Process for the synthesis of ivacaftor and related compounds

Abstract

The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and Ar.sub.1 are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides. ##STR00001##

Claims

1. A one pot process for the preparation of compounds of formula (I) and formula (II); ##STR00019## wherein, Ar.sup.1 is a 5-6 membered aromatic/hetero aromatic ring, which could be further substituted by alkyl, aryl, hetero aryl and having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar.sup.1 has m substituents, each selected independently from WR.sup.W; W is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NRTSIR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.W is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; m is 0-5; each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is hydrogen, XR.sup.X; X is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NRTSIR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.X is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; R.sup.6 is hydrogen, CF.sub.3, OR, SR, or an optionally substituted C.sub.1-6 aliphatic group; R.sup.7, R.sup.8 is hydrogen or a C.sub.1-6 aliphatic group optionally substituted with XR.sup.X; R is independently selected from hydrogen or an optionally substituted group selected from a C.sub.1-C.sub.8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; its tautomers or pharmaceutically acceptable salts thereof comprising the steps of; a) coupling indole acetic acid with corresponding amines using suitable coupling agent to obtain indole amides; b) oxidizing indole amides of step (a) using suitable oxidizing agent followed by treatment with base to obtain desired quinolone carboxamides with 40 to 65% yield, wherein the base is an organic base selected from pyridine, 2,6-lutidine, DMAP (4-dimethylaminopyridine), Et.sub.3N (triethylamine), DIPEA (N,N-diisopropyl ethyl amine), N,N-dimethylaniline, DBN (1,5-diazabicyclo(4.3.0)non-5-ene), DABCO (1,4-diazabicyclo[2.2.2]octane) and DBU (1,8-diazabicycloundec-7-ene) or mixture thereof.

2. The process as claimed in claim 1, wherein the quinolone carboxamide compound is selected from 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (23), 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24), N-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (27), N-(4-chlorophenyl)-4-oxo-1,4 dihydroquinoline-3-carboxamide (28), 4-oxo-N-(p-tolyl)-1,4-dihydroquinoline-3-carboxamide (29), N-(4-ethylphenyl)-4-oxo-1,4-dihydroquinoline-5 3-carboxamide (30), 4-Oxo-N-(4-propylphenyl)-1,4-dihydroquinoline-3-carboxamide (31), N-(4-isopropylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (32), 4-oxo-N-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxamide (33), N-(2-chloro-5-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (34), N-(2-ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (35), N-(2-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (36), 7-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (43), 6-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (44), 1-benzyl-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (45).

3. The process as claimed in claim 1, wherein the indole amides is selected from 2-(1H-indol-3-yl)-N-phenylacetamide (1), 5-(2-(H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2), N-(4-Fluorophenyl)-2-(1H-indol-3-yl)acetamide (4), N-(4-Chlorophenyl)-2-(1H-indol-3-yl)acetamide (5), 2-(1H-Indol-3-yl)-N-(p-tolyl)acetamide (6), N-(4-Ethylphenyl)-2-(1H-indol-3-yl)acetamide (7), 2-(1H-Indol-3-yl)-N-(4-propylphenyl)acetamide (8), 2-(1H-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9), 2-(1H-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10), N-(2-chloro-5-methoxyphenyl)-2-(1H-indol-3-yl)acetamide (11), N-(2-ethylphenyl)-2-(1H-indol-3-yl)acetamide (12), N-(2-bromophenyl)-2-(1H-indol-3-yl)acetamide (13), 2-(6-chloro-1H-indol-3-yl)-N-phenylacetamide (20), (5-chloro-1H-indol-3-yl)-N-phenylacetamide (21), 2-(1-benzyl-1H-indol-3-yl)-N-5 phenyl acetamide (22).

4. The process as claimed in claim 1, wherein the corresponding amines in step (a) is selected from compounds of Formula Ar.sub.1NHR.sup.7, wherein Ar.sup.1 is a 5-6 membered aromatic/hetero aromatic ring, which could be further substituted by alkyl, aryl, hetero aryl and having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar.sup.1 has m substituents, each independently selected from WR.sup.W; W is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NR NR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.W is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; m is 0-5; R.sup.7, R.sup.8 is hydrogen or a C.sub.1-6 aliphatic group optionally substituted with XR.sup.X; and R.sup.X is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3.

5. The process as claimed in claim 1, wherein the coupling agent in step (a) is selected from HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate) or HBTU (O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluoro-phosphate), hydroxybenzotriazole or (EDC) 1-ethyl-3-(3-25 dimethylaminopropyl)carbodiimide or DCC (N,N-dicyclohexylcarbodiimide), or DIC (N,N-diisopropylcarbodiimide) or CDI (1,1-carbonyldiimidazole) or TBTU (O-(benzotriazol-1-yl)-N,N,N-tetramethyluroniumtetrafluoroborate) or FDPP (pentafluorophenyldiphenylphosphinate).

6. The process as claimed in claim 1, wherein the coupling agent is carbodiimides.

7. The process as claimed in claim 1, wherein the oxidizing agent in step (b) is selected from sodium periodate, peroxides, potassium permanganate, CrO.sub.3, or ozone.

8. The process as claimed in claim 1, wherein the oxidizing agent in step (b) is ozone.

9. The process as claimed in claim 1, wherein the base is pyridine or triethylamine.

10. The process as claimed in claim 1, wherein said process is a one pot process for the synthesis of compounds of Formula (I), its tautomers or pharmaceutically acceptable salts thereof comprising the steps of: a) adding EDC.HCl and DIPEA to a solution of indole acetic acid, aniline and HOBt in acetonitrile followed by stirring the reaction mixture for 16 h at room temperature to obtain indole amides; b) passing a stream of O.sub.3 to a solution of compound of step (a) in DCM:MeOH and adding pyridine and triethylamine followed by stirring the reaction mixture for overnight at room temperature to obtain desired compounds.

11. The process as claimed in claim 1, wherein said process further comprising: deprotection of phenol in the quinolone carboxamides of step (b) under basic condition to afford ivacaftor.

