Process for the preparation of 1,3-substituted indenes and aryl-fused azapolycyclic componunds

• US 20030060624A1
• Filed: 04/17/2002
• Published: 03/27/2003
• Est. Priority Date: 04/20/2001
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Singer, Robert A.
• Granted Patent: US 7,091,372 B2
• Time in Patent Office: Days
• US Class Current: 544/59
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 253/30 by reactions not involving the formation of cyano groups
• CPC Class Codes: C07C 255/47 : to carbon atoms of rings being part of condensed ring systems
• CPC Class Codes: C07C 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 317/44 : having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton

Abstract

The present invention relates to processes for the preparation of any of the intermediate 1,3-substituted indenes of the formulae (Ia), (Ib) and (Ic) or a mixture thereof:

wherein R¹, R², R³, R⁴, and R⁵ are defined herein. Compounds of formulae (Ia), (Ib) and (IC) or mixtures thereof are useful in the preparation of compounds of formula (II):

wherein R², R³ and R⁶ are also defined herein.

Claims

1. A process for the preparation of any one of the compounds of formulae (Ia), (Ib) and (Ic) or a mixture thereof:

2. A process according to claim 1 wherein the palladium catalyst is formed from the combination of a palladium compound selected from the group consisting of palladium(II) acetate, palladium(II) chloride, bis-acetonitrile palladium(II) chloride, bis-benzonitrile palladium(II) chloride, palladium(II) bromide, tris(dibenzylideneacetone)dipalladium(0);

and a phosphine ligand selected from dicyclohexylphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, tri-isopropylphosphine, tri-n-propylphosphine, tri-isobutylphosphine, tri-n-butylphosphine, tri-o-tolylphosphine, triphenylphosphine, 2-(dicyclohexylphosphino)-biphenyl, or 2-dicyclohexylphosphino-2′

-(N,N-dimethylamino)biphenyl.

3. A process according to claim 1 wherein the palladium catalyst is formed from the combination of palladium(II) acetate and either tricyclohexylphosphine or tri-t-butylphosphine.

4. A process according to claim 1 wherein the base selected from sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, sodium ethoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, lithium hydride and potassium hydride.

5. A process according to claim 1 wherein the base is either sodium tert-butoxide and sodium tert-pentoxide.

6. A process according to claim 1 wherein R¹ is CN.

7. A process according to claim 1 further comprising the prior step of reacting a compound of formula (IV):

8. A process according to claim 7 wherein the base is selected from sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, and lithium hydride.

9. A process according to claim 7 wherein the base is selected from sodium tert-butoxide and sodium methoxide.

10. A process according to claim 7 wherein R¹ is CN.

17. A process according to claims 1, 7 or 11 wherein both R² and R³ are H.

18. A process according to claims 1, 7 or 11 wherein one or both of R² and R³ are (C₁-C₆)alkoxy, CF₃, fluoro or C₂F₅.

24. A process for the preparation of compounds of formula (VII):

25. A process according to claim 24 wherein the hydrogenolysis conditions comprise a hydrogenation catalyst selected from palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, and platinum oxide on carbon;

in the presence of an acid selected from sulfuric acid, hydrochloric acid, methane sulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid and perchloric acid.

26. A process according to claim 24 wherein the hydrogenolysis conditions comprise a hydrogenation catalyst selected from 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon;

in the presence of sulfuric acid, methane sulfonic acid, or a mixture of these two acids.

27. A process according to claim 24 wherein the single hydrogenation step is replaced by the two separate steps of

(a) subjecting any one of compounds of the formulae (Ia)′

, (Ib)′ and

(Ic)′

;

or mixtures thereof, wherein R², R³, R⁴ and R⁵ are as defined in claim 24;

to hydrogenolysis conditions to obtain a compound of formula (IX);

wherein R², R³ and R⁵ are as defined above;

(b) and then subjecting the compound of formula (IX) to reduction conditions to obtain a compound of formula (VII);

wherein R², R³ and R⁵ are as defined above.

