US2015259355A1PendingUtilityA1
Process for improved opioid synthesis
Est. expiryJul 16, 2032(~6 yrs left)· nominal 20-yr term from priority
A61P 25/20A61P 25/36A61P 25/24A61P 25/04A61P 25/30A61P 11/14A61P 1/10A61P 1/12Y02P20/55C07D 489/08
56
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Claims
Abstract
Compounds and compositions for use as starting materials or intermediate materials in the preparation of opioids including, e.g., oxycodone base and/or an oxycodone salt; processes for preparing these compounds and compositions; uses of these compounds and compositions in the preparation of APIs and pharmaceutical dosage forms; and uses of said APIs and pharmaceutical dosage forms in the treatment of medical conditions.
Claims
exact text as granted — not AI-modified1 . A process for preparing a compound of formula V or a solvate thereof
from a compound of formula I or a salt or solvate thereof, the process comprising:
(a) oxidizing the compound of formula I; and
(b) adding an acid H + n X n− to the reaction mixture before, during and/or after the oxidation reaction,
wherein,
R 1 is —CH 3 ;
R 2 is —H, —CH 3 , —(C 2 -C 7 )alkyl, —(C 2 -C 4 )alkenyl, benzyl, —(C 1 -C 7 )alkyl-(C 3 -C 7 )cycloalkyl, —CN, or an N-protecting group;
X n− is an anion selected from the group consisting of Cl − , HSO 4 − , SO 4 2− , methanesulfonate, tosylate, trifluoroacetate, H 2 PO 4 − , HPO 4 2− , PO 4 3− , oxalate, perchlorate, and any mixtures thereof; and
n is 1, 2 or 3.
2 . The process of claim 1 , wherein R 2 is —CH 3 , —CH 2 -cyclopropyl, —CH 2 -cyclobutyl, or allyl.
3 . The process of claim 1 , wherein R 2 is —CH 3 .
4 . The process of claim 1 , wherein R 2 is —H.
5 . The process of any one of the preceding claims, wherein n is 1 or 2.
6 . The process of any one of claims 1 to 5 , wherein n is 2.
7 . The process of any one of the preceding claims, wherein X n− is SO 4 2− or trifluoroacetate.
8 . The process of any one of the preceding claims, wherein X n− is SO 4 2− .
9 . The process of any one of the preceding claims, wherein the acid H + n X n− is H 2 SO 4 .
10 . The process of any one of the preceding claims, wherein the compound of formula I is
and the compound of formula V is
or a solvate thereof.
11 . The process of any one of the preceding claims, wherein the compound of formula I is
and the compound of formula V is
or a solvate thereof.
12 . The process of any one of the preceding claims, wherein the compound of formula V is a hydrate of the compound of formula V.
13 . The process of claim 12 , wherein the hydrate is a hydrate containing from 0.5 to 10.0 water molecules per molecule of the compound of formula V.
14 . The process of claim 12 , wherein the hydrate is the monohydrate or the pentahydrate of the compound of formula V.
15 . The process of any one of the preceding claims, wherein the acid H + n X n− is added to the reaction mixture before the oxidation reaction of step (a).
16 . The process of any of the preceding claims, wherein the acid H + n X n− is added during the oxidation reaction.
17 . The process of claim 15 or 16 , wherein the acid H + n X n− is added after the oxidation reaction.
18 . The process of any one of the preceding claims, comprising the additional step:
(c) precipitating the compound of formula V or solvate thereof.
19 . The process of claim 18 , wherein the precipitation is caused by the presence of the acid H + n X n− in the reaction mixture.
20 . The process of claim 18 or 19 , wherein the precipitation takes place during and/or after the oxidation reaction.
21 . The process of any one of claims 18 to 20 , wherein the precipitation is initiated and/or enhanced by adding an additional amount of the acid H + n X n− during step (b).
22 . The process of any one of claims 18 to 21 , wherein said precipitation is initiated and/or enhanced by one or more of the following:
(i) adjusting the temperature of the reaction mixture to the precipitation temperature;
(ii) addition of an antisolvent;
(iii) addition of a seed crystal;
(iv) lowering the pH;
(v) changing the ionic strength of the reaction mixture;
(vi) concentrating the reaction mixture;
(vii) reducing or stopping agitation of the reaction mixture.
23 . The process of any one of claims 18 to 22 , wherein the precipitation is initiated and/or enhanced by adjusting the temperature of the reaction mixture to reach the precipitation temperature.
24 . The process of any one of claims 18 to 23 , wherein the precipitation temperature is a temperature of ≦40° C., and preferably is ≦35° C., ≦30° C., ≦25° C., ≦20° C., ≦18° C., ≦15° C., ≦10° C., ≦5° C., or ≦0° C.
25 . The process of claim 24 , wherein the precipitation temperature is in a range of from about 0° C. to about 40° C., preferably from about 0° C. to about 35° C.
26 . The process of claim 25 , wherein the precipitation temperature is in a range of from about 5° C. to about 22° C.; preferably from about 8° C. to about 15° C.
27 . The process of any one of claims 18 to 26 , comprising the additional step:
(d) isolating the precipitate from the reaction mixture.
28 . The process of claim 27 , wherein the isolated precipitate is washed and/or (re)crystallized with a solvent which is suitable to remove from the precipitate a compound of formula III or a salt or solvate thereof
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 .
29 . The process of claim 28 , wherein the solvent is selected from the group consisting of an ether, a ketone, an ester, an alcohol, water, an alkane (which may be halogenated), an aromatic solvent (which may be halogenated) and any combination of the foregoing.
30 . The process of claim 29 , wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, tetrahydrofuran, ethyl acetate, heptane, tert-butyl methyl ether, 1,2-dichloroethane, toluene, 2-butanone (MEK), tert-amyl alcohol, chloroform, xylene, water, and any mixture of the foregoing.
31 . The process of claim 28 , 29 or 30 , wherein the solvent is tert-butyl methyl ether, tetrahydrofuran, methanol, ethanol, acetone, isopropanol, or a mixture of methanol:water, THF:water, acetone:water, isopropanol:water, or ethanol:water.
32 . The process of claim 28 , 29 or 30 , wherein the solvent is tert-butyl methyl ether, tetrahydrofuran, methanol or a methanol:water mixture.
33 . The process of any one of the preceding claims, wherein the oxidation in step (a) is performed in the presence of an oxidizing agent.
34 . The process of claim 33 , wherein the oxidizing agent is selected from the group consisting of peracids, peroxides including H 2 O 2 and peroxide salts, periodinanes, singlet oxygen and any combinations of the foregoing.
35 . The process of claim 34 , wherein the oxidizing agent comprises or is at least one peracid.
36 . The process of claim 35 , wherein the at least one peracid is generated in situ in the reaction mixture of step (a) from hydrogen peroxide and at least one acid.
37 . The process of claim 36 , wherein the at least one acid is selected from the group consisting of formic acid, acetic acid, 3-chlorobenzoic acid, potassium monosulfate, trifluoroacetic acid, and sulfuric acid.
38 . The process of any one of claims 35 to 37 , wherein the at least one peracid is selected from the group consisting of performic acid, peracetic acid, 3-chloroperoxybenzoic acid, potassium peroxymonosulfate, trifluoro peracetic acid, persulfuric acid, and any combinations of the foregoing.
39 . The process of claim 38 , wherein the at least one peracid is performic acid, which is generated in situ in step (a) from hydrogen peroxide and formic acid.
40 . The process of claim 38 , wherein the at least one peracid is a combination of performic acid and persulfuric acid, which is generated in situ in step (a) from hydrogen peroxide, sulfuric acid and formic acid.
41 . The process of claim 35 , wherein the peracid is generated ex situ and then added to the reaction mixture.
42 . The process of any one of the preceding claims, wherein X n− is an anion selected from the group consisting of HSO 4 − , SO 4 2− , methanesulfonate, tosylate, trifluoroacetate, and combinations of the foregoing.
43 . The process of any one of the preceding claims, wherein X n− is HSO 4 − , SO 4 2− , methanesulfonate, or trifluoroacetate.
44 . The process of any one of the preceding claims, wherein X n− is HSO 4 − or SO 4 2− .
45 . The process of any one of the preceding claims, wherein X n− is SO 4 2− .
46 . The process of any one of the preceding claims, wherein X n− is polymer-supported.
47 . The process of any one of the preceding claims, wherein X n− is not polymer-supported.
48 . The process of any one of the preceding claims, wherein H + n X n− is generated in situ by adding a salt containing X n− to the reaction mixture, wherein the salt containing X n− has the formula M m+ (H + ) (n-m) X n− , or M m+ ((n-l)/m) (H + ) l X n− , and wherein
M m+ is a monovalent or polyvalent metal cation; m and n are independently an integer selected from 1, 2, and 3, provided that m≦n; and l is an integer selected from 0, 1, and 2, provided that 1<n.
49 . The process of any one of the preceding claims, wherein step (b) is performed by adding a Lewis acid to the reaction mixture instead of the acid H + n X n− .
50 . The process of any one of the preceding claims, wherein n is 2 and the acid H + n X n− added in step (b) is added in an amount of from about 0.1 to about 1.5 molar equivalents, preferably of from about 0.1 to about 1.2 molar equivalents, more preferably of from about 0.1 to about 1 molar equivalents, even more preferably of from about 0.25 to about 0.75 molar equivalents, even more preferably of from about 0.4 to about 0.6 molar equivalents, even more preferably of from about 0.45 to about 0.55 molar equivalents per molar equivalent of the compound of formula I.
51 . The process of claim 50 , wherein the acid H + n X n− added in step (b) is added in an amount of from about 0.51 to about 0.55 molar equivalents per molar equivalent of the compound of formula I.
52 . The process of claim 50 or 51 , wherein H 2 SO 4 is the acid H + n X n− added in step (b).
53 . The process of any one of the preceding claims, wherein n is 1 and the acid H + n X n− added in step (b) is added in an amount of from about 0.2 to about 3 molar equivalents, preferably of from about 0.7 to about 2.4 molar equivalents, more preferably of from about 0.8 to about 2 molar equivalents, even more preferably of from about 0.8 to about 1.6 molar equivalents, even more preferably of from about 0.8 to about 1.2 molar equivalents, even more preferably of from about 0.9 to about 1.1 molar equivalents per molar equivalent of the compound of formula I.
54 . The process of claim 53 , wherein the acid H + n X n− added in step (b) is added in an amount of about 1 molar equivalents per molar equivalent of the compound of formula I.
55 . The process of claim 53 or 54 , wherein the acid H + n X n− added in step (b) is methanesulfonic acid or trifluoroacetic acid.
56 . The process of any one of the preceding claims, wherein n is 3 and the acid H + n X n− added in step (b) is added in an amount of from about 0.07 to about 1 molar equivalents, preferably of from about 0.23 to about 0.8 molar equivalents, more preferably of from about 0.26 to about 0.66 molar equivalents, even more preferably of from about 0.26 to about 0.53 molar equivalents, even more preferably of from about 0.26 to about 0.4 molar equivalents, even more preferably of from about 0.3 to about 0.36 molar equivalents per molar equivalent of the compound of formula I.
57 . The process of claim 56 , wherein the acid H + n X n− added in step (b) is added in an amount of about 0.33 molar equivalents per molar equivalent of the compound of formula I.
58 . The process of claim 56 or 57 , wherein H 3 PO 4 is the acid H + n X n− added in step (b).
59 . The process of any one of the preceding claims, wherein in step (b) the H + n X n− is added in an amount of about 1/n molar equivalents per molar equivalent of the compound of formula I.
60 . The process of any one of the preceding claims, wherein the oxidation is performed with an oxidizing agent, and the oxidizing agent comprises or is at least one peracid generated in situ from hydrogen peroxide and at least one acid in the reaction mixture.
61 . The process of claim 60 , wherein the at least one acid used for generating the peracid comprises or is formic acid.
62 . The process of claim 60 or 61 , wherein the amount of the at least one acid used for generating the peracid is from about 0.5 to about 14 molar equivalents, preferably from about 1 to about 12 molar equivalents, more preferably from about 1 to about 7 molar equivalents, more preferably from about 1.5 to about 6 molar equivalents, more preferably from about 2 to about 4.5 molar equivalents, even more preferably from about 2.5 to 4 molar equivalents per molar equivalent of the compound of formula I.
63 . The process of any one of claims 60 to 62 , wherein the total amount of acid in the reaction mixture, including the acid H + n X n− and the at least one acid used for generating the peracid, is from about 0.6 to about 14.0 molar equivalents of total acid per molar equivalent of the compound of formula I.
64 . The process of claim 63 , wherein the total amount of acid is from about 1 to about 12, from about 1 to about 10, from about 1 to about 8, from about 1 to about 7, from about 1 to about 6.5, from about 1 to about 6, from about 1 to about 5.5, from about 1 to about 4.5, from about 1 to about 4, from about 1 to about 3.5, or from about 1.5 to about 3.5 molar equivalents of total acid per molar equivalent of the compound of formula I.
65 . The process of claim 63 , wherein the total amount of acid is from about 1 to about 8 molar equivalents, preferably from about 1.5 to about 4.5 molar equivalents of total acid per molar equivalent of the compound of formula I.
66 . The process of any one of claims 60 to 65 , wherein the molar ratio of the acid H + n X n− to the at least one acid used for generating the peracid is from about 1:20 to about 1:0.5, from about 1:17 to about 1:1, from about 1:15 to about 1:1, from about 1:14 to about 1:1, from about 1:12 to about 1:1, from about 1:10 to about 1:1, from about 1:9 to about 1:2, from about 1:8 to about 1:3, from about 1:7 to about 1:3, from about 1:7 to about 1:5, or is a numeric value lying within these ranges.
67 . The process of claim 66 , wherein the molar ratio of the acid H + n X n− to the at least one acid used for generating the peracid is from about 1:8 to about 1:3, preferably from about 1:7.5 to about 1:4, more preferably from about 1:7 to about 1:5, or is a numeric value lying within these ranges.
68 . The process of claim 66 , wherein the molar ratio of the acid H + n X n− to the at least one acid used for generating the peracid is about 1:7, about 1:6.5, about 1:6, about 1:5.5, or about 1:5.
69 . The process of any one of the preceding claims, wherein the compound of formula V or the solvate thereof is precipitated and wherein the precipitation temperature is ≦40° C., and the total amount of acid present in the reaction mixture is from about 0.6 to about 14.0 molar equivalents of total acid per molar equivalent of the compound of formula I.
70 . The process of claim 69 , wherein the precipitation temperature is in a range of from about 0° C. to about 40° C., preferably from about 0° C. to about 35° C., and the total amount of acid present in the reaction mixture is from about 1 to about 8 molar equivalents, preferably from about 1 to about 5 molar equivalents, more preferably from about 1 to about 3 molar equivalents of total acid per molar equivalent of the compound of formula I.
71 . The process of claim 69 , wherein the precipitation temperature is in a range of from about 5° C. to about 22° C., and the total amount of acid present in the reaction mixture is from about 1 to about 7 molar equivalents, preferably from about 1 to about 5 molar equivalents of total acid per molar equivalent of the compound of formula I.
72 . The process of any one of the preceding claims, wherein the pH in step (a) and (b) is less than 7, preferably the pH is 4 or less, more preferably 2.5 or less, even more preferably from 1 to 2.
73 . The process of any one of the preceding claims, wherein X n− in step (b) is SO 4 2− and the compound of formula V is
or a solvate thereof.
74 . The process of claim 73 , wherein the SO 4 2 is provided by addition of sulfuric acid as acid H + n X n− in step (b).
75 . The process of claim 73 , wherein the SO 4 2− is provided by addition of NaHSO 4 instead of the acid H + n X n− in step (b).
76 . The process of any one of claims 73 to 75 , wherein the compound of formula V is 14-hydroxycodeinone sulfate.
77 . The process of any one of claims 73 to 75 , wherein the compound of formula V is a solvate of 14-hydroxycodeinone sulfate.
78 . The process of any one of claims 73 to 75 and 77 , wherein the solvate of the compound of formula V is a hydrate.
79 . The process of claim 78 , wherein the hydrate is a hydrate containing from 0.5 to 10 water molecules per molecule of the compound of formula V.
80 . The process of claim 78 or 79 , wherein the hydrate is a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate.
81 . The process of claim 80 , wherein the hydrate is a monohydrate or a pentahydrate.
82 . The process of any one of the preceding claims, wherein the reaction mixture comprises a solvent.
83 . The process of claim 82 , wherein the solvent is selected from the group consisting of water, alcohols, aromatic hydrocarbons (which are optionally halogenated), aliphatic hydrocarbons (which are optionally halogenated), ethers, (C 1 -C 4 ) alkyl esters of (C 1 -C 4 ) alkanoic acids, amides, N-methylpyrrolidone, formylmorpholine, and any combinations of the foregoing.
84 . The process of claim 82 , wherein the solvent is selected from the group consisting of water, ethers, alcohols, (C 1 -C 4 ) alkanes (which are optionally chlorinated), and combinations of the foregoing.
85 . The process of claim 83 , wherein the solvent is tetrahydrofuran, isopropanol, methanol, ethanol, butanol, isobutanol, tert-amyl alcohol, n-propanol, chloroform, or a combination of two or more of the foregoing.
86 . The process of any one of claims 82 to 85 , wherein the solvent is water or a combination of water with another solvent listed in claim 83 , 84 or 85 .
87 . The process of any one of claims 82 to 85 , wherein the solvent is isopropanol or a combination of isopropanol with water.
88 . The process of any one of claims 82 to 87 , wherein the oxidation reaction is performed in the presence of at least one peracid generated from at least one acid, and wherein the at least one acid used for generating the peracid acts as a solvent.
89 . The process of claim 88 , wherein the acid used for generating the peracid is formic acid.
90 . The process of any one of claims 82 to 89 , wherein the acid H + n X n− acts as a solvent.
91 . The process of claim 90 , wherein the acid H + n X n− is sulfuric acid.
92 . The process of any one of claims 82 to 91 , wherein the molarity of the compound of formula I in relation to the solvent is ≧0.8, and preferably is from 0.8 to 1.8, more preferably from 1.2 to 1.6 and even more preferably from 1.3 to 1.5.
93 . The process of any one of the preceding claims, wherein the compound of formula I is thebaine or a salt or solvate thereof.
94 . The process of claim 93 , wherein the thebaine, or the salt or solvate thereof is contained in CPS-T.
95 . The process of any one of the preceding claims, wherein
the compound of formula (I) is thebaine or a salt or solvate thereof, the oxidation agent comprises or is performic acid formed from hydrogen peroxide and formic acid, the acid H + n X n− in step (b) is sulfuric acid which is added to the reaction mixture, and the compound of formula V is 14-hydroxycodeinone sulfate or a solvate thereof.
96 . The process of claim 95 , wherein the total amount of acid in the reaction mixture, including the acid H + n X n− and the at least one acid used for generating the peracid, is from about 0.6 to about 14.0 molar equivalents of total acid per molar equivalent of the compound of formula I.
97 . The process of claim 95 , wherein the total amount of acid in the reaction mixture, including the acid H + n X n− and the at least one acid used for generating the peracid, is from about 1 to about 10 molar equivalents, more preferably from about 1 to about 8 molar equivalents, more preferably from about 1 to about 7, more preferably from about 1 to about 6, more preferably from about 1 to about 5.5 molar equivalents, more preferably from about 1 to about 4.5 molar equivalents, even more preferably from about 1 to about 3.5 molar equivalents of total acid per molar equivalent of the compound of formula I.
98 . The process of any one of claims 95 to 97 , wherein the sulfuric acid added in step (b) is added in an amount of from about 0.1 to about 1.5 molar equivalents, preferably of from about 0.1 to about 1.2 molar equivalents, more preferably of from about 0.1 to about 1 molar equivalents, even more preferably of from about 0.25 to about 0.75 molar equivalents, even more preferably of from about 0.4 to about 0.6 molar equivalents, even more preferably of from about 0.45 to about 0.55 molar equivalents per molar equivalent of the compound of formula I.
99 . The process of claim 98 , wherein the sulfuric acid is added in an amount of from about 0.5 to about 0.55 molar equivalents per molar equivalent of the compound of formula I.
100 . The process of claim 99 , wherein the sulfuric acid is added in an amount of about 0.54 molar equivalents per molar equivalent of the compound of formula I.
101 . The process of claim 99 , wherein the sulfuric acid is added in an amount of about 0.51 molar equivalents per molar equivalent of the compound of formula I.
102 . The process of any one of claims 95 to 101 , wherein the solvent comprises water.
103 . The process of any one of the preceding claims, wherein in the product containing the compound of formula V the amount of a compound having the formula III
wherein R 1 and R 2 are defined as in the compound of formula V,
or a salt or solvate thereof
in relation to the amount of the component of formula V which has the formula II
in the product resulting from step (b) and/or step (c) is reduced in comparison to a process performed without H + n X n− .
104 . The process of claim 103 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula II in the product is reduced by precipitating the compound of formula V or a solvate thereof and isolating it from the reaction mixture.
105 . The process of claim 103 or 104 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula II in the product is reduced because of the presence of H + n X n− during the oxidation reaction.
106 . The process of claim 103 or 104 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula II in the product is reduced by using sulfuric acid as the acid H + n X n− .
107 . The process of any one of claims 103 to 106 , wherein the total amount of acid in the reaction mixture is from about 0.6 to about 14.0 molar equivalents of total acid per molar equivalent of the compound of formula I, preferably from about 1 to about 10 molar equivalents, more preferably from about 1 to about 8 molar equivalents, more preferably from about 1 to about 7, more preferably from about 1 to about 6, more preferably from about 1 to about 5.5 molar equivalents, more preferably from about 1 to about 4.5 molar equivalents, even more preferably from about 1 to about 3.5 molar equivalents of total acid per molar equivalent of the compound of formula I.
108 . The process of any one of claims 103 to 107 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula II in the product is less than about 2500 ppm, less than about 2250 ppm, less than about 2000 ppm, less than about 1750 ppm, less than about 1500 ppm, or less than about 1250 ppm.
109 . The process of claim 108 , wherein the amount of the compound having the formula III in relation to the amount of the compound of formula II in the product is less than about 1000 ppm, less than about 750 ppm, less than about 500 ppm, less than about 400 ppm, less than about 300 ppm, less than about 275 ppm, less than about 250 ppm, less than about 225 ppm, less than about 200 ppm, less than about 175 ppm, less than about 150 ppm, or less than about 125 ppm.
110 . The process of claim 108 , wherein the amount of the compound having the formula III in relation to the amount of the compound of formula II in the product is from about 0.01 ppm to about 2500 ppm, from about 0.05 to about 2250 ppm, from about 0.1 ppm to about 2000 ppm, from about 0.3 to about 1750 ppm, from about 0.5 ppm to about 1500 ppm, or from about 1 ppm to about 1250 ppm.
111 . The process of any one of claims 103 to 109 , wherein the compound having the formula III is 8-hydroxyoxycodone and wherein the compound having the formula II is 14-hydroxycodeinone, and wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula II in the product is less than about 2500 ppm, less than about 2250 ppm, less than about 2000 ppm, less than about 1750 ppm, less than about 1500 ppm, less than about 1250 ppm, less than about 1000 ppm, less than about 750 ppm, less than about 500 ppm, less than about 400 ppm, less than about 300 ppm, or less than about 200 ppm.
112 . The process of any one of the preceding claims, with the proviso that the compound of formula V is not
14-hydroxycodeinone triflate or 14-hydroxycodeinone chloride.
113 . The process of any one of the preceding claims, with the proviso that the compound of formula V is not precipitated by adding the reaction mixture after the oxidation reaction to a solvent containing sulfuric acid, methanesulfonic acid, phosphoric acid or HCl, when R 2 is selected from —H, —CH 3 , optionally unsaturated —(C 2 -C 6 )alkyl, and —(C 1 -C 4 )alkyl substituted with a cycloalkyl group.
114 . The process of any one of the preceding claims, with the proviso that the compound of formula V is not 14-hydroxycodeinone oxalate prepared by oxidation with H 2 O 2 or a peracid in the presence of oxalic acid.
115 . A compound having the formula V or a solvate thereof
wherein R 1 , R 2 , X n− and n are defined as in any one of claims 1 to 8 .
116 . The compound having the formula V of claim 115 , wherein n is 1 or 2.
117 . The compound having the formula V of claim 115 or 116 , wherein n is 2.
118 . The compound having the formula V of claim 116 , wherein X n− is SO 4 2− or trifluoroacetate.
119 . The compound having the formula V of any one of claims 115 to 118 , wherein X n− is SO 4 2− .
120 . The compound having the formula V of any one of claims 115 to 119 , wherein R 2 is —CH 3 .
121 . The compound having the formula V of any one of claims 115 to 119 , wherein R 2 is —H.
122 . The compound having the formula V of any one of claims 115 to 121 , which is
or a solvate thereof.
123 . The compound having the formula V of claim 115 , which is
or a solvate thereof.
124 . The compound having the formula V of claim 115 , which is
or a solvate thereof.
125 . The compound having the formula V of any one of claims 115 to 124 , which is the hydrate of the compound of formula V.
126 . The compound having the formula V of claim 125 , wherein the hydrate is a hydrate containing from 0.1 to 6.9 water molecules per molecule of the compound of formula V.
127 . The compound of claim 125 , which is a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate.
128 . The compound of claim 125 , which is a monohydrate or a pentahydrate.
129 . The compound having the formula V of any one of claims 115 to 128 , with the proviso that the compound is not
14-hydroxycodeinone triflate or 14-hydroxycodeinone chloride.
130 . The compound having the formula V of any one of claims 115 to 128 , with the proviso that when
R 2 is selected from —H, —CH 3 , optionally unsaturated —(C 2 -C 6 )alkyl, and —(C 1 -C 4 )alkyl substituted with a cycloalkyl group, then
the compound having the formula V is not
131 . The compound having the formula V of any one of claims 115 to 128 , with the proviso that it is not
14-hydroxycodeinone perchlorate.
132 . The compound having the formula V of any one of claims 115 to 131 , which is obtainable by the process according to any one of claims 1 to 92 .
133 . A composition comprising the compound of formula V according to any one of claims 115 to 132 .
134 . The composition of claim 133 , which additionally comprises a compound of formula III
wherein R 1 and R 2 are defined as in the compound of formula V,
or a salt or solvate thereof.
135 . The composition of claim 134 , wherein the amount of the compound of formula III in the composition is less than about 2500 ppm, less than about 2250 ppm, less than about 2000 ppm, less than about 1750 ppm, less than about 1500 ppm, or less than about 1250 ppm of the compound of formula V (HPLC peak area ratio).
136 . The composition of claim 134 , wherein the amount of the compound of formula III in the composition is less than about 1000 ppm, less than about 750 ppm, less than about 500 ppm, less than about 400 ppm, less than about 300, less than about 250 ppm, less than about 200 ppm, or less than about 150 ppm of the compound of formula V (HPLC peak area ratio).
