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WO2019189749A1 - Procédé de production de dérivés de morphinane - Google Patents

Procédé de production de dérivés de morphinane Download PDF

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Publication number
WO2019189749A1
WO2019189749A1 PCT/JP2019/013973 JP2019013973W WO2019189749A1 WO 2019189749 A1 WO2019189749 A1 WO 2019189749A1 JP 2019013973 W JP2019013973 W JP 2019013973W WO 2019189749 A1 WO2019189749 A1 WO 2019189749A1
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group
substituent
carbon atoms
optionally substituted
moiety
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Japanese (ja)
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廣瀬　雅朗
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Nippon Chemiphar Co Ltd
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Nippon Chemiphar Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/09—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a morphinan derivative having a buprenorphine skeleton.
  • Buprenorphine is an opioid partial agonist for opioid receptors and is a compound used for analgesia and treatment of opioid dependence. For the first time as an analgesic, it is a compound that has been approved by the US Food and Drug Administration (FDA) for high-dose tablets as opioid addiction drugs.
  • FDA US Food and Drug Administration
  • Non-Patent Document 2 and Non-Patent Document 3 report on the synthesis and properties of PET ligand [18F] FBPN in which an 18F ethyl group is introduced at the 6-position of the buprenorphine skeleton.
  • Non-Patent Document 4 reports the synthesis of a PET ligand in which an 11C methyl group is introduced at the 6-position of the buprenorphine skeleton by the same approach. Furthermore, in Non-Patent Document 5, Srivastava et al. Reported the synthesis and application of a biochemical tool having a buprenorphine skeleton by introducing an aminoalkyl substituent at the 6-position of the buprenorphine skeleton and then modifying the amino group as a foothold. ing.
  • Kyle et al. Discloses a synthesis of a derivative in which a polyether functional group is introduced at the 6-position of a buprenorphine skeleton for the purpose of treating pain in Patent Document 1.
  • a compound (A) for the synthesis of derivatives modified at the 6-position of these buprenorphine skeletons, it was indispensable to prepare a compound (A) in which the 6-position hydroxyl group was unprotected as a precursor and only the phenolic hydroxyl group was protected.
  • the reactive agent used to remove the methyl group bonded to the tertiary alcohol is a reactive agent that requires extreme conditions such as LiAlH 4 or boron tribromide, or a reactive agent that is highly toxic or dangerous. It was necessary and difficult to apply to industrial production.
  • Opioid receptors are known to have several subtypes such as ⁇ , ⁇ , ⁇ and ⁇ . Morphine, which has a strong affinity for the ⁇ receptor, has been used as an analgesic for a long time. However, opioid ⁇ receptor agonists are known to cause adverse events such as dependence formation and respiratory depression via the ⁇ receptor. On the other hand, ⁇ receptor agonists also have analgesic effects, but are known not to participate in adverse events seen in morphine. Therefore, a ⁇ receptor selective agonist is expected as an excellent analgesic agent.
  • Patent Document 2 reports a compound represented by the following formula (B).
  • Patent Document 3 a compound represented by the following formula (C) is reported.
  • the intermediate (j) having a buprenorphine skeleton is set as a production intermediate for obtaining the final product, and (j) is unprotected at the 6-position hydroxyl group and protected only at the phenol hydroxyl group. It can be said that it is a compound corresponding to the above-mentioned (A).
  • boron tribromide is allowed to act on (h) to remove methyl groups of two hydroxyl groups at a time.
  • (J) is obtained by selectively reprotecting only the phenolic hydroxyl group after the dihydroxy compound (i) is obtained. That is, in order to obtain (j), the two methyl groups in (h) were completely removed once, and then only two phenolic hydroxyl groups were selectively reprotected.
  • Non-Patent Document 4 reports a method represented by the following formula.
  • the tertiary carbon can be converted to a tertiary carbon without damaging the alkyl group protecting the phenolic hydroxyl group with high versatility and high yield under mild conditions. Development of a one-step method capable of selectively dealkylating only the bonded alkoxy group is desired.
  • An object of the present invention is to provide an intermediate production method for producing a morphinan derivative having a buprenorphine skeleton.
  • one aspect of the present invention is the following general formula (I):
  • R 1 represents a hydrogen atom, an optionally substituted C 1-10 alkyl group, an optionally substituted cycloalkylalkyl group (the number of carbon atoms in the cycloalkyl moiety is 3 to 6, the alkylene moiety has 1 to 5 carbon atoms), and may have a substituent (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 carbon atom)
  • an optionally substituted heteroarylalkyl group heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, The number of carbon atoms is 1 to 5.
  • Heteroaryl group which may have (heteroaryl includes 1 to 4 heteroatoms selected
  • R 9 , R 10 and R 11 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-10 alkyl group, an optionally substituted C 3-6 cycloalkyl group, or a substituted group.
  • a cycloalkylalkyl group that may have a group (the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms), and may have a substituent.
  • aralkyl group (wherein the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), a heteroarylalkyl group which may have a substituent (heteroaryl is N, O And 1 to 4 heteroatoms selected from S and S as ring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atoms.), An optionally substituted C 6-10 aryl group Or, it may have a substituent.
  • Roariru group (heteroaryl N, includes 1 to 4 hetero atoms selected from O and S as a ring-constituting atom, the number of carbon atoms in the alkylene moiety shown.
  • R 9 R 10 represents an optionally substituted C 3-6 saturated hydrocarbon ring, and R 9 or R 10 may be bonded to R 11 to have a substituent.
  • R 12 represents a —C ( ⁇ O) OR 13 group (R 13 represents a hydrogen atom, an optionally substituted C 1-10 alkyl group or a carboxy protecting group), —C ( ⁇ O) — R 14 group (R 14 may have a hydrogen atom, an optionally substituted C 1-10 alkyl group, an optionally substituted C 6-10 aryl group, or an optionally substituted group.
  • heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring atoms, and the alkylene moiety has 1 to 5 carbon atoms).
  • R 15 is a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a C 3-6 cycloalkyl group which may have a substituent, or a substituent.
  • —NR 16 R 17 group R 16 and R 17 may be the same or different and each may have a hydrogen atom, a C 1-10 alkyl group which may have a substituent, or a substituent.
  • R 19 may be the same or different Ku, a hydrogen atom, which may have a substituent C 1-10 alkyl group which may have a substituent C 3-6 cycloalkyl group which may have a substituent C 6- 10 represents an aryl group or a heteroaryl group which may have a substituent.)
  • —C (NR 16 R 17 ) R 18 R 19 group R 16 , R 17 , R 18 and R 19 are the same as above.
  • -C ( O)
  • NR 20 R 21 group R 20 and R 21 may be the same or different, and may be a hydrogen atom or a C 1-10 alkyl group which may have a substituent.
  • An aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5), which may have a substituent
  • a heteroarylalkyl group (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring atoms, and the alkylene moiety has 1 to 5 carbon atoms), has a substituent
  • An optionally substituted C 2-6 alkenyl group, and an optionally substituted aryl alkenyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkenyl moiety has 2 to 6 carbon atoms.
  • heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkenyl moiety has 2 carbon atoms
  • a cycloalkylalkenyl group which may have a substituent (the cycloalkyl portion has 3 to 6 carbon atoms and the alkenyl portion has 2 to 6 carbon atoms), and has a substituent.
  • An aryl group which may optionally be substituted or a heteroaryl group which may have a substituent heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, The number of atoms is 1 to 5
  • R 20 and R 21 are bonded to each other to represent a 4- to 8-membered cyclic amino group which may have a substituent
  • R 20 or R 21 May be combined with any of R 9 , R 10 or R 11 to form a lactam ring which may have a substituent.
  • the following general formula (II) includes a step of reacting the compound (I) represented by formula (II) with a boron trifluoride complex in a solvent.
  • R 1 is a C 1-10 alkyl group which may have a substituent, a cycloalkylalkyl group which may have a substituent (carbon in the cycloalkyl moiety).
  • the number of atoms is 3-6, the number of carbon atoms in the alkylene moiety is 1-5, and an aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 6-10, The number of carbon atoms is 1 to 5.), a C 2-6 alkenyl group which may have a substituent, a C 6-10 aryl group which may have a substituent, or a substituent.
  • a heteroaryl group heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the alkylene moiety has 1 to 5 carbon atoms).
  • R 9 represents a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • the aryl which may have or the heteroaryl group which may have a substituent (the heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members, The number of carbon atoms is 1 to 5.
  • the production method according to any one of [1] to [5] above.
  • R 10 represents a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • the aryl which may have or the heteroaryl group which may have a substituent (the heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members, The number of carbon atoms is 1 to 5.
  • R 11 represents a hydrogen atom, a C 1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent.
  • R 12 is a —C ( ⁇ O) OR 13 group, a —C ( ⁇ O) —R 14 group, a —OR 15 group, a —NR 16 R 17 group, —C (OH) R 18 R 19 group, —C (NR 16 R 17 ) R 18 R 19 group or —C ( ⁇ O) NR 20 R 21 group (R 13 to R 20 and R 21 are the same as defined above.
  • One embodiment of the present invention also relates to the production method according to any one of the above [1] to [9], wherein R 3 is an optionally substituted C 1-10 alkyl group. .
  • one embodiment of the present invention relates to the production method according to any one of the above [1] to [10], wherein R 2 is an optionally substituted C 1-10 alkyl group. .
  • the compound represented by the general formula (II) is a compound selected from the compounds represented by the following numbers 1 to 48 or a salt thereof: [11] The production method according to any one of [11].
  • Another embodiment of the present invention relates to the production method according to any one of [1] to [12], wherein the compound described in the general formula (I) is in the form of an acid addition salt.
  • One embodiment of the present invention also relates to the production method according to [13], wherein the acid addition salt according to [13] is selected from mineral acids, organic carboxylic acids, or sulfonic acids.
  • the acid addition salt according to [13] or [14] is hydrochloric acid, sulfuric acid, formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid,
  • the present invention relates to the production method according to the above [13] or [14], which is selected from maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid.
  • One embodiment of the present invention is the boron trifluoride complex described in [1], wherein the boron trifluoride ether complex, boron trifluoride water complex, boron trifluoride alcohol complex, boron trifluoride. [1] to [1] above selected from amine complexes, boron trifluoride phenol complexes, boron trifluoride sulfide complexes, boron trifluoride sulfoxide complexes, boron trifluoride carboxylic acid complexes, boron trifluoride phosphate complexes, and the like. 15].
  • the boron trifluoride complex described in [16] is selected from a boron trifluoride ether complex, a boron trifluoride alcohol complex, or a boron trifluoride carboxylic acid complex.
  • One embodiment of the present invention also relates to the production method according to any one of [1] to [17], wherein the boron trifluoride complex is used in an amount of 1 to 50 times the weight of the compound (I). .
  • the solvent is a carboxylic acid, a carboxylic acid ester, an alcohol, a hydrocarbon, an alkyl halide, a nitrile, an ether, a ketone, an amide, a sulfoxide,
  • One embodiment of the present invention also relates to the production method according to [19], wherein the solvent is selected from carboxylic acids, hydrocarbons, nitriles, or ethers.
  • One aspect of the present invention also relates to the production method according to [19] or [20], wherein the solvent is selected from acetic acid, acetonitrile, toluene, or xylene.
  • the reaction temperature when the compound (I) is reacted with a boron trifluoride complex in a solvent is in the range of 20 to 150 ° C. The manufacturing method as described in any one of these.
  • Another embodiment of the present invention relates to an acid addition salt of the compound represented by the formula (I).
  • R 1 to R 12 are the same as defined above, and L represents a leaving group such as a halogen atom (for example, bromine atom or iodine atom), a methanesulfonyloxy group or a p-toluenesulfonyloxy group).
  • a halogen atom for example, bromine atom or iodine atom
  • methanesulfonyloxy group for example, bromine atom or iodine atom
  • the C 1-10 alkyl group in the C 1-10 alkyl group which may have a substituent represented by R 1 to R 4 , R 9 to R 11 and R 13 includes a methyl group, an ethyl group, n- Examples thereof include linear or branched alkyl groups such as propyl group, iso-propyl group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group or octyl group, preferably A C 1-6 alkyl group, more preferably a C 1-3 alkyl group, and still more preferably a methyl group.
  • alkyl groups may be deuterated, and examples of the deuterated alkyl group include methyl-d3, ethyl-1,1-d2, ethyl-d5, and the like.
  • substituent in the aforementioned alkyl group include those described in paragraph [0054], preferably a hydroxy group or a halogen atom (more preferably a fluorine atom), such as 2-fluoroethyl, 3-fluoro Examples include propyl, 4-fluorobutyl, 2-hydroxyethyl, trifluoromethyl groups and the like.
