Synthetic process for the manufacture of an ecteinaschidin compound

• US 20060111570A1
• Filed: 10/11/2005
• Published: 05/25/2006
• Est. Priority Date: 05/15/2000
• Status: Active Grant

• Current Assignee: Pharma Mar, S.A.
• Original Assignee: Pharma Mar, S.A.
• Inventors: Chicharro, Jose Luis, Perez, Marta, Fernandez, Carolina, Martin, Maria Jesus, Gallego, Pilar, Zarzuelo, Maria, Manzanares, Ignacio, Cuevas, Carmen, Munt, Simon, Francesch, Andres
• Granted Patent: US 7,420,051 B2
• Time in Patent Office: Days
• US Class Current: 544/339
• CPC Class Codes: C07D 471/18 Bridged systems
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 515/22 in which the condensed system contains four or more hetero rings

Abstract

Processes are provided for preparing compounds with a fused ring structure of formula (XIV). Such products include ecteinascidins and have a spiroamine-1,4-bridge. The process involving forming a 1,4 bridge using a 1-labile, 10-hydroxy, 18-protected hydroxyl, di-6,8-en-5-one fused ring compound. After formation of the 1,4 brige, C-18 protection is removed before spiroamine introduction.

Claims

1-27. -27. (canceled)

28. A process step in the manufacture of an ecteinascidin compound, wherein the step comprises deprotecting a compound of formula (A) to give an α

-aminelactone of formula (35), in accordance with the following scheme;

30. The process of claim 28, wherein Prot^NH is t-butyloxycarbonyl and Prot^OH is methoxymethoxy.

31. The process of claim 28, wherein Prot^NH is t-butyloxycarbonyl and Prot^OH is methoxyethoxymethoxy.

32. The process of claim 28, which further comprises the step of oxidising the α

-aminelactone of formula (35) to form an α

-ketolactone of formula (36) in accordance with the following scheme;

33. The process of claim 32, wherein oxidizing the α

-aminelactone of formula (35) comprises transaminating the α

-aminelactone of formula (35).

34. The process of claim 32, which further comprises converting stereo specifically the α

-ketolactone of formula (36) to a spirotetrahydroisoquinoline compound Et770, in accordance with the following scheme;

35. The process of claim 34, wherein converting stereospecifically the α

-ketolactone of formula (36) comprises performing a Pictet-Spengler reaction.

36. The process of claim 34, which further comprises replacing the nitrile group at C-21 of Et770 with a hydroxy group to form Et743:

29. (canceled)

37. A process step in the manufacture of an ecteinascidin compound, wherein the step comprises oxidizing an α

-aminelactone of formula (35) to form an α

-ketolactone of formula (36) in accordance with the following scheme;

38. The process of claim 37, wherein oxidizing the α

-aminelactone of formula (35) comprises transaminating the α

-aminelactone of formula (35).

39. The process of claim 37, which further comprises converting stereospecifically the α

-ketolactone of formula (36) to a spirotetrahydroisoquinoline compound Et770, in accordance with the following scheme;

40. The process of claim 39, wherein converting stereospecifically the α

-ketolactone of formula (36) comprises performing a Pictet-Spengler reaction.

41. The process of claim 39, which further comprises replacing the nitrile group at C-21 of Et770 with a hydroxy group to form Et743:

42. A process step in the manufacture of an ecteinascidin compound, wherein the step comprises converting stereospecifically an α

-ketolactone of formula (36) to a spirotetrahydroisoquinoline compound Et770, in accordance with the following scheme;

43. The process of claim 42, wherein converting stereospecifically the α

-ketolactone of formula (36) comprises performing a Pictet-Spengler reaction.

44. The process of claim 42, which further comprises replacing the nitrile group at C-21 of Et770 with a hydroxy group to form Et743:

45. An intermediate for the synthesis of an ecteinascidin compound, the intermediate being of the formula (35):

46. An intermediate for the synthesis of an ecteinascidin compound, the intermediate being of the formula (36):