Description:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules 2003
COMPLETE SPECIFICATION
(see sections 10 & rule 13)
1. TITLE OF THE INVENTION
“DEUTERATED SUFENTANIL COMPOUND AND PROCESS FOR SYNTHESISING THEREOF”
2. APPLICANT (S)
NAME NATIONALITY ADDRESS
CLEARSYNTH LABS LIMITED INDIAN 17th Floor, Lotus Nilkamal Business Park, New Link Road, Andheri [West], Mumbai - 400053, Maharashtra, India.
3. 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 analogue of Sufentanil. Most particularly, it relates to novel deuterated sufentanil compounds of formula I, their pharmaceutically acceptable salts, stereoisomers, solvates, and derivatives. The invention further relates to process for the synthesis of such deuterated sufentanil compounds. Said compounds are useful in the modulation of opioid receptor activity and may provide improved pharmacokinetic, pharmacodynamic, and metabolic stability properties relative to non-deuterated sufentanil.

BACKGROUND OF THE INVENTION
Sufentanil is chemically knows as N-[4-(Methoxymethyl)-1-(2-thiofuran-2-ylethyl)-4-piperidyl]-Nphenylpropanamide. It is represented by following structure formula.

Sufentanil citrate injection was first approved by the US Food and Drug Administration (FDA) in 1984 for a variety of uses, including as an adjunct to general anaesthesia, for epidural analgesia in labour and vaginal delivery, and as a primary anaesthetic. However, Sufentanil sublingual tablets (Dsuvia), received approval from the FDA on November 2, 2018.
Sufentanil is first disclosed in US3998834 by Janssen. The process described therein, however, is quite lengthy and complicated. There remains a need in the art for improved processes for producing piperidine derivatives including sufentanil.
Sufentanil is a powerful synthetic opioid analgesic that is similar to fentanyl. It is typically used in hospital settings for short-term pain relief after surgery or other procedures.
Although sufentanil and related opioids are highly effective, they are associated with certain limitations, including rapid metabolic degradation, variable pharmacokinetics, and the risk of adverse effects such as respiratory depression and dependence.
Metabolic transformations- particularly oxidative pathways mediated by cytochrome P450 enzymes- play a major role in the clearance of sufentanil from the body, thereby influencing both its duration of action and safety profile. These metabolic liabilities may necessitate repeated dosing, lead to inter-patient variability, and increase the likelihood of drug–drug interactions.
One approach to overcoming the limitations of conventional sufentanil is the strategic incorporation of deuterium atoms into specific positions of the sufentanil molecule. Deuterium is a stable isotope of hydrogen that contains an additional neutron. When incorporated into organic molecules, deuterium forms stronger carbon-deuterium (C-D) bonds compared to the corresponding carbon–hydrogen (C-H) bonds. These stronger bonds reduce the rate of metabolic cleavage at targeted sites, thereby slowing oxidative degradation.
This process, known as deuterium substitution or deuteration, can impart favorable changes to the pharmacological and pharmacokinetic profile of a drug. For sufentanil, deuteration may enhance binding affinity to the μ-opioid receptor, thereby improving its analgesic efficacy. In addition, deuteration may reduce adverse effects such as nausea and vomiting, improve metabolic stability, and extend the duration of action.
As a result, deuterated sufentanil compounds may require less frequent dosing and allow for administration at lower effective doses.
Accordingly, there exists a need to design and develop novel deuterated sufentanil compounds and methods for their synthesis. Such compounds may provide improved receptor-binding capacity, reduced side effects, greater metabolic stability, and more predictable therapeutic outcomes compared with conventional sufentanil.
OBJECTS OF THE INVENTION
One of the objects of the present invention is to provide analogue of Sufentanil.
Another object of the present invention is to provide novel deuterated sufentanil compounds of formula I and pharmaceutically acceptable salts, stereoisomers, solvates, and derivatives thereof.
Another object of the present invention is to provide efficient and reproducible process for synthesis of deuterated Sufentanil compound of formula I.
Yet another object of the present invention is to provide characterization of deuterated Sufentanil compound of formula I.
A further object of the present invention is to provide deuterated sufentanil compounds having improved pharmacokinetic and pharmacodynamic properties compared to conventional sufentanil.
Another object of the invention is to provide deuterated sufentanil compounds with enhanced metabolic stability and reduced susceptibility to oxidative degradation.
Another object of the invention is to provide deuterated sufentanil compounds that exhibit improved receptor binding, greater therapeutic efficacy, and reduced inter-patient variability.
Yet another embodiment of the present invention is to provide a simple, economical viable, large-scale production of deuterate Sufentanil compound of formula I with high yield and high purity.
Yet another object of the invention is to provide deuterated sufentanil compounds that reduce the frequency of dosing and allow for effective pain management at lower doses.
A still further object of the invention is to provide deuterated sufentanil compounds with an improved safety profile, including reduced incidence of adverse effects such as respiratory depression, nausea, and vomiting.

SUMMARY OF THE INVENTION
One of the aspects of the present invention provides a compound of formula I represented by

Wherein R1, R2, R3, R4 are independently selected from hydrogen (H), deuterium (D), deuterated C1-C5 alkyl group and aryl group and/or substituted aryl group.
Another aspect of the present invention provides a process for synthesising compound of formula I, the process comprising:
a. contacting a compound of formula 1 with a compound of formula 2, an alkyl cyanide in presence of an acid in a solvent to obtain a compound of formula 3;
b. treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4;
c. refluxing the compound of formula 4 with a base in a solvent to obtain a compound of formula 5;
d. reacting the compound of formula 5 with alkyl halide (R-X) in a solvent to obtain a compound of formula 6;
e. reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7;
f. reacting the compound of formula 7 with alkyl halide in presence of a base in a solvent to obtain compound of formula 8;
g. treating the compound of formula 8 with deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9;
h. debenzylating the compound of formula 9 in presence of a reagent and a hydrogen source in a solvent to obtain a compound of formula 10;
i. contacting the compound of formula 10 with a compound of formula 11 in presence of a base, an alkyl halide in a solvent to obtain compound of formula I.

BRIEF DESCRIPTION OF FIGURES
Figure 1 shows Verapamil Graphs for RLM (%PCR)
Figure 2 illustrates Verapamil Graphs for HLM(%PCR)
Figure 3 depicts Verapamil Graphs for MLM (%PCR)
Figure 4 shows Sufentanil Graphs for RLM(%PCR)
Figure 5 depicts Sufentanil Graphs for HLM (%PCR)
Figure 6 shows Sufentanil Graphs for MLM(%PCR)
Figure 7 illustrates Sufentanil -D8 Graphs for RLM(%PCR)
Figure 8 shows Sufentanil -D8Graphs for HLM(%PCR)
Figure 9 represents Sufentanil -D8 Graphs for MLM(%PCR)

DETAILED DESCRIPTION OF THE PRESENT INVENTION
In the present application, different terms are used to describe the invention. The definitions of the terms are provided below.
The term ‘compound’ or ‘compound of formula I’ or ‘formula I’ used herein refers to analogue of Sufentanil compound in which one or more hydrogen atoms are replaced by deuterium (D) atom. It 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’, ‘compound of formula I’ and ‘formula I’ may be used interchangeably in the specification.
The term ‘deuterated alky halide (RX-d)’ used herein refers to the alkyl halide compound in which one or more hydrogen (H) atoms of alkyl group (R) are replaced by deuterium (D) atom. In the present invention, deuterated alkyl halide may be used include such as but is not limited to deuterated C1 to C5 alkyl group which is selected from CD3, C2D5, C3D7, C4D9 group and wherein X is a halogen selected from fluorine, chlorine, bromine, and iodine and combinations thereof.
‘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 limited to water, alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), toluene, halogenated solvent(s) and/or deuterated form of water, alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s) and combinations thereof.
The term ‘alkyl’ group used in the compound of formula I includes straight chain or branched chain carbon atoms. The most particularly, it may ‘C1-C5 alkyl’ group which including such as but is not limited to methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, n-butyl and n-pentyl group.
The term ‘reagent’ used herein refers to an agent that can initiate or speed up the formation of product from reactant. The reagent may be deprotecting agent.
One of the embodiments of the present invention provides a compound of formula I, the formula I is represented by:

Wherein R1, R2, R3, R4 are independently selected from hydrogen (H), deuterium (D), deuterated C1-C5 alkyl group and aryl group and/or substituted aryl group.
Another embodiment of the present invention provides a compound of formula I, wherein R1 and R2 are selected from deuterium (D) and deuterated C1 to C5 group.
Another embodiment of the present invention provides a compound of formula I, wherein deuterated C1 to C5 alkyl group is selected from CD3, C2D5, C3D7, C4D9 group.
Another embodiment of the present invention provides a compound of formula I, wherein R1 or R2 is CD3.
Another embodiment of the present invention provides a compound of formula I, wherein R3 or R4 is deuterium (D).
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein the process comprises:
a. contacting a compound of formula 1 with a compound of formula 2, a cyanide compound in presence of an acid in a solvent to obtain a compound of formula 3;
b. treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4;
c. refluxing the compound of formula 4 with a base in a solvent to obtain a compound of formula 5;
d. reacting the compound of formula 5 with an alkyl halide (R-X) in a solvent to obtain a compound of formula 6;
e. reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7;
f. reacting the compound of formula 7 with an alkyl halide in presence of a base in a solvent to obtain compound of formula 8;
g. treating the compound of formula 8 with a deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9;
h. debenzylating the compound of formula 9 in presence of a reagent and a hydrogen source in a solvent to obtain a compound of formula 10;
i. contacting the compound of formula 10 with a compound of formula 11 in presence of a base, an alkyl halide in a solvent to obtain compound of formula I.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein a starting and/or an intermediate compound used in the said process are provided as follows:

In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein contacting a compound of formula 1 with a compound of formula 2, a cyanide compound in presence of an acid in a solvent to obtain a compound of formula 3 is carried out at a temperature in the range of 5oC to 50oC for a period in the range of 16 hrs to 19 hrs.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein the cyanide compound is selected from hydrogen cyanide, calcium cyanide, potassium cyanide, and sodium cyanide and combinations thereof, preferably potassium cyanide.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein the acid is organic and/or inorganic acid, wherein organic acid used include such as but is not limited to glacial 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, cinnamic acid, mandelic acid, methanesulfonic acid, , wherein acid is glacial acetic acid.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4 is carried out at 0oC to an ambient temperature for a period in the range of 16 hrs to 18 hrs and wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and/or combinations thereof, preferably 95% sulfuric acid.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein solvent is polar and/or non-polar solvent.
In another embodiment of the present invention there is provided a process for synthesising 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), toluene, 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, diols and mixtures thereof.
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).
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein refluxing the compound of formula 4 with a base in a solvent to obtain a compound of formula 5 is carried out at 180oC to 210oC for a period in the range of 22 hrs to 26 hrs, preferably 24 hrs, and wherein the base is organic and/or inorganic base.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein organic base may be selected from, but is not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, diethyl amine, N-methyl morpholine, pyridine, 4-dimethylamino pyridine, and like.
In another embodiment of the present invention there is provided a process for making compound of formula I, wherein inorganic base that may be selected from , but are not limited to, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, lithium carbonate, or the like; bicarbonates of alkali metals, such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; ammonia, sodium hydride; and any mixtures thereof.
In an embodiment, the base used is potassium hydroxide.
In an embodiment there is provided a process for synthesising compound of formula I, wherein reacting the compound of formula 5 with an alkyl halide (R-X) in a solvent to obtain a compound of formula 6 is carried out at a temperature in the range of 70oC to 75oC, and wherein the alkyl halide is represented by R-X, wherein R is C1 to C10 alkyl group, and wherein X is halogen selected from fluorine, chlorine, bromine, iodine and combinations thereof.
In most preferred embodiment of the present invention, alky halide is methyl iodide/iodomethane.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7 is carried out at -5oC to ambient temperature for about 16 hrs, and wherein the reducing agent is selected from Pd/C, Pt/C, Raney Ni, LiAlH4, NaBH4, diisobutyl aluminum hydride, sodium hydride and like, wherein reducing agent is LiAlH4.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein reacting the compound of formula 7 with an alkyl halide in presence of a base in a solvent to obtain compound of formula 8 is carried out at a 0oC to ambient temperature 2 hrs to 3 hrs in presence of sodium hydride, and wherein alkyl halide used is iodmethane-d3.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein treating the compound of formula 8 with a deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9 is carried out at 0oC to ambient temperature for a period in the range of 2 hrs to 4 hrs , and wherein deuterated acid halide is selected from ethanoyl chloride, propanoyl chloride, butanoyl chloride, benzoyl chloride and like, preferably deuterated propanoyl chloride (propionyl chloride-d3), and wherein the base is triethylamine.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein debenzylating the compound of formula 9 in presence of a reagent and a hydrogen source in a solvent to obtain a compound of formula 10 is carried out at a temperature in the range of 45oC to 55oC for a period in the range of 1.5 hrs to 3 hrs at 60 psi pressure, and wherein regent is selected from Pd/C, Pt/C, Raney Nickel; preferably palladium hydroxide (Pd (OH)2).
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein contacting the compound of formula 10 with a compound of formula 11 in presence of a base, an alkyl halide in a solvent to obtain compound of formula I is carried out in presence of triethylamine, anhydrous potassium carbonate and potassium iodide at reflux temperature for about 6 hrs.
In another embodiment of the present invention there is provided a process for making compound of formula I, wherein yield of the process is obtained in the range of 60% to 99.99%.
In another embodiment of the present invention there is provided a process for synthesising compound of formula I, wherein the purity is obtained in the range of 85% to 99.99%.
In another embodiment of the present invention there is provided a process for synthesising 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
i. compound of formula I or its pharmaceutically acceptable salt; and
ii. one or more pharmaceutically acceptable excipient.
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
A. Synthesis of deuterated Sufentanil (compound of formula I)
Step-1: Synthesis of 1-benzyl-4-(phenylamino) piperidine-4-carbonitrile (compound of formula 3)
While maintaining the internal temperature of the mixture at 5-8°C., glacial acetic acid (250 g; 238 mL, 5.0 mol) was added dropwise to a stirred mixture of l-benzyl-4-piperidone (30.0 g; 0.159 mol) (compound 2), aniline (59.0 g; 0.635 mol) (compound 1), potassium cyanide (41.3 g; 0.635 mol) and dichloromethane (316 mL) over a period of two hours. After the addition was complete, the reaction mixture was gradually warmed to about 50°C. over a period of about 1 hour. The mixture was stirred at this temperature for about 17 hours. It was then cooled, and crushed ice (2 kg) was added. While maintaining the internal temperature of the mixture below 20° C., a 10% aqueous sodium hydroxide solution (180 g) was added dropwise over a period of 1 hour. The mixture was then extracted with dichloromethane. The aqueous layer was treated with an aqueous permanganate solution to destroy excess potassium cyanide, before discarding. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to obtain a brown colour residue, which was triturated with 2-propanol to obtain a solid. This was solid was collected by filtration, washed with cold 2-propanol and dried to give the title compound as an off-white solid (37.0 g; 80%).
Step-2: Synthesis of l-benzyl-4-(phenylamino) piperidine-4-carboxamide (compound of formula 4):
At about 0°C, 1-benzyl-4-(phenylamino) piperidine-4-carbonitrile (24.0 g; 82.47 mmol) (compound 3) was added portion wise to 95% sulfuric acid (311 g; 3.01 mol) over a period of about 1 hour. The mixture was stirred at ambient temperature for about 16 hours. The mixture was poured onto crushed ice, and then stirred for about 1 hour. The resulting precipitate was collected by filtration to form a wet cake. The wet cake was dissolved in water (300 mL), cooled to about 0° C., and basified to pH greater than 12 using a 10% aqueous sodium hydroxide solution. The resulting precipitate was washed with water and dried to give the title compound as a white solid (20.0 g; 78%).
Step-3: Synthesis of sodium 1-benzyl-4-(phenylamino) piperidine-4-carboxylate (compound of formula 5)
A mixture of l-benzyl-4-(phenylamino) piperidine-4-carboxamide (20.0 g; 64.7 mmol) (compound 4), potassium hydroxide (14.35 g; 256 mmol) and ethane-l,2-diol (120 mL) was heated at reflux for about 24 hours. The mixture was diluted with distilled water (200 mL), cooled to about 0°C., and acidified to a pH of about 2.0 with conc. hydrochloric acid. At 0-5°C, the mixture was then basified to pH greater than 12 with a 30% aqueous sodium hydroxide solution, and then stirred at 0-5°C. for about 1 hour. The resulting precipitate was collected by filtration and dried in vacuo to form a slightly wet cake. At about 60°C., this slightly wet cake was dissolved in distilled water (50mL), and then 2-propanol (50 mL) was added. After cooling to ambient temperature, the resulting precipitate was collected by filtration, washed successively with a mixture of 2-propanol-water (4:1) and 2-propanol, and then dried in vacuo to give the title compound as an off-white solid (12.0 g; 60%).
Step-4: Synthesis of methyl 1-benzyl-4-(phenylamino) piperidine-4-carboxylate (compound of formula 6)
At 70-72°C., iodomethane (5.49 g; 2.41 mL; 38.7 mmol) was added dropwise to a suspension of sodium 1-benzyl-4-(phenylamino) piperidine-4-carboxylate (12.0 g; 38.7 mmol) (compound 5) in dry dimethyl sulfoxide (120 mL). After the addition was complete, the clear pale-yellow solution was stirred for about 10 minutes, and then poured into ice-cold water. Following standard extractive workup with n-hexane, the title compound was isolated as a white crystalline solid (5.30 g; 42.2%).
Step-5: Synthesis of (l-benzyl-4-(phenylamino) piperidin4-yl) methanol (compound of formula 7)
At about 0°C., a solution of methyl 1-benzyl-4-(phenylamino) piperidine-4-carboxylate (5.00 g; 15.43 mmol) (compound 6) in dichloromethane (10 mL) was added dropwise to a suspension of lithium aluminium hydride (1.17g;30.86 mmol) in dry tetrahydrofuran (100mL). The mixture was stirred at ambient temperature for about 16 hours. The mixture was cooled to about 0°C. and ice-cold water (1mL) was added. The mixture was filtered and the inorganic salts washed with ethyl acetate. The filtrate and washings were combined and concentrated in vacuo to give the title compound as a white solid (4.10 g; 90%).
Step-6: Synthesis of l-benzyl-4- (methoxymethyl)-N-phenylpiperidin-4-amine (compound of formula 8)
A solution of (l-benzyl-4-(phenylamino) piperidin4-yl) methanol (1.0 g, 3.37 mmol) (compound 7) in tetrahydrofuran (15 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil; 0.162 g; 4.05 mmol) in dry tetrahydrofuran (25 mL). The mixture was stirred at ambient temperature for about 30 minutes, and then a solution of iodomethane-d3 (270 (mL; 4.34 mmol) in tetrahydrofuran (10 mL) was added dropwise. The mixture was stirred at ambient temperature for about 2 hours, cooled to about 0°C., and then water (1 mL) was added to destroy excess sodium hydride. Standard extractive work up provided a crude residue which was purified by silica gel column chromatography (2% methanol in chloroform) to give the title compound as an oil (0.700 g; 67%).
Step-7: Synthesis of N-(l-benzyl-4-(methoxymethyl) piperidin-4-yl)-N-phenylpropionamide (compound of formula 9)
At about 0° C., propionyl chloride-d3 (270 mg; 2.92 mmol) was added to a mixture of l-benzyl-4- (methoxymethyl)-N-phenylpiperidin-4-amine (700 mg; 2.25 mmol) (compound 8), triethylamine (30 (xL; catalytic) and dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for about 3 hours. Standard extractive work up gave the title compound as pale-yellow oil (0.400 g; 48%).
Step-8: Synthesis of N-(4- (methoxymethyl)piperidin-4-yl)-N-phenylpropionamide-d6 (compound of formula 10)
At about 50°C., a mixture of N-(l-benzyl-4-(methoxymethyl)piperidin-4-yl)-N-phenylpropionamide (0.250 g; 0.682 mmol), 20% palladium hydroxide on carbon (0.030 g), and ethanol (20 mL) was hydrogenated at 60 psi for about 2 hours. After filtering with a pad of Celite, the filtrate was concentrated in vacuo to yield a pale-yellow liquid. Diethyl ether (5.0mL) was added to the pale-yellow liquid, and then a saturated solution of hydrochloric gas in diethyl ether (1.0mL) was added. After stirring for about 30 minutes, the solution was filtered and dried to obtain the title compound as off-white solid (0.110 g; 52%).
Step-9: Synthesis of deuterated Sufentanil (compound of formula I)
A mixture of N-(4- (methoxymethyl)piperidin-4-yl)-N-phenylpropionamide-d6 (0.190 g; 0.687 mmol) (compound 10), 2-(thiophen-2-yl)ethyl methanesulfonate-d2 (0.170 g; 0.825 mmol) (compound 11), triethylamine (190 mL; 1.38 mmol), anhydrous potassium carbonate (0.029 g; 0.210 mmol), potassium iodide (0.005 g; catalytic) and acetonitrile (5 ML) was heated at reflux for about 6 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to provide a crude residue which was purified by preparative HPLC on a Kromasil 100 C18 (250x30 rnm, 5 (x column, eluting with acetonitrile/0.05% formic acid (gradient) at a flow rate of 42 mL/min). The title product eluted at 5.5 minutes. Acetonitrile was removed by distillation and the remaining aqueous phase was basified to a pH of about 9.0 with a 10% sodium carbonate solution. Standard extractive workup with ethyl acetate gave the title compound as a yellow solid (0.090 g; 34%).
Reaction Scheme:

B. Intermediate compound:
Synthesis of 2-(thiophen-2-yl)ethyl methanesulfonate-d2 (compound of formula 11)
Step-A: Synthesis of 2-(thiophen-2-yl)ethanol:
Finely powdered sodium borohydride (6 eq., 24-30 mmol) was suspended in THF (40 mL) with the respective ester (1 g, 4-5 mmol). The resulting mixture was stirred for 15 min at 70°C. Methanol (8 ml) was then added dropwise during 15 min and effervescence was observed. Stirring at 70°C was maintained during a period of 0.5-2 h, depending on the ester. The reaction was cooled to room temperature, and quenched with satd. aq. NH4Cl (15 mL). Stirring was continued for 1.5 h. The organic layer was separated and the aqueous phase extracted with ethyl acetate (2 x 20mL). The combined extracts and organic phase were dried over MgSO4 and concentrated to give the respective spectroscopically pure alcohol, yield 94%.
Step-B: 2-(thiophen-2-yl)ethyl methanesulfonate-d2 (compound of formula 11)
At about 0°C., methanesulfonyl chloride (200mL; 2.58 mmol) was added dropwise to a mixture of 2-(thiophen-2-yl) ethanol (0.250 g; 1.95 mmol), triethylamine (0.40 mL; 2.87 mmol) and dichloromethane (5 mL). The mixture was stirred at about 0°C. for about 3 hours. Standard extractive work up provided the title compound as yellow oil which was used in the next step without further purification (0.3 10 g; 77%).
Reaction scheme:

C. Evaluation of Microsomal stability profiles for Sufentanil in native and deuterated versions (Sufentanil D8) in Rat, Human and Mouse liver Microsomes.
1. STUDY OBJECTIVE:
The objective of the study is to determine the metabolic stability for a series of compounds along with their deuterated forms.
2. SAFETY PRECATIONS:
Safety measures were adopted to ensure adequate personal health and safety. Personal protective equipment including aprons, gloves, cap, face mask and goggle (if required) was used in addition to protective laboratory wares and followed the necessary safety precautions as per the MSDS/TIDS. In case of eye or skin contact, it was washed with soap and water with subsequent medical aid.
3. CHEMICALS AND REAGENTS:
Milli Q water; Di-potassium hydrogen phosphate; Potassium di-hydrogen phosphate; Acetonitrile; Dimethyl sulfoxide (DMSO); NADPH; Carbamazepine
4. EXPERIMENTALPROCEDURE:
4.1: Metabolic stability:
• 5µL of the working solution (100µM in phosphate buffer) of compound is added to 432.5µL of phosphate buffer and 12.5µL of Liver microsome.
• Experiment is conducted in duplicates (n=2).
• Mix and incubate for 10 minutes in water bath at 37ºC.
• 50 µL of 20mM NADPH solution was added, vortexed and incubated in water bath at 37ºC
• At each time point (0, 5, 10, 20, 30 and 45 min) 50 µL of aliquots are withdrawn and added with 200 µL of ice-cold acetonitrile containing internal standard.
• Samples are vortexed and centrifuged at 10000rpm for 10minutes.
• Supernatant was diluted with milli-Q water and analysed using LCMS/MS.
• Verapamil is used as positive control and Atenolol is used as negative control.
Calculation:

Units=µL/min/mg protein
5. ANALYSIS OF THE SAMPLES
After transferring into vials it was subjected to analysis in LCMS/MS.
Mobile phase composition and column specifications are included in report.
LCMS/MS conditions:
Mass Spec Triple Quadrapole Waters Xevo-TQS-Cronos with Mass Lynx v 4.2 software
HPLC Waters Acquity UPLC
Column Phenomenox Kinetix 5uM 50 *2.1 mmC18 LC Column
Mode ESI Positive mode
Method Gradient
Mobile Phase - A 0.1% Formic Acid in Water
Mobile Phase - B 0.1% Formic Acid in Acetonitrile
Flow rate 0.350 mL/min
Run time 4 min
Injection volume 5 µL
Column oven Temp. 40˚C
Auto sampler Temp. 10˚C

MS tuning parameters:
Source parameters Values
Capillary voltage (kV) 2.45
Cone voltage (V) 28
Desolvation temp. (oC) 500
Desolvation Gas flow (L/hr) 1000
Cone Gas flow (L/hr) 50
Collision energy MS (V) 4

6. Results:
Table 1: Intrinsic Clearance Determination of Verapamil in Rat Liver Microsomes (RLM)
Verapamil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)
Rat Liver Microsome 0 min-1 332244 254120 1.3074 100.00 9.094 152.41
5 min-1 175269 256077 0.6844 52.35
10 min-1 87848 247738 0.3546 27.12
20 min-1 51939 249173 0.2084 15.94
30 min-1 36274 245889 0.1475 11.28
45 min-1 7572 248544 0.0305 2.33
0 min-2 327997 239495 1.3695 100.00 9.109 152.15
5 min-2 169669 257090 0.6600 48.19
10 min-2 87737 250735 0.3499 25.55
20 min-2 53367 251169 0.2125 15.52
30 min-2 35774 244828 0.1461 10.67
45 min-2 7331 235546 0.0311 2.27
45 min
(-NAD PH)-1 321918 242848 1.3256 101.39 NA
45 min (-NADPH)-2 328386 249628 1.3155 96.06

Table 2: Intrinsic Clearance Determination of Verapamil in Human Liver Microsome (HLM)
Verapamil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Human Liver Microsome 0 min-1 345026 270328 1.2763 100.00 8.994 154.10
5 min-1 181053 277868 0.6516 51.05
10 min-1 94519 277590 0.3405 26.68
20 min-1 54227 270981 0.2001 15.68
30 min-1 37281 272081 0.1370 10.73
45 min-1 7890 276051 0.0286 2.24
0 min-2 336222 267602 1.2564 100.00 9.043 153.27
5 min-2 179207 277015 0.6469 51.49
10 min-2 92229 272309 0.3387 26.96
20 min-2 55913 276525 0.2022 16.09
30 min-2 38339 276241 0.1388 11.05
45 min-2 7915 277241 0.0286 2.28
45 min
(-NAD PH)-1 347319 269590 1.2883 100.94 NA
45 min (-NADPH)-2 338341 267129 1.2666 100.81

Table 3: Intrinsic Clearance Determination of Verapamil in Mouse Liver Microsome (MLM)
Verapamil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Mouse Liver Microsome 0 min-1 332314 223330 1.4880 100.00 8.896 155.80
5 min-1 179261 235353 0.7617 51.19
10 min-1 94059 228244 0.4121 27.69
20 min-1 57085 239552 0.2383 16.01
30 min-1 38617 239503 0.1612 10.83
45 min-1 7929 246697 0.0321 2.16
0 min-2 333794 233786 1.4278 100.00 9.038 153.35
5 min-2 183991 236949 0.7765 54.38
10 min-2 95226 235003 0.4052 28.38
20 min-2 56646 243173 0.2329 16.31
30 min-2 39233 234917 0.1670 11.70
45 min-2 8269 250311 0.0330 2.31
45 min
(-NAD PH)-1 330916 217428 1.5220 102.28 NA
45 min (-NADPH)-2 329318 219488 1.5004 105.08

Table 4: Intrinsic Clearance Determination of Sufentanil in Rat Liver Microsome (RLM)
Sufentanil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)
Rat
Liver Microsome

0 min-1 163167 256833 0.6353 100.00 7.342 188.79
5 min-1 80991 260198 0.3113 49.00
10 min-1 51059 270128 0.1890 29.75
20 min-1 34010 266991 0.1274 20.05
30 min-1 8429 263993 0.0319 5.02
45 min-1 2065 263836 0.0078 1.23
0 min-2 163219 255477 0.6389 100.00 7.293 190.04
5 min-2 81858 258396 0.3168 49.59
10 min-2 50564 261332 0.1935 30.29
20 min-2 33994 266932 0.1274 19.94
30 min-2 8751 267018 0.0328 5.13
45 min-2 2014 263929 0.0076 1.19
45 min
(-NAD PH)-1 164874 256910 0.6418 101.02 NA
45 min (-NADPH)-2 165468 256595 0.6449 100.94

Table 5: Intrinsic Clearance Determination of Sufentanil in Human Liver Microsome (HLM)
Sufentanil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Human
Liver Microsome

0 min-1 172983 274223 0.6308 100.00 4.073 340.29
5 min-1 70681 278192 0.2541 40.28
10 min-1 25035 277224 0.0903 14.32
20 min-1 7116 277021 0.0257 4.07
30 min-1 2022 276024 0.0073 1.16
45 min-1 59 276747 0.0002 0.03
0 min-2 173277 277665 0.6240 100.00 3.795 365.18
5 min-2 70635 275299 0.2566 41.12
10 min-2 24454 273812 0.0893 14.31
20 min-2 7109 274248 0.0259 4.15
30 min-2 2112 276966 0.0076 1.22
45 min-2 38 272322 0.0001 0.02
45 min
(-NAD PH)-1 174852 282507 0.6189 98.11 NA
45 min (-NADPH)-2 177102 284140 0.6233 99.89

