Processes for making hydrazides
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.
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: