Process For The Preparation Of Oxymorphone Freebase
The present invention is directed to a process for the preparation oxymorphone freebase, comprising hydrogenation of 14-hydroxymorphinone in DMF, to yield oxymorphone freebase, preferably oxymorphone freebase of improved appearance, purity and/or yield. The present invention is further directed to oxymorphone freebase with improved impurity profile. The present invention is further directed to an HPLC or UPLC system/method for analysis of opioid compounds.
1 . A process for the preparation of oxymorphone freebase comprising the step of:
reacting 14-hydroxymorphinone with a hydrogenating agent; optionally in the presence of ethylenediaminetetracetic acid disodium salt; optionally in the presence of a proton source; in dimethylformamide; to yield oxymorphone as a freebase.
2 . A process as in claim 1 , wherein the hydrogenating agent is hydrogen gas and wherein the 14-hydroxymorphinone is reacted with the hydrogen gas in the presence of Pd/C catalyst.
3 . A process as in claim 1 , wherein the hydrogenating agent is hydrogen gas; wherein the hydrogen gas is present at a pressure in the range of from about 20 to about 50 psi; wherein the 14-hydroxymorphinone is reacted with the hydrogen gas in the presence of 5% Pd/C catalyst; and wherein the 5% Pd/C catalyst is present in an amount in the range of from about 1 wt % to about 2 wt %.
4 . A process as in claim 1 , wherein the hydrogenating agent is hydrogen gas; wherein the hydrogen gas is present at a pressure of about 35 psi; wherein the 14-hydroxymorphinone is reacted with the hydrogen gas in the presence of 5% Pd/C catalyst; and wherein the 5% Pd/C catalyst is present in an amount of about 1.8 wt %.
5 . A process as in claim 1 , wherein the 14-hydroxymorphinone is reacted in the presence of a proton source; and wherein the proton source is dibasic potassium phosphate.
6 . A process as in claim 1 , wherein the 14-hydroxymorphinone is reacted in the presence of a proton source; wherein the proton source is dibasic potassium phosphate; and wherein the dibasic potassium phosphate is present in an amount in the range of from about 0.005 to about 0.05 kg/kg relative to the amount of 14-hydroxymorphinone.
7 . A process as in claim 1 , wherein the 14-hydroxymorphinone is reacted in the presence of a proton source; wherein the proton source is dibasic potassium phosphate; and wherein the dibasic potassium phosphate is present in an amount of about 0.01 kg/kg relative to the amount of 14-hydroxymorphinone.
8 . A process as in claim 1 , wherein the dimethylformamide is present in an amount in the range of from about 1 L/kg to about 5 L/kg relative to the amount of 14-hydroxymorphinone.
9 . A process as in claim 1 , wherein the dimethylformamide is present in an amount of about 3 L/kg relative to the amount of 14-hydroxymorphinone.
10 . A process as in claim 1 , wherein the 14-hydroxymorphinone is reacted with the hydrogenating agent at a temperature is in a range of about 20° C. to about 50° C.
11 . A process as in claim 1 , wherein the 14-hydroxymorphinone is reacted with the hydrogenating agent at a temperature of about 35° C.
12 . A process as in claim 1 , further comprising precipitating the oxymorphone freebase by addition of water; and isolating the oxymorphone freebase precipitate as a solid.
13 . A process as in claim 12 , wherein the water is added in an amount in the range of from about 6 L/kg to about 12 L/kg relative to the amount of 14-hydroxymorphinone.
14 . A process as in claim 12 , wherein the water is added in an amount of about 10 L/kg relative to the amount of 14-hydroxymorphinone.
15 . A product prepared according to the process of claim 1 .