  • the C 3-6 cycloalkyl group in the C 3-6 cycloalkyl group which may have a substituent represented by R 1 , R 9 to R 11 , R 15 to R 20 and R 21 is a cyclopropyl group , A cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like, preferably a cyclopropyl group.
  • a cycloalkylalkyl group which may have a substituent represented by R 1 , R 3 , R 9 to R 11 , R 20 and R 21 (the cycloalkyl portion has 3 to 6 carbon atoms,
  • the cycloalkylalkyl group in 1 to 5 carbon atoms) is a methyl group, an ethyl group or the like substituted with a C 3-6 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, etc. are mentioned, More preferably, a cyclopropylmethyl group is mentioned.
  • the cycloalkylalkyl group may be deuterated, and examples thereof include a (cyclopropyl-d5) methyl group and a cyclopropylmethyl-d2 group.
  • cycloalkylalkenyl group which may have a substituent represented by R 20 and R 21 (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms).
  • the cycloalkylalkenyl group include a 2-propenyl group or a 3-methyl-2-butenyl group substituted with C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenylalkyl group which may have a substituent represented by R 20 and R 21 (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms).
  • the cycloalkenylalkyl group include a methyl group or an ethyl group substituted with a cyclopentenyl group or a cyclohexenyl group.
  • cycloalkenylalkenyl group which may have a substituent represented by R 20 and R 21 (the cycloalkenyl moiety has 4 to 6 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms).
  • the cycloalkenylalkenyl group include a 2-propenyl group or a 3-methyl-2-butenyl group substituted with a cyclopentenyl group or a cyclohexenyl group.
  • An aralkyl group which may have a substituent represented by R 1 to R 3 , R 9 to R 11 , R 20 and R 21 (the aryl moiety has 6 to 10 carbon atoms, and the carbon of the alkylene moiety)
  • Examples of the aralkyl group in 1) to 5) include a methyl group or an ethyl group substituted with phenyl or naphthyl, and a methyl group substituted with phenyl is preferable.
  • arylalkenyl group which may have a substituent represented by R 20 and R 21 (the aryl moiety has 6 to 10 carbon atoms and the alkenyl moiety has 2 to 6 carbon atoms).
  • the arylalkenyl group include 2-propenyl group and 3-methyl-2-butenyl group substituted with phenyl or naphthyl.
  • a heteroarylalkenyl group which may have a substituent represented by R 20 and R 21 (wherein heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and an alkenyl moiety;
  • the heteroarylalkenyl group in (2) represents a 2-propenyl group or a 3-methyl-2-butenyl group substituted with a pyridyl group, a furyl group, an imidazolyl group, a thiazolyl group, or the like. Is mentioned.
  • the C 4-6 cycloalkenyl group in the C 4-6 cycloalkenyl group which may have a substituent represented by R 20 and R 21 is preferably a cyclopentenyl group or a cyclohexenyl group.
  • the C 2-6 alkenyl group in the C 2-6 alkenyl group which may have a substituent represented by R 1 to R 3 , R 20 and R 21 is a 2-propenyl group or 3-methyl-2- A butenyl group is exemplified, and a 2-propenyl group is preferred.
  • C 3-6 saturated hydrocarbon ring in a C 3-6 saturated hydrocarbon ring which may have a substituent formed by combining R 9 and R 10 or any of R 9 and R 10 and R 11 includes a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring.
  • lactam ring in the lactam ring which may have a substituent formed by R 20 or R 21 together with any of R 9 , R 10 or R 11 include ⁇ -lactam and ⁇ -lactam. .
  • R 9, R 10 C 3-6 cycloalkene at any and R 11 is optionally C 3-6 cycloalkene which may have a substituent group formed by binding include cyclopentene or cyclohexene and the like.
  • C 6-10 aryl group in the C 6-10 aryl group which may have a substituent represented by R 1 , R 3 , R 9 to R 11 , R 14 to R 20 and R 21 includes a phenyl group or a naphthyl group.
  • Heteroaryl group in the heteroaryl group which may have a substituent represented by R 1 , R 3 , R 9 to R 11 , R 14 to R 20 and R 21 (heteroaryl is selected from N, O and S) 1 to 4 heteroatoms included as ring constituent atoms) are monocyclic such as pyridyl group, furyl group, imidazolyl group, pyrimidinyl group, pyrazinyl group or thiazolyl group having 5 to 10 ring atoms A heteroaryl group; bicyclic heteroaryl such as a quinolyl group or an indolyl group.
