Efficient synthesis of pyropheophorbide a and its derivatives

• US 20040044198A1
• Filed: 07/02/2003
• Published: 03/04/2004
• Est. Priority Date: 07/02/2002
• Status: Active Grant

• Current Assignee: Health Research Incorporated
• Original Assignee: Health Research Incorporated
• Inventors: Pandey, Ravindra K., Dougherty, Thomas J., Pallenberg, Alexander J.
• Granted Patent: US 7,053,210 B2
• Time in Patent Office: Days
• 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 chlorin e6 trimethyl ester with a base in an aromatic solvent.

2. A process for the preparation of pyropheophorbide a, comprising:

(a) treating chlorin e6 trimethyl ester with a base in a high-boiling aromatic solvent to give methyl pheophorbide a; and

(b) heating the methyl pheophorbide a to effect decarboxylation and saponification.

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

(a) treating chlorin e₆ trimethyl ester with a base in a high-boiling aromatic solvent to give methyl pheophorbide a;

(b) heating of the methyl pheophorbide a to effect decarboxylation and saponification to give pyropheophorbide a; and

(c) treating the pyropheophorbide 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).

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; and

(b) re-esterifying the resulting purpurin-18.

6. A process for the preparation of ether analogs 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;

(b) re-esterifying the purpurin-18; and

(c) treating the re-esterified purpurin-18 with an acid, followed by treating with an alcohol under basic conditions.

7. 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;

(b) re-esterifying the purpurin-18; and

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

8. 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;

(b) re-esterifying the purpurin-18;

(c) treating the re-esterified purpurin-18 with a primary amine to give a purpurinimide; and

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