Chiral synthesis of alpha-aminophosponic acids

• US 5,362,899 A
• Filed: 09/09/1993
• Issued: 11/08/1994
• Est. Priority Date: 09/09/1993
• Status: Expired due to Fees

• Current Assignee: Affymax Incorporated
• Original Assignee: Affymax Incorporated
• Inventors: Campbell, David A.
• Primary Examiner(s): Morris, Patricia L.
• Assistant Examiner(s): AMBROSE, MICHAEL GEORGE
• Application Number:
  US08/120,007
• Time in Patent Office: 425 Days
• Field of Search: 558/166, 558/122, 558/124, 558/131
• US Class Current: 558/108
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl

Abstract

A stereospecific method of preparing alpha-aminophosphonic acids and derivatives thereof is provided. A protected amino acid is converted to a acyl aroyl or diacyl peroxide which spontaneously rearranges to form an alpha-amino ester. This rearrangement occurs stereospecifically with retention of configuration. The ester is subsequently converted to an appropriate leaving group and displaced with a phosphite yielding a chiral alpha-aminophosphonic acid or derivative.

Alpha-aminophosphonic acids are useful for the synthesis of peptide analogs that possess a phosphonate linkage in the place of an amide linkage. This substitution can impart protease resistance in therapeutic peptides thereby increasing the serum half-life.

Claims

1. A method of preparing a compound of Formula V:

##STR9## in which PG₁ and PG₂ are protecting groups, R and R¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, provided that R is not the same as R¹ and provided that either R or R¹ is hydrogen, and R3 and R⁴ are independently lower alkyl or aryl, the method comprising the steps of;

a) treating a compound of Formula I;

##STR10## in which PG₁, PG₂, R, and R¹ are defined as above, with a peroxyacid having the structure R² (CO)OOH, in which R² is alkyl or aryl, to yield an ester of Formula III;

##STR11## in which PG₁, PG₂, R, R¹, and R² are defined as above;

b) stereospecifically replacing the R² COO-- group from the ester of Formula III with a leaving group X with retention of configuration, wherein the leaving group X is a halide or a sulfonate, to yield a compound of Formula IV ##STR12## in which PG₁, PG₂, R, R¹, and X are defined as above; and

c) treating the compound of Formula IV ##STR13## in which PG₁, PG₂, R, R¹, and X are defined as above, with a phosphite having the structure P(OR³)(OR⁴)(OR⁵), in which R³, R⁴, and R⁵ are independently lower alkyl or aryl, to yield a compound of Formula V.

2. The method of claim 1 wherein the step of replacing the R² COO-- group from the ester of Formula III with a leaving group comprises the step of treating the ester with (CH₃)₃ SiX, where X is bromide or iodide, to produce a compound of Formula IV where X is bromide or iodide.

4. The method of claim 1 wherein X is selected from the group consisting of bromide, iodide, p-toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, methanesulfonate, trifluorome thanesulfonate, nonafluorobutanesulfonate, and 2,2,2-trifluoroethanesulfonate.

5. The method of claim 4 wherein X is p-toluenesulfonate.

6. The method of claim 1 wherein the peracid is selected from the group consisting of peroxybenzoic acid and 3-chloroperoxybenzoic acid.

7. The method of claim 6 wherein the peracid is 3-chloroperoxybenzoic acid.

8. The method of claim 1, further comprising the steps of:

a) hydrolyzing the compound of Formula V ##STR16## in which PG₁ and PG₂ are protecting groups, R and R¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, provided that R is not the same as R¹ and provided that either R or R¹ is hydrogen, and R³ and R⁴ are independently lower alkyl or aryl, to produce a compound of Formula V ##STR17## in which PG₁, PG₂, R, and R¹ are defined as above, and either R³ or R⁴ is hydrogen with the other being defined as above, and

b) coupling the compound of Formula V ##STR18## in which PG₁, PG₂, R, R¹, R³, and R⁴ are defined as above, with a hydroxyl group of a hydroxyl substituted amino acid to yield a peptidylphosphonate.

3. The method of claim I wherein the step of replacing the R² COO-- group from the ester of Formula III with a leaving group comprises the steps of:

a) hydrolyzing the R² COO-- group to produce a compound of Formula IV ##STR14## in which PG₁, PG₂, R, and R¹ are defined as above and X is --OH;

b) stereospecifically converting the compound of Formula IV in which PG₁, PG₂, R, and R¹ are defined as above and X is --OH, with retention of configuration, to yield a compound of Formula IV ##STR15## in which PG₁, PG₂, R, and R¹ are defined as above and X is a halide or a sulfonate.

9. A method of preparing a compound of Formula VII:

##STR19## in which PG₁ and PG₂ are protecting groups, R and R¹ are independently selected from the group consisting of hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, provided that R is not the same as R¹ and provided that either R or R¹ is hydrogen, and R³ and R⁴ are independently lower alkyl or aryl, the method comprising the steps of;

a) treating a compound of Formula I;

##STR20## in which PG₁, PG₂, R, and R¹ are defined as above, with a peracid having the structure R² (CO)OOH, in which R² is alkyl or aryl, to yield an ester of Formula III;

##STR21## in which PG₁, PG₂, R, R¹, and R² are defined as above;

b) stereospecifically replacing the R² COO-- group from the ester of Formula III with a leaving group X with inversion of configuration, wherein the leaving group X is a halide or a sulfonate, to yield a compound of Formula VI ##STR22## in which PG₁, PG₂, R, R¹, and X are defined as above; and

c) treating the compound of Formula VI ##STR23## in which PG₁, PG₂, R, R¹, and X are defined as above, with a phosphite having the structure P(OR³)(OR⁴)(OR⁵), in which R³, R⁴, R⁵ are independently lower alkyl or aryl, to yield a compound of Formula VII.

10. The method of claim 9 wherein the step of replacing the R² COO-- group from the ester of Formula III with a leaving group comprises the step of treating the ester with (CH₃)₃ SiX, where X is bromide or iodide, to produce a compound of Formula IV where X is bromide or iodide.

11. The method of claim 9 wherein the step of replacing the R² COO-- group from the ester of Formula III with a leaving group comprises the steps of:

a) hydrolyzing the R² COO-- group to produce a compound of Formula IV ##STR24## in which PG₁, PG₂, R, and R¹ are defined as above and X is --OH;

b) stereospecifically converting the compound of Formula IV in which PG₁, PG₂, R, and R¹ are defined as above and X is --OH, with inversion of configuration, to a compound of Formula VI ##STR25## in which PG₁, PG₂, R, and R¹ are defined as above and X is a halide or a sulfonate.

12. The method of claim 9 wherein X is selected from the group consisting of bromide, iodide, p-toluenesulfonate, p-bromobenzenesulfonate, p-nitrobenzenesulfonate, methanesulfonate, trifluoromethanesulfonate, nonafluorobutanesulfonate, and 2,2,2-trifluoroethanesulfonate.

13. The method of claim 12 wherein X is p-toluenesulfonate.

14. The method of claim 9 wherein the peracid is selected from the group consisting of peroxybenzoic acid and 3-chloroperoxybenzoic acid.

15. The method of claim 13 wherein the peracid is 3-chloroperoxybenzoic acid.

16. The method of claim 9, further comprising the steps of:

a) hydrolyzing the compound of Formula VII ##STR26## in which PG₁ and PG₂ are protecting groups, R and R¹ are independently selected from tile group consisting of hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, alkylaryl, and aminoalkyl, provided that R is not the same as R¹ and provided that either R or R¹ is hydrogen, and R³ and R⁴ are independently lower alkyl or aryl, to produce a con, pound of Formula VII ##STR27## in which PG₁, PG₂, R, and R¹ are defined as above, and either R³ or R⁴ is hydrogen with the other being defined as above, and

b) coupling the compound of Formula VII ##STR28## in which PG₁, PG₂, R, R¹, R³, and R⁴ are defined as above, with a hydroxyl group of a hydroxyl substituted amino acid to yield a peptidylphosphonate.