12. The process as claimed in claim 10, wherein said process further comprising: addition of NaOH dissolved in H.sub.2O to a solution of compound of step (b) in methanol followed by stirring the reaction mixture for 5 h at room temperature to obtain ivacaftor.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

(2) In view of above the present invention provides a one pot process for the preparation of compounds of Formula (I), its tautomers or pharmaceutically acceptable salts thereof.

(3) In an embodiment, the present invention provides a one pot process for the preparation of compounds of Formula (I) and Formula (II),

(4) ##STR00011##
wherein, Ar.sup.1 is a 5-6 membered aromatic/hetero aromatic ring, which could be further substituted by alkyl, aryl, hetero aryl and having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, Wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar.sub.1 has m substituents, each independently selected from WR.sup.W; W is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NRNR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.W is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; m is 0-5; each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 is hydrogen, XR.sup.X; X is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of X are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NRNR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.X is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; R.sup.6 is hydrogen, CF.sub.3, OR, SR, or an optionally substituted C.sub.1-6 aliphatic group; R.sup.7 R.sup.8 is hydrogen or a C.sub.1-6 aliphatic group optionally substituted with XR.sup.X; R is independently selected from hydrogen or an optionally substituted group selected from a C.sub.1-C.sub.8 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; its tautomers or pharmaceutically acceptable salts thereof.

(5) In another embodiment, the present invention provides a one pot process for the synthesis of compounds of Formula (I), its tautomers or pharmaceutically acceptable salts thereof comprising the steps of: a) coupling indole acetic acid with corresponding amines using suitable coupling agent to obtain indole amides; b) oxidizing indole amides of step (a) using suitable oxidizing agent followed by treatment with base to obtain desired quinolone carboxamides.

(6) In a preferred embodiment, the corresponding amines in step (a) are compounds of Formula Ar.sub.1NHR.sup.7, Wherein Ar.sup.1 is a 5-6 membered aromatic/hetero aromatic ring, which could be further substituted by alkyl, aryl, hetero aryl and having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is optionally fused to a 5-12 membered monocyclic or bicyclic, aromatic, partially unsaturated, or saturated ring, Wherein each ring contains 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Ar.sub.1 has m substituents, each independently selected from WR.sup.W; W is a bond or is an optionally substituted C.sub.1-C.sub.6 alkylidene chain wherein up to two methylene units of W are optionally and independently replaced by CO, CS, COCO, CONR, CONRNR, CO.sub.2, OCO, NRCO.sub.2, O, NRCONR, OCONR, NRNR, NRNRCO, NRCO, S, SO, SO.sub.2, NR, SO.sub.2NR, NRSO.sub.2, or NRSO.sub.2NR; R.sup.W is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3; m is 0-5; R.sup.7, R.sup.8 is hydrogen or a C.sub.1-6 aliphatic group optionally substituted with XR.sup.X; and R.sup.X is independently R, halo, NO.sub.2, CN, CF.sub.3, or OCF.sub.3.

(7) In another preferred embodiment, the suitable coupling agent in step (a) is selected from HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate) or HBTU (O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluoro-phosphate), hydroxybenzotriazole or (EDC) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DCC (N,N-dicyclohexylcarbodiimide), or DIC (N,N-diisopropylcarbodiimide) or CDI (1,1-carbonyldiimidazole) or TBTU (O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumtetrafluoroborate) or FDPP (pentafluorophenyldiphenylphosphinate); preferably carbodiimides.

(8) In yet another preferred embodiment, the suitable oxidizing agent in step (b) is selected from sodium periodate, peroxides, potassium permanganate, CrO.sub.3, ozone and the like; preferably ozone.

(9) In still another preferred embodiment, the base in step (b) is organic base and is selected from pyridine,2,6-lutidine, DMAP (4-dimethylaminopyridine), Et.sub.3N (triethylamine), DIPEA (N,N-diisopropyl ethyl amine), N,N-dimethylaniline, DBN (1,5-diazabicyclo(4.3.0)non-5-ene), DABCO (1,4-diazabicyclo[2.2.2]octane) and DBU (1,8-diazabicycloundec-7-ene) or mixture thereof; preferably pyridine or triethylamine.

(10) In a more preferred embodiment, the present invention provides a one pot process for the synthesis of compounds of Formula (I), its tautomers or pharmaceutically acceptable salts thereof comprising the steps of: a) adding EDC.HCl and DIPEA to a solution of indole acetic acid, aniline and HOBt in acetonitrile followed by stirring the reaction mixture for 16 h at room temperature to obtain indole amides; b) passing the a stream of O.sub.3 to a solution of compound of step (a) in DCM:MeOH and adding pyridine and triethylamine followed by stirring the reaction mixture for overnight at room temperature to obtain desired compounds.

(11) In an aspect, the quinolone carboxamide compound is selected from 4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (23), 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24), (S)-4-oxo-N-(1-phenylethyl)-1,4-dihydroquinoline-3-carboxamide (25), N-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (27), N-(4-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (28), 4-oxo-N-(p-tolyl)-1,4-dihydroquinoline-3-carboxamide (29), N-(4-ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (30), 4-Oxo-N-(4-propylphenyl)-1,4-dihydroquinoline-3-carboxamide (31), N-(4-isopropylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (32), 4-oxo-N-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxamide (33), N-(2-chloro-5-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (34), N-(2-ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (35), N-(2-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (36), N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (37), N-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (38), N,N-dibenzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (39), 4-oxo-N-propyl-1,4-dihydroquinoline-3-carboxamide (40), N-hexyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (41), Methyl (4-oxo-1,4-dihydroquinoline-3-carbonyl)-L-alaninate (42), 7-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (43), 6-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (44), 1-benzyl-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (45).

