Process for the preparation of Zafirlukast and analogs thereof

Abstract

The present invention relates to a process for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs thereof. Further, this process is based on protection group free and CH bond activation strategy involving all step catalytic transformation sequence and comprises the following steps: Sonogashira coupling, indole formation by Sp.sup.3 CH activation, reductive hydrogenation and amidation.

Claims

1. A process for the preparation of compound of formula I ##STR00006## wherein ring A and B is any ring aryl, heteroaryl, cycloalkyl, fused aryl, fused alkyl or fused heteroaryl; R1, R2 is C1-C6 alkyl; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 is C1-12 alkyl, aryl, heteroaryl, C1-C12 cycloalkyl, heteroalkyl, thiol, H, OR where R=H, C1-C6 alkyl, aryl or heteroaryl, NO.sub.2, halogen, RNH where R=H, C1-C6 alkyl, aryl or heteroaryl; cyano, isothiocyano, isocyanate, azido, COOR where R=H, C1-C6 alkyl, aryl or heteroaryl; COR where R=H, C1-C6 alkyl, aryl or heteroaryl; wherein each of these groups may further be substituted with one or more substituents selected from H, OH, SH, halogen, CN, NO2, C1-C4 alkyl or phenyl; comprising the steps of: (a) sonagashira coupling of aryl bromide compound of formula VI ##STR00007## wherein R.sub.1 and R.sub.2 are as defined above, and aryl acetylene using palladium catalyst, copper catalyst, organic base and inorganic base in polar solvent at 70-120 C. for 5-15 hours to yield compound of formula V ##STR00008## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 are as defined above; (b) oxidative cyclization of compound of formula V obtained in step (a) by Sp.sup.3 CH activation using persulfate oxidizing agent in polar solvents at 70-120 C. for 2-10 hours to yield compound of formula IV ##STR00009## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5 are as defined above; (c) reductive hydrogenation of compound of formula IV obtained in step (b) using catalytic hydrogenation reagent, followed by acid hydrolysis in alcoholic solvent at 25-35 C. for 2-10 hours to yield compound of formula III ##STR00010## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.5 are as defined above; (d) amidation of acid group of the compound of formula III obtained in step (c) with sulfonamide using transition metal catalyst and anhydride in polar solvent at 25-35 C. for 1-5 hours to yield compound of formula II ##STR00011## wherein R.sub.1, R.sub.3, R.sub.4, R.sub.6, R.sub.7 are as defined above; (e) reduction of nitro group of the compound of formula II obtained in step (d) using catalytic reducing reagent in polar solvent at 25-35 C. for 1-5 hours, followed by amidation with haloformate using organic base in nonpolar solvent at 25-35 C. for 2-8 hours to obtain the desired compound of formula I.

2. The process as claimed in claim 1, wherein the aryl acetylene is selected from ##STR00012##

3. The process as claimed in claim 1, wherein the palladium catalyst is selected from palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium (II) trifluoroacetate, diacetobis(triphenylphosphine)palladium(II), bis [(diphosphanyl)methyl]laminepalladium(II) dichloride, bis [(diphenylphosphanyl)methyl] aminepalladium(II)diacetate, 1,1-dis(diphenylphosphino)ferrocene] dichloropalladium(II) or [1,1-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and the copper catalyst is selected from copper iodide, copper bromide, copper chloride or copper acetate.

4. The process as claimed in claim 1, wherein the organic base is selected from secondary amine, tertiary amine or heterocyclic amine and the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate or mixtures thereof.

5. The process as claimed in claim 1, wherein the polar solvent is selected from ethers, alcohols, halogenated solvents, esters, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof and the non-polar solvent is selected from toluene, hexane, benzene, pentane, heptane, xylene, mesitylene or mixtures thereof.

6. The process as claimed in claim 1, wherein the persulfate is selected from sodium persulfate, potassium persulfate or ammonium persulfate.

7. The process as claimed in claim 1, wherein the catalytic hydrogenation reagent is selected from palladium on carbon or raney nickel.

8. The process as claimed in claim 1, wherein the transition metal catalyst is selected from zinc chloride, zinc bromide, zinc iodide, nickel chloride or titanium tetrachloride.

9. The process as claimed in claim 1, wherein the anhydride is selected from benzoic anhydride, acetic anhydride, phthalic anhydride or maleic anhydride.

