WO2006035195A1 - Preparation of opiate analgesics by reductive alkylation - Google Patents

Preparation of opiate analgesics by reductive alkylation Download PDF

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Publication number
WO2006035195A1
WO2006035195A1 PCT/GB2005/003547 GB2005003547W WO2006035195A1 WO 2006035195 A1 WO2006035195 A1 WO 2006035195A1 GB 2005003547 W GB2005003547 W GB 2005003547W WO 2006035195 A1 WO2006035195 A1 WO 2006035195A1
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formula
compound
reacted
process according
cyclopropyl
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PCT/GB2005/003547
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French (fr)
Inventor
Neil John Goodwin
Melville Mitchell
Neil Kenneth Thomson
George Scott Wilson
Maureen Joan Young
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Johnson Matthey Public Limited Company
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Priority to US11/628,210 priority Critical patent/US8119803B2/en
Priority to DE602005013986T priority patent/DE602005013986D1/en
Priority to CN2005800326607A priority patent/CN101027307B/en
Priority to AT05782842T priority patent/ATE428715T1/en
Priority to DK05782842.8T priority patent/DK1794165T4/en
Application filed by Johnson Matthey Public Limited Company filed Critical Johnson Matthey Public Limited Company
Priority to PL05782842T priority patent/PL1794165T5/en
Priority to EP05782842.8A priority patent/EP1794165B2/en
Priority to AU2005288728A priority patent/AU2005288728B2/en
Priority to ES05782842T priority patent/ES2322486T5/en
Publication of WO2006035195A1 publication Critical patent/WO2006035195A1/en
Priority to ZA2007/01784A priority patent/ZA200701784B/en
Priority to US13/030,652 priority patent/US8318937B2/en

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • C07D221/28—Morphinans
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for preparing naltrexone and structurally similar compounds such as nalbuphine, nalmefene, oxilorphan, butorphanol, diprenorphine and buprenorphine. All these compounds contain a cyclic tertiary amine.
  • Naltrexone (1) is a narcotic analgesic:
  • Nalbuphine (2) and nalmefene (3) are structurally similar compounds:
  • Oxilorphan (4) and butorphanol (5) are also similar but there is no ether linkage between the so-called A and C rings:
  • Diprenorphine (6) and buprenorphine (7) contain an ethyl bridge on the C ring:
  • US 3,332,950 discloses methods for preparing this type of compound.
  • Naltrexone is prepared from noroxymorphone in four steps.
  • the method employs a hazardous metal hydride reagent in order to reduce the condensation product formed between a protected noroxymorphone and cyclopropylcarbonyl chloride.
  • the method incorporates protection and deprotection steps. The inventors believe that this type of process afford yields of approximately 33% naltrexone starting from noroxymorphone hydrochloride.
  • naltrexone is prepared by the direct coupling of cyclopropyhnethylbromide and noroxymorphone in dimethylformamide. The method employs high temperatures (7O 0 C) and prolonged reaction times (7 days) yet still only achieves a 60% theoretical yield.
  • the present invention provides a process for preparing a compound of formula (A), (B) or (C):
  • P is H, CH 3 or a hydroxyl protecting group
  • X is O, a protected ketone, OH, a protected hydroxyl group or H
  • Y is OH, a protected hydroxyl group or H
  • W is C(CH 3 ) 2 OH, C(CH 3 )(C(CHj) 3 )OH or COCH 3
  • Z is C 2 -C 10 alkyl or C 2 -C 10 arylalkyl
  • 1 ⁇ is a single bond or a double bond;
  • the method of the invention affords better yields than known processes and avoids the use of hazardous metal hydride reagents that are difficult to handle on a large scale. It does not require high temperatures or prolonged reaction times.
  • P is H or CH 3 , preferably H.
  • P is a hydroxyl protecting group such as an alkoxy, alkoxycarbonyl, aroxycarbonyl, arylmethyl, silyl ether, carbonate or sulphonate group and is preferably an alkoxy, alkoxycarbonyl, aroxycarbonyl or arylmethyl group.
  • Suitable alkoxycarbonyl groups include propoxycarbonyl and ethoxycarbonyl.
  • Suitable aroxycarbonyl groups include phenoxycarbonyl.
  • Suitable arylmethyl groups include napthylmethyl and benzyl.
  • X is preferably O (and therefore the bond between X and the C 6 ring is a double bond) or OH (and therefore the bond between X and the C 6 ring is a single bond).
  • X may be a protected ketone group, e.g. an acetal group. If X is a protected hydroxyl group, the protecting group may be any of the hydroxyl protecting groups as listed above for P.
  • Y is preferably OH. If Y is a protected hydroxyl group, the protecting group may be any of the hydroxyl protecting groups as listed above for P.
  • Z is C 2 -C 10 alkyl or C 2 -C 10 arylalkyl, preferably C 2 -C 5 alkyl.
  • alkyl includes straight chained, branched, cyclic and substituted alkyls, but preferably the alkyl group is unsubstituted.
  • Z is cyclopropyl or cyclobutyl.
  • bonds between the 6,7 carbons and the 7,8 carbons in the compounds of formula (A), (B), (D) and (E) may be double bonds or single bonds.
  • the bond between the carbons of the ethyl bridge in the compounds of formula (C) and (F) may be a double bond or a single bond.
  • Any double bonds in the compounds of formula (D), (E) or (F) may be hydrogenated in the presence of hydrogen and a reductive alkylation catalyst so compounds of formula (D), (E) and (F) with double bonds may provide compounds of formula (A), (B) and (C) with corresponding single bonds.
  • the skilled person can vary the reaction conditions to favour hydrogenation of double bonds.
  • a compound of formula (D) wherein P is H, X is O and Y is OH is reacted with a compound of formula (G) wherein Z is cyclopropyl.
  • This provides a compound of formula (A) wherein P is H, X is O, Y is OH and Z is cyclopropyl. If the 6,7 and 7,8 bonds are single bonds, this compound is naltrexone.
  • a compound of formula (D) wherein P is H, X is OH and Y is OH is reacted with a compound of formula (G) wherein Z is cyclobutyl.
  • This provides a compound of formula (A) wherein P is H, X is OH, Y is OH and Z is cyclobutyl. If the 6,7 and 7,8 bonds are single bonds, this compound is nalbulphine.
  • a compound of formula (E) wherein P is H, X is O and Y is OH or H is reacted with a compound of formula (G) wherein Z is cyclopropyl.
  • This provides a compound of formula (B) wherein P is H, X is O, Y is OH or H and Z is cyclopropyl. If the 6,7 and 7,8 bonds are single bonds, these compounds are oxilorphan and cyclorphan.
  • Z is cyclobutyl.
  • P is H
  • X is H
  • Y is OH
  • Z is cyclobutyl. If the 6,7 and 7,8 bonds are single bonds, this compound is butorphanol.
  • a compound of formula (F) wherein P is H and W is C(CH 3 ) 2 OH is reacted with a compound of formula (G) wherein Z is cyclopropyl.
  • a compound of formula (F) wherein P is H and W is C(CH 3 )(C(CHs) 3 )OH is reacted with a compound of formula
  • W is C(CH 3 ⁇ C(CH 3 ) 3 )OH and Z is cyclopropyl. If the ethyl bridge has a single bond, this compound is buprenorphine.
  • Suitable reductive alkylation catalysts are well known to the skilled person and include platinum group metal catalysts (e.g. platinum or palladium), nickel catalysts and mixtures of these catalysts.
  • the amount of catalyst required is suitably 2 mole% or less, preferably about 0.2 mole%.
  • the process is suitably carried out at room temperature or higher, preferably around 5O 0 C.
  • Hydrogen is suitably supplied to the reaction at a pressure of 1 bar or greater, preferably about 3 bar.
  • the solvent is suitably chosen from alcohols, ethers, amines, amides, alkanes, xylenes, chlorinated alkanes or mixtures - thereof.
  • a preferred solvent is methanol.
  • the process of the invention may take around 1 or more hours.
  • Noroxymorphone alkaloid (20.Og, equivalent to 60.9mmol dry) was added to a mixture of iV-methylpyrrolidinone (60ml) and methanol (140ml). Cyclopropanecarboxaldehyde (5.3ml, 70.9mmol) and platinum on carbon catalyst were added and the mixture hydrogenated at 40psi and 50°C for 1 hour. Upon completion, the catalyst was filtered off and the reaction liquors diluted with chloroform (60ml) and washed with water (200ml). The aqueous layer was extracted with chloroform (2 x 60ml) and the combined organic layer washed with water (5 x 140ml).