Table 6: Intrinsic Clearance Determination of Sufentanil in Human Liver Microsome (HLM)
Sufentanil Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Mouse
Liver Microsome

0 min-1 181054 275011 0.6584 100.00 4.973 278.68
5 min-1 9105 271808 0.0335 5.09
10 min-1 3922 276268 0.0142 2.16
20 min-1 2429 269664 0.0090 1.37
30 min-1 157 262317 0.0006 0.09
45 min-1 179 264821 0.0007 0.11
0 min-2 183401 276472 0.6634 100.00 5.009 276.69
5 min-2 9438 277357 0.0340 5.13
10 min-2 4042 284397 0.0142 2.14
20 min-2 2421 274210 0.0088 1.33
30 min-2 174 263830 0.0007 0.11
45 min-2 180 264245 0.0007 0.11
45 min
(-NAD PH)-1 181376 272895 0.6646 100.94
NA
45 min (-NADPH)-2 183656 277652 0.6615 99.71

Table 7: Intrinsic Clearance Determination of Sufentanil-D8 in Rat Liver Microsome (RLM)
Sufentanil-D8 Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Rat
Liver Microsome

0 min-1 118252 262587 0.4503 100.00 8.185 169.34
5 min-1 72193 275532 0.2620 58.18
10 min-1 24166 256413 0.0942 20.92
20 min-1 12315 259895 0.0474 10.53
30 min-1 6250 265038 0.0236 5.24
45 min-1 2471 266025 0.0093 2.07
0 min-2 117940 258262 0.4567 100.00 8.219 168.64
5 min-2 72076 270094 0.2669 58.44
10 min-2 24407 261935 0.0932 20.41
20 min-2 12570 261784 0.0480 10.51
30 min-2 6193 261235 0.0237 5.19
45 min-2 2520 262900 0.0096 2.10
45 min
(-NAD PH)-1 116248 261372 0.4448 98.78
NA
45 min (-NADPH)-2 118121 267249 0.4420 96.78

Table 8: Intrinsic Clearance Determination of Sufentanil-D8 in Human Liver Microsome (HLM)
Sufentanil-D8 Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Human
Liver Microsome

0 min-1 119023 275036 0.4328 100.00 6.647 208.50
5 min-1 76868 265513 0.2895 66.89
10 min-1 24321 269341 0.0903 20.86
20 min-1 6181 274993 0.0225 5.20
30 min-1 3712 266435 0.0139 3.21
45 min-1 1 272157 0.0000 0.00
0 min-2 119808 274325 0.4367 100.00 6.657 208.21
5 min-2 77910 272851 0.2855 65.38
10 min-2 24880 271769 0.0915 20.95
20 min-2 6300 270636 0.0233 5.34
30 min-2 3751 269732 0.0139 3.18
45 min-2 1 272698 0.0000 0.00
45 min
(-NAD PH)-1 120811 274940 0.4394 101.52
NA
45 min (-NADPH)-2 119782 277592 0.4315 98.81

Table 9: Intrinsic Clearance Determination of Sufentanil-D8 in Mouse Liver Microsome (MLM)
Sufentanil-D8 Sample ID Analyte Area ISTD Area Area Ratio % PCR T1/2
(min) Clint
(set 1 & set 2)

Mouse
Liver Microsome

0 min-1 123291 264220 0.4666 100.00 4.612 300.51
5 min-1 4774 261581 0.0183 3.92
10 min-1 3286 264336 0.0124 2.66
20 min-1 1803 265407 0.0068 1.46
30 min-1 70 263676 0.0003 0.06
45 min-1 92 263372 0.0003 0.06
0 min-2 123198 270817 0.4549 100.00 4.878 284.15
5 min-2 4903 268427 0.0183 4.02
10 min-2 3306 270073 0.0122 2.68
20 min-2 1940 269828 0.0072 1.58
30 min-2 117 267945 0.0004 0.09
45 min-2 102 258921 0.0004 0.09
45 min
(-NAD PH)-1 122314 266440 0.4591 98.39
NA
45 min (-NADPH)-2 123012 269327 0.4567 100.40

Table 10: Clint and T1/2 values with Rat Liver Microsomes

Liver Microsomal Intrinsic Clearance data Summary
Clearance category
Compound Name Rat Liver Microsomes
Intrinsic clearance (µL/min/mg protein) T 1/2
(min)
Atenolol 1.39 Not calculated Low
Verapamil 152.28 9.015 High
Sufentanil 189.42 7.317 High
Sufentanil_D8 168.99 8.201 High

7. RESULTS, SUMMARY & CONCLUSION
The acceptance criteria and the classification of compounds wrt their metabolic stabilities are as follows. For the assay results to be acceptable, the reference standards should qualify with the following limits:
• Clint value < 20 units = Low clearance
• Clint value 20-100 units = Intermediate clearance
• Clint value >100 units = High clearance
Results from the current in vitro metabolic stability experiments where test (Sufentanil and Sufentanil D8) and reference (Verapamil & Atenolol) compounds when incubated with Rat liver microsomes (RLM), Human liver microsomes (HLM) and Mouse liver microsomes (MLM) showed that test Sufentanil and Sufentanil-D8 compounds undergo fast metabolism in RLM, HLM and MLM with Clint units similar for high hepatic clearance. Verapamil and Atenolol were reference standards for high and low clearance compounds, respectively.
SUMMARY ANALYSIS:
The intrinsic clearance (Clint, µL/min/mg protein) of sufentanil and its deuterated analogue, sufentanil-D8, was evaluated using liver microsomes from mouse, rat, and human.
For sufentanil, the highest clearance was observed in human liver microsomes (352.73 µL/min/mg protein), followed by mouse (277.68 µL/min/mg protein) and rat (189.42 µL/min/mg protein). In contrast, sufentanil-D8 exhibited clearance values of 292.33 µL/min/mg protein (mouse), 168.99 µL/min/mg protein (rat), and 208.36 µL/min/mg protein (human).
Comparison between the parent and deuterated analogue indicates a species-dependent effect of deuteration:
• In human microsomes, sufentanil-D8 showed a ~41% reduction in clearance relative to sufentanil, suggesting markedly improved metabolic stability and potentially enhanced systemic exposure in vivo.
• In rat microsomes, sufentanil-D8 clearance was ~11% lower than the parent, reflecting a modest improvement in stability.
• In mouse microsomes, sufentanil-D8 clearance was slightly higher (+5%), indicating no stability advantage compared with the parent.
Overall, these results demonstrate that sufentanil-D8 confers a significant metabolic stability benefit in human microsomes, with moderate improvement in rat and negligible change in mouse. The data suggest that sufentanil-D8 may achieve improved pharmacokinetic performance in humans due to reduced intrinsic clearance.
CONCLUSION:
The observed reduction in intrinsic clearance of sufentanil-D8 in human liver microsomes indicates improved metabolic stability relative to sufentanil. This decrease in clearance is expected to translate into lower hepatic metabolic liability, resulting in increased systemic exposure and prolonged duration of action. Consequently, sufentanil-D8 may demonstrate enhanced in vivo efficacy and improved pharmacokinetic properties in humans, while maintaining comparable activity in preclinical species.
We claim:
1. A compound of formula I represented by

