U.S. patent application number 09/835525 was filed with the patent office on 2001-08-30 for preparation of opiates.
This patent application is currently assigned to Johnson Matthey Public Limited Company. Invention is credited to Sebastian, Alice.
Application Number | 20010018519 09/835525 |
Document ID | / |
Family ID | 10828597 |
Filed Date | 2001-08-30 |
United States Patent
Application |
20010018519 |
Kind Code |
A1 |
Sebastian, Alice |
August 30, 2001 |
Preparation of opiates
Abstract
A novel process for the preparation of codeinone and analogues
thereof comprising the oxidation of a compound of formula, 1 or a
salt thereof, wherein R.sup.1 is lower alkyl or a group 2 wherein
R.sup.4 is lower alkyl, lower alkyl substituted by halogen or
phenyl, phenyl or substituted phenyl; and R.sup.2 is lower alkyl,
allyl or lower alkyl substituted by cycloalkyl, characterised in
that the oxidation is carried out in an acidic environment is
disclosed.
Inventors: |
Sebastian, Alice; (Deptford,
NJ) |
Correspondence
Address: |
Intellectual Property Group
Pillsbury Winthrop LLP
East Tower, Ninth Floor
1100 New York Avenue, N.W.
Washington
DC
20005-3918
US
|
Assignee: |
Johnson Matthey Public Limited
Company
|
Family ID: |
10828597 |
Appl. No.: |
09/835525 |
Filed: |
April 17, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09835525 |
Apr 17, 2001 |
|
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09271349 |
Mar 17, 1999 |
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6235906 |
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Current U.S.
Class: |
546/45 |
Current CPC
Class: |
C07D 489/02
20130101 |
Class at
Publication: |
546/45 |
International
Class: |
C07D 489/02 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 1998 |
GB |
9805516.3 |
Claims
1. A process for the preparation of a compound of formula (I)
6wherein R.sup.1 is lower alkyl or a group 7wherein R.sup.4 is
lower alkyl, lower alkyl substituted by halogen or phenyl. phenyl
or substituted phenyl; and R.sup.2 is lower alkyl, allyl or lower
alkyl substituted by cycloalkyl; comprising the oxidation of a
compound of formula (II), 8or a salt thereof, wherein R.sup.1 and
R.sup.2 are as hereinbefore defined, characterised in that the
oxidation is carried out in an acidic environment:
2. A process according to claim 1 wherein each of R.sup.1 and
R.sup.2 may be the same or different and each is lower alkyl.
3. A process according to claim 2 wherein each of R.sup.1 and
R.sup.2 may be the same or different and is methyl or ethyl.
4. A process according to claim 3 wherein R.sup.1 and R.sup.2 are
both ethyl.
5. A process according to any one of claims 1 to 4 wherein when the
compound of formula (II) is present as a salt, the salt is the
phosphate salt.
6. A process according to any one of claims 1 to 5 wherein the
oxidation is carried out at a pH of between 0.1 and 7.
7. A process according to claim 6 wherein the oxidation is carried
out at a pH of between 0.8 and 4.5.
8. A process according to claim 7 wherein the oxidation is carried
out at a pH of from 0.8 to 1.2.
9. A process according to any one of claims 1 to 8 wherein the
oxidation reagent is manganese dioxide.
Description
[0001] The present invention relates to a novel process for the
preparation of codeinone and analogues thereof.
[0002] Codeinone is a key intermediate for the synthesis of many
morphinoid compounds. It is therefore desirable for a simple,
straightforward and cost effective process for its preparation.
[0003] In earlier works, codeinone was obtained from thebaine by
treating it with dry HBr in CH.sub.2Cl.sub.2 at -25.degree.,
followed by hydrolysis with water and dehydrobrominating with cold
NaOH (Vesely, Z., Hodkova, J. and Trojanek J., Cesk. Farm. 1986,
35, 222-6). In another method, thebaine was converted to a mixture
of codeinone and neopinone in aqueous HCO.sub.2H containing
Hg(OAc).sub.2 (U.S. Pat. No. 4,277,604). However, thebaine is very
expensive and does not occur naturally in a high yield; therefore
the preparation of codeinone from thebaine is not an attractive
method.
[0004] An alternative process for the preparation of codeinone is
the direct oxidation of codeine using variety of reagents, such as
silver carbonate (Rapoport, H. and Reist, N. H., J. Am. Chem. Soc.
1955, 27, 490-491) and Jones' reagent (Findlay, J .W. A., Butz, R.
