WO2003018588A2 - Process for the preparation of a 14-hydroxynormorphinone derivative - Google Patents
Process for the preparation of a 14-hydroxynormorphinone derivative Download PDFInfo
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- WO2003018588A2 WO2003018588A2 PCT/EP2002/009280 EP0209280W WO03018588A2 WO 2003018588 A2 WO2003018588 A2 WO 2003018588A2 EP 0209280 W EP0209280 W EP 0209280W WO 03018588 A2 WO03018588 A2 WO 03018588A2
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- Prior art keywords
- formula
- derivative
- benzyl
- hydroxynormoφhinone
- moφhine
- Prior art date
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- 0 CC(C([C@@]1(C2)c3c4O[C@]11)C=CC1=O)C2(C*)Cc3ccc4O Chemical compound CC(C([C@@]1(C2)c3c4O[C@]11)C=CC1=O)C2(C*)Cc3ccc4O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
Definitions
- the invention relates to a process for the production of 14-hydroxynormo ⁇ hinone derivatives, to a new synthetic route for producing noroxymorphone, as well as to new intermediates in said route.
- Noroxymorphone is a key intermediate for the production of important medicinal opioids, such as naltrexone and naloxone.
- the common starting material for the production of these opioids is thebaine from which they are readily synthesized.
- thebaine has only a low natural abundance in poppy heads and opium.
- many alternative approaches have been made for the preparation of 14- hydroxymo hine derivatives. See for example EP 0,158,476, US 5,922,876, and the references cited therein. Further, in an attempt to remove the requirement for (the preparation of) thebaine, Coop et al.
- Ri is (l-7C)alkyl optionally substituted with one or more chlorines (such as 1,1,1 - trichloroethyl), butenyl, vinyl, benzyl, phenyl or naphthyl; and R 2 is benzyl or benzyl substituted with one or more (l-6C)alkoxy group or benzyl substituted with one or more halogen.
- the oxidation process of the present invention is an efficient process with good yields, which are significantly improved when compared to the process described by Coop et al..
- the cobalt (II) oxidant according to the present invention may be selected from a range of cobalt (II) salts, such as CoF 2 , CoCl 2 , CoBr 2 , Co(II)sulfate, Co(II)nitrate, Co(II)acetate, Co(II)propionate, and the like, and mixtures thereof.
- the preferred oxidant in the process of this invention is Co(OAc) 2 and the preferred cooxidant is air.
- the reaction mixture of this oxidation process is a heterogeneous system; the oxidant dissolves only in minor amounts in the organic solvent that is used.
- the amount of cobalt (II) salts used is not very critical, as long as the system is heterogeneous, and a skilled person will know to choose sufficient amounts thereof.
- the cooxidant is introduced into the reaction mixture by bubbling it through the solution, while stirring.
- base A person skilled in the art is aware what type of base are meant with the term mild bases, however preferred bases are sodium acetate, potassium acetate, sodium phosphate and potassium phosphate. Most preferred is sodium acetate.
- R ⁇ is (l-7C)alkyl, and most preferred is ethyl.
- benzyl is most preferred.
- the oxidation process according to the present invention is performed in an organic solvent well-suited for dissolution of this type of compounds, preferably (l-4C)alcohols or mixtures thereof. Preferred is ethanol.
- the reaction temperature is usually higher than room temperature, and may be chosen dependent on the boiling point of the solvent used. However, the temperature may not be higher than about 100 °C in order to keep the oxygen sufficiently in solution.
- alkyl group is a branched or unbranched alkyl group having 1 to 7, 1 to 6 or 1 to 4 carbon atoms, respectively, such as methyl, ethyl, isopropyl, t-butyl, heptyl and the like.
- the compound of formula III may suitably prepared by methods well known in the art.
- the process for the preparation of a compound of formula III comprises reactively contacting a morphine derivative of formula II
- an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups, where a morphinone compound of the formula III is prepared.
- the oxidizing agent is sodium dichromate.
- Ri is ethyl. For R 2 benzyl is most preferred.
- the new process of this invention may conveniently be used in the production of noroxymorphone. Therefore, another aspect of this invention is a process for the production of noroxymorphone, comprising a reaction step wherein a morphinone compound of formula LU is oxidized into the 14-hydroxynormorphinone derivative of formula IN. In particular preferred is the process further comprising the oxidation of a morphine derivative of formula II into the compound of formula III as described above.
- the novel intermediates of formula II, III and IV form each another aspect of the present invention.
- the intermediates of formula II, III and IV are in particular preferred wherein is ethyl.
- Most preferred are the intermediates of formula II, III and IV wherein Ri is ethyl and R 2 is benzyl.
- the invention is further illustrated by the following example.
- Mo ⁇ hine (1, 8 g) was dissolved in 80 ml of toluene and the solution was dried by azeotropic distillation of water.
- Sodium carbonate (15 g) and sodium hydrogen carbonate (6 g) were added and the solution was again dried by azeotropic distillation.
- Ethyl chloro formate (30 g) was slowly and in portions added over a period of approximately 4 h at 78°C. Completion of the reaction was checked with TLC. The excess of reagent and the salts were dissolved by addition of water. The layers were separated and the toluene layer was washed with water. The toluene solution was evaporated to dryness and the residue was dissolved in 70 ml of ethanol.
- the 3- carboxylic acid ethyl ester group was saponified by 6 g potassium hydroxide (dissolved in 18 ml of ethanol) and 5 g potassium carbonate at 55°C. The pH was checked (in a 1:1 dilution in water) and was >11. To this basic solution 5 g benzylchloride was added and the reaction was performed for 4 h at 75°C. The product was precipitated by the addition of water (70 ml), filtered, washed with water and dried. The yield of product (2) was 10 g.
Abstract
The present invention relates to process for the preparation of a 14-hydroxynormorphinone derivative of formula (IV) comprising reacting the compound of formula (III), with a cobalt (II) oxidant in the presence of a mild base and air or oxygen as the cooxidant; wherein R1 is (1C-7C) alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R2 is benzyl or benzyl substituted with one ore more (1C-6C) alkoxy group or benzyl substituted with one or more halogen. The process is very suitable in the production of noroxymorphone.
Description
C-14 OXIDATION OF MORPHINE DERIVATIVES
The invention relates to a process for the production of 14-hydroxynormoι hinone derivatives, to a new synthetic route for producing noroxymorphone, as well as to new intermediates in said route.
Noroxymorphone is a key intermediate for the production of important medicinal opioids, such as naltrexone and naloxone. The common starting material for the production of these opioids is thebaine from which they are readily synthesized. However, thebaine has only a low natural abundance in poppy heads and opium. As the supply of thebaine is limited and the demand is increasing, many alternative approaches have been made for the preparation of 14- hydroxymo hine derivatives. See for example EP 0,158,476, US 5,922,876, and the references cited therein. Further, in an attempt to remove the requirement for (the preparation of) thebaine, Coop et al. (Tetrahedron 55 (1999), 11429-11436; WO 00/66588) recently described an oxidative method for the production of 14-hydroxycodeinone in a yield of 51% from codeinone, using Co(OAc)3 as the metallic oxidant in acetic acid at room temperature. Other oxidative conditions with metallic oxidants, such as Co(OAc)3 under other conditions, FeCl3, Co(OAc)2 in combination with several cooxidants, RuO , Mn(OAc)3, Cu(OAc)2, and others, proved to be not very useful according to Coop.
Surprisingly, and in spite of the findings of Coop, it has now been found that in the production of 14-hydroxynormorphinone derivatives of formula IN from compounds of formula III cobalt (II) salts can be used as efficient oxidants when the reaction is performed in the presence of a mild base and oxygen or air is used as cooxidant. Therefore, the invention relates to a process for the preparation of a 14-hydroxynormorphinone derivative of formula IN
The oxidation process of the present invention is an efficient process with good yields, which are significantly improved when compared to the process described by Coop et al..
The cobalt (II) oxidant according to the present invention may be selected from a range of cobalt (II) salts, such as CoF2, CoCl2, CoBr2, Co(II)sulfate, Co(II)nitrate, Co(II)acetate, Co(II)propionate, and the like, and mixtures thereof. The preferred oxidant in the process of this invention is Co(OAc)2 and the preferred cooxidant is air. The reaction mixture of this oxidation process is a heterogeneous system; the oxidant dissolves only in minor amounts in the organic solvent that is used. The amount of cobalt (II) salts used is not very critical, as long as the system is heterogeneous, and a skilled person will know to choose sufficient amounts thereof. The cooxidant is introduced into the reaction mixture by bubbling it through the solution, while stirring.
A person skilled in the art is aware what type of base are meant with the term mild bases, however preferred bases are sodium acetate, potassium acetate, sodium phosphate and potassium phosphate. Most preferred is sodium acetate. Preferably R} is (l-7C)alkyl, and most preferred is ethyl. For R2 benzyl is most preferred. The oxidation process according to the present invention is performed in an organic solvent well-suited for dissolution of this type of compounds, preferably (l-4C)alcohols or mixtures thereof. Preferred is ethanol.
The reaction temperature is usually higher than room temperature, and may be chosen dependent on the boiling point of the solvent used. However, the temperature may not be higher than about 100 °C in order to keep the oxygen sufficiently in solution.
In the terms (l-7C)alkyl, (l-6C)alkoxy and (l-4C)alcohols the alkyl group is a branched or unbranched alkyl group having 1 to 7, 1 to 6 or 1 to 4 carbon atoms, respectively, such as methyl, ethyl, isopropyl, t-butyl, heptyl and the like.
The compound of formula III may suitably prepared by methods well known in the art. Preferably, the process for the preparation of a compound of formula III comprises reactively contacting a morphine derivative of formula II
The new process of this invention may conveniently be used in the production of noroxymorphone. Therefore, another aspect of this invention is a process for the production of noroxymorphone, comprising a reaction step wherein a morphinone compound of formula LU is oxidized into the 14-hydroxynormorphinone derivative of formula IN. In particular preferred is the process further comprising the oxidation of a morphine derivative of formula II into the compound of formula III as described above.
Especially preferred is a process for the production of noroxymorphone comprising the steps: (a) converting morphine having the formula I
by reaction with a halo formate ester of the formula X-C(=O)ORι, wherein
is as previously defined and X is a halogen (F, Cl, Br or I, preferably Cl), followed by a reaction with R2-X, wherein X (preferably Cl) and R2 are as previously defined, to form a moφhine derivative of formula II;
(b) oxidizing the morphine of formula II to form a morphinone derivative of formula III according to the previously described process;
(c) oxidizing the morphinone derivative of formula III to form a 14-hydroxynormoφhinone derivative of formula IV according to the previously described process; (d) deprotecting the 3-position and (at the same time) reducing the double bond at the 7,8- position of the 14-hydroxynoιmorphinone derivative of formula IV to form a 3,14-hydroxynor- moφhinone derivative of formula V, using methods well known in the art for such type of reaction, e.g. using hydrogen and palladium-carbon as a catalyst,
In the process for the production of noroxymoφhone, the novel intermediates of formula II, III and IV form each another aspect of the present invention. The intermediates of formula II, III
and IV are in particular preferred wherein is ethyl. Also preferred are intermediates of formula II, III and IV wherein R2 is benzyl. Most preferred are the intermediates of formula II, III and IV wherein Ri is ethyl and R2 is benzyl.
The invention is further illustrated by the following example.
EXAMPLE 1
The underlined numbers refer to the numbers of the structures of Scheme I. (Bn = benzyl).
