Substituted berbines and processes for their synthesis
The present invention provides processes for the synthesis of substituted berbine compounds. Also provided are intermediates used in the synthesis of substituted berbine compounds.
1. A process for preparing compound 9, the process comprising forming a reaction mixture in which compound 6 is contacted with dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine to form compound 7, and adding RCHO to the reaction mixture to form compound 9 according to the following reaction scheme:
wherein:
R is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, OR 13 , hydrocarbyl, substituted hydrocarbyl, and together R 2 and R 3 form {—}O(CH 2 ) n O{—};
R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, halogen, OR 13 , hydrocarbyl, substituted hydrocarbyl, and together R 6 and R 7 form {—}O(CH 2 ) n O{—};
R 9 , R 10 , R 11 , and R 12 are independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 13 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl; and
n is an integer from 1 to 3.
2. The process of claim 1 , wherein R is selected from the group consisting of alkyl, substituted alkyl, aryl, and substituted aryl, and R 13 is alkyl.
3. The process of claim 1 , wherein each of R 9 , R 10 , R 11 , and R 12 is hydrogen.
4. The process of claim 1 , wherein R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, OR 13 , and together R 2 and R 3 form {—}O(CH 2 ) n O{—}; and R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, OR 13 , and together R 6 and R 7 form {—}O(CH 2 ) n O{—}; wherein R 13 is hydrogen or an alkyl having 1 to 8 carbon atoms, and n is 1 to 3.
5. The process of claim 1 , wherein compound 7 and RCHO are present at a molar ratio of about 1:0.5 to about 1:2.
6. The process of claim 1 , wherein the reaction is conducted in the presence of a solvent selected from the group consisting of acetone, acetonitrile, butanone, chloroform, 1,2,-dichloroethane, dichloromethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methanol, methyl t-butyl ether, methyl butyl ketone, tetrahydrofuran, toluene, and combinations thereof.
7. The process of claim 1 , wherein the reaction is conducted is conducted at a temperature ranging from about 00° C. to about 120° C.
8. The process of claim 1 , wherein compound 9 has a yield of at least about 80%.
9. The process of claim 1 , wherein R is alkyl; R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, OR 13 , and together R 2 and R 3 form {—}O(CH 2 )O{—}; R 5 , R 6 , R 7 , and R 8 are independently selected from the group consisting of hydrogen, OR 13 , and together R 6 and R 7 form {—}O(CH 2 )O{—}; and each of R 9 , R 10 , R 11 , and R 12 is hydrogen, wherein R 13 is hydrogen or methyl.
10. The process of claim 9 , wherein the reaction is conducted in the presence of a solvent selected from the group consisting of acetonitrile, chloroform, methanol, and combinations thereof.
11. The process of claim 10 wherein the reaction is conducted is conducted at a temperature ranging from about 10° C. to about 80° C.
12. The process of claim 11 , wherein compound 9 has a yield of about 80% to about 99.9%.