10. The process as claimed in claim 1, wherein the haloformate is selected from chloroformate, bromoformate or iodoformate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 represents the process steps for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs.

(2) FIG. 2 represents the process for the preparation of compounds of formula V from the compounds of Formula VI.

(3) FIG. 3 represents compounds of formula IVa-e

SUMMARY OF THE INVENTION

(4) Accordingly, present invention provides a process for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs compound of formula I, comprising the steps of:

(5) ##STR00002##
wherein ring A and B is any ring aryl, heteroaryl, cycloalkyl, fused aryl, fused alkyl or fused heteroaryl; R.sub.1, R.sub.2 is C1-C6 alkyl; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 is C1-12 alkyl, aryl, heteroaryl, C1-C12 cycloalkyl, heteroalkyl, thiol, H, OR where R=H, C1-C6 alkyl, aryl or heteroaryl, NO.sub.2, halogen, RNH where R=H, C1-C6 alkyl, aryl or heteroaryl; cyano, isothiocyano, isocyanate, azido, COOR where R=H, C1-C6 alkyl, aryl or heteroaryl; COR where R=H, C1-C6 alkyl, aryl or heteroaryl; wherein each of these groups may further be substituted with one or more substituents selected from H, OH, SH, halogen, CN, NO.sub.2, C1-C4 alkyl or phenyl;
(a) Sonagashira coupling of aryl bromide compound of formula VI and aryl acetylene using palladium catalyst, copper catalyst, organic base and inorganic base in polar solvent at 70-120 C. for 5-15 hours to yield compound of formula V; (b) oxidative cyclization of compound of formula V obtained in step (a) by Sp.sup.3 CH activation using persulfate oxidizing agent in polar solvents at 70-120 C. for 2-10 hours to yield compound of formula IV; (c) reductive hydrogenation of compound of formula IV obtained in step (b) using catalytic hydrogenation reagent, followed by acid hydrolysis in alcoholic solvent at 25-35 C. for 2-10 hours to yield compound of formula III; (d) amidation of acid group of the compound of formula III obtained in step (c) with sulfonamide using transition metal catalyst and anhydride in polar solvent at 25-35 C. for 1-5 hours to yield compound of formula II; (e) reduction of nitro group of the compound of formula II obtained in step (d) using catalytic reducing reagent in polar solvent at 25-35 C. for 1-5 hours, followed by amidation with haloformate using organic base in nonpolar solvent at 25-35 C. for 2-8 hours to obtain the desired compound of formula I.

(6) In an embodiment of the present invention, the palladium catalyst is selected from palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium (II) trifluoroacetate, diacetobis(triphenylphosphine)palladium(II), bis [(diphosphanyl)methyl]laminepalladium(II) dichloride, bis [(diphenylphosphanyl)methyl] aminepalladium(II)diacetate, 1,1-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), [1,1-Bis(di-tert-butylphosphino)ferrocene] dichloropalladium(II) or mixtures thereof.

(7) In yet another embodiment of the present invention, the aryl acetylene is selected from

(8) ##STR00003##

(9) In yet another embodiment of the present invention, the copper catalyst is selected from copper iodide, copper bromide, copper chloride, copper acetate or mixtures thereof. In yet another embodiment of the present invention, the organic base is selected from secondary amine, tertiary amine or heterocyclic amine.

(10) In yet another embodiment of the present invention, the inorganic base is selected from potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium phosphate or mixtures thereof. In yet another embodiment of the present invention, the polar solvent is selected from ethers, alcohols, halogenated solvents, esters, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.

(11) In yet another embodiment of the present invention, the non-polar solvent is selected from toluene, hexane, benzene, pentane, heptane, xylene, mesitylene or mixtures thereof. In yet another embodiment of the present invention, the persulfate is selected from sodium persulfate, potassium persulfate or ammonium persulfate.

(12) In yet another embodiment of the present invention, the catalytic hydrogenation reagent is selected from palladium on carbon or raney nickel.

(13) In yet another embodiment of the present invention, the transition metal catalyst is selected from zinc chloride, zinc bromide, zinc iodide or titanium tetrachloride.

(14) In yet another embodiment of the present invention, the anhydride is selected from benzoic anhydride, acetic anhydride, phthalic anhydride or maleic anhydride.

(15) In still another embodiment of the present invention, the haloformate is selected from chloroformate, bromoformate or iodoformate.

