Description:Technical Field

The present invention relates to a novel synthetic process of ivacaftor with the formula Ivacaftor. Particularly, the present invention relates to the synthesis of ivacaftor from 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butylphenol which can be performed in both batch as well as continuous flow chemistry synthesis. The present invention further relates to the synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butylphenol in continuous flow reactor

Background details
Ivacaftor is chemically known as N-(2, 4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquiniline-3-carboxamide, is represented structurally by a compound of formula 128.


Ivacaftor is classified as cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Ivacaftor is commercially available as Kalydeco in the form of pharmaceutical preparations. Kalydeco is indicated for the treatment of cystic fibrosis in patients with age group 6 years and older who have a G55ID mutation in the CFTR gene.
US20100267768A1 discloses the process for preparation of ivacaftor, which involves coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphine anhydride (T3P) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. Alternatively, protect amine group.
US20110230519A1 discloses the solid-state form of N-[2, 4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide.
IN374290 discloses the disclosed an improved process for the synthesis of ivacaftor starting from indole acetic acid ester which can be performed in batch as well as continuous flow synthesis.
WO2014/125506A2 discloses the process for preparation of ivacaftor and its intermediates like protected quinoline carboxylic acid and coupling a protected quinoline carboxylic acid an ester.
US11274081B2 discloses the process for the synthesis of ivacaftor starting from indole acetic acid which can be performed in batch as well as flow synthesis. Also, synthesis of Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate.
US2011064811 discloses a process for synthesis of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with 5- amino-2,4-di-(tert-butyl) phenol in presence of HBTU.
US20100267768 discloses the process of ivacaftor, which involves coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with hydroxyl protected phenol intermediates in the presence of propyl phosphonic anhydride and followed by deprotection of hydroxyl group.
WO2017/208253 discloses the synthesis of ivacaftor starting from indole acetic acid ester at lower temperature.
US9809551B2 discloses the polymorphic form APO-I of ivacaftor as well as process for the synthesis and also preparation of pure ivacaftor by using ivacaftor solvates.
Therefore, it is a need to develop mild, environmentally convenient method for the synthesis of ivacaftor and its KSMs, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butylphenol. According to the present invention, there is an improvement in the process for the synthesis of ivacaftor as well as 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butyl phenol which can be carried out both in batch and continuous flow process.
Summary of the Invention
The present invention relates to the synthesis of Ivacaftor as well as the related KSMs, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butylphenol which can be synthesized both in batch as well as using continuous flow reactor. Instead of batch process, by applying flow chemistry process, good purity & better yield of the compounds are achieved. Additional advantages of using the flow chemistry process are that the product is collected continuously without any isolation step.
In one embodiment, the present invention provides the synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid in batch as well as continuous flow reactor. By applying flow chemistry, we got good yield as well as pure compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
In one embodiment, the present invention provides the synthesis of 5-amino-2,4-di-tert-butylphenol in batch as well as continuous flow reactor. By applying flow chemistry, we got good yielded as well as pure compound of formula 5-amino-2,4-di-tert-butylphenol.
In one embodiment, the present invention provides the synthesis of Ivacaftor by using 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert-butylphenol in batch as well as continuous flow process using a flow reactor. By applying flow chemistry, we got good yield as well as pure compound of formula Ivacaftor.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING
The utility Synthesis of Ivacaftor and its Key starting materials using Flow process will now be described with the help of the accompanying drawing, in which:
Figure 1: Continuous flow process diagram for the synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Figure 2: Continuous flow process diagram for the synthesis of 5-amino-2,4-di-tert-butylphenol.
Figure 3: Continuous flow process diagram for the synthesis of Ivacaftor.
Figure 4: Continuous flow process diagram for the synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid by using Eaton’s reagent.
LIST OF REFERENCE NUMERALS
101- Aniline
102- Diethyl 2- (ethoxy methylene) malonate
103- Flow rate-2.5ml/min, Temperature- 110° C, Pressure- 7 bar
104- Diethyl 2-((phenylamino)methylene) malonate
105- Diphenyl ether
106- Flow rate-3ml/min, Temperature- 350° C, Pressure- 2 bar
107- Flow rate-10ml/min, Temperature- 120° C, Pressure- 2 bar
108- Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate
109- Hexane
110- NaOH, Water
111- 6N HCl
112- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
113- 3-aminophenol
114- Glacial acetic acid
115- Acetic anhydride
116- Flow rate-5ml/min, Temperature- 60° C, Pressure- 0 bar
117- Sat. NaHCO3
118- N-(3-hydroxyphenyl) acetamide
119- Flow rate-1ml/min, Temperature- 30° C, Pressure- 0 bar
120- T-butanol, Con.H2SO4
121- Sat. NaHCO3
122- N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide
123- Con. HCl, Ethanol
124- Flow rate-5ml/min, Temperature- 80° C, Pressure- 0 bar
125- Sat. NaHCO3
126- 5-amino-2,4-di-tert-butylphenol
127- Flow rate-0.5ml/min, Temperature- 30° C, Pressure- 0 bar
128-N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1-1,4-dihydroquinone-3-carboxamide (Ivacaftor)
129- Eaton’s reagent
130- Flow rate-5 ml/min, Temperature- 60° C, Pressure- 0 bar
DETAILED DESCRIPTION
• In one embodiment, the process for the synthesis of compound Diethyl 2-((phenylamino)methylene) malonate (104) comprising condensation of a compound of formula Aniline (101) with a compound of formula Diethyl 2- (ethoxy methylene) malonate (102).


