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:
  • C07D489/09—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: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems
  • C07D489/10—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: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14
  • C07D489/12—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: containing 4aH-8, 9 c-Iminoethano- phenanthro [4, 5-b, c, d] furan ring systems condensed with carbocyclic rings or ring systems with a bridge between positions 6 and 14 the bridge containing only two carbon atoms
• • 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

Definitions

• Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence.
• the main use of naltrexone is for the treatment of alcohol dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names REVIA and DEPADE.
• REVIA hydrochloride salt
• DEPADE hydrochloride salt
• VIVITROL a once-monthly extended-release injectable formulation is marketed under the trade name VIVITROL.
• Nalbuphine is a semi-synthetic opioid, available under the trade name of NUBAIN for the treatment of moderate to severe pain. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and deliver.
• Nalbuphine is a semi-synthetic opioid agonist-antagonist analgesic of the phenanthrene series, and is chemically related to the widely used opioid antagonists, naloxone and naltrexone, and the potent opioid analgesic, oxymorphone.
• HUDSON E.C., et al., in US Patent Publication 2010/0210843 A1 , published August 19, 2010 disclose a process for the reductive alkylation of normorphinans by a carboxaldehyde in the presence of a reducing agent.
• the present invention is directed to a process for the preparation of opioid compounds, opioid derivatives, and pharmaceutically acceptable salts thereof. More particularly, the present invention is directed to processes for N- alkylation in the presence of an organic amine base, followed by optional de- methylation; preferably without isolation of the intermediate(s).
• the present invention is further directed to a process for the preparation of a compound of formula (I)
• the present invention is directed to a process for the preparation of a compound of formula (II)
• the compound of formula (II) is a compound of formula (lib)
• the compound of formula (II) is a compound of formula (lie)
• Exemplifying the invention are methods for the treatment of pain (for example moderate or severe pain) comprising administering to a subject in need thereof a therapeutically effective amount of any of the products or pharmaceutical compositions described above.
• treating shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder and includes the administration of a compound or product of the present invention to prevent the onset of the symptoms or complications, alleviate the symptoms or complications, or eliminate the disease, condition, or disorder.
• acids which may be used in the preparation of pharmaceutically acceptable salts include, but are not limited to, the following: acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic
• organic amine base is sufficiently strong to neutralize the acid formed as a byproduct of the reaction of the compound of the opioid precursor and the alkylating agent (for example, HBr which is formed as a by-product of the reaction with cyclopropylmethylbromide), such as methylamine, ethylamine, butylamine, diethylamine, trimethylamine, triethylamine (TEA)
• diisopropylethylamine DIPEA
• aniline morpholine
• pyridine pyrimidine
• pyrrole quinoline
• indole imidazole
• benzimidazole and the like
• organic amine base is preferably present in an amount greater than about 1 molar equivalent (relative to the moles of the compound of formula (V)), preferably in an amount in the range of from about 1 to about 10 molar equivalents, preferably in an amount in the range of from about 1 to about 5 molar equivalents; preferably in an amount in the range of from about 1 .1 to about 3.5 molar equivalents, preferably in an amount in the range of from about 2 to about 3 molar equivalents, for example, in an amount of about 2.5 molar equivalents;
• DIPEA diisopropylethylamine
• a suitably selected first organic solvent for example a dipolar aprotic solvent
• a suitably selected first organic solvent such as DMF, DMA, NMP, DMSO, sulfolane, DMI, and the like, preferably DMF; at a temperature in the range of from about 40°C to about 70°C, preferably at a temperature in the range of from about 55°C to about 65°C, more preferably at a temperature of about 60°C;
• the compound of formula (VII) is preferably not isolated.
