PROCESS FOR THE PREPARATION OF 3-SUBSTITUTED (INDOL-1-YL)-ACETIC ACID ESTERS

Abstract

The invention relates to an industrial scale process for the preparation of a compound of general formula (I): (Formula (I)) wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. The process comprises reacting compounds of general formulae (II) and (III): (formulae (II), (III)) in the presence of a Lewis acid followed by a reduction with triethylsilane.

##STR00001##

Claims

1. A process for the preparation of a compound of general formula (I): ##STR00016## wherein R.sup.1 is fluoro, chloro or bromo; R.sup.2 is C.sub.1-C.sub.6 alkyl or benzyl; and R.sup.3 is aryl or heteroaryl optionally substituted with one or more substituents selected from halo, OH, CN, R.sup.4, COR.sup.4, CH.sub.2R.sup.4, OR.sup.4, SR.sup.4, SO.sub.2R.sup.4, or SO.sub.2YR.sup.4; R.sup.4 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, any of which may optionally be substituted with one or more substituents selected from halo, OH, CN, NO.sub.2, C.sub.1-C.sub.6 alkyl, or O(C.sub.1-C.sub.6 alkyl); and Y is NH or a straight or branched C.sub.1-C.sub.4 alkylene chain; the process comprising: i. reacting a compound of general formula (II): ##STR00017## wherein R.sup.1 and R.sup.2 are as defined for general formula (I); with a compound of general formula (III) ##STR00018## wherein R.sup.3 is as defined for general formula (I); in a suitable solvent and in the presence of titanium tetrachloride, wherein the ratio of the compound of general formula (II) to solvent is from 1:8 to 1:20 weight/volume; and ii. reacting the product of (i) with a reducing agent to give a compound of general formula (I).

2. The process of claim 1, wherein, in the compound of general formula (I), independently or in any combination: R.sup.1 is fluoro; R.sup.2 is C.sub.1-C.sub.4 alkyl; and R.sup.3 is quinoline, quinoxaline, isoquinoline, thiazole, phenyl, naphthalene, thiophene, pyrrole, or pyridine, any of which may optionally be substituted as set out in claim 1.

3. The process of claim 1, in the compound of general formula (I), R.sup.2 is methyl or ethyl.

4. The process of claim 1 wherein, in the compound of general formula (I), R.sup.3 is quinoline, isoquinoline, phenyl, naphthalene, thiophene, pyrrole or pyridine, any of which may optionally be substituted as set out in claim 1.

5. The process claim 4 wherein, in the compound of general formula (I), R.sup.3 is quinoline or isoquinoline, either of which is unsubstituted or substituted with one or more halo substituents.

6. The process of claim 1 wherein, in the compound of general formula (I), R.sup.3 is phenyl, naphthalene, thiophene, pyrrole, or pyridine, any of which is optionally substituted with one or more substituents, selected from OR.sup.4, SO.sub.2R.sup.4, or SO.sub.2YR.sup.4; where R.sup.4 and Y are as defined in claim 1.

7. The process of claim 1 for the preparation of a compound of formula (Ia): ##STR00019## wherein R.sup.1 and R.sup.2 are as defined in claim 1; and R.sup.5 is hydrogen, halo, —CN, —C.sub.1-C.sub.6 alkyl, —SOR.sup.7, —SO.sub.2R.sup.7, —SO.sub.2N(R.sup.6).sub.2, —N(R.sup.6).sub.2, —NR.sup.6C(O)R.sup.7, —CO.sub.2R.sup.6, —CONR.sup.6R.sup.7, —NO.sub.2, —OR.sup.6, —SR.sup.6, —O(CH.sub.2).sub.pOR.sup.6, or —O(CH.sub.2).sub.pO(CH.sub.2).sub.qOR.sup.6, wherein each R.sup.6 is independently hydrogen, —C.sub.1-C.sub.6 alkyl, —C.sub.3-C.sub.8 cycloalkyl, aryl, or heteroaryl; each R.sup.7 is independently, —C.sub.1-C.sub.6 alkyl, —C.sub.3-C.sub.8 cycloalkyl, aryl, or heteroaryl; and p and q are each independently an integer from 1 to 3.

8. The process of claim 7 wherein, in the compound of general formula (Ia), independently or in combination: R.sup.1 is fluoro; R.sup.2 is methyl or ethyl; and R.sup.5 is hydrogen, fluoro, or chloro.