  • the 4- to 8-membered cyclic amino group in the 4- to 8-membered cyclic amino group which may have a substituent formed by combining R 20 and R 21 includes an azetidinyl group, a pyrrolidinyl group, a piperazinyl group.
  • a cyclic amino group such as a group or a morpholinyl group.
  • Examples of the acyl group in the acyl group which may have a substituent represented by R 4 and R 22 include an acetyl group, a propionyl group, and a benzoyl group.
  • halogen atom represented by R 4 examples include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.
  • Examples of the amino protecting group represented by R 16 , R 17 , R 20 and R 21 include those generally known (for example, the amino protecting group described in Non-Patent Document 6), such as an acetyl group, a trifluoroacetyl group, a tert group.
  • Examples of the carboxy-protecting group represented by R 13 include those generally known (for example, the carboxy-protecting group described in Non-Patent Document 6).
  • a C 1-6 alkyl group such as a group, iso-butyl group, tert-butyl group, pentyl group, hexyl group or heptyl group; vinyl group, allyl group, 1-propenyl group, 1-butenyl group, 1-pentenyl group, C 1-6 alkenyl group such as 1-hexenyl group or 1-heptenyl group; aralkyl group having 7 to 11 carbon atoms such as benzyl group; hydrolysis of aryl group having 6 to 14 carbon atoms such as phenyl group or naphthyl group Or acyloxy C 1-6 alkyl groups such as acetoxymethyl group or pivaloyloxymethyl group that can be removed by treatment under mild conditions such as catalytic reduction C 1-6 alkoxycarbonyloxy C 1-6
  • di-C 1-6 alkylamino C 1-6 alkyl groups such as 1-dimethylaminoethyl group; the Rakutoniru group (5-methyl-2-oxo-1,3-dioxo --4-yl) methyl group or the like
  • a C 1-6 alkyl group, a C 1-6 alkenyl group, and an aralkyl group having 7 to 11 carbon atoms more preferably a methyl group, an ethyl group, an n-propyl group, an iso-propyl group.
  • C 1-4 alkyl groups (excluding tert-butyl group) such as n-butyl group and iso-butyl group; allyl group, 1-propenyl group, 1-butenyl group A C 3-5 alkenyl group such as benzyl group, more preferably a methyl group or an ethyl group.
  • Examples of the hydroxy protecting group represented by R 15 include those generally known (for example, the hydroxy protecting group described in Non-Patent Document 6), which has a substituent such as a benzyl group, a 4-methoxybenzyl group or a trityl group. And an aralkyl group which may be substituted; an acyl group such as an acetyl group; a silyl group having a substituent such as a trimethylsilyl group or tert-butyldimethylsilyl;
  • Substituents described herein include linear or branched C 1-6 alkyl groups such as methyl, ethyl, propyl, iso-propyl, butyl or tert-butyl; fluoro Halogenated methyl group such as methyl group, difluoromethyl group or trifluoromethyl group; linear or branched C 1-8 alkoxy group such as methoxy group, ethoxy group, propoxy group or iso-propoxy group; 2-propenyl group C 6-14 aryl groups such as phenyl;; C 3-8 cycloalkyl groups such as cyclopropyl or cyclohexyl; C 2-6 alkenyl group such as a pyridyl group, a heteroaryl group such as furyl group or an imidazolyl group; Halogen atom such as fluorine atom or chlorine atom; C 1-6 alkylamino group, di-C 1-6 alkylamino group, acylamino group,
  • amino group which may have a substituent an amino group which may have a protecting group; an acyl group such as a formyl group, an acetyl group, a cyclopropylcarbonyl group or a benzoyl group; a hydroxy group; a guanidyl group; Group; a cyano group, etc. are mentioned.
