Opiate intermediates and methods of synthesis
View Patent ↗Novel opiate intermediate compositions and methods of synthesis that include changing the substitution pattern on the aromatic ring of the pre-Grewe intermediate are provided. The intermediates are morphinane derivatives of formula (10), wherein X is a F or Cl and R is selected from the group consisting of an H, alkyl, aryl, acyl, formyl, COR″, CONHR″, COOR, Bn(benzyl), alkyl(methyl), and sulfonamide SO 2 CH 2 COPh.
1. A method for the synthesis of an opiate intermediate, the method comprising:
a) reacting a compound of Formula 1
wherein X is F or Cl;
with at least one halide selected from the group consisting of sulfonyl halide and phosphorous halide to form a compound of Formula 2;
wherein X is F or Cl; X 1 is Cl or Br; and Y is SO when a sulfonyl halide is used, and P when a phosphorous halide is used;
b) reacting the compound of Formula 2 with a compound of Formula 3
wherein R′ is an alkyl, aryl or acyl group;
in the presence of at least one base to form a compound of Formula 4;
wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group;
c) reacting the compound of Formula 4 with at least one phosphoryl halide and then hydrolyzing to form a compound of Formula 5;
wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group;
d) reacting the compound of Formula 5 as a free imine or imine salt with at least one reducing agent to form a compound of Formula 6;
wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group;
e) selectively reducing the compound of Formula 6 to form a compound of Formula 7;
wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl group;
f) reacting the compound of Formula 7 with at least one formic acid ester to form a compound of Formula 8;
wherein X is a F or Cl; and R′ is an alkyl, aryl or acyl; and R is selected from the group consisting of H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, alkyl and sulfonamide; and wherein R″ is selected from the group consisting of alkyl or aryl;
g) hydrolyzing the compound of Formula 8 forms a compound of Formula 9; and
wherein X is a F or Cl; and R is selected from the group consisting of an H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, and sulfonamide; and wherein R″ is selected from the group consisting of alkyl or aryl;
h) converting the compound of Formula 9 under Grewe cyclization conditions in at least one strong acid to form an opiate intermediate compound of Formula 10,
wherein X is a F or Cl; and R is selected from the group consisting of an H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, (methyl), and sulfonamide; wherein R″ is selected from the group consisting of alkyl or aryl.
2. A method for the synthesis of an opiate intermediate, the method comprising converting Formula 9
wherein X is a F or Cl; and R is selected from the group consisting of an H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, and sulfonamide; and wherein R″ is selected from the group consisting of alkyl or aryl;
by Grewe cyclization to form an opiate intermediate compound of Formula 10
wherein R is an H, alkyl, aryl, acyl, formyl, COR″, COOR″, benzyl, or sulfonamide; and wherein R″ is selected from the group consisting of alkyl or aryl.
3. The method of claim 2 wherein the Grewe cyclization is accomplished in acid medium including an acid selected from the group consisting of hydrofluoric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 2-mesitylenesulfonic acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, phosphoric acid, Lewis acids and mixtures thereof.
4. A method for the synthesis of an opiate intermediate, the method comprising:
a) reacting a compound of Formula 15
with at least one sulfinyl halide to form a compound of Formula 16;
b) reacting the compound of Formula 16 with a compound of Formula 17;
in the presence of at least one base to form a compound according to Formula 18;
c) reacting the compound of Formula 18 with at least one phosphoryl halide and then hydrolyzing to form a compound according to Formula 19;
d) reacting the compound of Formula 19 as a free imine with at least one reducing agent in at least one solvent to form a compound of Formula 20;
e) selectively reducing the compound of Formula 20 to form a compound of Formula 21;
f) reacting Formula 21 with at least one formic acid ester to form Formula 22;
g) hydrolyzing Formula 22 to form a compound of Formula 23; and
h) converting Formula 23 under Grewe cyclization conditions in a strong acid to form an opiate intermediate compound of Formula 24
5. A method for the synthesis of an opiate intermediate, the method comprising converting Formula 23
under Grewe cyclization conditions in at least one acid to form an opiate intermediate compound of Formula 24.
6. A compound according to Formula 24
7. The method of claim 1 wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, allyl and phenacyl sulfonamide.
8. The method of claim 1 wherein R is SO 2 CH 2 COPh.
9. The method of claim 2 wherein R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, allyl and phenacyl sulfonamide.
10. The method of claim 2 wherein R is SO 2 CH 2 COPh.