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
“A METHOD FOR CONTINUOUS PRODUCTION OF DEUTERATED BENZENE (BENZENE-D6)”
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 an economically viable method for continuous production of compound of formula (I). Most particularly, it relates to method for continuous production of deuterated benzene (benzene-d6). The synthesized deuterated benzene-d6 has wide applications in pharmaceuticals and chemical industries.
BACKGROUND OF INVENTION
In recent years, the H/D exchange reaction has attracted much attention in fundamental research on isotopically-labelled compounds, C-H bond activation or catalytic mechanism research, and reaction pathways. However, few studies were conducted in the field of H/D exchange reactions in the 1960s and 1970s. By the 1990s, people were increasingly interested in catalytic C-H bond activation, and the demand for isotopically-labelled compounds as internal standards for mass spectrometry began to increase.
Deuterium is a hydrogen isotope that exists in nature, which means that common drugs contain trace amounts of deuterated isotopes. Deuterium is non-toxic, non-radioactive, and safe for the human body. In addition, the C-D bond is more stable than the C-H bond (6-9 times). In other words, after hydrogen is replaced by deuterium, it can block the metabolic site and extend the half-life of the drug without affecting the pharmacological activity (the size difference between H and D is small).
Deuterated benzene, also known as benzene-d6, is a chemical compound in which all the hydrogen atoms of benzene (C₆H₆) are replaced with deuterium (D), a stable isotope of hydrogen. This results in the molecular formula C₆D₆. Deuterium has a nucleus containing one proton and one neutron, making it twice as heavy as ordinary hydrogen.
Deuterated benzene-d6 (C6D6) is a very important special deuterated solvent and an important intermediate for the synthesis of some fully deuterated compounds. It can be used in laboratory research and development processes and chemical and pharmaceutical research and development processes, and is mainly used as an analytical reagent.
The exchange with deuterium oxide catalyzed by platinum black yields compounds completely deuterated in the ring. The method is therefore inapplicable for the preparation of compounds containing deuterium in specific positions. Several methods of obtaining such compounds have, however, been investigated in the past.
Gardiner et al. (“Electrophilic RhI catalysts for arene H/D exchange in acidic media: Evidence for an electrophilic aromatic substitution mechanism”; Journal of Molecular Catalysis A: Chemical, Volume 426, Part B, January 2017, Pages 381-388) discloses deuteration of benzene, wherein said deuteration was carried out by reaction benzene with trifluoroacetic acid-d1 (DTFA) in presence of Rhodium (Rh) catalyst for 4 hrs.

Rhodium (Rh) catalysts face several challenges, including leaching during reactions, complex synthesis processes, low catalytic activity and selectivity, thermal instability, and structural changes that can affect performance. These drawbacks limit their efficiency and durability, making optimization or alternative catalysts essential for reliable applications.
Musa et al. (“New PC(sp3)P pincer complexes of platinum and palladium”; Journal of Organometallic Chemistry; Volume 699, 15 February 2012, Pages 92-95) describes H/D exchange of benzene in the presence of 2mol% of Pt catalyst in CD3CO2D, CF3CO2D, CD3OD or D2O although complete deuterium incorporation was achieved only in TFA-d.

Complexes of platinum (Pt) and palladium (Pd) have several drawbacks, including high cost, leaching during reactions, thermal instability, sensitivity to catalyst poisons, suboptimal selectivity, and environmental toxicity concerns. Additionally, their structures can degrade over time, reducing catalytic activity and stability, highlighting the need for improved or alternative catalytic systems.
Feng et al. (“Effect of Ancillary Ligands and Solvents on H/D Exchange Reactions Catalyzed by Cp*Ir Complexes”; Organometallics, 2010, 29, 2857–2867) discloses general procedure for catalytic H/D exchange experiments between C6H6 and Trifluoroacetic Acid-d. During the experiment catalyst (Cp*Ir Complexes), benzene, and trifluoroacetic acid-d were charged and the tube was sealed. The reaction mixture was heated to 1500C. Upon completion, the reaction mixture was cooled to room temperature. Aqueous K2CO3 was added slowly to quench trifluoroacetic acid-d. The resulting solution was filtered through Celite and washed with methylene chloride to obtain deuterated benzene.

Bischof et al. (“Correction: Iridium(iii) catalyzed trifluoroacetoxylation of aromatic hydrocarbons”; RSC Adv., 2014, 4, 35639–35648) discloses preparation of deuterated benzene by rapid catalytic H/D exchange between benzene and trifluoroacetic acid-d1 (DTFA) in presence of a tridentate, NNC-tb (where NNC-tb = 2-(pyridin-2-yl)benzo[h]quinoline) ligated Ir-III complex (NNC-tb)Ir(Ph)(4-MePy)(TFA) catalyst.