  • R 1 an optionally substituted C 1-10 alkyl group; an optionally substituted cycloalkylalkyl group (cycloalkyl The number of carbon atoms in the moiety is 3 to 6 and the number of carbon atoms in the alkylene moiety is 1 to 5) and deuterated products thereof; an optionally substituted C 2-6 alkenyl group, R 2 As an optionally substituted C 1-10 alkyl group, R 3 as an optionally substituted C 1-10 alkyl group, R 4 to R 8 as a hydrogen atom, R 9 R 11 is the same or different as a hydrogen atom; an optionally substituted C 1-10 alkyl group, more preferably a hydrogen atom, and R 12 is a —C ( ⁇ O) OR 13 group; —C ( ⁇ O) —R 14 groups; —OR 15 groups; —C (OR 15 ) R 18 R 19 group; —NR 16 R 17 group or —C
  • substituents include R 1 as a hydrogen atom, methyl group, cyclopropylmethyl group, cyclobutylmethyl group and its deuterated form, allyl group, R 2 and R 3 as A methyl group, R 4 to R 8 are hydrogen atoms, R 9 to R 11 are the same or different and are hydrogen atoms, C 1-10 alkyl groups, more preferably hydrogen atoms, R 12 is benzylamide, —C ( OH) Me (tert-Bu), —C (OH) Me 2 , —CH 2 OH, —C (OH) MeCF 3 and the like.
  • the compound represented by the general formula (I) can be produced by a generally known method, for example, a method described in Patent Document 2, Non-Patent Document 1, or Non-Patent Document 6.
  • boron trifluoride complex used in the present embodiment commercially available products or those prepared by a generally known method can be used.
  • the boron trifluoride complex used in this embodiment include boron trifluoride ether complexes (for example, boron trifluoride dimethyl ether, boron trifluoride diethyl ether, boron trifluoride diisopropyl ether, boron trifluoride di-n- Butyl ether, boron trifluoride tert-butyl methyl ether, boron trifluoride tetrahydrofuran, etc.), boron trifluoride water complex (eg, boron trifluoride monohydrate, boron trifluoride dihydrate, etc.), trifluoride Boron fluoride alcohol complexes (eg, boron trifluoride methanol, boron trifluoride ethanol, boron trifluoride propanol, boron trifluoride
  • Preferred morphinan derivatives (II) in the present embodiment include those having the following compound numbers 1 to 48.
  • the raw material morphinan derivative (I) can use not only the free form but also an acid addition salt.
  • the free form of the morphinan derivative (I) is a foam-like amorphous material, the volume becomes bulky, and handling on an industrial scale is often difficult.
  • the morphinan derivative (I) is a salt, it becomes a powdery substance, so that it is easier to handle than a foamy substance and effective for manufacturing on an industrial scale, which is effective. .
  • acid addition salts include salts with mineral acids such as hydrochloric acid or sulfuric acid, salts with organic carboxylic acids such as formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid, Examples thereof include salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid.
  • mineral acids such as hydrochloric acid or sulfuric acid
  • organic carboxylic acids such as formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid or maleic acid
  • sulfonic acids such as methanesulfonic acid, benzenesulfonic acid,
  • Production of a morphinan derivative having a buprenorphine skeleton represented by the general formula (II) can be carried out by allowing a boron trifluoride complex to act on the compound represented by the general formula (I).
  • solvents such as carboxylic acids, carboxylic acid esters, alcohols, hydrocarbons, alkyl halides, nitriles, ethers, ketones, amides, sulfoxides and carbonates.
  • carboxylic acids such as formic acid or acetic acid
  • carboxylic acid esters such as ethyl acetate
  • alcohols such as methanol, ethanol or propanol
  • aromatic hydrocarbons such as benzene, toluene or xylene
  • dichloromethane, chloroform or carbon tetrachloride etc.
  • Halogenated hydrocarbons of nitriles such as acetonitrile or propionitrile; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran or dioxane; ketones such as acetone or methyl ethyl ketone; dimethylformamide Or amides such as dimethylacetamide; sulfoxides such as dimethyl sulfoxide; carbonates such as diethyl carbonate and 1,3-dioxan-2-one; ureas such as N, N′-dimethylpropyleneurea; water or these
  • carboxylic acids, carboxylic esters, alcohols, hydrocarbons, alkyl halides, nitriles, ethers, ketones, amides, sulfoxides, ureas or carbonates are preferable.
  • carboxylic acids, hydrocarbons, nitriles or ethers are included, more preferably acetic acid, acetonitrile, xylene, toluene, and particularly preferably acetic acid or acetonitrile.
