Process for the preparation of quaternary N-alkyl morphinan alkaloid salts

1. A process for the preparation of a C(3)-O-protected quaternary morphinan alkaloid, the process comprising (i) generating a C(3)-O-protected tertiary morphinan alkaloid by reacting a C(3)-OH tertiary morphinan alkaloid with a protecting group precursor in a biphasic solvent system comprising water and a water immiscible solvent, (ii) isolating the C(3)-O-protected tertiary morphinan alkaloid, (iii) combining the C(3)-O-protected tertiary morphinan alkaloid with an alkylating agent in an anhydrous solvent system to form a reaction product mixture containing the C(3)-O-protected quaternary morphinan alkaloid and any unreacted C(3)-O-protected tertiary morphinan alkaloid, the anhydrous solvent system comprising an anhydrous aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt. % of the anhydrous solvent system, and (iv) adding a non-solubilizing solvent to the reaction product mixture to precipitate the C(3)-O-protected quaternary morphinan alkaloid, wherein the C(3)-OH tertiary morphinan alkaloid has the structure of Formula 11, the C(3)-O-protected tertiary morphinan alkaloid substrate has the structure of Formula 111 and the C(3)-O-protected quaternary morphinan alkaloid has the structure of Formula 111A:

wherein

A is —C(O)—, —C(S)—, —C(═CH 2 )—, —CH(A 1 )- or —C(A 1 )=,

A 1 is hydroxy, alkoxy, or acyloxy,

PG is a hydroxy protecting group;

R 1 is hydrocarbyl or substituted hydrocarbyl,

R 2 is hydrocarbyl or substituted hydrocarbyl,

X − is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y, if present, is hydrogen, hydroxy, alkoxy, or acyloxy, and

the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and 14.

2. The process of claim 1 , wherein PG comprises methyl, ethyl, propargyl benzyl, acetyl, trityl, silyl, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, trityl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl; and the protection reaction is carried out in the presence of a base comprising sodium bicarbonate, potassium carbonate, triethylamine, sodium hydroxide, potassium bicarbonate, or pyridine.

3. The process of claim 1 , further comprising removing the protecting group from the C(3)-O-protected quaternary morphinan alkaloid of Formula 111A to yield a C(3)-OH quaternary morphinan alkaloid of Formula 111B:

4. A process for the preparation of a C(3)-OH quaternary morphinan alkaloid, the process comprising the steps of:

(i) generating a C(3)-O-protected tertiary morphinan alkaloid corresponding to Formula 111 by reacting a C(3)-OH tertiary morphinan alkaloid corresponding to Formula 11 with a protecting group precursor in a biphasic solvent system comprising water and a water immiscible solvent;

(ii) isolating the generated C(3)-O-protected tertiary morphinan alkaloid;

(iii) combining the isolated C(3)-O-protected tertiary morphinan alkaloid with an alkylating agent in an anhydrous solvent system to form a reaction product mixture, the reaction product mixture containing a C(3)-O-protected quaternary morphinan alkaloid and any unreacted C(3)-O-protected tertiary morphinan alkaloid in the anhydrous solvent system, the anhydrous solvent system comprising an aprotic dipolar solvent with the aprotic dipolar solvent constituting at least 25 wt. % of the solvent system, the C(3)-O-protected quaternary morphinan alkaloid corresponding to Formula 111A;

(iv) adding a non-solubilizing solvent to the reaction product mixture to precipitate and isolate the C(3)-O-protected quaternary morphinan alkaloid from the reaction product mixture and;

(v) removing the protecting group from the isolated C(3)-O-protected quaternary morphinan alkaloid to yield the C(3)-OH quaternary morphinan alkaloid corresponding to Formula 111B; wherein Formulae 11, 111, 111A, and 111B have the following structures:

wherein

A is —C(O)—, —C(S)—, —C(═CH 2 )—, —CH(A 1 )- or —C(A 1 )=,

A 1 is hydroxy, alkoxy, or acyloxy,

PG is a hydroxy protecting group,

R 1 is hydrocarbyl or substituted hydrocarbyl,

R 2 is hydrocarbyl or substituted hydrocarbyl,

X − is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate:

Y, if present, is hydrogen, hydroxy, alkoxy, or acyloxy, and the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and 14.

5. The process of claim 4 , wherein PG is methyl, ethyl, propargyl, benzyl, acetyl, trityl, silyl, methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (8-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, trityl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

6. A process for the preparation of a C(3)-OH quaternary morphinan alkaloid, the process comprising:

(i) forming a C(3)-O-protected tertiary morphinan alkaloid, comprising:

(A) treating a C(3)-OH tertiary morphinan alkaloid with a protecting group precursor in a biphasic first solvent system comprising water and a water immiscible solvent to form a first reaction product mixture comprising the C(3)-O-protected tertiary morphinan alkaloid and the water immiscible solvent in an organic layer, and the protecting group precursor, the C(3)-OH tertiary morphinan alkaloid, and water in an aqueous layer;