Trifluoroacetic acid-d (TFA-d) has notable drawbacks, including high cost and hygroscopicity, which complicate handling and storage. It can be corrosive, posing safety risks during use, and its strong acidity may lead to side reactions, affecting the selectivity of certain processes. Additionally, its volatility makes it challenging to recover and reuse, increasing waste and overall expense.
WO2023240849A1 discloses a method for preparing deuterated benzene, wherein said method was carried out by benzene with polyfluoric acid anhydride (trifluoromethanesulfonic anhydride) and a deuterium source reagent (water, deuterated methanol, deuterated ethanol, deuterated isopropanol, deuterated benzene, and deuterated acid) in a solvent under inert atmosphere.

Trifluoromethanesulfonic anhydride (Tf2O) has several drawbacks, including its high cost and sensitivity to moisture, which necessitate careful storage and handling. It is highly reactive and corrosive, posing safety risks during use, and can lead to undesired side reactions in some cases. Furthermore, its volatility and toxic nature require stringent waste disposal measures, increasing operational challenges and environmental concerns.
Furthermore, WO’849A1 discloses benzene d6 was prepared using in Example 1 process for as compound 2-d. Deuteration reaction has been carried using Co-solvents, especially for benzene deuteration, cyclohexane co-solvent was utilized. Benzene and cyclohexane have very close boiling point. This poses another issue in separation of cyclohexane from benzene as it requirs difficult fractional distillation setup.
Therefore, it is necessary to develop efficient, scalable, and sustainable preparation methods, taking into account the above issues related to the prior art context, along with challenges such as cost, limited availability, and the need for high-purity products.
The present invention provides an economically viable method for the continuous production of deuterated benzene-d6. The synthesized deuterated benzene-d6 has wide application in pharmaceuticals and chemical industries. The present invention involves the use of a catalyst such as trifluoromethanesulfonic acid-d (triflic acid-d) which is mild, inexpensive, easily recovered and recycled for the continuous production of deuterated benzene-d6 thereby reducing the production cost and making the method economically viable.

OBJECTS OF THE INVENTION
One of the objects of the present invention is to provide a continuous method for producing deuterated analogues of benzene.
Another object of the present invention is to facilitate high-purity Benzene-d6 formation in isotope labeling.
Another object of the present invention is to provide reaction selectivity and kinetic studies due to its stable and inert characteristics.
Yet another embodiment of the present invention is to involve use of is mild, inexpensive, easily recovere and recycle for the continuous production of deuterated benzene-d6.
Yet another object of the present invention is to provide sstreamlines the isolation and purification process, preserving isotopic purity of benzene-d6.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides a method for continuous production of compound of formula (I),

the method comprising:
a) contacting benzene with a catalyst to obtain a reaction mass;
b) extracting the reaction mass with a solvent to obtain first layer comprising unreacted benzene & catalyst and second layer comprising a compound of formula (I);
c) recovering unreacted benzene & catalyst and recycling in a step (a) for continuous production of compound of formula (I); and
d) repeating steps (a) to step (c) to obtain a pure compound of formula (I).
wherein R1 to R6 is independently selected from hydrogen (H), deuterium (D).

DETAILED DESCRIPTION OF THE INVENTION
In the specification different terms are used to describe the invention. The definitions of the terms are provided below.
The term ‘compound of formula (I)’, ‘Deuterated benzene (C6D6)’ or ‘benzene-d6’ used herein refers to an isotopologue of benzene (C6H6) in which the hydrogen atom (‘H’) is replaced with deuterium (heavy hydrogen) isotope (‘D’). The terms ‘compound of formula (I)’, ‘Deuterated benzene (C6D6)’, ‘benzene-d6’ can be used interchangeably throughout specification.
The term ‘reaction mass’ used herein refers to a product obtained by reacting the reactant (benzene) and reagent (catalyst) at suitable reaction conditions. The reaction mass comprising product, unreacted benzene, benzene-d6 along side products.
The term ‘catalyst’ used herein refers to an acid used to carry out reaction to form desired product. In the present invention, the catalyst used include such as but is not limited to acetic anhydride, trifluoromethanesulfonic acid (triflic acid), triflic acid-d1, DCl, DBr, D2SO4, D3PO4, CF3COOD and CH3COOD and combinations thereof.
The term ‘first layer’ used herein refers to top layer formed during the extraction process carried out to isolate product of the present invention. In the present invention, first layer comprising unreacted benzene, catalyst and/or side product.
The term ‘second layer’ used herein refers to bottom layer formed during the extraction process carried out to isolate product of the present invention. In the present invention second layer comprising compound of formula (I).
The term ‘pure compound of formula (I)’ used herein refers to pure benzene-d6 obtained by the present invention which having isotopic enrichment ranging from 95% to 99%.
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 solvent includes such as but not limit to alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and/or deuterated form of alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s). Solvent may be used deuterated form of above-mentioned solvents.
One of the embodiments of the present invention provides a method for continuous production of compound of formula (I),