(16) In still another embodiment of the present invention, all the products are subjected to purification by chromatography, filtration, crystallization, distillation or extraction.

DETAILED DESCRIPTION OF THE INVENTION

(17) Present invention provides a highly effective process for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs. Zafirlukast is an oral leukotriene receptor antagonist (LTRA) and an FDA approved drug for the treatment of asthma. The present process could be operated by employing all catalytic transformations to produce (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs in high yields and purity. This newly developed process starts from a one-pot three sequence reaction and comprises of the following operations: Sonogashira coupling, indole formation by Sp.sup.3 CH activation, reductive hydrogenation, amidation and reductive amidation as illustrated in scheme 1.

(18) The present process can be performed very effectively in six overall steps with a short reaction time and is a highly viable strategy which could be most suitable for the industrial scale production of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs. Further, this process is most suitable for the generation of a large library of intermediates and analogues of the Zafirlukast. The first step of this process involves Sonogashira coupling wherein diverse functionalization is possible with the use of substrate screening methods. While, these Sonogashira products could be utilized to generate yet another library of indole derivatives employing Sp.sup.3CH bond activation strategy. Further, the amidation and reductive amidation sequences could be performed by using a variety of substrate partners to generate and build a vast library of Zafirlukast analogues with diverse functional modifications. All the reaction steps involve purification and systematic characterization of the individual reaction product at each stage of the process.

(19) The present process for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast and analogs compound of formula I as illustrated in scheme 1 is described as follows: This process is the most convenient and simple method involving six step reaction sequence employing simple key starting materials and reaction parameters comprising of following steps:

(20) ##STR00004##
wherein ring A and B is any ring aryl, heteroaryl, cycloalkyl, fused aryl, fused alkyl or fused heteroaryl; R.sub.1, R.sub.2 is C1-C6 alkyl; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 is C1-12 alkyl, aryl, heteroaryl, C1-C12 cycloalkyl, heteroalkyl, thiol, H, OR where R=H, C1-C6 alkyl, aryl or heteroaryl, NO.sub.2, halogen, RNH where R=H, C1-C6 alkyl, aryl or heteroaryl; cyano, isothiocyano, isocyanate, azido, COOR where R=H, C1-C6 alkyl, aryl or heteroaryl; COR where R=H, C1-C6 alkyl, aryl or heteroaryl; wherein each of these groups may further be substituted with one or more substituents selected from H, OH, SH, halogen, CN, NO.sub.2, C1-C4 alkyl or phenyl; (a) Sonagashira coupling of aryl bromide compound of formula VI and aryl acetylene using palladium catalyst, copper catalyst, organic base and inorganic base in polar solvent at 70-120 C. for 5-15 hours to yield compound of formula V; (b) oxidative cyclization of compound of formula V obtained in step (a) by Sp.sup.3 CH activation using persulfate oxidizing agent in polar solvents at 70-120 C. for 2-10 hours to yield compound of formula IV; (c) reductive hydrogenation of compound of formula IV obtained in step (b) using catalytic hydrogenation reagent, followed by acid hydrolysis in alcoholic solvent at 25-35 C. for 2-10 hours to yield compound of formula III; (d) amidation of acid group of the compound of formula III obtained in step (c) with sulfonamide using transition metal catalyst and anhydride in polar solvent at 25-35 C. for 1-5 hours to yield compound of formula II; (e) reduction of nitro group of the compound of formula II obtained in step (d) using catalytic reducing reagent in polar solvent at 25-35 C. for 1-5 hours, followed by amidation with haloformate using organic base in nonpolar solvent at 25-35 C. for 2-8 hours to obtain the desired compound of formula I.
In the above process step, aryl acetylene used in step (a) is selected from

(21) ##STR00005##

(22) In this process, all the reaction steps were monitored by chromatography and the crude products obtained were subjected to purification using crystallization or chromatography or distillation or extraction or filtration to get the pure compounds in good yields. Further, all the resultant compounds/products were systematically characterized using various analytical and spectral methods.

EXAMPLES

(23) Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

(24) General Procedure for the Sonagashira Cross-Coupling

(25) To a mixture of aryl bromide, compound of formula VIa-e as shown in scheme 2 (0.1 mmol), PdCl.sub.2 (PPh.sub.3).sub.2 (10 mol %), CuI (10 mol %) and Et.sub.3N (0.15 mmol) in dry DMF (4 mL) was slowly added trimethylsilyl acetylene (0.1 mmol). After complete addition the reaction mixture was stirred at 80 C. temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature and K.sub.2CO.sub.3 (0.15 mmol) was added and heated to 80 C. until the silylated acetylene was disappeared (monitored by TLC). The reaction was allowed to come to room temperature followed by the addition of PdCl.sub.2 (PPh.sub.3).sub.2 (10 mol %), Et.sub.3N (0.15 mmol) and CuI (10 mol %). After stirring for 30 min at room temperature aryl halides (0.1 mmol) in DMF (2 ml) was added dropwise and the reaction mixture was heated to 80 C. for 3 h. After completion of the reaction monitored by TLC, the reaction mixture was re-cooled to room temperature and quenched with cold water (7 mL) and the solid was filtered using EtOAc (15 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to provide the biaryl acetylene, compound of formula Va-e as a yellow solid in three steps.

Example 1

N,N-Dimethyl-4-nitro-2-(phenylethynyl)aniline (Va)

(26) 61 mg, 56% yield; R.sub.f=0.7 (silica, EtOAc:hexane=1:9); IR (neat): 3479, 3392, 2926, 2856, 1642, 1523, 1459, 1220, 1065, 772, 695 cm.sup.1; M.P: 87-92 C.; 1H NMR (400 MHz, CDCl.sub.3): 8.33 (d, J=2.8 Hz, 1H), 8.03 (dd, J=9.3, 2.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.38-7.33 (m, 3H), 6.76 (d, J=9.3 Hz, 1H), 3.25 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 154.0, 137.4, 132.0, 129.1, 129.0, 129.0, 127.0, 122.3, 108.0, 107.2, 96.5, 83.5, 30.4, 30.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.16H.sub.15N.sub.2O.sub.2.sup.+ 267.1134, found 267.1145.

Example 2

N,N-Dimethyl-4-nitro-2-(p-tolylethynyl)aniline (Vb)

(27) (58 mg, 51% yield; R.sub.f=0.8 (silica, EtOAc:hexane=1:9); IR (neat): 2954, 2854, 2209, 1597, 1511, 1444, 1323, 1269, 1079, 906, 820, 772, 750 cm.sup.1; M.P: 98-103 C.; 1H NMR (400 MHz, CDCl.sub.3): 8.32 (d, J=2.8 Hz, 1H), 8.02 (dd, J=9.3, 2.8 Hz, 1H), 7.40 (d, J=8.1 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 6.75 (d, J=9.3 Hz, 1H), 3.24 (s, 6H), 2.38 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 158.0, 139.1, 139.0, 131.4, 131.2, 129.5, 125.1, 120.1, 115.0, 111.1, 96.0, 87.2, 43.0, 22.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.17H.sub.17N.sub.2O.sub.2.sup.+ 281.1290, found 281.1302.

Example 3

N,N-Dimethyl-4-nitro-2-((2-nitrophenyl)ethynyl)aniline (Vc)

(28) (63 mg, 49% yield; R.sub.f=0.8 (silica, EtOAc:hexane=1:9); IR (neat): 3393, 2922, 2854, 1624, 1530, 1444, 1343, 1220, 1020, 898, 772, 670 cm.sup.1; M.P: 172-177 C.; 1H NMR (400 MHz, CDCl.sub.3): 8.41 (d, J=2.8 Hz, 1H), 8.13 (dd, J=8.3, 1.0 Hz, 1H), 8.08 (dd, J=9.4, 2.8 Hz, 1H), 7.73 (dd, J=7.8, 1.4 Hz, 1H), 7.64 (td, J=7.6, 1.2 Hz, 1H), 7.52-7.47 (m, 1H), 6.78 (d, J=9.4 Hz, 1H), 3.30 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 135.0, 133.1, 133.0, 129.0, 126.0, 125.0, 122.2, 122.0, 115.0, 43.0, 30.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.16H.sub.14N.sub.3O.sub.4.sup.+ 312.1023, found 312.1027.