(5α. 6 -3-rberi2yloxy -7.8-didehydro-4.5-epoxy-6-hyα^oxymoφhinan-17-carboxylic acid ethylester (2)
Moφhine (1, 8 g) was dissolved in 80 ml of toluene and the solution was dried by azeotropic distillation of water. Sodium carbonate (15 g) and sodium hydrogen carbonate (6 g) were added and the solution was again dried by azeotropic distillation. Ethyl chloro formate (30 g) was slowly and in portions added over a period of approximately 4 h at 78°C. Completion of the reaction was checked with TLC. The excess of reagent and the salts were dissolved by addition of water. The layers were separated and the toluene layer was washed with water. The toluene solution was evaporated to dryness and the residue was dissolved in 70 ml of ethanol. The 3- carboxylic acid ethyl ester group was saponified by 6 g potassium hydroxide (dissolved in 18 ml of ethanol) and 5 g potassium carbonate at 55°C. The pH was checked (in a 1:1 dilution in water) and was >11. To this basic solution 5 g benzylchloride was added and the reaction was performed for 4 h at 75°C. The product was precipitated by the addition of water (70 ml), filtered, washed with water and dried. The yield of product (2) was 10 g. 1H NMR (600 MHz, CDC13) δ 1.29 (m, 3H), 1.92 (m, 2H), 2.52 (s, 1H), 2.72 (m, 2H), 2.85 (m, 1H), 3.01 (m, 1H), 4.01 (m, 1H), 4.17 (m, 3H), 4.87 (d, 1H), 4.89 (d, 1H), 5.09 (d, 1H), 5.18 (d, 1H), 5.29 (t, 1H), 5.72 (t, 1H), 6.53 (d, 1H), 6.75 (d, 1H), 7.37 (m, 5H).
(5α)-3-(benzyloxyV7.8-didehydro-4.5-epoxy-6-oxomoφhinan-17-carboxylic acid ethylester (3 A solution of Jones reagent was prepared by dissolving 7,5 g sodium dichromate.2H2O in 22 ml water and 6 ml sulfuric acid. Compound (2) (7,5 g) was dissolved in 60 ml trichloro ethylene and
28 ml water was added. The pH was adjusted to 5 with sulfuric acid. The mixture was heated lunder reflux and the Jones reagens was slowly added over a period of 1 h. The oxidation was continued for another 1,5 h under reflux. The excess of oxidant was destroyed with 6 ml 2- propanol. The layers were separated and the organic layer was washed with 10% sodium hydrogen carbonate solution and water and dried with sodium sulfate. The solution was evaporated to dryness and the residue was dissolved in ethanol. Yield: ~ 9 g product (3). 1H NMR (200 MHz, CDC13) δ 1.28 (m, 3H), 1.92 (m, 2H), 2.8 (m, 2H), 2.9 (m, 1H), 3.05 (m, 1H), 4.02 (m, 1H), 4.19 (m, 2H), 4.72 (s, 1H)5 5.03 (m, 1H), 5.18 (s, 2H), 6.12 (dd, 1H), 6.57 (d, 1H), 6.64 (m, 1H), 6.74 (d, 1H), 7.34 (m, 5H).
(5α -3-(benzyloxy)-7,8-didehvdro-4.5-epoxy-14-hvdroxy-6-oxomoφhinan-17-carboxylic acid ethylester (4)
The solution of product (3) in ethanol (9 g in 135 ml) was heated to 60°C, 2,6 g cobalt (II) acetate and 0,5 g sodium acetate were added and air was bubbled through the solution under vigorous stirring. The reaction was followed with TLC. After completion of the reaction the solution was treated with charcoal (0,3 g) and filtered. The solution was distilled to volume and this concentrated solution (6,3 g (4) in 53 ml of ethanol) was transferred to the next step. 1H NMR of 4 (360 MHz, CH3OH-d4) δ 1.28 (m, 3H), 1.55 (m, 1H), 2.52 (m, 1H), 2.74 (m, 1H), 2.92 (m, 2H), 4.05 (m, 1H), 4.15 (m, 2H), 4.64 (m, 1H), 4.72 (s, 1H), 4.85 (m, 1H), 5.1 (s, 2H), 6.05 (d, 1H), 6.6 (d, 1H), 6.76 (d, 1H), 6.91 (m, 1H), 7.3 (m, 5H).
f5α)-4.5-epoxy-3.14-dihydroxy-6-oxomoφhinan-17-carboxylic acid ethylester (5) To the solution of the previous step 6 ml of acetic acid was added. The product (4) was reduced with hydrogen and palladium-carbon (5%) as a catalyst (0,9 g) at 20°C and normal pressure. After filtration and evaporation of ethanol 5,4 g of crude product (5) was obtained. The product was recrystallized from 2 parts (w/v) of ethyl acetate to obtain 4,7 g product (5).
('5αV4.5-epoxy-3.14-dihydroxymoφhinan-6-one (noroxymoφhone) (6) Product (5) (4,7 g) was dissolved in 28 ml of water and 5,6 ml of sulfuric acid and refluxed for approx. 24 h. The product was precipitated at pH = 9 by dilution with water and 4,6 g of crude product (6) was obtained after filtration and drying. The product was purified by dissolution in
ethanol, precipitation from this solvent at pH = 2, dissolution in water, charcoal treatment and precipitation at pH = 9. Η NMR (400 MHz, DMSO-d6) δ 1.17 (m, IH), 1.41 (m, IH), 1.72 (m, IH), 2.07 (m, IH), 2.29 (m, IH), 2.36 (m, IH), 2.62 (m, IH), 3.9 (m, 4H), 4.68 (s, IH), 6.52 (d, IH), 6.56 (d, IH).
SCHEME 1
Claims
1. A process for the preparation of a 14-hydroxynormoφhinone derivative of formula IV
2. The process of claim 1, wherein the oxidant is Co(OAc)2.
3. The process of claim 1 or 2, wherein the cooxidant is oxygen.
4. The process of any one of claims 1-3, wherein the mild base is sodium acetate, potassium acetate, sodium phosphate or potassium phosphate.
5. The process of claim 4, wherein the mild base is sodium acetate.
6. The process of any one of claims 1-5, wherein Rt is (l-7C)alkyl.
7. The process of claim 6, wherein RΪ is ethyl.
8. The process of any one of claims 1-7, wherein R2 is benzyl.
9. A 14-hydroxynormoφhinone derivative of the formula IV as set out in claim 1.
10. The 14-hydroxynormoφhinone derivative of claim 9, wherein Ri is ethyl.
11. The 14-hydroxynormoφhinone derivative of claim 9 or 10, wherein R2 is benzyl.
12. A moφhinone derivative of the formula HI as set out in claim 1.
13. The moφhinone derivative of claim 12, wherein Rt is ethyl.
14. The moφhinone derivative of claim 12 or 13, wherein R2 is benzyl.
15. A process for the preparation of a compound of formula III, comprising reactively
16. The process of claim 15, wherein the oxidizing agent is sodium dichromate.
17. The process of claim 15 or 16, wherein RΪ is ethyl and R2 is benzyl.
18. A morphine derivative of formula II as set out in claim 15.
19. The moφhine derivative of claim 18, wherein Ri is ethyl.
20. The moφhine derivative of claim 17 or 18, wherein R2 s benzyl.
21. A process for the production of noroxymoφhone, comprising a reaction step wherein a moφhinone derivative of formula III is oxidized into a 14-hydroxynormoφhinone derivative of formula IV as set out in claim 1.
22. The process of claim 21, further comprising the oxidation of a compound of formula II as defined in claim 15 to form a moφhinone derivative of formula as defined in claim 1.
