Sinomenine derivatives and processes for their synthesis

1. A compound having Formula (I):

wherein:

R 1 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 2 is halogen;

R 3 is selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl;

R 4 is OR 4a ;

R 4a is a bond that forms park of an ether-containing ring;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR 5a , and —O(CH 2 ) 2 O—;

R 5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;

R 7 is OR 7a ;

R 7a is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 8 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 9 and R 10 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 9 and R 10 together may form a group selected from the group consisting of ═O and ═S;

R 11 and R 12 are independently selected from the group consisting of hydrogen, OH, halogen, hydrocarbyl, and substituted hydrocarbyl;

Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;

m is an integer from 0 to 8; and

----- is a single bond or a double bond,

and further wherein C9, C13 and C14 reference carbon numbers 9, 13 and 14, respectively, of Formula (I).

2. The compound of claim 1 , wherein:

R 1 is selected from the group consisting of an alkyl group having from 1 to 8 carbon atoms, a vinyl group, an aryl group, cyclopropyl, cyclobutyl, {—}CH(CF 3 ) 2 , {—}CH(CH 3 )CF 3 , {—}CH═CF 2 , and {—}CH 2 CF 3 ;

R 2 is halogen;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, and NH 2 , wherein R 5 and R 6 together may form ═O;

R 3 and R 8 -R 12 are each hydrogen;

Y is selected from the group consisting of {—}CH 2 {—} and {—}CO{—}; and

m is 0.

3. The compound of claim 1 , wherein the compound has Formula (Ia):

wherein:

R 2 is halogen;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR 5a , and —O(CH 2 ) 2 O—;

R 5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;

R 7 is OR 7a ;

R 7a is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 8 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 9 and R 10 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 9 and R 10 together may form a group selected from the group consisting of ═O and ═S;

Z is {—}O{—}; and

----- is a single bond or a double bond.

4. The compound of claim 1 , wherein the compound has Formula (Ib):

wherein:

R 2 is halogen;

R 4 is OR 4a ;

R 4a is a bond that forms part of an ether-containing ring;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR 5a , and —O(CH 2 ) 2 O—;

R 5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;

R 7 is OR 7a ;

R 7a is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl; and

----- is a single bond or a double bond.

5. The compound of claim 1 , wherein the compound is selected from the group consisting of:

wherein X is halogen.

6. The compound of claim 1 , wherein the optical activity of the compound is (−) or (+) and the configuration of C13, C14, and C9, respectively, is selected from the group consisting of RRS, RSS, SRR, and SSR.

7. A process for preparing a compound of Formula (I) of claim 1 , the process comprising contacting a compound having Formula 5a with a proton acceptor to form a compound of Formula (I) according to the reaction scheme:

wherein

R 1 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 2 is halogen;

R 3 is selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl;

R 4 is OH;

R 9 and R 10 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 9 and R 10 together may form a group selected from the group consisting of ═O and ═S; and

X is halogen;

Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;

m is an integer from 0 to 8; and

Z is {—}O{—},

and further wherein C5, C9, C13 and C14 reference carbon numbers 5, 9, 13 and 14, respectively, of the compound of Formula (I).

8. The process of claim 7 , wherein the reaction is conducted in the presence of an aprotic solvent; the weight ratio of solvent to compound 5a is from about 5:1 to about 50:1; the proton acceptor has a pKa greater than about 13; the weight ratio of compound 5a to proton acceptor is from about 1:1.5 to about 1:20; the reaction is conducted at a temperature ranging from about −30° C. to about 0° C.; and the optical activity of compounds 5a and (I) is (−) or (+), and the configuration of C5, C13, C14, and C9, respectively, is selected from the group consisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, and SSSR.

9. A compound having Formula (Ic):

wherein:

R 2 is halogen;

R 4 is OR 4a ;

R 4a is a bond that forms part of an ether-containing ring;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR 5a , and —O(CH 2 ) 2 O—; and

R 5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl.

10. A process for preparing a compound of Formula (Ic) of claim 9 , the process comprising contacting a compound having Formula 6a with a scavenger and a proton donor to form the compound of Formula (Ic) according to the reaction scheme:

wherein

R 1 is selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl;

R 2 is halogen;

R 7 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 8 and R 9 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 8 and R 9 together may form a group selected from the group consisting of ═O and ═S;

Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl;

m is an integer from 0 to 8; and

Z is {—}O{—},

and further wherein C5, C9, C13 and C14 reference carbon numbers 5, 9, 13 and 14, respectively, of the compounds of Formulas 6 and (Ic).

11. The process of claim 10 , wherein the reaction is conducted in the presence of an aprotic solvent; the weight ratio of solvent to compound 6a is from about 5:1 to about 50:1; the scavenger is an alcohol scavenger; the proton donor has a pKa less than about 0; the weight ratio of compound 6a to scavenger to proton donor is from about 1:0.5:2 to about 1:2:20; the reaction is conducted at a temperature ranging from about 0° C. to about 100° C.; and the optical activity of compounds 6a and (Ic) is (−) or (+), and the configuration of C5, C13, C14, and C9, respectively, is selected from the group consisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, and SSSR.