• a suitably selected demethylating agent preferably an O-demethylating agent (for example, a a suitably selected mercaptan) such as n-CeSH (n-hexane thiol), n-C 7 SH (n- heptane thiol), n-CsSH (n-octane thiol), n-CgSH (n-nonane thiol, n-C-ioSH (n- decane thiol), n-C-nSH, (n-undecane thiol), n-C ⁇ SH (n-docecane thiol), t-C 4 SH (ferf-butyl mercaptan or 2-methyl-propane thiol), t-CeSH (2-methylpentane-2- thiol), t-C 7 SH (2-methylhexane-2-thiol), t-C
• O-demethylating agent for example, a
• demethylating agents preferably ferf-dodecyl mercaptan; wherein the demethylating agent is preferably present in an amount in the range of from about 2 to about 5 molar equivalents (relative to the moles of the compound of formula (V)), preferably in an amount in the range of from about 2.5 to about 4 molar equivalents; more preferably in an amount in the range of from about 2.8 to about 3.4 molar equivalents, more preferably in an amount of about 3.1 molar equivalents;
• a suitably selected base such as a suitably selected inorganic alcohol such as NaOH, KOH, LiOH, CsOH, and the like or a suitably selected alkoxide base such as NaOEt, NaOtBu, KOEt, KOtBu, LiOEt, LiOtBu, CsOEt, CsOtBu, and the like; or a suitably selected amine base such as LiNEt 2 , NaNEt 2 , CsNEt 2 , LiNH 2 , NaNH 2 , CsNH 2 , and the like, or a suitably selected hydride base such as NaH, KH, CsH, and the like, or a suitably selected base such as LDA, KDA, LiHMDS, KHMDS, n-BuLi, and the like; preferably NaOtBu; wherein the base is preferably present in an amount in the range of from about 2 to about 5 molar equivalents (relative to the moles of the compound of formula (V)),
• the present invention is directed to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable sa
• first organic solvent for example a dipolar aprotic solvent
• a suitably selected first organic solvent such as DMF, DMA, NMP, DMSO, sulfolane, DM I, and the like, preferably DMF
• a temperature in the range of from about 1 10°C to about 150°C preferably at a temperature in the range of 128°C to about 135°C, more preferably at a temperature of about 131 °C
• an inert atmosphere such as under nitrogen, under argon, under helium, and the like; to yield the corresponding compound of formula (VIII).
• the compound of formula (VIII) is reacted with a suitably substituted compound of formula (VI), wherein L 1 is a suitably selected leaving group such as Br, CI, I, mesylate, tosylate, nosylate, triflate, nonaflate, and the like, preferably Br, a known compound or compound prepared by known methods; wherein the compound of formula (VI) is preferably present in an amount greater than about 1 molar equivalent (relative to the moles of the compound of formula (V)), preferably in an amount in the range of from about 1 .1 to about 2.5 molar equivalents, preferably in an amount in the range of from about 1 .25 to about 1 .75 molar equivalents, preferably in an amount in the range of from about 1 .3 to about 1 .5 molar equivalents, more preferably in an amount of about 1 .4 molar equivalents; in the presence of a suitably selected organic amine base, wherein the organic amine base is sufficiently strong to neutralize the acid
• diisopropylethylamine DIPEA
• aniline morpholine
• pyridine pyrimidine
• pyrrole quinoline
• indole imidazole
• benzimidazole and the like
• organic amine base is preferably present in an amount greater than about 1 molar equivalent (relative to the moles of the compound of formula (V)), preferably in an amount in the range of from about 1 to about 10 molar equivalents, preferably in an amount in the range of from about 1 to about 5 molar equivalents; preferably in an amount in the range of from about 1 .1 to about 3.5 molar equivalents, preferably in an amount in the range of from about 2 to about 3 molar equivalents, for example, in an amount of about 2.5 molar equivalents;
• DIPEA diisopropylethylamine
• a promoter such as Nal, NaBr,
• tetralkylammonium iodide such as tetra(n-butyl)ammonium iodide, and the like
• tetralkylammonium bromide such as tetra(n-butyl)ammonium bromide, and the like
• triethylbenzylammonium iodide triethylbenzylammonium bromide, and the like
• the promoter is present in an amount in the range of from about 1 mole% to about 10 mole%, preferably in an amount in the range of from about 5 mole % to about 10 mole%;
• a suitably selected second organic solvent for example a dipolar aprotic solvent
• a suitably selected second organic solvent such as DMF, DMA, NMP, DMSO, sulfolane, DMI, and the like, preferably DMF
• the second organic solvent is preferably the same as the first organic solvent; at a temperature in the range of from about 40°C to about 70°C, preferably at a temperature in the range of from about 55°C to about 65°C, more preferably at a temperature of about 60°C; to yield the corresponding compound of formula (I).