(12) In another aspect, the indole amides is selected from 2-(1H-indol-3-yl)-N-phenylacetamide (1), 5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2), (S)-2-(1H-indol-3-yl)-N-(1-phenylethyl)acetamide (3), N-(4-Fluorophenyl)-2-(1H-indol-3-yl)acetamide (4), N-(4-Chlorophenyl)-2-(1H-indol-3-yl)acetamide (5), 2-(1H-Indol-3-yl)-N-(p-tolyl)acetamide (6), N-(4-Ethylphenyl)-2-(1H-indol-3-yl)acetamide (7), 2-(1H-Indol-3-yl)-N-(4-propylphenyl)acetamide (8), 2-(1H-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9), 2-(1H-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10), N-(2-chloro-5-methoxyphenyl)-2-(1H-indol-3-yl)acetamide (11), N-(2-ethylphenyl)-2-(1H-indol-3-yl)acetamide (12), N-(2-bromophenyl)-2-(1H-indol-3-yl)acetamide (13), N-benzyl-2-(1H-indol-3-yl)acetamide (14), 2-(1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (15), N,N-dibenzyl-2-(1H-indol-3-yl)acetamide (16), 2-(1H-indol-3-yl)-N-propylacetamide (17), N-hexyl-2-(1H-indol-3-yl)acetamide (18), Methyl (2-(1H-indol-3-yl)acetyl)-L-alaninate (19), 2-(6-chloro-1H-indol-3-yl)-N-phenylacetamide (20), 2-(5-chloro-1H-indol-3-yl)-N-phenylacetamide (21), 2-(1-benzyl-1H-indol-3-yl)-N-phenylacetamide (22).

(13) The process for the synthesis of compounds of Formula (I) is as depicted in scheme 1:

(14) ##STR00012##

(15) In yet another embodiment, the present invention provides a one pot process for the synthesis of ivacaftor starting from indole acetic acid comprising the steps of: a) coupling indole acetic acid with corresponding amine using suitable coupling agent; b) oxidizing indole amides of step (a) using suitable oxidizing agent followed by treatment with base to obtain quinolone carboxamides; c) deprotection of phenol in the quinolone carboxamides of step (b) under basic condition to afford ivacaftor.

(16) In a preferred embodiment, the corresponding amine in step (a) is aniline or derivative thereof.

(17) In another preferred embodiment, the suitable coupling agent in step (a) is selected from HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate) or HBTU (O-benzotriazole-N,N,N,N-tetramethyl-uronium-hexafluoro-phosphate), hydroxybenzotriazole or (EDC) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or DCC (N,N-dicyclohexylcarbodiimide), or DIC (N,N-diisopropylcarbodiimide) or CDI (1,1-carbonyldiimidazole) or TBTU (O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluroniumtetrafluoroborate) or FDPP (pentafluorophenyldiphenylphosphinate); preferably carbodiimides.

(18) In yet another preferred embodiment, the suitable oxidizing agent in step (b) is selected from sodium periodate, peroxides, potassium permanganate, chromium trioxide, ozone and the like; preferably ozone.

(19) In still another preferred embodiment, the base in step (b) is organic base and is selected from pyridine, 2,6-lutidine, DMAP (4-dimethylaminopyridine), Et.sub.3N (triethylamine), DIPEA (N,N-diisopropyl ethyl amine), N,N-dimethylaniline, DBN (1,5-diazabicyclo(4.3.0)non-5-ene), DABCO (1,4-diazabicyclo[2.2.2]octane) and DBU (1,8-diazabicycloundec-7-ene) or mixture thereof; preferably pyridine or triethylamine.

(20) In a more preferred embodiment, the present invention provides process for the synthesis of ivacaftor comprising the step of: a) adding EDC.HCl and DIPEA to a solution of indole acetic acid, aniline and HOBt in acetonitrile followed by stirring the reaction mixture for 16 h at room temperature to obtain 5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2); b) passing the a stream of O.sub.3 to a solution of compound of step (a) in DCM:MeOH and adding pyridine and Et.sub.3N followed by stirring the reaction mixture for overnight at room temperature to obtain 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (5); c) adding NaOH dissolved in H.sub.2O to a solution of compound of step (b) in methanol followed by stirring the reaction mixture for 5 h at room temperature to obtain ivacaftor.

(21) The process for the synthesis of ivacaftor is as depicted in scheme 2:

(22) ##STR00013##

(23) The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES

Example 1

(24) Procedure A:

(25) ##STR00014##
To a solution of indole acetic acid (500 mg, 2.85 mmol), aniline (2.85 mmol), HOBt (3.4 mmol) in acetonitrile (10 mL), EDC.HCl (3.4 mmol) followed by DIPEA (11.4 mmol) was added, and mixture was stirred for 16 h at ambient temperature. The reaction mixture was evaporated to dryness, diluted with EtOAc (25 mL), washed with saturated aqueous NaHCO.sub.3 solution (5 mL), H.sub.2O (5 mL), brine (5 mL), and dried over Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate-pet ether) to afford corresponding amide as a colorless solid.

Example 2

2-(1H-indol-3-yl)-N-phenylacetamide (1)

(26) Yield: 570 mg; 80%; .sup.1H NMR (200 MHz, DMSO-d.sub.6) =10.95 (brs, 1H), 10.14 (s, 1H), 7.64 (d, J=7.8 Hz, 3H), 7.47-7.24 (m, 4H), 7.21-6.92 (m, 3H), 3.76 (s, 2H); MS: 273 (M+Na).sup.+.

Example 3

5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl Methyl Carbonate (2)

(27) Yield: 800 mg; 64%; .sup.1H NMR (200 MHz, DMSO-d.sub.6) =11.51 (brs, 1H), 9.41 (s, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.96-7.78 (m, 3H), 7.71-7.42 (m, 3H), 4.34 (s, 3H), 4.30 (s, 2H), 1.79 (s, 9H), 1.64 (s, 9H); MS: 459 (M+Na).sup.+.

Example 4

(S)-2-(1H-indol-3-yl)-N-(1-phenylethyl)acetamide (3)

(28) Yield: 620 mg; 78%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) =10.88 (brs, 1H), 8.48 (d, J=8.1 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.39-7.26 (m, 5H), 7.25-7.16 (m, 2H), 7.08 (t, J=7.3 Hz, 1H), 7.02-6.95 (m, 1H), 4.96 (t, J=7.3 Hz, 1H), 3.59 (s, 2H), 1.38 (d, J=7.1 Hz, 3H).