Example 4

2-((4-Methoxyphenyl)ethynyl)-N,N-dimethyl-4-nitroaniline (Vd)

(29) (89 mg, 73% yield; R.sub.f=0.7 (silica, EtOAc:hexane=1:9); IR (neat): 3423, 3394, 2928, 2858, 1606, 1514, 1416, 1328, 1257, 1175, 1061, 805, 772, 675 cm.sup.1; M.P: 143-148 C.; 1H NMR (400 MHz, CDCl.sub.3): 8.32 (d, J=2.8 Hz, 1H), 8.03 (dd, J=9.3, 2.8 Hz, 1H), 7.44 (tt, J=5.4, 2.7 Hz, 2H), 6.92-6.87 (m, 2H), 6.77 (d, J=9.3 Hz, 1H), 3.84 (s, 3H), 3.24 (s, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3): 160.0, 157.5, 139.0, 133.0, 131.1, 131.0, 126.1, 125.0, 115.0, 114.2, 95.5, 86.3, 55.4, 43.0, 30.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.17H.sub.17N.sub.2O.sub.3.sup.+ 297.1239, found 297.1232.

Example 5

Methyl 4-((2-(dimethylamino)-5-nitrophenyl)ethynyl)-3-methoxybenzoate (Ve)

(30) To a mixture of aryl bromide VIe (3.0 g, 10.27 mmol), PdCl.sub.2 (PPh.sub.3).sub.2 (72 mg, 10 mol %), CuI (20 mg, 10 mol %) and Et.sub.3N (2.2 mL, 15.41 mmol) in dry DMF (30 mL) after 30 min was slowly added aryl acetylene (1.95 g, 10.27 mmol). Then the reaction mixture was heated at 80 C. for 2 h, and monitored by by TLC, after completion, the reaction was quenched by the addition of cold water (50 ml) and the resulting mixture was extracted with EtOAc (330 mL). The organic phases were dried over anhydrous sodium sulphate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give pure methyl 4-((2-(dimethyl amino)-5-nitrophenyl)ethynyl)-3-methoxybenzoate Ve (3.2 g, 89%). as a yellow solid; R.sub.f=0.7 (silica, EtOAc:hexane=3:7); IR (neat): 3476, 3226, 2951, 2925, 2850, 1723, 1622, 1582, 1435, 1293, 1108, 767 cm.sup.1;

(31) M.P.=152-156 C.; .sup.1H NMR (500 MHz, CDCl.sub.3): 8.38 (d, J=2.8 Hz, 1H), 8.05 (dd, J=9.3, 2.8 Hz, 1H), 7.64 (dd, J=7.9, 1.3 Hz, 1H), 7.57 (d, J=1.0 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 6.76 (d, J=9.4 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.29 (s, 6H); .sup.13C NMR (125 MHz, CDCl.sub.3): 167.0, 160.1, 157.4, 138.5, 133.0, 132.0, 131.2, 125.5, 122.0, 117.2, 115.0, 111.4, 110.1, 94.5, 91.3, 56.1, 52.5, 43.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.19H.sub.19N.sub.2O.sub.5.sup.+ 355.1294, found 355.1299.

General Procedure for the Preparation of 3-aryl indole (formula IVa-e)

(32) To a stirred solution of Sonogashira coupling product, compound of formula Va-e (0.1 mmol) in DMSO (3 mL) was added Na.sub.2S.sub.2O.sub.8 (0.3 mmol), the resultant mixture was put into a pre-heated oil bath 80 C. for 5 h. After completion of the reaction monitored by TLC, The resultant reaction mixture was quenched with water (5 mL) and the product was extracted with ethyl acetate (25 mL). The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-aroyl indole product, compound of formula IVa-e as yellow solid.

Example 6

(1-Methyl-5-nitro-1H-indol-3-yl)(phenyl)methanone (IVa)

(33) 71 mg, 68% yield; R.sub.f=0.5 (silica, EtOAc:hexane=1:9); IR (neat): 3485, 2954, 2926, 2854, 1726, 1634, 1459, 1220, 894, 772, 688 cm.sup.1; M.P: 134-139 C.; .sup.1H NMR (400 MHz, CDCl.sub.3): 8.29 (d, J=2.6 Hz, 1H), 8.15 (dd, J=9.2, 2.6 Hz, 1H), 7.57-7.51 (m, 2H), 7.42-7.36 (m, 3H), 6.58 (d, J=9.2 Hz, 1H), 5.47 (s, 1H), 3.05 (d, J=5.2 Hz, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) 158.0, 139.0, 131.5, 131.3, 129.0, 127.0, 125.2, 123.1, 115.0, 111.0, 95.5, 88.0, 43.0; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.16H.sub.13N.sub.2O.sub.2.sup.+ 281.1690, found 281.1702.

