U.S. patent application number 12/553144 was filed with the patent office on 2015-06-18 for process for the preparation of quaternary n-alkyl morphinan alkaloid salts.
This patent application is currently assigned to Mallinckrodt Inc.. The applicant listed for this patent is Henry J. Buehler, Gary L. Cantrell, Joseph P. Haar, Robert E. Halvachs, Kevin R. Roesch, Peter X. Wang. Invention is credited to Henry J. Buehler, Gary L. Cantrell, Joseph P. Haar, Robert E. Halvachs, Kevin R. Roesch, Peter X. Wang.
Application Number | 20150164886 12/553144 |
Document ID | / |
Family ID | 41653510 |
Filed Date | 2015-06-18 |
United States Patent
Application |
20150164886 |
Kind Code |
A9 |
Wang; Peter X. ; et
al. |
June 18, 2015 |
Process for the Preparation of Quaternary N-Alkyl Morphinan
Alkaloid Salts
Abstract
An improved process for the N-alkylation of tertiary morphinan
alkaloid bases to form the corresponding quaternary morphinan
alkaloid derivatives.
Inventors: |
Wang; Peter X.; (Clarkson
Valley, MO) ; Cantrell; Gary L.; (Troy, IL) ;
Halvachs; Robert E.; (Belleville, IL) ; Roesch; Kevin
R.; (Ofallon, IL) ; Buehler; Henry J.; (St.
Louis, MO) ; Haar; Joseph P.; (Edwardsville,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Wang; Peter X.
Cantrell; Gary L.
Halvachs; Robert E.
Roesch; Kevin R.
Buehler; Henry J.
Haar; Joseph P. |
Clarkson Valley
Troy
Belleville
Ofallon
St. Louis
Edwardsville |
MO
IL
IL
IL
MO
IL |
US
US
US
US
US
US |
|
|
Assignee: |
Mallinckrodt Inc.
Hazelwood
MO
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20100035910 A1 |
February 11, 2010 |
|
|
Family ID: |
41653510 |
Appl. No.: |
12/553144 |
Filed: |
September 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/US08/03070 |
Mar 6, 2008 |
|
|
|
12553144 |
|
|
|
|
60893163 |
Mar 6, 2007 |
|
|
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60953248 |
Aug 1, 2007 |
|
|
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Current U.S.
Class: |
514/282 ;
546/45 |
Current CPC
Class: |
Y02P 20/582 20151101;
A61P 25/04 20180101; A61K 31/485 20130101; C07D 489/02
20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 25/04 20060101 A61P025/04; C07D 489/02 20060101
C07D489/02 |
Claims
1. A process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid having a protected C(3)
hydroxy substituent, the process comprising (i) combining the
C(3)-O-protected tertiary N-substituted morphinan alkaloid
substrate with an alkylating agent in an anhydrous solvent system,
at a pressure less than about 2 atm., to form a reaction product
mixture containing the quaternary derivative of the
C(3)-O-protected tertiary N-substituted morphinan alkaloid
substrate and any unreacted tertiary N-substituted morphinan
alkaloid substrate, the solvent system comprising an anhydrous
aprotic dipolar solvent with the aprotic dipolar solvent
constituting at least 25 wt. % of the solvent system and (ii)
adding a non-solubilizing solvent to the reaction product mixture
to precipitate the quaternary derivative, the quaternary derivative
having less solubility in the non-solubilizing solvent than in the
dipolar aprotic solvent, wherein the C(3)-O-protected tertiary
N-substituted morphinan alkaloid substrate has the structure of
Formula 111 and the quaternary derivative has the structure of
Formula 111A, ##STR00015## wherein A is --C(O)--, --C(S)--,
--C(.dbd.CH.sub.2)--, --CH(A.sub.1)- or --C(A.sub.1)=, A.sub.1 is
hydroxy, alkoxy, or acyloxy, PG is a hydroxy protecting group;
A.sup.1 is hydrocarbyl or substituted hydrocarbyl, R.sup.2 is
hydrocarbyl or substituted hydrocarbyl, X.sup.1 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 a C(3)-O protected tertiary
morphinan alkaloid of Formula 111 is produced by reacting a C(3)-OH
morphinan alkaloid of Formula 11 with a protecting agent PG-L
wherein PG is the protecting group and L is a corresponding counter
ion or leaving group.
3. The process of claim 1, wherein PG comprises methyl, ethyl,
propargyl, benzyl, acetyl, trityl, silyl, methoxymethyl,
1-ethoxyethyl, benzyloxymethyl,
(.beta.-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 aqueous media or in toluene, chloroform, chloromethane,
chlorobenzene, acetone dimethyl formamide or combinations thereof,
and in the presence of a base comprising sodium bicarbonate,
potassium carbonate, triethylamine, sodium hydroxide, potassium
bicarbonate, or pyridine.
4. The process of claim 1, further comprising removal of the C(3)-O
protecting group from the C(3)-O-protected quaternary morphinan
alkaloid of Formula 111A by hydrolysis to yield a product of
Formula 111B: ##STR00016##
5. A process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid having a C(3)-hydroxy
substituent, 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-morphinan alkaloid corresponding
to Formula 11 with a protecting agent, PG-L; (ii) isolating the
generated C(3)-O-protected tertiary N-substituted morphinan
alkaloid; (iii) combining the isolated C(3)-O-protected tertiary
N-substituted 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
derivative of the C(3)-O-protected tertiary N-substituted morphinan
alkaloid substrate and any unreacted C(3)-O-protected tertiary
N-substituted morphinan alkaloid substrate 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
derivative corresponding to Formula 111A; (iv) isolating the
C(3)-O-protected quaternary derivative from the reaction product
mixture and (v) removing the protecting group from the isolated
C(3)-O-protected quaternary derivative to yield a quaternary
derivative of a tertiary N-substituted morphinan alkaloid having a
C(3)-hydroxy substituent corresponding to Formula 11A; wherein
Formulae 11, 11A, 111 and 111A have the following structures:
##STR00017## wherein A is --C(O)--, --C(S)--, --C(.dbd.CH.sub.2)--,
--CH(A.sub.1)- or --C(A.sub.1)=, A.sub.1 is hydroxy, alkoxy, or
acyloxy, PG is a hydroxy protecting group and L is a counterion of
the hydroxy protecting group; R.sup.1 is hydrocarbyl or substituted
hydrocarbyl, R.sup.2 is hydrocarbyl or substituted hydrocarbyl,
X.sup.1 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.
6. The process of claim 5, wherein PG is methyl, ethyl, propargyl,
benzyl, acetyl, trityl, silyl, methoxymethyl, 1-ethoxyethyl,
benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl,
tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, trityl,
t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and
2,2,2-trichloroethoxymethyl.
7. A process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid having a C(3)-hydroxy
substituent, the process comprising: (i) forming a C(3)-protected
hydroxy derivative of the tertiary N-substituted morphinan
alkaloid, comprising: (A) treating the tertiary N-substituted
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)-protected hydroxy derivative of the tertiary N-substituted
morphinan alkaloid and the water immiscible solvent in an organic
layer, and protecting group precursor, tertiary N-substituted
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 tertiary N-substituted morphinan alkaloid to the
C(3)-protected hydroxy derivative; (E) removing water immiscible
solvent from the treated organic layer produced in step (i)(D) to
form a concentrate comprising the C(3)-protected hydroxy
derivative; and (F) dissolving the concentrate produced in step
(i)(E) comprising the C(3)-protected hydroxy derivative in an
anhydrous solvent system; (ii) treating the C(3)-protected hydroxy
derivative in the anhydrous solvent system of step (i)(F) with an
alkylating agent to form a second reaction product mixture
comprising the quaternary derivative of the C(3)-protected hydroxy
derivative, unreacted alkylating agent, and any unreacted
C(3)-protected hydroxy derivative; and (iii) deprotecting the
quaternary derivative of the C(3)-protected hydroxy derivative to
form a third reaction product mixture comprising the quaternary
derivative of the tertiary N-substituted morphinan alkaloid, the
quaternary derivative of the tertiary N-substituted morphinan
alkaloid having a C(3)-hydroxy substituent, wherein the
C(3)-hydroxy tertiary N-substituted morphinan alkaloid has the
structure of Formula (11), the C(3)-O-protected tertiary
N-substituted morphinan alkaloid has the structure of Formula
(111), the quaternary derivative of the C(3)-O-protected tertiary
N-substituted morphinan has the structure of Formula (111A), and
the quaternary derivative of the C(3)-hydroxy tertiary
N-substituted morphinan alkaloid has the structure of Formula
(111B): ##STR00018## wherein A is --C(O)--, --C(S)--,
--C(.dbd.CH.sub.2)--, --CH(A.sub.1)- or --C(A).dbd., A.sub.1 is
hydroxy, alkoxy, or acyloxy, PG is a hydroxy protecting group,
R.sup.1 is hydrocarbyl or substituted hydrocarbyl, R.sup.2 is
hydrocarbyl or substituted hydrocarbyl, X.sup.1 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.
8. The process of claim 7, 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).
9. The process of claim 7, 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).
10. The process of claim 7, wherein the third reaction product
mixture includes no more than about 0.1% of a C(3)-O-alkyl
quaternary or tertiary N-substituted morphinan alkaloid impurity,
relative to the total alkaloid content of the third product
mixture.
11. The process of claim 10, 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.
12. The process of claim 7, wherein the alkylating agent is methyl
bromide; the water immiscible solvent is toluene; and the anhydrous
solvent system comprises 1-methyl-2-pyrrolidinone.
13. The process of claim 7, wherein the tertiary N-substituted
morphinan alkaloid substrate is naltrexone
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-on-
e), oxymorphone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one),
hydromorphone
((5.alpha.)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one), naloxone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6--
one), nalmefene
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-di-
ol), nalbuphine
((5.alpha.)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol),
or oripavine
((5.alpha.)-6,7,8,14-tetrahydro-4,5-epoxy-6-methoxy-17-methylmo-
rphinan-3-ol); step (ii) is carried out at a pressure of less than
1.25 atmospheres; Y and Z are independently --OCH.sub.3, --OAc,
--OTHP, --OSiR.sub.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.degree. C.
14. The process of claim 13, wherein PG is acetyl.
15. The process of claim 7, wherein the protection of step (i)(A)
is carried out with acetic anhydride in a water/toluene mixture and
sodium hydroxide.
16. The process of claim 7, wherein the tertiary N-substituted
morphinan alkaloid substrate is naltrexone or oxymorphone.
17. A composition comprising R-naltrexone methobromide,
S-naltrexone methobromide, the C(3)-O-methyl derivative of
naltrexone methobromide, and naltrexone wherein the composition
contains at least 70% (w/w) of R-naltrexone methobromide, at least
1% (w/w) of S-naltrexone methobromide, but no more than 0.2% (w/w)
of the C(3)-O-methyl derivative of naltrexone methobromide, based
upon the combined weight of the R-naltrexone methobromide,
S-naltrexone methobromide, C(3)-O-methyl derivative of naltrexone
methobromide, and naltrexone in the composition.
18. The composition of claim 17, the composition being in the form
of a mixture with the weight ratio of S-naltrexone methobromide to
C(3)-O-methyl derivative of naltrexone methobromide in the mixture
being at least 10:1.
19. The composition of claim 18, wherein the mixture is in the form
of a slurry or a solution.
20. The composition of claim 17, the composition being in the form
of a mixture with the weight ratio of naltrexone to C(3)-O-methyl
derivative of naltrexone methobromide in the mixture being at least
10:1.
21. The composition of claim 20, wherein the mixture is in the form
of a slurry or a solution.
22. The composition of claim 18, wherein the composition contains
no more than 0.1% (w/w) of the C(3)-O-methyl derivative of
naltrexone methobromide, based upon the combined weight of the
R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methyl
derivative of naltrexone methobromide, and naltrexone in the
composition.
23. The composition of claim 17, the composition being in the form
of a crystallized solid with the weight ratio of S-naltrexone
methobromide to C(3)-O-methyl derivative of naltrexone methobromide
in the crystallized solid being at least 10:1.
24. The composition of claim 17, the composition being in the form
of a crystallized solid with the weight ratio of naltrexone to
C(3)-O-methyl derivative of naltrexone methobromide in the
crystallized solid being at least 10:1.
25. The composition of claim 23, wherein the composition contains
no more than 0.1% (w/w) of the C(3)-O-methyl derivative of
naltrexone methobromide, based upon the combined weight of the
R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methyl
derivative of naltrexone methobromide, and naltrexone in the
composition.
26. 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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of PCT/US2008/003070,
filed Mar. 6, 2008, which claims the benefit of U.S. Provisional
Application No. 60/893,163 filed Mar. 6, 2007 and U.S. Provisional
Application No. 60/953,248 filed Aug. 1, 2007
FIELD OF THE INVENTION
[0002] The present invention generally relates to improved
processes for the synthesis of quaternary N-alkyl salts of
morphinan alkaloids such as naltrexone methobromide.
BACKGROUND OF THE INVENTION
[0003] N-methyl quaternary derivatives of morphinan alkaloids such
as naltrexone
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-on-
e sometimes referred to as N-cyclopropylmethyl-noroxymorphone) and
naloxone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6--
one sometimes referred to as N-allyl-noroxymorphone) have useful
pharmacological properties as potent antagonists of the mu
receptor. They bind to peripheral receptors primarily located in
the gastrointestinal tract, act as antagonists and effectively
mitigate some of the undesirable side effects of opiate therapy
such as constipation and nausea. Because of their ionic charge,
however, they do not traverse the blood brain barrier into the
central nervous system; hence, the central activity of opiates
responsible for pain relief is not blocked in the presence of these
quaternary derivatives.
[0004] In U.S. Pat. No. 4,176,186, Goldberg et al. generally
describe the preparation of quaternary derivatives of certain
morphinan alkaloids by quaternizing a tertiary N-substituted
morphinan alkaloid with a methylating agent such as methyl bromide,
methyl iodide or dimethyl sulfate. Goldberg et al. disclose that
the methylating agent itself may be used as the solvent or,
alternatively, another solvent medium such as methanol, ethanol, or
other alcohols, methylene chloride, chloroform tetrahydrofuran,
dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile,
nitromethane or hexamethylphosphoric triamide may be used. Goldberg
et al. state that they especially prefer acetone because the
product precipitates in pure crystalline form during the reaction,
and in their Example 5, they dissolve
N-cyclopropylmethylnoroxymorphone in a mixture consisting of 50 mL
of absolute acetone and 0.5 mL of dimethylformamide and then admix
the resulting solution with methyl bromide. Methyl bromide was used
in excess, greater than six-fold molar excess relative to the free
base, over a period of 3 weeks in a pressure vessel.
[0005] In WO 2004/043964, Cantrell et al. disclose a process for
the synthesis of naltrexone methobromide. For example, 100 g of
naltrexone base was reacted with methyl bromide (MeBr) in
1-methylpyrrolidinone (NMP) at 61 to 65.degree. C. to provide 85 g
of a crude naltrexone methobromide in approximately 60 mol. % yield
of approximately 90% pure naltrexone methobromide (see Example 1).
Purification of the crude product was carried out in three steps to
give pure naltrexone methobromide; in addition, 20% of unreacted
naltrexone was disposed of in the waste streams, a significant
loss. While this process constitutes significant progress in the
synthesis of naltrexone methobromide and other quaternary morphinan
alkaloids, a need remains for yet further improvement.
[0006] In WO 2006/127899, Doshan et al. disclose a stereoselective
synthesis of the R-isomer of naltrexone methobromide by
quaternization of a 3-O-protected-naltrexone with a methylating
agent followed by removal of the protecting group. N-methylation of
tertiary morphinan alkaloids has been shown in a previously
published NMR study to be highly stereoselective yielding the
R-isomer; (see Funke and de Graaf, J. Chem. Soc., Perkins Trans.
II, 1985, 385.). In the synthesis disclosed by Doshan et al
(Example 2), 3-O-isobutyryl-naltrexone was reacted with a 4-fold
excess of methyl iodide in a sealed glass pressure vessel in a
nitrogen atmosphere at 88 to 90.degree. C. for 17 hrs. The vessel
was then cooled to ambient temperature and evacuated to remove
unreacted methyl iodide. The product,
3-O-isobutyryl-methylnaltrexone iodide, a white solid, was
dissolved in a minimum volume of dichloromethane/methanol (4:1) and
purified by silica gel chromatography. The 3-O-protecting group was
removed by reaction with 48% HBr at 64 to 65.degree. C. for 6.5
hours and the mixture was concentrated to an oil by rotary
evaporation at 22 to 25.degree. C. Purification of the crude
product was carried out by ion exchange on a bromide column and a
solid was isolated from selected pooled fractions. Serial
recrystallization of the solid from methanol yielded a white
product (64% yield). Product analysis showed an isomer distribution
of approximately 97% R-isomer and 3% S-isomer. Additional
recrystallizations and/or chromatography (Up to 10 times) were
required to eliminate the S-isomer. Hence, a need remains for
further improvement.
SUMMARY OF THE INVENTION
[0007] Among the various aspects of the present invention is an
improved process for the preparation and/or recovery of quaternary
morphinan alkaloids.
[0008] Briefly, therefore, the present invention is directed to a
process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid, the process comprising:
(i) combining a tertiary N-substituted morphinan alkaloid
substrate, or a suspension of a tertiary N-substituted morphinan
alkaloid substrate in an anhydrous solvent system with an
alkylating agent, or a solution of the alkylating agent in the
anhydrous solvent system, to form a reaction product mixture
containing the quaternary derivative of the tertiary N-substituted
morphinan alkaloid substrate and any unreacted tertiary
N-substituted morphinan alkaloid substrate, the solvent system
comprising an anhydrous aprotic dipolar solvent(s) with the aprotic
dipolar solvent(s) constituting at least 25 wt. % of the solvent
system; and (ii) adding a non-solubilizing solvent to the reaction
product mixture to precipitate the quaternary derivative.
[0009] The present invention is further directed to a process for
the preparation of a quaternary derivative of a tertiary
N-substituted morphinan alkaloid having a C(3) hydroxy substituent,
the process comprising: (i) combining a tertiary N-substituted
morphinan alkaloid substrate, or a suspension of a tertiary
N-substituted morphinan alkaloid substrate in an anhydrous solvent
system with an alkylating agent, or a solution of the alkylating
agent in the anhydrous solvent system, to form a reaction product
mixture containing the quaternary derivative of the tertiary
N-substituted morphinan alkaloid substrate and any unreacted
tertiary N-substituted morphinan alkaloid substrate, the solvent
system comprising an anhydrous aprotic dipolar solvent with the
aprotic dipolar solvent constituting at least 25 wt. % of the
solvent system, and (ii) adding an acid to the reaction product
mixture to suppress ionization of the C(3) hydroxy substituent and
production of C(3) alkoxy side products.
[0010] The present invention is further directed to a process for
the preparation of a quaternary derivative of a tertiary
N-substituted morphinan alkaloid, the process comprising adding
less than 3 equivalents of an alkylating agent dissolved in an
anhydrous dipolar aprotic solvent to a tertiary N-substituted
morphinan alkaloid substrate dissolved in an anhydrous solvent
system, to form a reaction product mixture containing the
quaternary derivative of the tertiary N-substituted morphinan
alkaloid substrate and any unreacted tertiary N-substituted
morphinan alkaloid substrate, the rate of addition of the
alkylating agent being less than 0.02 equivalents of alkylating
agent per equivalent of substrate per minute. In addition, the
solvent system comprises an aprotic dipolar solvent with the
aprotic dipolar solvent constituting at least 25 wt. % of the
solvent system, and wherein the solution of the alkylating agent is
maintained at a temperature below about 0.degree. C. and is added
to the reaction mixture at a temperature of between about
50.degree. C. and about 85.degree. C. so as to limit O-alkylation
to less than 10% and inhibit evaporative loss of alkylating
agent.
[0011] Further still, the present invention is directed to a
process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid, the process comprising
adding less than 3 equivalents of a solution of an alkylating agent
dissolved in an anhydrous dipolar aprotic solvent to a tertiary
N-substituted morphinan alkaloid substrate dissolved in an
anhydrous solvent system, to form a reaction product mixture
containing the quaternary derivative of the tertiary N-substituted
morphinan alkaloid substrate and any unreacted tertiary
N-substituted morphinan alkaloid substrate, the rate of addition of
the alkylating agent being less than 0.02 equivalents of alkylating
agent per equivalent of substrate per minute based upon the
concentration of substrate in the reaction mixture; wherein the
solution of the alkylating agent is maintained at a temperature
below about 0.degree. C. and is added to the reaction mixture at a
temperature of between about 50.degree. C. and about 85.degree. C.
so as to inhibit O-alkylation at the C(3) hydroxide to less than
10% and inhibit evaporative loss of alkylating agent.
[0012] Further still, the present invention is directed to a
process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid having a protected C(3)
hydroxy substituent, the process comprising (i) combining the
C(3)-O-protected tertiary N-substituted morphinan alkaloid
substrate, or a suspension of the C(3)-O-protected tertiary
N-substituted morphinan alkaloid substrate in an anhydrous solvent
system, with an alkylating agent, or a solution of the alkylating
agent in the anhydrous solvent system, at a pressure of less than
about 2 atmospheres, to form a reaction product mixture containing
the quaternary derivative of the C(3)-O-protected tertiary
N-substituted morphinan alkaloid substrate and any unreacted
tertiary C(3)-O-protected N-substituted morphinan alkaloid
substrate, the solvent system comprising an anhydrous aprotic
dipolar solvent with the aprotic dipolar solvent constituting at
least 25 wt. % of the solvent system, and subsequently removing the
C(3)-O protecting group.
[0013] Further still, the present invention is directed to a
process for the preparation of a quaternary derivative of a
tertiary N-substituted morphinan alkaloid having a C(3-hydroxy
substituent, the process comprising the steps of (i) generating a
C(3)-O-protected tertiary morphinan alkaloid by reacting a
C(3)-OH-morphinan alkaloid with a protecting agent, PG-L; (ii)
isolating the generated C(3)-O-protected tertiary N-substituted
morphinan alkaloid; (iii) combining the isolated C(3)-O-protected
tertiary N-substituted 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 derivative of the C(3)-O-protected tertiary
N-substituted morphinan alkaloid substrate and any unreacted
C(3)-O-protected tertiary N-substituted morphinan alkaloid
substrate 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; (iv) isolating the C(3)-O-protected quaternary derivative
from the reaction product mixture; and (v) removing the protecting
group from the isolated C(3)-O-protected quaternary derivative to
yield a quaternary derivative of a tertiary N-substituted morphinan
alkaloid having a C(3)-hydroxy substituent.
[0014] The present invention is also directed to the preparation of
a quaternary derivative of a tertiary N-substituted morphinan
alkaloid having a C(3)-hydroxy substituent, the process
comprising:
[0015] (i) forming a C(3)-protected hydroxy derivative of the
tertiary N-substituted morphinan alkaloid, comprising: [0016] (A)
treating the tertiary N-substituted 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)-protected hydroxy
derivative of the tertiary N-substituted morphinan alkaloid and the
water immiscible solvent in an organic layer, and protecting group
precursor, tertiary N-substituted morphinan alkaloid, and water in
an aqueous layer; [0017] (B) separating the organic layer from the
aqueous layer; [0018] (C) drying the organic layer; [0019] (D)
treating the dried organic layer produced in step (i)(C) with
additional protecting group precursor to increase the conversion of
tertiary N-substituted morphinan alkaloid to the C(3)-protected
hydroxy derivative; [0020] (E) removing water immiscible solvent
from the treated organic layer produced in step (i)(D) to form a
concentrate comprising the C(3)-protected hydroxy derivative; and
[0021] (F) dissolving the concentrate produced in step (i)(E)
comprising the C(3)-protected hydroxy derivative in an anhydrous
solvent system;
[0022] (ii) treating the C(3)-protected hydroxy derivative in the
anhydrous solvent system of step (i)(F) with an alkylating agent to
form a second reaction product mixture comprising the quaternary
derivative of the C(3)-protected hydroxy derivative, unreacted
alkylating agent, and any unreacted C(3)-protected hydroxy
derivative; and
[0023] (iii) deprotecting the quaternary derivative of the
C(3)-protected hydroxy derivative to form a third reaction product
mixture comprising the quaternary derivative of the tertiary
N-substituted morphinan alkaloid, the quaternary derivative of the
tertiary N-substituted morphinan alkaloid having a C(3)-hydroxy
substituent.
[0024] Further still, the present invention is directed to a
composition comprising R-naltrexone methobromide, S-naltrexone
methobromide, the C(3)-O-methyl derivative of naltrexone
methobromide, and naltrexone wherein the composition contains at
least 70% (w/w) of R-naltrexone methobromide, at least 1% (w/w) of
S-naltrexone methobromide, but no more than 0.2% (w/w) of the
C(3)-O-methyl derivative of naltrexone methobromide, based upon the
combined weight of the R-naltrexone methobromide, S-naltrexone
methobromide, C(3)-O-methyl derivative of naltrexone methobromide,
and naltrexone in the composition.
[0025] Further still, the present invention is directed to 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.
[0026] Other objects and features will be in part apparent and in
part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] Among the various aspects of the present invention is an
improved process for the N-alkylation of tertiary morphinan
alkaloid bases to form a corresponding quaternary morphinan
alkaloid derivative. In general, the process comprises combining a
tertiary N-substituted morphinan alkaloid substrate with an
alkylating agent in an anhydrous solvent system to form the
corresponding quaternary derivative. In certain embodiments, the
tertiary morphinan alkaloid base possesses a C(3) hydroxy group; in
such embodiments, advantageously, undesired C(3)-O-alkylation of
this C(3) hydroxy group can be inhibited by including an anhydrous
acid in the reaction mixture. Alternatively, or additionally, it
has been found that by controlling the rate of addition of the
alkylating agent to the reaction mixture, evaporative loss of a
volatile alkylating agent such as methyl bromide can be inhibited.
Further, the solvent system may alternately or additionally
comprise solvents in which the quaternary derivative has less
solubility so as to precipitate the quaternary product and also
improve flowability and subsequent processing of the product
mixture. Still further, the C(3)-hydroxy group may be protected in
one or a series of protection reactions to form the C(3)-protected
hydroxy derivative of the tertiary morphinan starting material. The
reaction product mixtures (or portions thereof) containing the
desired compounds and intermediates (e.g., the solvent/organic
layer in a biphasic mixture) may be subjected to various wash and
extraction steps in order to remove impurities and by-products. In
various embodiments in which the C(3)-protected hydroxy derivative
is formed, the alkylating agent may be purged from the reaction
mixture prior to removal of the C(3)-hydroxy protecting group.
Tertiary Morphinan Alkaloid Bases and Quaternary Products
[0028] In one embodiment, the tertiary N-substituted morphinan
alkaloid substrate has the structure of Formula 1 and the
quaternary derivative has the structure of Formula 1A:
##STR00001##
wherein
[0029] A is --C(O)--, --C(S)--, --C(.dbd.CH.sub.2)--,
--CH(A.sub.1)- or --C(A.sub.1)=,
[0030] A.sub.1 is hydroxy, alkoxy, or acyloxy,
[0031] R.sup.1 is hydrocarbyl or substituted hydrocarbyl,
[0032] R.sup.2 is hydrocarbyl or substituted hydrocarbyl,
[0033] X.sup.1 is a halide, sulfate, sulfonate, fluoroborate,
fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethanesulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate;
[0034] Y, if present, is hydrogen, hydroxy, protected hydroxy,
alkoxy, or acyloxy,
[0035] Z is 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.
[0036] In one embodiment, Y and Z are independently protected
hydroxy comprising --OCH.sub.3, --OAc, --OTHP, --OSiR.sub.3, --OBn,
--OBz, --OBs, --OTs, or --OMs wherein each R is independently
hydrocarbyl.
[0037] As previously mentioned, in certain embodiments, the
tertiary morphinan alkaloid base possesses a hydroxy group, more
specifically a C(3) hydroxy group when the tertiary morphinan
alkaloid base corresponds to Formula 1. In this embodiment, the
tertiary N-substituted morphinan alkaloid substrate has the
structure of Formula 11 and the quaternary derivative has the
structure of Formula 11A:
##STR00002##
wherein A, A.sub.1, R.sup.1, R.sup.2, X.sup.1, and Y are as defined
in connection with Formulae 1 and 1A.
[0038] In one embodiment, the tertiary morphinan alkaloid base is
represented by Formula 2 and the product is represented by Formula
2A.
##STR00003##
wherein
[0039] A is --C(O)--, --C(S)--, --C(.dbd.CH.sub.2)--, or
--CH(A.sub.1)-,
[0040] A.sub.1 is hydroxy, alkoxy, or acyloxy,
[0041] R.sup.1 is hydrocarbyl or substituted hydrocarbyl,
[0042] R.sup.2 is hydrocarbyl or substituted hydrocarbyl,
[0043] X.sup.1 is a halide, sulfate, sulfonate, fluoroborate,
fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethanesulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate;
[0044] Y is hydrogen, hydroxy, protected hydroxy, alkoxy, or
acyloxy, and
[0045] Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.
Representative tertiary morphinan alkaloids falling within the
scope of Formula 2 include naltrexone
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-on-
e), oxymorphone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one),
oxycodone
((5.alpha.)-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one),
hydromorphone
((5.alpha.)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one), naloxone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6--
one), nalmefene
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-di-
ol) and nalbuphine
((5.alpha.)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol).
Preferred tertiary morphinan alkaloids and quaternary derivatives
thereof falling within the scope of Formulae 2 and 2A correspond to
Formulae 22 and 22A.
##STR00004##
wherein R.sup.1, R.sup.2, X.sup.1, Y and Z are as defined in
connection with Formulae 2 and 2A and A.sub.10 is oxygen, sulfur or
methylene; in one embodiment, A.sub.10 is preferably oxygen or
methylene. Tertiary morphinan alkaloids falling within the scope of
Formula 22 include naltrexone, oxymorphone, oxycodone,
hydromorphone, naloxone, and nalmefene.
[0046] Other preferred tertiary morphinan alkaloids and quaternary
derivatives thereof falling within the scope of Formulae 2 and 2A
correspond to Formulae 222 and 222A.
##STR00005##
wherein R.sup.1, R.sup.2, X.sup.1, Y and Z are as defined in
connection with Formulae 2 and 2A and A.sub.1 is hydroxy, alkoxy or
acyloxy. Tertiary morphinan alkaloids falling within the scope of
Formulae 222 include nalbuphine.
[0047] In one embodiment, the tertiary morphinan alkaloid base is
represented by Formula 3 and the product is represented by Formula
3A.
##STR00006##
wherein
[0048] A is --C(O)--, --C(S)--, --C(.dbd.CH.sub.2)--, or
--CH(A.sub.1)-,
[0049] A.sub.1 is hydroxy, alkoxy, or acyloxy,
[0050] R.sup.1 is hydrocarbyl or substituted hydrocarbyl,
[0051] R.sup.2 is hydrocarbyl or substituted hydrocarbyl,
[0052] X.sup.1 is a halide, sulfate, sulfonate, fluoroborate,
fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethanesulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate;
[0053] Y is hydrogen, hydroxy, protected hydroxy, alkoxy, or
acyloxy, and
[0054] Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.
Representative tertiary morphinan alkaloids falling within the
scope of Formula 3 include morphine
((5.alpha.,6.alpha.)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol)-
, codeine
((5.alpha.,6.alpha.)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-
morphinan-6-ol), codeinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one),
14-hydroxy-codeinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphin-
an-6-one), 14-hydroxymorphinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-3,14-dihydroxy-1,7-methylmorphinan-6--
one) and morphinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one).
[0055] In another embodiment, the tertiary morphinan alkaloid base
is represented by Formula 4 and the product is represented by
Formula 4A.
##STR00007##
wherein
[0056] A.sup.1 is hydroxy, alkoxy, or acyloxy,
[0057] R.sup.1 is hydrocarbyl or substituted hydrocarbyl,
[0058] R.sup.2 is hydrocarbyl or substituted hydrocarbyl,
[0059] X.sup.1 is a halide, sulfate, sulfonate, fluoroborate,
fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethanesulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate, and
[0060] Z is hydroxy, protected hydroxy, alkoxy, or acyloxy.
[0061] Representative tertiary morphinan alkaloids and quaternary
derivatives thereof falling within the scope of Formula 4 and
Formula 4A, respectively, include thebaine
((5.alpha.)-6,7,8,14-tetradehydro-4,5-epoxy-3,6-dimethoxy-17-methylmorphi-
nan) and oripavine
((5.alpha.)-6,7,8,14-tetrahydro-4,5-epoxy-6-methoxy-17-methylmorphinan-3--
ol).
