Process for preparation of folic acid derivatives

• US 4,337,339 A
• Filed: 10/31/1979
• Issued: 06/29/1982
• Est. Priority Date: 04/30/1979
• Status: Expired due to Term

• Current Assignee: Serono Diagnostics, Inc.
• Original Assignee: Baker Instruments Corporation
• Inventors: Farina, Peter R., Grattan, James A.
• Primary Examiner(s): Coughlan, Jr., Paul M.
• Application Number:
  US06/090,059
• Time in Patent Office: 972 Days
• Field of Search: 544/257, 544/258, 544/260
• US Class Current: 544/257
• CPC Class Codes: G01N 33/82 involving vitamins or their receptors

Abstract

Folic acid derivatives, such as radiolabeled pteroyltyrosine, are conveniently synthesized from either pteroic acid or by the direct condensation of 6-formylpterin with p-aminobenzoyltyrosine methyl ester. The radioiodinated derivatives are particularly useful in competitive protein binding and radioimmuno-assays of folate compounds.

Claims

1. A process for the preparation of a composition having the formula:

##STR8## wherein R represents hydrogen, lower alkyl, formyl or iminomethyl;

R'"'"' and R" individually represent lower alkyl, hydroxyl, halo, amino or acetamido;

R'"'"'" represents H or lower alkyl;

m has a value of 1, 3 or 4;

n has a value of zero or 1; and

X is an amino acid or des-carboxy amino acid moiety;

selected from the group consisting of;

##STR9## wherein Z is hydrogen or lower alkyl, said process comprising the steps of;

(a) contacting a pteroic acid of the above formula wherein X is --OH, with a blocking agent to protect the nitrogen at the 10 position when R'"'"'" is H.

(b) contacting the pteroic acid of step (a) with an acyl halide under basic conditions to form a mixed anhydride,

(c) condensing said mixed anhydride with HX wherein X is an amino acid moiety or a des-carboxy amino acid moiety as defined above, and

(d) hydrolyzing the product of condensation of step (c) under basic conditions, to provide said composition.

2. The process of claim 1 wherein said blocking reagent is trifluoroacetic anhydride.

3. The process of claim 1 wherein said acid halide is an alkanoyl halide.

4. The process of claim 3 wherein said alkanoyl halide is iso-butylchloroformate.

5. The process of claim 1 wherein the acid employed in step (a) is pteroic acid.

6. The process of claim 5 wherein HX is L-tyrosine methyl ester.

7. The process of claim 5 wherein HX is histamine.

8. The process of claim 5 wherein HX is tyramine.

9. The process of claim 5 wherein HX is 5-hydroxytryptophan methyl ester.

10. The process of claim 5 wherein HX is histidine methyl ester.

11. The process of claim 5 wherein HX is 2(4'"'"'-hydroxyphenyl) glycine methyl ester.