# US 9,040,705 B2 · Preparation of saturated ketone morphinan compounds

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- Number: US 9,040,705 B2
- Document ID: US9040705B2
- Status: Granted
- Kind: B2
- Application number: 12/757,098
- Filed: 2010-04-09
- Published: 2010-10-14
- Granted: 2015-05-26
- Earliest claimed: 2009-04-09
- Assignees: Mallinckrodt Inc.
- Applicants: Peter X. Wang; Tao Jiang; Narayanasamy Gurusamy; Catherine K. Jung
- Inventors: Peter X. Wang; Tao Jiang; Narayanasamy Gurusamy; Catherine K. Jung
- Web page: https://patentgrep.com/patent/US9040705B2

## CPC

- C07D 489/04: Salts; Organic complexes
- C07D 489/02: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides processes for the preparation of saturated ketone morphinan compounds. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an inorganic salt of a late transition metal.

## Claims

### Claim 1

A one-pot process for the preparation of a morphinan comprising a saturated ketone ring moiety, the process comprising contacting a morphinan comprising an allyl alcohol ring moiety with an inorganic salt of a late transition metal in the presence of a protic solvent, wherein the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety, and wherein the weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety is from 2:1 to 4:1.

### Claim 2 (depends on 1)

The process of claim 1, wherein the late transition metal is a group VIIIB metal selected from the group consisting of ruthenium, rhodium, palladium, osmium, iridium, and platinum; and the inorganic salt is selected from the group consisting of halide, sulfate, phosphate, and nitrate.

### Claim 3 (depends on 1)

The process of claim 1, wherein the inorganic salt of the late transition metal is selected from the group consisting of RuCl3, RuBr3, Ru(CF3SO3)2, Ru2(SO4)3, Ru(NO3)3, RhCl3, RhBr3, Rh2(SO4)3, [Rh(CO2)Cl]2, IrCl3, OsCl3, and PdCl2.

### Claim 4 (depends on 1)

The process of claim 1, wherein the weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety is from 2:1 to 3.6.

### Claim 5 (depends on 1)

The process of claim 1, wherein the process comprises a single inorganic salt of a late transition metal.

### Claim 6 (depends on 1)

The process of claim 1, wherein the morphinan comprising a saturated ketone ring moiety is produced with a yield in excess of 85%.

### Claim 7 (depends on 1)

The process of claim 1, wherein the morphinan comprising a saturated ketone ring moiety is produced with a yield in excess of 95%.

### Claim 8

A process for the preparation of a compound of Formula (III), the process comprising contacting a compound of Formula (II) with an inorganic salt of a late transition metal in the presence of a protic solvent to form the compound of Formula (III):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR1611, {—}OR1611, and {—}NR1611 R1612 hydrocarbyl, and substituted hydrocarbyl;
R5, R7, R8, R9, R10a, R10b, R14, R15aR15b, R16a, R16b, and R17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {-}SR1611, {—}OR1611, and {—}NR1611 R1612, hydrocarbyl, and substituted hydrocarbyl; provided that any of R10a and R10b, R15a and R15b, and R16a and R16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR1613;
R1611, R1612, and R1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl;
one or more of R1, R2, R3, R5, R7, R8, R9, R10a, R10b, R14, R15a, R15b, R16a, and R16b may form part of a ring or ring system chosen from carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof; and
Z is an anion, and
wherein the weight:weight ratio of the protic solvent to the compound of Formula (II) is from 2:1 to 4:1.

### Claim 9 (depends on 8)

The process of claim 8, wherein A is oxygen; R1, R2, R5, R7, R8, R9, R10a, R10b, R15a, R15b, R16a, and R16bare hydrogen; R3 is selected from the group consisting of hydroxy, protected hydroxy, alkyloxy, and acyloxy; R14 is hydrogen or hydroxy; and R17 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylmethyl, allyl, and aryl.

### Claim 10 (depends on 9)

The process of claim 9, wherein R3 is hydroxy or methyoxy; R14 is hydrogen; R17 is methyl; and Z is selected from the group consisting of hydrochloride, sulfate, and bitartrate.

