Efficient synthesis of pyropheophorbide a and its derivatives

• US 7,053,210 B2
• Filed: 07/02/2003
• Issued: 05/30/2006
• Est. Priority Date: 07/02/2002
• Status: Expired due to Fees

• Current Assignee: Health Research Incorporated
• Original Assignee: Health Research Incorporated
• Inventors: Pandey, Ravindra K., Dougherty, Thomas J., Pallenberg, Alexander J.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): FEDOWITZ, MATTHEW L
• Application Number:
  US10/613,474
• Publication Number:
  US 20040044198A1
• Time in Patent Office: 1,063 Days
• Field of Search: 540/145, 534/15, 514/185, 514/410, 424/9.1, 424/9.362, 424/9.61
• US Class Current: 540/145
• CPC Class Codes: C07D 471/22 in which the condensed systems contains four or more hetero rings
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings

Abstract

A process for the preparation of pyropheophorbide a and its derivatives, including 3-devinyl-3-(1′-hexyloxy)ethyl-pyropheophorbide-a, otherwise known as HPPH, is provided. The process involves treating chlorin e₆, in the form of its trimethyl ester, with a base, followed by heating to give pyropheophorbide a, which is converted to HPPH by treatment with acid, followed by hexyl alcohol under basic conditions.

Claims

1. A process for the preparation of methyl pheophorbide-a, comprising treating chorin e6 trimethyl ester with a base in an aromatic solvent having a boiling point at least as high as 144°

C., the boiling point of 2,6-lutidine.

2. A process for the preparation of methyl pheophorbide-a, comprising:

(a) treating chorin e6 trimethyl ester with a base in an aromatic solvent having a boiling point at least as high as 144°

C., the boiling point of 2,6-lutidine to give methyl pheophorbide-a; and

(b) without isolating the methyl pheophobide-a from the resulting reaction mixture, heating the methyl pheophorbide-a to a temperature sufficient to effect decarboxylation and saponification of the methyl pheophorbide-a.

11. The method of claim 2 where the aromatic solvent is sym-collidine.

3. A process for the preparation of ether analogs of pyropheophorbide-a comprising:

(a) treating chorin e6 trimethyl ester with a base in an aromatic solvent having a boiling point at least as high as 144°

C., the boiling point of 2,6-lutidine to give methyl pheophorbide-a;

(b) without isolating the methyl pheophobide-a from the resulting reaction mixture, heating the methyl pheophorbide-a to a temperature sufficient to effect decarboxylation and saponification of the methyl pheophorbide-a to give pheophorbide-a; and

(c) treating the pyropheophorbide-a with an acid, followed by an alcohol under basic conditions to effect addition of the alcohol across a vinyl group.

4. The process of claim 3, wherein the alcohol is 1-hexanol (n-hexyl alcohol) to obtain 3-devinyl-3-(hexyloxy)ethyl-pyropheophorbide-a (HPPH).

5. A process for the preparation of purpurin-18, comprising:

(a) treating chlorin e₆ trimethyl ester with a base in an aromatic solvent in the presence of air to give purpurin-18 having a —

CH₂CH₂COOH group.

6. A process for the preparation of purpurinimides, comprising:

(a) treating chlorin e₆ trimethyl ester with a base in an aromatic solvent in the presence of air to give purpurin-18 having a —

CH₂CH₂COOH group;

(b) esterifying the —

CH₂CH₂COOH group to obtain purpurin-18 ester; and

(c) treating the esterified purpurin-18 with a primary amine.

7. A process for the preparation of ether analogs of purpurinimides, comprising:

(a) treating chlorin e₆ trimethyl ester with a base in an aromatic solvent in the presence of air to give purpurin-18 having a —

CH₂CH₂COOH group;

(b) esterifying the —

CH₂CH₂COOH group to obtain purpurin-18 ester;

(c) treating the esterified purpurin-18 ester with a primary amine; and

(d) treating the resulting purpurinimide with an acid, followed by an alcohol under basic conditions.

8. A process for the preparation of purpurin-18 ester, comprising:

(a) treating chlorin e₆ trimethyl ester with a base in an aromatic solvent in the presence of air to give purpurin-18 having a —

CH₂CH₂COOH group; and

(b) esterifying the —

CH₂CH₂COOH group.

9. A process for the preparation of ether analogs of purpurin-18, comprising:

treating the esterified purpurin-18 obtained by the steps of claim 8 with an acid, followed by treating with an alcohol under basic conditions.

10. The method of claim 8 where the group is esterified using diazomethane to obtain purpurin 18 methyl ester.