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:
  • C07D489/02—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • C07D489/04—Salts; Organic complexes

Definitions

• the present application is directed to processes and intermediates for the preparation of various opioid analgesics, including morphinane and morphinone compounds such as naltrexone, R- methylnaltrexone, buprenorphine, nalbuphone and nalbuphine.
• morphinane and morphinone compounds such as naltrexone, R- methylnaltrexone, buprenorphine, nalbuphone and nalbuphine.
• Opioid analgesics are often the treatment of choice for patients with severe pain. Besides its beneficial analgesia, opioids induce undesired side effects such as addiction, constipation, nausea and respiratory depression.
• Commonly administered drugs are the naturally occurring opiates isolated from opium or poppy straw, morphine and codeine, as well as semi- synthetic opioids derived from thebaine such as oxycodone and buprenorphine. The intense biological response is caused by their agonistic action to specific opioid receptors in the human body.
• naltrexone which is used for rapid detoxification of opioid dependent patients and methylnaltrexone are examples of opioid antagonists.
• Dlubala reported the conversion of naltrexone to methylnaltrexone bromide by first protecting the 3-0 position with a benzyl group, reacting the benzyl-protected naltrexone with dimethylsulfate, followed by conversion of the resulting methylnaltrexone methylsulfate salt to the zwitterion, and then removal of the 3-O-benzyl protecting group and simultaneous precipitation of methylnaltrexone bromide by the addition of aqueous HBr, yielding also predominantly the (7?>methylnaltrexone [see Dlubala, WO 2008/034973, US 2008/0214817].
• a common feature of each of these routes is that at some point, the ⁇ /-17 methyl group, which is common to each of the biological raw materials, is removed, a cyclopropylmethylene group is added, and a methyl group is added back in the final step.
• quaternization of the nitrogen with a cyclopropylmethyl halide gives the undesired S configuration at the nitrogen.
• Schemes 7 - 8 show a common commercial route for the manufacture of naltrexone is the alkylation of noroxymorphone in the presence of cyclopropylmethyl bromide and sodium hydrogen carbonate in dimethylacetamide at 65 - 69°C for 6 hours to give naltrexone in 88.6% yield [Dlubala; US 2008/0214817 A1].
• Naltrexone may also be manufactured from noroxymorphone by reductive alkylation with cyclopropylcarboxaldehyde [Goodwin et al., WO 2006/035195; Scheme 8]. The yield of naltrexone isolated as the hydrochloride salt ranged from 74 - 83%.
• Noroxymorphone may in turn be prepared from morphine in 6 steps [Wallace, US 5112975] or from thebaine via oxymorphone in 6 steps by the procedure described in Kavka, [US 4639520].
• Oxymorphone may also be prepared from oripavine using the procedure described by Wang et al, 2008118654/WO-A1 , Dung et al., WO 2008072018 or Huang, WO 2008048711 and WO 2008048957.
• Huang et al [US Patent Nos. 5869669, 6008354 and 6013796] describe the synthesis of naltrexone from morphine and codeine in seven to nine chemical steps.
• Huang, [US 20080125592. assigned to Penick] describe the synthesis of naltrexone from oripavine in six chemical steps, combined into three unit operations.
• a new process has been developed for the synthesis of morphinane and morphinone compounds, including, but not limited to, naltrexone, R-methylnaltrexone, buprenorphine, nalbuphone and nalbuphine.
• This process involves the ⁇ /-substitution of oripavine or thebaine to provide a mixture of the corresponding (R)- and (S)- ⁇ /-substituted derivatives.
• the desirable R-isomer is isolated in substantially pure form using known methods such as precipitation, recrystallization or chromatography and is converted to, for example, R-methylnaltrexone or R-methylbuphenone.
• the remaining side products including the S-isomer and mixtures of the R- and S-isomers are demethylated and the resulting ⁇ /-substituted nororipavine, or analogs thereof, are converted to morphinane and morphinone compounds, including, but not limited to, naltrexone, R-methylnaltrexone, buprenorphine, nalbuphone and nalbuphine.
• naltrexone R-methylnaltrexone
• buprenorphine nalbuphone and nalbuphine.
• R-isomer the preparation of R- methylnaltrexone from the R-isomer advantageously does not suffer from the problems associated with stereoselective methylation of naltrexone.
• the N- demethylation route represents a way to advantageously utilize the side products from the initial ⁇ /-substitution reaction, reducing waste, and increasing the efficiency of the overall process in the synthesis of morphinane and
• the application includes a process for preparing intermediates useful in the synthesis of morphinane and morphinone compounds comprising:
• R 1 is selected from hydrogen, C h alky!, C(O)Ci -s alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, Ci- 6 alkyleneC 3-8 cycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, C-i- ⁇ alkyleneCi-sheterocyclyl and Ci- ⁇ alkyleneCi-ioheteroaryl; LG is a leaving group; PG is a protecting group; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated; and
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, C-i-ealkyleneCs-acycloalkyl, Ci -6 alkyleneC 6 -ioaryl, Ci-ealkyleneCi.sheterocyclyl and C-i-ealkylened-ioheteroaryl;
• LG is a leaving group;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the above process provides intermediates, i.e. compounds of formulae R-(Ia), S-(Ib) and (IV), that are useful as starting materials in the preparation of a number of morphinones and morphinanes.
• this process is performed early in the preparation of the morphinones and morphinanes and avoids the step of quaternization of the ⁇ /-17 nitrogen using a larger alkylating agent, such as cycloalkylmethylate, which generally provides the undesired S configuration at this nitrogen as the major product.
• the quaternization step if needed, is done at a later stage and is done with a smaller methylating reagent, which provides the desired R configuration as the major product.
• the compounds of formula R-(Ia) or S-(Ib), or mixtures thereof are used in the preparation of R- methylnaltrexone, S-methylnaltrexone or mixtures thereof, or analogs thereof.
• the compounds of the formula R-(Ia) and/or S-(Ib) are reacted with a source of singlet oxygen to form a novel endoperoxide intermediate or a peracid to form 14-hydroxymorphinone derivatives that are both reduced to R-methylnaltrexone and/or S-methylnaltrexone or analogs thereof.
• the present application also includes a process of preparing R-methylnaltrexone, or analogs thereof of the formula (Via), comprising:
• R 1 is selected from hydrogen, d- ⁇ alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, Ci-6alkyleneC 3 -8cycloalkyl, Ci-6alkyleneC6-i 0 aryl, Ci- ⁇ alkyleneC-i-sheterocyclyl and Ci- ⁇ alkyleneCi-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the present application also includes a process of preparing S- methylnaltrexone, or analogs thereof of the formula S-(VIb), comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from d- ⁇ a'kyl, d-ealkyleneCs-scycloalkyl, d- ⁇ alkyleneC ⁇ -ioaryl, d- ⁇ alkylened- ⁇ heterocyclyl and d- ⁇ alkylened-ioheteroaryl;
• PG is a protecting group
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the present application also includes a process of preparing R- methylnaltrexone, or analogs thereof of the formula R-(VIa), comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)d -6 alkyl and PG;
• R j2' is selected from R ⁇ , C(O)R 13 , S(O)R J and SO 2 R 3.
• R 3 is selected from Ci- 6 alkyl, Ci- 6 alkyleneC 3-8 cycloalkyl, Ci- ⁇ alkyleneCe-iQaryl, C 1-6 alkyleneCi -8 heterocyclyl and Ci-ealkyleneC-i.-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the present application also includes a process of preparing S- methylnaltrexone, or analogs thereof of the formula S-(VIb), comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci ⁇ alkyl, Ci 6 alkyleneC 3 8 cycloalkyl, Ci ealkyleneC ⁇ -ioaryl, Ci -6 alkyleneCi- 8 heterocyclyl and Ci-ealkyleneCi-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion, and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated
• the compounds of formula (IV) are converted to morphinones and morphinanes, for example, but limited to, naltrexone, R-methylnaltrexone, nalbuphine, nalbuphone and buprenorphine, and analogs thereof.
