Process and intermediates for the preparation of upadacitinib

A process for preparing a compound of formula (I′-cis) or a salt or solvate thereof

• wherein
• X is a leaving group, and
• R1 is selected from H and amino protecting group;
• which comprises:
• (a) converting a compound of formula (II) or a salt or solvate thereof
• wherein
• is a cis single bond or a double bond;
• Y is selected from OH, Cl, OR2 and OC(O)R2, wherein R2 is selected from C1-C6 alkyl, (C6-C15)aryl(C1-C6)alkyl and C6-C15 aryl;
• and
• R1 is selected from H and amino protecting group;
• into a compound of formula (III) or (IV), or a salt or solvate thereof
• wherein
• is a cis single bond or a double bond;
• and
• R1 is selected from H and amino protecting group;
• and
• (b) converting a compound of formula (III) or (IV), or a salt or solvate thereof, into a compound of formula (I′-cis), or a salt or solvate thereof, by a process comprising:
• (bi) reacting the compound of formula (III) or (IV), or a salt or solvate thereof, with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V) or a salt or solvate thereof
• wherein
• is a cis single bond or a double bond;
• and
• R1 is selected from H and amino protecting group;
• (bii) converting a ketone of formula (V), or a salt or solvate thereof, into an enol ether of formula (VI) or an enamine of formula (VII) or a salt or solvate thereof
• wherein
• is a cis single bond or a double bond;
• and
• R1 is selected from H and amino protecting group;
• R3 is selected from C1-C6 alkyl, (C6-C15)aryl(C1-C6)alkyl, C6-C15 aryl, COR′ and SiR′3, wherein each R′ is independently selected from C1-6 alkyl, C3-C10 cycloalkyl, C6-15 aryl and (C6-C15)aryl(C1-C6)alkyl;
• and
• R4 and R5 are independently selected from C1-C6 alkyl, (C6-C15)aryl(C1-C6)alkyl and C6-C15 aryl or they form, together with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyclic ring;
• and
• (biii) converting an enol ether of formula (VI) or an enamine of formula (VII), or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof;
• or
• (bi′) reacting the compound of formula (III) or (IV), or a salt or solvate thereof, with X—CH2—Li, X—CH2—MgCl or X—CH2—MgBr, to provide a compound of formula (I′-cis) or a salt or solvate thereof;
• or
• (bi″) reacting the compound of formula (III) or (IV), or a salt or solvate thereof, with R6O—CH2—Li, R6O—CH2—MgCl or R6O—CH2—MgBr, to provide a compound of formula (VIII) or a salt or solvate thereof
• wherein
• is a cis single bond or a double bond;
• R1 is selected from H and amino protecting group;
• and
• R6 is a selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C1-C6 alkyl, C6-C15 aryl and (C6-C15)aryl(C1-C6)alkyl;
• and
• (bii″) converting a compound of formula (VIII), or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof.