Exo- and diastereo- selective synthesis of himbacine analogs
View Patent ↗This application discloses a novel process for the preparation of himbacine analogs useful as thrombin receptor antagonists. The process is based in part on the use of a base-promoted dynamic epimerization of a chiral nitro center. The chemistry taught herein can be exemplified by the following:
1. A process for preparing Compound 17:
said process comprising the steps of:
(a) cyclizing Compound 18 in a first solvent at an elevated temperature
wherein R 7 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroaryl groups
to produce a first mixture comprising α and β of the exo isomers of Compound 17A:
and α and β of the endo isomers of Compound 17B:
said isomers of Compound 17A having a trans-[5,6]-ring-junction;
(b) epimerizing said trans-[5,6]-ring-junction of Compound 17A by treating said first mixture with a first base to produce a second mixture comprising cis-[5,6]-ring-junction-nitro-α isomer and cis-[5,6]-ring-junction-nitro β isomer of each Compound 17C and Compound 17B:
and
(c) treating said second mixture with a second solvent, causing said α-isomer of Compound 17C to precipitate to produce Compound 17.
2. The process of claim 1 further comprising the step of treating said second mixture with a second base, resulting in a dynamic resolution of said second mixture, in which said β-isomer of Compound 17C is converted to α-isomer of Compound 17C, and α-isomer of Compound 17C is precipitated to produce Compound 17.
3. The process of claim 1 , wherein said first solvent is selected from the group consisting of xylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether, and Dimethylacetamide, and mixtures of 2 or more thereof.
4. The process of claim 1 , wherein said temperature is between about 70 and about 190° C.
5. The process of claim 1 , wherein said temperature is between about 80 and about 170° C.
6. The process of claim 1 , wherein said temperature is between about 100 and about 160° C.
7. The process of claim 1 , wherein said temperature is between about 120 and about 150° C.
8. The process of claim 1 , wherein said first base is selected from the group consisting of triethylamine; 1,5-diazabicyclo[4,3,0]non-5-ene 1,4-diazabicyclo[2,2,2]octane; and 1,8-diazabicyclo[5,4,0]undec-7-ene; and mixtures of 2 or more thereof.
9. The process of claim 1 , wherein said second solvent is selected from the group consisting of alcohols, ethers, ketones, esters, xylene, and N-methylpyrrolidinone, and mixtures of 2 or more thereof.
10. The process of claim 1 , wherein said second solvent is selected from the group consisting of methanol, ethanol, propanols, and butanols, xylene, N-methylpyrrolidinone, and mixtures of 2 or more thereof.
11. The process of claim 2 , wherein said second base is selected from the group consisting of triethylamine; 1,5-diazabicyclo[4,3,0]non-5-ene 1,4-diazabicyclo[2,2,2]octane; 1,8-diazabicyclo[5,4,0]undec-7-ene; and mixtures of 2 or more thereof.