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 PROCESS FOR MANUFACTURING 5-NITRO-2, 4-DI TERTIARY BUTYL METHYL CARBONATES-D9
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 a process for manufacturing compound of formula I. Most particularly, it relates to deuterated analogue of compound of formula I. Said compound of formula I is used in the synthesis of deuterated Ivacaftor.

BACKGROUND OF INVENTION
Ivacaftor (brand name: Kalydeco, also known as VX-770) is an FDA-approved medication developed by Vertex Pharmaceuticals for treating cystic fibrosis (CF), specifically in patients with gating mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. Ivacaftor is represented by following formula

Approved on January 31, 2012, it was the first drug to target the underlying cause of CF by enhancing the function of defective CFTR proteins, thereby improving chloride ion transport across cell membranes. Ivacaftor is an aromatic amide belonging to the quinolone and phenol classes, acting as a CFTR potentiator and an orphan drug. It works as a chloride channel activator and inhibits Cytochrome P450 (CYP) 2C9 and 3A as well as P-Glycoprotein. By addressing the genetic defect rather than just symptoms, Ivacaftor improves lung function (FEV1), reduces mucus buildup, and enhances the quality of life for CF patients. It marked a significant advancement in CF management, shifting the focus from symptom control to targeting the root cause of the disease.
Deuterated compounds are increasingly utilized in pharmaceutical products due to their unique ability to enhance the properties of existing drugs. Replacing hydrogen atoms with deuterium, a heavier isotope of hydrogen, introduces subtle but impactful changes to a compound's metabolic, pharmacokinetic, and pharmacodynamic properties.
Deuterated Ivacaftor is a modified version of the cystic fibrosis drug Ivacaftor, where specific hydrogen atoms are replaced with deuterium, a stable isotope of hydrogen. This substitution enhances the drug's metabolic, pharmacokinetic, and pharmacodynamic properties while retaining its original therapeutic activity as a CFTR potentiator.
Cystic fibrosis patients benefit from therapies targeting the root cause of the disease, and deuterated Ivacaftor represents an advancement by improving the pharmacological profile of a proven CFTR potentiator. Its potential advantages in terms of efficacy, safety, and convenience make it an attractive option for future therapeutic development.
Therefore, there is a need to develop deuterated analogous of key starting material or intermediate of Ivacaftor that can be used in the synthesis of Deuterated Ivacaftor.
The present invention provides a process for manufacturing deuterated intermediate or key starting material that is used in the synthesis of deuterated Ivacaftor. Said intermediate synthesis is carried out using mild reagent, requires less or reduced reaction time, with maximum yield, and purity in the range of 98% to 99.5%.

OBJECTS OF THE INVENTION
Main object of the invention is to provide a process for manufacturing of compound of formula I.
Another object of the invention is to provide characterisation of manufactured compound of formula I.
Another object of the present invention is to provide the compound of formula I as intermediate compound in the synthesis of Deuterated Ivacaftor.
Yet another object of the invention is to offer numerous advantages that significantly enhance efficiency, quality, and overall productivity.
Yet another object of the present invention is to provide highly selective, leading to the production of compounds with precise isotope placement and minimal impurities.
Yet still another object of the present invention is to utilise appropriate solvents and catalysts that are essential for efficient reaction progress and product yield.
Yet still another object of the present invention is to design to be eco-friendly, reducing waste and energy consumption, which not only benefits the environment but also lowers costs.

SUMMARY OF THE INVENTION
One of the aspects of the present invention provides a process for manufacturing compound of formula I,

the process comprising:
a) alkylating a compound of formula 1

in presence of an acid in a solvent to obtain an intermediate compound comprising compound of formula 2a, formula 2b and formula 2c.

b) reacting the intermediate compound with a metal halide in a solvent to obtain a compound of formula 2a;

c) protecting the compound of formula 2a with a suitable O-protecting group in presence of a base in a solvent to obtain a compound of formula 3;

d) contacting the compound of formula 3 with Grignard reagent in a solvent to obtain a compound of formula 4;

e) reacting the compound of formula 4 with halogenated ester in presence of a base in a solvent to obtain a compound of formula 5;

f) nitrating the compound of formula 5 in presence of nitrating mixture in a solvent to obtain a compound of formula I;
wherein the compound of formula I is obtained with yield in the range of 60% to 99% and purity in the range of 98% to 99.5%.

