by a suitable acid-amine coupling reagent which includes but not limited to N,N'- Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl )-N'-ethylcarbodiimide hydrochloride (EDCI), N, N, N', N'-Tetramethyl-O-( 1 H-benzotriazol- 1 - yl)uroniumhexafluorophosphate (HBTU), 1 -[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(lH-Benzotriazole-l-yl)- 1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol-l-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic

anhydride(T3P) and 1, 1'-Carbonyldiimidazole (CDI). Specifically, the acid-amine coupling reagent may be HATU.

Alternatively, the compound of formula XI can be converted into its corresponding acid chloride (such as by its reaction with oxalyl chloride or thionyl chloride), or an activated ester (such as by its reaction with N-hydroxysuccinimide, 1-Hydroxy-7-azabenzotriazole or Hydroxybenzotriazole or a mixed anhydride (such as by its reaction with ethyl chloroformate, isobutyl chloroformate or .sec-butylchloroformate) prior to its reaction with compound of formula XVI.

The solvent that can be used includes, but not limited to polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvents such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvents such as toluene, xylene and the like; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; or any mixtures of two or more thereof. Specifically, the solvent may be a polar aprotic solvent. More specifically, the solvent may be dimethylformamide. The reaction is carried out at a temperature not lower than 0°C to about boiling point of the solvent. The reaction is carried out preferably at ambient temperature.

Step (f) of the process involves converting a compound of formula XVII to a compound of formula XVIII.

The reaction of step (f) may be carried out in the presence of a suitable combination of Mitsunobu reagent including but not limited to Diisopropylazodicarboxylate/PPh₃; Diethyl azodicarboxylate/PPh₃; Di-tert-butyl azodicarboxylate/PPh₃; 1,1'- (Azodicarbonyl)dipiperidine/PPh₃ and the likes thereof. Specifically, the reagent is

Diisopropylazodicarboxylate /PPh_3. The reaction is carried out at a temperature of about -20°C to about 35°C. Specifically, the reaction is carried out at a temperature about 0°C to 35°C.

The amount of the CD₃OD used is a theoretical amount; but the use thereof in a large amount is not economical. Therefore the lower limit of the amount is generally not less than 1 time by mol, and the higher limit is generally not more than 5 times by mol, preferably not more than 3 times by mol, more preferably not more than 2 times by mol relative to the compound of the formula XVII.

Optionally the reaction of step (f) of the process may be carried out with the agency of other suitable deuterated methylating reagents including but not limited to deuterated methanol, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethylsulfoniumhydroxide, deuterated dimethylsulfate, deuterated dimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide, deuterated methyl 2,2,2-trichloroacetate and the likes thereof.

The solvent used includes but is not limited to polar aprotic solvent such as

dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and so on; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; any mixtures of two or more thereof. Specifically, the solvent may be ether solvent. More specifically, the ether solvent may be tetrahydrofuran. Step (g) of the process involves converting a compound of formula XVIII to a compound of formula III.

In step (g), the deprotection of compound of formula XVIII is carried out in the presence of a suitable deprotecting reagents includes but is not limited to one electron donor reagents like lithium naphthalenide, sodium naphthalenide; acidic reagents like HBr and HClO₄; and alkaline reagents such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the likes thereof. Specifically, the deprotecting reagent is an alkaline reagent. More specifically, the alkaline reagent is potassium hydroxide.

The reaction may be carried out in organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; alcoholic solvent such as methanol, isopropanol and the likes thereof; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl /-butyl ether, tetrahydrofuran and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; water or any mixtures of two or more thereof. Specifically, the solvent is an alcoholic solvent. More specifically, the alcoholic solvent is methanol.

In third embodiment, the present application provides a process for preparation of compound of formula IV, with steps comprising:

a) reacting 3,4 dihydroxy benzaldehyde (a compound of formula VI) with CD3OD under Mitsunobu conditions to form a compound of formula XIX.

b) reacting the compound of formula XIX with hydroxylamine to get compound of formula XX.

(c) reacting a compound of formula XX with hydrogen to get compound of formula XXI.

(d) reacting a compound of formula XXI with a compound of formula XI to get compound of formula IV.

Step (a) of the process involves reacting 3,4-dihydroxybenzaldehyde with CD₃OD under Mitsunobu conditions to form a compound of formula XIX.

The reaction of step (a) may be carried out in the presence of a suitable combination of Mitsunobu reagent including but not limited to Diisopropylazodicarboxylate/PPh₃; Diethyl azodicarboxylate/PPh₃; Di-tert-butyl azodicarboxylate/PPh₃; 1 ,T- (Azodicarbonyl)dipiperidine/PPh₃ and the likes thereof. Specifically, the reagent is

Diisopropylazodicarboxylate/PPh_3. The reaction is carried out at a temperature of about -20°C to about 35°C. Specifically, the reaction is carried out at a temperature about 0°C to 35°C.

Optionally the reaction of step (a) of the process may be carried out with the agency of other suitable deuterated methylating reagents including but not limited to deuterated methanol, deuterated methoxy(diphenyl)phosphine, deuterated trimethoxyphosphine, deuterated trimethyl sulfoniumhydroxide, deuterated dimethylsulfate, deuterated dimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide, deuterated methyl 2,2,2-trichloroacetate and the likes thereof.

The solvent used includes but is not limited to polar aprotic solvent such as

dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and so on; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; any mixtures of two or more thereof. Specifically, the solvent may be ether solvent. More specifically, the ether solvent may be tetrahydrofuran.

Step (b) of the process involves reacting the compound of formula XIX with hydroxylamine to get compound of formula XX.

