US 9,809,547 B2
Process for the preparation of histamine H3 receptor modulators
Diego Fernando Domenico Broggini, Zurich (CH); Vit Lellek, Zurich (CH); Susanne Lochner, Singen (DE); Neelakandha S. Mani, San Diego, CA (US); Adrian Maurer, Schaffhausen (CH); Daniel J. Pippel, Del Mar, CA (US); and Lana K. Young, San Diego, CA (US)
Assigned to Janssen Pharmaceutica NV, Beerse (BE)
Filed by Janssen Pharmaceutica NV, Beerse (BE)
Filed on Nov. 11, 2016, as Appl. No. 15/349,521.
Application 15/349,521 is a division of application No. 14/261,713, filed on Apr. 25, 2014, granted, now 9,518,021.
Application 14/261,713 is a division of application No. 13/257,224, granted, now 8,748,596, previously published as PCT/US2010/027638, filed on Mar. 17, 2010.
Claims priority of provisional application 61/161,177, filed on Mar. 18, 2009.
Prior Publication US 2017/0057919 A1, Mar. 2, 2017
Int. Cl. C07D 213/82 (2006.01); C07D 405/12 (2006.01); C07D 401/06 (2006.01); C07D 401/14 (2006.01)
CPC C07D 213/82 (2013.01) [C07D 405/12 (2013.01); C07B 2200/13 (2013.01)] 1 Claim
 
1. A process for the preparation of a compound of formula (I)

OG Complex Work Unit Drawing
wherein
R1 is selected from the group consisting of C1-4alkyl and C3-10cycloalkyl;
m is is 2;
R2 is selected from the group consisting of —OCHR3R4 and —Z—Ar;
R3 is hydrogen and R4 is a C3-10cycloalkyl or heterocycloalkyl ring; wherein the C3-10cycloalkyl or the heterocycloalkyl ring is unsubstituted or substituted with —C1-4alkyl or acetyl;
alternatively, R3 and R4 are taken together with the carbon to which they are attached to form a C3-10cycloalkyl or heterocycloalkyl ring; wherein the C3-10cycloalkyl or the heterocycloalkyl ring is unsubstituted or substituted with —C1-4alkyl or acetyl;
Z is selected from the group consisting of S and O;
Ar is a phenyl or heteroaryl; wherein the phenyl or heteroaryl is unsubstituted or substituted with one, two, or three R5 substituents; wherein each R5 substituent is independently selected from the group consisting of halogen, —C1-4alkyl, —OH, —OC1-4alkyl, —SC1-4alkyl, —CN, —CONRaRb, and —NO2; and wherein Ra and Rb are each independently —H or —C1-4alkyl;
or a pharmaceutically acceptable salt, or a pharmaceutically active metabolite thereof; comprising

OG Complex Work Unit Drawing
reacting a compound of formula (V) with a compound of formula (VI), wherein LG1 is a first leaving group and LG2 is a second leaving group, in the presence of a base, in an organic solvent; to yield the corresponding compound of formula (VII);

OG Complex Work Unit Drawing
reacting the compound of formula (VII) with an aldehyde or ketone derivative of the desired R1 substituent group; in the presence of a reducing agent; in an organic solvent; to yield the corresponding compound of formula (X);

OG Complex Work Unit Drawing
reacting the compound of formula (X) with a compound of formula (XII); in the presence of a first inorganic base; in an organic solvent; or
reacting the compound of formula (X) with a compound of formula (XIII); in the presence of a second inorganic base; in an organic solvent;
to yield the corresponding compound of formula (I).