137 . The composition of claim 134 , wherein the amount of the compound of formula III in the composition is less than about 100 ppm, less than about 90 ppm, less than about 80 ppm, less than about 70 ppm, less than about 60 ppm, less than about 50 ppm, less than about 40 ppm, less than about 30 ppm, or less than about 20 ppm of the compound of formula V (HPLC peak area ratio).
138 . The composition of claim 134 , wherein the amount of the compound of formula III in the composition is less than about 10 ppm, less than about 8 ppm, less than about 6 ppm, less than about 4 ppm, or less than about 2 ppm of the compound of formula V (HPLC peak area ratio).
139 . The composition of claim 134 , wherein the amount of the compound of formula III in the composition is less than about 1 ppm, less than about 0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less than about 0.1 ppm of the compound of formula V (HPLC peak area ratio).
140 . Use of the compound of formula V according to any one of claims 115 to 139 or a solvate thereof as an intermediate or starting material for preparing an opioid or a pharmaceutically acceptable salt or solvate thereof, and/or a medicament containing an opioid or a pharmaceutically acceptable salt or solvate.
141 . Use of a compound of formula V or a solvate thereof
wherein R 1 , R 2 , X n− and n are defined as in any one of claims 1 to 8 ,
for the reduction of at least one by-product in the synthesis of a compound of formula IV or a salt or solvate thereof
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 .
142 . The use of claim 141 , wherein the at least one by-product is a compound of formula II
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof.
143 . The use of claim 142 , wherein the amount of the compound of formula II in relation to the amount of the compound having the formula IV in the synthesis product is less than about 500 ppm, less than about 250 ppm, less than about 200 ppm, less than about 100 ppm, less than about 50 ppm, less than about 40 ppm, less than about 30 ppm, less than about 25 ppm, less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, less than about 5 ppm, less than about 2.5 ppm, or less than about 1 ppm (HPLC peak area ratio).
144 . The use of any one of claims 141 to 143 , wherein the at least one by-product is a compound of formula III
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof.
145 . The use of claim 144 , wherein the amount of the compound of formula III in relation to the amount of the compound having the formula IV in the synthesis product is less than about 1000 ppm, less than about 500 ppm, less than about 300 ppm, less than about 250 ppm, less than about 200 ppm, less than about 150 ppm, less than about 100 ppm, less than about 50 ppm, less than about 20 ppm, or less than about 10 ppm of the compound of formula IV (HPLC peak area ratio).
146 . Use of the composition comprising the compound of formula V or a salt or solvate thereof according to any one of claims 133 to 139 as an intermediate or starting material for preparing an opioid or a pharmaceutically acceptable salt or solvate thereof, and/or a medicament containing an opioid or a pharmaceutically acceptable salt or solvate.
147 . Use of the composition comprising the compound of formula V or a salt or solvate thereof according to any one of claims 133 to 139
wherein R 1 , R 2 , X n− and n are defined as in any one of claims 1 to 8 ,
for the reduction of at least one by-product in the synthesis of a compound of formula IV or a salt or solvate thereof
wherein R 1 and R 2 are defined as in any one of claims 1 to 6 .
148 . The use of claim 147 , wherein the at least one by-product is a compound of formula II
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof.
149 . The use of claim 148 , wherein the amount of the compound of formula II in relation to the amount of the compound having the formula IV in the synthesis product is less than about 500 ppm, less than about 250 ppm, less than about 200 ppm, less than about 100 ppm, less than about 50 ppm, less than about 40 ppm, less than about 30 ppm, less than about 25 ppm, less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, less than about 5 ppm, less than about 2.5 ppm, or less than about 1 ppm (HPLC peak area ratio).
150 . The use of any one of claims 147 to 149 , wherein the at least one by-product is a compound of formula III
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof.
151 . The use of claim 150 , wherein the amount of the compound of formula III in relation to the amount of the compound having the formula IV in the synthesis product is less than about 1000 ppm, less than about 500 ppm, less than about 300 ppm, less than about 250 ppm, less than about 200 ppm, less than about 150 ppm, less than about 100 ppm, less than about 50 ppm, less than about 20 ppm, or less than about 10 ppm of the compound of formula IV (HPLC peak area ratio).
152 . A process for preparing a compound of formula IV or a salt or solvate thereof from a compound having formula V or a solvate thereof
the process comprising the steps of
(e) providing a solution or suspension of the compound having formula V or a solvate thereof as defined in any one of claims 115 to 132 ; and
(f) reducing the compound of formula V to the compound of formula IV,
wherein R 1 , R 2 , X n− and n are defined as in any one of claims 1 to 8 .
153 . The process of claim 152 , wherein the reduction reaction in step (f) is performed by hydrogenation.
154 . The process of claim 153 , wherein the hydrogenation is transfer hydrogenation or hydrogenation with H 2 .
155 . The process of any one of claims 152 to 154 , wherein the compound of formula V is
or a solvate thereof,
and the compound of formula IV is
or a salt or solvate thereof.
156 . The process of any one of claims 152 to 155 , wherein the compound of formula V is 14-hydroxycodeinone sulfate or a solvate thereof, and the compound of formula IV is oxycodone or a salt or solvate thereof.
157 . The process of any one of claims 152 to 156 , wherein the salt or solvate of the compound of formula IV is a pharmaceutically acceptable salt or solvate.
158 . The process of any one of claims 152 to 156 , wherein the compound of formula IV is prepared in the form of its salt
wherein R 1 , R 2 , X n− and n are defined as in any one of claims 1 to 8 ,
or a solvate thereof.