[0062] In each of these embodiments in which a tertiary alkaloid
base is alkylated to form the corresponding N-alkyl quaternary
alkaloid salt represented by Formula 1A, 2A, 22A, 222A, 3A, or 4A,
Z is preferably hydroxy, protected hydroxy, alkoxy or acyloxy, more
preferably hydroxy or methoxy. For example, in each of these
embodiments Z may be selected from --OCH.sub.3, --OAc, --OTHP,
--OSiR.sub.3 (wherein each R is independently hydrocarbyl,
preferably lower alkyl), --OBn, --OBz, --OBs, --OTs, or --OMs. By
way of further example, in each of these embodiments, Z may be
hydroxy. In each of these embodiments, Y, if present, is preferably
hydrogen, hydroxy, protected hydroxy, alkoxy or acyloxy, more
preferably hydrogen or hydroxy. For example, in each of these
embodiments Y, if present, may be selected from --OCH.sub.3, --OAc,
--OTHP, --OSiR.sub.3 (wherein each R is independently hydrocarbyl,
preferably lower alkyl), --OBn, --OBz, --OBs, --OTs, and --OMs. In
each of these embodiments, R.sup.1 is preferably methyl, ethyl,
propyl, allyl (--CH.sub.2CH.dbd.CH.sub.2), chloroallyl,
cyclopropylmethyl, cyclobutylmethyl, or propargyl. In each of these
embodiments, R.sup.2 is preferably alkyl, alkenyl or alkaryl, more
preferably lower alkyl, and typically methyl. In each of these
embodiments, X.sup.1 is preferably bromide.
N-Alkylation Reactions
[0063] In the process of the present invention, a tertiary
N-substituted morphinan alkaloid substrate reacts with an
alkylating agent in an anhydrous solvent system to form the
corresponding quaternary derivative.
[0064] A range of alkylating agents may be used for this purpose.
In general, alkylating agents comprising 1 to 8 carbons, optionally
substituted and optionally unsaturated are preferred. Typically,
the alkylating agent will be an alkyl, allyl, alkallyl, propargyl,
or benzyl salt of anions such as halides or optionally substituted
sulfates, sulfonates, borates, phosphates, or antimonates. Thus,
for example, the alkylating agent may be a methyl, ethyl, propyl,
allyl, cyclopropyl, cyclopropylmethyl, propargyl or benzyl salt of
an anion such as a halide, sulfate, sulfonate, fluorosulfonate,
methylsulfate, ethylsulfate, trifluoromethane-sulfonate,
hexachloroantimonate, hexafluorophosphate, or tetrafluoroborate.
Representative examples include methyl bromide, cyclopropylmethyl
bromide, dimethyl sulfate, diethyl sulfate,
di(cyclopropylmethyl)sulfate, methyl fluorosulfonate,
trimethyloxonium fluoroborate, triethyloxonium fluoroborate,
trimethyloxonium hexachloroantimonate, n-propyl or n-octyl
trifluoromethane sulfonate, trimethyloxonium hexafluorophosphate,
methyl trifluoromethane sulfonate, and allyl
trifluoromethanesulfonate. Amongst the alkyl halides, while the
chlorides and iodides may be used, the alkyl bromide is generally
preferred as an alkylating agent. Relative to the corresponding
alkyl bromides, under certain conditions, alkylations with alkyl
chlorides tend to proceed slowly and alkyl iodides tend to lead to
over alkylation of the tertiary alkaloid substrates. In one
embodiment, therefore, the alkylating agent is methyl, ethyl,
propyl, allyl, cyclopropyl, cyclopropylmethyl, or benzyl bromide.
In a typical embodiment, the alkylating agent is methyl bromide or
cyclopropylmethylbromide.
[0065] In general, an excess of alkylating agent will be employed
for the reaction. The alkylating agent may be preformulated as a
solution in an anhydrous solvent system (described below) prior to
use. As an example, methyl bromide is cooled down to a temperature
of about -10.degree. C., and an aliquot is added into a vessel
containing pre-cooled anhydrous 1-Methyl-2-Pyrrolidinone (NMP) also
at a temperature of about -10.degree. C. to form a stock solution
of the alkylating agent, i.e., methyl bromide in NMP at -10.degree.
C. (MeBr/NMP). Large excesses (e.g., more than 3 equivalents of
alkylating agent per equivalent of substrate), however, tend to
lead to over-alkylation of the substrate. It is generally
preferred, therefore, that the mole ratio of alkylating agent to
substrate employed for the reaction be about 1:1 to 1.5:1,
respectively. Further, the rate of addition of the alkylating agent
to the reaction mixture can also have an effect upon the amount of
undesired side-products with the amount of undesired side-products
tending to increase as a function of increasing rates of addition.
Thus, in some instances it may be preferred that the rate of
addition be controlled to minimize this effect. For example, in
certain embodiments, it is preferred that the rate of addition of
alkylating agent be less than 0.02 equivalents of alkylating agent
per minute per equivalent of tertiary N-substituted morphinan
alkaloid substrate in the reaction mixture. In certain embodiments,
it is preferred that the rate of addition be even slower; that is,
in such embodiments it is preferred that the rate of addition be
less than 0.01 equivalents of alkylating agent per minute per
equivalent of tertiary N-substituted morphinan alkaloid substrate
in the initial reaction mixture. In such embodiments, the rate of
addition of alkylating agent will typically be between about 0.002
and 0.02 equivalents of alkylating agent per minute per equivalent
of tertiary N-substituted morphinan alkaloid substrate in the
reaction mixture. Thus, for example, if the reaction is carried out
as a batch process, an initial reaction mixture is prepared
comprising the quantity of tertiary N-substituted morphinan
alkaloid substrate to be converted, and alkylating agent is
introduced to the initial reaction mixture at a rate of less than
0.02 equivalents of alkylating agent per minute per equivalent of
tertiary N-substituted morphinan alkaloid substrate in the initial
reaction mixture over the period of addition of the alkylating
agent. By way of further example, if the reaction is carried out as
a continuous process (in which substrate and alkylating agent are
continuously or semi-continuously introduced to the reaction
mixture), alkylating agent is introduced to the reaction mixture at
a rate of less than 0.02 equivalents of alkylating agent per minute
per equivalent of tertiary N-substituted morphinan alkaloid
substrate in the reaction mixture at the time of addition of the
alkylating agent.
[0066] The reaction mixture in which the N-alkylation occurs
contains a solvent system (that is, a solvent or mixture of
solvents) and is anhydrous. In a preferred embodiment, the solvent
system comprises an aprotic, dipolar solvent and is anhydrous. More
specifically, the solvent system preferably comprises less than
about 0.5 wt. % water, typically less than about 0.2 wt. % water,
still more typically less than 0.1 wt. % water, and in some
embodiments, less than 0.05 wt. % water. In addition, it is
preferred that the aprotic, dipolar solvent (or mixture of aprotic
dipolar solvents) constitute a significant fraction of the solvent
system; for example, in one embodiment the aprotic, dipolar
solvent(s) constitute(s) at least about 25 wt. % of the solvent
system. For example, in some embodiments it is preferred that the
aprotic, dipolar solvent(s) constitute(s) at least about 50 wt. %
of the solvent system. In some embodiments, it is preferred that
the aprotic, dipolar solvent(s) constitute(s) at least about 75 wt.
% of the solvent system. In a further embodiment, the aprotic,
dipolar solvent(s) constitute(s) at least about 90 wt. % of the
solvent system. Exemplary aprotic dipolar solvents include
dimethylacetamide, dimethylformamide, N-methylpyrrolidinone,
acetonitrile, hexamethylphosphoramide ("HMPA"), and mixtures
thereof. In one embodiment, the dipolar aprotic solvent is selected
from the group consisting of dimethyl acetamide, dimethyl
formamide, N-methylpyrrolidinone, HMPA and combinations thereof.
Ni-methylpyrrolidinone (1-methyl-2-pyrrolidinone, NMP) is typically
preferred, either alone or in combination with another aprotic,
dipolar solvent.
[0067] The reaction may be carried out over a wide range of
temperatures and pressures. In one embodiment, the reaction will be
carried out at a temperature somewhere in the range of room
temperature (about 25.degree. C.) to about 90.degree. C., typically
about 55.degree. C. to about 85.degree. C. For example, the rate,
conversion, yield and concentration of naltrexone base to the
N-methylated product in anhydrous 1-methyl-2-pyrrolidinone is
advantageously and dramatically increased at lower reaction
temperatures (<70.degree. C.) as compared to the reaction in
acetone carried out at 125.degree. C. to 140.degree. C. (>10
atm) over 24 hours.
[0068] The N-alkylation reaction may be carried out over a range of
pressures. For example, when the alkylating agent is methyl bromide
and the methyl bromide gas (MeBr) is dissolved in anhydrous
1-methyl-2-pyrrolidinone (NMP), the gas is predominantly retained
at temperatures of as high as 85.degree. C. at relatively modest
elevated pressures (e.g., .ltoreq.2 atmospheres) without the need
for expensive pressure vessels. In one embodiment, therefore, the
N-alkylation reaction is carried out at a pressure not in excess of
1.5 atmospheres in an aprotic dipolar solvent such as NMP, or in a
solvent mixture comprising NMP. Advantageously, for example, the
N-alkylation reaction may be carried out at a pressure of 1 to 1.25
atmospheres or even at atmospheric pressure.
[0069] In accordance with one aspect of the present invention, it
has been determined that addition of an acid to the reaction
mixture tends to suppress ionization of the phenolic C(3) hydroxy
group of a tertiary N-substituted morphinan alkaloid having a C(3)
hydroxy substituent. The acid is preferably an anhydrous acid. In
addition, it is preferably a strong mineral or organic acid. For
example, the acid may be a carboxylic acid, a phosphonic acid, a
sulfonic acid or a mixture thereof. Alternatively, a small amount
of a preformed alkaloid acid salt may be added to its alkaloid base
in order to suppress ionization of the alkaloid base; for example,
naltrexone hydrobromide may be added to naltrexone base. By way of
further example, the acid may be HBr, HCl, H.sub.2SO.sub.4,
NaHSO.sub.4, NaH.sub.2PO.sub.4, or Na.sub.2HPO.sub.4, containing
less than about 0.5 wt. % water, less than 0.2 wt. % water, less
than 0.1 wt. % water, or even less than 0.05 wt. % water. In one
embodiment, for example, it is preferred that the acid be HBr gas,
or HCl gas, particularly HBr gas. Conversion rates tend to decrease
with increasing acid concentrations. Thus, it is generally
preferred that the amount of acid included in the reaction mixture
be initially less than 0.25 equivalents of acid per equivalent of
substrate. In certain embodiments, it is preferred that the amount
of acid included in the reaction mixture be about 0.1 equivalents
of acid per equivalent of substrate. In some embodiments, it may be
preferred that even less acid be employed; for example, in some
embodiments it is preferred that the amount of acid be less than
0.10 equivalents of acid per equivalent of substrate, less than
0.05 equivalents of acid per equivalent of substrate, or even less
than 0.01 equivalents of acid per equivalent of substrate. In a
typical reaction, a stock solution of a strong, anhydrous acid is
prepared in the anhydrous solvent and added in aliquots. For
example, in a reaction in which HBr is the strong anhydrous acid, a
sample withdrawn from a source of hydrogen bromide (HBr) cooled to
a temperature of about -70.degree. C. is added to a sample of
1-methyl-2-pyrrolidinone (N-methylpyrrolidone; NMP) at a
temperature of about -20.degree. C. and the solution allowed to
warm to room temperature. The solution may then be further diluted
with NMP to form a stock solution of HBr in NMP (HBr/NMP) at a
desired concentration.
[0070] Typically, the substrate for the N-alkylation reactions
described herein (e.g., involving substrates containing a C(3)
hydroxide) is a dehydrated base. For example, in reactions
utilizing naltrexone, the anhydrous base may be prepared from
naltrexone hydrochloride which has been dried under vacuum until
the water content is reduced to about 2% or less by Karl-Fischer
analysis. A hydrated base (e.g., naltrexone dihydrate,
Naltrexone.2H.sub.2O) may be used in alkylations that involve prior
protection of the phenolic C(3) hydroxide. Further, it has been
observed advantageously that the presence of a strong acid (such as
HBr) in the reaction system permits use of partially hydrated
naltrexone (Naltrexone.2H.sub.2O) as a starting material instead of
anhydrous naltrexone. Therefore, acidification of the reaction
medium affords reduction in processing costs by eliminating the
costs associated with dehydration of naltrexone base prior to
alkylation.
[0071] In general, relatively concentrated solutions of the
substrate are preferred. That is, the initial reaction mixture
preferably comprises no more than about 2 equivalents of solvent
for each equivalent of N-substituted morphinan alkaloid substrate.
In some embodiments, the initial reaction mixture comprises no more
than about 1.75 equivalents of solvent for each equivalent of
N-substituted morphinan alkaloid substrate. In other embodiments,
the initial reaction mixture comprises no more than about 1.5
equivalents of solvent for each equivalent of N-substituted
morphinan alkaloid substrate.
[0072] In general, the quaternary derivative resulting from the
N-alkylation is more ionic than the N-substituted morphinan
alkaloid substrate. As a result, the quaternary derivative tends to
have less solubility in non-polar solvents than the N-substituted
morphinan alkaloid substrate. To aid in recovery of the quaternary
derivative from the reaction mixture, a solvent (or mixture of
solvents) less polar than the aprotic, dipolar solvent(s) may be
introduced to the reaction mixture to cause the quaternary
derivative to precipitate from solution while leaving the unreacted
N-substituted morphinan alkaloid substrate in solution. Such
solvents, sometimes referred to as non-solubilizing solvents (for
the quaternary derivative) are preferably employed in one
embodiment of the present invention. Typically, the
non-solubilizing solvent(s) is(are) introduced to the reaction
mixture upon completion of the N-alkylation reaction to cause the
quaternary derivative to precipitate from the reaction mixture.
Alternatively, however, a fraction of the non-solubilizing
solvent(s) may be added to the reaction mixture prior to, at the
initiation of, or during the course of the N-alkylation reaction.
In this alternative however, the kinetics of the alkylation may be
adversely affected. Preferably, the quaternary derivative has a
solubility of less than 5 wt. % in the non-solubilizing solvent at
1 atmosphere and 25.degree. C. In addition, the non-solubilizing
solvent is preferably more miscible with 1-methyl-2-pyrrolidinone
than with water; for example, the non-solubilizing solvent
preferably has a solubility of less than about 30 wt. % in water at
1 atmosphere and 25.degree. C. Exemplary non-solubilizing solvents
include chloroform, dichloromethane, ethyl acetate, propyl acetate,
methyl ethyl ketone, methyl butyl ketone, ether, hydrocarbon,
toluene, benzene, chlorobenzene, bromobenzene and mixtures thereof.
Of these, chloroform is sometimes preferred.
[0073] In general and regardless of synthetic route, N-alkylations
of morphinan substrates that contain a C(3) hydroxy moiety may
yield undesirable C(3) alkoxy morphinans. Crude product mixtures
containing C(3) hydroxy and C(3) alkoxy morphinans may be purified
by adding strong base, e.g., sodium methoxide, NaOH or KOH in
methanol/water, heating the mixture to convert the C(3) hydroxy
morphinan to its oxide salt (e.g., sodium salt), adding additional
methanol, cooling to precipitate the salt, filtering and drying.
Advantageously, the C(3) alkoxy morphinan remains in solution and
does not precipitate along with the salt; as a result, the salt and
the C(3) alkoxy morphinan may be readily separated.
[0074] The desired N-alkyl morphinan may be regenerated from the
salt by redissolving the salt (for example, in a methanol/water
solution), adjusting the solution to a low pH (for example, a pH of
0.5 to 1 using 45% hydrobromic acid) to regenerate a hydroxy group
at the C(3) position, and precipitating the product. In a preferred
embodiment, the precipitated product is recovered by vacuum
filtration, washing with additional methanol and drying to
75.degree. C.
[0075] In one embodiment, two or more of the aforementioned
preferred steps or features are combined. For example, in one
preferred embodiment, the average rate of addition of the
alkylating agent is controlled (as previously described) to
minimize over-alkylation of the substrate. By way of further
example, in one embodiment the average rate of addition of the
alkylating agent is controlled (as previously described) to
minimize over-alkylation of the substrate and a non-solubilizing
solvent for the quaternary derivative is added to the reaction
mixture to cause the quaternary derivative to precipitate from the
reaction mixture while the substrate substantially remains
dissolved in the solvent system. By way of further example, in one
embodiment the average rate of addition of the alkylating agent is
controlled (as previously described) to minimize over-alkylation of
the substrate and a strong anhydrous acid (in the amounts
previously described) is included in the reaction mixture to
inhibit alkylation of the C(3) hydroxy substituent of a tertiary
N-substituted morphinan alkaloid substrate. By way of further
example, in one embodiment the average rate of addition of the
alkylating agent is controlled (as previously described) to
minimize over-alkylation of the substrate, a strong anhydrous acid
(in the amounts previously described) is included in the reaction
mixture to inhibit alkylation of the C(3) hydroxy substituent of a
tertiary N-substituted morphinan alkaloid substrate, and a
non-solubilizing solvent for the quaternary derivative is added to
the reaction mixture to cause the quaternary derivative to
precipitate from the reaction mixture while the substrate
substantially remains dissolved in the solvent system. In one
preferred embodiment, in each of these aforementioned combinations,
methyl bromide is used as the alkylating agent, the pressure of the
reaction mixture is less than 2 atmospheres (preferably 1 to 1.5
atmospheres), and the temperature of the reaction mixture is not in
excess of 80.degree. C.