  • the amount of the solvent to be used is not particularly limited, but it is preferably in the range of 1 to 200, preferably 1 to 100, more preferably 1 to 50, still more preferably 1 to 20 times by weight with respect to compound (I).
  • the reaction temperature can be appropriately set depending on the solvent to be used.
  • the reaction temperature is 20 ° C to 150 ° C, preferably 40 ° C to 120 ° C, more preferably 50 ° C to 100 ° C, and further preferably 50 ° C to 90 ° C.
  • the reaction temperature is 5 minutes to 300 hours, preferably 1 hour to 20 hours.
  • the boron trifluoride complex can be used in an amount of 1.0 to 50 times, preferably 1 to 30 times, more preferably 1 to 10 times the compound (I).
  • reaction solution was cooled from 0 ° C. to 15 ° C., 4N aqueous sodium hydroxide solution (120 L) was slowly added, and finally the pH was adjusted to 10-12.
  • the reaction solution was extracted twice with ethyl acetate (30 L), and the collected organic layer was washed twice with saturated brine (20 L).
  • the organic layer was dried over anhydrous sodium sulfate (5 kg), the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give a yellow crystalline solid.
  • the obtained solid was stirred and washed in a mixed solvent of n-heptane and ethyl acetate (1: 1, 1.2 L) and water (1.8 L), and pulverized.
  • Example 2 The solvent of Example 1 was changed to acetic acid, and the following experiment was conducted in the same manner. (4R, 4aR, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4,7,7a into a 100 L three-necked flask -Hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-14-carboxamide (7.4 kg) was dissolved in acetic acid (45 kg). To the resulting solution was added boron trifluoride diethyl ether complex (20.5 kg) at room temperature.
  • a 100 L reaction vessel was charged with acetonitrile (47.6 kg) and (4R, 4aR, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7,9-dimethoxy-1,2,3,4, Add 7,7a-hexahydro-4a, 7-ethano-4,12-methanobenzofuro [3,2-e] isoquinoline-14-carboxamide p-toluenesulfonate 1p-toluenesulfonic acid adduct (6.02 kg) It was.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production de composés représentés par la formule générale suivante à l'aide d'une réaction de désalkylation utilisant un complexe de trifluorure de bore (dans la formule, R1 représente un groupe alkyle en C1-10, etc. R2 représente un groupe alkyle en C1-10, etc, R3 représente un atome d'hydrogène, etc. R4 représente un atome d'hydrogène, etc, R5 et R6 sont identiques ou différents et représentent des atomes d'hydrogène, etc., R7 et R8 sont identiques ou différents et représentent des atomes d'hydrogène, etc. R9, R10, R11 sont identiques ou différents et représentent des atomes d'hydrogène, des groupes alkyle en C1-10, etc. et R12 représente un groupe en -C(=O)OR13, un groupe en -C(=O)-R14, un groupe en -C(O=)NR20R21, etc.).
PCT/JP2019/013973 2018-03-30 2019-03-29 Procédé de production de dérivés de morphinane Ceased WO2019189749A1 (fr)

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WO1998043978A1 (fr) * 1997-03-27 1998-10-08 Toray Industries, Inc. Derives de morphinane et usage medical de ces derniers
WO2013035833A1 (fr) * 2011-09-09 2013-03-14 学校法人北里研究所 Dérivé de morphinane
JP2013543488A (ja) * 2010-09-21 2013-12-05 パーデュー、ファーマ、リミテッド、パートナーシップ ブプレノルフィン類似体
JP2016504346A (ja) * 2012-12-31 2016-02-12 ローズ テクノロジーズ ７β−置換６α，１４α−エテノモルフィナンおよび７β−置換６α，１４α−エタノモルフィナンを調製するための方法

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JP2013543488A (ja) * 2010-09-21 2013-12-05 パーデュー、ファーマ、リミテッド、パートナーシップ ブプレノルフィン類似体
WO2013035833A1 (fr) * 2011-09-09 2013-03-14 学校法人北里研究所 Dérivé de morphinane
JP2016504346A (ja) * 2012-12-31 2016-02-12 ローズ テクノロジーズ ７β−置換６α，１４α−エテノモルフィナンおよび７β−置換６α，１４α−エタノモルフィナンを調製するための方法

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WO2023190665A1 (fr) * 2022-03-29 2023-10-05 東レ株式会社 Dérivé de morphinane et son utilisation médicale

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