Synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs
View Patent ↗Novel methods of synthesis of known and novel 14-hydroxyl opiates through 1-halothebaine and derivatives are described.
1. A one-pot process for the conversion of a compound according to Formula 14 into a compound according to Formula 17, the process comprising:
a) heating the compound according to formula 14 in the presence of at least one acid to form a compound according to formula 15;
b) oxidizing the compound according to Formula 15 with at least one oxidizing agent to form a compound according to Formula 16; and
c) reducing the compound according to Formula 16 with at least one reductive agent to form a compound according to Formula 17;
wherein R 1 is H, methyl, a benzyl group, an aryl group, an acyl group, an alkoxycarbonyl group or tetrahydropyranyl group;
R 2 is H, methyl, a benzyl group, an aryl group, an acyl group, a formyl group, a formyl ester, an alkoxycarbonyl group or alkylamidocarbonyl group;
R 3 is H, an alkyl group, an aryl group or an acyl group; and,
X is a halogen.
2. The process of claim 1 , wherein the process is for the preparation of compounds according to Formula 17, the process additionally comprising:
a) catalytically converting a compound according to Formula 9 into a compound according to Formula 10 in the presence of at least one catalyst, wherein the catalyst is at least one transition metal complex of the formula [M(PR 4 R 5 R 6 ) n X m ] p ; wherein M is a Group VIII transition metal; R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1;
b) halogenating the compound according to Formula 10 with at least one halogenating reagent in at least one protic solvent in the presence of R 7 C(OR 3 ) 3 , wherein R 7 is H, an alkyl or an alkoxy, and at least one first acid to form a compound according to Formula 13;
c) reacting the compound according to Formula 13 with less than about two equivalents of at least one base to form a compound according to Formula 14; and
d) heating the compound according to formula 14 in the presence of at least one second acid to from a compound according to Formula 15.
3. The process of claim 2 wherein the at least one first acid includes an acid selected from the group consisting of sulfuric acid (H 2 SO 4 ), phosphoric acid (H 3 PO 4 ), methanesulfonic acid (MeSO 3 H), p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrogen chloride (HCl), hydrogen bromide (HBr) and mixtures thereof;
the at least one halogenating reagent includes a halogenating reagent selected from the group consisting of bromine (Br 2 ), N-bromoacetamide (NBA), N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS) and mixtures thereof;
the at least one second acid includes an acid selected from the group consisting of HOAc, HCO 2 H, RCO 2 H wherein R is an alkyl, benzyl or aryl, MeSO 3 H, p-toluenesulfonic acid, CF 3 CO 2 , POCl 3 and mixtures thereof;
the at least one oxidizing agent includes an oxidizing agent selected from the group consisting of hydrogen peroxide solution, peroxyacetic acid, 3-chloroperoxybenzoic acid, RCO 3 H wherein R is H, an alkyl, or an aryl, and mixtures thereof; and
the at least one reductive agent includes a reductive agent selected from the group consisting of a combination of pressurized hydrogen on metal supported catalyst having the formula M/C, wherein M is Pd, Pt, Ru, or Rh and C is carbon.
4. The process of claim 1 , wherein:
R 1 is H, CH 3 , PhCH 2 , R 8 CO, R 8 OCO or a tetrahydropyranyl group;
R 2 is H, CH 3 , PhCH 2 , CHO, R 8 CO or R 8 OCO;
R 8 is C 1-6 alkyl;
R 3 is C 1-4 alkyl or acetate; and
X is Cl or Br.
5. The process of claim 1 wherein the at least one oxidizing agent includes an oxidizing agent that is selected from the group consisting of hydrogen peroxide solution, peroxyacetic acid, 3-chloroperoxybenzoic acid, RCO 3 H wherein R is H, and alkyl, or an aryl, and mixtures thereof.
6. The process of claim 1 , wherein in step (b), R 3 in R 7 C(OR 3 ) 3 is Me.
7. The process of claim 6 , wherein R 1 and R 2 are methyl and X is Br.
8. The process of claim 2 , wherein the at least one reductive agent includes a reductive agent selected from the group consisting of a combination of pressurized hydrogen on metal supported catalyst having the formula M/C, wherein M is Pd, Pt, Ru, or Rh and C is carbon.