the method comprising:
a) contacting benzene with a catalyst to obtain a reaction mass;
b) extracting the reaction mass with a solvent to obtain first layer comprising unreacted benzene & catalyst and second layer comprising a compound of formula (I);
c) recovering unreacted benzene & catalyst and recycling in a step (a) for continuous production of compound of formula (I); and
d) repeating steps (a) to step (c) to obtain a pure compound of formula (I); wherein R1 to R6 is independently selected from hydrogen (H), deuterium (D).
In another embodiment of the present invention there is provided a method for for continuous production of compound of formula (I), wherein contacting benzene with a catalyst is carried out at a temperature ranging from 0oC to 100oC for a period ranging from 8 hrs to 16 hrs.
In most preferred embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein contacting benzene with a catalyst is carried out at a temperature ranging from 10oC to 60oC for a period ranging from 10 hrs to 12 hrs.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein the catalyst is an acid selected from acetic anhydride, trifluoromethanesulfonic acid (triflic acid), triflic acid-d1, DCl, DBr, D2SO4, D3PO4, CF3COOD and CH3COOD and combinations thereof.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein the catalyst is triflic acid-d1.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein the catalyst is used in a volume ranging from 1 volume (vol.) to 6 volume to the benzene.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein the solvent can be polar or nonpolar solvent. The said solvent may be used in anhydrous form. The solvent includes such as but not limit to alcohols, ethers, ketones, acids, esters, acetonitrile (ACN), halogenated solvent(s) and/or deuterated form of alcohols, ethers, ketones, acids, esters, and/or deuterated halogenated solvent(s).
In another embodiment of the present invention there is provided a method for continuous production of deuterated benzene (benzne-d6), wherein solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, DMF, dimethyl sulfoxide, THF, cyclohexane, toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, and combinations thereof.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein compound of formula (I) is benzene-d6.
In another embodiment of the present invention there is provided a method for continuous production of compound of formula (I), wherein the compound of formula (I) is having isotopic enrichment ranging from 90% to 99%.
Yet another embodiment of the present invention provides a a method for continuous production of compound of formula (I), wherein schematic representation of said method is provided as follows.

Advantages of the present invention:
1. The present invention provides a continuous method for producing deuterated analogues of benzene.
2. The present invention facilitates high-purity Benzene-d6 formation in isotope labeling.
3. The present invention provides reaction selectivity and kinetic studies due to its stable and inert characteristics.
4. The present invention provides sstreamlines the isolation and purification process, preserving isotopic purity of benzene-d6.
5. The present invention provides use of mild catalyst as comparative other catalyst for producing deuterated benzene-d6.
6. The present invention involves mild catalyst result in less or without formation of side product.
7. The catalyst used in the present invention is recovered, recycled for 5-7 cycle which ultimately reduce the production cost.
8. The present invention carried out at mild reaction conditions such temperature.
The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.
Examples
1. Preparation of deuterated benzene (compound of formula (I))
Benzene taken in 1 lit reactor followed by addition of Trifluoromethanesulfonic acid-d (Triflic acid-d). The quantity of Triflic acid-d was varies from 1 vol., 3 vol. and 6 vol. The resulted mixture was stirred for 12 hours at temperature ranging from 10C to 60 deg. After completion of 12 hrs. The reaction mixture was diluted with DCM. DCM layer comprising benzene. DCM layer was concentrated. Benzene d6 was isolated. The pure Benzene-d6 obtained was having isotopic enrichment ranging from 95 to 99%.
In order to reach the desired isotopic purity, 10 repeated experiments required as direct deuteration. In order to reduce the cost, the recovered Triflic acid-d was re-used for 5-7 cycles without loss of reactivity.