  • Nor-14-hydroxymorphinone (20.Og, equivalent to 62.1mmol dry), cyclopropane carboxaldehyde (5.3ml, 70.9mmol), 7V-methylpyrrolidinone (60ml) and methanol
  • Cyclobutane carbonyl chloride (1.44ml, 25.2mmol) was hydrogenated for 2 hours in JV-methylpyrrolidinone (30ml) at 40 psi and room temperature in the presence of palladium on charcoal catalyst.
  • the crude solution of cyclobutane carboxaldehyde was filtered through a bed of celite.
  • noroxymorphone (2.78g, 7.96mmol) was added followed by platinum on carbon catalyst and the mixture hydrogenated at 50°C and 40psi. After 2 hours the catalyst was filtered off and sodium borohydride (3g) added portionwise.
  • HPLC analysis of the crude reaction mixture and comparison against a known sample of nalbuphine confirmed the formation of nalbuphine.
  • Nordiprenorphine (2.Og) was added to a solution of cyclopropanecarboxaldehyde (0.57g) in methanol (16ml) and iV-methylpyrrolidinone (5ml).
  • Platinum on carbon catalyst added and mixture hydrogenated at 50°C and 40 psi. After 30 minutes, the catalyst was filtered off and the reaction liquors diluted with chloroform (6ml) and washed with water (20ml). The product was extracted from the aqueous phase with chloroform (3 x 6ml) and the combined organic layer washed with water (5 x 20ml). The solvent was removed under vacuum to yield an off-white solid. HPLC analysis of the residue confirmed that the product was consistent with a reference standard of diprenorphine alkaloid.
  • Example 6 Preparation of Buprenorph ⁇ ne from Norbuprenorph ⁇ ne
  • Norbuprenorphine (lO.Og, 24.2mmol), cyclopropanecarboxaldehyde (2.2ml, 29.0mmol), iV-methylpyrrolidinone (30ml) and methanol (70ml) were hydrogenated at

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

A process for preparing a compound of formula (A), (B) or (C): wherein P is H, CH3 or a hydroxyl protecting group; X is O, a protected ketone, OH, a protected hydroxyl group or H; Y is OH, a protected hydroxyl group or H; W is C(CH3)2OH, C(CH3)(C(CH3)3)OH or COCH3; Z is C2-C10 alkyl or C2-C10 arylalkyl; and ′ is a. single bond or a double bond, is disclosed. The process is a reductive alkylation in the presence of hydrogen and a reductive alkylation catalyst.

Description

PREPARATION OF OPIATE ANALGESICS BY REDUCTIVE ALKYLATION
The present invention relates to a process for preparing naltrexone and structurally similar compounds such as nalbuphine, nalmefene, oxilorphan, butorphanol, diprenorphine and buprenorphine. All these compounds contain a cyclic tertiary amine.
Naltrexone (1) is a narcotic analgesic:
Figure imgf000002_0001
Nalbuphine (2) and nalmefene (3) are structurally similar compounds:
Figure imgf000002_0002
Oxilorphan (4) and butorphanol (5) are also similar but there is no ether linkage between the so-called A and C rings:
Figure imgf000002_0003
Diprenorphine (6) and buprenorphine (7) contain an ethyl bridge on the C ring:
Figure imgf000003_0001
US 3,332,950 discloses methods for preparing this type of compound. In a first method, Naltrexone is prepared from noroxymorphone in four steps. The method employs a hazardous metal hydride reagent in order to reduce the condensation product formed between a protected noroxymorphone and cyclopropylcarbonyl chloride. In order to prevent side reactions occurring at the ketone functional group, the method incorporates protection and deprotection steps. The inventors believe that this type of process afford yields of approximately 33% naltrexone starting from noroxymorphone hydrochloride. In a second method, naltrexone is prepared by the direct coupling of cyclopropyhnethylbromide and noroxymorphone in dimethylformamide. The method employs high temperatures (7O0C) and prolonged reaction times (7 days) yet still only achieves a 60% theoretical yield.
