Process for preparing substituted 8-azabicyclo[3.2.1]octan-3-ols

A process for preparing a compound having the structural formula I

• or a pharmaceutically acceptable salt thereof,
• R is benzyl, -benzyl-R5, allyl, —C(O)R6, —C(O)OR8 or —CH(R7)2;
• each R7 is independently selected from the group consisting of -phenyl-R2 or R2-heteroaryl;
• R1 is R3-aryl, R3-heteroaryl, R3-arylalkyl- or R3-heteroarylalkyl-;
• R2 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy and alkoxy;
• R3 is 1-3 substituents independently selected from the group consisting of hydrogen, halogen and alkyl;
• R5 is 1 or 2 substituents independently selected from the group consisting of halogen, alkoxy and —NO2;
• R6 is H, alkyl, haloalkyl or benzyl;
• and
• R8 is alkyl, benzyl or allyl;
• comprising
• a)reacting an amine of formula II
• R—NH2 II
• wherein R is as defined above, with 2,5-dimethoxytetrahydrofuran or HC(O)(CH2)2C(O)H, and with C(O)(CH2C(O)OR4)2, wherein R4 is H or alkyl, in a buffer, optionally in the presence of a base, to obtain a compound of formula III
• b) reacting a compound of formula III with I-R1, wherein R1 is as defined above, with alkyl lithium, optionally in the presence of a lithium salt, to obtain a compound of formula I;
• c) optionally converting a compound of formula I wherein R is benzyl, -benzyl-R5, allyl, —C(O)R6 or —C(O)OR8 to a compound of formula I wherein R is —CH(R7)2 by
• i) reacting the compound of Formula III with a suitable reagent to remove the benzyl, -benzyl-R5, allyl, —C(O)R6 or —C(O)OR8 group to obtain a compound of formula I(c)(i)
• and
• ii) reacting the compound of I(c)(i) or a salt thereof with a compound of formula IV
• CH(R7)2—X IV
• wherein X is halogen, —OSO2CH3 or —O-(p-toluenesulfonyl) thereby yielding the compound of formula I wherein R is —CH(R7)2;
• and
• d) optionally recrystallizing the product of step b) or step c) to obtain a purified product.