Substituted berbines and processes for their synthesis
Inventors
Wang, Peter X. • Moser, Frank W. • Cantrell, Gary L. • Grote, Christopher W.
Assignees
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Publication Number
US-9458109-B2
Publication Date
2016-10-04
Expiration Date
Abstract
The present invention provides processes for the synthesis of substituted berbine compounds. Also provided are intermediates used in the synthesis of substituted berbine compounds.
Core Innovation
The disclosed process prepares compound 9 by contacting compound 6 with dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine to form compound 7, and then adding RCHO to form compound 9 according to a reaction scheme. The process is defined with substituent selections for multiple R groups, including hydrogen, halogen, OR13, NO2, hydrocarbyl, and substituted hydrocarbyl, and permits formation of rings that include —O(CH2)nO—, where n is an integer from 1 to 3.
The reaction scheme places compound 6, compound 7, and compound 9 in sequence and associates compound 7 formation with the reaction mixture containing dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine. The subsequent addition of RCHO is the defined step for converting compound 7 into compound 9 under the described scheme.
In the provided description, the sequence is framed as a conversion toward compound 9x, including converting compound 6c at C-13 to compound 6x, reducing compound 6x to compound 7x to form a hydroxyl, and then forming compound 9x by ring closure with an aldehyde in the presence of a proton donor/acceptor such as formaldehyde. The disclosure states that products may be obtained in high yield and highlights optical activity/configuration possibilities associated with the substituted berbine products and intermediates.
Claims Coverage
The document provides one independent claim directed to a process for preparing compound 9 by a two-stage reaction sequence using dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine, followed by addition of an aldehyde RCHO. The claim covers a reaction-scheme definition with broad substituent selection for multiple R groups, including optional cyclic —O(CH2)nO— ring formation where n is 1 to 3.
Ruthenium-catalyzed formation of compound 7 from compound 6
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.
Aldehyde-driven formation of compound 9 from compound 7
Adding RCHO to the reaction mixture to form compound 9 according to the reaction scheme, with R specified as hydrogen and with defined substituent selections for the various R groups, including optional formation of rings comprising —O(CH2)nO— (n an integer from 1 to 3).
Broad substituent definitions with cyclic —O(CH2)nO— ring option
The process defines R and multiple substituent groups with independent selection from hydrogen, halogen, OR13, NO2, hydrocarbyl, and substituted hydrocarbyl, while allowing ring formation comprising —O(CH2)nO— where n is an integer from 1 to 3.
Overall, the claim coverage centers on contacting compound 6 with dichloro-(p-cymene)-Ru(II) dimer and formic acid-triethylamine to produce compound 7, and adding an aldehyde RCHO to convert compound 7 into compound 9 within a reaction-scheme framework that includes broad substituent options and optional —O(CH2)nO— ring formation (n=1–3).
Stated Advantages
Products may be formed in high yield (>=80%, up to ~99.9%) as stated in the disclosure.
Improved efficiency/yield/potency versus unsubstituted berberine is stated in the disclosure.
The disclosure states optical activity/configuration possibilities associated with the substituted berbine products.
Documented Applications
Not explicitly described in patent.
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