Process for the preparation of histamine H3 receptor modulators

A process for the preparation of a compound of formula (I)

• 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
• 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);
• 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);
• 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).