• the present invention is directed to a process for the preparation of a compound of formula (I I) or a pharmaceutically acceptable salt thereof as described in Scheme 3, below.
• a promoter such as Nal, NaBr,
• the compound of formula (lie) may be reacted with a suitably selected reducing agent, according to known methods, for example, as described in REZAIE, R., et al., US Patent 8,236,957 B2, issued August 7, 2012, to yield nalbuphine, the corresponding compound of formula (II I).
• compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
• the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
• injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
• compositions of this invention one or more compounds or products of the present invention, as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
• a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
• any of the usual pharmaceutical media may be employed.
• suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
• suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
• the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
• injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
• the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
• compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.01 mg to about 500 mg or any amount or range therein, and may be given at a dosage of from about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or range therein, preferably from about 0.01 mg/kg/day to about 50 mg/kg/day, or any amount or range therein, preferably from about 0.05 mg/kg/day to about 15 mg/kg/day, or any amount or range therein, preferably from about 0.05 mg/kg/day to about 5 mg/kg/day, or any amount or range therein.
• the dosages may be varied depending upon the
• compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
• the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
• a pharmaceutical carrier e.g.
• a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
• preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.01 mg to about 500 mg, or any amount or range therein, preferably from about 1 mg to about 150 mg, or any amount or range therein, preferably from about 2 mg to about 50 mg, or any amount or range therein, of the active ingredient of the present invention.
• the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
• liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
• Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
• the method of treating disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the products as defined herein and a pharmaceutically acceptable carrier.
• the pharmaceutical composition may contain between about 0.5 mg and about 500 mg of the compound, or any amount or range therein; preferably from about 1 mg to about 150 mg of the compound, or any amount or range therein, preferably from about 2 mg to about 50 mg of the compound, or any amount or range therein, and may be constituted into any form suitable for the mode of
• Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
• Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
• Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• a product prepared according to any of the process(es) of the present invention is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
• a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
• Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
• Compounds or products of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders described herein is required.
• the daily dosage may be varied over a wide range from about 0.01 mg to about 1 ,000 mg per adult human per day, or any amount or range therein.
• the compositions are preferably provided in the form of tablets containing about 0.01 , 0.05, 0.1 , 0.5, 1 , 2.5, 4, 5, 10, 15, 25, 30, 40, 50, 60, 75, 80, 100, 150, 160, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 500 mg/kg of body weight per day, or any amount or range therein.
• the range is from about 0.05 to about 50 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.05 to about 15 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.05 to about 7.5 mg/kg of body weight per day, or any amount or range therein. More preferably, from about 0.05 to about 3 mg/kg of body weight per day, or any amount or range therein.
• the compound or product (as the active ingredient or drug) may be administered on a regimen of 1 to 4 times per day.
• Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
• a solution of BU1 (100 g theor.) in toluene (200 g) was charcoal treated and then filtered.
• the filtrate was subjected to hydrogenation with a 5% Pd/C catalyst (5 g) at 75-85°C and 40-45 psi hydrogen.
• the batch was filtered to remove charcoal and Pd/C catalyst.
• the resulting product/toluene solution was then solvent exchanged to ethanol.
• the product/ethanol solution was cooled to 18-22°C and the resulting slurry filtered.
• the filter cake was washed with ethanol and then dried under vacuum at 45- 55°C.
• a dry vessel was charged with magnesium (57.4 g, 9.04 eq.) and THF (193.4 g) and cyclohexane (413.4 g) were added. The resulting mixture was heated to reflux and a 3-5% of the total solvent mass was distilled as a drying step. The batch was then adjusted to 64-66°C.
• a solution of tert-butyl chloride (208 g, 8.61 eq.) in cyclohexane (166.6 g) was prepared. 5% of the total t-butyl chloride solution was added to the magnesium suspension. The resulting mixture was held with agitation until the Grignard formation reaction initiates as determined by the internal batch temperature exceeding jacket temperature by at least 2°C.
• An aqueous phosphate buffer was prepared by combining water (1326 g), 85% phosphoric acid (127.4 g) and 28- 30% ammonium hydroxide (59.4 g). The pH of the buffer was adjusted to 3.8- 4.0 with phosphoric acid and/or ammonium hydroxide. The organic layer was washed twice with the buffer (each wash is 1 ⁇ 2 total buffer volume), then once with water (200 g) to yield buprenorphine intermediate BU3.
• the resulting BU4 containing reaction mixture (100 g BU3 scale) was quenched by addition of water (68 g), ethanol (80 g) and ammonium hydroxide 28-30% (72.5 g). The resulting mixture was settled and the lower product containing layer combined with water (160 g) and ethanol (80 g). The mixture was settled again and the lower product containing DCM layer separated. The DCM solvent was then exchanged to ethanol by charging ethanol and distilling the batch to 75 °C to yield a solution of buprenorphine intermediate BU4 in ethanol.
• the BU4 / ethanol solution (prepared as in the previous step) was combined with diethylene glycol (100 g BU3) and then 45% aq. KOH was added (71 g). The resulting mixture was distilled until batch temperature reached 130°C. The mixture was then held at 130°C for 4 hrs and sampled for reaction completion.
• buprenorphine intermediate BU5 also known as of (4R,4aS,6R,7R,7aR,12bS)- 3-(cyclopropylmethyl)-6-((S)-2-hydroxy-3,3-dimethylbutan-2-yl)-7-methoxy- 1 ,2, 3,4, 5,6,7, 7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2- e]isoquinolin-9-ol).
• Bu5 (10 g), CPMB (4.2 g), DMF (30 ml.) and morpholine (20.4 g, 10 equiv.) were mixed and heated to 60°C, then held at this temperature for about 2 hours. The mixture was then heated to 80°C and maintained at this temperature for about 3 hours. IPC after 4 hours indicated no remaining starting material.
• Bu5 (10 g), CPMB (4.2 g), DMF (30 mL) and diethylamine (8.6 g, 5 eqv.) were mixed and heated to 60°C, then held at this temperature for about 2 hours. The mixture was then heated to 80°C and maintained at this
• Step 2 (O-demethylation) To the mixture prepared in Step 1 above, was added DMF (20 ml_), tert- dodecyl mercaptan (17.2 mL) and NaOfBu (7.2 g) and the mixture heated to 131 °C, for 4 hours. (HPLC indicated the starting material at 3.6 A% and desired product at >83 A%.).
• the following example describes a recipe / procedure for the synthesis of buprenorphine HCI. At least one batch of buprenorphine HCI was prepared according to said recipe / procedure, and the product isolated as a white to off- white crystalline powder.
• a glass lined reactor vessel was purge with N 2 .
• a suspension of BU in 2-propanol approximately 22.9 g per 100 g solvent
• the resulting mixture heated to 70°C to complete dissolution.
• a small portion of HCI was added and the resulting solution seeded with Bu HCI.
• a second portion of HCI was added at 70°C, over 3-5 hours.
• the total amount of HCI was 1 .05 M/M.
• NOMO Noroxymorphone
• DMA ⁇ , ⁇ -dimethylacetamide
• Noroxymorphone (4.0 g) was suspended DMA (7.05g, 1 .75 mass eq.) at 20-30°C. To the reaction mixture was then added allybromide (1 .68g, 1 .0 mol. eq.). The resulting suspension was stirred at 20-30°C for 60-70 min until a clear brown solution was formed. To the mixture was then added
• Noroxymorphone was converted to naltrexone, reacting with bromomethylcyclopropane in 1 -methyl-2-pyrrolidone (NMP) in the presence of diisopropylethylamine. Additionally, reaction time and temperature were also varied. Table 1 , below list experimental conditions for the completed experiments.
• 100 mg of the compound prepared as in Example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

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