Claims for Patent: 8,383,857

Summary for Patent: 8,383,857

Title:	Processes for making hydrazides
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.
Inventor(s):	Chiarello; George Anello (Morrisonville, NY), Sahli; Ayman (Amman, JO)
Assignee:	Wyeth LLC (Madison, NJ)
Application Number:	13/360,220
Patent Claims:	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: ##STR00014## 7. The method of claim 1, wherein the continuous addition of p-methoxybenzylthioether acid chloride is adjusted to maintain reaction temperature of -68.degree. C. to -75.degree. 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: ##STR00015## 14. The method of claim 9, wherein the addition of p-methoxybenzylthioether acid chloride is adjusted to maintain reaction temperature of -68.degree. C. to -75.degree. 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.

Details for Patent 8,383,857

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Wyeth Pharmaceuticals Llc	BESPONSA	inotuzumab ozogamicin	For Injection	761040	08/17/2017		2039-10-22
Wyeth Pharmaceuticals Llc	MYLOTARG	gemtuzumab ozogamicin	For Injection	761060	09/01/2017		2039-10-22