16 . A process for the preparation of oxymorphone freebase comprising the steps of
(a) charging 14-hydroxymorphinone, dibasic potassium phosphate, DMF and 5% Pd/C and optionally EDTA, to a nitrogen purged hydrogenation vessel;
wherein the dibasic potassium phosphate is added in an amount of about 0.01 kg/kg relative to the amount of 14-hydroxymorphinone; wherein the DMF is added in an amount of about 3 L/kg relative to the amount of 14-hydroxymorphinone; and wherein the 5% Pd/C is added in an amount of about 0.018 kg/kg relative to the amount of 14-hydroxymorphinone;
(b) hydrogenating the 14-hydroxymorphinone with H 2 gas at 35 psi and 35° C.; to yield a reaction mixture comprising oxymorphone freebase;
wherein the hydrogenation is continued until greater than about 95% of the 14-hydroxymorphinone is consumed;
(c) filtering the reaction mixture to remove the Pd/C catalyst; and yield a filtrate comprising oxymorphone freebase;
(d) adding water to the filtrate; to yield oxymorphone freebase as a precipitate; wherein the water is added in an amount of about 10 L/kg relative to the amount 14-hydroxymorphinone; and
(e) isolating the oxymorphone freebase as a solid.
17 . A product prepared according to the process of claim 16 .
18 . A process as in claim 1 , further comprising the step of:
reacting the oxymorphone base with hydrochloric acid, to yield the corresponding oxymorphone hydrochloric acid addition salt.
19 . A product prepared according to the process of claim 18 .
20 . A process as in claim 1 further comprising the step of:
reacting CPS oripavine to yield 14-hydroxymorphinone.
21 . A process as in claim 20 , wherein the CPS oripavine is reacted with a peroxyacid; in water; to yield 14-hydroxymorphinone.
22 . A process as in claim 21 , wherein the peroxyacid is prepared in situ by reacting a peroxyacid forming agent with hydrogen peroxide.
23 . A process as in claim 22 , wherein the peroxyacid forming agent is 90% formic acid; and wherein the 90% formic acid is present in an amount in the range of about 0.1 kg/kg to about 2 kg/kg relative to the amount of CPS oripavine; and wherein the hydrogen peroxide is present in an amount 0.5 molar equivalents to about 3 molar equivalents.
24 . A process as in claim 22 , wherein the peroxyacid forming agent is 90% formic acid; and wherein the 90% formic acid is present in an amount of in the range of about 1 kg/kg to about 1.1 kg/kg relative to the amount of CPS oripavine; and wherein the hydrogen peroxide is present in an amount 1.05 molar equivalents to about 1.2 molar equivalents.
25 . A process as in claim 21 , wherein the water is present in an amount in the range of from about 0.1 kg/kg to about 5 kg/kg relative to the amount of CPS oripavine.
26 . A process as in claim 21 , wherein the water is present in an amount in the range of from about 1.4 kg/kg to about 1.6 kg/kg, relative to the amount of CPS oripavine.
27 . A process as in claim 21 , wherein the CPS oripavine is reacted with the peroxyacid at a temperature in the range of from about 20° C. to about 28° C.
28 . A process as in claim 20 , wherein the 14-hydroxymorphinone is precipitated by addition of an organic amine base; and isolated by filtration.
29 . A process as in claim 28 , wherein the organic base amine is triethylamine; and wherein the triethylamine is added in an amount sufficient to adjust the pH of the reaction mixture to a pH in the range of from about pH 8 to abut pH 10.
30 . A process as in claim 20 , wherein the 14-hydroxymorphinone is isolated as a solid; wherein the isolated solid comprises less than about 5 wt % impurities.
31 . A product prepared according to the process of claim 20 .
32 . A process as in claim 1 , further comprising
reacting thebaine to yield 14-hydroxymorphinone; and
33 . A product prepared according to the process of claim 32 .
34 . A process as in claim 20 or claim 32 , further comprising
reacting the oxymorphone base with hydrochloric acid, to yield the corresponding oxymorphone hydrochloric acid addition salt.
35 . A product prepared according to the process of claim 34 .
36 . Oxymorphone freebase or oxymorphone hydrochloride; wherein the individual wt % of one or more of (a) 14-hydroxymorphinone, (b) 14-hydroxy-dihydromorphine (α), (c) 8-hydroxyoxymorphone, or (d) 2,2′-bis-oxymorphone is individually less than or equal to about 0.5 wt %.
37 . Oxymorphone freebase or oxymorphone hydrochloride; wherein the individual wt % of one or more of (a) 14-hydroxymorphinone, (b) 14-hydroxy-dihydromorphine (α), (c) 8-hydroxyoxymorphone, or (d) 2,2-bis-oxymorphone is individually less than or equal to about 0.1 wt %.