DETAILED DESCRIPTION OF THE INVENTION
In the specification different terms are used to describe the invention. The definitions of terms are provided below.
The term ‘compound of formula I’ or ‘formula I’ used herein refers to deuterated analogue of 5-nitro-2,4-di tertiary butyl methyl carbonates. In the present invention the compound of formula I is 5-nitro-2,4-di tertiary butyl methyl carbonates-d9. The terms ‘compound of formula I’, ‘formula I’ can be used interchangeably in the specification.
The term ‘intermediate compound’ used herein refers to product obtained by reacting compound of formula 1 with desired agent at suitable reaction conditions which contain one or more derivatives formed in different ratio which may be side product which can be converted into targeted compound. In the present invention intermediate compound comprises compound of formula 2a, formula 2b, formula 2c.
The term ‘nitrating mixture’ used herein refers to mixture of metal nitrate and metal halide that can be used to carry out nitration reaction to introduce NO2 at specific position of targeted moiety.
‘D’ and ‘d’ both refer to deuterium. ‘D’ and ‘d’ can be used interchangeably in the specification.
The term ‘halogenated ester’ used herein refers to an organic compound with the formula RCHXCO2R', where R and R' are organic substituents and X is a halide, usually chloride or bromide.
The term ‘solvent’ used herein refers to a substance that can dissolve another substrate, 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 hydrous and/or anhydrous form. The solvent includes such as but are 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).
One of the embodiments of the present invention provides a process for manufacturing compound of formula I,

the method comprising:
a) alkylating a compound of formula 1

in presence of an acid in a solvent to obtain an intermediate compound comprising compound of formula 2a, formula 2b and formula 2c.

b) reacting the intermediate compound with a metal halide in a solvent to obtain a compound of formula 2a;

c) protecting the compound of formula 2a with a suitable O-protecting group in presence of a base in a solvent to obtain a compound of formula 3;

d) contacting the compound of formula 3 with Grignard reagent in a solvent to obtain a compound of formula 4;

e) reacting the compound of formula 4 with halogenated ester in presence of a base in a solvent to obtain a compound of formula 5;

f) nitrating the compound of formula 5 in presence of nitrating mixture in a solvent to obtain a compound of formula I;
wherein the compound of formula I is obtained with yield in the range of 60% to 99% and purity in the range of 98% to 99.5%.
Another embodiment of the present invention provides a process for manufacturing compound of formula I, wherein the intermediate compound comprising compound of formula 2a, formula 2b and formula 2c is obtained by alkylating a compound of formula 1

in presence of an acid in a solvent is carried out at a temperature in the range of 0oC to room temperature (RT) for a time period in the range of 5min to 30min.
In an embodiment of the present invention, the compound of formula 1 is Methyl Saliyate.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein the alkylating agent is selected from tertiary butyl alcohol, tert-butyl chloride, tert-butyl bromide, tert-butyl hydrogen sulfate, tert-butyl tosylate and combinations thereof.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid and combinations thereof.
In an embodiment, acid is sulfuric acid.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein the compound of formula 2a is obtained by reacting the intermediate compound with a metal halide in a solvent is carried out at a temperature in the range of 15oC to 45oC for a time period in the range of 15 mins to 150 mins.
In an embodiment of the present invention, the compound of formula 2a is methyl 5-(tert-butyl)-2-hydroxybenzoate.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein metal halide is selected from aluminum chloride, iron chloride, zinc chloride, and antimony pentachloride, aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride and combinations thereof.
In an embodiment of the present invention, metal halide is aluminum chloride.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein the compound of formula 3 is obtained by protecting the compound of formula 2a with a suitable O-protecting group in presence of a base in a solvent at room temperature (~20oC to 40oC) for a time period in the range of 15min to 150mins.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein suitable O-protecting group is selected from trimethylsilyl chloride (TMS-Cl), tert-butyl dimethylsilyl (TBS or TBDMS) chloride, benzyl chloride (BnCl), benzyl bromide (BnBr), methoxymethyl ether (MOM), tetrahydropyranyl ether (THP), acetic anhydride (Ac₂O), propionic anhydride (Pr₂O), benzoic anhydride (Bz₂O), tert-butyloxycarbonyl anhydride (Boc₂O), succinic anhydride, phthalic anhydride and combinations thereof.
In an embodiment of the present invention, suitable O-protecting group is tert-butyloxycarbonyl anhydride (Boc₂O).
In an embodiment of the present invention, the compound of formula 3 is methyl 2-((tert-butoxycarbonyl) oxy)-5-(tert-butyl) benzoate.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein a compound of formula 4 is obtained by contacting the compound of formula 3 with Grignard reagent in a solvent at a temperature in the range of 15oC to 25oC for a period in the range of 30min to 15 hrs; preferably 2 hrs to 5 hrs.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein Grignard reagent is deuterated methyl magnesium iodide (CD3IMg).
In an embodiment of the present invention, the compound of formula 4 is 2,4-di-tert-butylphenol-D9.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein the compound of formula 5 is obtained by reacting the compound of formula 4 with halogenated ester in presence of a base in a solvent at a temperature in the range of 0oC to room temperature (RT) for a period in the range of 15 min to 150mins.
In yet another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein halogenated ester is selected from ethyl chloroacetate, methyl bromoacetate, Methylchlorofomate, ethyl fluoroacetate, methyl iodoacetate, ethyl 2-chloropropanoate, ethyl 2-bromopropanoate, ethyl trichloroacetate, methyl penta-fluoropropionate and combinations thereof.
In an embodiment of the present invention, the compound of formula 5 is 2,4-di-tert-butylphenyl methyl carbonate-D9.
In another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein compound of formula I is obtained by nitrating the compound of formula 5 in presence of nitrating mixture in a solvent at a temperature in the range of 0oC to -25oC for a period in the range of 15min to 4 hrs.
In yet another embodiment of the present invention there is provided a process for manufacturing compound of formula I, wherein nitrating mixture comprises metal nitrate and metal halide; wherein metal nitrate is selected from sodium nitrate, potassium nitrate, lithium nitrate, rubidium nitrate, cesium nitrate and combinations thereof; and wherein metal salt is selected from aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride and combinations thereof.
In an embodiment of the present invention, the compound of formula I is 5-nitro-2,4-di tertiary butyl methyl carbonates-D9.
The following examples are presented to further illustrate specific embodiments of the method of this invention. Said examples are for the purpose of illustration only and are not intended as a limitation in any manner on the generally broad scope of this invention.
Examples:
1. Synthesis of compound of formula 2a, formula 2b, formula 2c from compound of formula 1:

Raw material:
S. NO CHEMICAL WEIGHT MOL. Wt. MOLE EQUIVALENTS
1 Methyl salicylate 100 gm 152. 1 0.6574 1
2 Tert. butanol 146 gm 74.1 1.6722 3.0
3 H2SO4 193 ml 98 1.9723 3
4 AlCl3 131.4g 133.34 0.9861 1.5
Compound of formula 1 was charged at RT into clean and dry one litre round bottom flask (RBF) equipped with N2 gas. Tert. Butanol was added dropwise in the above RBF at RT and stirred for 10min. Then reaction mixture was maintained at 0oC. Thereafter conc. H2SO4 was added drop-wise at 0oC and stirred for 15min. Reaction was monitored by TLC. After completion of reaction, the reaction mass was quenched by ice cold water then added hexane in same flask. Organic and aqueous layers obtained were separated. Aqueous layer was extracted with hexane (2 times). Organic layer was distilled out on rota vapor. Crude product obtained was co-distilled with IPA.
2. Conversion of compound of formula 2b, formula 2c into compound of formula 2a:
DCM was charged in a clean & dry one litre RBF and cooled to 15oC to 25ºC. Then aluminum chloride was added in the same RBF and stirred for 30min at 15oC to 25ºC. After 30min, crude product obtained from example 1 was charged into reaction mixture drop wise at 15oC to 25ºC and maintained at the same temperature. After addition completed, reaction mixture was refluxed at 40ºC for 2hs. TLC was taken. After completion of reaction, reaction mass was allowed to settle at RT. Reaction mass was quenched with 6N HCl solution and stirred for 10min & then separated the layer. The aqueous layer was extracted with DCM (2 times) and washed the organic layer with water till pH 5 to 6 was obtained. The organic layer was dried over on sodium sulphate and stirred for 2 hrs. Organic layer was distilled out on rota vapour. Crude compound was obtained.
3. Purification of compound of formula 2a (Methyl-5-tert-butyl 2-Hydroxybenzoate):
Crude compound obtained from example 2 was mixed with hexane (~ 2 V-100ml). The reaction mixture was cooled to -40oC to -45ºC and stirred for 30 min and seeded. The obtained reaction mass was filtered. Solid obtained was washed with chilled hexane (-40oC) (50ml). Solid was sucked well and unloaded under vacuums at 35oC. Yield: 55 gm. (0.55% w/w); Purity: 99%.
4. Synthesis of compound of formula 3 from compound of formula 2a:

Raw material:
S. No. Raw Materials Qty.
(gm /ml) Mol. Wt. Moles Mol Ratio /
Vol Ratio
1. Methyl-5-tert-butyl 2-Hydroxybenzoate (compound of formula 2a) 100gm 208.26 1.4801 1.0
2. 4-Dimethylaminopyridine (DMAP) 0.29gm 122.2 0.0023 0.0050
3. BOC Anhydride 125.75gm 218.25 0.5762 1.2
4. Ammonium Chloride 30.75gm 53.4 0.5762 1.20
5. DCM 1000ml - - 10 V
6. Water 270ml - - 2.7V
The compound of formula 2a obtained from example 3 (100g, 1eq) was charged in a neat and clean 5 litre RBF at RT. DCM (800ml,8vol) was added to dissolve the compound of formula 2a at RT. DMAP (290 mg,.0050eq) was charged in to the reaction mixture. The reaction mixture was stirred for 15 mins at RT. The BOC anhydride (125.75g,1.2 eq) was dissolved with DCM (200ml, 2 eq) and added drop by drop to the reaction mixture and stirred for 120mins at RT. After completion of reaction, rection mixture was quenched by using ammonium chloride solution (Ammonium Chloride-30.75g, water -270ml) by adding drop by drop. Organic layer was separated and washed with water (2x400ml) then washed with brine solution (500ML). Organic layer was distilled off to get the product then co-distilled with acetone. Compound of formula 3 was obtained.
Qty.:145 gm; Yield: 94.5%; Appearance: white solid.

5. Compound of formula 4 from compound of formula 3:

Raw material:
S. No. Raw Materials Qty.
(g /ml) Mol. Wt. Moles Mol. Ratio /
Vol. Ratio
1. Compound of formula 3 200g 308 0.6493 1
2. CD3I 437g 144.9 3.0194 4.65
3. Mg (activated) 73.3g 24.30 3.0194 4.65
4. Di butyl ether (DBE) 1000ml - - 5V
5. THF (Lot-1) 1500ml - - 7.5V
6. THF for S No.1 380ml+36ml - - 1.9+0.18V
7. Tert-Butanol 91.4g 74.12 1.2337 1.9
8. Di-butyl ether 186ml - - 0.93
9. 6N HCl 1070ml - - 5.35V

GRIGNARD GENERATION:
Mg (73.3g,4.65eq) and iodine (~20balls) were charged into a clean and dry 5 litre 3 neck RBF and heated to activate that Mg-I. Dibutyl ether (400ml,2 vol) was added in the same RBF. CD3I (437g, 4.65eq) was dissolved in DBE (400ml,2vol) then added to above flask drop by drop at 200oC. Milky turning was observed. Reaction mass was stirred about 30mins. Finaly DBE (200ml,1 vol) was added and stirred for overnight.
ALKYLATION:
THF (1500ml. 7.5 vol) was charged in another RBF. Then CD3IMg was added drop by drop (Temp-15-200oC) for 30mins. The compound of formula 3 (200g,1eq) was dissolved in THF (380ml,1.9v) was added to above flask dropwise at 250oC in NMT 90 min. After addition reaction mixture was stirred for 3 hrs and checked TLC. After completion of reaction, reaction mass was maintained at 10-15oC then tert- butanol (91.4g, 1.9eq) in DBE (186ML,0.93v) was added. Finally, 6N HCl (1070ml) was added to the said reaction mass at 5oC to 10oC and stirred for 30mins. Organic layer was washed with water then sodium thio sulphate. Organic layer was extracted with water and brine solution. Organic phase was collected and distilled off. Crude product was purified by downward distillation to get the pure product (formula 4).
Wt.: 120gm; Yield: 85.7%; Appearance: Brownish Red liquid

6. Synthesis of compound of formula 5 from compound of formula 4:

Raw material:
No. Raw Materials Qty.
(gm/ vol) Mol. Wt. Moles Mol. Ratio/
Vol. Ratio
1. 2,4 Di tert butyl phenol-D9 (compound of formula 4) 120g 216 0.5555 1
2. Methyl Chloro Formate 81.8g 94.5 0.8665 1.56
3. TEA 112.4g 101.2 1.111 2.0
4. DMAP 0.330g 122.2 0.0027 0.005
5. DCM 636ml - - 5.3V
6. Heptane 960ml - - 8V

The compound of formula 4 (120g,1eq) obtained from example 5 was charged and dissolved with DCM (636ml,5.3vol) and heptane (960ml, 8vol) and stirred for 5 minutes. Then DMAP (0.33g,0.005eq) was added under stirring at 0oC. Thereafter, TEA (112.4g,2eq) was added drop by drop at 0oCthen stirred for 30 mins. Finally, Methyl Chloro Formate (81.8g,1.56eq) was added and raised the temperature to RT and stirred at RT for 2 hours. After completion of reaction, reaction mixture was quenched with 1N HCl (360ml) drop by drop at 0oC and stirred for 15 minutes. Organic layer was separated and washed with water (2x500ml) thereafter washed with brine solution. Organic layer was distilled out. Compound of formula 5 was obtained.
Wt.: 144gm; Yield: 90%; Appearance: orange to white color liquid.

7. Synthesis of compound of formula I from compound of formula 5:

Raw Materials:
S.NO. Raw Materials Qty.
(gm /vol) Mol. Wt. Moles Mol. Ratio/
Vol Ratio
1. 2,4 Di tert butyl methyl carbonate d9 (formula 5) 125g 273 0.4578 1
2. AlCl3 195g 133.24 1.4650 3.2
3. NaNO3 78g 84.99 0.9156 2.0
4. DCM 1125 ml - - 9 V
5. Methanol 1000 ml - - 8 V
6. HCL 120 ml - - 1 T

In a clean and dry 5 litre 3 neck RBF with stop key, DCM (1000ml,8 vol) was charged and cooled at -150C. AlCl3 (195g, 3.2 eq) and NaNO3 (50.5g,1.3 eq) were charged and stirred at to -5oC to -10oC for about 3.5 hours. Then the compound of formula 5 obtained from example 6 (125g, 1eq) was dissolved with DCM (125ml, 1 vol) and added to above flask at -20oC. Reaction mixture was maintained at -15oC to -20oC for 45 mins. After completion of reaction, reaction mass was quenched with 2N HCl (HCl-130ml, H2O -670ml) at -5oC to 10oC drop by drop. After addition reaction mass was stirred for 30 minutes at -5oC. Then organic layer was collected and washed with brine solution (2x500ml). DCM was removed by downward distillation. Crude compound of formula I was obtained.

8. Purification of compound of formula I:
Crude compound obtained from example 7 was dissolved MeOH (4v to 5 V) and refluxed for 30mins. Then reaction mass was stirred at RT for 8 hours. Finally, reaction mass was cooled to 0oC for 1 hour. Solid was filtered and washed with chilled MeOH. Pure compound of formula I was obtained. Wt.:93gm Yield: 64%; Appearance: white solid; Purity: 98%.
 