(B) separating the organic layer from the aqueous layer;

(C) drying the organic layer;

(D) treating the dried organic layer produced in step (i)(C) with additional protecting group precursor to increase the conversion of the C(3)-OH tertiary morphinan alkaloid to the C(3)-O-protected tertiary morphinan alkaloid;

(E) removing water immiscible solvent from the treated organic layer produced in step (i)(D) to form a concentrate comprising the C(3)-O-protected tertiary morphinan alkaloid; and

(F) dissolving the concentrate produced in step (i)(E) comprising the C(3)-O-protected tertiary morphinan alkaloid in an anhydrous solvent system;

(ii) treating the C(3)-O-protected tertiary morphinan alkaloid in the anhydrous solvent system of step (i)(F) with an alkylating agent to form a second reaction product mixture comprising a C(3)-O-protected quaternary morphinan alkaloid; and

(iii) deprotecting the C(3)-O-protected quaternary morphinan alkaloid to form a third reaction product mixture comprising the C(3)-OH quaternary morphinan alkaloid, wherein the C(3)-OH tertiary morphinan alkaloid has the structure of Formula 11, the C(3)-O-protected tertiary morphinan alkaloid has the structure of Formula 111, the C(3)-O-protected quaternary morphinan alkaloid has the structure of Formula 111A, and the C(3)-OH quaternary morphinan alkaloid has the structure of Formula 111B:

wherein

A is —C(O)—, —C(S)—, —C(═CH 2 )—, —CH(A 1 )- or —C(A)=,

A 1 is hydroxy, alkoxy, or acyloxy,

PG is a hydroxy protecting group,

R 1 ishydrocarbyl or substituted hydrocarbyl,

R 2 is hydrocarbyl or substituted hydrocarbyl,

X − is a halide, sulfate, sulfonate, fluoroborate, fluorosulfonate, methylsulfate, ethylsulfate, trifluoromethanesulfonate, hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate;

Y, if present, is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy, and

the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14, respectively, represent (i) carbon-carbon single bonds, (ii) carbon-carbon single bonds between positions 6 and 7 and between positions 8 and 14, and a double bond between positions 7 and 8, or (iii) conjugated carbon-carbon double bonds between positions 6 and 7 and positions 8 and 14, with the proviso that Y is not present if there is a double bond between the carbons at positions 8 and 14.

7. The process of claim 6 , further comprising treating the second reaction product mixture with a purge agent to remove unreacted alkylating agent from the second reaction product mixture prior to deprotecting in step (iii).

8. The process of claim 6 , further comprising washing the organic layer of step (i)(B) with a buffer to remove the unreacted protecting group precursor from the first reaction product mixture prior to reducing the water content of the organic layer in step (i)(C).

9. The process of claim 6 , wherein the third reaction product mixture includes no more than about 0.1% of a C(3)-O-alkyl quaternary or tertiary morphinan alkaloid impurity, relative to the total alkaloid content of the third product mixture.

10. The process of claim 9 , wherein the alkylating agent is methyl bromide, cyclopropylmethyl bromide, dimethyl sulfate, di(cyclopropylmethyl)sulfate, methyl fluorosulfonate, trimethyloxonium fluoroborate, trimethyloxonium hexachloroantimonate, trimethyloxonium hexafluorophosphate, or methyl trifluoromethane sulfonate.

11. The process of claim 6 , wherein the alkylating agent is methyl bromide; the water immiscible solvent is toluene; and the anhydrous solvent system comprises 1-methyl-2-pyrrolidinone.

12. The process of claim 6 , wherein the C(3)-OH tertiary morphinan alkaloid is naltrexone ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one), oxymorphone ((5α)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one), hydromorphone ((5α)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one), naloxone ((5α)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one), nalmefene ((5α)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-diol), nalbuphine ((5α)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol), or oripavine ((5α)-6,7,8,14-tetrahydro-4,5-epoxy-6-methoxy-17-methylmorphinan-3-ol); step (ii) is carried out at a pressure of less than 1.25 atmospheres; Y and Z are independently=OCH 3 , —OAc, =OTHP, ═OSiR 3 , —OBn, —OBz, —OBs, —OTs, or —OMs wherein each R is independently hydrocarbyl; the anhydrous solvent system contains less than 0.05 wt. % water; and step (ii) is carried out within a temperature range of 55-85° C.

13. The process of claim 12 , wherein PG is acetyl.

14. The process of claim 6 , wherein the protection of step (i)(A) is carried out with acetic anhydride in a water/toluene mixture and sodium hydroxide.

15. The process of claim 6 , wherein the C(3)-OH tertiary morphinan alkaloid is naltrexone or oxymorphone.

16. A composition comprising R-naltrexone methobromide, S-naltrexone methobromide, the C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, and oxymorphone wherein the composition contains at least 70% (w/w) of S-naltrexone methobromide, at least 1% (w/w) of R-naltrexone methobromide, but no more than 0.2% (w/w) of the C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, based upon the combined weight of the R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide, and oxymorphone in the composition.