The reaction of step (b) is carried out by treating compound of formula XIX with

hydroxylamine or a suitable source thereof including but not limited to hydroxylamine hydrochloride, hydroxylamine sulfate and hydroxylamine phosphate. The reaction is carried out in presence of a suitable base which includes, but not limited to, organic bases such as pyridine, triethylamine, diisopropylethylamine and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.

Preferably the reaction of step (b) is carried out with hydroxylamine hydrochloride and sodium acetate.

The reaction is carried out in a suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; alcoholic solvent such as methanol, isopropanol and the likes thereof ;ketone solvent such as acetone, ethyl methyl ketone and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; water; any mixtures of two or more thereof. Specifically, the solvent may be a mixture of acetonitrile and water.

The reaction is carried out at a temperature from 20°C to about boiling point of the solvent. More preferably, the reaction is carried out at 80°C.

Step (c) of the process involves reacting a compound of formula XX with hydrogen in presence of a metal catalyst to get compound of formula XXI.

The reaction of step (c) is carried out under the effect of hydrogen gas or ammonium formate and in the presence of a suitable metal catalyst selected from the group consisting of palladium, platinum and nickel. The amount of catalyst employed may be from 1 mol% to 50 mol%, preferably 10 mol%.

The hydrogenation is carried out with a hydrogen pressure ranging of 20 to 100 psi, preferably 25 psi. The reaction is carried out in a suitable solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvent such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the likes thereof; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichlorome thane, chloroform and the likes thereof; water; any mixtures of two or more thereof. Specifically, the solvent may be an alcohol solvent. More specifically, the alcohol solvent may be ethanol.

Alternatively, compound of formula XX can be converted to compound of formula XXI by a suitable hydride reducing agent such as lithium aluminum hydride.

Step (d) of the process involves reacting a compound of formula XXI with a suitably activated derivative of compound of formula XI to get compound of formula IV.

Activation of the compound of formula XI and its reaction with compound of formula XXI can be carried out by a suitable acid-amine coupling reagent which includes but not limited to N,N'- Dicyclohexylcarbodiimide (DCC), N-(3-Dimethyl aminopropyl )-N'-ethylcarbodiimide hydrochloride (EDCI), N, N, N', N'-Tetramethyl-O-( 1 H-benzotriazol-1-yl)uronium

hexafluorophosphate (HBTU), 1 -[Bis(dimethylamino)methylene]- 1 H- 1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3- tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic anhydride (T3P) and 1,1'- Carbonyldiimidazole (CDI). Specifically, the acid-amine coupling reagent may be HATU.

Hydroxybenzotriazole) or a mixed anhydride (such as by its reaction with ethyl chloroformate, isobutyl chloroformate or sec-butylchloroformate ) prior to its reaction with compound of formula XXI.

The reaction of step (d) of the process is carried out in presence of a suitable base and solvent. The base that can be used includes, but is not limited to organic bases such as triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole and the likes thereof, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and the likes thereof. Specifically, the base may be an organic base. More specifically, the organic base may be diisopropylethylamine.

The reaction is carried out at a temperature not lower than 0 °C to about boiling point of the solvent. The reaction is carried out preferably at ambient temperature.

In fourth embodiment, the present application provides a process for preparation of compound of formula V, with a step comprising of reacting a compound of formula X with a suitably activated derivative of oleic acid to get compound of formula V.

Activation of the compound of oleic acid and its reaction with compound of formula X can be carried out by a suitable acid-amine coupling reagent which includes but not limited to N,N'- Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl )-N'-ethylcarbodiimide hydrochloride (EDCI),N,N,N',N'-Tetramethyl-O-(1 H-benzotriazol-1- yl)uroniumhexafluorophosphate (HBTU), 1 -[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)- 1 , 1 ,3,3-tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic anhydride (T3P) and1,1'-Carbonyldiimidazole (CDI). Specifically, the acid-amine coupling reagent may be HATU.

Alternatively, oleic acid can be converted into its corresponding acid chloride (such as by its reaction with oxalyl chloride or thionyl chloride), or an activated ester (such as by its reaction with N-hydroxysuccinimide, 1-Hydroxy-7-azabenzotriazole or Hydroxybenzotriazole) or a mixed anhydride (such as by its reaction with ethyl chloroformate, isobutyl chloroformate or sec- butylchloroformate) prior to its reaction with compound of formula X.

The reaction is carried out in presence of a suitable base and solvent. The base that can be used includes, but is not limited to organic bases such as triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole and the likes thereof, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and the likes thereof. Specifically, the base may be an organic base. More specifically, the organic base may be diisopropylethylamine.

The solvent that can be used includes, but not limited to polar aprotic solvents such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the likes thereof; aliphatic hydrocarbon solvents such as hexane, heptane and the likes thereof; aromatic hydrocarbon solvents such as toluene, xylene and the likes thereof; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the likes thereof; nitrile solvents such as acetonitrile, proprionitrile and the likes thereof; chlorinated solvents such as dichloromethane, chloroform and the likes thereof; or any mixtures of two or more thereof. Specifically, the solvent may be a polar aprotic solvent. More specifically, the solvent may be dimethyl formamide.

Furthermore, the present invention provides novel deutrated compounds of general formula (A)

wherein R'= H, R" = alkyl and R = alkenyl group of any unsaturated fatty acid.

Deuterated variants of Formula (A) is represented by compounds of formula (III). In another embodiment, the present invention provides novel deutrated compounds of general formula (B)

wherein R' and R" = alkyl and R = alkenyl group of any unsaturated fatty acid.

Deuterated variants of Formula (B) is represented by compounds of formula (IV).

In another embodiment, the present invention provides novel deutrated compounds of general formula (C)

wherein R' = alkyl, and R" =H and R = alkenyl group of any unsaturated fatty acid.

