Exo- and diastereo- selective syntheses 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 1:
said process comprising the steps of:
(a) cyclizing Compound 2 in a first solvent at an elevated temperature
where R 5 and R 6 are each independently selected from the group consisting of II, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, heterocyclic and heteroaryl groups, or R 5 and R 6 , together with the nitrogen to which they are attached, for a 3- to 6-membered heterocyclic compound containing 1-4 heteroatoms,
to produce a first mixture of exo isomers
said isomers having a trans-[5,6]-ring junction:
and endo isomers:
(b) epimerizing said trans-[5,6]-ring-junction in Compound 29 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 Compound 30:
and
(c) treating said second mixture with a second solvent, causing said α-isomer of Compound 30 to precipitate to produce Compound 1.
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 30 is converted to α-isomer of Compound 30, and α-isomer of Compound 30 is precipitated to produce Compound 1.
3. The process of claim 1 , wherein said first solvent is selected from the group consisting of xylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether, Dimethylacetamide, and mixtures of 2 pr 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 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 ethers, ketones, esters, amides, sulfoxides, aliphatic hydrocarbons, aromatic hydrocarbons, and mixtures of 2 or more thereof.
10. The process of claim 1 , wherein said second solvent is selected from the group consisting of xylene, N-methylpyrrolidinone, dimethyl acetamide, DMSO, 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, and 1,8-diazabicyclo[5,4,0]undec-7-ene, and mixtures of 2 or more thereof.