Claims for Patent: 9,227,924

Summary for Patent: 9,227,924

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:	14/504,738
Patent Claims:	1. A method of preparing a hydrazide from hydrazine and an acyl halide comprising the steps of: (a) preparing a slurry comprising hydrazine and an inert solvent; and (b) adding an acyl halide continuously to said slurry, wherein the acyl halide further comprises a protected thiol. 2. The method according to claim 1 wherein the acyl halide is added substantially drop wise to the slurry. 3. The method according to claim 1 wherein the acyl halide comprises a benzyl thioether. 4. The method according to claim 1 wherein the acyl halide has the structure: ##STR00014## wherein P is a thiol protecting group; R.sub.1 and R.sub.2 are each selected from the group consisting of C.sub.1-C.sub.5 alkyl; X is a halide; and L is an alkylene linker. 5. The method according to claim 4 wherein L is --CH.sub.2--. 6. The method according to claim 4 wherein R.sub.1 and R.sub.2 are each independently methyl. 7. The method according to claim 4 wherein P is a benzyl group, optionally substituted on the phenyl ring. 8. The method according to claim 7 wherein P is p-methoxybenzyl group. 9. The method according to claim 1 wherein the acyl halide has the structure: ##STR00015## wherein X is a halide. 10. The method according to claim 1 wherein the inert solvent is methylene chloride. 11. The method according to claim 1 wherein said hydrazide product has the structure: ##STR00016## wherein P is a thiol protecting group; R.sub.1 and R.sub.2 are each selected from the group consisting of C.sub.1-C.sub.5 alkyl; and L is an alkylene linker. 12. The method according to claim 11 wherein L is --CH.sub.2--. 13. The method according to claim 11 wherein R.sub.1 and R.sub.2 are each independently methyl. 14. The method according to claim 11 wherein P is a benzyl group, optionally substituted on the phenyl ring. 15. The method according to claim 14 wherein P is p-methoxybenzyl group. 16. The method according to claim 11 wherein the hydrazide product is ##STR00017## or a salt thereof. 17. The method according to claim 1 wherein the hydrazide contains less than 5% of a bis-hydrazide by-product having the structure: ##STR00018## wherein R and R' are optionally substituted alkyl, heteroalkyl, or heteroalkaryl groups. 18. The method according to claim 17 wherein R and R' are ##STR00019## wherein P is a thiol protecting group; R.sub.1 and R.sub.2 are each selected from the group consisting of C.sub.1-C.sub.5 alkyl; and L is an alkylene linker. 19. The method according to claim 18 wherein L is --CH.sub.2--. 20. The method according to claim 19 wherein R.sub.1 and R.sub.2 are each independently methyl. 21. The method according to claim 18 wherein P is a benzyl group, optionally substituted on the phenyl ring. 22. The method according to claim 21 wherein P is p-methoxybenzyl group. 23. The method according to claim 22 wherein the bis-hydrazide by-product has the structure: ##STR00020## 24. The method according to claim 1 wherein the continuous addition of acid halide solution is adjusted to maintain reaction temperature of about -68.degree. C. to about -75.degree. C. 25. A method of preparing 3-methyl-3-mercaptobutanoic acid hydrazide comprising the step of preparing a hydrazide according to the method of claim 15. 26. 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 25 and using the 3-methyl-3-mercaptobutanoic acid hydrazide for preparing said immunoconjugate. 27. The method according to claim 26 wherein 3-methyl-3-mercaptobutanoic acid hydrazide is used as a linker to make gemtuzumab ozogamicin or inotuzumab ozogamicin. 28. A method of preparing gemtuzumab ozogamicin comprising the steps of preparing the linker 3-methyl-3-mercaptobutanoic acid hydrazide according to the method of claim 25 and using said linker to link calicheamicin to the monoclonal antibody gemtuzumab.

Details for Patent 9,227,924

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Wyeth Pharmaceuticals Llc	BESPONSA	inotuzumab ozogamicin	For Injection	761040	08/17/2017		2027-05-22
Wyeth Pharmaceuticals Llc	MYLOTARG	gemtuzumab ozogamicin	For Injection	761060	09/01/2017		2027-05-22