Process to make GLP1 RA and intermediates therefor
The present invention relates to the synthesis of 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl ]-4-methyl-6,7-dihydro-4H-pyrazolo [4,3-c] pyridine-5-carbonyl] indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one, or a salt thereof, and related synthetic intermediate compounds.
1. A compound of the following structure:
2. A compound of the following structure:
wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.
3. A compound of the following structure:
4. A compound of the following structure:
5. A process for making the compound of claim 3 of the following structure:
comprising multi-step chemical reactions starting from compound 1 of the following structure:
6. The process of claim 5 , comprising multi-step chemical reactions starting from compound 1 and going through compound 5:
wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl;
and arriving at compound 6.
7. The process of claim 6 , comprising a reaction step converting compound 1 to compound 2 as shown below:
wherein the reaction is carried out in a solvent selected from toluene, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO and CPME.
8. The process of claim 7 further comprising a reaction step converting compound 2 to compound 3 as shown below in a solvent and in the presence of a catalyst:
wherein the catalyst is selected from tetrakis (triphenylphosphine) [Pd(PPh 3 ) 4 ], palladium (0), palladium chloride (PdCl 2 ), palladium (II) acetate [Pd(OAc) 2 ], allylpalladium (II) chloride dimer [PdCl(C 3 H 5 ) 2 ], Pd(dppf)Cl 2 , Pd(dtbpf)Cl 2 and a combination of two or more of the listed catalysts; and
wherein the solvent is selected from toluene, MeCN, MTBE, THF, 2-MeTHF, DCM, EtOAc, isobutyl acetate, isopropyl acetate, dioxane, DMF, DMAc, NMP, DMI, DMSO, and CPME.
9. The process of claim 8 , further comprising a reaction step converting compound 3 to compound 4 as shown below:
wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.
10. The process of claim 8 , wherein the reaction step comprises a reaction of compound 3 with CDI in a solvent, followed by a coupling with (R)-4-phenyl-2-oxazolidone in the presence of 1,8-doazabicyclo [5.4.0]undec-7-ene in a solvent.
11. The process of claim 9 , wherein the reaction step comprises a reaction of compound 3 with CDI in ACN solvent, followed by a coupling with (R)-4-benyl-2-oxazolidone in the presence of 1,8-doazabicyclo [5.4.0]undec-7-ene in N,N-dimethylacetamide solvent.
12. The process of claims 11 , further comprising a reaction step converting compound 4 to compound 5 as shown below:
wherein R is phenyl or benzyl.
13. The process of claim 12 , wherein the reaction step comprises a copper-mediated addition of 2-methyl allyl magnesium chloride, 2-methyl allyl magnesium bromide, or 2-methyl allyl magnesium iodide in the presence of lithium chloride to compound 4 to give compound 5.
14. The process of claim 13 , further comprising a reaction step converting compound 5 to compound 6 as shown below:
wherein R is phenyl or benzyl.
15. The process of claim 14 , wherein the reaction step comprises reacting compound 5 with a reducing agent in a solvent to give compound 6;
wherein the reducing agent is selected from lithium borohydride, NaBH 4 , BH3, LAH, H 2 , DIBAl, and Red-Al; and
wherein the solvent is selected from toluene, THF, 2-MeTHF, DCM, MTBE, and CPME.
16. The process of claim 15 , comprising reaction steps as shown below:
wherein R is aryl, heteroaryl, alkyl, cycloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, arylalkyl, heteroarylalkyl, arylalkenyl, heteroarylalkenyl, arylalkynyl, or heteroarylalkynyl.
17. The process of claim 16 , further comprising multi-step chemical reactions to convert compound 6 into compound 12 having the following structure:
18. The process of claim 17 , comprising a reaction step of converting compound 6 to compound 7 as shown below:
19. The process of claim 17 , further comprising a reaction step of converting compound 10 to compound 11 as shown below:
20. The process of claim 18 , further comprising a reaction step of converting compound 10 to compound 11 as shown below: