Berberine compounds and processes for the preparation of berberine compounds
View Patent ↗The invention is directed to berberine compounds and processes for the preparation of berberine compounds through an intramolecular Bischler-Napieralski cyclization.
1. A compound of Formula (II):
wherein:
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of cyano, hydroxyl, amino, hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and OR 5 ;
R 5 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 7 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl.
2. The compound of claim 1 , wherein the compound comprises a counter-ion selected from the group consisting of chloride, bromide, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate, acetate, p-toluenesulfonate, sulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, furmarate, malonate, oxalate, formate, tartrate, benzoate, and a combination thereof.
3. The compound of claim 1 , wherein:
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl; and
R 7 is selected from the group consisting of hydrogen, alkyl, and aryl.
4. The compound of claim 1 , wherein: R 1 is halogen; R 2 is hydrogen; R 3 is OR 5 ; R 4 is hydroxyl; and R 7 is hydrogen.
5. A compound of Formula (IIa):
wherein:
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of cyano, hydroxyl, amino, hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and OR 5 ; and
R 5 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl.
6. The compound of claim 5 , wherein the compound comprises a counter-ion selected from the group consisting of chloride, bromide, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate, acetate, p-toluenesulfonate, sulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, furmarate, malonate, oxalate, formate, tartrate, benzoate, and a combination thereof.
7. The compound of claim 5 , wherein: R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl.
8. The compound of claim 5 , wherein: R 1 is halogen; R 2 is hydrogen; R 3 is OCH 3 ; and R 4 is hydroxyl.
9. A process for preparing a compound, the process comprising contacting a compound of Formula (I) with a proton donor and a proton donor anhydride, the molar ratio of proton donor to proton donor anhydride being from 5:1 to about 1:100, to form a compound of Formula (II) according to the following reaction scheme:
wherein:
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of cyano, hydroxyl, amino, hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and OR 5 ;
R 5 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 7 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl.
10. The process of claim 9 , wherein the molar ratio of proton donor to proton donor anhydride is from about 1:1 to about 1:20; the reaction is conducted at a temperature below about 15° C.;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl;
R 7 is selected from the group consisting of hydrogen, alkyl, and aryl; and
the proton donor is selected from the group consisting of benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, nitric acid, phosphoric acid, polyphoshoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, anhydrous hydrogen fluoride, fluorosulfonic acid, perchloric acid, perfluoroalkysulfonic acid, and combinations thereof; and the proton donor anhydride is an anhydride of a proton donor selected from the group consisting of benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, nitric acid, phosphoric acid, polyphoshoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, anhydrous hydrogen fluoride, fluorosulfonic acid, perchloric acid, perfluoroalkysulfonic acid, and combinations thereof.
11. The process of claim 9 , wherein the yield of the compound of Formula (II) is at least 80% by weight of the products formed.
12. The process of claim 9 , wherein the compound of Formula (I) of a compound corresponding to Formula (Ia):
and the compound of Formula (II) is a compound corresponding to Formula (IIa):
wherein:
R 1 , R 2 , R 3 , and R 4 are as defined in claim 9 .
13. The process of claim 12 , wherein the molar ratio of proton donor to proton donor anhydride is from about 1:2 to about 1:10; the reaction is conducted at a temperature below about 15° C.; R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl; and the proton donor is selected from the group consisting of benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, nitric acid, phosphoric acid, polyphoshoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, anhydrous hydrogen fluoride, fluorosulfonic acid, perchloric acid, perfluoroalkysulfonic acid, and combinations thereof; and the proton donor anhydride is an anhydride of a proton donor selected from the group consisting of benzenesulfonic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, methanesulfonic acid, nitric acid, phosphoric acid, polyphoshoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid, anhydrous hydrogen fluoride, fluorosulfonic acid, perchloric acid, perfluoroalkysulfonic acid, and combinations thereof.
14. The process of claim 9 , wherein the compound of Formula (I) is a compound corresponding to Formula (Ib):
and the compound of Formula (II)is a compound corresponding to Formula (IIb):
15. The process of claim 14 , wherein the proton donor is trifluoromethanesulfonic acid and the proton donor anhydride is trifluoromethanesulfonic anhydride.
16. The process of claim 15 , wherein the ratio of trifluoromethanesulfonic acid to trifluoromethanesulfonic anhydride is from about 1:2 to about 1:10.
17. A process for preparing a compound, the process of contacting a compound of Formula (I) with a proton donor anhydride, wherein the equivalents of proton donor anhydride to the compound of Formula (I) is from about 1.5 to about 1000, to form a compound of Formula (II) according to the following reaction scheme:
wherein:
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of cyano, hydroxyl, amino, hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and OR 5 ;
R 5 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and
R 7 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl.
18. The process of claim 17 , wherein the reaction is conducted at a temperature below about 15° C.; the yield of the compound comprising Formula (II) is at least 65% by weight of the products formed;
R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl; and
R 7 is hydrogen, alkyl, or aryl.
19. The process of claim 17 , wherein the compound of Formula (I) is a compound corresponding to Formula (Ia):
and the compound of Formula (II) is a compound corresponding to Formula (IIa):
wherein:
R 1 , R 2 , R 3 , and R 4 are as defined in claim 17 .
20. The process of claim 19 , wherein R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, substituted and unsubstituted acyl, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkylthio, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylether, haloalkoxy, haloalyl, heteroaryl, heterocyclic, hydroxyalkyl, and hydroxyl.
21. The process of claim 17 , wherein the compound of Formula (I) is a compound corresponding to Formula (Ib):
and the compound of Formula (II) is a compound corresponding to Formula (IIb):
22. The process of claim 21 , wherein the proton donor anhydride is trifluoromethanesulfonic anhydride.