[0076] In one preferred embodiment the N-alkylation reaction is
carried out at a pressure of less than 1.25 atmospheres, the
aprotic dipolar solvent constitutes at least 75 wt. % of the
solvent system, and the aprotic dipolar solvent is
1-methyl-2-pyrrolidinone. In addition, in this preferred embodiment
the anhydrous solvent system contains less than 0.2 wt. % water,
preferably less than 0.1 wt. % water, more preferably less than
0.05 wt. % water, and said anhydrous system is maintained in a
moisture-free atmosphere in a reaction vessel. The substrate in
this preferred embodiment corresponds to Formula 1 wherein Y and Z
are independently --OCH.sub.3, --OAc, --OTHP, --OSiR.sub.3, --OBn,
--OBz, --OBs, --OTs, or --OMs wherein each R is independently
hydrocarbyl. In one particularly preferred embodiment, the
substrate is naltrexone
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-on-
e), oxymorphone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one),
oxycodone
((5.alpha.)-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one),
hydromorphone
((5.alpha.)-4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one), naloxone
((5.alpha.)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6--
one), nalmefene
((5.alpha.)-17-(cyclopropylmethyl)-4,5-epoxy-6-methylenemorphinan-3,14-di-
ol) or nalbuphine
((5.alpha.)-17-(cyclobutylmethyl)-4,5-epoxymorphinan-3,6,14-triol).
Alternatively, the substrate in this preferred embodiment
corresponds to Formula 3 and the substrate is, for example,
morphine
((5.alpha.,6.alpha.)-7,8-didehydro-4,5-epoxi-17-methylmorphinan-3,6-diol)-
, codeine
((5.alpha.,6.alpha.)-7,8-didehydro-4,5-epoxi-3-methoxy-17-methyl-
morphinan-6-ol), codeinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one)
or 14-hydroxy-codeinone
((5.alpha.)-7,8-didehydro-4,5-epoxy-14-hydroxy-3-methoxy-17-methylmorphin-
an-6-one).
Alternate Embodiment for N-alkylation of C(3)-Hydroxy Morphinan
Alkaloids
[0077] N-alkylation of a C(3)-hydroxy morphinan alkaloid substrate
(Formula 11) can produce undesired C(3)-alkoxy morphinan side
products because of a parallel alkylation of the unprotected
C(3)-hydroxy group. This process is exemplified in Scheme 1 below
where the undesired side products are C(3)-methoxy morphinan
(Formula 11B) and N-alkylated C(3)-methoxy morphinan (Formula 11C)
resulting from O-alkylation of the phenolic C(3)-OH, wherein
R.sup.1, R.sup.2, A, X, and Y are as defined in connection with
Formulae 1 and IA.
##STR00008##
[0078] To inhibit the side reaction (i.e., C(3)-O-alkylation), the
phenolic group (C(3)-OH) of the tertiary morphinan alkaloid may
first be protected to generate the C(3)-OH-protected tertiary
morphinan alkaloid. A single protection reaction may be carried
out, or a series of protecting reactions may be carried out in
order to affect more complete conversion of the C(3)-O-protected
derivative from the C(3)-hydroxy morphinan starting material. In
one embodiment, a single protection step is carried out to convert
the C(3)-hydroxy morphinan starting material to the C(3)-protected
hydroxy derivative. In another embodiment, two protection steps are
carried out to convert the C(3)-hydroxy morphinan starting material
to the C(3)-protected hydroxy derivative. In another embodiment,
three protection steps are carried out to convert the C(3)-hydroxy
morphinan starting material to the C(3)-protected hydroxy
derivative. In another embodiment, three or more protection steps
are carried out to convert the C(3)-hydroxy morphinan starting
material to the C(3)-protected hydroxy derivative. Regardless of
the number of protection reactions employed, the protected
substrate is then N-alkylated to yield a protected quaternary
morphinan alkaloid. The protecting group is subsequently removed to
yield the desired quaternary morphinan alkaloid salt.
[0079] Accordingly, in certain embodiments, the tertiary morphinan
alkaloid base possesses a protected C(3)-OH wherein the tertiary
N-substituted morphinan alkaloid substrate has the structure of
Formula 111 and the quaternary derivative has the structure of
Formula 111A:
##STR00009##
wherein A, A.sub.1, R.sup.1, R.sup.2, X.sup.1, and Y are as defined
in connection with Formulae 1 and 1A; and wherein PG is a hydroxy
protecting group. In these embodiments, a compound of Formula 111B
is produced upon removal of the hydroxy protecting group.
[0080] Representative hydroxy protecting groups include optionally
substituted hydrocarbyl, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.10-alkyloxyalkoxy; C.sub.2-C.sub.6-alkenyl;
C.sub.2-C.sub.6-alkynyl; saturated cyclic C.sub.3-C.sub.6-alkyl;
C.sub.4-C.sub.16-(cyclical saturated)alkenyl;
C.sub.4-C.sub.16-(cyclical saturated)alkynyl;
C.sub.7-C.sub.16-arylalkyl; C.sub.8-C.sub.16-arylalkenyl;
C.sub.8-C.sub.6-arylalkynyl; C.sub.2-C.sub.6-alkanoyl;
C.sub.3-C.sub.6-alkenoyl; C.sub.3-C.sub.6-alkynoyl;
C.sub.8-C.sub.16-arylalkanoyl; C.sub.9-C.sub.16-arylalkenoyl;
C.sub.9-C.sub.16-arylalkynoyl; sulfonyl or phosphonyl.
[0081] A range of hydroxy protecting groups which may be used
comprise ethers (alkoxy) and esters (acyloxy); (see T. W. Greene
and P. G. M. Wuts, Protective Groups in Organic Synthesis (3rd
edition), J. Wiley & Sons In., NY 1999, chapter 3). Common
ether protective groups comprise methyl, methoxymethyl, propargyl,
benzyl, trityl, silyl, tris-(C.sub.1-C.sub.6-alkyl)silyl or
tris-(C.sub.7-C.sub.16-arylalkyl)silyl. Common ester protective
groups comprise, formate, acetate, alkyl carbonate, aryl carbonate,
aryl carbamate alkylsulfonate, arylsulfonate, triflate, phosphonate
or phoshinates. Exemplary hydroxy protecting groups include
methoxymethyl, 1-ethoxyethyl, benzyloxymethyl,
(.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl,
2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl,
trialkylsilyl, trichloromethoxycarbonyl and
2,2,2-trichloroethoxymethyl.
[0082] Introduction of a protective group such as benzyl, trityl or
silyl to the C(3)-hydroxy group is achieved by C(3)-O-benzylation,
C(3)-O-tritylation or C(3)-O-silylation of the morphinan compounds
using benzyl halogenides, trityl halogenides, or trialkyl halogen
silanes. Such derivatization is effected in a solvent such as
toluene, chloroform, chloromethane, chlorobenzene, acetone,
dimethyl formamide, or combinations thereof, and in the presence of
a base comprising sodium bicarbonate, potassium carbonate,
triethylamine, sodium hydroxide, potassium bicarbonate, or
pyridine. Alternately, ester protective groups may be introduced in
the form of the corresponding acyl halide or anhydride in aqueous
media or in dimethyl formamide in the presence of a base such as
sodium bicarbonate, sodium hydroxide, potassium carbonate,
potassium bicarbonate, pyridine or triethylamine. Further still,
the hydroxy protection reaction may be carried out in
aqueous-organic solvent mixtures being combinations of the above
listed solvents in the presence of a base listed above. In one
particular embodiment, the protective group is an acyl moiety, such
as an acetyl group, introduced by treatment of the C(3)-hydroxy
morphinan with an acyl protecting group precursor. Following the
hydroxy protection step and the optional washing/filtration/solvent
exchange steps discussed below, the protected morphinan is then
quaternized (see Scheme 1).
[0083] The C(3)-hydroxy morphinan may be in the free base or salt
form; typically, however, the C(3)-hydroxy morphinan is in the free
base form. In either case, the morphinan is preferably combined
with water and a base (e.g., sodium hydroxide) to assist in the
formation of a substantially homogeneous reaction mixture (e.g., to
solubilize the compound). Typically, the C(3)-hydroxy morphinan
starting material is combined with the water in the reaction vessel
prior to the addition of the base. Alternatively, however, the
water and the base may be combined and thereafter added to the
reaction vessel containing the C(3)-hydroxy morphinan starting
material. It will be understood that where C(3)-hydroxy morphinan
salt forms are employed, the amount of water and base to solubilize
the morphinan may vary. For instance, where the C(3)-hydroxy
morphinan salt is the hydrochloric acid salt two or more
equivalents of the base may be necessary to completely solubilize
the compound.
[0084] After solubilization, the solubilized compound is combined
with a water immiscible solvent, resulting in the formation of a
biphasic solvent system; the organic layer of the biphasic mixture
includes the water immiscible solvent (and any water that combined
with the solvent in the form of an emulsion), and the aqueous layer
of the biphasic mixture includes the C(3)-hydroxy morphinan
starting material and water. Exemplary water immiscible solvents
that may be used include, but are not limited to, chlorobenzene,
chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether,
ethyl acetate, propyl acetate, tetrahydrofuran, toluene, xylene,
combinations thereof, and the like. In a particular embodiment, the
water immiscible solvent is toluene.
[0085] In order to affect C(3)-protection of the C(3) hydroxy
group, the layers of the biphasic mixture are treated with a
protecting group precursor. The protecting group precursor will
generally vary depending on the particular protecting group that is
desired for the C(3)-hydroxy position (as described above). In one
embodiment, the protecting group is an acyl protecting group; more
preferably an acetyl protecting group. According to this preferred
embodiment, for example, the protecting group precursor is
typically acetic anhydride. While the discussion herein may focus
on the use of acetic anhydride as the protecting group precursor in
a multi-stage protection protocol, it will be understood that other
protecting group precursors may be used to introduce a protecting
group to the C(3)-hydroxy position with minor modifications to
conditions that are within the ambit of one of skill in the
art.
[0086] In a typical C(3)-hydroxy protection reaction involving the
introduction of an acetyl group at the C(3)-hydroxy position, for
example, the treatment of the biphasic mixture with acetic
anhydride causes the C(3)-protected hydroxy derivative of the
C(3)-hydroxy morphinan starting material to precipitate out of the
aqueous phase and dissolve into the organic phase of the biphasic
mixture. Thereafter, the organic layer includes the C(3)-protected
hydroxy derivative (the predominant, but not exclusive, morphinan
species in the solvent layer), the water immiscible solvent, and
typically a small quantity of the unreacted C(3)-hydroxy morphinan
starting material, and the aqueous layer includes any unreacted or
excess protecting group precursors a majority of the unreacted
C(3)-hydroxy morphinan starting material, and water.
[0087] In the initial (i.e., first) protection reaction, an excess
of the protecting group precursor (e.g., acetic anhydride) is
generally preferred. In the second, third, and further protection
reactions, lesser amounts of protecting group precursor may be
employed, as smaller quantities of C(3)-hydroxy morphinan typically
remain. As a result of excess acetic anhydride in an initial
protection reaction, the pH of the biphasic reaction mixture tends
to decrease as a result of the formation of acetic acid which may
hydrolyze the C(3)-protected hydroxy derivative and/or extract the
protected derivative from the organic layer into the aqueous layer.
Thus, after treatment with the protecting group precursor, the pH
of the reaction product mixture may be optionally adjusted to a
more basic pH; for example, to a pH of about 9.5 to about 10.5,
more preferably 10.0, with a base such as sodium hydroxide or
potassium hydroxide. In general, adjusting the pH of the protection
reaction mixture can improve downstream yields of the desired
products. Thus, in certain embodiments, the pH of the protection
reaction mixture is preferably adjusted (i.e., to a more basic pH)
after the protection reaction and prior to the next process
step.
[0088] The pH adjustment step, if performed, may cause an
undesirable hydrolysis (i.e., removal) of the C(3)-hydroxy
protecting group. Additionally or alternatively, unreacted (i.e.,
unprotected) C(3)-hydroxy tertiary N-unsubstituted morphinan
alkaloid may still be present in the reaction mixture. Thus, as
noted above, it may be desirable to perform a second C(3)-hydroxy
protection reaction, a third C(3)-hydroxy protection reaction, or
more. For example, the protection reaction may be carried out once,
twice, three times, or more, in order to protect the C(3)-hydroxy
group of any unreacted or hydrolyzed C(3)-hydroxy tertiary
N-unsubstituted morphinan alkaloid that remains after the initial
(or subsequent) protection reactions and/or pH adjustment steps. In
one embodiment, the C(3)-hydroxy protection reaction is repeated at
least once. In another embodiment, the C(3)-hydroxy protection
reaction is repeated twice; according to this embodiment, for
example, the C(3)-O-protected tertiary morphinan alkaloid substrate
is formed after a first protection reaction, and additional
quantities of the C(3)-O-protected tertiary morphinan alkaloid
substrate are formed after a second and third protection
reaction.
[0089] Each successive protection reaction may be carried out in
substantially the same manner as the previous protection reaction,
and may or may not be followed by a pH adjustment step as described
above. Additionally or alternatively, minor modifications in the
protection reaction may be made. For instance, in one embodiment,
the first protection reaction generally involves treating the
reaction mixture containing C(3)-hydroxy tertiary N-unsubstituted
morphinan alkaloid with a protecting group precursor (e.g., acetic
anhydride or other precursor capable of protecting the C(3)-hydroxy
group with a acyl or acetyl moiety), and subsequently adjusting the
pH of the reaction mixture to about 9.5 to about 10.5. While
additional protection reactions may be carried out in a similar
manner, smaller quantities of the protecting group precursor are
generally employed in the subsequent (i.e., second and third)
protection reactions since lesser quantities of unprotected
C(3)-hydroxy morphinan alkaloid are generally present.
[0090] Where at least two protection reactions are performed, the
resulting C(3)-protected product mixture may be optionally filtered
to remove any sediment or other insoluble components or byproducts
from the mixture. In general, conventional filtration techniques
may be employed (e.g., macro- or micro-filtration). In the
embodiments in which three protection reactions, or more, are
employed, the filtration step is preferably carried out after the
second protection reaction.
[0091] After the first one or two protection steps have been
performed and the resulting mixture is optionally filtered, the
biphasic reaction product mixture may be subjected to an
aqueous/organic extraction to remove by-products and other
impurities. In general, conventional aqueous/organic extraction
techniques may be utilized. In a particular embodiment, additional
water immiscible solvent (e.g., toluene) is added to the biphasic
mixture containing the C(3)-protected hydroxy derivative in the
organic layer. Regardless of whether additional solvent is added to
the biphasic mixture, the organic layer containing the desired
C(3)-protected hydroxy derivative is extracted and separated from
the aqueous layer containing the by-products and impurities, and
the aqueous layer is discarded. The aqueous/organic extraction may
be repeated as desired, and the organic layers collected and
combined.
[0092] In order to remove unreacted, excess, or residual protecting
group precursor and/or undesirable salts of the morphinan alkaloid
(e.g., formed by reaction with the protecting group precursor) from
the reaction mixture prior to solvent exchange and quaternization
(described in detail herein), the combined organic layer fractions
are preferably washed with a buffer solution. Typically, the
separated organic mixture including the C(3)-protected hydroxy
derivative is buffered to a pH of about 8.5 to about 9.5 with the
buffer solution. In a particular embodiment, the pH of the organic
layer is buffered after the protection reaction(s) to a pH of about
9.0. In general, a variety of pH buffers may be employed, provided
the buffer solution(s) is/are capable of buffering the reaction
product mixture to a pH within the desired pH range and/or the
buffer solutions do not otherwise affect the morphinan alkaloid
backbone and the substituents thereon. Suitable buffer solutions
include, for example, those comprising a borate buffer (e.g.,
tetraborate), a carbonate buffer, a phosphate buffer, a tertiary
amine buffer (e.g., triethanolamine and
tris(hydroxymethyl)aminomethane), and combinations thereof. In a
particular embodiment, the buffer solution comprises a phosphate
buffer. In another particular embodiment, the buffer solution is a
phosphate buffer. In order to remove a substantial portion of the
protecting group precursor, reaction times for the buffer wash can
range anywhere from several minutes to several hours depending on
the particular reagents utilized. Typically, the organic phase
containing the C(3)-protected hydroxy derivative is treated with
the buffer solution for about 30 minutes to about 90 minutes;
preferably about 60 minutes.