Wherein R1, R2, R3, R4 are independently selected from hydrogen (H), deuterium (D), deuterated C1-C5 alkyl group and aryl group and/or substituted aryl group.
2. The compound of formula I as claimed in claim 1, wherein R1 and R2 are selected from Deuterium (D) and deuterated C1 to C5 group.
3. The compound of formula I as claimed in claim 1, wherein deuterated C1 to C5 alkyl group is selected from CD3, C2D5, C3D7, C4D9 group.
4. The compound of formula I as claimed in claim 1, wherein R1 or R2 is CD3; and wherein R3 or R4 is Deuterium (D).
5. The compound of formula I as claimed in claim 1 is Sufentanil-D8

6. A process for synthesising compound of formula I, the process comprising:
a) contacting a compound of formula 1 with a compound of formula 2, alkyl cyanide in presence of an acid in a solvent to obtain a compound of formula 3;
b) treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4;
c) refluxing the compound of formula 4 with a base (KOH) in a solvent (diol) to obtain a compound of formula 5;
d) reacting the compound of formula 5 with alkyl halide (R-X) in a solvent to obtain a compound of formula 6;
e) reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7;
f) reacting the compound of formula 7 with alkyl halide in presence of a base in a solvent to obtain compound of formula 8;
g) treating the compound of formula 8 with deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9;
h) debenzylating the compound of formula 9 in presence of a reagent and hydrogen in a solvent to obtain a compound of formula 10;
i) contacting the compound of formula 10 with a compound of formula 11 in presence of a base, alkyl halide in a solvent to obtain compound of formula I; wherein the compound of formula I obtained having yield in the range of 95% to 99.99% and purity in the range of 98% to 99.99% (by HPLC);
wherein the compounds of formulae 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 & 11 for use as a starting material or as an intermediate in the synthesis of a compound of formula (I) represented herein

7. The process as claimed in claim 6, wherein
a) contacting a compound of formula 1 with a compound of formula 2, a cyanide compound in presence of an acid in a solvent to obtain a compound of formula 3 is carried out at a temperature in the range of 5oC to 50oC for a period in the range of 16 hrs to 19 hrs; wherein cyanide compound is selected from hydrogen cyanide, calcium cyanide, potassium cyanide, and sodium cyanide and combinations thereof, preferably potassium cyanide; wherein acid used is selected from glacial 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, cinnamic acid, mandelic acid, methanesulfonic acid, preferably glacial acetic acid;
b) treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4 is carried out at a temperature in the range of 0oC to an ambient temperature for a period in the range of 16 hrs to 18 hrs; wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and/or combinations thereof, preferably 95% sulfuric acid;
c) refluxing the compound of formula 4 with a base in a solvent to obtain a compound of formula 5 is carried out at 180oC to 210oC for a period in the range of 22 hrs to 26 hrs, preferably 24 hrs; wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonia, sodium hydride and any mixtures thereof, preferably potassium hydroxide;
d) reacting the compound of formula 5 with an alkyl halide (R-X) in a solvent to obtain a compound of formula 6 is carried out at a temperature in the range of 70oC to 75oC, and wherein the alkyl halide is represented by R-X, wherein R is C1 to C10 alkyl group, and wherein X is halogen selected from fluorine, chlorine, bromine, iodine and combinations thereof, preferably methyl iodide/iodomethane;
e) reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7 is carried out at -5oC to ambient temperature for about 16 hrs, and wherein the reducing agent is selected from Pd/C, Pt/C, Raney Ni, LiAlH4, NaBH4, preferably LiAlH4;
f) reacting the compound of formula 7 with an alkyl halide in presence of a base in a solvent to obtain compound of formula 8 is carried out at a 0oC to ambient temperature 2 hrs to 3 hrs in presence of sodium hydride, and wherein alkyl halide used is iodmethane-d3;
g) treating the compound of formula 8 with a deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9 is carried out at 0oC to ambient temperature for a period in the range of 2 hrs to 4 hrs , and wherein deuterated acid halide is selected from ethanoyl chloride, propanoyl chloride, butanoyl chloride, benzoyl chloride, preferably deuterated propanoyl chloride (propionyl chloride-d3), and wherein the base is triethylamine;
h) debenzylating the compound of formula 9 in presence of a reagent and a hydrogen source in a solvent to obtain a compound of formula 10 is carried out at a temperature in the range of 45oC to 55oC for a period in the range of 1.5 hrs to 3 hrs at 60 psi pressure, and wherein the regent is selected from Pd/C, Pt/C, Raney Nickel; preferably palladium hydroxide (Pd (OH)2); and
i) contacting the compound of formula 10 with a compound of formula 11 in presence of a base, an alkyl halide in a solvent to obtain compound of formula I is carried out in presence of triethylamine, anhydrous potassium carbonate and potassium iodide at reflux temperature for about 6hrs.
8. The process as claimed in claim 6, wherein solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK) dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), toluene, dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, 2-butanol, ethane-l,2-diol and mixtures thereof.
9. The process as claimed in claim 6, wherein sufentanil-D8 exhibits clearance values of 292.33 µL/min/mg protein (mouse), 168.99 µL/min/mg protein (rat), and 208.36 µL/min/mg protein (human).

Dated this: September 11, 2025

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

ABSTRACT

“DEUTERATED SUFENTANIL AND PROCESS FOR SYNTHESIS THEREOF”

The present invention provides analogue of Sufentanil of compound of formula I and process for synthesising therefore. The compound of formula I is represented by

Wherein R1, R2, R3, R4 are independently selected from hydrogen (H), deuterium (D), deuterated C1-C5 alkyl group and aryl group and/or substituted aryl group.

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

Wherein R1, R2, R3, R4 are independently selected from hydrogen (H), deuterium (D), deuterated C1-C5 alkyl group and aryl group and/or substituted aryl group.
2. The compound of formula I as claimed in claim 1, wherein R1 and R2 are selected from Deuterium (D) and deuterated C1 to C5 group.
3. The compound of formula I as claimed in claim 1, wherein deuterated C1 to C5 alkyl group is selected from CD3, C2D5, C3D7, C4D9 group.
4. The compound of formula I as claimed in claim 1, wherein R1 or R2 is CD3; and wherein R3 or R4 is Deuterium (D).
5. The compound of formula I as claimed in claim 1 is Sufentanil-D8

6. A process for synthesising compound of formula I, the process comprising:
a) contacting a compound of formula 1 with a compound of formula 2, alkyl cyanide in presence of an acid in a solvent to obtain a compound of formula 3;
b) treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4;
c) refluxing the compound of formula 4 with a base (KOH) in a solvent (diol) to obtain a compound of formula 5;
d) reacting the compound of formula 5 with alkyl halide (R-X) in a solvent to obtain a compound of formula 6;
e) reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7;
f) reacting the compound of formula 7 with alkyl halide in presence of a base in a solvent to obtain compound of formula 8;
g) treating the compound of formula 8 with deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9;
h) debenzylating the compound of formula 9 in presence of a reagent and hydrogen in a solvent to obtain a compound of formula 10;
i) contacting the compound of formula 10 with a compound of formula 11 in presence of a base, alkyl halide in a solvent to obtain compound of formula I; wherein the compound of formula I obtained having yield in the range of 95% to 99.99% and purity in the range of 98% to 99.99% (by HPLC);
wherein the compounds of formulae 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 & 11 for use as a starting material or as an intermediate in the synthesis of a compound of formula (I) represented herein

7. The process as claimed in claim 6, wherein
a) contacting a compound of formula 1 with a compound of formula 2, a cyanide compound in presence of an acid in a solvent to obtain a compound of formula 3 is carried out at a temperature in the range of 5oC to 50oC for a period in the range of 16 hrs to 19 hrs; wherein cyanide compound is selected from hydrogen cyanide, calcium cyanide, potassium cyanide, and sodium cyanide and combinations thereof, preferably potassium cyanide; wherein acid used is selected from glacial 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, cinnamic acid, mandelic acid, methanesulfonic acid, preferably glacial acetic acid;
b) treating the compound of formula 3 with an acid in a solvent to obtain a compound of formula 4 is carried out at a temperature in the range of 0oC to an ambient temperature for a period in the range of 16 hrs to 18 hrs; wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and/or combinations thereof, preferably 95% sulfuric acid;
c) refluxing the compound of formula 4 with a base in a solvent to obtain a compound of formula 5 is carried out at 180oC to 210oC for a period in the range of 22 hrs to 26 hrs, preferably 24 hrs; wherein the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonia, sodium hydride and any mixtures thereof, preferably potassium hydroxide;
d) reacting the compound of formula 5 with an alkyl halide (R-X) in a solvent to obtain a compound of formula 6 is carried out at a temperature in the range of 70oC to 75oC, and wherein the alkyl halide is represented by R-X, wherein R is C1 to C10 alkyl group, and wherein X is halogen selected from fluorine, chlorine, bromine, iodine and combinations thereof, preferably methyl iodide/iodomethane;
e) reducing the compound of formula 6 with a reducing agent in a solvent to obtain a compound of formula 7 is carried out at -5oC to ambient temperature for about 16 hrs, and wherein the reducing agent is selected from Pd/C, Pt/C, Raney Ni, LiAlH4, NaBH4, preferably LiAlH4;
f) reacting the compound of formula 7 with an alkyl halide in presence of a base in a solvent to obtain compound of formula 8 is carried out at a 0oC to ambient temperature 2 hrs to 3 hrs in presence of sodium hydride, and wherein alkyl halide used is iodmethane-d3;
g) treating the compound of formula 8 with a deuterated acid halide in presence of a base in a solvent to obtain a compound of formula 9 is carried out at 0oC to ambient temperature for a period in the range of 2 hrs to 4 hrs , and wherein deuterated acid halide is selected from ethanoyl chloride, propanoyl chloride, butanoyl chloride, benzoyl chloride, preferably deuterated propanoyl chloride (propionyl chloride-d3), and wherein the base is triethylamine;
h) debenzylating the compound of formula 9 in presence of a reagent and a hydrogen source in a solvent to obtain a compound of formula 10 is carried out at a temperature in the range of 45oC to 55oC for a period in the range of 1.5 hrs to 3 hrs at 60 psi pressure, and wherein the regent is selected from Pd/C, Pt/C, Raney Nickel; preferably palladium hydroxide (Pd (OH)2); and
i) contacting the compound of formula 10 with a compound of formula 11 in presence of a base, an alkyl halide in a solvent to obtain compound of formula I is carried out in presence of triethylamine, anhydrous potassium carbonate and potassium iodide at reflux temperature for about 6hrs.
8. The process as claimed in claim 6, wherein solvent is selected from water, acetone, methyl ethyl ketone, methylisobutylketone (MIBK) dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), toluene, dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, 2-butanol, ethane-l,2-diol and mixtures thereof.
9. The process as claimed in claim 6, wherein sufentanil-D8 exhibits clearance values of 292.33 µL/min/mg protein (mouse), 168.99 µL/min/mg protein (rat), and 208.36 µL/min/mg protein (human).