Example 5

N-(4-Fluorophenyl)-2-(1H-indol-3-yl)acetamide (4)

(29) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.93 (brs, 1H), 10.17 (s, 1H), 7.68-7.61 (m, 3H), 7.36 (d, J=8.1 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.15-7.13 (m, 3H), 7.11-6.99 (m, 1H), 3.73 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 170.1, 159.5, 157.1, 136.6, 136.3, 127.7, 124.4, 121.5, 121.3, 121.2, 119.1, 118.9, 115.8, 115.6, 111.8, 108.9, 34.2; MS: 269 (M+H).sup.+

Example 6

N-(4-Chlorophenyl)-2-(1H-indol-3-yl)acetamide (5)

(30) .sup.1H NMR (200 MHz, DMSO-d.sub.6): 10.93 (brs, 1H), 10.24 (s, 1H), 7.67-7.59 (m, 3H), 7.36-7.27 (m, 4H), 7.12-6.98 (m, 2H), 3.74 (s, 2H); .sup.13CNMR (100 MHz, DMSO-d.sub.6): 170.4, 138.9, 136.7, 129.1, 127.8, 127.1, 124.5, 121.6, 121.2, 119.2, 119.0, 115.7, 111.9, 108.9, 34.3; MS: 285 (M+H).sup.+.

Example 7

2-(1H-Indol-3-yl)-N-(p-tolyl)acetamide (6)

(31) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.50 (d, J=8.6 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.29-7.26 (m, 1H), 7.10-7.07 (m, 3H), 7.01-6.99 (m, 1H), 3.71 (s, 2H), 2.23 (s, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 170.0, 137.4, 136.6, 132.4, 129.5, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 34.2, 20.9; MS: 265 (M+H).sup.+.

Example 8

N-(4-Ethylphenyl)-2-(1H-indol-3-yl)acetamide (7)

(32) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.91 (brs, 1H), 10.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.15-7.04 (m, 3H), 6.99 (s, 1H), 2.55 (t, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.9, 138.9, 137.6, 136.6, 128.3, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 34.2, 28.0, 16.2; MS: 279 (M+H).sup.+.

Example 9

2-(1H-Indol-3-yl)-N-(4-propylphenyl)acetamide (8)

(33) .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.48 (brs, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.50-7.42 (m, 2H), 7.33-7.15 (m, 6H), 7.07 (d, J=8.3 Hz, 2H), 3.92 (s, 2H), 2.52 (t, J=7.6 Hz, 2H), 1.65-1.53 (m, 2H), 0.91 (t, J=7.3 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.7, 138.9, 136.5, 135.2, 128.8, 126.9, 124.0, 122.8, 120.4, 120.1, 118.7, 111.6, 108.7, 37.4, 34.5, 24.6, 13.7; MS: 315 (M+Na).sup.+.

Example 10

2-(1H-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9)

(34) yield 79%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.55-7.49 (m, J=8.6 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.18-7.11 (m, J=8.6 Hz, 2H), 7.11-7.05 (m, 1H), 7.02-6.95 (m, 1H), 2.95-2.71 (m, 1H), 1.17 (d, J=6.8 Hz, 6H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.9, 143.5, 137.6, 136.6, 127.7, 126.8, 124.3, 121.4, 119.7, 119.2, 118.8, 111.8, 109.2, 24.4; MS: 315 (M+Na).sup.+.

Example 11

2-(1H-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10)

(35) Yield 85%; .sup.1H NMR (400 MHz, CDCl.sub.3): 8.35 (brs., 1H), 7.44-7.38 (m, 2H), 7.27-7.21 (m, 3H), 7.12-7.05 (m, 1H), 7.03-6.95 (m, 2H), 6.93 (d, J=8.6 Hz, 2H), 3.75 (s, 2H); .sup.13C NMR (100 MHz, CDCl.sub.3): 170.0, 145.3, 136.5, 136.2, 126.8, 124.1, 123.0, 121.6, 121.2, 120.5, 118.5, 111.7, 108.2, 34.4; MS: 335 (M+Na).sup.+.

Example 12

N-(2-chloro-5-methoxyphenyl)-2-(1H-indol-3-yl)acetamide (11)

(36) Yield 75%; .sup.1H NMR (200 MHz, DMSO-d.sub.6): 10.98 (brs, 1H), 9.27 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.53 (d, J=2.9 Hz, 1H), 7.39-7.32 (m, 3H), 7.09-6.99 (m, 2H), 6.74 (dd, J=3.0, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 3H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 170.4, 160.1, 141.1, 136.7, 130.0, 127.8, 124.4, 121.6, 119.2, 119.0, 111.9, 109.1, 105.4, 55.4, 34.4; MS: 315 (M+Na).sup.+.

Example 13

N-(2-ethylphenyl)-2-(1H-indol-3-yl)acetamide (12)

(37) Yield 78%; .sup.1H NMR (400 MHz, CDCl.sub.3): 8.68 (brs, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.48-7.44 (m, 2H), 7.29-7.23 (m, 1H), 7.22-7.20 (m, 3H), 7.05 (d, J=4.4 Hz, 2H), 2.00 (q, J=7.4 Hz, 2H), 0.67 (t, J=7.6 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 169.9, 136.6, 135.0, 134.3, 128.7, 126.7, 125.1, 124.1, 123.0, 122.5, 120.4, 118.7, 111.6, 108.6, 34.4, 24.2, 13.6.

Example 14

N-(2-bromophenyl)-2-(1H-indol-3-yl)acetamide (13)

(38) Yield 76%; .sup.1H NMR (200 MHz, DMSO-d.sub.6): 11.00 (brs, 1H), 9.30 (s, 1H), 7.81-7.77 (m, 1H), 7.63-7.56 (m, 2H), 7.41-7.35 (m, 3H), 7.11-7.05 (m, 3H), 3.85 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.9, 136.2, 132.5, 128.0, 127.2, 126.4, 125.5, 124.4, 121.2, 118.7, 118.5, 116.4, 111.4, 108.0, 33.2.

