N-demethylation of N-methyl morphinans
View Patent ↗The present invention provides a synthetic process for the N-demethylation of N-methyl morphinans. In particular, the invention provides improved synthetic methods for the preparation of N-demethylated morphinan compounds that may be employed as starting materials, for example, commonly available N-methyl opiates such as oripavine and thebaine, and C(3)-protected hydroxy derivatives of oripavine.
1. A process comprising: preparing a compound of Formula 2 from a compound of Formula 1 according to the following reaction scheme:
wherein:
R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, substituted alkyl, substituted alkenyl, substituted aryl, acyl, alkoxycarbonyl, acetal, ether, silyl ether, alkylsulfonyl, and an oxygen protecting group;
R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, {—}OR 8 , acyl, alkyl, alkenyl, aryl, substituted alkyl, substituted alkenyl, substituted aryl, and alkoxycarbonyl;
R 6 is an atom selected from the group consisting of oxygen and nitrogen;
R 8 is selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
L is halogen;
Y is an atom selected from the group consisting of oxygen, nitrogen and sulfur;
Z is selected from the group consisting of alkyl, alkenyl, alkylaryl, aralkyl, aryl, substituted alkyl, substituted alkenyl, substituted alkylaryl, substituted aralkyl, and substituted aryl; and
n is 1 or 2.
2. The process of claim 1 , wherein:
L is selected from the group consisting of bromo and chloro; and
Y is oxygen.
3. The process of claim 2 , wherein Z is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benryl, methoxymethyl, vinyl, or 2-chloroethyl.
4. The process of claim 1 , wherein
Y is oxygen; R 2 , R 3 , and R 4 are each hydrogen; and Z is selected from the group consisting of alkyl and benzyl.
5. The process of claim 4 , wherein R 6 is oxygen and n is 1.
6. The process of claim 4 , wherein R 6 is nitrogen and n is 2.
7. The process of claim 1 , wherein LC(O)OZ is a hydrocarbylhaloformate selected from the group consisting of a C 1-8 alkyl chloroformate, phenyl chloroformate, benzyl chloroformate, and a combination thereof.
8. The process of claim 1 , wherein C(O)NZ 2 is a N,N-dihydrocarbylformamide selected from the group consisting of N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N,N-diisobutylformamide, and a mixture thereof.
9. The process of claim 1 , wherein the molar ratio of LC(O)OZ or C(O)NZ 2 to the compound comprising Formula 1 is from about 1:1 to about 3:1; the proton acceptor has a pKa greater than about 7 and is selected from the group consisting of NaHCO 3 , KHCO 3 , Na 2 CO 3 , K 2 CO 3 , NaOH, KOH, and combinations thereof; and the molar ratio of the proton acceptor to the compound comprising Formula 1 is from about 1.5:1 to about 6:1.
10. The process of claim 1 , wherein the reaction is conducted in the presence of a solvent system.
11. The process of claim 10 , wherein the solvent system comprises an organic solvent selected from the group consisting of benzene, chloroform, diethyl ether, ethyl acetate, n-propyl acetate, heptane, hexane, toluene, and a combination thereof; and the molar ratio of organic solvent to the compound comprising Formula 1 is from about 0.5:1 to about 20:1.
12. The process of claim 11 , wherein the solvent system further comprises a protic solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, t-butyl alcohol, n-propyl alcohol, n-butyl alcohol, and a combination thereof.
13. The process of claim 11 , wherein the solvent system further comprises a water-miscible solvent selected from the group consisting of water, acetonitrile, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide, N,N-formamide, acetone, tetrahydrofuran, and a combination thereof.
14. The process of claim 1 , wherein the reaction is conducted at a temperature ranging from about 0° C. to about 40° C.
15. The process of claim 1 , wherein the yield of the compound comprising Formula 2 is from about 65% to about 95%.
16. The process of claim 1 , wherein the optical activity of compounds comprising Formulas 1 and 2 is selected from the group consisting of (−) enantiomer, (+) enantiomer, and a combination thereof.
17. The process of claim 1 , wherein the configuration of carbons 5, 13, 14, and 9, respectively, of compounds comprising Formulas 1 and 2 is selected from the group consisting RRRS, RRSS, SRRS, SRSS, RSRR, RSSR, SSRR, and SSSR.
18. An N-carboxylic acid ester morphinan derivative compound of Formula 2:
wherein R 3 is —C(O)OZ and Z is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, phenyl, benzyl, methoxymethyl, vinyl, and 2-chloroethyl.