9. The process of claim 1 for the preparation of a C.sub.1-C.sub.6 alkyl or benzyl ester of: {3-[1-(4-Chloro-phenyl)-ethyl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid; {5-Fluoro-2-methyl-3-[1-(4-trifluoromethyl-phenyl)-ethyl]-indol-1-yl}-acetic acid; {3-[1-(4-tert-Butyl-phenyl)-ethyl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid; {5-Fluoro-3-[1-(4-methanesulfonyl-phenyl)-ethyl]-2-methyl-indol-1-yl}-acetic acid; [5-Fluoro-2-methyl-3-(1-naphthalen-2-yl-ethyl)-indol-1-yl]-acetic acid; (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-naphthalen-2-ylmethyl-indol-1-yl)-acetic acid; [5-Fluoro-3-(8-hydroxyquinolin-2-ylmethyl)-2-methyl-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(quinoxalin-2-ylmethyl)indol-1-yl]-acetic acid; [5-Fluoro-3-(4-methoxy-benzyl)-2-methyl-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(1,3-thiazol-2-ylmethyl)indol-1-yl]-acetic acid; [3-(4-Chloro-benzyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(4-trifluoromethyl-benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(4-tert-butyl-benzyl)-indol-1-yl]-acetic acid; {5-Fluoro-2-methyl-3-[(4-phenylphenyl)methyl]indol-1-yl}-acetic acid; [5-Fluoro-3-(4-methanesulfonyl-benzyl)-2-methyl-indol-1-yl]-acetic acid; {5-Fluoro-3-[(6-fluoroquinolin-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; (2-Methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid; (5-Chloro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid; (3-{[1-(Benzenesulfonyl)pyrrol-2-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; [5-Fluoro-2-methyl-3-({1-[(4-methylbenzene)sulfonyl]pyrrol-2-yl}methyl)indol-1-yl]-acetic acid; [3-({1-[(2,4-Difluorobenzene)sulfonyl]pyrrol-2-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; (3-{[2-(Benzenesulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; [3-({2-[(4-Chlorobenzene)sulfonyl]phenyl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]phenyl}methyl)-2-methylindol-1-yl]-acetic acid; (3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid; [3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; 2-(3-(4-(Benzylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(4-(4-Chlorobenzylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(3-(Benzylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(5-Fluoro-3-(3-(4-fluorobenzylsulfonyl)benzyl)-2-methyl-indol-1-yl)-acetic acid; 2-(3-(2-(Benzylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(4-(4-Fluorobenzylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(2-(Cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(5-Fluoro-2-methyl-3-(2-(piperidin-1-ylsulfonyl)benzyl)-indol-1-yl)-acetic acid; 2-(3-(2-(Cyclopentylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(5-Fluoro-2-methyl-3-(3-(piperidin-1-ylsulfonyl)benzyl)-indol-1-yl)-acetic acid; 2-(5-Fluoro-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-indol-1-yl)-acetic acid; 2-(3-(4-(Cyclohexylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(4-(Cyclopentylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(3-(2-(Cyclobutylsulfonyl)benzyl)-5-fluoro-2-methyl-indol-1-yl)-acetic acid; 2-(5-Fluoro-2-methyl-3-(3-(pyrrolidin-1-ylsulfonyl)benzyl)-indol-1-yl)-acetic acid; 2-(5-Fluoro-2-methyl-3-(4-(piperidin-1-ylsulfonyl)benzyl)-indol-1-yl)-acetic acid; [5-Fluoro-2-methyl-3-(2-phenoxybenzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(4-methoxyphenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(4-methylphenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(2,4-dichlorophenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(4-fluorophenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(3,4-difluorophenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(4-cyanophenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(4-chlorophenoxy)benzyl)-indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(2-(2-cyanophenoxy)benzyl)-indol-1-yl]-acetic acid; (5-Fluoro-2-methyl-3-{[2-(4-methylphenoxy)pyridin-3-yl]methyl}indol-1-yl)-acetic acid; {5-Fluoro-3-[(3-methanesulfonylnaphthalen-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; {5-Fluoro-3-[(1-methanesulfonylnaphthalen-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; {5-Fluoro-3-[(6-methanesulfonylnaphthalen-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; [5-Fluoro-2-methyl-3-(quinolin-3-ylmethyl)indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(quinoxalin-6-ylmethyl)indol-1-yl]-acetic acid; [5-Fluoro-2-methyl-3-(quinolin-7-ylmethyl)indol-1-yl]-acetic acid; {5-Fluoro-3-[(6-methanesulfonylquinolin-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; {5-Fluoro-3-[(4-methanesulfonylquinolin-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; (5-Fluoro-2-methyl-3-{pyrazolo[1,5-a]pyridin-3-ylmethyl}indol-1-yl)-acetic