Example 15

N-benzyl-2-(1H-indol-3-yl)acetamide (14)

(39) Yield 85%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.89 (brs., 1H), 8.40 (t, J=5.7 Hz, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.32-7.18 (m, 6H), 7.08 (t, J=7.5 Hz, 1H), 7.03-6.90 (m, 1H), 4.28 (d, J=5.9 Hz, 2H), 3.60 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 171.2, 140.1, 136.6, 128.7, 127.7, 127.2, 124.3, 121.4, 119.2, 118.7, 111.8, 109.3, 42.7, 33.2.

Example 16

2-(1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (15)

(40) Yield 85%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.87 (brs, 1H), 8.32 (t, J=5.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22-7.13 (m, 3H), 7.11-7.05 (m, 1H), 7.00-6.94 (m, 1H), 6.84 (d, J=8.6 Hz, 2H), 4.20 (d, J=6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 171.1, 158.6, 136.6, 132.0, 129.0, 127.7, 124.2, 121.4, 119.2, 118.7, 114.1, 111.8, 109.4, 55.5, 42.1, 33.2.

Example 17

N,N-dibenzyl-2-(1H-indol-3-yl)acetamide (16)

(41) Yield 70%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.91 (brs, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.37-7.34 (m, 3H), 7.30 (d, J=6.6 Hz, 1H), 7.25-7.19 (m, 3H), 7.17 (t, J=6.6 Hz, 5H), 7.16 (d, J=7.8 Hz, 1H), 7.00-6.97 (m, 1H), 4.59 (s, 2H), 4.50 (s, 2H), 3.86 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 171.7, 138.2, 136.6, 129.2, 128.8, 128.1, 127.8, 127.7, 127.5, 127.1, 124.2, 121.5, 119.2, 118.8, 111.8, 108.5, 50.7, 48.4, 31.2.

Example 18

2-(1H-indol-3-yl)-N-propylacetamide (17)

(42) Yield 75%; .sup.1H NMR (200 MHz, DMSO-d.sub.6): 10.86 (brs, 1H), 7.88-7.80 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.06-6.92 (m, 2H), 3.48 (s, 2H), 3.00 (q, J=6.8 Hz, 2H), 1.39 (sxt, J=7.2 Hz, 2H), 0.88-0.75 (t, J=7.2 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 171.0, 136.6, 127.8, 124.2, 121.4, 119.2, 118.7, 111.8, 109.6, 39.4, 33.3, 22.9, 11.9.

Example 19

N-hexyl-2-(1H-indol-3-yl)acetamide (18)

(43) Yield 87%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 10.84 (brs, 1H), 7.83 (brs, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.21-7.13 (m, 1H), 7.06 (t, J=7.6 Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 3.47 (s, 2H), 3.03 (q, J=6.8 Hz, 2H), 1.37 (t, J=6.5 Hz, 2H), 1.30-1.15 (m, 6H), 0.84 (t, J=6.7 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 170.9, 136.6, 127.7, 124.2, 121.3, 119.1, 118.7, 111.7, 109.5, 39.06, 33.2, 31.5, 29.6, 26.5, 22.5, 14.4.

Example 20

Methyl (2-(1H-indol-3-yl)acetyl)-L-alaninate (19)

(44) Yield 79%; .sup.1H NMR (400 MHz, CDCl.sub.3): 8.53 (brs, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.25-7.23 (m, 1H), 7.19-7.14 (m, 2H), 6.27 (d, J=7.3 Hz, 1H), 4.63 (t, J=7.3 Hz, 1H), 3.78 (s, 2H), 3.68 (s, 3H), 1.31 (d, J=7.3 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 173.4, 171.2, 136.4, 127.0, 123.8, 122.5, 119.9, 118.7, 111.5, 108.5, 52.4, 48.0, 33.3, 18.2.

Example 21

2-(6-chloro-1H-indol-3-yl)-N-phenylacetamide (20)

(45) ##STR00015##
To a solution of 6-Chloro indole 20a (300 mg, 1.98 mmol) in anhydrous THF, Oxalyl chloride (186 L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-Diisopropylethylamine (758 L, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 C., and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (10-20% EtOAc:Petroleum ether) to afford 20b (295 mg, 51% yield) as a yellow coloured solid. IR .sub.max (film): 3346, 3307, 2853, 1724, 1678 cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.62 (d, J=1.7 Hz, 1H), 7.41-7.30 (m, 3H), 7.19-7.13 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 182.5, 162.5, 140.0, 138.4, 137.4, 129.2, 128.5, 125.4, 124.8, 123.4, 122.9, 120.8, 113.0, 112.3; HRMS (ESI) Calculated for C.sub.16H.sub.11N.sub.2OCl[M+H].sup.+: 299.0582, found 299.0580;
A solution of 20b (300 mg, 0.99 mmol) dissolved in MeOH (40 mL) was added to NaBH.sub.4 (45 mg, 1.23 mmol). The reaction was stirred for 4 h and then added to saturated solution of Na.sub.2SO.sub.4. The reaction mixture was further stirred for 1 h and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N.sub.2 atmosphere, TMSCl (1.272 mL, 9.9 mmol) in CH.sub.3CN (40 mL) was added to sodium iodide (1.488 mg, 9.9 mmol) and stirred for 2 h. The reaction mixture was cooled to 0 C. and a solution of above crude alcohol (0.99 mmol) in CH.sub.3CN (10 mL) was then added dropwise over 30 min, followed by stirring for 3 h. The reaction mixture was poured into NaOH (7 g in 40 mL of water) and then extracted with ethyl acetate (152). The organic layer was washed with aq.Na.sub.2S.sub.2O.sub.3, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 20 as a off white solid (two steps 38%); IR .sub.max (film): 3273, 3084, 2953, 2857, 1629, 1562 cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 11.06 (br. s., 1H), 10.13 (br. s., 1H), 7.62-7.57 (m, 3H), 7.40 (s, 1H), 7.30-7.25 (m, 3H), 7.04-6.99 (m, 2H), 3.71 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 170.1, 139.7, 136.9, 129.2, 126.5, 126.3, 125.5, 123.7, 120.6, 119.6, 119.3, 111.5, 109.4, 34.0; HRMS (ESI): Calculated for C.sub.16H.sub.14N.sub.2OCl[M+H].sup.+: 285.0789, found 285.0786.