28. A process according to claim 27 wherein the hydrogenolysis conditions in step (a) for the reduction of the compounds of formulae (Ia)′

, (Ib)′ and

(Ic)′

or mixture thereof to one of formula (IX) comprise treatment with a hydrogenation catalyst selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, platinum oxide on carbon;

in the presence of an acid selected from acetic acid, formic acid, benzoic acid, or salicylic acid.

29. A process according to claim 27 wherein the hydrogenolysis conditions in step (a) comprise treatment with a hydrogenolysis catalyst that is either 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon;

in the presence of either formic acid or acetic acid.

30. A process according to claim 27 wherein the reduction conditions in step (b) for reducing the nitrile compound of formula (IX) to one of formula (VII) comprise treatment with a hydrogenation catalyst selected from the group consisting of palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum oxide, and platinum oxide on carbon;

in the presence of an acid selected from sulfuric acid, hydrochloric acid, methane sulfonic acid, toluenesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, phosphoric acid and perchloric acid.

31. A process according to claim 27 wherein the reduction conditions in step (b) comprise treatment with a hydrogenation catalyst that is 5% palladium on carbon, 10% palladium on carbon or 5% platinum on carbon;

in the presence of any of sulfuric acid, methane sulfonic acid, or a combination thereof.

36. A process for the preparation of a compound of formula (VIII):

37. A process according to claim 36 wherein the basic conditions comprise the treatment with a base selected from the group consisting of sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, potassium methoxide, potassium ethoxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, triethylamine, methylimidazole, lutidine, pyridine, methylmorpholine, ethylmorpholine, diisopropylethylamine and any combination of these bases.

38. A process according to claim 36 wherein the basic conditions comprise treatment with sodium tert-butoxide, sodium ethoxide or sodium methoxide.

39. A process for the preparation of compounds of formula (II):

40. A process according to claim 39 wherein the reducing agent is selected from the group consisting of borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, lithium aluminum hydride, and a combination of sodium borohydride and boron trifluoride.

41. A process according to claim 39 wherein the reducing agent is a combination of sodium borohydride and boron trifluoride.

42. A process for the preparation of a compound of formula (II′

);

43. A process for the preparation of compounds of formula (II″

);

44. A process according to claim 43 wherein the reducing agent is selected from the group consisting of sodium borohydride (NaBH₄), sodium cyanoborohydride (NaBH₃CN) and sodium triacetoxyborohydride (NaB(OAc)₃H), boranes, aluminum-based reagents and trialkylsilanes.

45. A process for the preparation of the compounds of formula (XIV-Q):

46. A process according to claim 45 wherein the nitrogen protecting group Q is selected from —

COCF₃, —

COCCl₃, —

COOCH₂CCl₃, —

COO(C₁-C₆)alkyl and —

COOCH₂C₆H₅.

47. A process according to claim 45 wherein Q is a trifluoroacetyl or a t-butoxycarbonyl group.

48. A process according to claim 45 wherein step (ii) is carried out in a mixture of 4 or more equivalents of trifluoromethanesulfonic acid (CF₃SO₂OH) and 2 to 3 equivalents of nitric acid.

49. A process according to claim 45 wherein step (iii) is accomplished using hydrogen gas and a palladium catalyst such as palladium hydroxide, 5% palladium on carbon or 10% palladium on carbon.

50. A process for the preparation of a compound of formula (IA):

51. A process according to claim 50 wherein the nitrogen protecting group Q is trifluoroacetyl or a t-butoxycarbonyl group.

52. A process for the preparation of a compound of formula (IB):

53. A process according to claim 52 wherein the leaving group Z is selected from the group consisting of halo, halosulfonate, mesylate and tosylate, and the base is an alkali metal hydride, hydroxide or carbonate.

54. A process for preparing a compound of formula (IC):

55. A process according to claim 54 wherein the protecting group Q is a trifluoroacetate group or a t-butoxycarbonyl group.

56. A process according to claim 54 wherein in step (i) the compound of formula (XIV-Q) is reacted with a compound of formula

11. A process for the preparation of any one of compounds of the formulae (Ia), (Ib) and (Ic) or a mixture thereof:

12. A process according to claim 11 wherein the base is selected from the group consisting of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium hydride, or lithium hydride.

13. A process according to claim 11 wherein the base is sodium tert-butoxide, sodium ethoxide or sodium methoxide.

14. A process according to claim 11 wherein the palladium catalyst is prepared by the addition of a palladium compound selected from palladium(II) acetate, palladium(II) chloride, bis-acetonitrile palladium(II) chloride, bis-benzonitrile palladium(II) chloride, palladium(II) bromide, tris(dibenzylideneacetone)dipalladium(0);

and a phosphine ligand such as dicyclohexylphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, tri-isopropylphosphine, tri-n-propylphosphine, tri-isobutylphosphine, tri-n-butylphosphine, tri-o-tolylphosphine, triphenylphosphine, 2-(dicyclohexylphosphino)biphenyl, or 2-dicyclohexylphosphino-2′

-(N,N-dimethylamino)biphenyl.

15. A process according to claim 11 wherein the palladium catalyst is prepared by the addition of palladium(II) acetate to either tricyclohexylphosphine or tri-t-butylphosphine.

16. A process according to claim 11 wherein R¹ is CN.

19. A compound of any one of the formulae (Ia), (Ib) and (Ic):

20. A compound according to claim 19 wherein both R² and R³ are H.

21. A compound according to claim 19 wherein one or both of R² and R³ are (C₁-C6)alkoxy, CF₃, fluoro or C₂F₅.

22. A compound according to claim 19 wherein R¹ is CN.

23. A compound according to claim 19 selected from:

3-(Hydroxy-methoxy-methylene)-5-trifluoromethyl-3H-indene-1-carbonitrile, sodium salt;

3-(Hydroxy-methoxy-methylene)-3H-indene-1-carbonitrile, sodium salt;

3-(Ethoxy-hydroxy-methylene)-3H-indene-1-carbonitrile, sodium salt;

3-(Ethoxy-hydroxy-methylene)-5,6-dimethoxy-3H-indene-1-carbonitrile, sodium salt;

3-(Hydroxy-ethoxy-methylene)-5-trifluoromethyl-3H-indene-1-carbonitrile, sodium salt;

3-(Ethoxy-hydroxy-methylene)-7-fluoro-3H-indene-1-carbonitrile, sodium salt;

3-(Ethoxy-hydroxy-methylene)-5-fluoro-3H-indene-1-carbonitrile, sodium salt;

3-[1,3]Dioxolan-2-ylidene-5-trifluoromethyl-3H-indene-1-carbonitrile;

3-[1,3]Dioxolan-2-ylidene-3H-indene-1-carbonitrile; and

3-Benzenesulfonyl-3H-indene-1-carboxylic acid ethyl ester.

32. A compound of formula (IX):

33. A compound according to claim 32 wherein both R² and R³ are H.

34. A compound according to claim 32 wherein one or both of R²and R³ are (C₁-C₆)alkoxy, CF₃, fluoro or C₂F₅.

35. A compound according to claim 32 selected from:

3-Cyano-indan-1-carboxylic acid, ethyl ester;

6-Trifluoromethyl-3-cyano-indan-1-carboxylic acid, ethyl ester;

5,6-Dimethoxy 3-cyano-indan-1-carboxylic acid, ethyl ester;

4-Fluoro-3-cyano-indan-1-carboxylic acid, ethyl ester;

6-Fluoro-3-cyano-indan-1-carboxylic acid, ethyl ester; and

3-Benzenesulfonyl-3-Cyano-indan-1-carboxylic acid, ethyl ester.