23. The process of claim 21, wherein moφhine is converted into noroxymoφhone comprising (a) converting moφhine having the formula I
(b) oxidizing the moφhine of formula II to form a morphinone derivative of formula III according to the process set out in claim 15; (c) oxidizing the moφhinone derivative of formula III to form a 14-hydroxynormoφhinone derivative of formula IV according to process set out in claim 1;
(d) deprotecting the 3-position and reducing the double bond at the 7,8-position of the 14- hydroxynormorphinone derivative of formula IV to form a 3,14-hydroxynormoφhinone derivative of formula V, 
(e) and hydrolyzing the 3,14-hydroxynormoφhinone derivative of formula V into noroxymoφhone of formula VI,
Priority Applications (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ531152A NZ531152A (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14 hydroxynormorphinone derivative |
| CA2457671A CA2457671C (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
| KR1020047002513A KR100901402B1 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
| AU2002331163A AU2002331163B2 (en) | 2001-08-23 | 2002-08-15 | Process for the Preparation of a 14-hydroxynormorphinone Compound |
| JP2003523248A JP4559730B2 (en) | 2001-08-23 | 2002-08-15 | Preparation method of 14-hydroxynormorphinone derivative. |
| IL16019302A IL160193A0 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
| US10/487,884 US7435817B2 (en) | 2001-08-23 | 2002-08-15 | C-14 oxidation of morphine derivatives |
| AT02767405T ATE466016T1 (en) | 2001-08-23 | 2002-08-15 | METHOD FOR PRODUCING A 14-HYDROXYNORMORPHINONE DERIVATIVE |
| HU0401600A HUP0401600A3 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of 14-hydroxymorphine derivatives |
| MXPA04001647A MXPA04001647A (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative. |
| DE60236171T DE60236171D1 (en) | 2001-08-23 | 2002-08-15 | PROCESS FOR FOR THE PREPARATION OF A 14-HYDROXYNORMORPHINONE DERIVATIVE |
| BRPI0211899A BRPI0211899B8 (en) | 2001-08-23 | 2002-08-15 | processes for the preparation of a 14-hydroxynormorphinone derivative and for the production of noroxymorphone |
| EP02767405A EP1421085B1 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
| IS7153A IS7153A (en) | 2001-08-23 | 2004-02-13 | A process for the preparation of a 14-hydroxynormorphinone derivative |
| HR20040161A HRP20040161A2 (en) | 2001-08-23 | 2004-02-19 | Process for the preparation of a 14-hydroxynormorphinone derivative |
| NO20040724A NO328655B1 (en) | 2001-08-23 | 2004-02-19 | Morphine derivatives and processes for the preparation of such as well as intermediates |
| HK04106705.9A HK1063803A1 (en) | 2001-08-23 | 2004-09-06 | Process for the preparation of a 14-hydroxynormorphinone derivative |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01203187 | 2001-08-23 | ||
| EP01203187.8 | 2001-08-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2003018588A2 true WO2003018588A2 (en) | 2003-03-06 |
| WO2003018588A3 WO2003018588A3 (en) | 2003-11-27 |
| WO2003018588B1 WO2003018588B1 (en) | 2004-02-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP2002/009280 WO2003018588A2 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
Country Status (26)
| Country | Link |
|---|---|
| US (1) | US7435817B2 (en) |
| EP (1) | EP1421085B1 (en) |
| JP (1) | JP4559730B2 (en) |
| KR (1) | KR100901402B1 (en) |
| CN (1) | CN1271072C (en) |
| AR (1) | AR035289A1 (en) |
| AT (1) | ATE466016T1 (en) |
| AU (1) | AU2002331163B2 (en) |
| BR (1) | BRPI0211899B8 (en) |
| CA (1) | CA2457671C (en) |
| DE (1) | DE60236171D1 (en) |
| EC (1) | ECSP044984A (en) |
| ES (1) | ES2345327T3 (en) |
| HK (1) | HK1063803A1 (en) |
| HR (1) | HRP20040161A2 (en) |