Deuterated variants of Formula (B) is represented by compounds of formula (V).

In another embodiment, the present application provides novel intermediates of the compounds of formula IX, XIV, XV, XVI, XVII, XVIII, XX and XXI.

In yet another embodiment, the present application provides use of the compounds of formula VIII and IX in the synthesis of the deuterated capsaicinoid II; compounds of formula XIII, XIV, XV, XVI, XVII and XVIII in the synthesis of the deuterated capsaicinoid III; compounds of formula XIX, XX and XXI in the synthesis of the deuterated capsaicinoid IV and compounds of formula X in the synthesis of the deuterated capsaicinoid V.

The invention is further defined by reference to the following examples describing in detail the processes of the invention and should not be construed as limiting the scope of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Also, by skillfully maneuvering with the reagents and conditions, the yields of the steps could be further increased easily by any person skilled in the art which is thus intrinsic to the invention.

EXAMPLES

Example 1: Preparation of 4-(benzyloxy)-3-hydroxybenzaldehydeVII

To a solution of 3,4-dihydroxybenzaldehyde VI (500mg, 3.623 mmol) in acetonitrile (13 mL) was added potassium carbonate (750mg, 5.42 mmol) and the mixture was stirred for 5 min. Benzyl bromide was added dropwise at room temperature to the resulting solution which was then heated to 60°Cand maintained at the same temperature for 6 h. The resulting reaction mixture was quenched with ice cold water (5 mL) and extracted with EtOAc (2 X 20 mL). The organic layers were combined, washed with brine (5 mL), dried over anhydrous Na₂SO ₄ and concentrated under vacuum. Purification by column chromatography on silica gel (20%

EtOAc/Hexane) afforded the 4-(benzyloxy)-3-hydroxybenzaldehyde VII as white colored solid (490 mg, 60 %).

¹H NMR (400 MHz, CDCl₃) d 9.84 (d, J = 2.4 Hz, 1H), 7.47-7.39 (m, 7H), 7.04 (d, J = 8.0 Hz, 1H), 5.80 (d, J = 14.0 Hz, 1H), 5.21 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): d 190.95, 150.89, 146.30, 135.21, 130.85, 128.89(2C), 128.79, 127.89(2C), 124.29, 114.40, 111.49, 71.28.

Example 2: Preparation of 4-(benzyloxy)-3-methoxy-d;-benzaldehydeVIII

DAID (2.56 mL, 13.14 mmol)was added to a solution of triphenylphosphine (3.44 g, 13.14 mmol) in THF (18mL)and the resulting mixture was stirred till a white cake was formed. The reaction mass was then cooled to 0°C, followed by addition of CD₃OD (0.56 mL, 17.63 mmol). The resulting mixture was stirred for 5 min at 0°C, followed by the dropwise addition of a solution of the aldehyde VII (2.0 g, 8.76 mmol) in THF (8mL). The reaction was then allowed to warm to room temperature on its own. After lh, the solvent was evaporated under vacuum and the crude product was subjected to column chromatography on silica gel (20% EtO Ac/Hexane) afforded the VIII (1.6g, 75%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl3) d 9.83 (s, 1H), 7.46-7.44 (m, 3H), 7.40-7.36 (m, 3H), 7.34-7.30 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 5.24 (s, 2H). ¹³C NMR (100 MHz, CDC13): d 190.87, 153.55, 150.03, 135.97, 130.26, 128.68(2C), 128.17, 127.16(2C), 126.53, 112.35, 109.28, 70.82.

Example 3: Preparation of 4-(benzyloxy)-3-methoxy-d₃-benzaldehyde oxime IX

Deuterated aldehyde VIII (1.0 g, 4.08 mmol) was taken in a mixture of H₂O (5 mL) and CH3CN (5 mL)and NaOAc (583mg 4.28 mmol), followed by NH₂OH.HCI (311 mg,4.47mmol), were added. The resulting reaction mass was heated to reflux and stirred at the same temperature for 2 h. The reaction mixture was then quenched with ice-cold water (10 mL) and NaHCO₃ solution (20 mL), and then extracted with CH₂Cl₂(30 mLx2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO ₄ and concentrated under vacuum. Purification by column chromatography on silica gel (20% EtO Ac/Hexane and 35% EtO Ac/Hexane) afforded the oximeIXas off-white colored solid (1.05 g, 99 %)

¹H NMR (400 MHz, CDCl₃) d 8.05 (s, 1H), 7.44-7.42 (m, 2H), 7.39-7.35 (m, 2H), 7.33-7.28 (m, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.13 (brs, 1H), 6.95 (dd, J = 8.4, 2.0 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.18 (s, 2H).¹³C NMR (100 MHz, CDCl₃): d 150.25, 149.88, 136.66, 128.61(2C), 127.96, 127.20(20), 125.29, 121.44, 113.25, 108.40, 70.85.

Example 4: Preparation of 4-(aminomethyl)-2-methoxy-d₃-phenolX

To a solution of theoxime IX (1.0g, 3.84 mmol) in absolute ethanol (20 mL) and

concentratedHCl (3 mL), 40 mg of 10% Pd/C was added. The resulting solution was degassed and subjected to hydrogenation at room temperature for 3 h at 30 psi pressure. The obtained mixture was filtered through a Celite pad; the filtrate was evaporated to obtain the product X as its hydrochloride salt (700 mg, 95 %) in the form of a green colored solid.

¹H NMR (400 MHz, DMSO -d₆) d 9.15 (brs, 1H), 8.31 (brs, 3H), 7.13 (brs, 1H), 6.82-6.76 (m, 2H), 3.85(brs, 2H).