In one embodiment, the above process may be carried out in the presence or absence of suitable solvent selected from the group consisting of polar solvents like ethanol, methanol, acetonitrile, dimethyl formamide.
In one embodiment, Condensation of compound of formula Diethyl 2-((phenylamino)methylene) malonate (104) in the presence of suitable reactant from the following, diethyl 2-(methoxy methylene) malonate, diethyl 2-(ethoxy methylene) malonate, 2-(hydroxy methylene) malonic acid, 1-ethyl 3-methyl (Z)-2-(methoxy methylene) malonate, diethyl 2-(hydroxy methylene) malonate, dimethyl 2-(ethoxy methylene) malonate, (Z)-2-(ethoxycarbonyl-3-hydroxyacrylic acid.
In one embodiment, the present invention provides a process for preparation of compound of formula Diethyl 2-((phenylamino)methylene) malonate (104), comprising:
a) Condensation between the compound of formula Aniline (101) with a compound of formula Diethyl 2- (ethoxy methylene) malonate (102): and


b) Converting the compound of formula Aniline (101) to a compound of formula Diethyl 2-((phenylamino)methylene) malonate (104)
The solution of compound of formula Diethyl 2-((phenylamino)methylene) malonate (104) without solvent may be achieved by heating the mixture at 140-150 °C. The solution is cooled to a temperature of about 25°C to about 30°C.
• In one embodiment, the process for the synthesis of compound Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) comprising cyclization of compound of formula Diethyl 2-((phenylamino)methylene) malonate (104).


• In one embodiment, the above process may be carried out in the presence of suitable cyclization agents selected from the group consisting of high boiling point solvents like diphenyl ether, dimethyl formamide and also Friedel-crafts acylation by using agents like Ferric Chloride (FeCl3), Aluminum chloride (AlCl3), Magnesium chloride (MgCl2) also carried out.
In one embodiment, the present invention provides a process for preparation compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108), comprising:
a) Cyclization between the compound of formula Diethyl 2-((phenylamino)methylene) malonate (104) to obtain a compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108); and


c) Converting the compound of formula Diethyl 2-((phenylamino)methylene) malonate (104) to compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108)
The solution of compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) without solvent may be achieved by heating the mixture of compound Diethyl 2-((phenylamino)methylene) malonate (104) in diphenyl ether (105) at 310-320°C. The solution is cooled to temperature of about 25°C to about 30°C.
• In one embodiment, the preparation of compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) followed by purification in a suitable solvent. Suitable solvent may be selected from the group consisting of hydrocarbons such as hexane, heptane, toluene, cyclohexane. Preferably, the solvent is hexane or heptane.
• In one embodiment, the compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) is mixed with hexane to obtain a slurry. The slurry is stirred and maintained for a period of about 30 min to 1 hour. Preferably, the slurry is stirred and maintained for a period of about 1 hour then filtered and dried under the vacuum for overnight to a temperature of about 25°C to about 30°C.
In one embodiment, compound Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) is hydrolyzed to obtain compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112).