159 . The process of claim 158 , additionally comprising the step
(g) isolating the salt
or the solvate thereof.
160 . The process of claim 159 , wherein the salt is isolated by precipitation.
161 . The process of claim 160 , wherein the precipitation is performed by adding an antisolvent during and/or after the reduction reaction.
162 . The process of any one of claims 158 to 161 , wherein X n− is SO 4 2− .
163 . The process of any one of claims 158 to 161 , wherein X n− is trifluoroacetate.
164 . The process of any one of claims 158 to 162 , wherein the salt of the compound of formula IV is oxycodone sulfate or a solvate thereof.
165 . The process of any one of claims 158 to 162 , wherein the salt of the compound of formula IV is oxycodone trifluoroacetate or a solvate thereof.
166 . The process of any one of claims 152 to 165 , additionally comprising the step of preparing the salt or solvate of formula V according to the process of any one of claims 1 to 114 .
167 . The process of claim 166 , wherein
the compound of formula (I) is thebaine or a salt or solvate thereof, the oxidation agent comprises or is performic acid formed in situ from hydrogen peroxide and formic acid, the acid H + n X n− in step (b) is sulfuric acid which is added to the reaction mixture, the compound having formula V is 14-hydroxycodeinone sulfate or a solvate thereof, and the compound of formula IV is oxycodone or a salt or solvate thereof.
168 . The process of any one of claims 158 to 167 , wherein the compound having formula V or a solvate thereof is precipitated and isolated before the reduction step.
169 . The process of any one of claims 158 to 168 , wherein the component of the compound having formula V which is a compound of formula II is liberated from the compound of formula V as free base before the reduction step.
170 . A compound of formula IV
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof,
obtainable by the process according to any one of claims 152 to 169 .
171 . Oxycodone trifluoroacetate or a pharmaceutically acceptable solvate thereof.
172 . A composition comprising a compound of formula IV
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof,
which additionally comprises an amount of a compound of formula III
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof,
wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula IV is less than about 2500 ppm, less than about 2000 ppm, less than about 1500 ppm, less than about 1000 ppm, or less than about 500 ppm (HPLC peak area ratio).
173 . The composition of claim 172 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula IV is less than about 300 ppm, less than about 250 ppm, less than about 200 ppm, less than about 150 ppm, less than about 100 ppm, less than about 50 ppm, or less than about 20 ppm (HPLC peak area ratio).
174 . The composition of claim 172 , wherein the amount of the compound having the formula III in relation to the amount of the compound having the formula IV is less than about 10 ppm, less than about 6 ppm, less than about 2 ppm, less than about 1 ppm, less than about 0.8 ppm, less than about 0.6 ppm, less than about 0.4 ppm, less than about 0.3 ppm, less than about 0.2 ppm, or less than about 0.1 ppm (HPLC peak area ratio).
175 . A composition comprising a compound of formula IV
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof,
which additionally comprises an amount of a compound of formula II
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof,
wherein the amount of the compound of formula II in relation to the amount of the compound having the formula IV is less than about 500 ppm, less than about 250 ppm, less than about 200 ppm, less than about 100 ppm, less than about 50 ppm, less than about 40 ppm, or less than about 30 ppm (HPLC peak area ratio).
176 . The composition of claim 175 , wherein the amount of the compound of formula II in relation to the amount of the compound having the formula IV is less than about 25 ppm, less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, less than about 5 ppm, less than about 2.5 ppm, or less than about 1 ppm (HPLC peak area ratio).
177 . A composition comprising a compound of formula IV
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof,
which additionally comprises an amount of a compound of formula III
wherein R 1 and R 2 are defined as in any one of claims 1 to 4 ,
or a salt or solvate thereof, and
which additionally comprises an amount of a compound of formula II
wherein R 1 and R 2 , are defined as in any one of claims 1 to 4 ,
or a pharmaceutically acceptable salt or solvate thereof, wherein the combined amount of the compound of formula II and III in the composition is less than about 3000 ppm, less than about 2500 ppm, less than about 2000 ppm, less than about 1500 ppm, less than about 1000 ppm, less than about 500 ppm, less than about 400 ppm, or less than about 300 ppm in relation to the amount of the compound of formula IV (HPLC peak area ratio).
178 . The composition of claim 177 , wherein the combined amount of the compound of formula II and III in the composition is less than about 250 ppm, less than about 200 ppm, less than about 150 ppm, less than about 100 ppm, less than about 50 ppm, or less than about 20 ppm in relation to the amount of the compound of formula IV (HPLC peak area ratio).
179 . The composition of claim 177 ,
wherein the amount of the compound of formula III in relation to the amount of the compound of formula IV is less than about 1000 ppm, less than about 500 ppm, less than about 300 ppm, less than about 250 ppm, less than about 200 ppm, less than about 150 ppm, less than about 100 ppm, less than about 50 ppm, less than about 20 ppm, or less than about 10 ppm of the compound of formula IV (HPLC peak area ratio), and wherein the amount of the compound of formula II in relation to the amount of the compound of formula IV is less than about 200 ppm, less than about 100 ppm, less than about 50 ppm, less than about 25 ppm, less than about 20 ppm, less than about 15 ppm, less than about 10 ppm, less than about 5 ppm, less than about 2.5 ppm, or less than about 1 ppm of the compound of formula IV (HPLC peak area ratio).