Example 22

2-(5-chloro-1H-indol-3-yl)-N-phenylacetamide (21)

(46) ##STR00016##
To a solution of 5-Chloro indole 21a (300 mg, 1.98 mmol) in anhydrous THF (20 mL), Oxalyl chloride (186 L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-diisopropylethylamine (758 L, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 C., and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (10-20% EtOAc:Petroleum ether) to afford (21b) (305 mg, 53% yield) as a yellow coloured solid. IR .sub.max (film): 3346, 3307, 2853, 1724, 1678 cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, J=3.2 Hz, 1H), 8.25 (d, J=8.6 Hz, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.62 (d, J=1.7 Hz, 1H), 7.42-7.30 (m, 3H), 7.20-7.14 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 182.4, 162.4, 140.3, 138.4, 135.4, 129.2, 127.9, 124.8, 124.1, 120.8, 114.8, 112.0; HRMS (ESI) Calculated for C.sub.16H.sub.11N.sub.2OCl[M+H].sup.+: 299.0582, found 299.0580; A solution of 21b (200 mg, 0.66 mmol) dissolved in MeOH (30 mL) was added to NaBH.sub.4 (30 mg, 0.82 mmol). The reaction was stirred for 4 h and then added to saturated solution of Na.sub.2SO.sub.4. The reaction mixture was further stirred for 1 h and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N.sub.2 atmosphere, TMSCl (848 mL, 6.6 mmol) in CH.sub.3CN (25 mL) was added to sodium iodide (992 mg, 6.6 mmol) and stirred for 2 h. The reaction mixture was cooled to 0 C. and a solution of above crude alcohol (0.66 mmol) in CH.sub.3CN (5 mL) was then added dropwise over 30 min, followed by stirring for 3 h. The reaction mixture was poured into NaOH (5 g in 30 mL of water) and then extracted with ethyl acetate (152). The organic layer was washed with aq.Na.sub.2S.sub.2O.sub.3, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 22 as a off white solid (two steps 42%); IR .sub.max (film): 3273, 3084, 2955, 2857, 1629, 1562 cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 11.13 (br. s., 1H), 10.11 (s, 1H), 7.67 (s, 1H), 7.60 (d, J=7.8 Hz, 2H), 7.39-7.27 (m, 4H), 7.13-7.02 (m, 2H), 3.16 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.9, 139.8, 135.0, 129.2, 128.9, 126.2, 123.6, 121.4, 119.6, 118.6, 113.4, 109.0, 34.0; HRMS (ESI) Calculated for C.sub.16H.sub.14N.sub.2OCl[M+H].sup.+: 285.0789, found 285.0786.

Example 23

2-(1-benzyl-1H-indol-3-yl)-N-phenylacetamide (22)

(47) Yield 79%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.67 (d, J=7.8 Hz, 1H), 7.54 (brs, 1H), 7.43-7.31 (m, 6H), 7.31-7.25 (m, 3H), 7.23-7.15 (m, 4H), 7.12-7.06 (m, 1H), 5.36 (s, 2H), 3.91 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 169.7, 137.7, 137.2, 137.0, 128.9, 128.9, 127.9, 127.6, 126.9, 124.3, 122.7, 120.2, 119.9, 119.0, 110.2, 107.9, 77.4, 77.1, 76.8, 50.1, 34.5.

Example 24

(48) Procedure B:

(49) ##STR00017##
2-(1H-indol-3-yl)-N-phenylacetamide 1 (100 mg; 0.4 mmol) was dissolved in DCM:MeOH (50 mL; 5:1), then a stream of O.sub.3 was passed through the solution until a blue color developed (10 min). The O.sub.3 stream was continued for 4 min. Then surplus O.sub.3 was removed by passing a stream of O.sub.2 through the solution for 10 min or until the blue color completely vanished. Afterwards pyridine (0.1 mL; 1.2 mmol) was added to the cold (78 C.) mixture. The mixture was allowed to warm to room temperature (1 h) and then Et.sub.3N (0.35 mL; 2.4 mmol) were added. After stirring at room temperature overnight the reaction mass was concentrated under reduced pressure to dryness, diluted with EtOAc (30 mL), washed with H.sub.2O (5 mL), brine (5 mL), and dried over Na.sub.2SO.sub.4. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, MeOH-DCM) to give desired quinolone carboxamide as colorless solid.

Example 25

4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (23)

(50) Yield: 65 mg; 62%; .sup.1H NMR (200 MHz, DMSO-d.sub.6) =12.97 (brs, 1H), 12.49 (s, 1H), 8.89 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 7.91-7.69 (m, 4H), 7.62-7.50 (m, 1H), 7.37 (t, J=7.8 Hz, 2H), 7.18-7.01 (m, 1H); MS: 287 (M+Na).sup.+.

Example 26

2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl Methyl Carbonate (24)

(51) Yield: 35 mg; 34%; .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.96 (brs, 1H), 12.08 (s, 1H), 8.94-8.82 (m, 1H), 8.44-8.28 (m, 1H), 7.86-7.79 (m, 1H), 7.78-7.73 (m, 1H), 7.59 (s, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.39 (s, 1H), 3.86 (s, 3H), 1.46 (s, 9H), 1.32 (s, 9H).

Example 27

(S)-4-oxo-N-(1-phenylethyl)-1,4-dihydroquinoline-3-carboxamide (25)

(52) Yield: 56 mg; 53%; .sup.1H NMR (500 MHz, DMSO-d.sub.6) =12.75 (brs, 1H), 10.54 (d, J=7.6 Hz, 1H), 8.73 (brs, 1H), 8.28 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.73-7.68 (m, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.42-7.34 (m, 4H), 7.29-7.23 (m, 1H), 5.18 (t, J=7.2 Hz, 1H), 1.50 (d, J=6.7 Hz, 3H).

