Granted Patent B2

US 12,552,746 · App. 17/787,000 · Granted Feb 17, 2026

Inventors: Yolanda Fernández Sainz (Valladolid, ES); Antonio Lorente Bonde-Larsen (Valladolid, ES); Alfonso Pérez Encabo (Valladolid, ES); José Ángel Turiel Hernandez (Valladolid, ES); José Enrique Gómez Pulido (Valladolid, ES); Mario Laderas Muñoz (Valladolid, ES)

Assignee: CURIA SPAIN, S.A.U.

C07D207/08C07D207/16C07D207/20C07D207/22C07D487/14C07F7/1804C07F7/188

Abstract

Claims (136)

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

wherein

X is a leaving group, and

R 1 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, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and

R 1 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

R 1 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

R 1 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

R 1 is selected from H and amino protecting group;

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl; and

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 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—CH 2 —Li, X—CH 2 —MgCl or X—CH 2 —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 R 6 O—CH 2 —Li, R 6 O—CH 2 —MgCl or R 6 O—CH 2 —MgBr, to provide a compound of formula (VIII) or a salt or solvate thereof

wherein

is a cis single bond or a double bond;

R 1 is selected from H and amino protecting group; and

R 6 is a selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )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.

2 . The process according to claim 1 , wherein in the compound of formula (II), or a salt or solvate thereof, is a double bond and the process further comprises a hydrogenation step after step (a), or (bi), or (bii), or (biii), or (bi′), or (bi″), or (bii″).

3 . The process according to claim 1 , wherein is a cis single bond in the compounds of formula (II), (III), (IV), (V), (VI), (VII) and (VIII).

4 . The process according to claim 3 , wherein the compound of formula (II) wherein is a cis single bond, or a salt or solvate thereof, is obtained by hydrogenating a compound of formula (II″) or a salt or solvate thereof

wherein

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and

R 1 is selected from H and amino protecting group.

5 . The process according to claim 1 , comprising:

(a) converting a compound of formula (II″) or a salt or solvate thereof

wherein

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and

R 1 is selected from H and amino protecting group;

into a compound of formula (III″) or (IV″) or a salt or solvate thereof

(b1) hydrogenating a compound of formula (III″) or (IV″), or a salt or solvate thereof, to provide a compound of formula (III′-cis) or (IV′-cis) or a salt or solvate thereof

and

(b2) converting a compound of formula (III′-cis) or (IV′-cis), 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′-cis) or (IV′-cis), or a salt or solvate thereof, with MeMgCl, MeMgBr or MeLi to provide a ketone of formula (V′-cis) or a salt or solvate thereof

(bii) converting a ketone of formula (V′-cis), or a salt or solvate thereof, into an enol ether of formula (VI′-cis) or an enamine of formula (VII′-cis) or a salt or solvate thereof

wherein

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl; and

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl or they form, together with the nitrogen atom, a 5- to 7-membered heterocyclic ring; and

(biii) converting an enol ether of formula (VI′-cis) or an enamine of formula (VII′-cis), 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′-cis) or (IV′-cis), or a salt or solvate thereof, with X—CH 2 —Li, X—CH 2 —MgCl or X—CH 2 —MgBr, to provide a compound of formula (I′-cis) or a salt or solvate thereof; or

(bi″) reacting the compound of formula (III′-cis) or (IV′-cis), or a salt or solvate thereof, with R 60 —CH 2 —Li, R 60 —CH 2 —MgCl or R 60 —CH 2 —MgBr, to provide a compound of formula (VIII′-cis) or a salt or solvate thereof

wherein

R 1 is selected from H, and amino protecting group; and

R 6 is selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl; and

(bii″) converting a compound of formula (VIII′-cis), or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof.

6 . The process according to claim 1 , comprising:

(a) converting a compound of formula (II″) or a salt or solvate thereof

wherein

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and

R 1 is selected from H and amino protecting group;

into a compound of formula (III″) or (IV″) or a salt or solvate thereof

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:

(bi1) 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

(bi2) hydrogenating a compound of formula (V″), or a salt or solvate thereof, to provide a compound of formula (V′-cis) or a salt or solvate thereof

(bii) converting a ketone of formula (V′-cis), or a salt or solvate thereof, into an enol ether of formula (VI′-cis) or an enamine of formula (VII′-cis) or a salt or solvate thereof

wherein

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl or they form, together with the nitrogen atom, a 5- to 7-membered heterocyclic ring; and

(biii) converting an enol ether of formula (VI′-cis) or an enamine of formula (VII′-cis), or a salt or solvate thereof, into a compound of formula (I′-cis) or a salt or solvate thereof.

