Process for preparing quinuclidinium carbamate derivatives

A process for preparing compounds of formula (I):

• wherein
• R1 represents a group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, or thiophen-3-ylmethyl;
• R2 represents a group chosen from optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, saturated or unsaturated cycloalkyl, saturated or unsaturated cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl, or pyridylmethyl;
• wherein the carbocyclic moieties in the cycloalkyl, cycloalkylmethyl, phenyl, benzyl and phenethyl groups are optionally bridged or fused to another saturated, unsaturated or aromatic carbocyclic moiety or to a cyclic moiety comprising carbon atoms and 1 or 2 oxygen atoms;
• cyclic groups present in R1 and R2 are optionally substituted by one, two or three substituents chosen from halogen;
• optionally substituted straight lower alkyl, optionally substituted branched lower alkyl, hydroxy, optionally substituted straight lower alkoxy, optionally substituted branched lower alkoxy, —SH, optionally substituted straight lower alkylthio, optionally substituted branched lower alkylthio, nitro, cyano, —NR′R″, —CO2R′, —C(O)—NR′R″, —N(R′″)C(O)—R′, and —N(R′″)—C(O)NR′R″, wherein R′, R″ and R′″ each independently represents a hydrogen atom or a straight or branched, optionally substituted lower alkyl group or R′ and R″ together with the atom to which they are attached form a cyclic group;
• p is 1 or 2 and the carbamate group is attached at positions 2, 3 or 4 of the azoniabicyclic ring,
• m is an integer from 0 to 8;
• n is an integer from 0 to 4;
• A represents a group chosen from —CH2—, —CH═CR′—, —CR′═CH—, —CR′R″—, —C(O)—, —O—, —S—, —S(O)—, —S(O)2— or —NR′—
• B represents a hydrogen atom, or a group chosen from optionally substituted straight lower alkyl, optionally substituted branched lower alkyl, hydroxy, optionally substituted straight lower alkoxy, optionally substituted branched lower alkoxy, cyano, nitro, —CH═CR′R″, —C(O)OR′, —OC(O)R′, —SC(O)R′, —C(O)NR′R″, —NR′C(O)OR″, —NR′″C(O)NR′R″, cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, heteroaryl or heterocyclyl;
• and wherein the cyclic groups present in group B are optionally substituted by one, two or three substituents chosen from halogen, hydroxy, optionally substituted straight lower alkyl, optionally substituted branched lower alkyl, phenyl, —OR′, —SR′, —NR′R″, —NHCOR′, —CONR′R″, —CN, —NO2 and —COOR′;
• X− represents a pharmaceutically acceptable anion of a mono or polyvalent acid;
• including all individual stereoisomers of formula (I) and mixtures thereof;
• the process comprising:
• a) Reacting at least one compound of formula (II)
• with at least one compound of formula (III)
• B—(CH2)n-A-(CH2)m—W (III)
• wherein W is a leaving group,
• to yield at least one compound of formula (IV)
• b) subsequently reacting the compound of formula (IV) with at least one acylating agent of formula (V)
• wherein G represents a leaving group;
• and
• c) when W− represents a group other than X−, exchanging the ion W− in the product of step b) by the ion X− using standard methods of anion exchange
• to yield the compounds of formula (I).