### Claim 11 (depends on 8)

The process of claim 8, wherein the compound of Formula (III) is isolated as a free base of Formula (IV):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR1611, {—}OR1611, and {—}NR1611R1612, hydrocarbyl, and substituted hydrocarbyl;
R5, R7, R8, R9, R10a, R10b, R14, R15aR15b, R16a, R16b, and R17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {—}SR1611, {—}OR1611 , and {—}NR1611 R1612, hydrocarbyl, and substituted hydrocarbyl; provided that any of R10a and R10b, R15a and R15b, and R16a and R16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {—}NR1613;
R1611 , R1612 , and R1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
one or more of R1, R2, R3, R5, R7, R8, R9, R10a, R10b, R14, R15a, R15a, R16a, and R16b may form part of a ring or ring system selected from the group consisting of carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof.

### Claim 12 (depends on 8)

The process of claim 8, wherein the compound of Formula (II) is formed in situ by contacting an acid with a compound of Formula (I):
wherein:
A is a heteroatom selected from the group consisting of oxygen and sulfur;
R1, R2, and R3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, protected hydroxy, {—}SH, {—}SR1611, {—}OR1611and {—}NR1611, R1612, hydrocarbyl, and substituted hydrocarbyl;
R5, R7, R8, R9, R10a, R10b, R14, R15a, R15b, R16a, R16b, and R17 are independently selected from the group consisting of hydrogen, halogen, hydroxy, {—}SH, {—}SR1611, {—}OR1611, and {—}NR1611 R1612, hydrocarbyl, and substituted hydrocarbyl; provided that any of R10a and R10b, R15a and R15b, and R16a and R16b may together form a moiety selected from the group consisting of {═}O, {═}S, and {═}NR1613;
R1611, R1612, and R1613 are independently selected from the group consisting of hydrocarbyl, and substituted hydrocarbyl; and
one or more of R1, Rb 2,R3, R5, R7, R8, R9, R10a, R10b, R14, R15a, R15b, R16a, and R16b may form part of a ring or ring system selected from the group consisting of carbocyclic, heterocyclic, aryl, heteroaryl, and combinations thereof.

### Claim 13 (depends on 12)

The process of claim 12, wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, and tartaric acid.

### Claim 14 (depends on 8)

The process of claim 8, wherein the late transition metal is a group VIIIB metal selected from the group consisting of ruthenium, rhodium, palladium, osmium, iridium, and platinum; and the inorganic salt is selected from the group consisting of halide, sulfate, phosphate, and nitrate.

### Claim 15 (depends on 8)

The process of claim 8, wherein the inorganic salt of the late transition metal is selected from the group consisting of RuCl3, RuBr3, Ru(CF3SO3)2, Ru2(SO4)3, Ru(NO3)3, RhCl3, RhBr3, Rh2(SO4)3, [Rh(CO2)Cl]2, IrCl3, OsCl3, and PdCl2.

### Claim 16 (depends on 8)

The process of claim 8, wherein the weight:weight ratio of the compound of Formula (II) to the late transition metal salt is from about 1:0.0001 to about 1:0.1; the protic solvent is selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof; and the reaction is conducted at a temperature from about 10° C. to about 120° C.

### Claim 17 (depends on 16)

The process of claim 16, wherein the protic solvent comprises a mixture of alcohol and water.

### Claim 18 (depends on 8)

The process of claim 8, further comprising a co-reactant selected from the group consisting of acetone, acetonitrile, 1-hexene, cyclohexene, H3PO2, NaH2PO2, and combinations thereof.

### Claim 19 (depends on 8)

The process of claim 8, wherein the optical activity of the compounds of Formulas (II) and (III) is (−) or (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is selected from the group consisting of RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.

### Claim 20 (depends on 10)

The process of claim 10, wherein the late transition metal salt is RuCl3; the weight:weight ratio of the compound of Formula (II) to RuCl3 is from about 1:0.01 to about 1:0.2; the protic solvent comprises ethanol and water; the reaction is conducted at a temperature from about 65° C. to about 90° C.; and the compound of Formula (III) has a yield of at least about 60%.

### Claim 21 (depends on 17)

The process of claim 17, further comprising a co-reactant selected from the group consisting of acetone, acetonitrile, 1-hexene, cyclohexene, H3PO2, NaH2PO2, and combinations thereof; and the weight:weight ratio of the compound of Formula (II) to the co-reactant is from about 1:0.005 to about 1:0.05.

### Claim 22 (depends on 20)

The process of claim 20, wherein the optical activity of the compounds of Formulas (II) and (III) is (−), and the configuration of C-5, C-13, C-14, and C-9, respectively, is RSRR.

### Claim 23 (depends on 20)

The process of claim 20, wherein the optical activity of the compounds of Formulas (II) and (III) is (+), and the configuration of C-5, C-13, C-14, and C-9, respectively, is SRSS.