38 . An HPLC or UPLC system for analyzing the purity or impurity profile of an opioid compound comprising
(a) a HPLC or UPLC column for receiving mobile phases;
(b) a Mobile Phase A and a Mobile Phase B, wherein the Mobile Phase A and/or Mobile Phase B comprises a buffer and further wherein at least one of the mobile phases has (or is buffered to have) a pH equal to or within 0.5 units of the pK of the opioid compound to be analyzed.
39 . A system as in claim 38 , wherein the opioid compound is selected from the group consisting of oxymorphone, oxycodone, hydrocodone, hydromorphone, buprenorphine, morphine, codeine, benzhydrocodone, and pharmaceutically acceptable salts thereof.
40 . A system as in claim 38 , wherein the opioid compound is selected from the group consisting of oxmorphone freebase, oxymorphone hydrochloride, oxycodone, oxycodone hydrochloride, hydromorphone, hydrocodone bitartrate and benzhydrocodone.
41 . A system as in claim 38 , wherein the Mobile Phase A is a mixed phosphate buffer in water, wherein the pH of the mixed phosphate buffer is in the range of from about pH 9.3 to about pH 9.4; or an ammonium formate buffer in water, wherein the pH of the ammonium formate buffer is about pH 9.6.
42 . An HPLC or UPLC method for analyzing the purity or impurity profile of an opioid compound, comprising the step of applying at least one mobile phase to an HPLC or UPLC column, wherein at least one of the mobile phases has (or is buffered to have) a pH equal to or within 0.5 units of the pK of the opioid compound to be analyzed.
43 . An HPLC and UPLC method for analyzing an opioid compound comprising the steps of:
(a) selecting a Mobile Phase A and a Mobile Phase B; wherein Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water and wherein Mobile Phase B is acetonitrile; and
(b) applying Mobile Phase A and Mobile Phase B with a gradient timetable selected to achieve separation of the opioid compound from any impurities present in the sample.
44 . An HPLC or UPLC method for analyzing the purity or impurity profile of an opioid compound comprising the steps of:
(a) injecting a sample of an opioid compound into an HPLC or UPLC column;
(b) applying a Mobile Phase A and a Mobile Phase B to the column; wherein Mobile Phase A is a mixed phosphate buffer in water or an ammonium formate buffer in water; wherein the pH of the mixed phosphate buffer in water is in the range of from about pH 8 to about pH 9; and wherein the pH of the ammonium formate buffer in water is in the range of from about pH 9 to about pH 10; and wherein Mobile Phase B is acetonitrile; and further wherein the Mobile Phase A and the Mobile Phase B are applied with a Mobile Phase gradient selected to separate the opioid compound peaks from the impurity peaks.
45 . A method as in claim 43 , wherein the Mobile Phase gradient is selected from the group consisting of
Gradient Timetable A:
Gradient Timetable A
Mobile
Phase
Time (min.)
% A
% B
Curve
Initial
95
5
Initial
1.00
84
16
6
2.00
84
16
6
4.00
70
30
9
6.00
65
35
9
8.50
45
55
3
10.00
95
5
1
Gradient Table B:
Gradient Timetable B
Mobile
Phase
Time (min.)
% A
% B
Gradient Change
0.00
96
4
N/A
1.00
86
14
Linear
3.00
76
24
Linear
8.00
70
30
Linear
12.00
70
30
Linear
18.00
60
40
Linear
21.00
40
60
Linear
26.00
40
60
Linear
26.10
96
4
Step @26 minutes
30.00
96
4
Linear
Gradient Table C:
Gradient Timetable C
Mobile
Phase
Time (min.)
% A
% B
Gradient Change
Initial
96
4
N/A
0.30
86
14
Linear
0.85
76
24
Linear
2.40
70
30
Linear
3.70
70
30
Linear
5.00
60
40
Linear
6.50
40
60
Linear
7.50
40
60
Linear
9.00
96
4
Ste @ 7.5 min
and Gradient Table D:
Gradient Table D
Mobile
Phase
Time (min.)
% A
% B
Gradient Change
0.0
90
10
N/A
10.0
70
30
Linear
25.0
45
55
Linear
25.1
90
10
Linear
30.0
90
10
Linear