We Claim:
1. A process for manufacturing compound of formula I,

the method comprising:
a) alkylating a compound of formula 1

in presence of an acid in a solvent to obtain an intermediate compound comprising compound of formula 2a, formula 2b and formula 2c.

b) reacting the intermediate compound with a metal halide in a solvent to obtain a compound of formula 2a;

c) protecting the compound of formula 2a with a suitable O-protecting group in presence of a base in a solvent to obtain a compound of formula 3;

d) contacting the compound of formula 3 with Grignard reagent in a solvent to obtain a compound of formula 4;

e) reacting the compound of formula 4 with halogenated ester in presence of a base in a solvent to obtain a compound of formula 5;

wherein the compound of formula I is obtained with yield in the range of 60% to 99% and purity in the range of 98% to 99.5%.
2. The process as claimed in claim 1, wherein the alkylating agent is selected from tertiary butyl alcohol, tert-butyl chloride, tert-butyl bromide, tert-butyl hydrogen sulfate, tert-butyl tosylate and combinations thereof.
3. The process as claimed in claim 1, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid and combinations thereof.
4. The process as claimed in claim 1, wherein metal halide is selected from aluminum chloride, iron chloride, zinc chloride, and antimony pentachloride, aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride.
5. The process as claimed in claim 1, wherein suitable O-protecting group is selected from trimethylsilyl chloride (TMS-Cl), tert-butyl dimethylsilyl (TBS or TBDMS) chloride, benzyl chloride (BnCl), benzyl bromide (BnBr), methoxymethyl ether (MOM), tetrahydropyranyl ether (THP), acetic anhydride (Ac₂O), propionic anhydride (Pr₂O), benzoic anhydride (Bz₂O), tert-butyloxycarbonyl anhydride (Boc₂O), succinic anhydride, phthalic anhydride and combinations thereof.
6. The process as claimed in claim 1, wherein base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, 4-Dimethylaminopyridine, isopropyl ethylamine, di-isopropyl amine, di-isopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and combinations thereof.
7. The process as claimed in claim 1, wherein solvent is selected from water, alcohol selected from methanol, ethanol, isopropanol, n-butanol, tert-butyl alcohol; acid selected from formic acid, nitromethane, acetic acid, water, ether selected from tetrahydrofuran, dimethyl ether, di-isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, Di butyl ether hydrocarbon selected from hexane, heptane, toluene, xylene; halogenated solvent selected from dichloromethane, Chloroform, carbon tetrachloride, 1,1,1-Trichloroethane and combinations thereof.
8. The process as claimed in claim 1, wherein Grignard reagent is deuterated methyl magnesium iodide (CD3IMg).
9. The process as claimed in claim 1, wherein halogenated ester is selected from ethyl chloroacetate, methyl bromoacetate, Methylchlorofomate, ethyl fluoroacetate, methyl iodoacetate, ethyl 2-chloropropanoate, ethyl 2-bromopropanoate, ethyl trichloroacetate, methyl pentafluoropropionate and combinations thereof.
10. The process as claimed in claim 1, wherein nitrating mixture comprises metal nitrate and metal halide; wherein metal nitrate is selected from sodium nitrate, potassium nitrate, lithium nitrate, rubidium nitrate, cesium nitrate and combinations thereof; and wherein metal salt is selected from aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride and combinations thereof.

Dated this: 13th January 2025

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

 
ABSTRACT

“A PROCESS FOR MANUFACTURING 5-NITRO-2, 4-DI TERTIARY BUTYL METHYL CARBONATES- D9”

The present invention provides a process for manufacturing compound of formula I. Said process is carried out by (a) a) alkylating a compound of formula 1 in presence of an acid in a solvent to obtain an intermediate compound comprising compound of formula 2a, formula 2b and formula 2c; (b) reacting the intermediate compound with a metal halide to obtain a compound of formula 2a; c) protecting the compound of formula 2a with a suitable O-protecting group in presence of a base to obtain a compound of formula 3; (d) contacting the compound of formula 3 with Grignard reagent to obtain a compound of formula 4; (e) reacting the compound of formula 4 with halogenated ester in presence of a base to obtain a compound of formula 5; f) nitrating the compound of formula 5 in presence of nitrating mixture to obtain a compound of formula I; wherein the compound of formula I is obtained with yield in the range of 60% to 99% and purity in the range of 98% to 99.5%.