F. and Jones, E. C., Clin. Chem. 1981, 77, 1524-1535); however,
these reagents only gave codeinone in poor yield. Only Oppenauer
oxidation (U.S. Pat. No. 2,654,756) has given codeinone in
reasonably good yield and high purity. All these methods have their
drawbacks, however. Oxidation with silver carbonate is not
preferred due to its cost and incomplete reaction, whereas in the
case of Jones's oxidation and Oppenauer oxidation the isolation of
the product is difficult and complex.
[0005] The direct oxidation of codeine with active manganese
dioxide (Ninan, A. and Sainsbury, M., Tetrahedron, 1992, 48, 6709)
and .gamma.-manganese dioxide (Highet, R. J. and Wildman, W. C., J.
Am. Chem. Soc., 1955, 77, 4399) has also been reported. However, in
both cases pure codeinone was obtained in only low yield due to the
formation of 14.beta.-hydroxycodeinone and low conversion.
[0006] The object of the present invention is to provide a simple
process for the preparation of codeinone and analogues thereof, and
which provides the desired product in high yield and purity. The
present inventors have found that if oxidation of codeine or a salt
thereof, for example the phosphate salt, is carried out at acidic
pH, a high yield of codeinone is obtained which is not obtainable
by any of the methods heretofore disclosed.
[0007] Accordingly, the present invention provides a novel process
for the preparation of a compound of formula (I) 3
[0008] wherein R.sup.1 is lower alkyl or a group 4
[0009] wherein R.sup.4 is lower alkyl, lower alkyl substituted by
halogen or phenyl, phenyl or substituted phenyl; and
[0010] R.sup.2 is lower alkyl, allyl or lower alkyl substituted by
cycloalkyl;
[0011] comprising the oxidation of a compound of formula (II),
5
[0012] or a salt thereof, wherein R.sup.1 and R.sup.2 are as
hereinbefore defined; characterised in that the oxidation is
carried out in an acidic environment.
[0013] Preferably, each of R.sup.1 and R.sup.2 may be the same or
different and each is lower alkyl, for example C.sub.1-6 alkyl,
such as C.sub.1-4 alkyl, for example methyl or ethyl and preferably
ethyl.
[0014] When the compound of formula (II) is present as a salt,
preferably the salt is the phosphate salt (H.sub.3PO.sub.4).
[0015] Suitably the oxidation is carried out at a pH of from
0.1<pH>7; preferably, the oxidation is carried out at a pH of
from 0.8<pH>4.5; most preferably the oxidation is carried out
at a pH of from 0.8 to 1.2.
[0016] The solvent may be any solvent suitable for use in such an
oxidation reaction. Acetone was found to be the most suitable
solvent for giving the desired product in high yield and high
purity. Other solvents were also found to be particularly useful
and were preferred in the order: acetone
>THF>IPA>CH.sub.3CN >NMP. Preferably, the solvent is
used as a 50:50 (v/v) solvent/water mixture.
[0017] The oxidation reagent is suitably manganese dioxide, such as
activated manganese dioxide or .gamma.-manganese dioxide,
preferably .gamma.-manganese dioxide. Suitably, the oxidation
reagent is present in an amount of at least 3 equivalents or more
with respect to the compound of formula (I).
[0018] The invention will now be further described by way of
example only.
GENERAL PROCEDURE FOR THE PREPARATION OF CODEINONE FROM CODEINE
PHOSPHATE OR CODEINE
[0019] A solution of codeine or codeine phosphate was dissolved in
the appropriate solvent system and a specified volume of
hydrochloric acid of varying concentration was added. Manganese
dioxide (either freshly prepared .gamma.-manganese dioxide or
activated manganese dioxide from Aldrich) was added and the
reaction mixture was stirred at ambient temperature for 1.5 to 4
hours. The progress of the reaction was monitored by HPLC. The
reaction mixture was filtered through a celite pad, washed with
additional solvent or water, and neutralised with ammonium
hydroxide. The product was extracted with methylene chloride
(3.times.150 ml) and the combined extracts washed with water and
dried over anhydrous sodium sulphate. The organic layer was then
evaporated to yield codeinone.