acid; (5-Fluoro-3-{imidazo[1,2-a]pyridin-2-ylmethyl}-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(methylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[3-(methylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(ethylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid(3-{[4-(Ethylsulfanyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(n-propylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(i-propylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(t-butylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(pentan-3-ylsulfanyl)phenyl]methyl}indol-1-yl)-acetic acid; [3-({4-[(Cyclopropylmethyl)sulfanyl]phenyl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; {3-[(4,4-Dimethyl-2,3-dihydro-1-benzothiopyran-6-yl)methyl]-5-fluoro-2-methylindol-1-yl}-acetic acid; (3-{[2-(Ethanesulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(propane-1-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(propane-2-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[2-(Butane-1-sulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (3-{[2-(Butane-2-sulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(2-methylpropane-2-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(pentane-1-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[2-(Cyclopropylmethane)sulfonylphenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(propyl sulfamoyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[2-(Butylsulfamoyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[3-(propylsulfamoyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[3-(Butylsulfamoyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(trifluoromethane)sulfonylphenyl]methyl}indol-1-yl)-acetic acid; (3-{[4-(Ethanesulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(propane-1-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(propane-2-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[4-(Butane-1-sulfonyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(2-methylpropane-2-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(pentane-1-sulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(pentan-3-ylsulfonyl)phenyl]methyl}indol-1-yl)-acetic acid; [3-({4-[(Cyclopropylmethyl)sulfonyl]phenyl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; (5-Fluoro-2-methyl-3-{[4-(propylsulfamoyl)phenyl]methyl}indol-1-yl)-acetic acid; (3-{[4-(Butylsulfamoyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[4-(trifluoromethoxy)phenyl]methyl}indol-1-yl)-acetic acid; (5-Fluoro-3-{[4-methanesulfonyl-3-(trifluoromethyl)phenyl]methyl}-2-methylindol-1-yl)-acetic acid; (5-Fluoro-3-{[4-methanesulfonyl-3-(trifluoromethoxy)phenyl]methyl}-2-methylindol-1-yl)-acetic acid; {5-Fluoro-3-[(5-methanesulfonylthiophen-2-yl)methyl]-2-methylindol-1-yl}-acetic acid; {3-[(4,4-dimethyl-1,1-dioxo-2,3-dihydro-1λ.sup.6-benzothiopyran-6-yl)methyl]-5-fluoro-2-methylindol-1-yl}-acetic acid; [3-({1-[(4-Chlorobenzene)sulfonyl]pyrrol-2-yl}methyl)-5-fluoro-2-methylindol-1yl]-acetic acid; [5-Fluoro-3-({1-[(4-fluorobenzene)sulfonyl]pyrrol-2-yl}methyl)-2-methylindol-1-yl]-acetic acid; [5-Fluoro-3-({1-[(4-methoxybenzene)sulfonyl]pyrrol-2-yl}methyl)-2-methylindol-1-yl]-acetic acid; {3-[1-(2,4-Dichloro-benzenesulfonyl)pyrrol-2-ylmethyl]-5-fluoro-2-methyl-indol-1-yl}-acetic acid; [5-Fluoro-3-({1-[(4-methanesulfonylbenzene)sulfonyl]pyrrol-2-yl}methyl)-2-methylindol-1-yl]-acetic acid; {5-Fluoro-2-methyl-3-[(2-phenylphenyl)methyl]indol-1-yl}-acetic acid; (3-{[1-(Benzenesulfonyl)indol-2-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (3-{[2-(4-Chlorophenyl)phenyl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; (5-Fluoro-2-methyl-3-{[2-(4-methylphenyl)phenyl]methyl}indol-1-yl)-acetic acid; {5-Fluoro-2-methyl-3-[(3-phenoxyphenyl)methyl]indol-1-yl}-acetic acid; [5-Fluoro-3-({4-[(4-fluorophenyl)carbonyl]-1-methylpyrrol-2-yl}methyl)-2-methylindol-1-yl]-acetic acid; {5-Fluoro-2-methyl-3-[(6-{[3-(trifluoromethyl)phenyl]methyl}pyridin-3-yl)methyl]in 1-yl}-acetic acid; {5-Fluoro-2-methyl-3-[(3-phenoxythiophen-2-yl)methyl]indol-1-yl}-acetic acid; (3-{[2-(Benzenesulfonyl)-1,3-thiazol-5-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; {3-[(1-Benzylpyrazol-4-yl)methyl]-5-fluoro-2-methylindol-1-yl}-acetic acid; (3-{[5-(4-Chlorophenoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; [3-({5-[(4-Chlorobenzene)sulfonyl]furan-2-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; [3-({5-[(4-Chlorobenzene)sulfonyl]thiophen-2-yl}methyl)-5-fluoro-2-methylindol-1yl]-acetic acid; [3-({3-[(4-Chlorobenzene)sulfonyl]thiophen-2-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid; or {3-[(2-Benzylphenyl)methyl]-5-fluoro-2-methylindol-1-yl}-acetic acid.