[0093] Because the C(3)-O-protecting group may be undesirably
removed (i.e., deprotected) in the presence of water, relatively
anhydrous conditions are generally preferable for both the
protection reaction(s) and the subsequent quaternization. Thus, the
organic layer is preferably subjected to drying step to reduce the
water content of the organic layer. A variety of drying techniques
may be employed in this stage including, for example, distillation,
molecular sieves, anhydrous salts, and Dean-Stark traps, for
example, are generally effective, among other conventional drying
methods. Where a water scavenger is employed, for example, a
variety of water scavengers may be utilized, provided that the
presence of the water scavenger does not adversely affect the
quaternization reaction or the morphinan alkaloid backbone and the
substituents thereon (e.g., by deprotection of the C(3)-hydroxy
group). Suitable water scavengers include, but are not limited to,
compounds corresponding to the formula: R.sub.YC(OR.sub.Z).sub.3,
wherein R.sub.Y is hydrogen or hydrocarbyl and R.sub.Z is
hydrocarbyl. Preferably, R.sub.Y is hydrogen or alkyl and R.sub.Z
is alkyl; in this embodiment, for example, the water scavenger may
correspond to trimethoxymethane, trimethoxyethane,
trimethoxypropane, trimethoxybutane, trimethoxypentane,
triethyoxyethane, triethoxypropane, combinations thereof and the
like. Alternatively, the water scavenger may be a desiccant such as
anhydrous inorganic salts that can form hydrates, e.g., magnesium
sulfate (MgSO.sub.4) or sodium sulfate (Na.sub.2SO.sub.4).
Desiccants, however, are generally less preferred due to their
tendency to form a suspension in the reaction mixture.
[0094] In one embodiment, the water content of the organic layer is
reduced by distillation to remove any water present in the organic
layer (e.g., through formation of an emulsion with the water
immiscible solvent). According to this technique, the water removal
can be observed, and once a substantial portion is withdrawn from
the system the resulting dewatered organic layer is preferably
further treated with additional protecting group precursor (e.g.,
acetic anhydride) to provide more complete conversion of the
C(3)-hydroxy morphinan to the C(3)-protected derivative. As noted
above with additional protection reactions, this further protection
reaction may require less acetic an hydride (or other protecting
group precursor) as compared to the first or second protection
reaction, since there will typically be less unprotected
C(3)-hydroxy morphinan present in the organic layer.
[0095] After the C(3)-hydroxy protection steps and optional washing
and filtration steps discussed above, the C(3)-O-protected
morphinan may be quaternized. Typically, methyl bromide is the
preferred agent for methylating C(3)-OH-protected tertiary
morphinan alkaloids and the quaternization is carried out in NMP as
previously described. It has been discovered, however, that
dimethyl sulfate can also be employed as the methylating agent for
the C(3)-hydroxy protected substrate with high yields of the
quaternized product. The alkylation using dimethyl sulfate is
preferably carried out in toluene in the presence of sodium
carbonate, however, other bases (NaHCO.sub.3, K.sub.2HPO.sub.4,
i-Pr.sub.2Net, 2,6-lutidine, and
1,8-bis(dimethylamino)naphthalene), also afford the desired
product, albeit typically in lower yields.
[0096] In one embodiment, the hydroxy protecting group is the
acetate group when the alkaloid substrate is naltrexone and a
typical sequence of reactions is shown in Scheme 2 below, wherein
R.sup.2 and X are as defined in connection with Formulae 1 and
1A.
##STR00010##
[0097] In this embodiment, the C(3)-OH protection is effected in a
basic medium comprising i-Pr.sub.2NEt, 2,6-Lutidine, or aqueous
solutions of NaOH, NaHCO.sub.3, Na.sub.2CO.sub.3, or
K.sub.2HPO.sub.4. Further, in this embodiment, the alkylating agent
(i.e., R.sub.2X) comprises a methyl, ethyl, propyl, allyl,
cyclopropyl, propargyl or benzyl salt of an anion such as a halide,
sulfate, sulfonate, fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethane-sulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate. Representative examples
include methyl bromide, dimethyl sulfate, diethyl sulfate, methyl
fluorosulfonate, trimethyloxonium fluoroborate, triethyloxonium
fluoroborate, trimethyloxonium hexachloroantimonate, n-propyl or
n-octyl trifluoromethane sulfonate, trimethyloxonium
hexafluorophosphate, methyl trifluoromethane sulfonate, and allyl
trifluoromethanesulfonate. Typically, the alkylating agent is an
alkyl halide or sulfate. Preferably, the alkylating agent is MeBr.
Alternatively, oxymorphone may be substituted for naltrexone and a
cyclopropylmethyl alkylating agent may be substituted for the
methylating agent in Reaction Scheme 2 to yield
S-methylnaltrexone.
[0098] The quaternization of the C(3)-OH-protected alkaloid
morphinan substrate is typically carried out at a low pressure
(.ltoreq.2 atm) in the temperature range of from about 60 to about
105.degree. C. Preferably, the reaction is carried out within a
temperature range of about 60 to 85.degree. C. Typically, the
reaction lasts for a duration of about 6 h-24 h; preferably the
duration is for about 16 h-22 h. In a preferred embodiment,
N-alkylation of the C(3)-OH-protected alkaloid morphinan substrate
is carried out with MeBr in NMP; at about 60-85.degree. C.; for a
duration of between 16 h-22 h. Typically, modest pressure
differentials of about 4 psi are realized upon addition of MeBr.
Upon completion of the quaternization reaction, the naltrexone
methobromide is generated by acid hydrolysis to remove the
C(3)-O-protecting group and precipitation from alcohol.
[0099] In order to provide the C(3)-O-protected morphinan in the
desired solvent for the quaternization (e.g., NMP), certain
embodiments employ solvent exchange techniques on the reaction
product mixture resulting from the single or multiple protection
reaction(s) (i.e., the organic phase containing the C(3)-protected
hydroxy derivative). Generally, in the solvent exchange, the first
solvent preferred in the protection reactions (e.g., the water
immiscible solvent) is removed and replaced with a second solvent
preferred in the quaternization reaction (e.g., NMP). Thus, the
solvent exchange is accomplished by concentrating the protection
reaction mixture, thus forming a concentrate including the
C(3)-protected hydroxy derivative, and adding the second solvent
preferred for the quaternization reaction to the concentrate. In a
preferred embodiment, the concentrate is formed by distilling the
organic phase to remove all, substantially all, or part of the
organic solvent, leaving a concentrate or oil including the
C(3)-protected hydroxy derivative. To affect the solvent exchange
by distillation, for example, the organic phase may be heated to
the boiling point of the protection reaction solvent (i.e., the
water immiscible solvent) to distill (either atmospheric or reduced
pressure) such solvent from the reaction product. Similarly, if the
water immiscible solvent for the protection reaction forms an
azeotrope with water, then part or all of the organic solvent with
water may be removed by distillation of the azeotrope. Other
methods of concentrating the organic layer, however, may be
employed and will be apparent to one of skill in the art.
[0100] After concentration of the C(3)-protected hydroxy derivative
and removal of the water immiscible solvent and other undesirable
substances in the reaction mixture (e.g., water, excess or
unreacted protecting group precursor, by-products, etc.) is
accomplished (e.g., by distillation), the C(3)-O-protected
morphinan generally remains in the form of concentrate. Where all
or substantially all of the organic solvent has been removed, the
concentrate may be in the form an oil including the
C(3)-O-protected morphinan. In the instances where the preferred
alkylating agent cannot be effectively added to the concentrate in
a manner that will result in quaternization, the concentrate may be
dissolved in the preferred solvent for the quaternization reaction
(i.e., dissolution of the concentrate or oil in the solvent).
Suitable solvents for the quaternization reaction are described
elsewhere herein, and include NMP and dimethyl sulfate. Preferably,
the dissolution solvent is an anhydrous solvent system as described
above. In a particular embodiment, additional protecting group
precursor may be added to the concentrate in addition to the second
(quaternization) solvent in an effort to further provide
C(3)-O-protected morphinan substrate material (i.e., in a second,
third, etc., protection reaction).
[0101] In an embodiment, hydrolysis of the C(3)-O-protected
quaternized product is effected in aqueous HBr. Approximately 0.5
to about 1.5 equivalents of HBr is typically employed (based on
C(3)-acetoxy naltrexone); preferably the ratio of HBr to
C(3)-acetoxy naltrexone is about 1:1. The acidic mixture is stirred
at about 60-65.degree. C. for approximately 30-60 minutes for
removal of residual MeBr, then heated to about 75-85.degree. C.,
and stirred until hydrolysis of C(3)-acetoxy naltrexone
methobromide is complete as monitored by periodic HPLC analysis of
samples. Typically, the hydrolysis is complete within 5 hours.
[0102] Upon removal of the C(3)-hydroxy group by way of hydrolysis
as described above, any residual or unreacted alkylating agent
present in the reaction mixture may result in undesirable
C(3)-O-alkylation of the C(3)-hydroxy group. For instance, methyl
bromide alkylating agent can cause the undesirable formation of a
C(3)-O-methyl morphinan quaternary product. Thus, it is generally
preferable to quench the quaternization reaction and purge the
alkylating agent from the system. This can be accomplished, for
example, by introducing a purge agent into the reaction
mixture/vessel following quaternization and prior to hydrolysis. A
variety of quench/purge agents may be employed, and the choice of a
particular purge agent may depend on the particular alkylating
agent selected and/or the various other process conditions. For
instance, where methyl bromide is used as the alkylating agent, the
purge agent preferably comprises a bromide-containing agent to
assist in the removal (purge) of the methyl bromide from the
system.
[0103] In a particular embodiment in which methyl bromide is
employed in the quaternization reaction, the purge agent introduced
to the system after quaternization is hydrogen bromide or a salt
thereof (e.g., a trialkylammonium hydrobromide such as
triethylammonium hydrobromide). The bromide-containing purge agent
is generally introduced in the presence of a solvent. The solvent
for the purge agent is generally one which is compatible with
hydrogen bromide (or salts thereof) and which will not adversely
affect the quaternary morphinan. Suitable solvents include various
carboxylic acids such as acetic acid; aprotic, non-nucleophilic
solvents (e.g., NMP); esters (such as, for example, methyl acetate,
ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,
isobutyl acetate, and ethyl formate); and combinations thereof. The
concentration of bromide in the purge agent is not narrowly
critical; generally only a catalytic amount of bromide is necessary
to affect the desired removal of methyl bromide from the reaction
vessel. Thus, the concentration of hydrogen bromide (or salt
thereof) in the solvent can vary from less than 1% (w/w) to nearly
100% (w/w); in a preferred embodiment, the purge agent comprises
33% hydrogen bromide or salt thereof in acetic acid.
[0104] The product of the acid hydrolysis of the quaternized
C(3)-hydroxy-protected alkaloid morphinan is precipitated by
addition of alcohol to the cooled acidic solution under a nitrogen
atmosphere. In the embodiment described above, the mixture is
cooled to about 50-55.degree. C. and an optimal amount of methanol
(1.0 wt. equiv based on the initial NMP) is added for precipitation
of naltrexone methobromide. Finally, the mixture is cooled to room
temperature and then stirred for about 1 hour at approximately
0-5.degree. C. for complete precipitation of the product (monitored
by HPLC analysis). The product is then filtered, washed with cold
methanol (about 1-2 mL/g C(3)-acetoxy naltrexone), and isolated as
a wet cake. The product is optimally recrystallized utilizing
optimized conditions (about 1.5-2.0 mL water/g naltrexone
methobromide, about 3.0-4.0 mL methanol/g naltrexone methobromide,
and about 12-24 mole % HBr based on naltrexone methobromide) to
afford purified naltrexone methobromide in high yields and
purity.
[0105] The protection, quaternization, purge, and hydrolysis steps
may be carried out in the order as described, and/or various
extraction/separation and wash steps may be interdispersed between
these various stages as described above.
[0106] In one embodiment, the process of the invention comprises
(a) a first protection step, (b) a solvent extraction/separation
step, (c) a drying step, (d) a second protection step, (e) a
concentration step, (f) a dissolving step, (g) a quaternization
step, and (h) a deprotection step, whereby each of steps (a)-(h)
are substantially as described above. In another embodiment, the
process of the invention comprises (a) a first protection step, (b)
a solvent extraction/separation step, (c) a second protection step,
(d) a concentration step, (e) a dissolving step, (f) a
quaternization step, and (g) a deprotection step, whereby each of
steps (a)-(g) are substantially as described above. In another
embodiment, the process of the invention comprises (a) a first
protection step, (b) a pH adjustment step, (c) a solvent
extraction/separation step, (d) a drying step, (e) a second
protection step, (f) a concentration step, (g) a dissolving step,
(h) a quaternization step, and (i) a deprotection step, whereby
each of steps (a)-(i) are substantially as described above.
According to each of these embodiments, for example, the process
may further comprise one or more of the following steps: (1)
repeating the protection step and the pH adjustment step (if
present); (2) a purge step prior to the deprotecting step; and (3)
a buffer wash step prior to the drying step. In another embodiment,
the process of the invention comprises (a) a first protection step,
(b) a second protection step, (c) a filtration step, (d) an solvent
extraction/separation step, (e) a buffer wash step, (f) a water
reduction step; (g) a third protection step, (h) a concentration
step, (i) a quaternization step, (j) a purge step, and (k) a
hydrolysis step, whereby each of steps (a)-(k) are substantially as
described above.
[0107] The sequence of steps for the preparation of naltrexone
methobromide in accordance with certain of the preferred
embodiments of the process of the present invention are described
above. Advantageously, these steps lead to the conversion of
naltrexone base to naltrexone methobromide in high yield, with high
stereoselectivity for the R-isomer (relative to the nitrogen atom)
over the S-isomer (relative to the nitrogen atom) of naltrexone
methobromide and relatively low levels of the C(3)-O-methyl
derivatives of naltrexone methobromide (in either of its R- or
S-isomeric forms (i.e., R-MNTX and S-MNTX, respectively)), with
R-MNTX and S-MNTX corresponding to the following structures:
##STR00011##
and the C(3)-O-methyl derivatives of R-MNTX and S-MNTX
corresponding to the above structures with the phenolic
C(3)-hydroxy group being replaced with a C(3)-O-methyl group. For
example, the reaction product mixture will typically contain at
least 70% (w/w) of R-naltrexone methobromide, at least 1% (w/w) of
S-naltrexone methobromide, at least 1% (w/w) naltrexone, but no
more than 0.2% (w/w) of C(3)-O-methyl derivative of naltrexone
methobromide (in each of its isomeric forms), based upon the
combined weight of the R-naltrexone methobromide, S-naltrexone
methobromide, C(3)-O-methyl derivative of naltrexone methobromide,
and naltrexone in the reaction product mixture (i.e., in the
composition). More typically, the reaction product mixture
typically includes from 2% to 5% (w/w) naltrexone, more typically
2% to 4% (w/w) naltrexone, based upon the combined weight of the
R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methyl
derivative of naltrexone methobromide, and naltrexone in the
reaction product mixture (i.e., in the composition). The reaction
product mixture also typically includes from 5% to 10% (w/w) of
S-naltrexone methobromide, more typically 6% to 7% (w/w), based
upon the combined weight of the R-naltrexone methobromide,
S-naltrexone methobromide, C(3)-O-methyl derivative of naltrexone
methobromide, and naltrexone in the reaction product mixture. In a
preferred embodiment, the reaction product mixture contains less
than 0.15% (w/w) C(3)-O-methyl derivative of naltrexone
methobromide (in each of its isomeric forms), more preferably less
than 0.1% (w/w) C(3)-O-methyl derivative of naltrexone methobromide
(in each of its isomeric forms), and still more preferably about
0.05% to 0.10% (w/w) C(3)-O-methyl derivative of naltrexone
methobromide (in each of its isomeric forms), based upon the
combined weight of the R-naltrexone methobromide, S-naltrexone
methobromide, C(3)-O-methyl derivative of naltrexone methobromide,
and naltrexone in the reaction product mixture (i.e., in the
composition). The reaction product mixture preferably comprises at
least 75% (w/w) R-naltrexone methobromide, more preferably at least
80% (w/w) R-naltrexone methobromide, and still more preferably at
least 85% R-naltrexone methobromide, based upon the combined weight
of the R-naltrexone methobromide, S-naltrexone methobromide,
C(3)-O-methyl derivative of naltrexone methobromide, and naltrexone
in the reaction product mixture (i.e., in the composition). Stated
differently, in certain embodiments the weight ratio of the
R-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the reaction product mixture is at
least 150:1. More preferably in these embodiments, the weight ratio
of the R-isomer of naltrexone methobromide to the C(3)-O-methyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 250:1 (R-isomer:C(3)-O-methyl). Thus, for
example, the weight ratio of the R-isomer of naltrexone
methobromide to the C(3)-O-methyl derivative of naltrexone
methobromide in the reaction product mixture may be at least 500:1,
or at least 750:1, or at least 1,000:1 (R-isomer:C(3)-O-methyl).
