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1. NZ582668 - PREPARATION OF N-ALKYLATED OPIATES BY REDUCTIVE AMINATION

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

RECEIVED at IPONZ on 12 April 201 1

Example 2(b): Synthesis of 8- etal Naltrexone from 6-Ketalnorcixymorphorie


6-ketal naltrexone

[0059] 6-ketalnoroxymorphone (0.95 g, 3.0 mmol), cyclopropanecarboxaldehyde (0.40 g, 6.0 mmol, 0.43 mL), and acetonitriSe (5.0 mL) were combined and the slurry stirred for 2 hours at room temperature. The mixture was evaporated to dryness and dissolved in fresh acetonitrile (5.0 mL). At that time, a 5 to 2 mixture of 98% formic acid/ triethylamine [prepared by adding 98% formic acid (1.78 g, 38.7 mmol, 1.46 mL) to triethylamine (1.45 g, 14.3 mmol, 2.0 mL)] in 10 mL of acetonitrile was added. Dichloro(p~cymene)ruthenium (II) dimer (19 mg) was added followed by (1S, 2S)-(+)~N-tosyl~diphenylethylene diamine (26 mg). The reaction was purged by nitrogen gas (argon) for 30 minutes. After that, a flow of nitrogen was allowed to pass over the reaction. The reaction was stirred for 24 hours at room temperature. HPLC analysis indicated the reaction was complete. The reaction mixture was evaporated to a thick oil. To this thick slurry, fresh acetonitrile (5.0 mL) was added. After stirring at room temperature for 2 hours, a white solid formed. The precipitate was removed by filtration and washed with 5 mL cold (5°C) acetonitrile. The precipitate was dried yielding the title product (1.06 g, 92% yield). HPLC analysis = 99.0%.

Example 2(c): Synthesis of Naltrexone from 6-ketal Naltrexone


Naltrexone

[0060] 6-ketal naltrexone (1.06 g, 2.76 mmol) was added to a stirred solution of 88% HC02H

(5.0 mL) and distilled water (1.0 mL). After stirring for 2 hours at room temperature, the reaction was complete, The reaction mixture was slowly added to 30 mL 29% NH3/ H2O, and a white precipitate formed. The white precipitate was isolated by filtration, washed with distilled water (5,0 mL), and dried yielding naltrexone (895 mg, 95% yield). HPLC analysis = 99.0%.

RECEIVED at IPONZ on 21 December 201 1

CLAIMS

1. A process for the preparation of a N-alkylated morphinan (II) having the formula


the process comprising reducing an N-imine morphinan or hemiaminai morphinan in the presence of a

ruthenium, rhodium, or iridium asymmetric catalyst and a hydrogen source that is a protic compound,

wherein the catalyst comprises a bidentate, chirai ligand complexed with the ruthenium, rhodium, or iridium via

nitrogen, oxygen, or phosphorous donor atoms,

the N-imine morphinan or hemiaminai morphinan (I) having the formula:


wherein

Ri is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or -ORw;

R2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or -OR211;

R3 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -ORsn;

6 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -ORsn

R? is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -OR711;

Re is hydrogen, hydrocarbyl, substituted hydrocarbyl, or -OReu;

R14 is hydrogen or hydroxy;

RECEIVED at IPONZ on 21 December 201 1

Rm is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R211 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R311 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

Re is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R711 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

Ren is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

Zi is >NCH(OH)( R9) or >N+=CH(R9);

Z2 is >NCH2(R9); and

R9 is hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

2. The process of claim 1 wherein the catalyst comprises a ruthenium complex or a rhodium

complex, and/or

wherein the catalyst comprises dichloro(arene)Ru(ll) dimer,

dichloro(pentamethylcyclopentadienyl)Rh(ll) dimer, BINAP-Ru (II) diacetate, BINAP-Ru (II) dichloride, BINAP-Ru

(II) dibromide, BINAP-Ru (II) diiodide, [RuCI((R or 'S)BINAP)(CBH8)]CI, or

dichloro(pentamethylcyclopentadienyl)iridium (III) dimer.

3. The process of any one of claims 1-2 wherein the catalyst comprises a chiral ligand having

Formula (670), Formula (680), Formula (690), or Formula (700):


wherein R$?i, R6 2, 673, Reei, R69i, 692, R701, and 02 are independently alkyl oraryl and wherein R691 and R692,

and the carbon atoms to which they are attached, may optionally form a cyclic or bicyclic compound;

wherein the ligand preferably has the Formula (670) and R672 and R673 are preferably phenyl, and R67i is preferably aryl and more preferably tolyl, mesityl, or naphthyl;

or wherein the ligand preferably has the Formula (680) and Reei is preferably tolyl, mesityl, 2,4,6- triisopropylphenyl, or naphthyl; or

wherein the ligand preferably has the Formula (700) and R701 and R702 are preferably hydrogen.

RECEIVED at IPONZ on 21 December 201 1

4. The process of claim 3 wherein the ligand is (1S,2S)-(+)-N-4-toluenesulfonyl-1 ,2-diphenylethylene-1 ,2-diamine, (1 R,2R)-(-)-N-4-toluenesulfonyl-1 ,2-diphenylethylene-1 ,2-diamine, dl-N-tosyl-1 ,2-diphenylethylenediamine, N-tosyl-1 ,2-diphenylethylenediamine, N-tosyl-1 ,2-ethylenediamine, or N-tosyl-1 ,2-diaminocyclohexane.