12. A process for preparation of a compound of Formula (Ic) of claim 9 according to the following reaction scheme:

wherein:

R 1 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, hydrocarbyl, and substituted hydrocarbyl;

R 4 is selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, ═S, ═CHR 5a , and —O(CH 2 ) 2 O—;

R 5a is selected from the group consisting of hydrogen, halogen, hydrocarbyl, and substituted hydrocarbyl;

R 7 and R 8 are independently selected from the group consisting of hydrogen, OH, NH 2 , SH, hydrocarbyl, and substituted hydrocarbyl, wherein R 7 and R 8 together may form a group selected from the group consisting of ═O and ═S;

X is halogen;

Y is selected from the group consisting of alkyl, substituted alkyl, carbonyl, and alkyl carbonyl; and

Z is {—}O{—},

and further wherein C9, C13 and C14 reference carbon numbers 9, 13 and 14, respectively, of Formulas 2, 3, 4, 5, 6, and (Ic), and C5 references carbon number 5 of Formulas 6 and (Ic).

13. The process of claim 12 , wherein:

R 1 is selected from the group consisting of an alkyl group having from 1 to 8 carbon atoms, a vinyl group, an aryl group, cyclopropyl, cyclobutyl, {—}CH(CF 3 ) 2 , {—}CH(CH 3 )CF 3 , {—}CH═CF 2 , and {—}CH 2 CF 3 ;

R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, OH, NH 2 , CN, acyl, an alkyl, alkenyl, aryl, alkoxyl, and alkylamino;

R 4 is selected from the group consisting of hydrogen and alkyl;

R 5 and R 6 are independently selected from the group consisting of hydrogen, OH, and alkoxyl, wherein R 5 and R 6 together may form a group selected from the group consisting of ═O, ═NOH, and —O(CH 2 ) 2 O—;

R 7 and R 8 are independently selected from the group consisting of hydrogen, OH and NH 2 , wherein R 7 and R 8 together may form ═O;

X is selected from the group consisting of bromide and chloride;

Y is selected from the group consisting of {—}CH 2 {—} and {—}CO{—}; and

Z is {—}O{—}.

14. The process of claim 13 , wherein:

R 1 is cyclopropyl;

R 2 is hydrogen;

R 3 is {—}O(CH 2 ) m CH 3 ;

R 5 and R 6 together form ═O;

R 4 , R 7 , and R 8 are each hydrogen; and

m is an integer from 0 to 8.

15. The process of claim 12 , wherein the weight ratio of compound 2 to vinyl chloroformate or 1-chloroethyl chloroformate to proton acceptor or proton donor is from about 1:2:1 to about 1:20:20, the reaction of Step A is conducted in the presence of an aprotic solvent, and at a temperature ranging from about 50° C. to about 120° C.; the weight ratio of compound 3 to R 1 YX or R 1 Y is from about 1:1 to about 1:3, the reaction of Step B is conducted in the presence of an aprotic solvent, and at a temperature ranging from about 20° C. to about 100° C.; the weight ratio of compound 4 to X 2 is from about 1:2 to about 1:2.5, the reaction of Step C is conducted in the presence of an organic solvent, and at a temperature ranging from about −30° C. to about 0° C.; the weight ratio of compound 5 to proton acceptor is from about 1:1.5 to about 1:20, the reaction of Step D is conducted in the presence of an aprotic and/or a protic solvent, and at a temperature ranging from about −30° C. to about 0° C.; and the weight ratio of compound 6 to scavenger to proton donor is from about 1:0.5:2 to about 1:2:20, the reaction of Step E is conducted in the presence of an aprotic solvent, and at a temperature ranging from about 0° C. to about 100° C.

16. The process of claim 15 , wherein the proton acceptor has a pKa greater than about 13 and is selected from the group consisting of NaOH, KOH, LiOH, Ca(OH) 2 , and NaH; the scavenger is an alcohol scavenger selected from the group consisting of P 2 O 5 , POCl 3 , POBr 3 , PCl 3 , PBr 3 , SOCl 2 , SOBr 2 , MeSO 2 Cl, (MeSO 2 ) 2 O, SO 3 , (CF 3 SO 2 ) 2 O, and (CF 3 CO) 2 O; and the proton acceptor has a pKa less than about 0 and is selected from the group consisting of MeSO 3 H, poly H 3 PO 4 , H 3 PO 4 , H 2 SO 4 , HCl, HBr, HlO 4 , HNO 3 , CF 3 SO 3 H, and p-methyltoluenesulfonic acid.

17. The process of claim 12 , wherein the optical activity of compounds 2, 3, 4 and 5 is (−) or (+), and the configuration of C13, C14, and C9, respectively, is selected from the group consisting of RRS, RSS, SRR, and SSR.

18. The process of claim 12 , wherein the optical activity of compounds 6 and (Ic) is (−) or (+), and the configuration of C5, C13, C14, and C9, respectively, is selected from the group consisting of RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, and SSSR.

19. The compound of claim 9 , wherein R 5 and R 6 together form ═O.

20. The compound of claim 9 , wherein R 5 is OH.

21. The compound of claim 9 , wherein R 5 is NH 2 .