| HU (1) | HUP0401600A3 (en) |
| IL (1) | IL160193A0 (en) |
| IS (1) | IS7153A (en) |
| MX (1) | MXPA04001647A (en) |
| NO (1) | NO328655B1 (en) |
| NZ (1) | NZ531152A (en) |
| PE (1) | PE20030460A1 (en) |
| PL (1) | PL368732A1 (en) |
| RU (1) | RU2297419C2 (en) |
| WO (1) | WO2003018588A2 (en) |
| ZA (1) | ZA200401016B (en) |
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| US8217175B2 (en) * | 2007-03-23 | 2012-07-10 | Mallinckrodt Llc | Preparation of oxymorphone from oripavine |
| CN101033228B (en) * | 2007-04-04 | 2010-05-19 | 复旦大学 | Method of preparing 14-hydroxy-7,8-dihydromorphone |
| WO2008130553A1 (en) | 2007-04-16 | 2008-10-30 | Mallinckrodt Inc. | Novel opiate reduction utilizing catalytic hydrogen transfer reaction |
| JP5579076B2 (en) * | 2007-12-17 | 2014-08-27 | マリンクロッド エルエルシー | Sinomenin derivatives and processes for their synthesis |
| EP2580218B1 (en) | 2010-06-11 | 2015-02-25 | Rhodes Technologies | Process for n-dealkylation of tertiary amines |
| AU2011263417B2 (en) | 2010-06-11 | 2014-03-27 | Rhodes Technologies | Transition metal-catalyzed processes for the preparation of N-allyl compounds and use thereof |
| RU2014112493A (en) | 2011-09-08 | 2015-10-20 | МАЛЛИНКРОДТ Эл-Эл-Си | PRODUCTION OF ALKALOIDS WITHOUT ISOLATION OF INTERMEDIATE PRODUCTS |
| GB2517000B (en) * | 2013-08-02 | 2018-05-09 | Johnson Matthey Plc | Process for the synthesis of oxymorphone alkaloid and oxymorphone salts |
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| WO2000066588A1 (en) * | 1999-05-05 | 2000-11-09 | The Government Of The United States Of America, Represented By The Secretary, Departmentof Health A Nd Human Services | Direct c-14 oxidation of opioids |
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| FR2562072B1 (en) | 1984-03-27 | 1989-07-07 | Mallinckrodt Inc | PROCESS FOR THE PREPARATION OF NOROXYMORPHONE FROM MORPHINE, AND INTERMEDIATE COMPOUNDS USED IN THIS PROCESS |
| US5112975A (en) * | 1984-03-27 | 1992-05-12 | Mallinckrodt Specialty Chemicals Company | Preparation of noroxymorphone from morphine |
| US5869669A (en) * | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
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| WO2006138020A2 (en) | 2005-06-16 | 2006-12-28 | Mallinckrodt Inc. | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
| WO2006138020A3 (en) * | 2005-06-16 | 2007-03-22 | Mallinckrodt Inc | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
| US8067597B2 (en) | 2005-06-16 | 2011-11-29 | Mallinckrodt Llc | Synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
| AU2006259780B2 (en) * | 2005-06-16 | 2012-04-12 | SpecGx LLC | A synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
| WO2009078987A1 (en) * | 2007-12-17 | 2009-06-25 | Mallinckrodt Inc. | Process and compounds for the production of (+) opiates |
| WO2009078990A1 (en) | 2007-12-17 | 2009-06-25 | Mallinckrodt Inc. | N-demethylation of n-methyl morphinans |
| US7671204B2 (en) | 2007-12-17 | 2010-03-02 | Mallinckrodt Inc. | N-demethylation of N-methyl morphinans |
| US9700508B2 (en) | 2010-05-10 | 2017-07-11 | Euro-Celtique S.A. | Pharmaceutical compositions comprising hydromorphone and naloxone |
| US9901540B2 (en) | 2010-05-10 | 2018-02-27 | Euro-Celtique S.A. | Combination of active loaded granules with additional actives |
| US9993433B2 (en) | 2010-05-10 | 2018-06-12 | Euro-Celtique S.A. | Manufacturing of active-free granules and tablets comprising the same |
| US9814710B2 (en) | 2013-11-13 | 2017-11-14 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
| US10258616B2 (en) | 2013-11-13 | 2019-04-16 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
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