FIELD

The present disclosure sets forth synthetic processes and chemical reagents for making glycopyrronium salts, stereospecifically and stereoselectively, including particular stereoisomers and mixtures of stereoisomers in high yield and with high selectivity. Also set forth herein are derivatives and analogs of glycopyrronium salts.

BACKGROUND

Certain glycopyrronium salts and related compounds, as well as processes for making and methods of using these glycopyrronium salts and related compounds, are known. See, for example, U.S. Pat. No. 8,558,008, which issued to assignee Dermira, Inc. See also, for example, U.S. Pat. No. 2,956,062, which issued to assignee Robins Co Inc. A H. See also, for example, International Patent Application Publication Nos. WO 98/00132 A1 and WO 2009/00109A1, both of which list applicant Sepracor, Inc., as well as U.S. Pat. Nos. 6,063,808 and 6,204,285, both of which issued to assignee Sepracor, Inc. Certain methods of treating hyperhidrosis using glycopyrronium salts and related compounds are known. See, for example GB 1,080,960. Certain forms of applying glycopyrrolate compounds to a subject are known. See, for example U.S. Pat. Nos. 6,433,003 and 8,618,160, both of which issued to assignee Rose U; also U.S. Pat. Nos. 7,060,289; 8,252,316; and 8,679,524, which issued to PurePharm, Inc.

One glycopyrronium salt which is useful in certain medical applications is the following compound:



As illustrated above, the absolute configuration at the three asymmetric chiral positions is 2R3′R1′RS. This means that the carbon indicated with the number, 2, has the stereochemical R configuration. The carbon indicated with the number, 3′, also has the stereochemical R configuration. The quaternary ammonium nitrogen atom, indicated with a positive charge, may have either the R or the S stereochemical configuration. As drawn, the compound above is a mixture of two diastereoisomers.

Certain processes for making glycopyrronium salts are known. However, these processes are not as safe, efficient, stereospecific, or stereoselective as the new processes disclosed herein, for example with respect to large-scale manufacturing processes. Certain publications show that higher anticholinergic activity is attributed to the 2R3′R configuration. However, to date, processes for making the 2R3′R isomers, as well as the 2R3′R1′R isomers are low yielding, involve too many reaction steps to be economically feasible, use toxic materials, and/or are not sufficiently stereospecific or stereoselective with respect to the products formed.

SUMMARY

In one embodiment, set forth herein is a process for making a compound of Formula (I):


wherein:R1and R2are each, independently in each instance, selected from alkyl and alkyl substituted with alkoxycarbonyl;the stereochemical configuration about the carbon atom indicated by 2 is R;the stereochemical configuration about carbon atom indicated by 3′ is R; X−is an anion;
wherein the process includes step (1) contacting a compound of Formula (Ia) with a compound of Formula (Ib) under coupling conditions to form a compound of Formula (Ic):


and step (2) contacting a compound of Formula (Ic) with a compound of Formula (Id) to make a compound of Formula (I):



In a second embodiment, set forth herein is a process for making a compound of Formula (Ib):


In some embodiments, R1is selected from alkyl and alkyl substituted with alkoxycarbonyl.
In some embodiments, the process includes step (1): providing a compound (5):


In some embodiments, the process includes step (2): contacting compound (5) with an alkyl-amine (e.g., R1—NH2) to form a compound of Formula (Ibc):


In some embodiments, the process includes contacting compound of Formula (Ibc) with reducing agent (indicated by [H+], below) to form a compound of Formula (Ib):



In a third embodiment, set forth herein is a composition including a mixture of compounds having following structures (Ia1) and (Ia2):


In some embodiments, the compounds having structures (Ia1) and (Ia2) are prepared by a process disclosed herein. In some embodiments, the compounds are formulated with a pharmaceutically acceptable excipient, diluent, or salt. R1R2, and X−are as defined above for Formula (I).

In a fourth embodiment, set forth herein is a process for treating hyperhidrosis, including administering to a subject in need thereof a composition comprising a compound prepared by a process disclosed herein or a composition disclosed herein.

In a fifth embodiment, set forth herein is a method of treating a disease or disorder marked by a need for an anticholinergic agent, including administering to a subject in need thereof a composition comprising a compound prepared by a process disclosed herein or a composition disclosed herein.

