Enzymatic resolvation for obtaining a (−)-3,4-trans-diarylchroman

A preparation of (−)-3,4-trans-compounds of the formula I

• wherein R1 and R4 are individually hydrogen, C1-6alkyl or C1-6alkoxy, R5 is —O—(CH2)n—NR6R7 wherein n is an integer in the range of 1 to 6 and R6 and R7 independently are C1-6alkyl or R6 and R7 together with the N atom is a saturated or unsaturated 5- or 6-membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C1-6alkyl;
• and R2 and R3 are individually hydrogen or C1-6alkyl;
• or a salt thereof, which comprises
• a) treating a trans-racemate of a compound of formula II
• or a salt thereof, wherein R1, R2, R3 and R4 are as defined above with an agent of formula R—CO—X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III
• or a salt thereof, wherein R1, R2, R3 and R4 are as defined above,
• b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula IIIa
• or a salt thereof, and a compound of formula IV
• or a salt thereof;
• or a mixture comprising a compound of formula IIIb
• or a salt thereof, and a compound of formula IVa
• or a salt thereof;
• c) separating said mixture of compound IIIa and IV or said mixture of compound IIIb and IVa, thereby obtaining a compound of formula IV or a compound of formula IIIb, which compound IIIb is then hydrolyzed to said compound of formula IV,
• d) treating said compound of formula IV with an agent of formula Y—R5 wherein Y is a leaving group, thereby obtaining the compound of formula I or a salt thereof.

A process for the preparation of (3R,4S)-cis-compounds of the formula VII

• wherein R1 and R4 are individually hydrogen, C1-6alkyl or C1-6alkoxy, and R2 and R3 are individually hydrogen or C1-6alkyl;
• or a salt thereof, which comprises
• a) treating a cis-racemate of a compound of formula V
• or a salt thereof, wherein R1, R2, R3 and R4 are as defined above with an agent of formula R—CO—X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI
• or a salt thereof, wherein R, R1, R2, R3 and R4 are as defined above,
• b) treating said cis-racemate of formula VI with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula VIa
• or a salt thereof, and a compound of formula VII
• or a salt thereof;
• or a mixture comprising a compound of formula VIb
• or a salt thereof, and a compound of formula VIIa
• or a salt thereof,
• c) separating said mixture of compound VIa and VII or said mixture of compound VIb and VIIa, thereby obtaining a compound of formula VII or a compound of formula VIb, which compound VIb is then hydrolyzed to said compound of formula VII.

A process for the preparation of (3R,4R)-trans-compounds of the formula IV

• wherein R1 and R4 are individually hydrogen, C1-6alkyl or C1-6alkoxy, and R2 and R3 are individually hydrogen or C1-6alkyl;
• or a salt thereof, which comprises
• a) treating a trans-racemate of a compound of formula II
• or a salt thereof, wherein R1, R2, R3 and R4 are as defined above with an agent of formula R—CO—X, wherein R is C1-12alkyl, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl or C1-12alkoxy, optionally substituted with C1-6alkyl, C1-6alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III
• or a salt thereof, wherein R1, R2, R3 and R4 are as defined above,
• b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula IIIa
• or a salt thereof, and a compound of formula IV
• or a salt thereof;
• or a mixture comprising a compound of formula IIIb
• or a salt thereof, and a compound of formula IVa
• or a salt thereof,
• c) separating said mixture of compound IIIa and IV or said mixture of compound IIIb and IVa, thereby obtaining a compound of formula IV or a compound of formula IIIb, which compound IIIb is then hydrolyzed to said compound of formula IV, or a salt thereof.