Process for production of 2-phosphated esters of ascorbic acid

• US 5,118,817 A
• Filed: 10/17/1990
• Issued: 06/02/1992
• Est. Priority Date: 10/31/1989
• Status: Expired due to Fees

• Current Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Kawashima, Yasushi, Yoshida, Kokichi
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): Owens, Amelia A.
• Application Number:
  US07/599,079
• Time in Patent Office: 594 Days
• Field of Search: 549/222
• US Class Current: 549/222
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A process for the production of 2-phosphated esters of ascorbic acid by subjecting an ascorbic acid optionally protected at the 5- and 6-positions to phosphorylation with maintaining the concentration of the optionally protected ascorbic acid in a reaction mixture at less than 0.3 M and, if necessary, removing any protecting group is disclosed. 2-Phosphated ester of ascorbic acid can be produced with a good yield in an industrial scale by this process.

Claims

1. In an improved process for the production of 2-phosphated esters of ascorbic acid which comprises subjecting an ascorbic acid optionally protected at the 5- and 6-positions to phosphorylation, followed, if necessary, by removing any protecting group, the improvement is characterized by maintaining the concentration of the optionally protected ascorbic acid in a reaction mixture at less that 0.25M.

2. A process according to claim 1, wherein a mixture of ascorbic acid optionally protected at the 5- and 6-positions and a phosphorylating agent selected from the group consisting of phosphorus oxychloride, hydrates and alcoholate thereof, dichlorophosphoric acid and tetrachloropyrophosphoric acid is intermittently or continuously added dropwise to a reaction mixture to conduct phosphorylation.

3. A process according to claim 1, wherein phosphorylation is conducted in an atmosphere of nitrogen gas or argon gas.

4. A process according to claim 1, wherein phosphorylation is conducted in the presence of pyridine.

5. A process according to claim 1, wherein the optionally protected ascorbic acid is a compound selected from the group consisting of ascorbic acid, 5,6-O-isopropylidene ascorbic acid, 5,6-O-sec-butylidene ascorbic acid, 5,6-O-1-ethylbutylidene ascorbic acid, 5,6-O-cyclopentylidene ascorbic acid and 5,6-O-cyclohexylidene ascorbic acid.

6. A process according to claim 1, wherein the optionally protected ascorbic acid is ascorbic acid or 5,6-O-isopropylidene ascorbic acid.

7. A process according to claim 1, wherein the concentration of the optionally protected ascorbic acid in the reaction mixture is 0.25M or lower.

8. A process according to claim 1, wherein phosphorylation is conducted by using a phosphorylating agent in an amount of about 1.5 to about 2.5 times equivalent based on the optionally protected ascorbic acid used.

9. A process according to claim 1, wherein phosphorylation is conducted at pH 12.5 to 13.5.

10. A process according to claim 1, wherein the deprotection is conducted by adjusting the pH of the reaction mixture to pH 1 or lower.

11. In an improved process for the production of 2-phosphated esters of ascorbic acid which comprises subjecting an ascorbic acid optionally protected at the 5- and 6-positions to phosphorylation, followed, if necessary, by removing any protective group, the improvement is characterized by maintaining the concentration of the optionally protected ascorbic acid in a reaction mixture at less than 0.25M, said optionally protected ascorbic acid being a compound selected from the group consisting of ascorbic acid, 5,6-O-isopropylidene ascorbic acid, 5,6-O-sec-butylidene ascorbic acid, 5,6-O-1-ethylbutylidene ascorbic acid, 5,6O-cyclopentylidene ascorbic acid and 5,6-O-cyclohexylidene ascorbic acid, and said phosphorylation being conducted by intermittently or continuously adding dropwise a mixture of said optionally protected ascorbic acid and a phosphorylating agent selected from the group consisting of phosphorus oxychloride, hydrates and alcoholates thereof, dichlorophosphoric acid and tetrachloropyrophosphoric acid to the reaction mixture in the presence of pyridine in an atmosphere of nitrogen gas or argon gas.