Process for production of piperidine derivatives
View Patent ↗Processes are disclosed for preparing piperidine derivative compounds of the formulae I, II or III: The processes involve reacting a compound of formula Ia, IIa or IIIa with isobutyrate or an isobutyrate equivalent.
1. A process for preparing a piperidine derivative compound of formula III:
wherein
R 4 is selected from the group comprising H, alkyl, and aryl;
A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, fluorine, chlorine, alkyl, aryl, hydroxyl, alkoxy, and aryloxy;
said process comprising:
(a) reacting a compound of formula VIIa
wherein
X is a group chosen from chlorine, bromine, iodine, —OSO 2 R 5 , and diazonium salt displaceable via oxidative metallic addition; and
LG is a leaving group displaceable by a secondary amine, said leaving group chosen from chlorine, bromine, iodine, and —OSO 2 R 5 , wherein R 5 is chosen from alkyl, fluoro, fluoroalkyl, aryl, and substituted aryl, or LG is a group able to be converted to said leaving group displaceable by a secondary amine, said leaving group chosen from chlorine, bromine, iodine, and —OSO 2 R 5 ;
with an isobutyrate equivalent of formula IV
wherein R 8 is a trialkylsilyl,
in the presence of a transition metal catalyst having a metal selected from the group comprising of Ni and Pd, and ZnF 2 to provide a compound of formula VII
(b) reacting the compound of formula VII with a piperidine compound of formula IX
in the presence of a base to provide the compound of formula III.
2. A process according to claim 1 , wherein the compound of formula VII, in which A is hydrogen and LG is a methane or toluene sulfonate, is prepared by reacting a compound of formula VIIab
with the compound of formula IV, followed by reaction with methanesulfonyl chloride or toluenesulfonylchloride.
3. A process according claim 1 wherein X is displaceable by the isobutyrate equivalent of formula IV by reaction in the presence of a phosphorous compound chosen from trialkyl phosphine, triaryl phosphine, and mixed alkyl/aryl phosphine, and the transition metal catalyst.
4. A process according to claim 1 wherein R 8 is trimethylsilyl.
5. A process according claim 1 for preparing a piperidine derivative compound of formula III wherein A, B and C are hydrogen and R 4 is methyl, comprising:
(a) reacting a compound of formula XV
with an isobutyrate equivalent of formula IVa
in the presence of Pd(0) catalyst, a trialkyl or triaryl phosphine, and ZnF 2 to provide a compound of formula XVIII
(b) converting the compound of formula XVIII to a compound of formula XVIIIa
(c) reacting the compound of formula XVIIIa with a piperidine compound of formula XIXa
in the presence of a base to provide a compound of formula 18
6. A process according to claim 5 wherein, the compound of XV is prepared by reacting a compound of formula XVa
with 1-bromo-4-iodobenzene in the presence of a transition metal catalyst.
7. A process for preparing a piperidine derivative compound of formula II
wherein A, B, C and R 4 are hydrogen, comprising:
(a) reacting a compound of formula XV
with an isobutyrate equivalent of formula IVa
in the presence of Pd(0) catalyst, a trialkyl or triaryl phosphine, and ZnF 2 to provide a compound of formula XVIII
(b) converting the compound of formula XVIII to a compound of formula XVIIIa
(c) reacting the compound of formula XVIIIa with a piperidine compound of formula XIXa
in the presence of a base to provide a compound of formula 18
(d) oxidizing the acetylene in compound 18 to a ketone, reducing the ketone to an alcohol and saponifying the methyl ester to provide fexofenadine.