10. The process of claim 1 for the preparation of a C.sub.1-C.sub.6 alkyl or benzyl ester of: (3-{[2-(Benzenesulfonyl)pyridin-3-yl]methyl}-5-fluoro-2-methylindol-1-yl)-acetic acid; [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid; or [3-({2-[(4-Chlorobenzene)sulfonyl]pyridin-3-yl}methyl)-5-fluoro-2-methylindol-1-yl]-acetic acid.

11. The process of claim 1, wherein the solvent is a halogenated solvent.

12. The process of claim 11, wherein the solvent is dichloromethane.

13. The process of claim 1, wherein the ratio of the compound of general formula (II) to solvent is from 1:10 to 1:12 weight/volume.

14. The process of claim 1, wherein the molar ratio of titanium tetrachloride to the compound of formula (II) is from 1:1 to 3:1.

15. The process of claim 14, wherein the molar ratio of titanium tetrachloride to the compound of formula (II) is from about 1.8:1 to 2.2:1.

16. The process of claim 1, wherein the reaction temperature of (i) is −10 to 25° C.

17. The process of claim 1, wherein, in (i) after the addition of the compounds of general formulae (II) and (III), the reaction mixture is stirred for about 12 to 18 hours.

18. The process of claim 1, wherein, in (ii), the reduction is carried out using triethylsilane.

19. The process of claim 19, wherein the molar ratio of triethylsilane to the compound of general formula (II) is from about 2:1 to 4:1.

20. The process of claim 1, further comprising: (iii) isolating and purifying the compound of general formula (I).

21. The process of claim 1, further comprising: (iv) converting the compound of formula (I) to a compound of general formula (V): ##STR00020## wherein R.sup.1 and R.sup.3 are as defined in claim 1; the process comprising hydrolysing the compound of formula (I).

22. The process of claim 1, further comprising, before (i), a process for the preparation of a compound of formula (II) comprising: reacting 5-fluoro-2-methyl indole with a compound of the formula (VI):
X—CH.sub.2—COOR.sup.1  (VI) where X is a leaving group and R.sup.1 is as defined for formula (I).

Description

[0206] The invention will now be described in greater detail with reference to the examples.

[0207] In the examples, the following abbreviations are used:

TABLE-US-00001 TFA Trifluoroacetic acid TES Triethyl silane Et Ethyl DCM dichloromethane IPC In process control TMSOTf Trimethylsilyl trifluoromethane sulfonate TLC Thin layer chromatography HPLC High performance liquid chromatography

[0208] In the examples set out below, and in the whole specification values for amounts of various compounds are expressed in terms of % area. This refers to the percentage of the area of the peak representing a particular molecule on an HPLC trace. Suitable HPLC methods may be developed by those of skill in the art.

[0209] The HPLC parameters used in Comparative Example 4 and Example 5 are summarised in the table below.

TABLE-US-00002 HPLC Parameter Condition/Details Additional Information Detection UV@ 220 HM N/A Type/Wavelength Column Waters Eclipse 150 mm × 4.6 mm id 5μ XDB-C18 Injection Volume   5 μL N/A Flow Rate 1.5 mL/min N/A Run Time 15 minutes N/A Mobile Phase A 100% water N/A Mobile Phase B  0.1% Formic Acid N/A Mobile Phase C 100% Acetonitrile N/A Starting Conditions 50:5:45% A:B:C Gradient System Time % A:B:C  5 50:5:45 10 15:5:80 12 15:5:80 14 50:5:45 Column Temperature 35° C. N/A

EXAMPLE 1—PREPARATION OF 5-FLUORO-2-METHYL-INDOLE N-ETHYL ACETATE (PROCESS STAGE 1)

Experimental Protocol

[0210] Into a reaction mixture of 1.0 Kg of 5-fluoro-2-methylindole (1.0 eq., 6.70 mol) and 0.99 kg of caesium carbonate (3.02 mol-0.45 eq.) with 9 L acetonitrile is added at 20-25° C. over ˜12 h a solution of 1.34 kg ethylbromoacetate (8.04 mol-1.2 eq.) in 1 L acetonitrile. Two additional charges of 0.99 kg caesium carbonate each are added after 4 hours and after 8 hours of reaction (3.02 mol-0.45 eq.). A final charge of 0.33 kg caesium carbonate is added (1.01 mol-0.15 eq.) and 0.056 kg of ethyl bromoacetate (0.335 mol 0.15 eq.) are added after 18 hours. The reaction mixture is maintained under agitation at 20-25° C. until the reaction is complete. 5 L of water is added to dissolve the inorganic salts. The agitation is maintained at 20-25° C. until complete dissolution of the inorganic salts then the reaction mixture is allowed to separate. The organic phase is concentrated to approximately 3 L. Toluene (5 L) is added then the mixture is concentrated to approximately 3 L. Toluene (5 L) is added to the reaction mixture; which is then washed with water (3 L) to eliminate the residual salts and concentrated to approximately 3 L under vacuum. Expected Yield: 90±5%.

Scaled Up Method

[0211] The above method has been carried out with a batch size of up to 234 kg of 5-fluoro-2-methyl indole.

[0212] The quantity of (5-fluoro-2-methylindol-1-yl)-acetic acid ethyl ester recovered was 337 kg, a yield of 91.3%; which compared well with the expected yield of 90±5%.

EXAMPLE 2—INVESTIGATION OF REACTION CONDITIONS FOR SYNTHESIS OF [5-FLUORO-3-({2-[(4-FLUOROBENZENE)SULFONYL]PYRIDIN-3-YL}METHYL)-2-METHYLINDOL-1-YL]-ACETIC ACID ETHYL ESTER

[0213] The reaction between 2-(4-Fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde and 5-fluoro-2-methyl-indole N-ethyl acetate proceeds in two steps according to the scheme set out below. 2-(4-Fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde may be prepared as described in WO2009/090414.

##STR00014##

[0214] When conducted on a laboratory scale, the process described in WO2009/090414 leads to good quality material with acceptable yield but the very high dilution (50 vol of methylene chloride) and high cost of trimethylsilyl trifluoromethanesulfonate TMSOTf) as the Lewis acid were not considered acceptable for larger scale production.

[0215] Trials using TMSOTf were performed at higher concentration (about 10 volumes solvent per mass of starting indole) but in these experiments, the intermediate alcohol precipitated as a gummy material that agglomerated on the stirrer blade. This could lead to equipment damage at larger scale. At higher dilution (50 volumes solvent per mass of starting indole), the insoluble material was still present but did not agglomerate on the stirrer.

a) Step 1—Production of Intermediate Alcohol

[0216] A screen was performed in order to determine whether other Lewis acids could be used instead of TMSOTf. TFA, Trifluoromethanesulfonic acid (triflic acid), BF.sub.3, AlCl.sub.3, ZnBr.sub.2 all led either to a high content of bis-indolyl impurity of the formula:

##STR00015##

or to an insoluble gummy material. With titanium chloride, however the alcohol intermediate precipitated as a brown solid leading to a stirrable suspension.

[0217] The results of six representative experiments are presented in Table 1 below which summarises the HPLC profile (area %) of the major components of the reaction mixtures before the reduction step. All of the reactions were carried out in 10-12 volumes of methylene chloride per mass of indole starting material.

[0218] The starting materials were introduced over 60-150 minutes at temperatures from −10 to +20° C. Several Lewis acids were tested and results are shown for AlCl.sub.3, ZnBr.sub.2 and TiCl.sub.4.

TABLE-US-00003 TABLE 1 Bis- Starting indolyl Alcohol.sup.(2) indole Lewis (RRT (RRT 0.75 + (RRT Extent of reaction when Expt. Addition time .sup.(1) Acid/eq 1.18) 0.95) 0.78) sample taken (i)  60 min/0° C. AlCl.sub.3 55.1 28.2 ND End of addition of starting 2 eq materials (ii)  60 min/0° C. ZnBr.sub.2 30.8 46.6 19.5 End of addition of starting 2 eq materials (iii) 120 min/−10° C. TiCl.sub.4 10.8 85.8 0.1 a) Approximately halfway 2 eq through addition of starting materials 9.6 83.3 0 b) End of addition of starting materials (iv)  90 min/0° C. TiCl.sub.4 9.9 86.6 ND a) Approximately halfway 1.1 eq through addition of starting materials 18.2 72.8 0 b) End of addition of starting materials +105 min aging at 20° C. (v) 120 min/0° C. TiCl4 8.36 88.59 ND End of addition of starting 2 eq materials (vi) 120 min/20° C. TiCl.sub.4 10.4 86.2 ND a) End of addition of starting 2 eq materials 4.6 89.8 0.1 b) 20 h after the addition of starting materials .sup.(1) i.e. time taken to add starting materials and reaction temperature upon dosing of a solution of the aldehyde and the indole onto the Lewis acid .sup.(2)the HPLC chromatograms show two peaks that disappeared during the reduction step. The major one was identified as the alcohol by LC/MS. The value in the table is the sum of the area % of the two peaks.

[0219] When the results for experiments (i) and (ii) are compared with those for experiments (iii) to (vi) it can be seen that the amount of bis-indolyl impurity was significantly higher and the amount of alcohol was significantly lower using AlCl.sub.3 or ZnBr.sub.2 as the Lewis acid than when TiCl.sub.4 was used.

[0220] The results of experiments (iii) (v) and (vi) show that varying the reaction temperature from −10° C. to 20° C. had no significant impact on the analytical profile of the reaction mixture.