180 . The composition of claim 177 ,
wherein the amount of the compound of formula III in relation to the amount of the compound of formula IV is less than about 10 ppm, less than about 5 ppm, less than about 4 ppm, less than about 3 ppm, less than about 2 ppm, less than about 1 ppm, or less than about 0.5 ppm, and wherein the amount of the compound of formula II in relation to the amount of the compound of formula IV is less than about 10 ppm, less than about 5 ppm, less than about 3 ppm, less than about 2 ppm, less than about 1 ppm, or less than about 0.5 ppm.
181 . The composition of any one of claims 172 to 180 , wherein the compound of formula IV is oxycodone or a pharmaceutically acceptable salt or solvate thereof.
182 . The composition of any one of claims 172 to 180 , wherein the compound of formula IV is oxycodone sulfate or a solvate thereof.
183 . The composition of any one of claims 172 to 180 , wherein the compound of formula IV is oxycodone trifluoroacetate or a solvate thereof.
184 . Use of the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 as an intermediate or starting material for preparing an opioid or a pharmaceutically acceptable salt or solvate thereof, and/or for preparing a medicament containing the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof, or containing another opioid or a pharmaceutically acceptable salt or solvate thereof.
185 . Use of the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 for preparing a medicament containing the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one other opioid or pharmaceutically acceptable salt or solvate thereof.
186 . The use of claim 185 , wherein the medicament contains oxycodone hydrochloride as the compound of formula IV according to claim 170 or 171 .
187 . The use of claim 186 , wherein the medicament additionally contains naloxone hydrochloride.
188 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 for use as a medicament.
189 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 188 , wherein the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof is combined with at least one other opioid or pharmaceutically acceptable salt or solvate thereof in the medicament.
190 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 188 , wherein the medicament contains oxycodone hydrochloride as the compound of formula IV according to claim 170 or 171 .
191 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 190 , wherein the medicament additionally contains naloxone hydrochloride.
192 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 for use in the treatment or prevention of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, or a combination of two or more of the foregoing.
193 . The compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 for use in the treatment of pain.
194 . A method for treating or preventing a medical condition selected from the group consisting of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, and combinations of two or more of the foregoing, in an animal using the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of claim 170 or 171 .
195 . A method for treating or preventing pain in an animal using the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to claim 170 or 171 .
196 . A method for treating or preventing a medical condition selected from the group consisting of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, and combinations of two or more of the foregoing in an animal, comprising administering to an animal in need thereof an effective amount of the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to claim 170 or 171 .
197 . A method for treating or preventing pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to claim 170 or 171 .
198 . The method of any one of claims 194 to 197 , wherein the animal is a mammal.
199 . The method of any one of claims 194 to 197 , wherein the animal is a human.
200 . Use of a composition comprising the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of any one of claims 172 to 183 as an intermediate or starting material for preparing an opioid or a pharmaceutically acceptable salt or solvate thereof, and/or for preparing a medicament containing the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof, or containing another opioid or a pharmaceutically acceptable salt or solvate thereof.
201 . Use of the composition comprising the compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of any one of claims 172 to 183 for preparing a medicament containing the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof, optionally in combination with at least one other opioid or pharmaceutically acceptable salt or solvate thereof.
202 . The use of claim 201 , wherein the medicament contains oxycodone hydrochloride as the compound of formula IV comprised in the composition according to any one of claims 172 to 183 .
203 . The use of claim 201 , wherein the medicament additionally contains naloxone hydrochloride.
204 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of any one of claims 172 to 183 for use as a medicament.
205 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 204 , wherein the compound of formula IV or the pharmaceutically acceptable salt or solvate thereof is combined with at least one other opioid or pharmaceutically acceptable salt or solvate thereof in the medicament.
206 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 204 , wherein the medicament contains oxycodone hydrochloride as the compound of formula IV comprised in the composition according to any one of claims 172 to 183 .
207 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof for use of claim 204 , wherein the medicament additionally contains naloxone hydrochloride.
208 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of any one of claims 172 to 183 for use in the treatment or prevention of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, or a combination of two or more of the foregoing.
209 . The composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof of any one of claims 172 to 183 for use in the treatment of pain.
210 . A method for treating or preventing a medical condition selected from the group consisting of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, and combinations of two or more of the foregoing, in an animal using the composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to any one claims 172 to 183 .
211 . A method for treating or preventing pain in an animal using the composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to any one claims 172 to 183 .
212 . A method for treating or preventing a medical condition selected from the group consisting of pain, addiction, cough, constipation, diarrhea, insomnia associated with and/or caused by pain, cough or addiction, depression associated with and/or resulting from pain, cough or addiction, and combinations of two or more of the foregoing in an animal, comprising administering to an animal in need thereof an effective amount of the composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 172 to 183 .
213 . A method for treating or preventing pain in an animal, comprising administering to an animal in need thereof an effective amount of the composition comprising a compound of formula IV or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 172 to 183 .
214 . The method of any one of claims 210 to 213 , wherein the animal is a mammal.
215 . The method of any one of claims 210 to 213 , wherein the animal is a human.
216 . The process, compound, composition or use of any one of the preceding claims, wherein the solvate is a hydrate.
217 . The process, compound, composition or use of claim 216 , wherein the hydrate is a hydrate containing from 0.5 to 10.0 water molecules per molecule of the compound.
218 . The process, compound, composition or use of claim 216 , wherein the hydrate is a hydrate containing from 0.1 to 6.9 water molecules per molecule of the compound.
219 . The process, compound, composition or use of claim 216 , wherein the solvate is a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, or hexahydrate.
220 . The process, compound, composition or use of claim 216 , wherein the solvate is a monohydrate.
221 . The process, compound, composition or use of claim 216 , wherein the solvate is a pentahydrate.Cited by (0)
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