[0020] In all the experiments the reaction was followed by HPLC and
the retention time of the product was compared with that of the
standard. In some cases the crude product was quantitated to obtain
the purity. The HPLC analysis was done on a Shimadzu system. The
column used was Phenomenex's Prodigy 5.mu. ODS (3)
100.degree..ANG., 250.times.4.6 mm. The method was isocratic. The
mobile phase was: water (1450 ml)+ acetonitrile (550 ml)+Et.sub.3N
(2 ml)+1.73 g of 1-octanesulphonate, sodium salt+pH 3.5 (adjusted
with 85% phosphoric acid). In the cases where the product was
isolated, it was also characterised by comparing its .sup.1H NMR
with that of the standard: .sup.1H NMR
(CDCl.sub.3).delta.1.85-1.92(1H,m,15.sub..alpha.),2.05-2.15(1H,m,16.alpha-
.),2.27-2.4(2H,m,15.sub.62,10.sub..alpha.),
2.45(3H,s,N-CH.sub.3),2.58-2.6-
2(1H,m,H.sub.16.beta.)3.07-3.14(1H,d,H.sub.10.beta.),3.19-3.21(1H,d,
H.sub.9.alpha.),3.39-3.44(1H,m,H.sub.14),3.84(3H,s,OCH.sub.3),4.70(1H,s,H-
.sub.5.beta.),6.05-6.11(1H,dd,
H.sub.8),6.59-6.70(3H,m,H.sub.1,H.sub.2,H.s- ub.7).
[0021] The following examples were carried out using the starting
material and reagents indicated.
1 Starting Solvent Purity Example Material System Acid Oxidant
Yield (HPLC No (g) (ml) (ml) (g) pH (%) area %) 1 Codeine IPA (14)
6N HCl .gamma.-MnO.sub.2 1.62 94 .about.95 (0.5) H.sub.2O (14)
(0.5) (1.6) 2 Codeine IPA (22) -- .gamma.-MnO.sub.2 4.5 NA
.about.34 phosphate H.sub.2O (22) (3.2) (1) 3 Codeine IPA (14) 6N
HCl .gamma.-MnO.sub.2 1.6 80 91.8 phosphate H.sub.2O (14) (0.5)
(1.6) (0.5) 4 Codeine IPA (40) 6N HCl .gamma.-MnO.sub.2 1.44 NA
60.3 (2) H.sub.2O (40) (2) (4) 5 Codeine IPA (40) 6N HCl
.gamma.-MnO.sub.2 1.3 86 .about.91.8 (2) H.sub.2O (40) (3) (7) 6
Codeine IPA (10) 6N HCl .gamma.-MnO.sub.2 0.73 75 82 (0.5) H.sub.2O
(10) (2) (1.5) 7 Codeine IPA (10) 6N HCl .gamma.-MnO.sub.2 1.16 92
.about.97 (0.5) H.sub.2O (10) (1) (1.5) 8 Codeine IPA (10) 6N HCl
.gamma.-MnO.sub.2 1.41 95 .about.95 (0.5) H.sub.2O (10) (0.75)
(1.5) 9 Codeine CH.sub.3CN (10) 6N HCl .gamma.-MnO.sub.2 0.9 89.7
.about.93 (0.5) H.sub.2O (10) (0.75) (1.5) 10 Codeine IPA (10) 6N
HCl .gamma.-MnO.sub.2 <0.1 50.4 .about.71 (0.5) H.sub.2O (10)
(4) (1.5) 11 Codeine Acetone (10) 6N HCl .gamma.-MnO.sub.2 0.92
95.2 94 (0.5) H.sub.2O (10) (0.75) (1.5) 12 Codeine THF (10) 6N HCl
.gamma.-MnO.sub.2 1.21 89 93 (0.5) H.sub.2O (10) (0.75) (1.5) 13
Codeine NMP (20) -- .gamma.-MnO.sub.2 -- NA .about.21.6 (0.5) 14
Codeine NMP (10) 6N HCl .gamma.-MnO.sub.2 1.45 NA .about.90 (0.5)
H.sub.2O (10) (1) 15 Codeine Acetone (200) 6N HCl .gamma.-MnO.sub.2
1.02 83.5 95.5 (11.45) H.sub.2O (200) (16) (36) 16 Codeine Acetone
(10) 6N HCl Activated 0.87 NA .about.45 (0.5) H.sub.2O (10) (0.75)
85% MnO.sub.2 (Aldrich) 17 Codeine IPA (25) -- .gamma.-MnO.sub.2(3)
-- NA .about.41 (1) CH.sub.2Cl.sub.2 (25) NA = Not Available (the
product was not isolated)
Preparation of .gamma.-Manganese Dioxide
[0022] Manganese (II) sulphate monohydrate (140 g) was dissolved in
2.66 liters of water and heated to 60.degree. C. Potassium
permanganate (97.3 g) in 1.85 liter of water was added over a
period of 15 minutes and stirred at 60.degree. C. for 1 hour, until
manganese dioxide precipitated out. The reaction mixture was
filtered and the residue was washed with deionised water until no
sulphate ion was present. The solid was dried under suction for 2
hours followed by drying at 70.degree. C. under vacuum to a
constant weight (.about.8 days) to give 115 g of a dark brown
powder.
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