Process for preparing alpha-carboxamide pyrrolidine derivatives
AssigneeBiogen MA Inc.
InventorsDonald G. Walker, Dino Alberico, Joshua Clayton, Chandrasekhar Navuluri
Life of this patent
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Abstract
Disclosed are processes for preparing α-carboxamide pyrrolidine derivatives, in particular (2S,5R)-5-(4-((2-fluorobenzyl)oxy)phenyl)pyrrolidine-2-carboxamide, and intermediates for use in said processes along with processes for preparing said intermediates.
Claims50
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (II) with a compound of formula (IV) in the presence of a base, such as lithium bis(trimethylsilyl amide), thereby producing a compound of formula (V):
- wherein:
- L1 is a leaving group;
- R1 is an oxygen-protecting group;
- R2 is a resonance-accepting nitrogen-protecting group;
- and
- R3 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising deprotecting a compound of formula (V), thereby producing a compound of formula (VI):
- wherein:
- R1 is an oxygen-protecting group;
- R2 is a resonance-accepting nitrogen-protecting group;
- and
- R3 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (VI) with an acid, such as hydrochloric acid, thereby producing a compound (1), or a salt thereof:
- wherein R1 is an oxygen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (VIII) with a compound of formula (IX), thereby producing a compound of formula (X):
- wherein:
- L2 is hydroxyl or a leaving group;
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- and
- R6 is a resonance-accepting nitrogen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (X) with an acid, such as methanesulfonic acid and/or sulfuric acid, thereby producing a compound of formula (XI):
- wherein:
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- and
- R6 is a resonance-accepting nitrogen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XI) with NH4OH, thereby producing a compound of formula (XII):
- wherein R5 is 2-fluorobenzyl or an oxygen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XXII) with a compound of formula (VIII), thereby producing a compound of formula (XXIII):
- wherein:
- L1 is a leaving group;
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- R6 is a resonance-accepting nitrogen-protecting group;
- and
- R8 is C1-6alkyl, C2-6 alkenyl, or C2-6 alkynyl.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XXI) with NH4OH, thereby producing a compound of formula (XII):
- wherein:
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- R6 is a resonance-accepting nitrogen-protecting group;
- and
- R8 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (X) with NH4OH, thereby producing a compound of formula (XIII):
- wherein:
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- and
- R6 is a resonance-accepting nitrogen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising deprotecting a compound of formula (XIII), thereby producing a compound of formula (XII):
- wherein:
- R5 is 2-fluorobenzyl or an oxygen-protecting group;
- and
- R6 is a resonance-accepting nitrogen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XII) with hydrogen gas in the presence of a catalyst, such as PtO2, thereby producing a compound of wherein R5 is 2-fluorobenzyl or an oxygen-protecting group.
A process for preparing a compound of formula (I)
- or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (XII) with hydrogen gas in the presence of a catalyst, thereby producing a compound of formula (XVI):
- wherein R5 is 2-fluorobenzyl or an oxygen-protecting group.
The process of any one of claims 80-85, wherein R5 is benzyl.
A compound of formula (XXIV), formula (XXV), formula (XXVI), formula (XXVII), or formula (XXVIII)
- or a pharmaceutically acceptable salt thereof, wherein
- R10 is hydrogen or a resonance-accepting nitrogen-protecting group;
- R11 is
- wherein R12 is 2-fluorobenzyl, benzyl or hydroxyl;
- L3 is a leaving group;
- R5 is benzyl, 2-fluorobenzyl, or an oxygen-protecting group;
- and
- R13 is hydrogen, benzyl, 2-fluorobenzyl, or an oxygen-protecting group.
Dependencies are inferred from the claim text.