The present inventors have sought to provide an improved method for preparing naltrexone and similar compounds. Accordingly, the present invention provides a process for preparing a compound of formula (A), (B) or (C):
Figure imgf000003_0002
Figure imgf000004_0001
wherein P is H, CH3 or a hydroxyl protecting group; X is O, a protected ketone, OH, a protected hydroxyl group or H; Y is OH, a protected hydroxyl group or H; W is C(CH3)2OH, C(CH3)(C(CHj)3)OH or COCH3; Z is C2-C10 alkyl or C2-C10 arylalkyl; and 1^ is a single bond or a double bond; wherein a compound of formula (D), (E) or (F):
Figure imgf000004_0002
wherein P, X, Y, W and are as defined above; is reacted with a compound of formula (G):
Figure imgf000004_0003
wherein Z is as defined above, in the presence of hydrogen and a reductive alkylation catalyst.
The method of the invention affords better yields than known processes and avoids the use of hazardous metal hydride reagents that are difficult to handle on a large scale. It does not require high temperatures or prolonged reaction times.
In a preferred embodiment, P is H or CH3, preferably H. In an alternative embodiment, P is a hydroxyl protecting group such as an alkoxy, alkoxycarbonyl, aroxycarbonyl, arylmethyl, silyl ether, carbonate or sulphonate group and is preferably an alkoxy, alkoxycarbonyl, aroxycarbonyl or arylmethyl group. Suitable alkoxycarbonyl groups include propoxycarbonyl and ethoxycarbonyl. Suitable aroxycarbonyl groups include phenoxycarbonyl. Suitable arylmethyl groups include napthylmethyl and benzyl.
X is preferably O (and therefore the bond between X and the C6 ring is a double bond) or OH (and therefore the bond between X and the C6 ring is a single bond). X may be a protected ketone group, e.g. an acetal group. If X is a protected hydroxyl group, the protecting group may be any of the hydroxyl protecting groups as listed above for P.
Y is preferably OH. If Y is a protected hydroxyl group, the protecting group may be any of the hydroxyl protecting groups as listed above for P.
Z is C2-C10 alkyl or C2-C10 arylalkyl, preferably C2-C5 alkyl. The term "alkyl" includes straight chained, branched, cyclic and substituted alkyls, but preferably the alkyl group is unsubstituted. Preferably, Z is cyclopropyl or cyclobutyl.
The bonds between the 6,7 carbons and the 7,8 carbons in the compounds of formula (A), (B), (D) and (E) may be double bonds or single bonds. Similarly, the bond between the carbons of the ethyl bridge in the compounds of formula (C) and (F) may be a double bond or a single bond. Any double bonds in the compounds of formula (D), (E) or (F) may be hydrogenated in the presence of hydrogen and a reductive alkylation catalyst so compounds of formula (D), (E) and (F) with double bonds may provide compounds of formula (A), (B) and (C) with corresponding single bonds. The skilled person can vary the reaction conditions to favour hydrogenation of double bonds.
In a preferred embodiment of the invention, a compound of formula (D) wherein P is H, X is O and Y is OH, is reacted with a compound of formula (G) wherein Z is cyclopropyl. This provides a compound of formula (A) wherein P is H, X is O, Y is OH and Z is cyclopropyl. If the 6,7 and 7,8 bonds are single bonds, this compound is naltrexone.
In another preferred embodiment of the invention, a compound of formula (D) wherein P is H, X is OH and Y is OH, is reacted with a compound of formula (G) wherein Z is cyclobutyl. This provides a compound of formula (A) wherein P is H, X is OH, Y is OH and Z is cyclobutyl. If the 6,7 and 7,8 bonds are single bonds, this compound is nalbulphine.
In another preferred embodiment of the invention, a compound of formula (E) wherein P is H, X is O and Y is OH or H, is reacted with a compound of formula (G) wherein Z is cyclopropyl. This provides a compound of formula (B) wherein P is H, X is O, Y is OH or H and Z is cyclopropyl. If the 6,7 and 7,8 bonds are single bonds, these compounds are oxilorphan and cyclorphan.
In another preferred embodiment of the invention, a compound of formula (E) wherein P is H, X is H and Y is OH, is reacted with a compound of formula (G) wherein
Z is cyclobutyl. This provides a compound of formula (B) wherein P is H, X is H, Y is OH and Z is cyclobutyl. If the 6,7 and 7,8 bonds are single bonds, this compound is butorphanol.
In another preferred embodiment of the invention, a compound of formula (F) wherein P is H and W is C(CH3)2OH, is reacted with a compound of formula (G) wherein Z is cyclopropyl. This provides a compound of formula (C) wherein P is H, W is C(CH3)2OH and Z is cyclopropyl. If the ethyl bridge has a single bond, this compound is diprenorphine. In another preferred embodiment of the invention, a compound of formula (F) wherein P is H and W is C(CH3)(C(CHs)3)OH, is reacted with a compound of formula
(G) wherein Z is cyclopropyl. This provides a compound of formula (C) wherein P is H,
W is C(CH3χC(CH3)3)OH and Z is cyclopropyl. If the ethyl bridge has a single bond, this compound is buprenorphine.
Compounds of formula (D), (E), (F) and (G) are known and can be manufactured by a skilled person using known techniques. For example, compounds of formula (D) can be synthesised as described by Olofson et al in Tet. Lett., 1977, pages 1567-70. Compounds of formula (E) can be synthesised as described by Monkovic et al in J. Amer. Chem. Soα, 95, 1973, pages 9710-12. Compounds of formula (F) can be synthesised as described by Bentley et al in J. Amer. Chem. Soc, 89, 1967, 3281-92. Compounds of formula (G) can be synthesised as described in Organic Syntheses, Collective Volume 6, page 312.
Suitable reductive alkylation catalysts are well known to the skilled person and include platinum group metal catalysts (e.g. platinum or palladium), nickel catalysts and mixtures of these catalysts. The amount of catalyst required is suitably 2 mole% or less, preferably about 0.2 mole%. The process is suitably carried out at room temperature or higher, preferably around 5O0C. Hydrogen is suitably supplied to the reaction at a pressure of 1 bar or greater, preferably about 3 bar. The solvent is suitably chosen from alcohols, ethers, amines, amides, alkanes, xylenes, chlorinated alkanes or mixtures - thereof. A preferred solvent is methanol. The process of the invention may take around 1 or more hours.
Compounds of formula (A), (B) and (C) can be further reacted to provide useful compounds, e.g. naltrexone produced according to the process of the present invention can be further reacted to provide nalmefene.
The following examples are illustrative but not limiting of the invention.
Example 1: Preparation of Naltrexone from Noroxymorphone
To a solution of noroxymorphone (2g, 6.14mmol) in methanol (20ml) was added cyclopropylcarboxaldehyde (0.63ml, 8.43mmol). 5% Palladium on carbon catalyst (1 mole% Pd) was added and the mixture was hydrogenated at 50°C under 3 bar hydrogen pressure for 1 hour. On completion, the catalyst was filtered off and the reaction liquors diluted with chloroform (20ml) and washed with water (3 x 20ml). Evaporation of the solvent yielded naltrexone alkaloid.
Example 2: Preparation of Naltrexone Hydrochloride from Noroxymorphone
Noroxymorphone alkaloid (20.Og, equivalent to 60.9mmol dry) was added to a mixture of iV-methylpyrrolidinone (60ml) and methanol (140ml). Cyclopropanecarboxaldehyde (5.3ml, 70.9mmol) and platinum on carbon catalyst were added and the mixture hydrogenated at 40psi and 50°C for 1 hour. Upon completion, the catalyst was filtered off and the reaction liquors diluted with chloroform (60ml) and washed with water (200ml). The aqueous layer was extracted with chloroform (2 x 60ml) and the combined organic layer washed with water (5 x 140ml). The organic layer was concentrated down to dryness and the solid residue redissolved in ethanol (100ml). Hydrochloric acid was added until pH < 4.0. The resulting precipitate was filtered, washed with ethanol (10ml) and dried in oven to yield a white solid. 16.7g (74% theory). 1H NMR (d6-DMSO, δ /ppm): 0.60 (IH, m), 0.70 (IH, m), 0.80 (2H, m), 1.30 (IH, m), 1.70 (2H, m), 2.20 (lH,m), 2.30 (lH,m), 2.65 (2H,m), 2.85 (lH,m), 3.15 (3H, br m), 3.50 (2H,m), 4.17 (IH, br d), 5.20 (lH,s), 6.80 (IH, d, J = 8Hz), 6.85 (IH, d, J = 8Hz), 7.18 (IH, s), 9.20 (IH, brs), and 9.70 (IH, s). 13C NMR (d6-DMSO δ /ppm): 2.72, 5.24, 5.81, 22.98, 27.18, 30.73, 35.16, 46.11, 48.66, 56.73, 60.82, 69.83, 88.64, 118.09, 119.83, 120.59, 127.89, 140.22, 143.54, and 207.94. HPLC and IR spectra were consistent against a Naltrexone reference standard.