Example 7

(1-Methyl-5-nitro-1H-indol-3-yl)(p-tolyl)methanone (IVb)

(34) 75 mg, 71%) yield; R.sub.f=0.6 (silica, EtOAc:hexane=1:9); IR (neat): 2954, 2854, 2209, 1597, 1511, 1444, 1323, 1269, 1079, 906, 820, 772, 750 cm.sup.1; M.P: 113-118 C.; .sup.1H NMR (500 MHz, CDCl.sub.3): 8.58 (d, J=2.2 Hz, 1H), 8.15 (dd, J=9.0, 2.2 Hz, 1H), 7.42-7.39 (m, 2H), 7.36 (d, J=9.0 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 6.69 (d, J=0.7 Hz, 1H), 3.79 (s, 3H), 2.45 (s, 3H); .sup.13C NMR (125 MHz, CDCl.sub.3): 145.1, 142.0, 141.1, 139.0, 130.0, 129.4, 129.0, 127.3, 118.0, 117.3, 109.5, 104.0, 32.0, 21.5; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.17H.sub.15N.sub.2O.sub.3.sup.+ 295.1083, found 295.1084.

Example 8

(1-methyl-5-nitro-1H-indol-3-yl)(2-nitrophenyl)methanone (IVc)

(35) 9 mg, 91% yield; R.sub.f 0.6 (silica, EtOAc:hexane=2:8); IR (neat): 3423, 3098, 2946, 1740, 1614, 1577, 1524, 1326, 1142, 1068, 855, 756, 670 cm.sup.1; M.P: 187-192 C.; .sup.1H NMR (500 MHz, CDCl.sub.3): 8.58 (d, J=2.2 Hz, 1H), 8.19-8.14 (m, 2H), 7.77 (td, J=7.5, 1.3 Hz, 1H), 7.70 (td, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.5, 1.5 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H), 6.66 (d, J=0.6 Hz, 1H), 3.60 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3): 149.5, 142.1, 140.4, 139.4, 134.0, 133.3, 131.0, 127.0, 127.0, 125.0, 118.1, 118.0, 110.0, 105.0, 31.2; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.16H.sub.11N.sub.3O.sub.5.sup.+ 326.1489, found 598.1474.

Example 9

(4-methoxyphenyl)(1-methyl-5-nitro-1H-indol-3-yl)methanone (IVd)

(36) 77 mg, 73% yield; R.sub.f=0.5 (silica, EtOAc:hexane=3:7); IR (neat): 3415, 2928, 2838, 1738, 1627, 1534, 1416, 1318, 1219, 894, 772, 685 cm.sup.1; M.P: 142-147 C.; .sup.1H NMR (400 MHz, CDCl.sub.3): 9.25 (d, J=1.9 Hz, 1H), 8.22 (dd, J=9.0, 1.5 Hz, 1H), 7.85 (t, J=5.5 Hz, 2H), 7.69 (s, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.02-6.98 (m, 2H), 3.93 (s, 3H), 3.90 (s, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) 189.0, 163.0, 144.0, 140.2, 139.1, 132.5, 131.1, 121.0, 120.0, 119.1, 117.5, 114.0, 110.0, 57.0, 34.1; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.17H.sub.15N.sub.2O.sub.4.sup.+ 311.1032, found 311.1039.

Example 10

Methyl 3-methoxy-4-(1-methyl-5-nitro-1H-indole-3-carbonyl) benzoate (IVe)

(37) To a stirred solution of methyl 4-((2-(dimethyl amino)-5-nitrophenyl)ethynyl)-3-methoxybenzoate (Ve) (3.0 g, 8.47 mmol) in dry DMSO (50 mL) was added Na.sub.2S.sub.2O.sub.8 (6.05 g, 25.42 mmol), The resultant mixture was put into a preheated oil bath (80 C.) for 5 h. The resultant reaction mixture was quenched with water (60 mL) and the product was extracted with ethyl acetate (250 mL). The organic phase was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3-methoxy-4-(1-methyl-5-nitro-1H-indole-3-carbonyl) benzoate (2.75 g, 88%) as a yellow solid; R.sub.f=0.5 (silica, EtOAc:hexane=4:6); IR (neat): 2924, 2854, 1724, 1634, 1527, 1464, 1371, 1293, 1232, 1142, 1026, 952, 770 cm.sup.1; M.P.=197-202 C.; .sup.1H NMR (400 MHz, CDCl.sub.3): 9.29 (d, J=2.2 Hz, 1H), 8.23 (dd, J=9.0, 2.3 Hz, 1H), 7.73 (dd, J=7.7, 1.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.45 (d, J=5.6 Hz, 1H), 7.42 (d, J=1.0 Hz, 1H), 7.38 (d, J=17.6 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H), 3.85 (s, 3H).