Similarly, the weight ratio of the S-isomer of naltrexone
methobromide to the C(3)-O-methyl derivative of naltrexone
methobromide in the reaction product mixture is typically at least
5:1 (S-isomer:C(3)-O-methyl). More typically, the weight ratio of
S-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the reaction product mixture is at
least 10:1 (S-isomer:C(3)-O-methyl). Still more typically, the
weight ratio of S-isomer of naltrexone methobromide to the
C(3)-O-methyl derivative of naltrexone methobromide in the reaction
product mixture is at least 50:1 (S-isomer:C(3)-O-methyl). Finally,
the weight ratio of naltrexone to C(3)-O-methyl derivative of
naltrexone methobromide in the reaction product mixture is
typically at least 5:1 (naltrexone:C(3)-O-methyl). More typically,
the weight ratio of naltrexone to the C(3)-O-methyl derivative of
naltrexone methobromide in the reaction product mixture is at least
10:1 (naltrexone:C(3)-O-methyl). Still more typically, the weight
ratio of naltrexone to the C(3)-O-methyl derivative of naltrexone
methobromide in the reaction product mixture is at least 50:1
(naltrexone:C(3)-O-methyl). In combination, in one embodiment the
weight ratio of R-isomer of naltrexone methobromide to the
C(3)-O-methyl derivative of naltrexone methobromide in the reaction
product mixture is at least 150:1 (R-isomer:C(3)-O-methyl), the
weight ratio of S-isomer of naltrexone methobromide to the
C(3)-O-methyl derivative of naltrexone methobromide in the reaction
product mixture is at least 5:1 (S-isomer:C(3)-O-methyl), and the
weight ratio of naltrexone to C(3)-O-methyl derivative of
naltrexone methobromide in the reaction product mixture is at least
5:1 (naltrexone:C(3)-O-methyl). More typically, the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the reaction product mixture is at
least 250:1 (R-isomer:C(3)-O-methyl), the weight ratio of S-isomer
of naltrexone methobromide to the C(3)-O-methyl derivative of
naltrexone methobromide in the reaction product mixture is at least
10:1 (S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone
to C(3)-O-methyl derivative of naltrexone methobromide in the
reaction product mixture is at least 5:1
(naltrexone:C(3)-O-methyl). Still more typically, the weight ratio
of R-isomer of naltrexone methobromide to the C(3)-O-methyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 500:1 (R-isomer:C(3)-O-methyl), the weight
ratio of S-isomer of naltrexone methobromide to the C(3)-O-methyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 50:1 (S-isomer:C(3)-O-methyl), and the weight
ratio of naltrexone to C(3)-O-methyl derivative of naltrexone
methobromide in the reaction product mixture is at least 5:1
(naltrexone:C(3)-O-methyl).
[0108] The final reaction product mixture is generally in the form
of a solution or a slurry (which may include precipitated material)
containing the above-described species. Because the reaction
product mixture (e.g., the slurry or the solution) contains such
low levels of C(3)-O-methyl derivative of naltrexone methobromide,
purification steps are simplified. Thus, a crystallization product
obtained from the reaction product mixture will contain relatively
low levels of the C(3)-O-methyl derivative of naltrexone
methobromide relative to R-naltrexone methobromide, S-naltrexone
methobromide, and naltrexone. For example, the crystallization
product will contain no more than 0.25% (w/w) of C(3)-O-methyl
derivative of naltrexone methobromide (in each of its isomeric
forms), based upon the combined weight of the R-naltrexone
methobromide, S-naltrexone methobromide, C(3)-O-methyl derivative
of naltrexone methobromide, and naltrexone in the crystallization
product (i.e., in the composition). More typically, the
crystallization product typically includes from 0.25% to 1% (w/w)
naltrexone, more typically 0.5% to 0.75% (w/w) naltrexone, based
upon the combined weight of the R-naltrexone methobromide,
S-naltrexone methobromide, C(3)-O-methyl derivative of naltrexone
methobromide, and naltrexone in the crystallization product (i.e.,
in the composition). The crystallization product also typically
includes from 1% to 2% (w/w) of S-isomer of naltrexone
methobromide, more typically 1% to 1.5% (w/w), based upon the
combined weight of the R-naltrexone methobromide, S-naltrexone
methobromide, C(3)-O-methyl derivative of naltrexone methobromide,
and naltrexone in the crystallization product. In a preferred
embodiment, the crystallization product contains less than 0.15%
(w/w) C(3)-O-methyl derivative of naltrexone methobromide (in each
of its isomeric forms), more preferably less than 0.1% (w/w)
C(3)-O-methyl derivative of naltrexone methobromide (in each of its
isomeric forms), and still more preferably about 0.05% to 0.10%
(w/w) C(3)-O-methyl derivative of naltrexone methobromide (in each
of its isomeric forms), based upon the combined weight of the
R-naltrexone methobromide, S-naltrexone methobromide, C(3)-O-methyl
derivative of naltrexone methobromide, and naltrexone in the
crystallization product (i.e., in the composition). Stated
differently, in certain embodiments the weight ratio of the
R-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the crystallization product is at
least 150:1 (R-isomer:C(3)-O-methyl). More preferably in these
embodiments, the weight ratio of the R-isomer of naltrexone
methobromide to the C(3)-O-methyl derivative of naltrexone
methobromide in the crystallization product is at least 250:1
(R-isomer:C(3)-O-methyl). Thus, for example, the weight ratio of
the R-isomer of naltrexone methobromide to the C(3)-O-methyl
derivative of naltrexone methobromide in the crystallization
product may be at least 500:1, or at least 750:1, or at least
1,000:1 (R-isomer:C(3)-O-methyl). Similarly, the weight ratio of
the S-isomer of naltrexone methobromide to the C(3)-O-methyl
derivative of naltrexone methobromide in the crystallization
product is typically at least 2:1 (S-isomer:C(3)-O-methyl). More
typically, the weight ratio of S-isomer of naltrexone methobromide
to the C(3)-O-methyl derivative of naltrexone methobromide in the
crystallization product is at least 5:1 (S-isomer:C(3)-O-methyl).
Still more typically, the weight ratio of S-isomer of naltrexone
methobromide to the C(3)-O-methyl derivative of naltrexone
methobromide in the crystallization product is at least 10:1
(S-isomer:C(3)-O-methyl). Still more typically, the weight ratio of
S-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the crystallization product is at
least 15:1 (S-isomer:C(3)-O-methyl). Finally, the weight ratio of
naltrexone to C(3)-O-methyl derivative of naltrexone methobromide
in the crystallization product is typically at least 2:1
(naltrexone:C(3)-O-methyl). More typically, the weight ratio of
naltrexone to the C(3)-O-methyl derivative of naltrexone
methobromide in the crystallization product is at least 5:1
(naltrexone:C(3)-O-methyl). Still more typically, the weight ratio
of naltrexone to the C(3)-O-methyl derivative of naltrexone
methobromide in the crystallization product is at least 10:1
(naltrexone:C(3)-O-methyl). In combination, in one embodiment the
weight ratio of R-isomer of naltrexone methobromide to the
C(3)-O-methyl derivative of naltrexone methobromide in the
crystallization product is at least 150:1 (R-isomer:C(3)-O-methyl),
the weight ratio of S-isomer of naltrexone methobromide to the
C(3)-O-methyl derivative of naltrexone methobromide in the
crystallization product is at least 2:1 (S-isomer:C(3)-O-methyl),
and the weight ratio of naltrexone to C(3)-O-methyl derivative of
naltrexone methobromide in the crystallization product is at least
2:1 (naltrexone:C(3)-O-methyl). More typically, the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-methyl derivative
of naltrexone methobromide in the crystallization product is at
least 250:1 (R-isomer:C(3)-O-methyl), the weight ratio of S-isomer
of naltrexone methobromide to the C(3)-O-methyl derivative of
naltrexone methobromide in the crystallization product is at least
5:1 (S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone to
C(3)-O-methyl derivative of naltrexone methobromide in the
crystallization product is at least 2:1 (naltrexone:C(3)-O-methyl).
Still more typically, the weight ratio of R-isomer of naltrexone
methobromide to the C(3)-O-methyl derivative of naltrexone
methobromide in the crystallization product is at least 500:1
(R-isomer:C(3)-O-methyl), the weight ratio of S-isomer of
naltrexone methobromide to the C(3)-O-methyl derivative of
naltrexone methobromide in the crystallization product is at least
10:1 (S-isomer:C(3)-O-methyl), and the weight ratio of naltrexone
to C(3)-O-methyl derivative of naltrexone methobromide in the
crystallization product is at least 2:1
(naltrexone:C(3)-O-methyl).
[0109] Similarly, the process of the present invention may be used
when the desired product is S-naltrexone methobromide. In this
embodiment, however, oxymorphone is used instead of naltrexone as
the substrate and the nitrogen atom of the substrate is alkylated
with a cyclopropylmethyl alkylating agent such as
cyclopropylmethylbromide. To minimize the formation of the
corresponding C(3)-O-cyclopropylmethyl-S-naltrexone methobromide,
the C(3)-hydroxy group of oxymorphone may be protected with a
hydroxy protecting group during the cyclopropylmethylation reaction
as otherwise described herein for the N-methylation of naltrexone
and N-alkylation of other morphinan alkaloid substrates
corresponding to Formula 1, 2, 3, 4, 11, 22, 222, etc. For example,
the C(3)-hydroxy group of oxymorphone may be protected with an
acetyl group as otherwise described in connection with the
protection of the C(3)-hydroxy group of naltrexone in the synthesis
of R-naltrexone methobromide and the C(3)-hydroxy protected
oxymorphone substrate is N-alkylated using a cyclopropylmethyl
alkylating agent as otherwise described in connection with the
N-methylation of naltrexone in the synthesis of R-naltrexone
methobromide. Advantageously, these steps lead to the conversion of
oxymorphone base to naltrexone methobromide in high yield, with
high stereoselectivity for the S-isomer (relative to the nitrogen
atom) over the R-isomer (relative to the nitrogen atom) of
naltrexone methobromide and relatively low levels of the
C(3)-O-cyclopropylmethyl derivatives of naltrexone methobromide in
either of its R- or S-isomeric forms (i.e., R-MNTX and S-MNTX,
respectively). For example, the reaction product mixture will
typically contain at least 70% (w/w) of S-naltrexone methobromide,
at least 1% (w/w) of R-naltrexone methobromide, at least 1% (w/w)
oxymorphone, but no more than 0.25% (w/w) of
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in
each of its isomeric forms), 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 reaction product mixture (i.e., in the
composition). More typically, the reaction product mixture
typically includes from 2% to 5% (w/w) oxymorphone, more typically
2% to 4% (w/w) oxymorphone, 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 reaction product mixture (i.e., in the
composition). The reaction product mixture also typically includes
from 5% to 10% (w/w) of R-naltrexone methobromide, more typically
6% to 7% (w/w), 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
reaction product mixture. In a preferred embodiment, the reaction
product mixture contains less than 0.15% (w/w)
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in
each of its isomeric forms), more preferably less than 0.1% (w/w)
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide (in
each of its isomeric forms), and still more preferably about 0.05%
to 0.10% (w/w) C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide (in each of its isomeric forms), 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 reaction product mixture
(i.e., in the composition). The reaction product mixture preferably
comprises at least 75% (w/w) S-naltrexone methobromide, more
preferably at least 80% (w/w) S-naltrexone methobromide, and still
more preferably at least 85% S-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 reaction product mixture
(i.e., in the composition). Stated differently, in certain
embodiments the weight ratio of the S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the reaction product mixture is at least
150:1. More preferably in these embodiments, the weight ratio of
the S-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the reaction product mixture is at least 250:1
(S-isomer:C(3)-O-cyclopropylmethyl). Thus, for example, the weight
ratio of the S-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the reaction product mixture may be at least 500:1, or at least
750:1, or at least 1,000:1 (S-isomer:C(3)-O-cyclopropylmethyl).
Similarly, the weight ratio of the R-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the reaction product mixture is
typically at least 5:1 (R-isomer:C(3)-O-cyclopropylmethyl). More
typically, the weight ratio of R-isomer of naltrexone methobromide
to the C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide in the reaction product mixture is at least 10:1
(R-isomer:C(3)-O-cyclopropylmethyl). Still more typically, the
weight ratio of R-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the reaction product mixture is at least 50:1
(R-isomer:C(3)-O-cyclopropylmethyl). Finally, the weight ratio of
oxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide in the reaction product mixture is typically at least
5:1 (oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the
weight ratio of oxymorphone to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 10:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
Still more typically, the weight ratio of oxymorphone to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the reaction product mixture is at least 50:1
(oxymorphone:C(3)-O-cyclopropylmethyl) In combination, in one
embodiment the weight ratio of S-isomer of naltrexone methobromide
to the C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide in the reaction product mixture is at least 150:1
(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer
of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 5:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 5:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
More typically, the weight ratio of S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the reaction product mixture is at least
250:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 10:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 5:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
Still more typically, the weight ratio of S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the reaction product mixture is at least
500:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 50:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the reaction product
mixture is at least 5:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
[0110] The final reaction product mixture is generally in the form
of a solution or a slurry (which may include precipitated material)
containing the above-described species. Because the reaction
product mixture (e.g., the slurry or the solution) contains such
low levels of C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide, purification steps are simplified. Thus, a
crystallization product obtained from the reaction product mixture
will contain relatively low levels of the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide relative to R-naltrexone
methobromide, S-naltrexone methobromide, and oxymorphone. For
example, the crystallization product will typically contain no more
than 0.25% (w/w) of C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide (in each of its isomeric forms), 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 crystallization product (i.e.,
in the composition). More typically, the crystallization product
typically includes from 0.25% to 1% (w/w) oxymorphone, more
typically 0.5% to 0.75% (w/w) oxymorphone, 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 crystallization product (i.e., in the
composition). The crystallization product also typically includes
from 1% to 2% (w/w) of R-isomer of naltrexone methobromide, more
typically 1% to 1.5% (w/w), 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 crystallization product. In a preferred
embodiment, the crystallization product contains less than 0.15%
(w/w) C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide (in each of its isomeric forms), more preferably less
than 0.1% (w/w) C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide (in each of its isomeric forms), and still more
preferably about 0.05% to 0.10% (w/w) C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide (in each of its isomeric
forms), 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
crystallization product (i.e., in the composition). Stated
differently, in certain embodiments the weight ratio of the
S-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 150:1 (S-isomer:C(3)-O-cyclopropylmethyl). More
preferably in these embodiments, the weight ratio of the S-isomer
of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 250:1 (S-isomer:C(3)-O-cyclopropylmethyl).
Thus, for example, the weight ratio of the S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the crystallization product may be at
least 500:1, or at least 750:1, or at least 1,000:1
(R-isomer:C(3)-O-cyclopropylmethyl). Similarly, the weight ratio of
the R-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the crystallization product is typically at least 2:1
(R-isomer:C(3)-O-cyclopropylmethyl). More typically, the weight
ratio of R-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the crystallization product is at least 5:1
(R-isomer:C(3)-O-cyclopropylmethyl). Still more typically, the
weight ratio of R-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the crystallization product is at least 10:1
(R-isomer:C(3)-O-cyclopropylmethyl). Still more typically, the
weight ratio of R-isomer of naltrexone methobromide to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the crystallization product is at least 15:1
(R-isomer:C(3)-O-cyclopropylmethyl). Finally, the weight ratio of
oxymorphone to C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide in the crystallization product is typically at least
2:1 (oxymorphone:C(3)-O-cyclopropylmethyl). More typically, the
weight ratio of oxymorphone to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 5:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
Still more typically, the weight ratio of oxymorphone to the
C(3)-O-cyclopropylmethyl derivative of naltrexone methobromide in
the crystallization product is at least 10:1
(oxymorphone:C(3)-O-cyclopropylmethyl). In combination, in one
embodiment the weight ratio of S-isomer of naltrexone methobromide
to the C(3)-O-cyclopropylmethyl derivative of naltrexone
methobromide in the crystallization product is at least 150:1
(S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of R-isomer
of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 2:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 2:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
More typically, the weight ratio of S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the crystallization product is at least
250:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 5:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 2:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
Still more typically, the weight ratio of S-isomer of naltrexone
methobromide to the C(3)-O-cyclopropylmethyl derivative of
naltrexone methobromide in the crystallization product is at least
500:1 (S-isomer:C(3)-O-cyclopropylmethyl), the weight ratio of
R-isomer of naltrexone methobromide to the C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 10:1 (R-isomer:C(3)-O-cyclopropylmethyl), and
the weight ratio of oxymorphone to C(3)-O-cyclopropylmethyl
derivative of naltrexone methobromide in the crystallization
product is at least 2:1 (oxymorphone:C(3)-O-cyclopropylmethyl).
[0111] Viewed more generally, purification of the reaction product
mixture to a crude product from the synthesis described above
yields N-alkyl product of about 98% purity; assessed by HPLC
relative to an analytical standard. The treatment of the protection
and quaternization reaction mixtures according to the various
processes and embodiments described herein results in a
significantly reduced concentration of C(3)-O-alkyl morphinan
alkaloid impurity in the compositions of the invention.
Compositions that may include the quaternized product(s) described
above include both final product mixtures (i.e., the crude final
product mixture, e.g., dissolved in a solution) and/or the final
crystallized products (i.e., a solid comprising the quaternized
product in a crystalline form). In a particular embodiment, the
composition includes the final crude product mixture. In another
particular embodiments the composition includes the final product
mixture after a first crystallization.
[0112] Another aspect of the present invention, therefore, is a
composition comprising a C(3)-hydroxy quaternary N-substituted
morphinan alkaloid corresponding to Formula 11A and no more than
0.1% (w/w) of a C(3)-alkoxy alkaloid corresponding to Formula 11C,
relative to the amount of the C(3)-hydroxy quaternary N-substituted
morphinan alkaloid corresponding to Formula 11A in the composition,
wherein the alkaloids corresponding to Formula 11A and Formula 11C
have the structures:
##STR00012##
wherein
[0113] A is --C(O)--, --C(S)--, --C(.dbd.CH.sub.2)--,
--CH(A.sub.1)- or --C(A.sub.1)=,
[0114] A.sub.1 is hydroxy, alkoxy, or acyloxy,
[0115] R.sup.1 is hydrocarbyl or substituted hydrocarbyl;
[0116] R.sup.2 is alkyl,
[0117] X.sup.1 is a halide, sulfate, sulfonate, fluoroborate,
fluorosulfonate, methylsulfate, ethylsulfate,
trifluoromethanesulfonate, hexachloroantimonate,
hexafluorophosphate, or tetrafluoroborate;
[0118] Y, if present, is hydrogen, hydroxy, protected hydroxy,
alkoxy, or acyloxy, and
[0119] 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.
[0120] As noted above, the compositions of the invention may
include the crude final product mixtures (i.e., prior to any
crystallization steps), the final product mixture after an initial
crystallization, or the final crystallized active pharmaceutical
ingredient (e.g., that this in final form). The processes of the
present invention are particularly advantageous in that the
presence of undesirable impurities and other species is
significantly reduced at the crude final product mixture stage,
prior to any crystallization. Subsequent crystallization steps may
serve to further reduce the levels of such species below their
already desirably low levels. In one embodiment, the C(3)-hydroxy
quaternary N-substituted morphinan alkaloid present in the
composition is naltrexone methobromide.
[0121] As noted above, the composition includes no more than about
0.1% of a C(3)-O-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. For example, the composition may include less than about
0.05% of a C(3)-O-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. Preferably, the composition includes no more than about
0.01% of a C(3)-Q-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. For example, the composition may include less than about
0.005% of a C(3)-O-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. More preferably, the composition includes no more than
about 0.001% of a C(3)-O-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. For example, the composition may include less than about
0.0005% of a C(3)-O-alkyl quaternary or tertiary N-substituted
morphinan alkaloid impurity, relative to the total alkaloid
content. Still more preferably, no detectable amount of a
C(3)-O-alkyl quaternary or tertiary N-substituted morphinan
alkaloid impurity is present in the composition.
DEFINITIONS
[0122] As used herein, "Ac" means acetyl, "Bn" means benzyl, "Bs"
means brosyl, "Bz" means benzoyl, "Ms" means mesyl, "THP" means
tetrahydropyranyl, and "Ts" means tosyl.
[0123] The term "anhydrous solvent" as used herein refers to
solvents containing less than 0.5% by weight water, preferably
maintained and handled under nitrogen gas during a reaction.
[0124] The terms "hydrocarbon" and "hydrocarbyl" as used herein
describe organic compounds or radicals consisting exclusively of
the elements carbon and hydrogen. These moieties include alkyl,
alkenyl, alkynyl, and aryl moieties. These moieties also include
alkyl, alkenyl, alkynyl, and aryl moieties substituted with other
aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl
and alkynaryl. Unless otherwise indicated, these moieties
preferably comprise 1 to 20 carbon atoms.
[0125] The "substituted hydrocarbyl" moieties described herein are
hydrocarbyl moieties which are substituted with at least one atom
other than carbon, including moieties in which a carbon chain atom
is substituted with a hetero atom such as nitrogen, oxygen,
silicon, phosphorous, boron, sulfur, or a halogen atom. These
substituents include halogen, heterocyclo, alkoxy, alkenoxy,
alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, tertiary
amino, amido, nitro, cyano, ketals, acetals, esters and ethers.
[0126] Unless otherwise indicated, the alkyl groups described
herein are preferably lower alkyl containing from one to eight
carbon atoms in the principal chain. They may be straight or
branched chain or cyclic and include methyl, ethyl, propyl,
isopropyl, allyl, benzyl, hexyl and the like.
[0127] Unless otherwise indicated, the alkenyl groups described
herein are preferably lower alkenyl containing from two to eight
carbon atoms in the principal chain and up to 20 carbon atoms. They
may be straight or branched chain or cyclic and include ethenyl,
propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the
like.
[0128] Unless otherwise indicated, the alkynyl groups described
herein are preferably lower alkynyl containing from two to eight
carbon atoms in the principal chain and up to 20 carbon atoms. They
may be straight or branched chain and include ethynyl, propynyl,
butynyl, isobutynyl, hexynyl, and the like.
[0129] The terms "aryl" or "ar" as used herein alone or as part of
another group denote optionally substituted homocyclic aromatic
groups, preferably monocyclic or bicyclic groups containing from 6
to 12 carbons in the ring portion, such as phenyl, biphenyl,
naphthyl, substituted phenyl, substituted biphenyl or substituted
naphthyl. Phenyl and substituted phenyl are the more preferred
aryl.
[0130] The term "acyl," as used herein alone or as part of another
group, denotes the moiety formed by removal of the hydroxyl group
from the group --COOH of an organic carboxylic acid, e.g., RC(O)--,
wherein R is R.sup.1, R.sup.1O--, R.sup.1R.sup.2N--, or R.sup.1S--,
R.sup.1 is hydrocarbyl, heterosubstituted hydrocarbyl, or
heterocyclo, and R.sup.2 is hydrogen, hydrocarbyl or substituted
hydrocarbyl.
[0131] The term "acyloxy," as used herein alone or as part of
another group, denotes an acyl group as described above bonded
through an oxygen linkage (--O--), e.g., RC(O)O-- wherein R is as
defined in connection with the term "acyl."
[0132] The terms "halogen" or "halo" as used herein alone or as
part of another group refer to chlorine, bromine, fluorine, and
iodine.
[0133] The term "halide" refers to fluoride, chloride, bromide, or
iodide ions.
[0134] The term "narcotics" as used herein refers to drugs that
depress the central nervous system and relieve pain when used in
moderate doses.
[0135] The term "opioid" as used herein refers to non-opium-derived
(synthetic or naturally occurring) narcotics that act on the
central nervous system to decrease the sensation of pain.
[0136] Having described the invention in detail, it will be
apparent that modifications and variations are possible without
departing from the scope of the invention defined in the appended
claims.
[0137] The following non-limiting examples are provided to further
illustrate the present invention.
Reagents
[0138] A dehydrated naltrexone base was used in experiments that
did not require phenolic C(3)-hydroxide protection. This base was
prepared from naltrexone hydrochloride which was dried under vacuum
until the water content was about 2% by Karl-Fischer analysis. A
hydrated naltrexone base (the dihydrate) was used in the
experiments that require protection of the phenolic hydroxide.
[0139] A bottle of hydrogen bromide (HBr) was cooled to -70.degree.
C. and 1-methyl-2-pyrrolidinone (N-methylpyrrolidone; NMP) was
cooled down to -20.degree. C. HBr (13.01 g; 160 mmol) was added
into the NMP (130 mL) and the solution was allowed to warm to room
temperature. The solution was then diluted with NMP to 160.0 mL to
form a 1N solution of HBr in NMP (HBr/NMP).
[0140] A bottle containing methyl bromide (MeBr; b.p. 4.degree. C.)
was cooled down to -10.degree. C. MeBr (50.00 mL) was poured out
and weighed (88.53 g; d=1.77 g/mL). The methyl bromide was added
into a pre-cooled bottle containing 1-Methyl-2-Pyrrolidinone (NMP)
{50.00 mL; 54.39 g, -10.degree. C.} to form approximately 100 mL
solution at -10.degree. C. (MeBr/NMP).
Comparative Example A
Synthesis of Naltrexone Methobromide
[0141] A comparative N-methylation was performed, by addition of
1.5 equiv. MeBr/NMP to a bulk suspension of 12.5 Kg anhydrous
naltrexone in NMP (1.5 volume equivalents (vol. equiv.)) following
the scaled-up version of the general procedure disclosed in Example
1 of WO 2004/043964 The yield of crude naltrexone methobromide
product was 9.43 Kg. The product yield was 60.9 mol. % in
Comparative Example A, and 12.6 mol. % of side products were
produced.
Example 1
Synthesis of Naltrexone Methobromide
Slow Addition of MeBr
[0142] 1-methyl-2-pyrrolidinone (N-methylpyrrolidinone, NMP, 150
mL) was added into a three-necked, 1000-mL flask and heated to
58.degree. C. under a nitrogen flow. Naltrexone base (100.00 g, a
solid, containing 2% water; 287 mmol) was added. The funnel was
washed with 25 mL of NMP. The mixture remained a suspension after 1
hour of heating.
[0143] A 50-mL solution of MeBr/NMP (466 mmol MeBr) was transferred
into a pre-cooled dropping funnel (-10.degree. C.) equipped with a
cooling system to maintain the MeBr at a temperature between
-10.degree. C. and 0.degree. C. Nitrogen was passed over the top of
the condenser. The MeBr/NMP solution was added drop-wise from the
funnel into the naltrexone/NMP suspension over 30 minutes and the
temperature increased over this time period up to 58.degree. C. The
resulting mixture was heated at about 55-58.degree. C. for 20
minutes to form a solution and the heating was continued at about
65.degree. C. with stirring under nitrogen for 12 hours. Solids
started to form after 2 hours at 65.degree. C. The reaction mixture
was cooled to room temperature to yield a thick suspension, 250 mL
of acetone was added, and the mixture was stirred for 1 hour and
filtered. The solid was washed with two 25-mL aliquots of acetone
and dried under vacuum at 55.degree. C. to give 92.26 g of a crude
product as a white solid. The combined filtrate and washes were
collected (452 g of liquid) for recovery of unreacted
naltrexone.
Example 2
Synthesis of Naltrexone Methobromide
Slow Addition of MeBr
[0144] 1-methyl-2-pyrrolidinone (NMP, 50 mL) was added to a
three-necked, 250-mL flask which was heated to 54.degree. C. and
blanketed under nitrogen. 40 g of naltrexone base, containing 2%
water was added and the funnel was washed with 10 mL of NMP. The
mixture remained as a suspension after 0.5 hour of heating.
[0145] A 20-mL solution of MeBr/NMP (93.2 mmol MeBr) was
transferred into a pre-cooled dropping funnel (-10.degree. C.)
equipped with a cooling system to maintain MeBr at between -10 and
0.degree. C. Nitrogen was introduced at the top of the water
condenser (about 20.degree. C.). A 10-mL portion of the MeBr/NMP
solution was added drop-wise into the suspension over 15 minutes at
about 56-58.degree. C. The resulting mixture was heated at about
56-58.degree. C. under nitrogen for another 30 minutes. Most of the
solid substrate was dissolved at this point. The remaining MeBr/NMP
solution was added drop-wise into the reaction mixture over a
10-minute period at about 56-58.degree. C. and stirring was
maintained at about 57.degree. C. for another 10 minutes followed
by further heating to about 63-65.degree. C. for 12 hours. After
this period, the suspension was cooled to room temperature and
stirred for 4 hours. Ninety (90) mL of acetone was added to the
reaction mixture and heat was released. The mixture was stirred for
1 hour allowed to cool to room temperature and then filtered. The
solid was washed with four 10-mL aliquots of acetone and dried
under vacuum at 55.degree. C. for 19 hours to give 40.22 g of crude
product as a white solid. The combined washes (mother liquor: 177.5
mL) were collected for recovery of unreacted naltrexone.
Example 3
Synthesis of Naltrexone Methobromide
Slow Addition of MeBr; and Substitution of Chloroform for
Acetone
[0146] 1-methyl-2-pyrrolidinone (NMP, 25 mL) was added into a
three-necked 250-mL flask and heated to 57.degree. C. under
nitrogen. 20 g of naltrexone base (containing 2% water) was added
via a funnel and the funnel was washed with 5 mL of NMP. The
mixture remained as a suspension after heating for 30 minutes.
[0147] A 10-mL solution of MeBr/NMP (93.2 mmol MeBr) was
transferred into a pre-cooled dropping funnel (-10.degree. C.)
equipped with a cooling system to maintain the MeBr solution at
below 0.degree. C. A nitrogen sweep was introduced at the top of
the attached water-cooled condenser (about 20.degree. C.) and about
7 mL of the MeBr/NMP solution was added drop-wise to the suspension
over 15 minutes at about 56-58.degree. C. The resulting mixture was
heated at about 56-58.degree. C. under nitrogen for 30 minutes by
which time most of the solid was dissolved. The remaining MeBr/NMP
solution was added drop-wise to the reaction mixture over 10
minutes at about 56-58.degree. C. and stirring was continued for an
additional 10 minutes followed by heating at about 63-65.degree. C.
under nitrogen for 12 hours. A precipitate formed after 2-3 hours.
At the end of the 12-hour period, the suspension was cooled to room
temperature and stirring was continued for an additional 4
hours.
[0148] To the reaction mixture was added 45 mL of CHCl.sub.3. The
addition was exothermic and the temperature of mixture rose to
35.degree. C. from room temperature. The mixture was then allowed
to cool to room temperature with stirring for 1 hour after which
the solid suspension was separated by filtration, washed with three
10-mL portions of CHCl.sub.3 and vacuum dried at 55.degree. C. for
19 hours to yield 19.55 g of elude product as a white solid. The
combined filtrate and washes were collected (mother liquor, 84.5
mL) for recovery of unreacted naltrexone base.
Example 4
Synthesis of Naltrexone Methobromide in Presence of HBr
Slow Addition of MeBr and Substitution of Chloroform for
Acetone
[0149] 1-methyl-2-pyrrolidinone (NMP, 33.3 mL) and 15 g of
naltrexone base (containing 2% water) were added into a
three-necked 250-mL flask under nitrogen. An 11.7 mL solution of
1.00N HBr/NMP and 14 mL of t-BuOH were added. The solution was
heated to about 54.degree. C., an extra 25.00 g of naltrexone base
(containing 2% water) was added via a funnel, and the funnel was
washed with 10 mL of NMP. The final mixture remained as a
suspension after heating for 30 minutes.
[0150] A 20-mL aliquot of MeBr/NMP (186.4 mmol MeBr) was
transferred into a pre-cooled dropping funnel (-10.degree. C.)
equipped with a cooling system to maintain the MeBr at below
0.degree. C. Nitrogen was introduced at the top of the attached
water-cooled condenser (about 20.degree. C.). 13 mL of the MeBr/NMP
solution was added drop-wise to the suspension over 15 minutes at
about 55-57.degree. C. The resulting mixture was heated at
approximately 55-57.degree. C. under nitrogen for another 30
minutes to form a clear solution. The remaining MeBr/NMP solution
was added drop-wise to the reaction mixture over 10 minutes at
approximately 55-57.degree. C., stirred for an additional 10
minutes, then heated to approximately 61-63.degree. C. for 19
hours. The resultant suspension was cooled to room temperature,
stirred for 4 hours, and 90 mL of chloroform was added which
resulted in heat release. After cooling to room temperature and
stirring for approximately 1 hour, the solids were separated by
filtration, washed with four 10-mL portions of chloroform, and
dried under vacuum at about 55.degree. C. for 19 hours. This
afforded 38.58 g of crude product as a white solid. The combined
washes were collected (mother liquor, 166.5 mL) for recovery of
unreacted naltrexone.
