Trifluoromethyl alcohols as modulators of RORγt

Patent metadata

Field	Value
Publication number	US-10150762-B2
Application number	US-201715664673-A
Country	US
Kind code	B2
Filing date	Jul 31, 2017
Priority date	Oct 30, 2014
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

The present invention comprises methods of making 5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-(2-hydroxy-2-methylpropyl)-4-(R 1 -1-carbonyl)thiazole-2-carboxamide, wherein R 1 is defined in the specification.

First claim

What is claimed is:

1. A method of making a 5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-(2-hydroxy-2-methylpropyl)-4-(R 1 -1-carbonyl)thiazole-2-carboxamide comprising the step of reacting R 1 —H with 5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylic acid in the presence of N,N-diisopropylethylamine and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, as shown in the reaction below:

wherein R 1 is selected from the group consisting of:

2. The method of claim 1 , further comprising the step of making 5-(2,3-dichloro-4-(1, 1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylic acid by reacting methyl 5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylate with KOH, methanol, and water, as shown in the reaction below:

3. The method of claim 2 , further comprising the step of making methyl 5-(2,3-dichloro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylate by reacting 2-(4-bromo-2,3-dichlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol with methyl 2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylate, KOAc, Pd(OAc) 2 , and PPh 3 , as shown in the reaction below:

4. The method of claim 3 , further comprising the step of making methyl 2-((2-hydroxy-2-methylpropyl)carbamoyl)thiazole-4-carboxylate by reacting 4-bromro-N-(2-hydroxy-2-methylpropyl)thiazole-2-carboxamide, TEA, MeOH, and Pd(dppf)Cl 2 , as shown in the reaction below:

5. The method of claim 4 further comprising the step of making 4-bromo-N-(2-hydroxy-2-methylpropyl)thiazole-2-carboxamride by reacting 4-bromothiazole-2-carboxylic acid, HOBt, 1-amino-2-methyl-propan-2-ol, EDCI, and TEA as shown in the reaction below:

6. The method of claim 1 , wherein R 1 is further selected from the group consisting of:

7. The method of claim 5 , wherein R 1 is

8. The method of claim 5 , wherein R 1 is

9. The method of claim 5 , wherein R 1 is

10. The method of claim 5 , wherein R 1 is

11. A method of making a (S)-5-(R 2 )—N-(2-hydroxy-2-methylpropyl)-4-(2-methylpyrrolidine −1-carbonyl)thiazole-2-carboxamide comprising the step of reacting (S)—N-(2-hydroxy-2-methylpropyl)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxamide, R 2 —Br, K 2 CO 3 , pivalic acid, Pd 2 (dba) 3 .CHCl 3 , and cataCXium® A, as shown in the reaction below:

wherein R 2 is selected from the group consisting of:

12. The method of claim 11 further comprising the synthesis of (S)—N-(2-hydroxy-2-methylpropyl)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxamide by means of reacting lithium (S)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate and 1-amino-2-methylpropan-2-ol, TEA, and HATU, as shown in the reaction below:

13. The method of claim 12 further comprising the synthesis of lithium (S)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate by means of reacting ethyl (S)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate with LiOH, as shown in the reaction below:

14. The method of claim 13 further comprising the synthesis of ethyl (S)-4-(2-methylpyrrolidine-1-carbonyl)thiazole-2-carboxylate by means of reacting 2-(ethoxycarbonyl)thiazole-4-carboxylic acid, (S)-2-methylpyrrolidine, TEA, and HATU, as shown in the reaction below:

15. The method of claim 14 , wherein R 2 is:

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Goldberg Steven
• Venkatesan Hariharan
• Kinzel Olaf
• Gege Christian
• Steeneck Christoph
• Kleymann Gerald
• Hoffmann Thomas

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title