Example 3: Preparation of Naltrexone Hydrochloride from Nor-14- hydroxymorphinone
Nor-14-hydroxymorphinone (20.Og, equivalent to 62.1mmol dry), cyclopropane carboxaldehyde (5.3ml, 70.9mmol), 7V-methylpyrrolidinone (60ml) and methanol
(140ml) were hydrogenated at 50°C and 40psi for 2 hours in the presence of palladium and platinum on carbon catalysts. The crude mixture was filtered, diluted with chloroform (60ml), and then washed with water (200ml). The aqueous phase was extracted with chloroform (2 x 60ml) and the combined organic layer washed with water (5 x 140ml). The chloroform was removed under reduced pressure and the resulting solid redissolved in ethanol (100ml). The pH was lowered to < 4.0 with hydrochloric acid and the precipitate filtered, washed with ethanol (10ml) and dried to recover 19.2g (83% theory) of a white solid corresponding with naltrexone hydrochloride by HPLC analysis.
Example 4: Preparation of Nalbuphine from Noroxymorphone
Cyclobutane carbonyl chloride (1.44ml, 25.2mmol) was hydrogenated for 2 hours in JV-methylpyrrolidinone (30ml) at 40 psi and room temperature in the presence of palladium on charcoal catalyst. The crude solution of cyclobutane carboxaldehyde was filtered through a bed of celite. To 15ml of the above filtered solution, noroxymorphone (2.78g, 7.96mmol) was added followed by platinum on carbon catalyst and the mixture hydrogenated at 50°C and 40psi. After 2 hours the catalyst was filtered off and sodium borohydride (3g) added portionwise. HPLC analysis of the crude reaction mixture and comparison against a known sample of nalbuphine confirmed the formation of nalbuphine.
Example 5: Preparation of Diprenorphine from Nordiprenorphine
Nordiprenorphine (2.Og) was added to a solution of cyclopropanecarboxaldehyde (0.57g) in methanol (16ml) and iV-methylpyrrolidinone (5ml). Platinum on carbon catalyst added and mixture hydrogenated at 50°C and 40 psi. After 30 minutes, the catalyst was filtered off and the reaction liquors diluted with chloroform (6ml) and washed with water (20ml). The product was extracted from the aqueous phase with chloroform (3 x 6ml) and the combined organic layer washed with water (5 x 20ml). The solvent was removed under vacuum to yield an off-white solid. HPLC analysis of the residue confirmed that the product was consistent with a reference standard of diprenorphine alkaloid. Example 6: Preparation of Buprenorphϊne from Norbuprenorphϊne
Norbuprenorphine (lO.Og, 24.2mmol), cyclopropanecarboxaldehyde (2.2ml, 29.0mmol), iV-methylpyrrolidinone (30ml) and methanol (70ml) were hydrogenated at
50°C and 40psi for 2 hours in the presence of platinum on carbon catalysts. Upon completion, the catalyst was filtered off and water (200ml) added. The product was extracted into chloroform (3 x 60ml) and washed with water (5 x 140ml). Chloroform was removed under vacuum and the residue redissolved in ethanol (50ml). The pH was adjusted to < 3.0 with hydrochloric acid. The product was filtered, washed with ethanol
(5ml) and dried in oven to yield 7.2g of a white crystalline solid. HPLC analysis confirms the material is consistent with buprenorphine hydrochloride.

