Processes for the preparation of nlrp3 inhibitors

A process of preparing a N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof, wherein the process comprises converting a thiourea adduct (I) to the N-protected-4-(halosulfonyl)-piperidine (J) or the salt thereof:

• wherein:
• R2 is a nitrogen protecting group;
• each R4 is independently selected from hydrogen or a C1-C20 hydrocarbyl group, wherein
• each C1-C20 hydrocarbyl group is straight-chained or branched, or is or includes one or more cyclic groups, wherein
• each C1-C20 hydrocarbyl group is optionally substituted with one or more oxo (═O) and/or one or more halo, and wherein
• each C1-C20 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S, or wherein
• any two or more R4, together with the atom or atoms to which they are attached, form a 3- to 16-membered heterocyclic group, wherein
• the heterocyclic group is monocyclic, bicyclic or tricyclic, and wherein
• the heterocyclic group is optionally substituted with one or more groups selected from halo and/or R50, wherein
• each R40 is independently selected from —CN, —OH, —NH2, oxo (═O), ═NH and C1-C6 hydrocarbyl, wherein
• each C1-C6 hydrocarbyl is straight-chained, branched, or is or includes one or more cyclic groups, wherein
• each C1-C6 hydrocarbyl group is optionally substituted with one or more halo, and wherein
• each C1-C6 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S;
• and
• Hal is Cl or Br.

A process comprising one or more steps selected from:

• (i) converting 4-hydroxy piperidine (F) to a N-protected-4-hydroxy piperidine (G):
• wherein the conversion is performed in a biphasic solvent system;
• (ii) converting a N-protected-4-hydroxy piperidine (G) to a N-protected-4-derivatised piperidine (H):
• wherein the conversion is performed in the presence of a non-polar solvent;
• (iii) converting a N-protected-4-derivatised piperidine (H) to a thiourea adduct (I):
• (iv) converting a thiourea adduct (I) to a N-protected-4-(halosulfonyl)-piperidine (J):
• (v) converting a N-protected-4-(halosulfonyl)-piperidine (J) to a N-protected-4-piperidinesulfonamide (K):
• wherein the conversion comprises (1) forming a solution of ammonia in a solvent, and (2) adding the N-protected-4-(halosulfonyl)-piperidine (J) to the solution formed in (1);
• and
• (vi) converting a N-protected-4-piperidinesulfonamide (K) to 1-ethyl-4-piperidinesulfonamide (A):
• wherein the conversion is performed in the presence of a C3-C5 alcohol;
• and wherein:
• R2 is a nitrogen protecting group;
• R3 is a leaving group;
• each R4 is independently selected from hydrogen and a C1-C20 hydrocarbyl group, wherein
• each C1-C20 hydrocarbyl group is straight-chained, branched, or is or includes one or more cyclic groups, wherein
• each C1-C20 hydrocarbyl group mas optionally substituted with one or more oxo (═O) and/or halo, and wherein
• each C1-C20 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S, or wherein
• any two or more R4, together with the atom or atoms to which they are attached, form a 3- to 16-membered heterocyclic group, wherein
• the heterocyclic group is monocyclic, bicyclic or tricyclic, and wherein
• the heterocyclic group is optionally substituted with one or more halo and/or R40, wherein
• each R40 is independently selected from a —CN, —OH, —NH2, oxo (═O), ═NH and C1-C6 hydrocarbyl group, wherein
• each C1-C6 hydrocarbyl group is straight-chained or branched, or is or includes one or more cyclic groups, wherein
• each C1-C6 hydrocarbyl group is optionally substituted with one or more halo, and wherein
• each C1-C6 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S;
• and
• Hal is Cl or Br.

A thiourea adduct (I) or a salt thereof:

• wherein:
• R2 is a nitrogen protecting group;
• and
• each R4 is independently selected from hydrogen and a C1-C20 hydrocarbyl group, wherein
• each C1-C20 hydrocarbyl group is straight-chained, branched, or is or includes one or more cyclic groups, wherein
• each C1-C20 hydrocarbyl group is optionally substituted with one or more oxo (═O) and/or halo, and wherein
• each C1-C20 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S, or wherein
• any two or more R4, together with the atom or atoms to which they are attached, form a 3- to 16-membered heterocyclic group, wherein
• the heterocyclic group is monocyclic, bicyclic or tricyclic, and wherein
• the heterocyclic group is optionally substituted with one or more halo and/or R40, wherein
• each R40 is independently selected from a —CN, —OH, —NH2, oxo (═O), ═NH and C1-C6 hydrocarbyl, wherein
• each C1-C6 hydrocarbyl group is straight-chained, branched, or is or includes one or more cyclic groups, wherein
• each C1-C6 hydrocarbyl group is optionally substituted with one or more halo, and wherein
• each C1-C6 hydrocarbyl group optionally includes one or more heteroatoms independently selected from N, O and S.

A compound selected from the group consisting of:

• (i) an N-protected-4-(halosulfonyl)-piperidine (J) or a salt thereof:
• wherein R2 is a nitrogen protecting group and Hal is Cl or Br;
• and
• (ii) an N-protected-4-piperidinesulfonamide (K) or a salt thereof:
• wherein R2 is a nitrogen protecting group.