The process of any one of claims 1-2 wherein the catalyst is selected from the group consisting


wherein Ar is aryl.

6. The process of any one of claims 1-5 wherein the hydrogen source is preferably isopropanol,

formic acid, organic or inorganic salts of formic acid, or a combination thereof, and

wherein the hydrogen source is more preferably a mixture of formic acid and triethylamine, the ratio of

formic acid to triethylamine being about 5:2.

RECEIVED at IPONZ on 21 December 201 1

7. The process of any one of claims 1-6 wherein the process occurs in an aprotic, polar solvent,

wherein the solvent is preferably a nitrile, tetrahydrofuran, an alcohol, a halocarbon, dimethylformamide,

dimethylacetamide, N-methyl pyrrolidinone, an alkyl acetate, toluene, water, or a combination thereof, and

wherein the solvent is more preferably methanol, acetonitrile, ethyl acetate, propyl acetate, or a

combination thereof.

8. The process of any one of claims 1-7 wherein Ri is hydrogen or -ORm and Rm is hydrogen,

alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group, and/or

wherein R2 is hydrogen or -OR211 and R211 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting

group, and/or

wherein R3 is hydrogen or -OR311 and R311 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting

group,

wherein R311 is preferably hydrogen or alkyl.

9. The process of any one of claims 1-8 wherein Re is hydrogen, or substituted or unsubstituted

C1.8 alkyl, C2-8 alkenyl, phenyl, or -OR611 and R611 is C1-3 alkyl, C2-8 alkenyl, hydrogen or a hydroxy protecting

group,

wherein R6 is preferably -ORen and Ren is preferably methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, hydrogen, or a hydroxy protecting group,

wherein Ren is more preferably methyl, ethyl, hydrogen, or a hydroxy protecting group,

wherein Ren is most preferably hydrogen or a hydroxy protecting group.

10. The process of any one of claims 1-9 wherein

Ri is hydrogen;

R2 is hydrogen;

R3 is -OR311; and

R311 is hydrogen or Ct-eaikyl, and/or

RECEIVED at I PONZ on 21 December 201 1

wherein F¾ is -ORsu and Ren is hydrogen, methyl, or a hydroxy protecting group, and/or

wherein Re is hydrogen, and/or

wherein R7 is hydrogen or 3,3-dimethylbutan-2-ol.

11. The process of any one of claims 1-10 wherein Zi is >NCH(OH)( R9) or >N*=CH(Rg) and R9 is

methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl or cyclopentyl, wherein

R9 is preferably cyclopropyl or cyclobutyl.

12. The process of claim 1 wherein the N-alkylated morphinan (II) is buprenorphine:


13. The process of any one of claims 1-12 wherein the process occurs within a temperature range

of about 0°C to about 120°C, or

wherein the process occurs within a temperature range of about 20°C to about 40°C.

1 . The process of claim 1 wherein the hemiaminal morphinan (I) is prepared from a nor- morphinan (X) having the formula:

RECEIVED at IPONZ on 21 December 201 1


the process comprising reacting the nor-morphinan (X) with an aldehyde of the formula CH(O) Rg in a solvent to

form the hemiaminal morphinan (I) having the formula:


wherein

Zi is >NCH(OH)( ¾); and

Rg is hydrocarbyl, acyl, substituted hydrocarbyl, orheterocyclo,

wherein the hemiaminal morphinan preferably is in equilibrium with the corresponding N-imine

morphinan, the hemiaminal having a >NCH(OH)( Rg) moiety for Zi and the N-imine morphinan having a

>N*=CH(R9) moiety for Zi.

15. The process of claim 14 wherein R3 is -OR311 and R311 is hydrogen, and/or

wherein R6 is -OR611 and R611 is methyl, and/or

wherein R? is substituted alkyl, or

RECEIVED at IPONZ on 21 December 201 1

wherein R7 is 3 ,3-dimethy lbutan-2-ol , and/or

wherein Rs is cyclopropyl, and/or

wherein the reaction occurs at about room temperature, and/or

wherein the solvent is acetonttrile, and/or

wherein the nor-morphinan (X) is Nor-buprenorphine.

16. The process of claim 1 wherein the hemiaminal morphinan (I) is prepared by reacting a 6-keto

nor-morphinan having the Formula (XI):


with ethylene glycol and an acid to form a 6-ketal nor-morphinan having the Formula (XII):


wherein the acid is preferably methanesulfonic acid, and/or

RECEIVED at IPONZ on 21 December 201 1

wherein'the reaction occurs at about room temperature, and/or

wherein the 6-keto nor-morphinan (XI) is noroxymorphone and the 6-ketal nor-morphinan (XII) is 6-ketalnoroxymorphone, and/or

wherein the 6-ketal nor-morphinan (XII) is further reacted with an aldehyde of the formula CH(O) R9in a

solvent to form the hemiaminal morphinan (I) having the formula:


wherein

Zi is >NCH(OH)( R9); and

Rg is hydrocarbyl, acyl, substituted hydrocarbyl, or heterocyclo.

17. The process of claim 16 wherein the hemiaminal morphinan is in equilibrium with the

corresponding N-imine morphinan, the hemiaminal morphinan having a >NCH(OH)( Rg) moiety for Zi and the N-imine morphinan having a >N+=CH(R9) moiety for Zi, and/or

wherein R3 is -OR311 and R311 is hydrogen, and/or

wherein R9 is cyclopropyl, and/or

wherein the reaction occurs at about room temperature, and/or

wherein the solvent is acetonitrile.