Example 28

Synthesis of Ivacaftor (26)

(53) ##STR00018##
To a solution of 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06 mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13 mmol) dissolved in H.sub.2O (2 mL), and the reaction mixture was stirred at room temperature for 5 h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40 C.) and acidified with aq.2N HCl to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) =12.88 (d, J=6.6 Hz, 1H), 11.81 (s, 1H), 9.20 (s, 1H), 8.86 (d, J=6.6 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 7.88-7.65 (m, 2H), 7.51 (t, J=7.5 Hz, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.36 (s, 9H).

Example 29

N-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (27)

(54) Yield 56%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.96 (br. s., 1H), 12.50 (s, 1H), 8.88 (s, 1H), 8.33 (d, J=7.3 Hz, 1H), 7.86-7.72 (m, 4H), 7.54 (t, J=7.3 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 176.8, 163.2, 159.7, 157.3, 144.6, 139.6, 135.7, 133.5, 126.4, 125.9, 125.8, 121.8, 119.7, 116.1, 115.9, 110.9.

Example 30

N-(4-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (28)

(55) Yield 51%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.00 (brs., 1H), 12.59 (br. s., 1H), 8.89 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.83-7.76 (m, 4H), 7.56 (s, 1H), 7.42 (d, J=7.9 Hz, 2H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 176.8, 163.4, 144.7, 139.6, 138.2, 133.5, 129.4, 127.4, 126.4, 125.9, 125.8, 121.6, 119.7, 110.8.

Example 31

4-oxo-N-(p-tolyl)-1,4-dihydroquinoline-3-carboxamide (29)

(56) Yield 57%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.94 (brs., 1H), 12.40 (s, 1H), 8.88 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 7.82-7.80 (m, 1H), 7.76-7.7 (m, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.53 (t, J=7.3 Hz, 1H), 7.17 (d, J=8.1 Hz, 2H), 2.29 (s, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.8, 163.1, 144.5, 139.6, 136.8, 133.4, 132.8, 129.9, 126.4, 125.9, 125.7, 120.0, 119.6, 111.1, 20.9; HRMS (ESI): Calculated for C.sub.17H.sub.15O.sub.2N.sub.2[M+H].sup.+: 279.1128, found 279.1127.

Example 32

N-(4-ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (30)

(57) Yield 51%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.95 (br. s., 1H), 12.40 (d, J=7.8 Hz, 1H), 8.87 (d, J=6.1 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.81-7.76 (m, 2H), 7.66-7.62 (m, J=8.3 Hz, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.22-7.17 (m, J=8.3 Hz, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 181.5, 167.8, 149.3, 144.3, 144.0, 141.7, 138.2, 133.4, 131.1, 130.7, 130.5, 124.8, 124.4, 115.9, 32.8, 20.9.

Example 33

4-Oxo-N-(4-propylphenyl)-1,4-dihydroquinoline-3-carboxamide (31)

(58) Yield 51%; .sup.1H NMR (500 MHz, DMSO-d6): 12.93 (brs, 1H), 12.40 (s, 1H), 8.87 (s, 1H), 8.36-8.29 (m, 1H), 7.86-7.78 (m, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.68-7.61 (m, J=8.2 Hz, 2H), 7.54 (t, J=7.6 Hz, 1H), 7.22-7.14 (m, J=8.2 Hz, 2H), 2.55-2.51 (m, 2H), 1.64-1.53 (m, 2H), 0.90 (t, J=7.3 Hz, 3H); .sup.13C NMR (500 MHz, DMSO-d6): 176.8, 163.1, 144.5, 139.6, 137.6, 137.0, 133.5, 129.3, 126.4, 125.9, 125.7, 120.0, 119.7, 111.1, 37.2, 24.6, 14.1.

Example 34

N-(4-isopropylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (32)

(59) Yield 46%; .sup.1H NMR (500 MHz, DMSO-d.sub.6): 12.93 (br. s., 1H), 12.40 (br. s., 1H), 8.89-8.86 (m, 1H), 8.33 (d, J=7.6 Hz, 1H), 7.81-7.50 (m, 5H), 7.25-7.21 (m, 2H), 2.90-2.83 (m, 1H), 1.22-1.11 (m, 6H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.8, 163.1, 144.5, 143.9, 139.6, 137.1, 133.4, 127.2, 126.4, 125.9, 125.7, 120.1, 119.6, 111.1, 33.4, 24.4.

Example 35

4-oxo-N-(4-(trifluoromethoxy)phenyl)-1,4-dihydroquinoline-3-carboxamide (33)

(60) Yield 57%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.98 (br. s., 1H), 12.63 (s, 1H), 8.88 (d, J=4.9 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 7.89-7.83 (m, J=8.8 Hz, 2H), 7.79 (d, J=7.6 Hz, 1H), 7.77-7.73 (m, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.40-7.34 (m, J=8.6 Hz, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.8, 163.5, 144.7, 144.0, 139.5, 138.5, 133.5, 126.3, 125.9, 125.8, 122.3, 121.4, 119.7, 110.7.

Example 36

N-(2-chloro-5-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (34)

(61) Yield 54%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.98 (br. s., 1H), 12.49 (s, 1H), 8.88 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 7.83-7.75 (m, 1H), 7.56-7.48 (m, 3H), 7.27-7.21 (m, 1H), 6.67 (d, J=7.8 Hz, 1H), 3.77 (s, 3H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 176.8, 163.4, 160.2, 144.7, 140.4, 139.6, 133.5, 130.3, 126.4, 125.9, 125.8, 119.7, 112.3, 111.0, 109.5, 105.7, 55.5.

Example 37

N-(2-ethylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (35)

(62) Yield 58%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.94 (br. s., 1H), 12.37 (s, 1H), 8.90 (s, 1H), 8.36 (dd, J=8.1, 1.4 Hz, 2H), 8.32 (dd, J=8.1, 1.4 Hz, 2H), 7.82-7.74 (m, 1H), 7.53-7.19 (m, 3H), 7.15-7.06 (m, 1H), 2.79 (q, J=7.3 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H); 293 (M+H).sup.+.

