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 method of preparing 3-methyl-3-mercaptobutanoic acid hydrazide from hydrazine and a p-methoxybenzylthioether acid chloride comprising the steps of:
(a) preparing a stirred substantially uniform slurry comprising hydrazine and an inert solvent; and
(b) adding p-methoxybenzylthioether acid chloride continuously to said slurry.
2. The method of claim 1 , further comprising:
(c) removing the p-methoxybenzyl protecting group to give 3-methyl-3-mercaptobutanoic acid hydrazide.
3. The method of claim 1 , wherein the p-methoxybenzylthioether acid chloride is added substantially drop wise to the slurry.
4. The method of claim 1 , wherein the p-methoxybenzylthioether acid chloride is added in the form of a solution comprising the p-methoxybenzylthioether acid chloride and the inert solvent.
5. The method of claim 1 , wherein the inert solvent is methylene chloride.
6. The method of claim 1 , wherein the 3-methyl-3-mercaptobutanoic acid hydrazide contains less than 5% of a bis-hydrazide by-product having the structure:
7. The method of claim 1 , wherein the continuous addition of p-methoxybenzylthioether acid chloride is adjusted to maintain reaction temperature of −68° C. to −75° C.
8. The method of claim 1 , wherein the hydrazine slurry is stirred at a speed sufficient to maintain the substantially uniform slurry.
9. A method of preparing 3-methyl-3-mercaptobutanoic acid hydrazide from hydrazine and p-methoxybenzylthioether acid chloride comprising the steps of:
(a) cooling a reaction vessel comprising a stirred inert solvent to a desired low temperature;
(b) adding hydrazine in a continuous fashion to said reaction vessel, thereby preparing a stirred substantially uniform slurry comprising the hydrazine and the inert solvent;
(c) adding p-methoxybenzylthioether acid chloride to said slurry in a continuous fashion, thereby forming a hydrazide linkage.
10. The method of claim 9 , further comprising:
(d) removing the p-methoxybenzyl protecting group to give 3-methyl-3-mercaptobutanoic acid hydrazide.
11. The method of claim 9 , wherein the p-methoxybenzylthioether acid chloride is added in the form of a solution comprising the p-methoxybenzylthioether acid chloride and the inert solvent.
12. The method of claim 9 , wherein the inert solvent is methylene chloride.
13. The method of claim 9 , wherein the hydrazide contains less than 5% of a bis-hydrazide by-product having the structure:
14. The method of claim 9 , wherein the addition of p-methoxybenzylthioether acid chloride is adjusted to maintain reaction temperature of −68° C. to −75° C.
15. The method of claim 9 , wherein the hydrazine slurry is stirred at a speed sufficient to maintain the substantially uniform slurry.
16. A method of preparing an immunoconjugate of a member of the family of calicheamicins with a monoclonal antibody as carrier, which comprises preparing 3-methyl-3-mercaptobutanoic acid hydrazide according to the method of claim 2 and using the 3-methyl-3-mercaptobutanoic acid hydrazide for preparing said immunoconjugate.
17. A method of preparing an immunoconjugate of a member of the family of calicheamicins with a monoclonal antibody as carrier, which comprises preparing 3-methyl-3-mercaptobutanoic acid hydrazide according to the method of claim 10 and using the 3-methyl-3-mercaptobutanoic acid hydrazide for preparing said immunoconjugate.
18. The method of claim 16 , wherein 3-methyl-3-mercaptobutanoic acid hydrazide is used as a linker to make gemtuzumab ozogamicin or inotuzumab ozogamicin.
19. The method of claim 17 , wherein 3-methyl-3-mercaptobutanoic acid hydrazide is used as a linker to make gemtuzumab ozogamicin or inotuzumab ozogamicin.