[0221] In Exp. (iv), the stoichiometry of the titanium chloride was decreased from 2.0 to 1.1 and this led to the formation of a larger amount of bis-indolyl impurity (˜20%).

b) Step 2 Reduction of Intermediate Alcohol to Give [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid ethyl ester

[0222] The reduction was performed with 3 equivalents of triethylsilane (TES) at room temperature.

Stability of the Intermediate Alcohol

[0223] The main impurity generated in the reaction is the bis-indolyl product resulting from the condensation of the intermediate with a second equivalent of indole starting material.

[0224] It is believed that, when a protic acid is used, the reaction proceeds as shown in Scheme 3 above, where the bis-indolyl impurity is in equilibrium with the alcohol.

[0225] With some Lewis acids, particularly TMSOTf, the bis-indolyl impurity can be completely removed during the reduction step by the addition of water, which brings about reversion to the alcohol and indole starting material. However, this leads to a yield loss.

[0226] When the reaction was conducted using TiCl.sub.4 as the Lewis acid, it was surprisingly found that under certain conditions the bis-indolyl product could be converted to the required product. This led the inventors to speculate that the reaction may proceed via one or more alternative intermediates instead of, or in addition to the alcohol. However, the nature of these intermediates has not been investigated at this time.

[0227] Thus, during a stability study of the reaction mixture (Experiment vi) it was demonstrated that at 20° C. the reverse reaction leading from the bis-indolyl to an intermediate is favoured; leading after 24 h of stirring to a level of bis-indolyl by-product lower than 5%. At 40° C., a degradation of the alcohol is observed.

[0228] Results from the whole reaction, including the reduction step are shown below in Table 2. Results are provided for the reduction stage of the experiments (iii), (v) and (vi) shown in Table 1 above; together with additional experiments carried out using TMSOTf as the Lewis acid. All reactions were performed in 10-12 volumes of methylene chloride per mass of indole starting material apart from Experiment (ix), which was performed in 50 volumes. With the titanium chloride process, the viscosity of the reaction mixture increases during the reduction and it is therefore necessary to add the TES slowly to the reaction mixture.

[0229] Our results show that using TiCl.sub.4 or TMSOTf as a Lewis acid did not lead to a significant difference in the content of the bis-indolyl at the end of the reduction step.

[0230] When TMSOTf is used, the addition of a small amount of water leads to the disappearance of the bis-indolyl impurity over a period of 1-3 hours and to the formation of the indole starting material and the required product. Thus, although the bis-indolyl impurity can be removed without difficulty, Table 2 shows that a decrease in yield of the required product and, an increase in the amount of starting indole is observed for Experiments (vii), (viii) and (ix) when compared to Experiments (iii), (v) and (vi).

[0231] With titanium chloride as Lewis acid, the bis-indolyl slowly reverts to an intermediate, which is then reduced to the required product.

[0232] The HPLC profile of the reaction mixture after reduction is similar or better if using titanium chloride instead of TMSOTf.

TABLE-US-00004 TABLE 2 Bis- Alcohol Starting indolyl RRT material Lewis RRT 0.75 + RRT Expt Addition time.sup.(1) Acid/eq TES.sup.(2).sub.Charging time/Temp 1.18 0.95 Prod 0.78 When measured (iii) 120 min/−10° C. TiCl.sub.4  20 min/0° C. 10.8 85.8 ND 0.1 a) Approximately 2 eq half way through addition 9.6 83.3 4.8 0 b) End of addition ND ND 92.1 4.8 c) after overnight stirring with TES (v) 120 min/0° C. TiCl.sub.4 110 min 8.36 88.59 1.05 ND a) End addition of starting 2 eq 20° C. materials 2.74 93.29 2.109 ND b) Before TES charge = 23 H at 20° C. ND ND 94.0 1.17 c) TES 18 H (vi) 120 min/20° C. TiCl.sub.4  80 min/20° C. 10.4 86.2 1.2 ND a) End addition of starting 2 eq materials 4.6 89.8 2.9 0.1 b) Before TES charge = 21 H 15 at 20° C. 0.9 1.1 94.8 1.2 c) TES 4 h 15 (vii) 120 min/0° C. TMS-  2 min/0° C. 13.1 ND 77.6 1.5 a) 1 h after TES addition OTf 5.2 ND 83.5 4.8 b) 20 h after TES addition 2 eq (viii) 100 min/0° C. TMS-  2 min/0° C. 11.2 ND 76.6 1.3 a) 2 h 45 after TES charge OTf 1.7 83.8 5.7 b) After 1.0 eq water 2 eq (ix) 120 min/0° C. TMS-  2 min/0° C. 11.5 ND 83 1.5 a) 1 h after TES charge OTf 0.1 ND 89.5 5.2 b) After 1.0 eq water 2 eq .sup.(1)i.e. time taken to add starting materials and reaction mixture temperature of the dosing of a solution of the aldehyde and the indole onto the Lewis acid .sup.(2)TES dosing time and reaction mixture temperature