Example 5: Preparation of (ii)-N-(4-hydroxy-3-methoxy-d₃-benzyl)-8-methylnon-6-enamide II To a solution of the acid XI (260 mg, 1.35 mmol) in DMF (5mL) was added DIPEA (0.7 ml, 4.06 mmol) dropwise at room temperature. The reaction mixture was cooled to 0°C. HATU (0.616 mg, 1.62 mmol) was added and the mixture was allowed to stir at 0°Cfor 15 min. Amine X as its hydrochloride salt (230 mg, 1.35 mmol) was added at 0°C and the reaction was allowed to warm to room temperature on its own. After 2 h, the reaction mass was quenched with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated in vacuum. Purification by column chromatography on silica gel (solvent gradient: 60% EtOAc/hexanes) afforded the title compound deuterated capsaicin II as a colorless thick syrup(295 mg, 70 % yield).

¹H NMR (400 MHz, DMSO -d₆) d 8.79 (s, 1H), 8.15 (t, J = 6.0 Hz, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 6.62 (dd, J = 2.0, 8.0 Hz, 1H), 5.39-5.28 (m, 2H), 4.13 (d, J = 6.0 Hz, 2H), 2.23-2.18 (m, 1H), 2.12-2.08 (m, 2H), 1.96-190 (m, 2H), 1.541.46 (m, 2H), 1.33-1.23(m, 2H), 0.93 (d, J = 6.8 Hz, 6H)

Example 6: Preparation of 5-formyl-2-methoxyphenyl 4-methylbenzenesulfonateXIII

To a solution of isovanillin XII (0.66 g, 4.34 mmol) in CH₂Cl₂ (5 mL) was added Et₃N (5 mL). The resulting mixture was cooled to 0°C, followed by addition of p-toluene sulfonyl chloride (0.9g, 4.72 mmol) portion wise. The reaction was allowed to warm to room temperature on its own and was stirred at the same temperature for 4 h. The reaction was diluted with water (10 mL) and the product was extracted into CH₂Cl₂(2 X 10 mL). The combined organic layers were washed with brine, dried over Na₂SO ₄ and concentrated under vacuum to obtain the sulfonate XIII as a white solid (1.30g, 98.4%).

¹H NMR (400 MHz, CDCl₃) d 9.83 (s, 1H), 7.79-7.75 (m, 3H), 7.62 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 2.46 (s, 3H).

Example 7: Preparation of 5-formyl-2-hydroxyphenyl 4-methylbenzenesulphonateXIV

BBr₃ (81 ml, 1M in CH₂Cl₂) was added dropwise to a solution of the aldehyde XIII (10 g, 32.67 mmol) in dry CH₂Cl₂ (100mL), maintained at0°C. Thereafter the reaction was allowed to gradually warm to 10°C. After 30 min, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO ₄ and concentrated to afford the phenol XIV (3.65g, 41%) as pale brown colored thick syrup.

¹H NMR (400 MHz, DMSO -d₆) d 11.09 (s, 1H), 9.76 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H).

¹³C NMR (100 MHz, DMSO -d₆): d 190.47, 155.70, 145.66, 137.04, 132.02, 130.61, 129.96(2C), 128.29(2C), 124.28, 117.60(2C), 21.17.

Example 8: Preparation of 2-hydroxy-5-((hydroxyimino)methyl)phenyl 4- methylbenzenesulfonate XV

To a solution of the aldehyde XIV(0.25 g, 8.6 mmol) in CH₃CN(1.25 mL) was added an aqueous solution (1.25ml) of NaOAc (0.116g 0.9 mmol) and NH₂OH.HCI (0.062g, 0.9 mmol). The resulting mixture was warmed to 80°C and stirred for 4 h. After 4 h, the solvent was evaporated under vacuum and the compound was extracted into MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated to obtain the oxime XV (0.245g, 90%) as a brown colored syrup.

¹H NMR (400 MHz, DMSO -d₆) d 7.97 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.30-7.28 (m, 2H), 6.84 (d, J = 9.2 Hz, 1H), 2.40(s, 3H).

Example 9: Preparation of 5-(amino methyl)-2-hydroxyphenyl 4- methylbenzenesulfonateXVI

40 mg of 10% Pd/C, followed by 0.5 ml of concentrated HC1, was added to a solution of the oxime XV (0.22 g, 3.71 mmol) in absolute ethanol (12 ml). The reaction mixture was degassed and subjectedto hydrogenation at room temperature for 2 h at 25 psi pressure. Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate obtained was evaporated to obtain the amine XVI as its hydrochloride salt (0.22g, 92%) in form of a yellow colored solid.

Example 10: Preparation of (E)-2-hydroxy-5-((8-methylnon-6-enamido)methyl)phenyl 4- methylbenzenesulfonate XVII

To a solution of the acid XI (170 mg, 0.9 mmol) in DMF (1.7 mL) was added DIPEA (0.43 ml) dropwise at room temperature. The reaction mixture was cooled to 0°C. HATU (0.45 mg, 1 mmol) was added and the mixture was allowed to stir at 0°Cfor 15 minutes. Amine XVI as its hydrochloride salt (173 mg, 0.9 mmol) was added to the resulting solution at 0°C and the reaction was allowed to warm to room temperature on its own. After 16 hours, the reaction mass was quenched with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated under vacuum. The crude product was subjected to purification by column chromatography on silica gel (solvent gradient: 25%

EtOAc/hexanes to 30% EtOAc/hexanes) to obtain the amide XVII (0.165g, 82% yield)as a pale yellow syrup.