• the present application includes a process for the synthesis of compounds of formula (VIII) comprising reacting the compounds of formula (IV) with a source of singlet oxygen or a peracid under conditions to form compounds of the formula (IX), which are reduced under conditions to form compounds of the formula (VIII):
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci- 6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from d- ⁇ alkyl, Ci- ⁇ alkyleneCs-scycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci-ealkyleneC-i-sheterocyclyl and d- ⁇ alkyleneCi-ioheteroaryl;
• PG is a protecting group; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the compounds of formula (IV) are used in the preparation of buprenorphine or analogs thereof.
• the compounds of formula (IV) are reacted with methyl vinyl ketone under [4 +2] cycloaddition conditions, followed by reduction of the double bond, installation of an alkyl group in the C-7 pendant group using, for example, a Grignard reagent and removal of any protecting groups if needed, to provide buprenorphine or analogs thereof.
• the application includes a process for preparing a compound of the formula (X), which includes buprenorphine and analogs thereof, comprising reacting a compound of the formula (IV) with methyl vinyl ketone under cycloaddition reaction conditions, followed by reduction under conditions to form a compound of the formula (Xl) which is then reacted with a reagent of the formula (XII) under conditions to form a compound of the formula (X):
• R 1 is selected from hydrogen, Ci -6 alkyl and C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci- 6 alkyl, Ci- 6 alkyleneC 3 - 8 cycloalkyl, C-i- ⁇ alkyleneCe-ioaryl,
• R 4 is selected from C-i -6 alkyl, C 3-8 cycloalkyl and C6-i 0 aryl;
• Y is a suitable counter cation; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• R 1 is selected from hydrogen, Ci -6 alkyl, C(0)Ci-6alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, d-ealkyleneCs-scycloalkyl, Ci- ⁇ alkyleneCe-ioaryl,
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• a process to enrich a ratio of the R isomer of the formula R- ⁇ a) relative to S-isomer of the formula S-(Ib) as defined above comprising heating a mixture comprising the R-isomer of the formula (I) and the S-isomer of the formula (I) at about 100° C to about 130° C to selectively degrade the S-isomer and cooling to provide a cooled mixture and passing the cooled mixture through an alumina column to selectively absorb degradation products of the S- isomer and collecting the column eluent which comprises a mixture enriched in the R-isomer.
• the present application also includes a method for separating a mixture of R- and S-isomer of methylnaltrexone comprising subjecting the mixture to HPLC or SMB chromatography.
• the present application also includes a method of separating a mixture of R- and S-isomer of methylnaltrexone chloride comprising converting the methylnaltrexone chloride to a zwitterion and separating the mixture of R- and S- zwitterions by HPLC or SMB chromatography and converting the separated zwitterions to a bromide salt by addition of hydrobromic acid.
• Figure 1 shows an example of a HPLC chromatogram of a mixture of (R,S)-methylnaltrexone and impurities ((R,S)-reduced methylnaltrexone).
• alkyl whether used alone or as part of a substituent group, includes straight and branched chains.
• alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
• C- ⁇ - 6 1 ' when used with alkyl means a straight or branched carbon chain composition of 1 , 2, 3, 4, 5 or 6 carbon atoms.
• cycloalkyl as used herein means a monocyclic or polycyclic saturated carbocylic rings and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[2.2.2]octane, and the like.
• halo means halogen and includes chloro, flouro, bromo and iodo.
• halide as used herein means a halogen anion, including Cl “ , Br “ , F “ and I " .
• fluoro-substituted' means that one or more, including all, of the hydrogens on a group are replaced with fluorine. Examples of a fluoro-substituted alkyl group are CF 3 , CF 2 CF 3 , CH 2 CF 3 and the like. Examples of flouro-substituted aryl groups are C ⁇ Fs, C ⁇ H 4 F and the like.
• deuterated means that one or more, including all, of the hydrogens on a group are replaced with deuterium (I.e. [ 2 H].
• aryl refers to a cyclic or polycyclic carbocyclic ring systems containing at least one aromatic ring.
• the aryl group is phenyl or naphthyl.
• heteroaryl refers to aromatic cyclic or polycyclic ring systems having at least one heteroatom chosen from N, O, S, and P and at least one aromatic ring.
• the heteroaryl groups include, but are not limited to, furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, and quinazolinyl, among others.
• heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring having at least one heteroatom (such as nitrogen, oxygen, sulfur or phosphorus).
• the heterocyclyl groups include all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
• heterocyclic groups include, without limitation, pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.
• heteroatom when a heteroatom is part of a claimed grouping, the heteroatom may need to be substituted to fulfill the valency requirements of that atom.
• substituents will be a hydrogen atom, or a Ci -6 alkyl group.
• ring system refers to ring structures that include monocycles, fused bicyclic and polycyclic rings, bridged rings and metalocenes.
• polycyclic as used herein means cyclic groups that contain more than one ring linked together and includes, for example, groups that contain two (bicyclic), three (tricyclic) or four (quadracyclic) rings.
• the rings may be linked through a single bond, a single atom (spirocyclic) or through two atoms (fused and bridged).
• linker grouping comprises at least one atom but may also comprise several atoms, for example up to 20 atoms, which optionally includes monocyclic and polycyclic ring systems.
• protection group or “protecting group” or “Pg” or the like as used herein refer to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protection group is typically removed under conditions that do not destroy or decompose the molecule.
• Many conventional protecting groups are known in the art for example as described in "Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973 and in Greene, T.W.
• the protecting group when it is a counterion, it may be a cation or anion depending on the group being protected.
• a suitable cation such as an alkali metal cation (e.g. Na + , K + , and Li + ).
• an alkali metal cation e.g. Na + , K + , and Li + .
• the term "anti-solvent" refers to a solvent which does not dissolve a specific substance and is added to a solution of said substance, directly or by vapor diffusion, to cause precipitation of said substance.
• peracid refers to a compound comprising the moiety "OOH” that acts as an oxidizing agent.
• the term “peracid” also includes mixtures of compounds wherein at least one compound comprises the moiety "OOH” and the mixture acts as an oxidizing agent.
• major isomer refers to a stereochemical isomer that is the most abundant isomer in a mixture of isomers of the same compound.
• minor isomer refers to a stereochemical isomer that is not the most abundant isomer in a mixture of isomers of the same compound
• the compounds, including starting materials and products it is typical for the compounds, including starting materials and products to be present as a mixture of isomers.
• the R- or S-isomer is a product or starting material of a reaction, this means that that isomer is present in greater than 80%, 85%, 90%, 95%, 98% or 99% by weight based on the total amount of R- and S-isomers.
• reaction temperatures for continuous processes can be 25 0 C, 50 0 C, 100 0 C, 150 0 C, or 200 0 C higher than the corresponding reaction temperature for batch processes.
• suitable means that the selection of the particular compound, group, atom or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process steps described herein are to be conducted under conditions sufficient to provide the product shown.
• reaction conditions including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.
• the products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.
• a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
• the application includes a process for preparing intermediates useful in the synthesis of morphinane and morphinone compounds comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci.
• R 1 is selected from hydrogen, C- ⁇ - 6 alkyl, C(O)Ci-6alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from C h alky!, C-i- ⁇ alkyleneCs-scycloalkyl, Ci- 6 alkyleneC 6 -ioaryl,
• PG is a protecting group; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the conditions to form the compounds of the formulae R-(Ia) and S-(Ib) comprise treating the compound of formula Il in a suitable solvent at a temperature of about 40 0 C to about 200
• the compound of formula (II) is reacted with excess amounts of a compound of formula (III) in suitable solvent at a temperature of about 40 0 C to about 200 0 C, or about 60 0 C to about 100 0 C, the reaction mixture is then cooled and treated with a suitable base, for example an alkali metal carbonate, followed by treatment with further amount of a compound of formula (III) and heating to a temperature of about 40 0 C to about 200 0 C, or about 60 0 C to about 100 0 C, to provide a final reaction mixture.