(38) .sup.13C NMR (100 MHz, CDCl.sub.3): 189.0, 166.5, 157.0, 144.3, 141.0, 140.4, 134.3, 133.0, 129.0, 126.0, 122.0, 120.0, 119.4, 118.5, 113.0, 110.1, 56.2, 53.0, 34.2; HRMS (m/z): [M+H].sup.+ calcd. for C.sub.19H.sub.17N.sub.2O.sub.6.sup.+ 369.1087, found 369.1085.

Example 11

3-Methoxy-4-(1-methyl-5-nitro-1H-indole-3-carbonyl) benzoic acid (IIIe)

(39) To a stirred solution of compound IVe (2.0 g, 5.43 mmol) in MeOH (20 mL) was added 10% PdC (0.2 g, 10 mol %) and conc. HCl (25 l) sequentially. The flask was evacuated and pressurized with H.sub.2 (balloon) and the reaction mixture was stirred for 6 h. After completion of reaction, The solvent was removed under reduced pressure and the pH value of the reaction mixture was adjusted to 2 with aq. HCl (2.0 M). The reaction mixture was filtered using diethyl ether and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure and purified by column chromatography to give compound of formula III (1.4 g, 76%) as a yellow solid; R.sub.f=0.5 (silica, EtOAc:hexane=7:3); IR (neat): 3417, 2951, 2852, 1725, 1622, 1661, 1583, 1435, 1293, 1047, 995, 825, 769 cm.sup.1; M.P.=162-187 C.; 1H NMR (400 MHz, DMSO-d.sub.6): 8.51 (d, J=2.2 Hz, 1H), 8.02 (dd, J=9.1, 2.3 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.50-7.45 (m, 2H), 7.36 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 4.11 (s, 2H), 3.91 (s, 3H), 3.81 (s, 3H); .sup.13C NMR (100 MHz, DMSO-d.sub.6): 167.2, 157.0, 140.3, 139.4, 134.1, 132.0, 130.1, 130.0, 126.5, 122.0, 116.4, 116.0, 115.3, 111.0, 110.3, 55.5, 33.0, 24.4; HRMS (m/z): [M+H].sup. calcd. for C.sub.18H.sub.15N.sub.2O.sub.5.sup.+ 339.0981, found 339.0967.

Example 12

3-Methoxy-4-(1-methyl-5-nitro-1H-indole-3-carbonyl)-N-(o-tolylsulfonyl) benzamide (IIe)

(40) To a stirred solution of anhydrous ZnCl.sub.2 (2 mg, 30 mol %) in anhydrous dichloromethane (2 ml), carboxylic acid compound of formula IIIe (300 mg, 0.88 mmol) was added followed by the addition of benzoic anhydride (0.12 ml, 1.05 mmol) under a nitrogen atmosphere at room temperature. After 10 min, a solution of sulphonamide (16 mg, 0.88 mmol) in CH.sub.2Cl.sub.2 (1 ml) was added dropwise and the resulting reaction mixture was stirred at room temperature for 2 h. After completion, the reaction quenched with water (5 ml) and the mixture was extracted with CHCl.sub.3 (210 mL) then the organic layer was washed with brine and the combined organic layer were dried over sodium sulphate and evaporated under reduced pressure. The crude compound was purified by column chromatography to afford compound of formula II (406 mg, 92%) as a yellow solid.

(41) R.sub.f=0.5 (silica, EtOAc:hexane=8:2); IR (neat): 3479, 2925, 2850, 1723, 1622, 1582, 1435, 1293, 1108, 767, 671 cm.sup.1; M.P.=152-156 C.; .sup.1H NMR (400 MHz, CDCl.sub.3): 9.43 (s, 1H), 8.51 (d, J=2.2 Hz, 1H), 8.25 (dd, J=8.0, 1.1 Hz, 1H), 8.10 (dd, J=9.1, 2.2 Hz, 1H), 7.52 (td, J=7.5, 1.2 Hz, 1H), 7.40 (dd, J=13.9, 5.9 Hz, 2H), 7.31-7.26 (m, 3H), 7.14 (d, J=7.8 Hz, 1H), 6.92 (s, 1H), 4.10 (s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.68 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): 164.2, 157.7, 141.4, 140.0, 138.0, 137.0, 136.0, 134.2, 133.0, 132.0, 130.5, 130.4, 130.1, 127.2, 127.0, 120.0, 117.5, 117.0, 116.0, 110.1, 109.3, 56.2; HRMS (m/z): [M+Na].sup.+ calcd. for C.sub.25H.sub.23N.sub.3O.sub.6S.sup.+ 516.1988, found 516.1975.

