Efficient preparation of drastatin and auristatin analogs via common intermediates

Abstract

The present invention provides a method for producing drastatin, auristatin, or related compounds. [Solution] Formula I JPEG2026098000000081.jpg38137 A method comprising the steps of providing a universal drastatin core represented by , reacting the C-terminal carboxylic acid group with an amine (A) to form an amide bond, and reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond. Also provided are isolated salts of the universal drastatin core for use in the preparation of drastatin, auristatin, and related compounds. Furthermore, several intermediates and process steps useful for the preparation of high-purity drastatin cores and high-purity drastatin and auristatin compounds are also provided.

Claims

1. A method for producing drastatin, auristatin, or related compounds, wherein formula I: 【Chemistry 1】 [In the formula, R 1 、R 2 、R 3 、R 4 、R 5 and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, -OR 11 、-NR 11 R 12 、-SR 11 and halo, R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups, R 6 and R 7 These are, independently, H or C 1 -C 4 It is alkyl, R 9 is H or an acid protecting group, and R 10 [is an H or amino protecting group] A step of providing a compound represented by or a salt thereof; R 9 If it is an acid protecting group, the step of deprotecting the C-terminal carboxylic acid group, A step of reacting the C-terminal carboxylic acid group with amine (A) to form an amide bond; R 10 If it is an amino protecting group, the step is to deprotect the N-terminal amine. A step of reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond. A method that includes this.

2. R 9 If it is an acid protecting group, the step is to deprotect the C-terminal carboxylic acid group, then, The step of reacting the C-terminal carboxylic acid group with amine (A) to form an amide bond is R 10 If it is an amino protecting group, the step is to deprotect the N-terminal amine, then, The method according to claim 1, wherein the step of reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond is performed before the step of reacting the N-terminal amine with a carboxylic acid (CA).

3. R 10 If it is an amino protecting group, the step is to deprotect the N-terminal amine, then, The step of reacting the N-terminal amine with a carboxylic acid (CA) to form an amide bond is, R 9 If it is an acid protecting group, the step is to deprotect the C-terminal carboxylic acid group, then, The method according to claim 1, wherein the step of reacting the C-terminal carboxylic acid group with amine (A) to form an amide bond is performed before the step of reacting the C-terminal carboxylic acid group with amine (A).

4. Amine (A) is selected from the group consisting of alkylamines, alkanolamines, arylalkanolamines, amino acids, amino acid derivatives, peptides, and peptide derivatives. Here, amine (A) may have one or more substituents, and The method according to any one of claims 1 to 3, wherein the amine (A) may have a protecting group.

5. The method according to any one of claims 1 to 4, wherein the amine (A) is selected from the group consisting of phenylalanine, phenylalanine derivatives, substituted phenylalanine, substituted phenylalanine derivatives, tryptophan, tryptophan derivatives, substituted tryptophan, substituted tryptophan derivatives, phenylpropanolamine, protected phenylpropanolamine, substituted phenylpropanolamine, protected substituted phenylpropanolamine, draphenine, and protected draphenine, substituted draphenine, protected substituted draphenine, draphenine derivatives, protected draphenine derivatives, substituted draphenine derivatives, and protected draphenine derivatives.

6. The carboxylic acid (CA) is selected from the group consisting of amino acids, amino acid derivatives, peptides, and peptide derivatives. Here, the carboxylic acid (CA) may have one or more substituents, and The method according to any one of claims 1 to 5, wherein the carboxylic acid (CA) may have a protecting group.

7. The method according to any one of claims 1 to 6, wherein the carboxylic acid (CA) is selected from the group consisting of valine, protected valine, substituted valine, protected substituted valine, valine derivative, protected valine derivative, substituted valine derivative, protected substituted valine derivative, alanine, protected alanine, substituted alanine, protected substituted alanine, alanine derivative, protected alanine derivative, substituted alanine derivative, and protected substituted alanine derivative.

8. The method according to any one of claims 1 to 7, wherein the carboxylic acid (CA) comprises one or more spacers, linkers, and bonding groups.

9. The compound represented by formula I, 【Chemistry 2】 The method according to any one of claims 1, 2, or 4 to 8.

10. Formula II: 【Transformation 3】 [In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 8 These are H and C, respectively, independently. 1 -C 6 Alkyl, C 1 -C 6 Substituting alkyl, -OR 11 , -NR 11 R 12 , -SR 11 Selected from the group consisting of and halos, R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups, R 6 and R 7 These are, independently, H or C 1 -C 4 It is alkyl, R 10 is an H or amino protecting group; and Y + [is the counterion] The isolated salt indicated by [this symbol].

11. R 1 , R 2 , R 3 , R 4 , R 5 and R 8 Each of these is independently selected from the group consisting of H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, and isobutyl; R 6 and R 7 However, each is independently either H or methyl, R 10 However, it is H or tert-butoxycarbonyl (Boc), and Y + However, formula: N + HR 13 R 14 R 15 [In the formula, R 13 C may be substituted depending on the circumstances. 1 -C 8 Alkyl and optionally substituted C 3 -C 8 Selected from the group consisting of cycloalkyl groups; R 14 and R 15 H may be substituted for C, depending on the case. 1 -C 8 Alkyl and optionally substituted C 3 -C 8 Selected from the group consisting of cycloalkyl groups; Here, each substituent, if present, is selected from the group consisting of alkyl and aryl compounds. The isolated salt according to claim 10, wherein the ammonium ion is...

12. Y + The isolated salt according to claim 10 or 11, wherein the isolated salt is selected from the group consisting of diethylammonium ion, dibutylammonium ion, dicyclohexylammonium ion, methylcyclohexylammonium ion, and methylbenzylammonium ion. 【Request Item 13】 【Chemistry 4】 The salt according to any one of claims 10 to 12.

14. Formula III: 【Transformation 5】 [In the formula, R 1 、R 2 、R 3 、R 5 and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, -OR 11 、-NR 11 R 12 、-SR 11 and halo, R 11 and R 12 each independently is selected from the group consisting of H and C 1 -C 6 alkyl R 6 and R 7 These are, independently, H or C 1 -C 4 Selected from the group consisting of alkyl groups, and Z - [is the counterion] The compound shown by [this symbol].

15. R 1 , R 2 , R 3 , R 5 and R 8 However, each is independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, R 6 and R 7 However, each is independently selected from the group consisting of H and methyl, and Z - The compound represented by formula III as described in claim 14, which is selected from the group consisting of halide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, mesylate, tosylate, benzenesulfonate, ethylsulfonate, nitrate, formate, acetate, trifluoroacetate, oxalate, and citrate. 【Request Item 16】 【Chemistry 6】 The compound represented by formula III as described in claim 14 or 15.

17. Amino acids, Formula III 【Transformation 7】 [In the formula, R 1 , R 2 , R 3 , R 5 and R 8 These are H and C, respectively, independently. 1 -C 6 Alkyl, C 1 -C 6 Substituting alkyl, -OR 11 , -NR 11 R 12 , -SR 11 Selected from the group consisting of and halos, R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups, R 6 and R 7 These are, independently, H or C 1 -C 4 Selected from the group consisting of alkyl groups, and Z - A method of coupling a compound represented by [the counterion] with the counterion, A step of contacting the compound represented by formula III with an aqueous base to remove the counterion, and When the compound represented by formula III is brought into contact with an N-protected amino acid N-carboxyanhydride, formula IV: 【Transformation 8】 [In the formula, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 and R 8 As defined above, R 16 It is the side chain of an amino acid, and R 17 A method comprising the step of obtaining a compound represented by [a protecting group].

18. R 1 , R 2 , R 3 , R 5 and R 8 However, each is independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, R 6 and R 7 However, each is independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, Z - However, it is selected from the group consisting of halides, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, mesylates, tosylates, benzenesulfonates, ethylsulfonates, nitrates, formates, acetates, trifluoroacetates, oxalates, and citrates; Aqueous base, Na 2 CO 3 NaHCO 3 NaOH, Na 2 Hpo 4 and Na 3 PO 4 Selected from the group consisting of, The method according to claim 17, wherein the N-protected amino acid N-carboxyanhydride is a Boc-protected amino acid N-carboxyanhydride.

19. The compound represented by formula III is 【Chemistry 9】 And, Aqueous base, Na 2 CO 3 And, The N-protected amino acid N-carboxyanhydride is Boc-Val-NCA, and The compound represented by formula IV, 【Chemistry 10】 The method according to any one of claims 17 or 18.

20. A method for purifying a crude product of a hydroxy acid represented by formula V without using column chromatography, Formula V: 【Chemistry 11】 [In the formula, R 2 , R 3 , and R 5 These are H and C, respectively, independently. 1 -C 6 Alkyl, C 1 -C 6 Substituting alkyl, -OR 11 , -NR 11 R 12 , -SR 11 Selected from the group consisting of and halos; R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups, and R 6 H and C 1 -C 4 A step of providing a crude product of a hydroxy acid represented by [selected from the group consisting of alkyl groups]; A step of dissolving the crude hydroxy acid in a soluble solvent, Steps to add an insoluble solvent, A process to initiate crystallization, and A method comprising the step of completing crystallization to obtain a purified hydroxy acid represented by formula V.

21. The hydroxy acid represented by formula V, 【Chemistry 12】 [In the formula, R 2 , R 3 and R 5 Each of these is independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. R 6 [is selected from the group consisting of H and methyl] The soluble solvent contains tert-butyl methyl ether (MTBE), The insoluble solvent contains heptane, and The method according to claim 20, wherein crystallization is initiated by seeding, thermal cycling, or a combination thereof.

22. The hydroxy acid represented by formula V, 【Chemistry 13】 The method according to any one of claims 20 or 21.

23. The method according to any one of claims 20 to 22, further comprising the step of isolating a purified hydroxy acid represented by formula V.

24. Equation VI: 【Chemistry 14】 [In the formula, R 2 , R 3 , and R 5 These are H and C, respectively, independently. 1 -C 6 Alkyl, C 1 -C 6 Substituting alkyl, -OR 11 , -NR 11 R 12 , -SR 11 Selected from the group consisting of and halos; R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups, and R 6 H and C 1 -C 4 Selected from the group consisting of alkyl groups; and R 13 C may be substituted depending on the circumstances. 1 -C 8 Alkyl and optionally substituted C 3 -C 8 Selected from the group consisting of cycloalkyl groups; R 14 and R 15 H may be substituted for C, depending on the case. 1 -C 8 Alkyl and optionally substituted C 3 -C 8 Selected from the group consisting of cycloalkyl groups; Here, each substituent, if present, is selected from the group consisting of alkyl and aryl compounds. The compound shown by [this symbol].

25. The compound represented by formula VI, 【Chemistry 15】 [In the formula, R 2 , R 3 and R 5 Each of these is independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. R 6 is selected from the group consisting of H and methyl; and NHR 13 R 14 R 15 The compound according to claim 24, wherein is selected from the group consisting of diethylammonium ion, dibutylammonium ion, dicyclohexylammonium ion, methylcyclohexylammonium ion, and methylbenzylammonium ion.

26. The compound represented by formula VI, 【Chemistry 16】 The compound according to claim 24 or 25.

27. The compound according to any one of claims 24 to 26, wherein the compound represented by formula VI is a solid.

28. Formula VII 【Chemistry 17】 [In the formula, R 1 and R 8 H and C are independent of each other. 1 -C 6 Alkyl, C 1 -C 6 Substituting alkyl, -OR 11 , -NR 11 R 12 , -SR 11 Selected from the group consisting of and halos; R 11 and R 12 H and C are independent of each other. 1 -C 6 Selected from the group consisting of alkyl groups; R 7 is H or C 1 -C 4 Selected from the group consisting of alkyl groups; and X - [These are selected from the group consisting of halides, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, mesylates, tosylates, benzenesulfonates, ethylsulfonates, nitrates, formates, acetates, oxalates, and citrates.] The compound shown by [this symbol].

29. The compound represented by formula VII, [Chemistry 18] [In the formula, R 1 and R 8 These are independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. R 7 is selected from H and methyl; and X - The compound according to claim 28, wherein [is a halide].

30. The compound represented by formula VII, 【Chemistry 19】 The compound according to claim 28 or 29.

31. The compound according to any one of claims 28 to 30, wherein the compound represented by formula VII is a solid.

32. Formula VIII: 【Chemistry 20】 The compound shown by [this symbol].

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