AU2002331163A1 - Process for the Preparation of a 14-hydroxynormorphinone Compound - Google Patents
Process for the Preparation of a 14-hydroxynormorphinone CompoundInfo
- Publication number
- AU2002331163A1 AU2002331163A1 AU2002331163A AU2002331163A AU2002331163A1 AU 2002331163 A1 AU2002331163 A1 AU 2002331163A1 AU 2002331163 A AU2002331163 A AU 2002331163A AU 2002331163 A AU2002331163 A AU 2002331163A AU 2002331163 A1 AU2002331163 A1 AU 2002331163A1
- Authority
- AU
- Australia
- Prior art keywords
- formula
- derivative
- benzyl
- hydroxynormoφhinone
- moφhine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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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
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 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 R2 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 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
with an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups, where a morphinone compound of the formula III is prepared. Preferably, the oxidizing agent is sodium dichromate. Preferably Ri is ethyl. For R2 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.
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,
(e) and hydrolyzing the 3,14-hydroxynormoφhinone derivative of formula V into noroxymoφhone of formula VI, using methods well known in the art for such type of hydrolysis, e.g. using sulfuric acid,
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 (23)
1. A process for the preparation of a 14-hydroxynormoφhinone 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 ! is (lC-7C)alkyl optionally substituted with one or more chlorines, butenyl, vinyl, benzyl, phenyl or naphthyl; and R2 is benzyl or benzyl substituted with one or more (lC-6C)alkoxy group or benzyl substituted with one or more halogen.
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
contacting a moφhine derivative of formula II with an oxidizing agent effective for oxidizing allylic hydroxy groups to form keto groups, where a compound of formula III as set out in claim 1 is prepared, Rj and R2 being as defined in claim 1.
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
by reaction with a haloformate ester of the formula X-C(=O)ORl5 wherein Ri is as previously defined and X is a halogen, followed by a reaction with R2-X, wherein X and R2 are as previously defined, to form a moφhine derivative of formula II as defined in claim 15;
(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,
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01203187.8 | 2001-08-23 | ||
EP01203187 | 2001-08-23 | ||
PCT/EP2002/009280 WO2003018588A2 (en) | 2001-08-23 | 2002-08-15 | Process for the preparation of a 14-hydroxynormorphinone derivative |
Publications (2)
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AU2002331163A1 true AU2002331163A1 (en) | 2003-06-05 |
AU2002331163B2 AU2002331163B2 (en) | 2008-02-21 |
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AU2002331163A Expired AU2002331163B2 (en) | 2001-08-23 | 2002-08-15 | Process for the Preparation of a 14-hydroxynormorphinone Compound |
Country Status (26)
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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) |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
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US8067597B2 (en) | 2005-06-16 | 2011-11-29 | Mallinckrodt Llc | Synthetic route to 14-hydroxyl opiates through 1-halo-thebaine or analogs |
CA2681740A1 (en) * | 2007-03-23 | 2008-10-02 | Mallinckrodt Inc. | Improved 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 |
CA2684458A1 (en) | 2007-04-16 | 2008-10-30 | Mallinckrodt Inc. | Novel opiate reduction utilizing catalytic hydrogen transfer reaction |
EP2222642B1 (en) * | 2007-12-17 | 2014-02-12 | Mallinckrodt LLC | Process and compounds for the production of (+) opiates |
CN101896487A (en) | 2007-12-17 | 2010-11-24 | 马林克罗特公司 | N-demethylation of N-methyl morphinans |
WO2009078988A1 (en) * | 2007-12-17 | 2009-06-25 | Mallinckrodt Inc. | Sinomenine derivatives and processes for their synthesis |
NZ603173A (en) | 2010-05-10 | 2014-10-31 | Euro Celtique Sa | Manufacturing of active-free granules and tablets comprising the same |
PE20130657A1 (en) | 2010-05-10 | 2013-06-15 | Euro Celtique Sa | PHARMACEUTICAL COMPOSITIONS INCLUDING HYDROMORPHONE AND NALOXONE |
NZ603170A (en) | 2010-05-10 | 2015-04-24 | Euro Celtique Sa | Combination of active loaded granules with additional actives |
CA2802295C (en) | 2010-06-11 | 2016-09-20 | Rhodes Technologies | Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof |
ES2537610T3 (en) | 2010-06-11 | 2015-06-10 | Rhodes Technologies | Process for the N-desalkylation of tertiary amines |
US8624031B2 (en) | 2011-09-08 | 2014-01-07 | Mallinckrodt Llc | Production of alkaloids without the isolation of intermediates |
AU2014298257B2 (en) * | 2013-08-02 | 2016-11-10 | Macfarlan Smith Limited | Process for the preparation of oxymorphone |
US9814710B2 (en) | 2013-11-13 | 2017-11-14 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
Family Cites Families (4)
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US5112975A (en) * | 1984-03-27 | 1992-05-12 | Mallinckrodt Specialty Chemicals Company | Preparation of noroxymorphone from morphine |
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 |
US5869669A (en) * | 1996-07-26 | 1999-02-09 | Penick Corporation | Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates |
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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- 2002-08-15 JP JP2003523248A patent/JP4559730B2/en not_active Expired - Lifetime
- 2002-08-15 WO PCT/EP2002/009280 patent/WO2003018588A2/en active IP Right Grant
- 2002-08-15 BR BRPI0211899A patent/BRPI0211899B8/en not_active IP Right Cessation
- 2002-08-15 RU RU2004108210/04A patent/RU2297419C2/en active
- 2002-08-15 AT AT02767405T patent/ATE466016T1/en active
- 2002-08-15 PL PL02368732A patent/PL368732A1/en not_active Application Discontinuation
- 2002-08-15 CA CA2457671A patent/CA2457671C/en not_active Expired - Lifetime
- 2002-08-15 HU HU0401600A patent/HUP0401600A3/en unknown
- 2002-08-15 MX MXPA04001647A patent/MXPA04001647A/en active IP Right Grant
- 2002-08-15 US US10/487,884 patent/US7435817B2/en not_active Expired - Lifetime
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- 2002-08-15 KR KR1020047002513A patent/KR100901402B1/en not_active IP Right Cessation
- 2002-08-15 ES ES02767405T patent/ES2345327T3/en not_active Expired - Lifetime
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- 2002-08-15 IL IL16019302A patent/IL160193A0/en unknown
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- 2002-08-15 NZ NZ531152A patent/NZ531152A/en not_active IP Right Cessation
- 2002-08-15 AU AU2002331163A patent/AU2002331163B2/en not_active Expired
- 2002-08-21 PE PE2002000800A patent/PE20030460A1/en not_active Application Discontinuation
- 2002-08-21 AR ARP020103130A patent/AR035289A1/en active IP Right Grant
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- 2004-02-19 NO NO20040724A patent/NO328655B1/en not_active IP Right Cessation
- 2004-02-19 HR HR20040161A patent/HRP20040161A2/en not_active Application Discontinuation
- 2004-02-19 EC EC2004004984A patent/ECSP044984A/en unknown
- 2004-09-06 HK HK04106705.9A patent/HK1063803A1/en not_active IP Right Cessation
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