Discussion of the Results of Examples 1-4 and the Comparative
Example
[0151] In each of the above examples, the components of the final
reaction mixture were analyzed by HPLC and the results tabulated;
see Tables 1 and 3, and Scheme 3. The identified components are
grouped as follows: [0152] (1) Nal-MeBr=naltrexone methobromide,
desired product; [0153] (2) Nal=naltrexone=recyclable starting
material; and [0154] (3) Other side products=Nal-MeBr-isomer,
MeO-Nal, MeO-Nal-MeBr; not recyclable.
##STR00013##
[0155] The data entered for Examples 1-3 in Table 3 indicate that
slow addition of MeBr/NMP over 10-30 minutes increases the yield of
naltrexone methobromide to about 68 to 79%.
[0156] The entry for Example 4 in Table 3 represents the effect of
the addition of acid (0.1 equiv. HBr). Incorporation of this
reagent increased the yield of the product (naltrexone
methobromide) to about 77.5% and decreased the side products to
about 5.1%. Addition of HBr suppresses the ionization of the C(3)
hydroxide (phenolic hydroxide) of naltrexone to form Nal.sup.- (see
Scheme 4) and thereby reduces the chemical reactivity of the C(3)
hydroxide toward MeBr. Further, addition of a strong anhydrous acid
(HBr) to the reaction system permits use of partially hydrated
naltrexone (Naltrexone.2H.sub.2O) as a starting material instead of
anhydrous naltrexone thereby eliminating the processing costs
associated with dehydration of naltrexone. Since an additional
reaction step is required to prepare anhydrous naltrexone from the
hydrate (Naltrexone.2H.sub.2O), addition of HBr would reduce
processing costs.
##STR00014##
[0157] Approximately 13 mol. % of C(3)-O-methyl side products were
realized in Comparative Example A. In Examples 1-3, the
C(3)-O-methyl side products are reduced about 3-fold to 5-fold. In
Example 4 which incorporated the process improvements of Examples
1-3, increases in the yield and purity of the quaternized product,
naltrexone methobromide was observed (see summary in Table 2).
The procedures of Examples 1-3 differ from that of Comparative
Example A by
[0158] (i) slowing the addition of MeBr/NMP;
[0159] (ii) reducing the temperature of the MeBr/NMP (maintained at
about 0.degree. C. to -10.degree. C. during addition) into the NMP
solution of naltrexone (containing 2% water) at approximately
55-58.degree. C.; and
[0160] (iii) extending the reaction period from 10 to 12 hours.
The processes of Examples 1-3 yielded a higher molar percentage of
the product, naltrexone methobromide (Nal-MeBr) compared to the
process of Comparative Example A. In Example 4, 0.1 equiv. of HBr
was also added into the reaction mixture. The increased hydrogen
ion (H.sup.+) concentration was found to depress the formation of
side products, e.g., O-methyl naltrexone and O-methyl naltrexone
methobromide, thus improving the purity of the crude product.
TABLE-US-00001 TABLE 1 Yield of crude product Example No. Nal.
charged KF* % LOD** % Crude Yield Comp. A 12.5 Kg 0.61 0~0.2 9.43
Kg 1 100.00 g 1.22 0.04 92.26 g 2 20.00 g 3.06 0.07 18.90 g 3 40.00
g 1.13 0.06 35.92 g 4 40.00 g 1.18 0.12 37.56 g *KF is Karl-Fischer
test for water. **LOD is the weight loss on drying.
TABLE-US-00002 TABLE 2 Crude product quality* Example No. Crude
Yield % Nal. MeBr % Nal % O-Methyl Nal Comp A 9.43 Kg 90.26 2.63
6.0 1 92.26 g 84.98 1.81 4.62 (area %) 2 18.90 g 96.7 2.10 4.70
(area %) 3 35.92 g 89.32 1.48 5.11 (area %) 4 37.56 g 97.36 2.65
1.57 (area %) *The data in Table 2 are wt./wt. % except O-Methyl
Nal area % from HPLC analysis.
TABLE-US-00003 TABLE 3 Distribution of product and by-products
Example No. Mol. % Nal. MeBr* Mol. % Nal** Mol. % Others*** Comp A
60.9 26.5 12.6 1 68.3 14.8 16.9 2 79.0 10.3 10.7 3 75.1 9.7 15.2 4
77.5 17.4 5.1 *Nal. MeBr: naltrexone methobromide; **Nal:
naltrexone; ***O-methyl-Nal: C(3)-O-methyl-naltrexone.
Example 5
Synthesis of C(3)-Acetoxy Naltrexone
[0161] Deionized water (600 mL) and naltrexone base (90. g, 0.26
moles (mol)) were mixed in a 2-L, three-necked round bottomed flask
equipped with a mechanical stirrer, addition funnel, and
thermocouple. Toluene (300 mL) was added, the mixture was stirred
under a nitrogen atmosphere for 5 minutes, and NaOH (0.26 mol) was
then added as a 10% w/w aqueous solution via an addition funnel
over a 10 minute period. A temperature increase from 21.5.degree.
C. to 22.6.degree. C. was observed. The resulting solution was then
stirred for 15 minutes (all solid dissolved) and acetic anhydride
(29.61 g, 0.29 mol) was added over a 15-minute period and the
temperature was increased to 27.1.degree. C. The resulting mixture
was then stirred for 15 minutes and the pH was adjusted from 6.55
to 10.15 with 10 wt. % solution of NaOH (24.2 g, 0.06 mol.). The
mixture was stirred for 10 minutes, the layers were separated and
the aqueous layer was extracted once with toluene (100 mL). The
combined organic layers were then filtered through a Whatman Glass
Microfibre Filter (GF/A, 90 mm) and the resulting filtrate was
allowed to sit undisturbed for further separation of water. The
residual water was removed, and C(3)-acetoxy naltrexone/toluene
solution was obtained (459.8 g). The solution was concentrated
under reduced pressure to afford an amber/yellow oil and then
dissolved in NMP to prepare a 30.0 wt. % solution of the
product.
Example 6
Synthesis of Naltrexone Methobromide
[0162] To a 1-L, 5-neck, jacketed pressure reactor equipped with a
polished glass stirring shaft, mechanical stirrer, reflux
condenser, pressure manifold, thermowell, and 1/8'' ID MeBr
addition line was added a solution of C(3)-acetoxy naltrexone in
NMP (732.2 g of 30% wt/wt solution, 0.57 moles). Methyl bromide
(107.9 g, 1.14 moles) was then added via a subsurface addition with
vigorous stirring over a 1 hour period. The amount of MeBr added to
the reactor was ascertained by a difference in the initial and
final weights of a MeBr lecture bottle. During the addition, the
temperature of the reaction mass increased from 20.8.degree. C. to
32.9.degree. C. (yellow solution) and a maximum pressure of 3-4 psi
was observed. After the appropriate amount of MeBr was added, the
reactor headspace was evacuated and repressurized with MeBr (to
about 2 psi) twice before heating to 60.degree. C. At 60.degree.
C., a pressure of 2-4 psi was observed. The reaction mixture was
stirred overnight (15 hours) and no pressure was observed (a yellow
solution resulted). Aqueous HBr (1.0 equiv, 0.57 moles, 96.58 g of
48 wt. %) was added slowly at 60.degree. C. over a 30-minute
period. The reactor was vented into NMP in order to trap gaseous
methyl bromide that was generated during the HBr addition. During
the addition, the reaction temperature increased to 63.7.degree. C.
The reaction temperature was then increased to 80.degree. C. over a
1.5 hour period and the methyl bromide evolution ceased. The
mixture was stirred at 80.degree. C. for 2 hours and precipitation
was observed. After 5 hours at 80.degree. C., the slurry was
analyzed by HPLC and a minor amount of C(3)-acetoxy naltrexone
methobromide was observed (<0.5% by area) was observed. The
mixture was then transferred to a 2-L three-neck round bottomed
flask equipped with a glass stirring shaft, mechanical stirrer,
reflux condenser, and thermocouple under a nitrogen atmosphere. The
mixture was cooled to 56.2.degree. C. and methanol (512.5 g, 1.0 wt
equiv. based on the amount of NMP charged) was added quickly. The
temperature decreased quickly to 41.2.degree. C. and then increased
to 42.5.degree. C. upon crystallization of naltrexone methobromide.
The slurry was then cooled to 29.7.degree. C. over a 30 minute
period and then to 5-10.degree. C. in an ice bath. The slurry was
stirred for 1 hour at 5-10.degree. C., filtered, and the product
was washed with cold methanol (319 mL, 1.45 mL/g C(3)-acetoxy
naltrexone assuming 212.5 g naltrexone methobromide (85% overall
yield)) to afford 236.1 g of a white solid. The crude product was
analyzed by HPLC. This example was repeated two additional times
and the results are summarized in Table 4. The HPLC assay data for
the solid product is an average of two separate injections.
TABLE-US-00004 TABLE 4 Summary of Results: Example 6 - Synthesis of
Naltrexone Methobromide. 3- Hydrolysis AcNal.sup.a Time
NalMeD.sup.a NalMe.sup.a Nal.sup.a Yield Run (moles) (hours) (wt.
%) (wt. %) (wt. %) (mole %) 1 0.3915 25 1.47 86.54 0.49 87.2 2
0.4890 17 1.39 86.73 0.60 85.6 3 0.5729 5 1.25 87.98 0.57 83.1
.sup.a3-AcNal = C(3)-Acetoxy Naltrexone, NalMeD = Naltrexone
Methobromide Diastereomer, NalMe = Naltrexone Methobromide, Nal =
Naltrexone Base.
Example 7
Recrystallization of Naltrexone Methobromide
[0163] A mixture of water (15.82 mL, 1.58 mL water/g naltrexone
methobromide) and methanol (33.47 mL, 3.35 mL methanol/g naltrexone
methobromide) were mixed and heated under a nitrogen atmosphere in
a 100 mL three-necked round bottomed flask equipped with a glass
stirring shaft, mechanical stirrer, reflux condenser, and
thermocouple to 60.degree. C., and solid naltrexone methobromide
(10.00 g, 22.92 mmoles) was added. After 15 minutes, the solid
dissolved and aqueous HBr (0.93 g of a 48% solution, 5.5 mmoles, 24
mol %) was added to obtain an aqueous methanol mixture comprised of
1.63 mL water/g naltrexone methobromide and 3.52 mL methanol/g
naltrexone methobromide. The heating mantle was removed and the
mixture was allowed to slowly cool to room temperature.
Crystallization was observed at 48.degree. C. The mixture was
cooled to 25.degree. C. over a period of 1 hour, then cooled to
5-10.degree. C. in an ice bath, stirred for 2 hours, filtered, and
the solid was washed with cold methanol (15 mL, 1.5 mL/g naltrexone
methobromide). The solid was then dried on the Buchner funnel for
15 minutes to afford 10.84 g of naltrexone methobromide as a white
solid contaminated with methanol. The product was analyzed by HPLC.
The HPLC assay data for the solid product is an average of two
separate injections. The results of several experiments are
summarized in Table 5.
TABLE-US-00005 TABLE 5 Summary of Results: Example 7 - Naltrexone
Methobromide Recrystallization HBr Water Methanol 3- Recovery (mol
(mL/g (mL/g NalMeD.sup.a NalMe.sup.a Nal.sup.a MeNalMe.sup.a (mole
Run %) NalMe.sup.a) NalMe) (wt. %) (wt. %) (wt. %) (wt. %) %) 1
12.0 1.81 3.52 0.30 93.53 0.08 0.07 87.4 2 18.0 1.72 3.71 0.35
86.45 0.12 0.06 95.4 3 24.0 1.81 3.89 0.36 94.21 0.14 0.08 87.0 4
12.0 1.63 3.52 0.37 85.32 0.14 0.06 93.3 5 18.0 1.72 3.71 0.31
93.45 0.12 0.07 88.3 6 12.0 1.81 3.89 0.31 80.92 0.12 0.06 91.1 7
24.0 1.81 3.52 0.32 93.59 0.12 0.08 87.7 8 24.0 1.63 3.52 0.40
90.23 0.15 0.07 96.0 9 12.0 1.63 3.89 0.31 91.10 0.12 0.07 84.9 10
24.0 1.63 3.89 0.31 88.81 0.12 0.06 92.8 .sup.aNalMeD = Naltrexone
Methobromide Diastereomer, NalMe = Naltrexone Methobromide, Nal =
Naltrexone Base, 3-MeNalMe = C(3)-Methoxy Naltrexone
Methobromide.
Example 8
Preparation of Methylnaltrexone Bromide
[0164] Methylnaltrexone bromide (R-MNTX). To a mixture of
naltrexone base (110 Kg@100.0%, 323 moles) and USP Purified water
(330 Kg, 3.00 Kg/Kg naltrexone base, 87 gal, 0.79 gal/Kg naltrexone
base) was added 50% NaOH (25.7 Kg, 0.234 Kg/Kg naltrexone base).
Toluene (288 Kg, 2.62 Kg/Kg naltrexone base) was added to the
aqueous layer. The mixture was stirred and acetic anhydride (37.8
Kg, 0.344 kg/kg naltrexone base) was added. The resulting mixture
was then stirred and the pH was adjusted to 9.5-10.5 with 50% NaOH
(7.59 Kg, 0.069 Kg/Kg naltrexone base). Acetic anhydride (36.7 Kg,
0.030 Kg/Kg naltrexone base) was added and the mixture was stirred
and the pH was adjusted to 9.5-10.5 with 50% NaOH (5.06 Kg, 0.046
Kg/Kg naltrexone base). The mixture was allowed to settle and the
layers were separated. The aqueous layer was extracted with toluene
(45.5 Kg, 0.414 Kg/Kg naltrexone base) and the layers were
separated. The organic layers were combined and the aqueous layer
was discarded. A pH 9.0, 0.375 M phosphate buffer solution (165 Kg,
1.5 Kg/Kg naltrexone base) was prepared by mixing 5.80 Kg of 85%
H.sub.3PO.sub.4 (0.0527 Kg/Kg naltrexone base), 9.39 Kg 50% NaOH
(0.0854 Kg/Kg naltrexone base), and 150 Kg DI water (1.36 Kg/Kg
naltrexone base). The combined toluene layers were then washed with
the pH 9.0 phosphate buffer (165 Kg, 1.5 Kg/Kg naltrexone base).
The layers were separated and the toluene layer was concentrated.
The vacuum was broken with nitrogen and acetic anhydride (330 g,
0.003 Kg/Kg naltrexone base) was added. The mixture was stirred at
50-55.degree. C. Vacuum was again applied and remaining toluene was
removed by distillation. The vacuum was broken with nitrogen and
1-methyl-2-pyrrolidinone (268 Kg, 2.44 Kg/Kg naltrexone base) was
added. The mixture was stirred for 60 minutes and cooled to room
temperature to afford a solution of 3-acetylnaltrexone in NMP.
Methyl bromide (61.2 Kg, 0.556 Kg/Kg naltrexone base) was then
added with vigorous stirring. The reaction mixture was stirred at
60-65.degree. C. to afford a solution. Reaction completion was
ascertained via HPLC analysis. A 33% HBr/HOAc (w/w) solution (19.8
Kg, 0.180 Kg/Kg naltrexone base) was added. The mixture was stirred
at .about.60.degree. C. Aqueous 48% HBr (54.3 Kg, 0.494 Kg/Kg
naltrexone base) was added at 60.degree. C. The mixture was then
stirred at .about.80.degree. C. and cooled to .about.55.degree. C.
Methanol (288 Kg, 2.62 Kg/Kg naltrexone base) was added at
.about.55.degree. C. and the slurry was cooled to 10.degree. C.,
stirred at 5-10.degree. C., filtered, and the product was washed
with methanol (220 Kg, 2.0 Kg/Kg naltrexone base) to afford a
white, crystalline solid. The purity of the crude methylnaltrexone
bromide product was ascertained by an HPLC assay method and
subsequent raw material charges for recrystallization were
calculated employing the weight of the product on a 100% basis.
[0165] To a mixture of water (1.58 Kg/Kg methylnaltrexone
bromide@100%) and methanol (2.78 Kg/Kg methylnaltrexone
bromide@100%) was added crude methylnaltrexone bromide. The mixture
was heated to 60-65.degree. C. under a nitrogen atmosphere and a
solution resulted. The solution was filtered and aqueous 48% HBr
(0.094 kg/kg methylnaltrexone bromide@100%) was added. The mixture
was cooled to 10.degree. C., filtered, and the solid was washed
with methanol (1.2 Kg/Kg methylnaltrexone bromide@100%). The
product was dried at 70-75.degree. C. to afford 100 Kg of a white
crystalline solid.
[0166] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a", "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0167] In view of the above, it will be seen that the several
objects of the invention are achieved and other advantageous
results attained.
[0168] As various changes could be made in the above methods and
processes without departing from the scope of the invention, it is
intended that all matter contained in the above descriptions shall
be interpreted as illustrative and not in a limiting sense.
* * * * *