Hydrolysis may be carried out using suitable base selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide: alkoxides such as sodium methoxide, tert-butoxide or a suitable acid such as hydrochloric acid, sulphuric acid and the like. Preferably, hydrolysis is carried out using is sodium hydroxide.
• In one embodiment, the compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) is reacted with sodium hydroxide in ethanol and water mixture at a temperature of about 80-100°C and neutralization from the group consisting of hydrochloric acid such as concentration hydrochloric acid, 6N hydrochloric acid, 5N hydrochloric acid, 4N hydrochloric acid, 3N hydrochloric acid, 2N hydrochloric acid and 1N hydrochloric acid.
Preferably, neutralization is carried out using 6N hydrochloric acid and pH is 1 to obtain a compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112)
• In one embodiment, the present invention provides a process for preparation a compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112), comprising:
a) Hydrolysis the compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) to obtain a compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112); and


d) Converting the compound of formula Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) to a compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112)
The compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) may be achieved by heating the mixture of compound Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (108) in ethanol and water mixture at 80-100°C. The solution is cooled to a temperature of about 25°C to about 30°C.
In one embodiment, the preparation of compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) followed by neutralization in a suitable solvent mixture of 6N hydrochloric acid.
In one embodiment, the compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) filtered and dried overnight under the vacuum to a temperature of about 25°C to about 30°C.
Scheme 1:

• In one embodiment, the present invention provides a process for the preparation of compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) wherein the process neither includes chromatographic separation nor chromatographic purification.
In one embodiment, the process for the synthesis of compound N-(3-hydroxyphenyl) acetamide (118) comprising protection of amine (-NH2) compound of formula 3-aminophenol (113).


• In one embodiment, the above process may be carried out in the presence of glacial acetic acid (114) and suitable amine protection methods like using protecting groups selected from the group consisting such as BOC anhydrides (di-tert-butyl carbonate), Benzyl, Fmoc and acylation methods like using suitable reagents like isopropyl chloride, propanoyl chloride, butanoyl chloride, sulfonyl chloride, acetyl chloride, benzyl chloride, benzoyl chloride, acetic anhydride also carried out.
Preferably, acetic anhydride (115) used.
• In one embodiment, the present invention provides a process for preparation a compound of formula N-(3-hydroxyphenyl) acetamide (118), comprising:
a) Acylation of the compound of formula 3-aminophenol (113): and



b) Converting compound of formula 3-aminophenol (113) to a compound of formula N-(3-hydroxyphenyl) acetamide (118)
• In one embodiment, the preparation of compound of formula N-(3-hydroxyphenyl) acetamide (118) followed by neutralization in a suitable solvent mixture of saturated sodium hydrogen carbonate (121).
• In one embodiment, the compound of formula N-(3-hydroxyphenyl) acetamide (118) is mixed with water to obtain a slurry. The slurry is stirred and maintained for a period of about 30 min to 1 hour. Preferably, the slurry is stirred and maintained for a period of about 1 hour then filtered and dried under the vacuum for overnight to a temperature of about 25°C to about 30°C under nitrogen atmosphere.
In one embodiment, the process for the synthesis of compound N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) comprising alkylation of compound of formula N-(3-hydroxyphenyl) acetamide (118).


In one embodiment, the above process may be carried out, in the presence of suitable solvent selected from the group consisting of hydrocarbons such as hexane, toluene, cyclohexane, dichloromethane and ethers such as diethyl ether, tetrahydrofuran as well as presence of suitable alkylation agents selected from the group consisting of IPA (iso-propyl alcohol), t-butanol (tert-butanol) and protic solvents like hydrochloric acid, sulphuric acid also carried out.
Preferably the solvent is dichloromethane, alkylating agents is t-butanol (tert-butanol) and protic solvent is sulphuric acid.
• In one embodiment, the present invention provides a process for preparation a compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122), comprising:
a) Alkylation of the compound of formula N-(3-hydroxyphenyl) acetamide (118) to obtain a compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122);