Claims

Claims
1. A process for preparing a compound of formula (A), (B) or (C):
Figure imgf000011_0001
wherein P is H, CH3 or a hydroxyl protecting group; X is O, a protected ketone, OH, a protected hydroxyl group or H; Y is OH, a protected hydroxyl group or H; W is C(CH3)2OH, C(CH3XC(CH3)3)OH or COCH3; Z is C2-C1O alkyl or C2-C10 arylalkyl; and ^^ is a single bond or a double bond; wherein a compound of formula (D), (E) or (F):
Figure imgf000011_0002
Figure imgf000012_0001
wherein P, X, Y, W and zz=zz are as defined above, is reacted with a compound of formula (G):
H γZ (G) O wherein Z is as defined above, in the presence of hydrogen and a reductive alkylation catalyst.
2. A process according to claim 1, wherein P is H or CH3.
3. A process according to claim 1 or claim 2, wherein X is O or OH.
4. A process according to any preceding claim, wherein Y is OH.
5. A process according to any preceding claim, wherein Z is cyclopropyl or cyclobutyl.
6. A process according to any preceding claim, wherein a compound of formula (D) is reacted with a compound of formula (G) to provide a compound of formula (A), and wherein P is H, X is O, Y is OH, and Z is cyclopropyl.
7. A process according to any preceding claim, wherein a compound of formula (D) is reacted with a compound of formula (G) to provide a compound of formula (A), and wherein P is H, X is OH, Y is OH and Z is cyclobutyl. 15
8. A process according to any preceding claim, wherein a compound of formula (E) is reacted with a compound of formula (G) to provide a compound of formula (B), and wherein P is H, X is O, Y is OH or H and Z is cyclopropyl.
9. A process according to any preceding claim, wherein a compound of formula (E) is reacted with a compound of formula (G) to provide a compound of formula (B), and wherein P is H, X is H, Y is OH and Z is cyclobutyl.
10. A process according to any preceding claim, wherein a compound of formula (F) is reacted with a compound of formula (G) to provide a compound of formula (C), and wherein P is H, W is C(CHs)2OH and Z is cyclopropyl.
11. A process according to any preceding claim, wherein a compound of formula (F) is reacted with a compound of formula (G) to provide a compound of formula (C), and wherein P is H, W is C(CH3)(C(CH3)3)OH and Z is cyclopropyl.
PCT/GB2005/003547 2004-09-30 2005-09-14 Preparation of opiate analgesics by reductive alkylation WO2006035195A1 (en)

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ES05782842T ES2322486T5 (en) 2004-09-30 2005-09-14 Preparation of opioid analgesics by reductive alkylation
DE602005013986T DE602005013986D1 (en) 2004-09-30 2005-09-14 PREPARATION OPIATER ANALGETICS BY REDUCING ALKYLATION
CN2005800326607A CN101027307B (en) 2004-09-30 2005-09-14 Preparation of opiate analgesics by reductive alkylation
AT05782842T ATE428715T1 (en) 2004-09-30 2005-09-14 PRODUCTION OF OPIATER ANALGESICS BY REDUCTIVE ALKYLATION
DK05782842.8T DK1794165T4 (en) 2004-09-30 2005-09-14 Preparation of opiate analgesic by reductive alkylation
US11/628,210 US8119803B2 (en) 2004-09-30 2005-09-14 Preparation of opiate analgesics by reductive alkylation
PL05782842T PL1794165T5 (en) 2004-09-30 2005-09-14 Preparation of opiate analgesics by reductive alkylation
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AU2005288728A AU2005288728B2 (en) 2004-09-30 2005-09-14 Preparation of opiate analgesics by reductive alkylation
ZA2007/01784A ZA200701784B (en) 2004-09-30 2007-02-28 Preparation of opiate analgesics by reductive alkylation
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US8318937B2 (en) 2012-11-27
AU2005288728B2 (en) 2012-05-03
EP1794165B2 (en) 2020-04-29
CN101027307B (en) 2011-12-21
ZA200701784B (en) 2008-11-26
ES2322486T5 (en) 2021-02-05
PL1794165T5 (en) 2020-11-16
US8119803B2 (en) 2012-02-21
AU2005288728A1 (en) 2006-04-06
CN101027307A (en) 2007-08-29
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PT1794165E (en) 2009-05-06
US20080045715A1 (en) 2008-02-21
ES2322486T3 (en) 2009-06-22
EP1794165B1 (en) 2009-04-15
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US20120046466A9 (en) 2012-02-23
US20110144341A1 (en) 2011-06-16

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