Example 13

Cyclopentyl (3-(2-methoxy-4-((o-tolylsulfonyl)carbamoyl)benzyl)-1-methyl-1H-indol-5-yl)carbamate (Zafirlukast) (I)

(42) A solution of N-{3-methyl-4-[(N-methyl-5-nitro-1H-3-indolyl) methyl benzoyl}-2-methyl-1-benzenesulfonamide, compound of formula II (100 mg, 0.20 mmol) in MeOH (2 mL), and Raney-nickel (2 mg, 30 mol %) was placed under hydrogen pressure at room temperature for 2 h. The reaction mass was filtered through a celite bed, and the catalyst was washed with diethyl ether (210 mL). The combined filtrates were concentrated under reduced pressure and dried using height vacuo for 1 h. The obtained residue and N-methyl morphine (26 l, 0.24 mmol) in CH.sub.2Cl.sub.2 (2 ml) was slowly added cyclopentyl chloroformate (25 l, 0.20 mmol) at 0 C., and the resulting reaction mass was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed under reduced pressure and the solid precipitate was washed with water (5 ml) and extracted with CHCl.sub.3 (10 ml) and dried over sodium sulphate and evaporated in under reduced pressure. The crude compound was purified by column chromatography to afford title product compound of formula I (102 mg, 89%) as a pale yellow solid; R.sub.f=0.7 (silica, EtOAc:hexane=4:6); IR (neat): 3476, 2951, 2925, 2850, 1723, 1689, 1554, 1499, 1431, 1270, 1163, 1062, 1036, 872, 758 cm.sup.1; M.P.=136-141 C.; 1H NMR (500 MHz, CDCl.sub.3): 9.18 (s, 1H), 8.26 (dd, J=8.0, 1.3 Hz, 1H), 7.51 (td, J=7.5, 1.3 Hz, 2H), 7.40 (t, J=7.5 Hz, 1H), 7.31 (d, J=1.5 Hz, 1H), 7.29 (d, J=7.5 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.16 (dd, J=7.9, 1.6 Hz, 1H), 7.09 (d, J=7.9 Hz, 2H), 6.77 (s, 1H), 6.51 (s, 1H), 5.18 (ddd, J=8.9, 5.9, 2.6 Hz, 1H), 4.03 (s, 2H), 3.85 (s, 3H), 3.70 (s, 3H), 2.68 (s, 3H), 1.86 (s, 2H), 1.74 (d, J=12.6 Hz, 4H), 1.60 (s, 2H); .sup.13C NMR (125 MHz, CDCl.sub.3): .sup.13C NMR (125 MHz, CDCl.sub.3) 164.4, 158.0, 138.0, 137.0, 137.0, 134.4, 134.1, 133.0, 138.0, 130.1, 130.0, 128.4, 128.1, 127.0, 119.4, 115.2, 112.0, 110.0, 110.0, 56.0, 33.0, 33.0, 25.4, 24.0, 21.0; HRMS (m/z): [M+Na].sup.+ calcd. for C.sub.31H.sub.33N.sub.3O.sub.6S.sup.+ 598.1988, found 598.1975.

Advantages of the Invention

(43) The various advantages of the present process are given below. 1. The present process serves as a highly efficient and scalable production method for the preparation of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast, an FDA approved drug for the treatment of asthma. 2. The advantage of the present invention is that the process could be operated by engaging all catalytic transformations and using CH bond activation strategy. 3. Another advantage of the present invention is protection group free synthesis involving feasible reaction parameters. 4. Isolation and/or purification of the product/s is straight forward. 5. This is an attractive and economic method for the production of (1-alkylindol-3-ylmethyl) benzoic acid derivatives, in particular Zafirlukast. 6. This process could be adopted to generate a large library of process intermediates and Zafirlukast analogues.