• the final reaction mixture is cooled and is filtered to provide a product that comprises R-(Ia) the major isomer.
• a non-polar solvent such as toluene, ether, or equivalent
• suitable solvents for reacting the compound of the formula (II) with the compound of the formula (III) include, but are not limited to, chloroform, dichloromethane (DCM), ⁇ /-methylpyrrolidone (NMP), acetonitrile, dimethylformamide (DMF), dimethylpropylidene urea (DMPU), dimethylacetamide, morpholine, hexamethylphosphoramide (HMPA), alcohols (for e.g., methanol, ethanol, 1-octanol), nitromethane, acetone, dioxane, 3- butanone, toluene, dimethyl sulfoxide (DMSO), naphthalene, dimethylbenzamide, ionic liquids (
• the reaction of the compound of the formula (II) with the compound of the formula (III) is performed at a temperature of about 40 0 C to about 200 0 C, or about 60 0 C to about 100 0 C, for about 1 minute to about 48 hours, about 10 minutes to 40 hours, about 1 hour to about 35 hours, about 2 hours to about 30 hours, about 10 hours to about 20 hours, or about 10 hours to about 15 hours.
• the compound of the formula (III) is added to the compound of the formula (II) over a set period of time, in two or more portions or continuously.
• the R-( ⁇ a) isomer is isolated using any known means, such as, but not limited to recrystallization, chromatography, differential precipitation and/or derivatization with another chiral molecule.
• the use of DMF as the reaction solvent results in precipitation of the R-(Ia) isomer from the reaction mixture.
• the R-(Ia) isomer is obtained from a mixture of R- and S- isomers by recrystallization using DMF as the recrystallization solvent.
• the ⁇ /-demethylation conditions to form the compound of formula (IV) comprise treating the compound of the formula R-(Ia), the compound of the formula S-(Ib) or a mixture of the compound of the formula R-(Ia) and S-(Ib) with a suitable nucleophile under conditions to form the compound of the formula (IV).
• suitable nucleophiles include, but are not limited to, salts of halides, RS ' , RSe “ , R 2 N “ , R 3 N, R 2 P “ , RC(O)O “ or RC(O)S “ or is R 3 N, wherein R is any suitable aliphatic, heteroalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group, or inorganic sulfur, selenium, phosphorous or nitrogen anionic salts or its neutral forms.
• the nucleophile is a thiolate nucleophile such as salts of d ⁇ oalkylS " or C ⁇ -isarylS " or an inorganic thiolate salt (e.g. S 2 " ).
• the nucleophile is salt of C 6 - 15 alkylS " or an inorganic thiolate salt (e.g. S 2 " ).
• the salt is formed with any suitable cation, for example alkali metal cations or organic cations (such as tetraalkylammonium cations).
• the thiolate salt is prepared by reacting the corresponding thiol with a strong base, such as sodium methoxide, sodium, lithium or potassium hydride and sodium, lithium or potassium carbonate.
• a strong base such as sodium methoxide, sodium, lithium or potassium hydride and sodium, lithium or potassium carbonate.
• the ⁇ /-demethylation conditions to form the compound of formula (IV) further comprise a suitable solvent at a temperature of about 40 0 C to about 150 0 C, or about 60 0 C to about 100 0 C.
• the suitable solvent is dimethylsulfoxide (DMSO).
• higher reaction temperatures are used, for example up to about 250 0 C or 200 0 C, in continuous processes with shorter contact times.
• R 1 in the compounds of formulae R-(Ia), S-(Ib), (II) and (IV) is selected from hydrogen, methyl and -C(O)-Ci -4 alkyl.
• R 2 in the compounds of formulae R-(Ia), S-(Ib), (III) and (IV) is R 3 .
• R 3 is selected from d ⁇ alkyl, Ci. 4 alkyleneC3-6cycloalkyl, Ci- 4 alkyleneC 6- ioaryl, Ci -4 alkyleneC 3-6 heterocyclyl and Ci-ealkyleneC ⁇ -ioheteroaryl.
• R 3 is Ci ⁇ alkyleneCs- ⁇ Cycloalkyl.
• R 3 is CHacyclopropyl or CHacyclobutyl.
• Z in the compounds of formulae R-(Ia) and S-(Ib) is halogen, mesylate, tosylate or brosylate and the like.
• Z is chlorine or bromine.
• Z is bromine.
• LG is the compound of formula (III) is any suitable leaving group, for example, but not limited to halogen, such as bromine or chlorine, or mesylate, tosylate or brosylate and the like.
• halogen such as bromine or chlorine
• mesylate tosylate or brosylate and the like.
• the anionic LG becomes the counter anion Z.
• the compounds of the formula R-(Ia) and/or S-(Ib) are converted to R-methylnaltrexone and/or S- methylnaltrexone and analogs thereof.
• the present application also includes a process of preparing R-methylnaltrexone, or analogs thereof of the formula R-(VIa), comprising: (a) reacting a compound of the formula R-(Ia) with a source of singlet oxygen under conditions to form a compound of the formula R-(Va); and
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, Ci-6alkyleneC 3-8 cycloalkyl, Ci -6 alkyleneC 6- ioaryl, C-i-ealkyleneCi-sheterocyclyl and Ci- ⁇ alkylened-ioheteroaryl; PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the present application also includes a process of preparing S- methylnaltrexone, or analogs thereof of the formula S-(VIb), comprising: (a) reacting a compound of the formula S-(Ib) with a source of singlet oxygen under conditions to form a compound of the formula S-(Vb); and
• R 1 is selected from hydrogen, C h alky!, C(O)C-
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci- 6 alkyl, Ci-6alkyleneC 3- 8cycloalkyl, Ci-6alkyleneC 6- ioaryl, d- ⁇ alkyleneCi-sheterocyclyl and C-i-ealkylened-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the source of singlet oxygen for the conversion of the compound of formula R-( ⁇ a) or S-(Ia) to the compound of formula R-(VIa) or S-(VIb), respectively is that provided using well-known photooxidation procedures (see, for example, CRC Handbook of Organic Photochemistry and Photobiology, Ed. William Horspool and Francesco Lend, CRC Press, 2004).
• photooxidation procedures see, for example, CRC Handbook of Organic Photochemistry and Photobiology, Ed. William Horspool and Francesco Lend, CRC Press, 2004.
• TPP tetraphenylporphyrin
• Rose Bengal Rose Bengal
• methylene blue or a porphyrin or polymer-supported versions thereof
• oxygen gas in the presence of irradiation.
• Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• compounds of formula R-(Ia) or S-(Ia) are dissolved in a suitable solvent or mixture of solvents and photo- oxygenated, for example, by adding a photosensitizer and bubbling oxygen through the reaction mixture for several hours, while irradiating the mixture (e.g., with a lamp having a power output of about 10 W to about 5000W, depending on the sensitizer, suitably having a power output of 500W) to provide the endoperoxides (Va) or (Vb), respectively.
• a photosensitizer e.g., a lamp having a power output of about 10 W to about 5000W, depending on the sensitizer, suitably having a power output of 500W
• solvents useful in the photo-oxygenation reaction include, but are not limited to, alcohols (e.g., methanol (MeOH), ethanol (EtOH), isopropanol, butanol (BuOH), 1- octanol), chloroform, dichloromethane (DCM), N-methyl-2-pyrrolidone (NMP), acetonitrile, dimethylformamide (DMF), morpholine, hexamethylphosphoramide (HMPA), nitromethane, acetone, dioxane, 3-butanone, toluene, dimethyl sulfoxide (DMSO), naphthalene, dimethylbenzamide, ionic liquids (e.g., ethylammonium nitrate, 3-methylimidazolium (BMIM) salt), fluorous phase, or any aliphatic, heteroaliphatic, heterocyclic (ring size 3 - 10 atoms), or carbocyclic (ring size 3 -
• a mixture of a chlorinated solvent e.g., chloroform, DCM
• an alcohol e.g., MeOH, EtOH, isopropanol, BuOH, 1-octanol
• a mixture of DCM and MeOH is used.
• the photo-oxygenation reaction is run at a temperature of about -40 0 C to about 80 0 C, in a particular embodiment about 5 0 C to about 15 0 C.
• alternative sources of singlet oxygen are used, for example that described in Nardello, Veronique et al.
• Lanthanum(lll)-catalyzed disproportionation of hydrogen peroxide a heterogeneous generator of singlet molecular oxygen - 1 O 2 (1D g)-in near-neutral aqueous and organic media for peroxidation of electron-rich substrates.
• the endoperoxide of formula R-(Va) or S-(Vb) is isolated by first precipitating the crude endoperoxide material by addition of a nonpolar solvent, such as diethyl ether or hexane.
• a nonpolar solvent such as diethyl ether or hexane.
• the precipitate is isolated by either filtration or centrifugation.
• the conditions to form the compound of the formula R-(VIa) or S-(VIb) from the compound of the formula R-(Va) or S- (Vb), respectively comprise any of the known methods for the hydrogenation of compounds, including for example, transfer hydrogenation, or the use of hydrogen gas in the presence of a catalyst, such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide. Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• the conditions to form the compound of the formula R-(VIa) or S- (VIb) from the compound of the formula R-(Va) or S-(Vb), respectively comprise dissolving the compound of the formula R-(Va) or S-(Vb) in a solvent or mixture of solvents with or without acid in the presence of a suitable hydrogenation catalyst.
• suitable acids include, for example, HCI, HBr, HI, H 2 SO 4 and any other mineral acid, or any organic acids such as formic acid or acetic acid, or a mixture thereof.
• suitable hydrogenation catalysts include, for example, Pd, Pd(II), Pt, Rh and Ir and their derivatives.
• the reaction mixture is treated with hydrogen (for example at 1 atm or any other suitable pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include, for example, alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1- octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid and acetic acid, and mixtures thereof.
• the reaction mixture is filtered through a filter agent, such as Celite or silica, and the filtrate is concentrated to provide a crude product.
• the crude product is purified by flash column chromatography or crystallization to provide the compound of formula R-(VIa) or S-(VIb).
• the conditions to form the compound of the formula R-(VIIa) or S-(VIIb) from the compound of the formula R-(Va) or S- (Vb), respectively comprise any of the known methods for the hydrogenation of compounds, including for example, transfer hydrogenation, or the use of hydrogen gas in the presence of a catalyst, such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide.
• a catalyst such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide.
• Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• the conditions to form the compound of the formula R-(VIIa) or S-(VIIb) from the compound of the formula R-(Va) or S-(Vb), respectively comprise dissolving the compound of the formula R-(Va) or S-(Vb) in a solvent or mixture of solvents, with or without acid, in the presence of a suitable hydrogenation catalyst and a catalyst poison.
• suitable acids include HCI, HBr, HI, H 2 SO 4 and any other mineral acid, or any organic acids such as formic acid or acetic acid.
• suitable hydrogenation catalysts include Pd, Pd(II), Pt, Rh and Ir and their derivatives.
• catalyst poisons include, for example, sulfur compounds (such as elemental sulfur and thiourea), barium sulfate, lead salts (such as lead acetate or lead oxide) and quinoline.
• the reaction mixture is treated with hydrogen (for example at 1 atm or any other suitable pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include, for example, alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1-octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid and acetic acid, and mixtures thereof.
• the reaction mixture when the reaction is complete, the reaction mixture is filtered through a filter agent, such as Celite or silica, and the filtrate is concentrated to provide a crude product.
• a filter agent such as Celite or silica
• the crude product is purified by flash column chromatography or crystallization to provide the compound of formula R-(VIIa) or S-(VIIb).
• the conditions to form the compound of the formula R-(VIa) or S-(VIb) from the compound of the formula R-(VIIa) or S- (VIIb), respectively comprise any of the known methods for the hydrogenation of compounds, including for example, transfer hydrogenation, or the use of hydrogen gas in the presence of a catalyst, such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide.
• a catalyst such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide.
• Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• the conditions to form the compound of the formula R-(VIa) or S-(VIb) from the compound of the formula R-(VIIa) or S-(VIIb), respectively comprise dissolving the compound of the formula R-(VIa) or S-(VIb) in a solvent or mixture of solvents with or without acid in the presence of a suitable hydrogenation catalyst.
• suitable acids include, for example, HCI, HBr, Hl 1 H 2 SO 4 and any other mineral acid, or any organic acids such as formic acid or acetic acid, or a mixture thereof.
• suitable hydrogenation catalysts include, for example, Pd, Pd(II), Pt, Rh and Ir and their derivatives.
• the reaction mixture is treated with hydrogen (for example at 1 atm or any other suitable pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include, for example, alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1-octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid and acetic acid, and mixtures thereof.
• the reaction mixture is filtered through a filter agent, such as Celite or silica, and the filtrate is concentrated to provide a crude product.
• the crude product is purified by flash column chromatography or crystallization to provide the compound of formula R-(VIa) or S-(VIb).
• the present application also includes a process of preparing R-methylnaltrexone, or analogs thereof of the formula (Via), comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, Ci- ⁇ alkyleneCs-scycloalkyl, C-i- ⁇ alkyleneCe-ioaryl, d-salkylened-sheterocyclyl and Ci-ealkylened-ioheteroaryl;
• PG is a protecting group
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the present application also includes a process of preparing S- methylnaltrexone, or analogs thereof of the formula (VIb), comprising:
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci- 6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, d-ealkyleneCs-scycloalkyl, Ci- 6 alkyleneC 6 -ioaryl, Ci-ealkylened- ⁇ heterocyclyl and Ci-ealkylened-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the conditions for the formation of the compound of formula R-(VIIa) or S-(VIIb) from the compound of the formula R-(Ia) or S-(Ib), respectively comprise dissolving the compound of the formula R-(Ia) or S-(Ib) in a suitable solvent or mixture of solvents and adding a peracid.
• the conditions for the formation of the compound of formula R-(VIIa) or S-(VIIb) from the compound of the formula R-(Ia) or S-(Ib), respectively further comprise a temperature of about -20 0 C to about 50 0 C, or about -10 0 C to about 20 0 C, and a time of about 10 minutes to about 10 hours, or about 1 hour to 3 hours.
• suitable peracids include performic acid, peracetic acid and m- chloroperbenzoic acid, hydrogen peroxide and OxoneTM.
• R 1 in the compounds of formulae R-( ⁇ a), S-(Ib), R-(Va), S-(Vb), R-(VIa), S-(VIb), R-(VIIa) and S-(VIIb) is selected from hydrogen, methyl and -C(O)-C-i -4 alkyl.
• R 2 in the compounds of formulae R-(Ia), S-(Ib), R-(Va), S-(Vb), R-(VIa), S-(VIb), R-(VIIa) and S-(VIIb) is R 3 .
• R 3 is selected from Ci-4alkyl, Ci- 4 alkyleneC 3-s cycloalkyl, Ci -4 alkyleneC 6 -ioaryl, Ci- 4 alkyleneC 3-6 heterocyclyl and d-ealkyleneCe-ioheteroaryl.
• R 3 is Ci -4 alkyleneC 3 . 6 cycloalkyl.
• R 3 is CHacyclopropyl or Ch ⁇ cyclobutyl.
• Z in the compounds of formulae R-(Ia), S-(Ib), R-(Va), S-(Vb), R-(VIa), S-(VIb), R-(VIIa) and S-(VIIb) is halogen, mesylate, tosylate or brosylate and the like.