We claim:
1. A method for continuous production of compound of formula (I)
, the method comprising:
a) contacting benzene with a catalyst to obtain a reaction mass;
b) extracting the reaction mass with a solvent to obtain first layer comprising unreacted benzene & catalyst; and second layer comprising a compound of formula (I);
c) recovering unreacted benzene & catalyst and recycling in a step (a) for continuous production of compound of formula (I); and
d) repeating steps (a) to step (c) to obtain a pure compound of formula (I).
wherein R1 to R6 is independently selected from hydrogen (H), deuterium (D).
2. The method as claimed in claim 1, wherein contacting benzene with a catalyst is carried out at a temperature ranging from 0oC to 100oC for a period ranging from 8 hrs to 16 hrs.
3. The method as claimed in claim 2, wherein contacting benzene with a catalyst is carried out at a temperature ranging from 10oC to 60oC for a period ranging from 10 hrs to 12 hrs.
4. The method as claimed in claim 1, wherein the catalyst is an acid selected from acetic anhydride, trifluoromethanesulfonic acid (triflic acid), triflic acid-d1, DCl, DBr, D2SO4, D3PO4, CF3COOD and CH3COOD and combinations thereof.
5. The method as claimed in claim 1, wherein the catalyst is triflic acid-d1.
6. The method as claimed in claim 1, wherein the catalyst is used in a volume ranging from 1 volume (vol.) to 6 volume to the benzene.
7. The method as claimed in claim 1, wherein solvent is selected from solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, DMF, dimethyl sulfoxide, THF, cyclohexane, toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, and combinations thereof; preferably ethanol.
8. The method as claimed in claim 1, wherein compound of formula (I) is benzene-d6.
9. The method as claimed in claim 1, wherein the compound of formula (I) is having isotopic enrichment ranging from 90% to 99%.

Dated this: 23rd day of November, 2024

Vijaykumar Shivpuje
IN/PA-3417
Agent for the Applicant
To
The Controller of Patents
The Patent Office, Mumbai

ABSTRACT

“A METHOD FOR CONTINUOUS PRODUCTION OF DEUTERATED BENZENE (BENZENE-D6)”

The present invention provides a method for continuous production of deuterated benzene (benzene-d6). The method comprising: (a) contacting benzene with a catalyst at a temperature ranging from 0oC to 100oC for a period ranging from 8 hrs to 16 hrs. to obtain a reaction mass; (b) extracting the reaction mass with a solvent to obtain first layer comprising unreacted benzene & catalyst and second layer comprising deuterated benzene (benzene-d6); (c) recovering unreacted benzene & catalyst and recycling in a step (a) for continuous production of deuterated benzene; and (d) repeating steps (a) to step (c) to obtain a pure deuterated benzene, wherein the deuterated benzene obtained is having isotopic enrichment ranging from 90% to 99%.

, Claims:We claim:
1. A method for continuous production of compound of formula (I)
, the method comprising:
a) contacting benzene with a catalyst to obtain a reaction mass;
b) extracting the reaction mass with a solvent to obtain first layer comprising unreacted benzene & catalyst; and second layer comprising a compound of formula (I);
c) recovering unreacted benzene & catalyst and recycling in a step (a) for continuous production of compound of formula (I); and
d) repeating steps (a) to step (c) to obtain a pure compound of formula (I).
wherein R1 to R6 is independently selected from hydrogen (H), deuterium (D).
2. The method as claimed in claim 1, wherein contacting benzene with a catalyst is carried out at a temperature ranging from 0oC to 100oC for a period ranging from 8 hrs to 16 hrs.
3. The method as claimed in claim 2, wherein contacting benzene with a catalyst is carried out at a temperature ranging from 10oC to 60oC for a period ranging from 10 hrs to 12 hrs.
4. The method as claimed in claim 1, wherein the catalyst is an acid selected from acetic anhydride, trifluoromethanesulfonic acid (triflic acid), triflic acid-d1, DCl, DBr, D2SO4, D3PO4, CF3COOD and CH3COOD and combinations thereof.
5. The method as claimed in claim 1, wherein the catalyst is triflic acid-d1.
6. The method as claimed in claim 1, wherein the catalyst is used in a volume ranging from 1 volume (vol.) to 6 volume to the benzene.
7. The method as claimed in claim 1, wherein solvent is selected from solvent is selected from water, methanol, ethanol, propyl alcohol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, n-amyl alcohol, isoamyl alcohol, ethylene glycol, propane diols, glycerine, DMF, dimethyl sulfoxide, THF, cyclohexane, toluene, acetonitrile, dioxane, 1-methyl-2-pyrrolidinone, dichloromethane, chloroform, ether, and combinations thereof; preferably ethanol.
8. The method as claimed in claim 1, wherein compound of formula (I) is benzene-d6.
9. The method as claimed in claim 1, wherein the compound of formula (I) is having isotopic enrichment ranging from 90% to 99%.