¹H NMR (400 MHz, CDCl₃) d 7.77 (d, 7 = 8.4 Hz, 2H), 7.35 (d, 7 = 8.4 Hz, 2H), 7.06 (dd, 7 = 8.4, 1.6 Hz, 1H), 6.95 (d, 7 = 8.0 Hz, 1H), 6.77 (d, J =1.6 Hz, 1H), 6.05 (brs, 1H), 5.60 (brs, 1H), 5.36-5.31 (m, 2H), 4.25 (d, 7 = 6.4 Hz, 2H), 2.47 (s, 3H), 2.24-2.15 (m, 2H), 2.05-1.96 (m, 2H), 1.67-1.55 (m, 3H), 1.41-1.33 (m, 2H), 0.95 (d, 7 = 6.8 Hz, 6H).

Example 11: Preparation of (E)-2-methoxy-d₃-5-((8-methylnon-6-enamido)methyl)phenyl 4-methylbenzenesulfonate XVIII

DAID (60 mg, 0.30 mmol) was added dropwise to a solution of triphenylphosphine (80 mg, 0.30 mmol) in dry THF (0.5 mL) at room temperature. The resulting white cake was cooled to 0°C; to this, CD₃OD (16 mg, 0.30 mmol) was added and the mixture was stirred for 5 min at 0°C. A solution of the phenolic compound XVII (90 mg, 0.2 mmol) in dry THF (0.5 mL) added to the reaction mixture which was then allowed to warm to room temperature and stir for 1 h. The solvent was evaporated from the reaction mass under vacuum and the crude product obtained was purified by column chromatography on silica gel (solvent gradient: 35% EtOAc/hexanes to 40% EtOAc/hexanes) to obtain the deuterated compound XVIII (60 mg, 65% yield) as a brown liquid.

¹H NMR (400 MHz, CDCI₃) d 7.76 (d, 7 = 8.0 Hz, 2H), 7.31 (d, 7 = 8.4 Hz, 2H), 7.14 (dd, 7 = 8.4, 2.0 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.79 (d, 8.0 Hz, 1H), 5.65 (brs, 1H), 5.37-5.34 (m, 2H), 4.34 (d, J = 5.6 Hz, 2H), 2.45 (s, 3H), 2.23-2.18 (m, 3H), 2.05-1.96 (m, 2H), 1.69-1.61 (m, 2H), 1.42-1.34 (m, 2H), 0.95 (d, 7 = 7.2 Hz, 6H).

Example 12: Preparation of(E)-N-(3-hydroxy-4-methoxy-d₃-benzyl)-8-methylnon-6- enamidelll 15% methanolic KOH (3 mL) was added to the compound XVIII (60 mg, 0.12 mmol) and the resulting solution was stirred for 1 h at room temperature. The solvent was then evaporated under vacuum, and the residue obtained was diluted with water and ethyl acetate. The product was extracted twice with EtOAc. The combined organic layers were washed with brine and concentrated under vacuum to obtain the crude product which upon purification by column chromatography on silica gel (solvent gradient: 1% MeOH/DCM) afforded III (30mg,76%) as an off-white solid.

¹H NMR (400 MHz, CDCl₃) d 7.30-7.26 (m, 1H), 6.84 (d, J = 1.6 Hz, 1H), 6.81-6.74 (m, 2H), 5.69 (brs, 1H), 5.40-5.27 (m, 2H), 4.34 (d, J = 5.2 Hz, 2H), 2.26-2.18 (m, 3H), 2.01-1.95 (m,

2H), 1.68-1.60 (m, 2H), 1.42-1.33 (m, 2H), 0.91 (d, J = 6.8 Hz, 6H).

Example 13: Preparation of N-(4-hydroxy-3-methoxy-d₃-benzyl)oleamideV

To a solution of oleic acid (294 mg, 1.04 mmol) in DMF (2.0 mL) was added DIPEA(0.54 ml). The reaction mixture was cooled to 0°C. HATU (474 mg, 1.24 mmol) was added and the mixture was allowed to stir at 0°Cfor 15 minutes. Amine X as its hydrochloride salt (200 mg,

1.04 mmol) was added to the resulting solution at 0°C and the reaction was then allowed to slowly warm to room temperature on its own. After 16 hours, the reaction mass was quenched with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated under vacuum. The crude product obtained was purified by column chromatography on silica gel (solvent gradient: 25% EtOAc/hexanes to 30% EtO Ac/hexanes) to afford the title amide V(220 mg, 50% yield)as a white solid.

¹H NMR (400 MHz, CDCl₃) d 6.86 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.0, 2.0 Hz, 1H), 5.63-5.59 (m, 2H), 5.37-5.31 (m, 2H), 4.35 (d, J = 5.6 Hz, 2H), 2.19 (m, 2H), 2.04-1.97(m, 4H), 1.66-1.58(m, 4H), 1.39-1.21 (m, 18H), 0.88 (t, J = 6.8 Hz, 3H).

¹³C NMR (100 MHz, CDCl₃): d 172.87, 145.66, 145.10, 130.34, 129.99, 129.69, 120.74, 114.33, 110.64, 43.51, 36.83, 31.87, 29.74, 29.67, 29.63, 29.49, 29.33, 29.29, 29.27, 29.24, 29.11, 27.19, 27.14, 25.75, 22.65, 14.09.

Example 14: Preparation of 3,4-dimethoxy-d₆-benzaldehyde XIX

DAID (5.7 mL, 28.9 mmol)was added dropwise to a solution of triphenylphosphine (7.6 g, 29 mmol) in dry THF (12 mL) and the resulting mixture was stirred until a white cake was formed. The reaction mass was then cooled to 0°C, followed by addition of CD₃OD (1.8 mL, 43.4 mmol). The resulting mixture was stirred for 5 min at 0°C, followed by the dropwise addition of a solution of the aldehyde VI (1.0 g, 7.2 mmol) in THF (8 mL). The reaction was then allowed to warm to room temperature on its own. After lh, the solvent was evaporated under vacuum and the crude product was purified by column chromatography on silica gel (20% EtOAc/Hexane) to afford the title compound (885 mg, 71 %) as thick yellow syrup.