• Z is chlorine or bromine.
• Z is bromine.
• the reactants and products i.e. compounds of formula R-(Ia), S-(Ib), R-(Va) 1 S-(Vb), R-(VIa), S-(VIb), R-(VIIa) and S-(VIIb)] to comprise a certain amount, for example, less than 20%, less than 15%, less than 10%, less than 5% or less than 1 %, of alternate isomers. It is also possible for the reactants and products to comprise a racemic mixture of isomers [i.e.
• the compounds of formula (IV) are converted to morphinones and morphinanes, for example, but limited to, naltrexone, R-methylnaltexone, nalbuphine, nalbuphone and buprenorphine, and analogs thereof.
• the present application includes a process for the synthesis of compounds of formula (VIII) comprising reacting the compounds of formula (IV) with a source of singlet oxygen or a peracid under conditions to form compounds of the formula (IX), which are reduced under conditions to form compounds of the formula (VIII):
• R 1 is selected from hydrogen, C-i- ⁇ alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci -6 alkyl, C-i-ealkyleneCs-acycloalkyl, Ci- 6 alkyleneC 6- ioaryl, Ci- ⁇ alkyleneCi. ⁇ heterocyclyl and d-ealkyleneCi-ioheteroaryl; PG is a protecting group; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• the conditions for the formation of the compound of formula (IX) from the compound of the formula (IV) comprise dissolving the compound of the formula (IV) in a suitable solvent or mixture of solvents and adding a peracid.
• the conditions for the formation of the compound of formula (IX) from the compound of the formula (IV) further comprise at a temperature of about -20 0 C to about 50 0 C, or about -10 0 C to about 20 0 C, and a time of about 10 minutes to about 10 hours, or about 1 hour to 3 hours.
• suitable peracids include, but are not limited to, performic acid, peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide and OxoneTM.
• the source of singlet oxygen for the conversion of the compound of formula (IV) to the compound of formula (IX) is that provided using well-known photooxidation procedures (see, for example,
• TPP tetraphenylporphyrin
• Rose Bengal methylene blue or a porphyrin
• oxygen gas in the presence of irradiation.
• Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• compounds of formula (IV) are dissolved in a suitable solvent or mixture of solvents and photo-oxygenated, for example, by adding a photosensitizer and bubbling oxygen through the reaction mixture for several hours, while irradiating the mixture (e.g., with a lamp having a power output of about 10 W to about 5000W, depending on the sensitizer, suitably having a power output of 500W) to form compounds of the formula (IX).
• a photosensitizer e.g., a lamp having a power output of about 10 W to about 5000W, depending on the sensitizer, suitably having a power output of 500W
• solvents useful in the photo-oxygenation reaction include, but are not limited to, alcohols (e.g., methanol (MeOH), ethanol (EtOH), isopropanol, butanol (BuOH), 1-octanol), chloroform, dichloromethane (DCM), N-methyl-2-pyrrolidone (NMP), acetonitrile, dimethylformamide (DMF), morpholine, hexamethylphosphoramide (HMPA), nitromethane, acetone, dioxane, 3-butanone, toluene, dimethyl sulfoxide (DMSO), naphthalene, dimethylbenzamide, ionic liquids (e.g., ethylammonium nitrate, 3-methylimidazolium (BMIM) salt), fluorous phase, or any aliphatic, heteroaliphatic, heterocyclic (ring size 3 - 10 atoms), or carbocyclic (ring size 3 -
• a mixture of a chlorinated solvent e.g., chloroform, DCM
• an alcohol e.g., MeOH, EtOH, isopropanol, BuOH, 1-octanol
• a mixture of DCM and MeOH is used.
• the photo-oxygenation reaction is run at a temperature of about -4O 0 C to about 8O 0 C, in a particular embodiment about 5°C to about 15°C.
• alternative sources of singlet oxygen are used, for example that described in Nardello, Veronique et al.
• Lanthanum(lll)-catalyzed disproportionation of hydrogen peroxide a heterogeneous generator of singlet molecular oxygen - 1 O ⁇ (1D g)-in near-neutral aqueous and organic media for peroxidation of electron-rich substrates.
• the compound of the formula (IX) is not isolated but is treated directly, with or without removal of the reaction solvent, under conditions to form the compound of the formula (VIII).
• the conditions to form the compound of the formula (VIII) from the compound of the formula (IX) comprise any of the known methods for the hydrogenation of compounds, including for example, transfer hydrogenation, or the use of hydrogen gas in the presence of a catalyst, such as Pd/C or any of the well known transition metal hydrogenation catalysts or by the use of diimide. Suitable solvents and reaction temperatures and reactant ratios are selected using known methods by a person skilled in the art.
• the conditions to form the compound of the formula (VIII) from the compound of the formula (IX) comprise dissolving the compound of the formula (IX) in a solvent or mixture of solvents with or without acid in the presence of a suitable hydrogenation catalyst.
• suitable acids include, for example, HCI, HBr, HI, H 2 SO 4 and any other mineral acid, or any organic acids such as formic acid or acetic acid, or a mixture thereof.
• suitable hydrogenation catalysts include, for example, Pd, Pd(II), Pt, Rh and Ir and their derivatives.
• the reaction mixture is treated with hydrogen (for example at 1 atm or any other suitable pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include, for example, alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1-octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid and acetic acid, and mixtures thereof.
• alcohols such as MeOH, EtOH, isopropanol, BuOH and 1-octanol
• water aqueous solutions of mineral acids and aqueous organic acids, such as formic acid and acetic acid
• a filter agent such as Celite or silica
• the filtrate is concentrated to provide a crude product.
• the crude product is purified by flash column chromatography or crystallization to provide the compound of formula (VIII).
• R 1 in the compounds of formulae (IV), (IX) and (VIII) is selected from hydrogen, methyl and -C(O)-Ci -4 alkyl.
• R 2 in the compounds of formulae (IV), (IX) and (VIII) is R 3 .
• R 3 is selected from Ci -4 alkyleneC6-ioaryl, Ci- 4 alkyleneC 3-6 heterocyclyl and C-i-ealkyleneC ⁇ -ioheteroaryl.
• R 3 is Ci -4 alkyleneC 3 .. 6 cycloalkyl.
• R 3 is CH 2 cyclopropyl or CH 2 cyclobutyl.
• Compounds of the formula (VIII) are intermediates that can be converted to, for example, R-methyl naltrexone or nalbuphine, or analogs thereof, using known procedures.
• methylation of the compounds of formula (VIII) provides methylnaltrexone and analogs thereof, including R- methylnalbuphone, predominantly in the ⁇ -configuration.
• Representative examples of such preparations of f?-methyl naltrexone are Goldberg et al. [US 4176186], Cantrell et al. [WO2004/043964], Doshan, H. D. and Perez, J. [WO2006/127899], Wang et al., [WO 2008/109156], Dlubala et al.
• nalbuphine is converted to nalbuphine using known procedures, for example, in the presence of a suitable reducing agent.
• the compounds of formula (IV) are used in the preparation of buprenorphine or analogs thereof.
• the compounds of formula (IV) are reacted with methyl vinyl ketone under [4 +2] cycloaddition conditions, followed by reduction of the double bond, installation of an alkyl group in the C-7 pendant group using, for example, a Grignard reagent and removal of any protecting groups if needed, to provide buprenorphine or analogs thereof.
• the application includes a process for preparing a compound of the formula (X), which includes buprenorphine and analogs thereof, comprising reacting a compound of the formula (IV) with methyl vinyl ketone under cycloaddition reaction conditions, followed by reduction under conditions to form a compound of the formula (Xl) which is then reacted with a reagent of the formula (XII) under conditions to form a compound of the formula (X):
• R 1 is selected from hydrogen, Ci_ 6 alkyl and C(0)C-
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from C h alky!, Ci- 6 alkyleneC 3 - 8 cycloalkyl, C-i-ealkyleneC ⁇ -ioaryl,
• R 4 is selected from Ci -6 alkyl, C 3 -8cycloalkyl and Ce-ioaryl;
• Y is a suitable counter cation; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• R 1 in the compounds of formulae (IV), (Xl) and (X) is selected from hydrogen, methyl and -C(O)-C 1-4 alkyl.
• R 2 in the compounds of formulae (IV), (Xl) and (X) is R 3 .
• R 3 is selected from C 1-4 alkyl, Ci- 4 alkyleneC 3-6 cycloalkyl, Ci -4 alkyleneC 6- ioaryl, Ci- 4 alkyleneC 3- 6heterocyclyl and Ci -6 alkyleneC 6 -ioheteroaryl.
• R 3 is C- M alkyleneCs-ecycloalkyl.
• R 3 is CH 2 cyclopropyl or CH 2 cyclobutyl.
• R 4 in the compounds of formulae (XII) and (X) is Ci -6 alkyl.
• Y in the compound of formula (XII) is Li or MgCI.
• the concentration of the R-isomer in a mixture can be increased relative to the S-isomer by selective thermal degradation of the S-isomer at 125 0 C, and then passing the mixture through a column, for example an alumina column to selectively absorb the degradation products of the S-isomer, thus producing a solution enriched in the R-isomer.
• a column for example an alumina column to selectively absorb the degradation products of the S-isomer
• a process to enrich a ratio of the R-isomer of the formula (R-Ia) relative to S-isomer of the formula (S-Ib) as defined above comprising heating a mixture comprising the R-isomer of the formula (Ia) and the S-isomer of the formula (Ib) at about 100 0 C to about 130 0 C to selectively degrade the S-isomer and cooling to provide a cooled mixture and passing the cooled mixture through an alumina column to selectively absorb degradation products of the S-isomer and collecting the column eluent which comprises a mixture enriched in the R-isomer.
• Suitable conditions for the conversion of quaternary ammonium salt 9a to endoperoxide 10a were developed. Hydrogenation of the endoperoxide intermediate furnished a mixture of methylnaltrexone chloride salts 11 in 70 - 71 % yield. Exchange of the counter ion from chloride to bromide was achieved by ion exchange chromatography and furnished a mixture of (R)- to fSj-methylnaltrexone bromide in an approximate ratio of 10 :1.
• the chloride counter ion was converted to the bromide by first converting the methylnaltrexone chloride to the corresponding zwitterion by precipitating with potassium carbonate, and then adding hydrobromic acid to the zwitterion [see Dlubala, WO 2008/034973, US 2008/0214817 for the conversion ⁇ /-methy I naltrexone methylsulfate to ⁇ /-methyl naltrexone bromide].
• the conversion of the oripavine chloride salt 9a to the bromide salt 9b proceeded in excellent yield.
• Subsequent oxidation with singlet oxygen followed by hydrogenation gave N- methylnaltrexone bromide salt 8 in a similar overall yield compared to the results of the chloride series.
• the present application includes a process for preparing compounds of formula (Vl), wherein R 1 is H and R 2 is cyclopropylmethylene as shown in Scheme 9.
• oripavine (4) is reacted with an excess of cyclopropyl methylhalide, under conditions to provide ⁇ /-cyclopropylmethylene-nororipavine methochloride (9a).
• the reaction is conducted in an organic solvent at elevated temperature.
• the cyclopropylmethylhalide is present in an amount in the range of from about 2 to about 20 molar equivalents [relative to the amount of oripavine (4)] in a further embodiment, the cyclopropyl methylhalide is present in an amount in a range of from about 10 to about 15 molar equivalents, in still a further embodiment, the amount is about 15 molar equivalents.
• the reaction of oripavine (4) with cyclopropyl methylhalide is carried out neat or in an organic solvent.
• organic solvents which are used include, but are not limited to, chloroform, DCM, NMP, acetonitrile, DMF, DMPU, morpholine, HMPA, alcohols (e.g., MeOH, EtOH, 1-octanol), nitromethane, acetone, dioxane, 3-butanone, toluene, DMSO, naphthalene, dimethylbenzamide, ionic liquids (e.g., ethylammonium nitrate, BMIM) salt), fluorous phase, or any aliphatic, heteroaliphatic, heterocyclic (ring size 3 - 10 atoms), or carbocyclic (ring size 3 - 10 atoms) solvent, or mixtures thereof.
• solvents include chloroform and ⁇ /-methyl saturated heterocycles, such as NMP.
• the elevated temperature is a temperature of from about 80 0 C to about 200 0 C, in an embodiment the temperature is about 80 0 C to about 200 0 C. In a further embodiment the temperature is about 120 0 C, to yield the corresponding compound (9a).
• reaction time for the formation of (9a) is optimized to provide the more stable and desirable f?-isomer, for example, for about 5 minutes to about 40 hours.
• reaction time for the formation of (9a) is optimized to increase the proportion of the more stable and desirable R-isomer and is about 10 hours to about 15 hours.
• the concentration of the f?-isomer in the mixture is increased relative to the S-isomer by selective thermal degradation of the S-isomer at 125 0 C, and then passing the mixture through an alumina column to selectively absorb the degradation products of the S-isomer, thus producing a solution enriched in the f?-isomer.
• the compound (9a) is then dissolved in a suitable solvent or mixture of solvents and photo-oxygenated, for example, by adding a photosensitizer (for example TPP Rose Bengal, methylene blue or a porphyrin, or polymer-supported versions thereof) and bubbling oxygen through the reaction mixture for several hours, while irradiating the mixture (e.g., with a lamp having a power output of about 10 W to about 5000 W, depending on the sensitizer, suitably having a power output of 500 W) to provide the endoperoxide (10a).
• a photosensitizer for example TPP Rose Bengal, methylene blue or a porphyrin, or polymer-supported versions thereof
• irradiating the mixture e.g., with a lamp having a power output of about 10 W to about 5000 W, depending on the sensitizer, suitably having a power output of 500 W
• solvents useful in this photo-oxygenation reaction include, but are not limited to, alcohols (e.g., MeOH, EtOH, isopropanol, BuOH, 1-octanol), chloroform, DCM, NMP, acetonitrile, DMF, morpholine, HMPA, nitromethane, acetone, dioxane, 3-butanone, toluene, DMSO, naphthalene, dimethylbenzamide, ionic liquids (e.g., ethylammonium nitrate, BMIM salt), fluorous phase, or any aliphatic, heteroaliphatic, heterocyclic (ring size 3 - 10 atoms), or carbocyclic (ring size 3 - 10 atoms) solvents, or mixtures thereof.
• alcohols e.g., MeOH, EtOH, isopropanol, BuOH, 1-octanol
• chloroform DCM
• NMP acet
• a mixture of a chlorinated solvent e.g., chloroform, DCM
• an alcohol e.g., MeOH, EtOH, isopropanol, BuOH, 1-octanol
• a mixture of DCM and MeOH is used.
• the photo-oxygenation reaction is run at a temperature of about - 40 0 C to about 80 0 C, in a particular embodiment about 5 0 C to about 15 0 C.
• the compound (9a) is then dissolved in a suitable solvent or mixture of solvents and oxidized, for example, by adding peracids such as performic, peracetic and m-chloroperbenzoic acids or other oxidizing agents such as hydrogen peroxide or OxoneTM to provide endoperoxide (10a).
• peracids such as performic, peracetic and m-chloroperbenzoic acids or other oxidizing agents such as hydrogen peroxide or OxoneTM
• other oxidizing agents such as hydrogen peroxide or OxoneTM
• the endoperoxide (10a) is isolated by first precipitating the crude endoperoxide material by addition of a nonpolar solvent, such as diethylether or hexane. The precipitate is isolated by either filtration or centrifugation.
