Processes for making hydrazides

Patent metadata

Field	Value
Publication number	US-9738602-B2
Application number	US-201514973869-A
Country	US
Kind code	B2
Filing date	Dec 18, 2015
Priority date	May 22, 2007
Publication date	Aug 22, 2017
Grant date	Aug 22, 2017

Abstract

A method is disclosed for preparing hydrazides from hydrazine and an acyl chloride which comprises the steps of (a) preparing a stirred substantially uniform slurry comprising hydrazine and an inert solvent at low temperature; and (b) adding an acyl chloride continuously to said slurry. The method avoids or limits production of undesired bis-hydrazide by-products. The method is used to prepare 3-methyl-3-mercaptobutanoic acid hydrazide, a molecule used to link calicheamicin to a monoclonal antibody.

First claim

We claim:

1. A stirred, uniform slurry comprising hydrazine in an inert solvent, prepared by dropwise addition of the hydrazine to a cold inert solvent, wherein the volume ratio of hydrazine to the inert solvent is about 14% to about 19%, and wherein the inert solvent is selected from the group consisting of methylene chloride, carbon tetrachloride, chloroform, ethylene dichloride, chlorobenzene, and mixtures thereof.

2. The slurry of claim 1 , wherein the volume ratio of hydrazine to the inert solvent is about 14%.

3. The slurry of claim 1 , wherein the inert solvent is methylene chloride.

4. The slurry of claim 1 , wherein the temperature of the slurry is about −68° C. to about −75° C.

5. The slurry of claim 1 , further comprising an acyl halide, a hydrazide product of the acyl halide and hydrazine, or both an acyl halide and hydrazide product of the acyl halide and hydrazine.

6. The slurry of claim 5 , prepared by continuous addition of the acyl halide to the slurry comprising hydrazine.

7. The slurry of claim 5 , prepared by addition of the acyl halide to the slurry comprising hydrazine so as to maintain the temperature of the slurry at about −68° C. to about −75° C.

8. The slurry of claim 5 , prepared by drop-wise addition of the acyl halide to the slurry.

9. The slurry of claim 5 , wherein the acyl halide comprises a methoxybenzylthioether acid chloride and the hydrazide product comprises 3-methyl-3-mercaptobutanoic acid hydrazide.

10. The slurry of claim 5 , wherein the hydrazide product has the structure:

wherein P is a thiol protecting group;
R 1 and R 2 are each selected from the group consisting of C 1 -C 5 alkyl; and
L is an alkylene linker.

11. The slurry of claim 10 , wherein L is —CH 2 —.

12. The slurry of claim 10 , wherein R 1 and R 2 are each independently methyl.

13. The slurry of claim 10 , wherein P is a benzyl group, optionally substituted on the phenyl ring.

14. The slurry of claim 10 , wherein P is p-methoxybenzyl group.

15. The slurry of claim 5 , wherein the hydrazide product has the structure:

or a salt thereof.

16. The slurry of claim 5 , comprising less than about 5% bis-hydrazide by-product by weight, based on the weight of hydrazide product.

17. The slurry of claim 5 , comprising about 3 to 5% bis-hydrazide by-product, based on the weight of hydrazide product.

18. The slurry of claim 5 , comprising less than about 3% bis-hydrazide by-product, based on the weight of hydrazide product.

19. The slurry of claim 16 , wherein the bis-hydrazide by-product has the structure:

wherein R and R′ are optionally substituted alkyl, heteroalkyl, or heteroalkaryl groups.

20. The slurry of claim 19 , wherein R and R′ are

wherein P is a thiol protecting group;
R 1 and R 2 are each selected from the group consisting of C 1 -C 5 alkyl; and
L is an alkylene linker.

21. The slurry of claim 19 , wherein L is —CH 2 —.

22. The slurry of claim 19 , wherein R 1 and R 2 are each independently methyl.

23. The slurry of claim 19 , wherein P is a benzyl group, optionally substituted on the phenyl ring.

24. The slurry of claim 19 , wherein P is p-methoxybenzyl group.

25. The slurry of claim 16 , wherein the bis-hydrazide by-product has the structure:

Assignees

• Wyeth Llc

Inventors

• Chiarello George Anello
• Sahli Ayman

Classifications

• C07C319/20 Primary

  by reactions not involving the formation of sulfide groups · CPC title

• C07C241/04

  Preparation of hydrazides · CPC title

• C07C243/28

  to hydrogen atoms or to carbon atoms of a saturated carbon skeleton · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61K47/6889

  Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment · CPC title