Converting the compound of formula N-(3-hydroxyphenyl) acetamide (118) to a compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122)
• In one embodiment, the preparation of compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) followed by neutralization in a suitable solvent mixture of saturated sodium hydrogen carbonate.
• In one embodiment, the preparation of compound of formula 10 followed by purification using a suitable solvent.
Suitable solvent may be selected from the group consisting of hydrocarbons polar such as ethanol, methanol, water, acetone.
Preferably the solvent is water.
• In one embodiment, the compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) is mixed with water to obtain a slurry. The slurry is stirred and maintained for a period of about 30 min to 1 hour. Preferably, the slurry is stirred and maintained for a period of about 1 hour then filtered and dried under the vacuum for overnight to a temperature of about 25°C to about 30°C under nitrogen atmosphere.
In one embodiment, compound N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) is hydrolyzed to obtain compound of formula 5-amino-2,4-di-tert-butylphenol (126).


Hydrolysis may be carried out using suitable base selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide: alkoxides such as sodium methoxide, tert-butoxide or a suitable acid such as hydrochloric acid, sulphuric acid and the like.
Preferably, hydrolysis is carried out hydrochloric acid.
In one embodiment, the compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) is reacted with hydrochloric acid in ethanol and water mixture at a temperature of about 80-100°C. Preferably, pH is 7-8 to obtain a compound of formula 5-amino-2,4-di-tert-butylphenol (126).
In one embodiment, the present invention provides a process for preparation a compound of formula 5-amino-2,4-di-tert-butylphenol (126), comprising:
a) Hydrolysis the compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) to obtain a compound of formula 5-amino-2,4-di-tert-butylphenol (126); and



e) Converting the compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) to a compound of formula 5-amino-2,4-di-tert-butylphenol (126)
• In one embodiment, the preparation of compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) followed by neutralization in a suitable solvent mixture of saturated sodium hydrogen carbonate.
• In one embodiment, the preparation of compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) followed by purification in a suitable solvent.
Suitable solvent may be selected from the group consisting of hydrocarbons polar such as ethanol, methanol, water, acetone.
Preferably the solvent is water.
• In one embodiment, the compound of formula N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide (122) is mixed with water to obtain a slurry. The slurry is stirred and maintained for a period of about 30 min to 1 hour. Preferably, the slurry is stirred and maintained for a period of about 1 hour then filtered and dried under the vacuum for overnight to a temperature of about 25°C to about 30°C under nitrogen atmosphere.
Scheme 2:

• In one embodiment, the present invention provides a process for the preparation of compound of formula 5-amino-2,4-di-tert-butylphenol (126) as represented schematically in scheme 2, wherein the process neither includes chromatographic separation nor chromatographic purification.
• In one embodiment, compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) is coupled with compound of formula 5-amino-2,4-di-tert-butylphenol (126) to obtain compound of formula Ivacaftor (128).




• In one embodiment, the process comprises reacting compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) and is reacted with a compound of formula 5-amino-2,4-di-tert-butylphenol (126) in the presence of a coupling agent from HATU (O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate), BOP (Benzotriazol-1-yloxy)tris(dimethyl amino)phosphonium hexafluorophosphate), HBTU (O-Benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluorophosphate) and PFP-TFA (pentafluorophenyltrifluoroacetate), DIC (N,N’-Diisopropylcarbodiimide), EDC (1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, TBTU [O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate, DCC (N,N’-dicyclohexyl carbodiimide), PyBOP (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), Isobutyl chloroformate and 1-methyl-2-chloropyridinium iodide.
Preferably, the reaction is carried out in the presence of HBTU.
• In one embodiment, the reaction may be carried out in the presence of suitable solvent and a suitable base.
A suitable base may be organic or inorganic bases. Inorganic base may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkoxides such as sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate, bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. Organic bases may be selected from the group consisting of tertiary amine, trimethyl amine, pyridine, Di isopropyl ethyl amine, pyridine and dimethyl amino pyridine.
Preferably, the base is tertiary amine.
A suitable solvent may be selected from, but is not limited to halogenated hydrocarbons such as methylene chloride, chloroform, ethylene chloride and carbon tetrachloride; alcohol such as methanol, ethanol, 1-propyl alcohol, 2-propanol, tert-butanol; esters such as ethyl acetate, isopropyl acetate and butyl acetate; amides such as N,N-dimethylformamide, formamide, N,N- dimethylacetamide; dimethyl sulfoxide; nitrile such as acetonitrile, propionitrile; ethers such as diethyl ether, t-butyl methyl ether, diisopropyl ether, 1,4-dioxane, tetrahydrofuran; hydrocarbons such as benzene, cyclohexane, toluene, methyl cyclohexane.
Preferably, the solvent is N, N-dimethylformamide.
• In one embodiment, the present invention provides a process for preparation a compound of formula Ivacaftor (128), comprising:
a) Coupling the compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) and the compound of formula 5-amino-2,4-di-tert-butylphenol (126) to obtain a compound of formula Ivacaftor (128); and