Example 38

N-(2-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (36)

(63) Yield 47%; .sup.1H NMR (200 MHz, DMSO-d.sub.6): 12.98 (br. s., 1H), 12.69 (s, 1H), 8.90 (d, J=5.9 Hz, 1H), 8.54 (dd, J=1.4, 8.3 Hz, 1H), 8.34 (d, J=7.6 Hz, 1H), 7.86-7.67 (m, 3H), 7.57-7.49 (m, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.10-7.05 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.7, 163.7, 145.0, 139.5, 137.7, 133.5, 133.1, 128.6, 126.4, 126.0, 125.8, 125.3, 122.9, 119.7, 113.4, 110.8.

Example 39

N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (37)

(64) Yield 58%; .sup.1H NMR (400 MHz, CD.sub.3OD-d.sub.6): 8.82 (s, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.79-7.77 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.42-7.34 (m, 4H), 7.31-7.26 (m, 1H), 4.67 (s, 2H); .sup.13C NMR (400 MHz, DMSO-d.sub.6): 176.6, 165.0, 144.2, 140.0, 139.5, 133.2, 128.9, 128.7, 127.8, 127.3, 126.6, 125.9, 125.4, 119.5, 111.2, 42.6.

Example 40

N-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (38)

(65) Yield 56%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.73 (br. s., 1H), 10.35 (t, J=5.3 Hz, 1H), 8.78 (d, J=6.1 Hz, 1H), 8.24 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.1 Hz, 1H), 7.73-7.68 (m, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.1 Hz, 2H), 4.49 (d, J=5.6 Hz, 2H), 3.74 (s, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.6, 164.8, 158.8, 144.1, 139.5, 133.1, 131.9, 129.2, 126.6, 125.8, 125.4, 119.5, 114.3, 111.3, 55.5, 42.0.

Example 41

N,N-dibenzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (39)

(66) Yield 43%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.21 (br. s., 1H), 8.27 (d, J=4.9 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.49-7.41 (m, 2H), 7.41-7.35 (m, 3H), 7.33-7.20 (m, 5H), 7.20-7.11 (m, J=7.1 Hz, 2H), 4.59 (br. s., 2H), 4.42 (s, 2H).

Example 42

4-oxo-N-propyl-1,4-dihydroquinoline-3-carboxamide (40)

(67) Yield 47%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.7 (br.s., 1H) 10.05 (t, J=5.5 Hz, 1H), 8.74 (s, 1H), 8.26 (d, J=8.1 Hz, 1H), 7.83-7.66 (m, 2H), 7.52-7.44 (m, 1H), 3.33-3.22 (m, 2H), 1.61-1.49 (m, 2H), 0.93 (t, J=7.5 Hz, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 39.3, 23.1, 12.0

Example 43

N-hexyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (41)

(68) Yield 51%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.68 (m, 1H), 10.02 (t, J=5.5 Hz, 1H), 8.73 (d, J=6.1 Hz, 1H), 8.27-8.25 (m, 1H), 7.77-7.67 (m, 2H), 7.47 (t, J=7.5 Hz, 1H), 3.33-3.29 (m, 2H), 1.56-1.45 (m, 2H), 1.34-1.25 (m, 6H), 0.88-0.82 (m, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 38.7, 31.5, 29.8, 26.7, 22.5, 14.4.

Example 44

Methyl (4-oxo-1,4-dihydroquinoline-3-carbonyl)-L-alaninate (42)

(69) Yield 38%; .sup.1H NMR (400 MHz, CD.sub.3OD): 8.74 (s, 1H), 8.47-8.29 (m, 1H), 7.86-7.76 (m, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.58-7.44 (m, 1H), 4.69 (d, J=7.3 Hz, 1H), 3.79 (s, 3H), 1.55 (d, J=7.3 Hz, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD): 177.3, 173.3, 165.5, 143.6, 139.2, 132.9, 126.3, 125.4, 125.2, 118.5, 110.3, 51.5, 47.0, 17.0.

Example 45

7-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (43)

(70) Yield 48%; IR .sub.max (film): 2920, 2868, 1661, 1601 cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.91 (br. s., 1H), 12.30 (s, 1H), 8.90 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.80-7.67 (m, 3H), 7.58-7.51 (m, 1H), 7.36 (t, J=7.7 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.3, 162.9, 145.4, 140.3, 139.2, 138.0, 129.5, 128.2, 126.1, 125.1, 123.9, 120.1, 118.8, 111.6.

Example 46

6-chloro-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (44)

(71) Yield 52%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.05 (brs, 1H), 12.27 (s, 1H), 8.88 (s, 1H), 8.21 (d, J=2.2 Hz, 1H), 7.86-7.67 (m, 4H), 7.36 (t, J=7.8 Hz, 2H), 7.16-7.04 (m, 1H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 175.6, 162.9, 144.9, 139.1, 138.2, 133.5, 130.4, 129.5, 127.5, 124.9, 123.9, 122.0, 120.1, 111.4.

Example 47

1-benzyl-4-oxo-N-phenyl-1,4-dihydroquinoline-3-carboxamide (45)

(72) Yield 55%; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 12.30 (s, 1H), 9.05 (s, 1H), 8.60 (dd, J=1.7, 8.1 Hz, 1H), 7.82 (d, J=7.8 Hz, 2H), 7.69-7.62 (m, 1H), 7.55-7.45 (m, 2H), 7.43-7.34 (m, 5H), 7.24-7.18 (m, 2H), 7.17-7.10 (m, 1H), 5.53 (s, 2H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 176.9, 162.9, 148.7, 139.3, 138.7, 134.1, 133.1, 129.4, 128.9, 128.7, 128.0, 127.4, 126.2, 125.5, 123.9, 120.5, 116.9, 112.3, 57.9; HRMS (ESI): Calculated for C.sub.23H.sub.18O.sub.2N.sub.2Na [M+Na].sup.+: 377.1260, found 377.1259; MS: 355 (M+H).sup.+.

(73) Advantages of Invention:

(74) 1. Cost-effective process for synthesis.

(75) 2. Carried out at environmentally benign conditions.

(76) 3. Short synthetic route.

(77) 4. Useful for making several related compounds of medicinal use.