¹H NMR (400 MHz, CDCI₃) d 9.84 (d, J = 2.4 Hz 1H), 7.45 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (t, J = 2.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H).

Example 15: Preparation of (E)-3,4-dimethoxy-d₆-benzaldehyde oxime XX

To the solution of the aldehyde XIX (1.2 g, 6.9 mmol) in CH₃CN(6 mL) was added an aqueous solution (6 ml) of NaOAc (0.996 g 7.3 mmol) and NH₂OH.HCI (0.532 g, 7.6 mmol). The resulting mixture was warmed to 80°C and stirred for 4 h. After 4 h, the solvent was evaporated under vacuum and the compound was extracted into MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated to obtain the oxime XX (1.14 g, 90%) as a pale yellow solid.

¹H NMR (400 MHz, CDCI₃) d 8.68 (brs, 1H), 8.08 (s, 1H), 7.21 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.0, 1.6 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H).

¹³C NMR (100 MHz, CDCl₃): d 150.74, 150.13, 149.23, 124.73, 121.62, 110.68, 107.95.

Example 16: Preparation of (3,4-dimethoxy-d₆-phenyl)methanamineXXI

226 mg of 10% Pd/C (50% w/w), followed by 3.0 ml of concentrated HC1, was added to a solution of theoxime XX (1.0 g, 5.34 mmol) in absolute ethanol (40 ml). The reaction mixture was degassed and subjected to hydrogenation at room temperature for 2 h at 25 psi pressure. Upon completion, the reaction mixture was filtered through a pad of Celite. The filtrate obtained was evaporated to obtain the amine XXI as its hydrochloride salt (0.72g, 65%) in form of a brown colored solid.

¹H NMR (400 MHz, DMSO -d₆) d 8.25 (brs, 3H), 7.13 (s, 1H), 6.91-6.89 (m, 2H), 3.87 (s, 2H)

Example 17: Preparation of (E)-N-(3,4-dimethoxy-d₆-benzyl)-8-methylnon-6-enamide IV To a solution of the acid XXI (238 mg, 1.4 mmol) in DMF (3.0 mL) was added DIPEA (0.75 ml, 4.2 mmol). The reaction mixture was cooled to 0°C. HATU (638 mg, 1.68 mmol) was added and the mixture was allowed to stir at 0°Cfor 15 minutes. Amine XXI as its hydrochloride salt (300 mg, 1.4 mmol) was added to the resulting solution at 0°Cand the reaction was then allowed to slowly warm to room temperature on its own. After 16 hours, the reaction mass was quenched with water and extracted with MTBE. The combined organic layers were washed with brine, dried over anhydrous Na₂SO ₄ and concentrated under vacuum. The crude product obtained was purified by column chromatography on silica gel (solvent gradient: 25% EtOAc/hexanes to 30% EtO Ac/hexanes) to obtain corresponding amide IV(230 mg, 50.5 % yield)as a dark brown syrup.

¹H NMR (400 MHz, CDCl₃) d 6.79 (s, 3H), 5.89 (brs, 1H), 5.39-5.26 (m, 2H), 4.36 (d, J = 5.6

Hz, 2H), 2.24-2.17 (m, 3H), 2.00-1.95 (m, 2H), 1.68-1.60 (m, 2H), 1.41-1.24 (m, 2H), 0.91 (d, J = 6.8 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃): d 173.49, 149.17, 148.52, 138.16, 130.68, 126.39, 120.11, 111.18, 111.16, 43.57, 36.60, 32.18, 30.96, 29.23, 25.29, 22.64(2C).

Claims

CLAIMS We Claim:

1. A process for making deuterated capsaicin II, comprising the steps of:

(a) reacting 3,4-dihydroxybenzaldehyde (compound of formula VI) with a benzyl halide in presence of a base to form a compound of formula VII.

(b) converting a the compound of formula VII to obtain a compound of formula VIII.

(c) reacting the compound of formula VIII with hydroxylamine to obtain a compound of formula IX.

(d) reacting the compound of formula IX with hydrogen to get compound of formula X.

(e) reacting the compound of formula X with a compound of formula XI to get compound of formula II.

2. The process as claimed in claim 1, wherein step (a) is carried out in the presence of a base selected from organic or inorganic base, wherein the said organic base is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine, dimethylaminopyridine (DMAP) and imidazole, and wherein the said inorganic base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide or combination of two or more bases.

3. The process as claimed in claim 1, wherein step (a) is carried out in the presence of a polar aprotic solvent dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent toluene or xylene, ketone solvent selected from acetone or ethyl methyl ketone, ether solvent selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvent selected from acetonitrile or proprionitrile, chlorinated solvent selected from dichloromethane or chloroform or water, or combination of two or more solvents.

4. The process as claimed in claim 1 , wherein step (b) is carried out in the presence of a combination of Mitsunobu reagent selected from Diisopropylazodicarboxylate/PPh₃, Diethyl azodicarboxylate/PPh₃, Di-tert-butyl azodicarboxylate/PPh₃ or 1,1'- (Azodicarbonyl)dipiperidine/PPh₃.

5. The process as claimed in claim 1, wherein step (b) is carried out in the presence of deuterated methylating reagents selected from deuterated methanol,

deuteratedmethoxy(diphenyl)phosphine, deuteratedtrimethoxyphosphine, deuterated

trimethylsulfoniumhydroxide, deuterateddimethylsulfate, deuterateddimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide, or deuterated methyl 2,2,2- trichloroacetate.

6. The process as claimed in claim 1 , wherein step (b) is carried out in the presence of a polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, ketone solvent selected from acetone or ethyl methyl ketone, ether solvent selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvent selected from acetonitrile or proprionitrile, chlorinated solvent selected from dichloromethane or chloroform or a combination of two or more solvents.

7. The process as claimed in claim 1, wherein step (c) is carried out in the presence of organic base selected from pyridine, triethylamine, diisopropylethylamine, inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate or potassium acetate.

8. The process as claimed in claim 1, wherein step (c) is carried out in the presence of organic base selected from polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate , nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water or a combination of two or more solvents.

9. The process as claimed in claim 1, wherein step (d) is carried out in the presence of metal catalyst selected from the group consisting of palladium, platinum and nickel.

10. The process as claimed in claim 1, wherein step (d) is carried out in the presence of organic base selected from polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate , nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water or a combination of two or more solvents.

11. The process as claimed in claim 1 , wherein step (d) is carried out in the presence of acid- amine coupling reagent selected from N,N'-Dicyclohexylcarbodiimide (DCC), N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI),N,N,N',N'-Tetramethyl-O- ( 1 H-benzotriazol- 1 -yl)uroniumhexafluorophosphate (HBTU), 1-

[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate(TBTU),Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic anhydride(T3P) or 1, 1'-Carbonyldiimidazole (CDI).

12. The process as claimed in claim 1, wherein step (e) is carried out in the presence of organic base selected from triethylamine, diisopropylethylamine (DIPEA), pyridine,

dimethylaminopyridine (DMAP), imidazole, and inorganic bases selected from potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.

13. The process as claimed in claim 1, wherein step (e) is carried out in the presence of polar aprotic solvents selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvents selected from hexane or heptane, aromatic hydrocarbon solvents selected from toluene or xylene, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a

combination of two or more solvents.

14. The process for making the deuterated capsaicin III, comprising the steps of:

(a) reacting isovanillin (a compound of formula XII) with p-toluene sulfonyl chloride to get a compound of formula XIII.

(g) converting a compound of formula XVIII to a compound of formula III.

15. The process as claimed in claim 14, wherein step (a) is carried out in the presence of organic bases selected from triethylamine, diisopropylethylamine (DIPEA), pyridine,

dimethylaminopyridine (DMAP) or imidazole, inorganic bases selected from potassium carbonate, cesium carbonate, sodium hydroxide or lithium hydroxide.

16. The process as claimed in claim 14, wherein step (a) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a combination of two or more solvents.

17. The process as claimed in claim 14, wherein step (b) is carried out in the presence of demethylating agent selected from boron tribromide, cerium chloride, aluminum iodide, aluminum chloride-thiourea, trimethylsilyl iodide, hydrobromic acid, hydroiodic acid, methanesulfonic acid-methionine, pyridinium-hydrochloride, alkaline thiolate,

methylmagnesium iodide, lithium tri-sec-butylborohydride, trisiamylborohydride or lithium triethylborohydride.

18. The process as claimed in claim 14, wherein step (b) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform.

19. The process as claimed in claim 14, wherein step (c) is carried out in the presence of organic bases selected from pyridine, triethylamine or diisopropylethylamine, inorganic bases selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate or potassium acetate.

20. The process as claimed in claim 14, wherein step (c) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water or a combination of two or more solvents.

21. The process as claimed in claim 14, wherein step (d) is carried out in the presence of metal catalyst selected from the group palladium, platinum and nickel.

22. The process as claimed in claim 14, wherein step (d) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, alcoholic solvent selected from methanol or isopropanol, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water; or a combination of two or more solvents.

23. The process as claimed in claim 14, wherein step (e) is carried out in the presence of acid- amine coupling reagent selected from the group consisting of N,N'-Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), N,N,N',N'- Tetramethyl-O-(1 H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU), 1 - [Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP),

Propylphosphonic anhydride(T3P) and 1, 1'-Carbonyldiimidazole (CDI).

24. The process as claimed in claim 14, wherein step (e) is carried out in the presence of organic base selected from triethylamine, diisopropylethylamine (DIPEA), pyridine,

dimethylaminopyridine (DMAP) or imidazole, inorganic base selected from potassium carbonate, cesium carbonate, sodium hydroxide or lithium hydroxide.

25. The process as claimed in claim 14, wherein step (e) is carried out in the presence of polar aprotic solvents selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvents selected from hexane or heptane, aromatic hydrocarbon solvents selected from toluene or xylene, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a combination of two or more solvents.

26. The process as claimed in claim 14, wherein step (f) is carried out in the presence of Mitsunobu reagent selected from the group consisting of Diisopropylazodicarboxylate/PPh₃, Diethyl azodicarboxylate/PPh₃, Di-tert-butyl azodicarboxylate/PPh₃ and 1,1'- (Azodicarbonyl)dipiperidine/PPh₃.

27. The process as claimed in claim 14, wherein step (f) is carried out in the presence of deuterated methylating reagents selected from the group consisting of deuterated methanol, deuteratedmethoxy(diphenyl)phosphine, deuteratedtrimethoxyphosphine,

deuteratedtrimethylsulfoniumhydroxide, deuterateddimethylsulfate,

deuterateddimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide and deuterated methyl 2,2,2-trichloroacetate.

28. The process as claimed in claim 14, wherein step (f) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a combination of two or more solvents.

