Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds

Abstract

The present invention relates to a method of making novel dipeptidyl peptidase-IV (“DPP-IV’) inhibitor compounds useful for treating, inter alia, diseases that are associated with proteins that are subject to processing by DPP-IV, such as Type 2 diabetes mellitus, metabolic syndrome (Syndrome X or insulin resistance syndrome), hyperglycemia, impaired glucose tolerance, glucosuria, metabolic acidosis, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, Type 1 diabetes, obesity, hypertension, hyperlipidemia, atherosclerosis, osteoporosis, osteopenia, frailty, bone loss, bone fracture, acute coronary syndrome, infertility due to polycystic ovary syndrome, short bowel syndrome and to prevent disease progression in Type 2 diabetes. The invention also relates to a method of making 3,3,4,4-tetrafluoropyrrolidine, a starting material utilized in the afore-mentioned method for preparing DPP-IV compounds.

1 - 15  (canceled).  
     
     
         16 . A process of making [[2,2,3,3,-tetrafluoropyrrolidine]]3,3,4,4-tetrafluoropyrrolidine hydrochloride comprising: 
 (a) treating 2,2,3,3-tetrafluorobutanediol with an activating reagent or combination of activating reagents to form a compound of Formula VI,                          wherein R 8  is a leaving group;    (b) reacting the compound of Formula VI with a protected primary amine, NH 2 R 9 , in a solvent, to form a compound of Formula VII;                          and;    (c) removing the protecting group, R 9 , from the N-protected amine to form [[2,2,3,3,-tetrafluoropyrrolidine]]3,3,4,4-tetrafluoropyrrolidine or a salt thereof.    
     
     
         17 . A process of  claim 16  wherein the activating reagent of step (a) is HBr, PBr 3 , PBr 5 , SOBr 2  or HI, or the combination of activating reagents is trifluoromethanesulfonic anhydride/organic base, alkylsulfonyl chloride/organic base, arylsulfonyl chloride/organic base, Ph 3 P/CBr 4 , Ph 3 P/N-bromosuccinimide, KI/H 3 PO 4 , Ph 3 P/I 2 , or Me 3 SiCl/NaI.  
     
     
         18 . A process of  claim 17  wherein the activating reagent combination is trifluoromethanesulfonic anhydride and an organic base.  
     
     
         19 . A process of  claim 19  wherein the organic base is pyridine.  
     
     
         20 . A process of  claim 16  wherein R 8  is Br, I or OSO 2 R 11 , wherein R 11  is (1) a C 1 -C 8  straight or branched alkyl, optionally substituted with fluorine or (2) an aryl group, optionally substituted with halogen or a C 1 -C 8  straight or branched alkyl optionally substituted with one to four fluorines.  
     
     
         21 . A process of  claim 17  wherein R 8  is Br, I or OSO 2 R 11 , wherein R 11  is (1) a C 1 -C 8  straight or branched alkyl, optionally substituted with fluorine or (2) an aryl group, optionally substituted with halogen or a C 1 -C 8  straight or branched alkyl optionally substituted with one to four fluorines.  
     
     
         22 . A process of  claim 18  wherein R 8  is Br, I or OSO 2 R 11 , wherein R 11  is (1) a C 1 -C 8  straight or branched alkyl, optionally substituted with fluorine or (2) an aryl group, optionally substituted with halogen or a C 1 -C 8  straight or branched alkyl optionally substituted with one to four fluorines.  
     
     
         23 . A process of  claim 19  wherein R 8  is Br, I or OSO 2 R 11 , wherein R 11  is (1) a C 1 -C 8  straight or branched alkyl, optionally substituted with fluorine or (2) an aryl group, optionally substituted with halogen or a C 1 -C 8  straight or branched alkyl optionally substituted with one to four fluorines.  
     
     
         24 . A process of  claim 20  wherein R 8  is trifluoromethylsulfonyloxy.  
     
     
         25 . A process of  claim 21  wherein R 8  is trifluoromethylsulfonyloxy.  
     
     
         26 . A process of  claim 22  wherein R 8  is trifluoromethylsulfonyloxy.  
     
     
         27 . A process of  claim 23  wherein R 8  is trifluoromethylsulfonyloxy.  
     
     
         28 . A process of  claim 20  wherein the N-protected amine of step (b) is benzyl amine.  
     
     
         29 . A process of  claim 21  wherein the N-protected amine of step (b) is benzyl amine.  
     
     
         30 . A process of  claim 22  wherein the N-protected amine of step (b) is benzyl amine.  
     
     
         31 . A process of  claim 23  wherein the N-protected amine of step (b) is benzyl amine.  
     
     
         32 . A process of  claim 20  wherein the protecting group, R 9 , is benzyl, tert-butyl, allyl or benzhydryl.  
     
     
         33 . A process of  claim 21  wherein the protecting group, R 9 , is benzyl, tert-butyl, allyl or benzhydryl.  
     
     
         34 . A process of  claim 22  wherein the protecting group, R 9 , is benzyl, tert-butyl, allyl or benzhydryl.  
     
     
         35 . A process of  claim 23  wherein the protecting group, R 9 , is benzyl, tert-butyl, allyl or benzhydryl.  
     
     
         36 . A process of  claim 20  wherein the protecting group, R 9 , is benzyl, and is removed in step (c) by hydrogenolysis in the presence of palladium.  
     
     
         37 . A process of  claim 21  wherein the protecting group, R 9 , is benzyl, and is removed in step (c) by hydrogenolysis in the presence of palladium.  
     
     
         38 . A process of  claim 22  wherein the protecting group, R 9 , is benzyl, and is removed in step (c) by hydrogenolysis in the presence of palladium.  
     
     
         39 . A process of  claim 23  wherein the protecting group, R 9 , is benzyl, and is removed in step (c) by hydrogenolysis in the presence of palladium.