• the crude endoperoxide material is then dissolved in a solvent or mixture of solvents (e.g., water:isopropanol:formic acid) with or without the addition of acid in the presence of a suitable hydrogenation catalyst.
• suitable acids include HCI, HBr, HI, H 2 SO 4 or any other mineral acid, or with any organic acids such as formic acid or acetic acid.
• suitable hydrogenation catalyst include Pd, Pd(II), Pt, Rh and Ir and derivative thereof.
• the reaction mixture is treated with hydrogen (for example at 1 atm or at other pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1-octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid, and acetic acid, and mixtures thereof.
• the reaction mixture is then filtered through a filter agent, such as Celite or silica, and the filtrate is concentrated.
• the product is purified by flash column chromatography or crystallization to provide the compound (11).
• compound (11) is dissolved in a minimum amount of solvent or solvent mixture, for example, waterMeOH (3:1), and filtered through an ion exchange column to exchange the counter ion from chloride to bromide to provide MNTX, compound (8).
• solvent or solvent mixture for example, waterMeOH (3:1)
• the chloride counter ion may be converted to the bromide by first converting compound (11) to the corresponding zwitterion by precipitating with potassium carbonate, and then adding hydrobromic acid to the zwitterion to provide MNTX 1 compound (8).
• compound (9a) is dissolved in a minimum amount of solvent or solvent mixture, such as water: methanol (3:1) and filtered through an ion-exchange column to exchange the counterion from chloride to bromide to provide compound (9b).
• solvent or solvent mixture such as water: methanol (3:1)
• the chloride counter ion may be converted to the bromide by first converting compound (9a) to the corresponding zwitterion by precipitating with potassium carbonate, and then adding hydrobromic acid to the zwitterion to provide MNTX, compound (9b).
• the compound (9b) is dissolved in a suitable solvent or mixture of solvents and photo- oxygenated, for example, by adding a photosensitizer (for example TPP Rose Bengal, methylene blue or a porphyrin, or polymer-supported versions thereof) and bubbling oxygen through the reaction mixture for several hours, while irradiating the mixture (e.g., with a lamp having a power output of about 10 W to about 5000 W, depending on the sensitizer, suitably having a power output of 500 W) to provide the endoperoxide (10b).
• a photosensitizer for example TPP Rose Bengal, methylene blue or a porphyrin, or polymer-supported versions thereof
• irradiating the mixture e.g., with a lamp having a power output of about 10 W to about 5000 W, depending on the sensitizer, suitably having a power output of 500 W
• solvents useful in this photo-oxygenation reaction include alcohols, for example MeOH, EtOH, isopropanol, butanol and 1-octanol, chloroform, DCM, NMP, acetonitrile, DMF, morpholine, HMPA, nitromethane, acetone, dioxane, 3-butanone, toluene, DMSO, naphthalene, dimethylbenzamide, ionic liquids, for example ethylammonium nitrate and BMIM salt, fluorous phase, or any aliphatic, heteroaliphatic, C 3 -ioheterocyclic, or C 3 -iocarbocyclic solvents, or mixtures thereof.
• alcohols for example MeOH, EtOH, isopropanol, butanol and 1-octanol
• chloroform DCM, NMP, acetonitrile, DMF, morpholine, HMPA, nitrome
• a mixture of a chlorinated solvent for example chloroform, DCM and an alcohol for example MeOH, EtOH, isopropanol, BuOH or 1-octanol is used; or, a mixture of DCM and MeOH is used.
• the photo-oxygenation reaction is run at a temperature of about - 40 0 C to about 80 0 C, for example, about 5 0 C to about 15 0 C.
• the compound (9a) is dissolved in a suitable solvent or mixture of solvents and oxidized, for example, by adding peracids such as performic, peracetic and m-chloroperbenzoic acids or other oxidizing agents such as hydrogen peroxide or oxone to provide endoperoxide (10b).
• peracids such as performic, peracetic and m-chloroperbenzoic acids or other oxidizing agents such as hydrogen peroxide or oxone
• the endoperoxide (10b) is isolated by first precipitating the crude endoperoxide material by addition of a nonpolar solvent, such as diethylether or hexane. The precipitate is isolated by either filtration or centrifugation. The crude endoperoxide material is then dissolved in a solvent or mixture of solvents (e.g., water.isopropanol.formic acid) with or without the addition of acid in the presence of a suitable hydrogenation catalyst.
• suitable acids include HCI, HBr, HI, H 2 SO 4 or any other mineral acid, or with any organic acids such as formic acid or acetic acid.
• a suitable hydrogenation catalyst include Pd, Pd(II), Pt, Rh and Ir, and derivatives thereof.
• the reaction mixture is treated with hydrogen (for example at 1 atm or at other pressures) at a temperature of about 0 0 C to about 100 0 C until complete consumption of the starting material has occurred.
• solvents useful in the hydrogenation reaction include alcohols, such as MeOH, EtOH, isopropanol, BuOH and 1-octanol, water, aqueous solutions of mineral acids and aqueous organic acids, such as formic acid, and acetic acid, or mixtures thereof.
• the reaction mixture is then filtered through a filter agent, such as Celite or silica, and the filtrate is concentrated.
• the product is purified by flash column chromatography or crystallization to provide MNTX compound (8) as a mixture containing ratios of R to S diastereomers anywhere from 1 :3 to 18:1.
• the desired R-diastereomer is separated from the S-diastereomer by high performance liquid chromatography (HPLC) or variations such as simulated moving bed (SMB) chromatography.
• HPLC high performance liquid chromatography
• SMB simulated moving bed
• a solution comprising an alkyl thiolate such as dodecanethiolate, is prepared by reacting the corresponding alkylthiol with about 1 equivalent of a strong base, such as sodium ethoxide, in a suitable solvent, such as DMSO.
• a strong base such as sodium ethoxide
• the resulting mixture is stirred and heated to a temperature of about 80 0 C to about 100 0 C, suitably about 90 0 C, for about 5 minutes to about 30 minutes, suitably about 10 minutes, prior to decreasing the temperature to about 70 0 C to about 90 0 C, suitably about 80 0 C, for the addition of a solution of ⁇ /-cyclopropylmethylene oripavine ammonium bromide (9b) or ⁇ /-cyclobutylmethylene oripavine ammonium bromide (18) in the suitable solvent at room temperature, over about 5 minutes to about 20 minutes, suitably about 10 minutes.
• ⁇ /-cyclopropylmethylene oripavine ammonium bromide (9b) or ⁇ /-cyclobutylmethylene oripavine ammonium bromide (18) in the suitable solvent at room temperature, over about 5 minutes to about 20 minutes, suitably about 10 minutes.
• Either the R- or the S-isomers of (9b) and (18) or a mixture thereof can
• the organic layers are combined, optionally washed, for example with water and brine, optionally dried, and the desired product, N- cyclopropylmethylene nor-oripavine (17) or ⁇ /-cyclobutylmethylene nor- oripavine (19) isolated by known methods.
• the /V-alkyl nor-oripavine compounds are useful intermediates for the preparation of morphinane and morphinone compounds.
• compounds (17) and (19) can be reacted with a peracid, for example peracetic acid, in a suitable solvent, for example aqueous acetic acid, at a temperature of about -5 0 C to about 10 0 C, suitably about 5 0 C.
• the resulting intermediate compound is isolated or the reaction mixture is diluted with an alcoholic solvent, such as isopropanol and treated under hydrogenation conditions, for example using palladium on carbon in a hydrogen atmosphere at room temperature until hydrogenation is complete, for example about 5 hours to about 25 hours, or as determined, for example, by HPLC.
• the mixture is filtered through a pad of celite and washed with alcohol and the product isolated using known methods.
• the product of this reaction sequence is naltrexone [from (17)] or nalbuphone [from (19)]. Naltrexone and nalbuphone are converted to other morphinane and morphinone compounds, such as R- methyl-naltrexone and nalbuphine using known methods.