, Claims:We Claim:
1. A process for manufacturing compound of formula I,

the method comprising:
a) alkylating a compound of formula 1

in presence of an acid in a solvent to obtain an intermediate compound comprising compound of formula 2a, formula 2b and formula 2c.

b) reacting the intermediate compound with a metal halide in a solvent to obtain a compound of formula 2a;

c) protecting the compound of formula 2a with a suitable O-protecting group in presence of a base in a solvent to obtain a compound of formula 3;

d) contacting the compound of formula 3 with Grignard reagent in a solvent to obtain a compound of formula 4;

e) reacting the compound of formula 4 with halogenated ester in presence of a base in a solvent to obtain a compound of formula 5;

wherein the compound of formula I is obtained with yield in the range of 60% to 99% and purity in the range of 98% to 99.5%.
2. The process as claimed in claim 1, wherein the alkylating agent is selected from tertiary butyl alcohol, tert-butyl chloride, tert-butyl bromide, tert-butyl hydrogen sulfate, tert-butyl tosylate and combinations thereof.
3. The process as claimed in claim 1, wherein acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, sulfamic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid, tartaric acid, salicylic acid, benzoic acid, glycolic acid, methane sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lactic acid, maleic acid, malonic acid, malic acid, isethionic acid, lactobionic acid, mandelic acid and combinations thereof.
4. The process as claimed in claim 1, wherein metal halide is selected from aluminum chloride, iron chloride, zinc chloride, and antimony pentachloride, aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride.
5. The process as claimed in claim 1, wherein suitable O-protecting group is selected from trimethylsilyl chloride (TMS-Cl), tert-butyl dimethylsilyl (TBS or TBDMS) chloride, benzyl chloride (BnCl), benzyl bromide (BnBr), methoxymethyl ether (MOM), tetrahydropyranyl ether (THP), acetic anhydride (Ac₂O), propionic anhydride (Pr₂O), benzoic anhydride (Bz₂O), tert-butyloxycarbonyl anhydride (Boc₂O), succinic anhydride, phthalic anhydride and combinations thereof.
6. The process as claimed in claim 1, wherein base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, 4-Dimethylaminopyridine, isopropyl ethylamine, di-isopropyl amine, di-isopropyl ethylamine, N-methyl morpholine, piperidine, pyridine and combinations thereof.
7. The process as claimed in claim 1, wherein solvent is selected from water, alcohol selected from methanol, ethanol, isopropanol, n-butanol, tert-butyl alcohol; acid selected from formic acid, nitromethane, acetic acid, water, ether selected from tetrahydrofuran, dimethyl ether, di-isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, Di butyl ether hydrocarbon selected from hexane, heptane, toluene, xylene; halogenated solvent selected from dichloromethane, Chloroform, carbon tetrachloride, 1,1,1-Trichloroethane and combinations thereof.
8. The process as claimed in claim 1, wherein Grignard reagent is deuterated methyl magnesium iodide (CD3IMg).
9. The process as claimed in claim 1, wherein halogenated ester is selected from ethyl chloroacetate, methyl bromoacetate, Methylchlorofomate, ethyl fluoroacetate, methyl iodoacetate, ethyl 2-chloropropanoate, ethyl 2-bromopropanoate, ethyl trichloroacetate, methyl pentafluoropropionate and combinations thereof.
10. The process as claimed in claim 1, wherein nitrating mixture comprises metal nitrate and metal halide; wherein metal nitrate is selected from sodium nitrate, potassium nitrate, lithium nitrate, rubidium nitrate, cesium nitrate and combinations thereof; and wherein metal salt is selected from aluminum chloride, aluminum bromide, ferric chloride, ferric bromide, zinc chloride, zirconium chloride, gallium chloride, titanium tetrachloride, antimonic chloride, antimonic bromide, bismuth chloride and combinations thereof.