EXAMPLE 3—PREPARATION OF [5-FLUORO-3-({2-[(4-FLUOROBENZENE)SULFONYL]PYRIDIN-3-YL}METHYL)-2-METHYLINDOL-1-YL]-ACETIC ACID ETHYL ESTER

Experimental Protocol

[0233] A reactor is charged with 1.612 kg of TiCl.sub.4 (2 equivalents with respect to 5-fluoro-2-methyl-indole N-ethyl acetate) and 5 litres of dichloromethane. The vessel is cooled to 0±3° C. A solution of 1 kg 5-fluoro-2-methyl-indole N-ethyl acetate and 1.18 kg of 2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde (1.05 equiv.) in 6 litres of dichloromethane is prepared using another vessel and is added to the TiCl.sub.4 solution over a period of 2 hours, keeping the temperature at 0±3° C. (the formation of a precipitate is observed during the addition). The vessel is rinsed with 1 litre of dichloromethane, which is then added to the reaction mixture. The mixture is heated up to 20±3° C. and held at this temperature for 15 hours until completion of the reaction.

[0234] 1.483 kg of triethylsilane (3 equiv) is added to the mixture, at 20±3° C., over about 2 hours. The charging vessel and lines are rinsed with 0.5 litre of dichloromethane, which is added to the reaction and the slurry is maintained at 20±3° C. for 4 hours until judged complete by HPLC.

Work-Up

[0235] The slurry is cooled to 0-5° C. and 4 litres of water is added quickly, keeping the temperature below 20° C. The aqueous layer is separated and washed with 2 litres of dichloromethane. The organic layers are combined and washed with 3 litres of water, followed by an aqueous solution of sodium bicarbonate (9% w/w), until pH of the aqueous phase reaches 8.0±1. The aqueous layer is discarded and the organic phase is further washed with 2 litres of water and the pH is checked (pH=8.0±1). The objective at this point is to neutralise the HCl from the hydrolysis of titanium tetrachloride.

[0236] The organic layer is dried by azeotropic distillation under atmospheric pressure. The dried solution is filtered into another vessel and the filtrate is concentrated to a residual volume of about 6 litres (6 vol). Ethanol (6 litres) is then added keeping the temperature above 50° C. and the mixture is concentrated to a residual volume of about 6 litres. The product crystallizes during concentration. A further 2 litres of ethanol are added and the suspension is concentrated again to 6 litres. At the end of this step the temperature at the top of the distillation column is above 76° C.

[0237] The suspension is cooled to 20±3° C. and filtered. The wet cake is washed twice with 3 litres of ethanol at 20±3° C., air dried and transferred to a vacuum dryer. The product is dried at 55° C. under vacuum.

[0238] Yield=85±7%.

Scaled Up Method

[0239] The reaction described above was carried out using 8 kg 5-fluoro-2-methyl-indole N-ethyl acetate and 9.5 kg of 2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde in 48 L dichloromethane which was added to 12.9 kg of titanium tetrachloride in 40 L dichloromethane. During introduction of the starting materials, the intermediate alcohol precipitated but the mixture did not become too thick and stirring remained efficient. The amount of triethylsilane used for the reduction was 12 kg. The amount of [5-fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid ethyl ester obtained was 13.8 kg, an overall yield of 84.2%. The purity of the product was 99% area by HPLC or 96.1% w/w.

[0240] A further pilot run was carried out using 7.7 kg 5-fluoro-2-methyl-indole N-ethyl acetate and 9.1 kg of 2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde in 46 L dichloromethane which was added to 12.4 kg of titanium tetrachloride in 39 L dichloromethane. The amount of triethylsilane used in the reduction step was 11.4 kg.

[0241] 13.5 kg (85.6% yield) of product was obtained and analysis showed that the purity of the product was 99% area by HPLC or 98.2% w/w.

[0242] The process of the invention was therefore demonstrated to give a product with a yield which was consistently greater than 80% and of which the purity was consistently greater than 95% w/w.

[0243] The product obtained may be converted to [5-Fluoro-3-({2-[(4-fluorobenzene)sulfonyl]pyridin-3-yl}methyl)-2-methylindol-1-yl]-acetic acid using the method set out in WO2009/090414.