29. The process as claimed in claim 14, wherein step (g) is carried out in the presence of deprotecting reagents selected from one electron donor reagents selected from lithium

naphthalenide or sodium naphthalenide, acidic reagents selected from HBr and HCIO ₄, alkaline reagents selected from a group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide.

30. The process as claimed in claim 14, wherein step (g) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether pr tetrahydrofuran, nitrile solvents selected from acetonitrile or proprionitrile or water or a combination of two or more solvents.

31. The process for making the dideuterated capsaicin IV, comprising the steps of:

a) reacting 3,4-dihydroxybenzaldehyde (compound of formula VI) with CD₃OD under Mitsunobu conditions to form a compound of formula XIX.

XX.

(d) reacting a compound of formula XXI with a compound of formula XI to get a compound of formula IV.

32. The process as claimed in claim 31, wherein step (a) is carried out in the presence of

Mitsunobu reagent selected from the group consisting of Diisopropylazodicarboxylate/PPh₃, Diethyl azodicarboxylate/PPh₃, Di-tert-butyl azodicarboxylate/PPh₃ and 1,1'- (Azodicarbonyl)dipiperidine/PPh₃.

33. The process as claimed in claim 31, wherein step (a) is carried out in the presence of deuterated methylating reagents selected from the group consisting deuterated methanol, deuteratedmethoxy(diphenyl)phosphine, deuteratedtrimethoxyphosphine, deuterated trimethyl sulfoniumhydroxide, deuterated dime thy lsulf ate, deuterated dimethylcarbonate, deuterated methyl iodide, deuterated methyl bromide and deuterated methyl 2,2,2-trichloroacetate.

34. The process as claimed in claim 31 , wherein step (a) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide, aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a combination of two or more solvents.

35. The process as claimed in claim 31, wherein step (b) is carried out in the presence of hydroxylamine selected from the group consisting of hydroxylamine hydrochloride,

hydroxylamine sulfate and hydroxylamine phosphate.

36. The process as claimed in claim 31, wherein step (b) is carried out in the presence of organic base selected from pyridine, triethylamine, diisopropylethylamine and inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate and potassium acetate.

37. The process as claimed in claim 31, wherein step (b) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide (DMSO), alcoholic solvent selected from methanol or isopropanol, ketone solvent selected from acetone or ethyl methyl ketone, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water or a combination of two or more solvents.

38. The process as claimed in claim 31, wherein step (c) is carried out in the presence of metal catalyst selected from the group consisting of palladium, platinum and nickel.

39. The process as claimed in claim 31, wherein step (c) is carried out in the presence of polar aprotic solvent selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvent selected from hexane or heptane, aromatic hydrocarbon solvent selected from toluene or xylene, alcoholic solvent selected from methanol or isopropanol, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or water; or a combination of two or more solvents.

40. The process as claimed in claim 31 , wherein step (d) is carried out in the presence of acid- amine coupling reagent selected from N,N'-Dicyclohexylcarbodiimide (DCC), N-( 3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), N, N, N' N'-Tetramethyl-O- (1 H-benzotriazol-l-yl)uronium hexafluorophosphate (HBTU), 1-

[Bis(dimethylamino)methylene]- 1 H-1,2,3-triazolo[4,5-b ]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP),

Propylphosphonic anhydride (T3P) andl,l'-Carbonyldiimidazole (CDI).

41. The process as claimed in claim 31, wherein step (d) is carried out in the presence of organic base selected from triethylamine, diisopropylethylamine (DIPEA), pyridine,

42. The process as claimed in claim 31, wherein step (d) is carried out in the presence of polar aprotic solvents selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvents selected from hexane or heptane, aromatic hydrocarbon solvents selected from toluene or xylene, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or a combination of two or more solvents.

43. The process for making the deuterated capsaicin V, comprising the step of reacting a compound of formula X with oleic acid to get a compound of formula V.

44. The process as claimed in claim 43, wherein the said process is carried out in the presence of acid-amine coupling reagent selected from the group consisting of N,N'- Dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI), N, N, N', N'-Tetramethyl-(O-( 1 H-benzotriazol-1- yl)uroniumhexafluorophosphate (HBTU), 1 -[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)- 1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), Benzotriazol-1-yl- oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), Propylphosphonic anhydride (T3P) andl, l'-Carbonyldiimidazole (CDI).

45. The process as claimed in claim 43, wherein the said process is carried out in the presence of organic base selected from the group consisting of triethylamine, diisopropylethylamine

(DIPEA), pyridine, dimethylaminopyridine (DMAP), imidazole, inorganic base selected from the group consisting of potassium carbonate, cesium carbonate and sodium hydroxide, lithium hydroxide.

46. The process as claimed in claim 43, wherein the said process is carried out in the presence polar aprotic solvents selected from dimethylformamide or dimethylsulfoxide (DMSO), aliphatic hydrocarbon solvents selected from hexane or heptane, aromatic hydrocarbon solvents selected from toluene or xylene, ether solvents selected from methyl t-butyl ether or tetrahydrofuran, ester solvent selected from ethyl acetate or isopropyl acetate, nitrile solvents selected from acetonitrile or proprionitrile, chlorinated solvents selected from dichloromethane or chloroform or a combination of two or more solvents.

47. A pharmaceutical composition of deuterated compounds of the formula (A) comprising:

wherein R'= H, R" = alkyl and R = alkenyl group of any unsaturated fatty acid.

48. A pharmaceutical composition of deuterated compounds of the formula (B) comprising:

wherein R' and R" = alkyl and R = alkenyl group of any unsaturated fatty acid.

49. A pharmaceutical composition of deuterated compounds of the formula (C) comprising:

50. A pharmaceutical composition of intermediate compounds utilized in the process of making deuterated capsaicin II, III, IV and V, selected from the group consisting of