7 . The process according to claim 1 , comprising:

(a) converting a compound of formula (II″) or a salt or solvate thereof

wherein

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and

R 1 is selected from H and amino protecting group;

into a compound of formula (III″) or (IV″) or a salt or solvate thereof

(b) converting a compound of formula (III″) or (IV″), or a salt or solvate thereof, into a compound of formula (I′), 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

(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

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl; and

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 ) aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl or they form, together with the nitrogen atom, 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″) or a salt or solvate thereof

wherein

X is a leaving group, and

R 1 is selected from H, and amino protecting group; and

(biv) hydrogenating a compound of formula (I″), or a salt or solvate thereof, 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 X—CH 2 —Li, X—CH 2 —MgCl or X—CH 2 —MgBr, wherein X is a leaving group, to provide a compound of formula (I″) or a salt or solvate thereof

and

(bii′) hydrogenating a compound of formula (I″), or a salt or solvate thereof, 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 R 6 O—CH 2 —Li, R 6 O—CH 2 —MgCl or R 6 O—CH 2 —MgBr, to provide a compound of formula (VIII′) or a salt or solvate thereof

wherein

R 1 is selected from H, and amino protecting group; and

R 6 is selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl;

(bii″) converting a compound of formula (VIII″), or a salt or solvate thereof, into a compound of formula (I″) or a salt or solvate thereof

and

(biii″) hydrogenating a compound of formula (I″), or a salt or solvate thereof, to provide a compound of formula (I′-cis) or a salt or solvate thereof.

8 . The process according to claim 1 , wherein:

X is selected from Cl, Br and I; and/or

R 1 is an amino protecting group; and/or

Y is selected from OH and OR 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl; and/or

R 6 is selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl.

9 . The process according to claim 1 , wherein when is a cis single bond in the compound of formula (I′-cis), or (II), or (III), or (IV), or (V), or (VI), or (VII), or (VIII), said compound is a compound of formula (I′-cis-3R), or (II′-cis-3R), or (III′-cis-3R), or (IV′-cis-3R), or (V′-cis-3R), or (VI′-cis-3R), or (VII′-cis-3R), or (VIII′-cis-3R), respectively

or a salt or solvate thereof, wherein

X is a leaving group;

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl;

R 1 is selected from H and amino protecting group;

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl;

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl or they form, together with the nitrogen atom, a 5- to 7-membered heterocyclic ring; and

R 6 is selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl.

10 . The process according to claim 1 , wherein the compound of formula (II), or a salt or solvate thereof, is obtained by a process comprising:

reacting a compound of formula (IX) or a salt or solvate thereof

wherein

Z is selected from halogen, C 1 -C 6 alkylsulfonates, C 1 -C 6 haloalkylsulfonates, C 6 -C 10 arylsulfonates and (C 1 -C 6 )alkyl(C 6 -C 10 )arylsulfonates;

R 1 is selected from H and amino protecting group; and

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl;

with Et 2 CuLi, Et 2 CuMgBr or Et 2 CuMgCl, to provide a compound of formula (II), or a salt or solvate thereof, wherein is a double bond; and

if a compound of formula (II) wherein is a cis single bond is desired, hydrogenating the double bond to provide a compound of formula (II), or a salt or solvate thereof, wherein is a cis single bond.

11 . The process according to claim 1 , wherein the compound of formula (I′-cis), or a salt or solvate thereof, is converted into Upadacitinib, or a salt or solvate or stereoisomer thereof.

12 . The process according to claim 1 , wherein the compound of formula (I′-cis) or a salt or solvate thereof is a compound of formula (I′-cis-3R) or a salt or solvate thereof

wherein

X is a leaving group, and

R 1 is selected from H, and amino protecting group; and

wherein the compound of formula (II), (III), (IV), (V), (VI), (VII) and (VIII) are, respectively, a compound of formula (II′-cis-3R), (III′-cis-3R), (IV′-cis-3R), (V′-cis-3R), (VI′-cis-3R), (VII′-cis-3R), or (VIII′-cis-3R)

or a salt or solvate thereof, wherein

X is a leaving group;

Y is selected from OH, Cl, OR 2 and OC(O)R 2 , wherein R 2 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl;

R 1 is selected from H and amino protecting group;

R 3 is selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl, C 6 -C 15 aryl, COR′ and SiR′ 3 , wherein each R′ is independently selected from C 1-6 alkyl, C 3 -C 10 cycloalkyl, C 6-15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl;

R 4 and R 5 are independently selected from C 1 -C 6 alkyl, (C 6 -C 15 )aryl(C 1 -C 6 )alkyl and C 6 -C 15 aryl or they form, together with the nitrogen atom, a 5- to 7-membered heterocyclic ring; and

R 6 is selected from H, —COR′ and —CONR′R″, wherein R′ and R″ are independently selected from C 1 -C 6 alkyl, C 6 -C 15 aryl and (C 6 -C 15 )aryl(C 1 -C 6 )alkyl.

Assignments (2)

Priority Claims (1)

Continuity (1)

References Cited (23)