COMPARATIVE EXAMPLE 4—SYNTHESIS OF (3-{[2-(BENZENESULFONYL)PYRIDIN-3-YL]METHYL}-5-FLUORO-2-METHYLINDOL-1-YL)-ACETIC ACID ETHYL ESTER USING TMSOTF

[0244] Using a similar method to that set out in WO2009/090414, an experiment was conducted using TMSOTf as the Lewis acid for the coupling of 5-fluoro-2-methyl-indole N-ethyl acetate and 2-(benzenesulfonyl)-pyridine-3-carboxaldehyde, followed by reduction with TES. 2-(Benzenesulfonyl)-pyridine-3-carboxaldehyde was prepared according to the method similar to that set out in WO2009/090414.

[0245] A solution of TMSOTf (31.0 g, 0.139 mol) in dichloromethane (310 mL) was cooled to −5° C. under a nitrogen atmosphere. A solution of 5-fluoro-2-methyl-indole N-ethyl acetate (10.92 g, 0.046 mol) and 2-(benzenesulfonyl)-pyridine-3-carboxaldehyde (11.46 g, 0.046 mol) in dichloromethane (310 mL) was added to the triflate solution over 40 min maintaining the temperature at 0° C. The reaction mixture was aged for a further 30 min, then triethylsilane (16.2 g, 0.140 mol) was added and warmed to ambient temperature. Sodium bicarbonate solution (saturated, 225 mL) was added, the phases separated and the organic phase was washed with water (100 ml) then concentrated to dryness. Some supernatant liquid was removed from the oil by decantation and the residual oil was triturated with water (140 mL) to produce a solid. The solid was dissolved in acetone (90 mL) at 50° C. and crystallized by the addition of water (35 mL) at 0° C. The product was filtered and dried in a vacuum oven overnight to yield the desired product (14.7 g, 68%). LC-MS analysis showed the product to be a single component.

[0246] Because of the high dilution necessary and the low yield obtained using this method, an alternative synthesis was attempted using titanium tetrachloride as the Lewis acid rather than TMSOTf.

EXAMPLE 5—SYNTHESIS OF (3-{[2-(BENZENESULFONYL)PYRIDIN-3-YL]METHYL}-5-FLUORO-2-METHYLINDOL-1-YL)-ACETIC ACID ETHYL ESTER USING TITANIUM TETRACHLORIDE AS THE LEWIS ACID

[0247] The method of Example 3 was repeated using 2-(benzenesulfonyl)-pyridine-3-carboxaldehyde as a starting material in place of 2-(4-fluorobenzenesulfonyl)-pyridine-3-carboxaldehyde. This may be prepared by the method set out in WO2009/090414. The reaction was first conducted on an 11 g scale of 2-(benzenesulfonyl)-pyridine-3-carboxaldehyde and was subsequently repeated on a 150 g and a 230 g scale. The method for the 150 g scale experiment is as follows.

[0248] Titanium tetrachloride (219.2 g, 1.155 mol, Aldrich 99.9%) was dissolved in DCM (0.54 L) and cooled to −5° C. A solution of 2-(benzenesulfonyl)-pyridine-3-carboxaldehyde (150.0 g, 0.607 mol) and 5-fluoro-2-methyl-indole N-ethyl acetate (135.9 g, 0.578 mol) in dichloromethane (0.81 L) was added over 2 hours 10 minutes maintaining the temperature below 0° C. (typically −1° C.). The reaction was aged for a further 2 hours with the mixture developing into a thick slurry. TLS (ethyl acetate/heptane 1:1) and LC-MS indicated complete consumption of starting materials. Triethylsilane (201.5 g, 1.737 mol, Aldrich 99%) was added over 2 hours, maintaining the temperature at 20-25° C., then stirred at 20-25° C. overnight. A darkening of the reaction mixture was observed during the addition of the reducing agent. The reaction mixture was cooled to 0-5° C. and water (0.54 L) was added maintaining the exotherm at <15° C. The solids dissolved during the water addition and the resulting aqueous and organic phases were separated. The organic phase was sequentially washed with water (0.70 L), sodium bicarbonate (saturated 2×0.50 L) and water (0.50 L). The organic product solution was concentrated to half volume and ethanol (1.30 L) was added resulting in crystallization of the product. The volume of the slurry was again concentrated to half volume and then diluted with additional ethanol (0.75 L). The slurry was stirred for 1 hour at 20-25° C., filtered and the cake washed with ethanol (0.30 L), then dried under vacuum at <40° C. to give the product as a white solid (213.5 g, 79% yield). HPLC analysis showed 99.6% area of the required product with three impurities at relative retention times of 0.15 (0.06%), 0.87 (0.08%) and 1.07 (0.25%).

[0249] The method of the present invention represents a significant improvement over methods described in earlier documents as it is generally applicable to many different indole acetic acid derivatives, which methods using TFA are not. Furthermore, the reaction may be carried out using a greatly reduced amount of solvent compared with methods employing TMSOTf as the Lewis acid and it is also higher yielding.