• R 1 is selected from hydrogen, Ci -6 alkyl, C(O)Ci -6 alkyl and PG;
• R 2 is selected from R 3 , C(O)R 3 , S(O)R 3 and SO 2 R 3 ;
• R 3 is selected from Ci- 6 alkyl, Ci -6 alkyleneC3 -8 cycloalkyl, Ci-6alkyleneC6-ioaryl, Ci- ⁇ alkyleneCi-sheterocyclyl and C-i-ealkylened-ioheteroaryl;
• PG is a protecting group;
• Z is a suitable counter anion; and each alkyl, alkylene and aryl is optionally fluoro-substituted and/or deuterated.
• R 1 in the compound of formula R-(Va) or S-(Vb) is selected from hydrogen, methyl and -C(O)-Ci -4 alkyl.
• R 2 in the compound of formula R-(Va) or S-(Vb) is R 3 .
• R 3 is selected from Ci_ 4 alkyl, Ci ⁇ alkyleneCs-scycloalkyl, Ci -4 alkyleneC6-ioaryl, Ci- 4 alkyleneC 3-6 heterocyclyl and Ci-ealkyleneCe-ioheteroaryl.
• R 3 is C- M alkyleneCs- ⁇ cycloalkyl.
• R 3 is CH 2 cyclopropyl or CH 2 cyclobutyl.
• Z in the compound of formula R-(Va) or S-(Vb) is halogen, mesylate, tosylate or besylate and the like.
• Z is chlorine or bromine.
• Z is bromine.
• Flash column chromatography was performed using Natland 200-400 mesh silica gel. Melting points were recorded on a Hoover Unimelt apparatus and are uncorrected. Mass spectra were recorded on Kreatus/Msl Concept 1S mass spectrometer.
• Examples 1-4 refer to the compounds shown in Scheme 9.
• Example 1 N-cyclopropylmethylene-nororipavine methylchloride 9a
• Example 2 N-cyclopropylmethylene-nororipavine methylbromide 9b [00130] Compound 9a (150 mg, 0.39 mmol) dissolved in minimum amount of H 2 OiMeOH, 3:1 was filtered through a column packed with Dowex ® - 1 resin (Sigma, strongly basic bromine loaded, 50-100 mesh) and eluted with dist. H 2 O (500 ml_). The majority of the solvent was removed under reduced pressure. The residue was lyophilized to give the title compound 9b as a white solid (159 mg, 95%). 1 H and 13 C NMR spectra were identical to spectra of compound 9a. MS (FAB + ) 785 [(C 22 H 26 NOg) 2 Br] + .
• Example 4 General procedure for the reduction of endoperoxide intermediates [00136] To a solution of the endoperoxide intermediate (0.20 - 0.30 mmol) dissolved in a mixture of H 2 O:isopropanol:formic acid (1 :1 :1) (2.4 ml_) was added Pd/C (10%) (10 weight %). The reaction mixture was flushed three times with hydrogen and then stirred at 1 atm of hydrogen for 24 h. The suspension was filtered through a short plug of Celite ® and washed with MeOH. The filtrate was concentrated in vacuo and the residue was lyophilized. Flash column chromatography on silica using dichloromethane:MeOH (9:1) as eluent provided the corresponding product.
• Example 5 3-O-acetyl oripavine 12 [00142] To oripavine 4 (500 mg, 1.68 mmol) dissolved in dichloromethane (DCM) (10 mL) were added acetic anhydride (0.32 mL, 3.37 mmol) and triethylamine (0.94 ml_, 6.73 mmol) at O 0 C. The mixture was warmed to room temperature (rt) and stirred for 18 hours. Then the reaction mixture was diluted with DCM (10 ml.) and extracted three times with aq. sat. Na 2 CO 3 . The organic layer was dried over anhydrous Na 2 SO 4 , filtered and the solvent was removed under reduced pressure.
• DCM dichloromethane
• Example 6 N-cyclopropylmethylene-northebaine methylbromid ⁇ 13 [00143] A solution of thebaine (3) (600 mg, 1.93 mmol) in chloroform (12 mL) and (bromomethyl)cyclopropane (1.82 ml_, 19.28 mmol) was heated at reflux for 18 hrs. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound as colourless solid (858 mg, quant.).
• Example 7 N-cyclopropyimethyleneS-O-acetyl oripavine methylbromide 14 [00145] A solution of 3-O-acetyl oripavine (12) (300 mg, 1.32 mmol) in chloroform (6 ml_) and (bromomethyl)cyclopropane (1.24 nriL, 13.16 mmol) was heated at reflux for 18 hrs. The solvent was evaporated and the residue was dried under reduced pressure to give the title compound as colourless solid (392 mg, quant.).
• Example 8 O-methyl methylnaltrexone bromide salt 15 [00146] Following the general procedure for photo-oxygenation described in Example 3, compound 13 (500 mg, 1.12 mmol) yielded the endoperoxide intermediate as slightly brown solid (509 mg, 95%).
• Example 9 3-O-acetyl methylnaltrexone bromide salt 16 [00148] Following the general procedure for photo-oxygenation described in Example 3, compound 14 (200 mg, 0.42 mmol) yielded endoperoxide intermediate as slightly brown solid (181 mg, 85%).
• a sharp colour change from a clear, slightly yellow solution to a black colored mixture occurred after the first several drops of the /V-cyclopropylmethylene oripavine ammonium bromide solution.
• reaction mixture at room temperature was diluted with isopropanol (2.5 ml_), palladium on charcoal (51 mg, 10 wt%) was added, and the reaction mixture subjected to a hydrogen atmosphere (Parr shaker, 50 PSI) for 15 hours.
• the mixture was filtered through a pad of celite and washed with isopropanol. Acetic acid was removed as an azeotrope with toluene prior to concentration to dryness.
• Example 14 Synthesis of Nalbuphone and Nalbuphine
• nalbuphone was prepared from oripavine using an analogous sequence of reactions as that described in Examples 11-13 for the preparation of naltrexone.
• a suspension of oripavine 2.0 g, 6.73 mmol
• anhydrous DMF 10 mL
• (Bromomethyl)cyclobutane 3.01 g, 20.2 mmol, 3.0 eq) was added to the vigorously stirred suspension of oripavine as one portion and at room temperature.
• the reaction mixture was immersed in a pre-heated oil-bath at 85 0 C and allowed to stir under argon atmosphere for 18 hours.
• the reaction mixture was removed from heat and an aliquot was analyzed by HPLC (285 nm) and determined to contain approximately 9.5% (AUC) oripavine (as the HBr salt).
• Potasium carbonate 88 mg, 0.68 mmol, 9.5 mol%) was added to the reaction mixture and allowed to stir for 1 hour prior to the addition of (bromomethyl)cyclobutane (0.5 g, 3.4 mmol, 0.5 eq) at room temperature.
• the reaction mixture was immersed in the pre-heated oil-bath at 85 0 C for an additional 5 hours prior to analysis by HPLC (285 nm).
• a sharp color change from a clear, slightly yellow solution to a black colored mixture occurred after the first several drops of the N-cyclobutyllmethyl oripavine ammonium bromide solution.
• f-butylmagnesiumchloride was prepared from 2 g of Mg turnings, 6.94 mL THF, 9.8 g f-BuCI, 24.5 mL cyclohexane.
• An aliquot of Grignard reagent ( ⁇ 1 mL) was dissolved in solution of 1 ,10-phenatroline monohydrate (1-2 mg) in 4 mL THF and titrated with 1 M solution of menthol in THF until loss of purple color of magnesium-phenantroline complex.
• Grignard reagent was used as a slurry.
• CCMNO Cyclopropylmethylenenororipavine
• Example 17 HPLC Method for the Resolution Of (R)- and (S)- Isomers of Quaternized Oripavine, Cyclopropylmethylene Nororipaine and Naltrexone

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