f) Converting the compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) to a compound of formula Ivacaftor (128)
In one embodiment, the compound of formula 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) is reacted with a compound of formula 126 in the presence of triethyl amine and HBTU in N, N- dimethylformamide.
Preferably the reaction transpires over a period of about 4 to 24 hours at a temperature of about 25°C to 30°C.
• In one embodiment, the preparation of compound of formula Ivacaftor (128) followed by purification in a suitable solvent.
Suitable solvent may be selected from the group consisting of alcohols such as ethanol, methanol, 1-propanol, iso-propyl alcohol; hydrocarbons such as toluene, hexane, heptane, benzene and water.
Preferably the solvent is methanol.
• In one embodiment, the compound of formula 1 is mixed with methanol to obtain a slurry. The slurry is stirred and maintained for a period of about 1 hour to 30 hours. Preferably, the slurry is stirred and maintained for a period of about 30 hours then filtered and dried under the vacuum for overnight to a temperature of about 25°C to about 30°C.
• In one embodiment, the present invention provides a process for the preparation of compound of formula Ivacaftor (128) as represented, wherein the process neither includes chromatographic separation nor chromatographic purification. , Claims:1. Synthesis of Ivacaftor and its Key starting materials using Flow process comprising of:
- aniline, diethyl-2-(ethoxy methylene)malonate, diethyl-2-((phenylamino)methylene)malonate, ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 3-aminophenol, N-(3-hydroxyphenyl) acetamide, N-(2,4-di-tert-butyl-5-hydroxyphenyl) acetamide, 5-amino-2,4-di-tert-butylphenol, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinone-3-carboxamide (Ivacaftor), diphenyl ether, t-butanol, glacial acetic acid, acetic anhydride, hexane, sodium hydroxide, water, 6N hydrochloric acid, saturated sodium bicarbonate, concentrated sulfuric acid, concentrated hydrochloric acid, ethanol, Eaton’s reagent, Flow rate – 0.5 ml/min, 1 ml/min, 2.5 ml/min, 3 ml/min, 5 ml/min, 10 ml/min, Temperature – 30° C, 60° C, 80° C, 110° C, 120° C, 350° C, Pressure – 0 bar, 2 bar, 7 bar.
2. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein the synthesis of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112), diethyl ethoxy methylene malonate in 2 equivalence was used in one pot synthesis to produce 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) with a yield of 80%. This alteration of the equivalence dramatically changed the reaction yield.
3. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein protection of amine group of the compound 3-amino phenol (113) using 1.01 equivalence of acetic anhydride and 3.2 equivalence of acetic acid. So, no need for the nitration as well as reduction. Its beneficial for the large-scale production of KSM-5-amino-2,4-di-tert-butyl phenol (126).
4. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein synthesis of one of the Ivacaftor KSM- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) by Continuous flow process using Flow Reactor. By using this method, we got proper yield as well as pure product of the compound of KSM- 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (112).
5. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein synthesis of one of the Ivacaftor KSM- 5-amino-2,4-di-tert-butyl phenol (126) by continuous flow process using Flow Reactor. By using this method, we got proper yield as well as pure product of the compound of KSM 5-amino-2, 4-di-tert-butyl phenol (126).
6. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein synthesis of Ivacaftor by continuous flow process using Flow Reactor. By using this method, we got proper yield as well as pure product of the compound of Ivacaftor (128).
7. Synthesis of Ivacaftor and its Key starting materials using Flow process as claimed in claim 1, wherein synthesis of one of the Ivacaftor KSM- 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (112) by Continuous flow process using Flow Reactor using Eaton’s reagent (129). By using this method, we got proper yield as well as pure product of the compound of KSM- 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (112).