WO2010073974A1 - Practical method for reducing amides and lactams - Google Patents

Practical method for reducing amides and lactams Download PDF

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WO2010073974A1
WO2010073974A1 PCT/JP2009/071092 JP2009071092W WO2010073974A1 WO 2010073974 A1 WO2010073974 A1 WO 2010073974A1 JP 2009071092 W JP2009071092 W JP 2009071092W WO 2010073974 A1 WO2010073974 A1 WO 2010073974A1
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group
general formula
represented
substituted
aromatic ring
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PCT/JP2009/071092
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Japanese (ja)
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隆雄 碇屋
正人 伊藤
隆史 大塚
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国立大学法人東京工業大学
セントラル硝子株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/189—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms containing both nitrogen and phosphorus as complexing atoms, including e.g. phosphino moieties, in one at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2282—Unsaturated compounds used as ligands
    • B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/16—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/821—Ruthenium

Definitions

  • the present invention relates to a method for reducing amides and lactams that are important as production techniques for pharmaceutical and agrochemical intermediates.
  • the group 8 (VIII) transition metal complex used in the present invention has been reported to be effective in the reduction of ketones, epoxides, imides and esters in the presence of a base and hydrogen gas (Non-Patent Documents). 2). However, no adaptation to amides and lactams, which are much more difficult to reduce than these substrates, has been reported.
  • An object of the present invention is to provide a practical method for reducing amides and lactams.
  • the method of using a hydride reducing agent in a stoichiometric manner is not suitable for production on a large scale because the reducing agent is expensive and careful in handling, and the post-treatment is complicated and waste is large. Accordingly, there has been a strong demand for a reduction method using hydrogen gas that does not involve such a problem, in particular, a method using a homogeneous catalyst that can be relatively easily scaled up for industrialization.
  • the present invention targets amides and lactams that are extremely difficult to reduce, it is necessary to design a highly active catalyst. In such a case, there is a lot of knowledge, and it is a good idea to select a metal complex that can change the ligand relatively easily.
  • the group 8 (VIII) transition metal complex used in the present invention has such a requirement and is suitable.
  • the catalyst system derived from the metal complex is effective for the reduction of amides and lactams, and it is an object of the present invention to clarify this effectiveness.
  • the target products targeted in the present invention are alcohols and aminoalcohols, and it was completely unknown whether a desired product can be obtained with high selectivity and high yield in the above catalyst system.
  • group 8 (VIII) transition metal complexes include “cyclopentadienyl (Cp) group or 1,2,3,4,5-pentamethylcyclopentadienyl (Cp * ) group, halogen, carbon monoxide”.
  • Fe, Ru or Os complexes having a bidentate ligand of acetonitrile, phenyl isocyanide or triphenylphosphine, and nitrogen-nitrogen (NN) or phosphorus-nitrogen (PN) "Ru complexes with a Cp * group, halogen or acetonitrile, and a bidentate ligand (PC 2 -N) in which phosphorus and nitrogen are connected via two carbons” are preferred, especially "Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ] (Ph; phenyl group) ”was newly clarified.
  • an alkali metal hydroxide or alkoxide is preferable, and an alkali metal alkoxide is particularly preferable.
  • tert-butanol which is a sterically bulky tertiary alcohol
  • side reactions such as alcoholysis of an amide bond can be controlled, and the target product can be selected with high selectivity.
  • the pressure of hydrogen gas by introducing an electron withdrawing group suitable for R 3 which is a substituent on nitrogen, the reaction proceeds smoothly even at a relatively low hydrogen pressure compared to the prior art. I found. Considering practicality, this is a preferred embodiment, and the pressure of such a suitable hydrogen gas is 2.5 to 3.5 MPa.
  • reaction temperature it was found that the reaction proceeds smoothly even at a considerably lower temperature than in the prior art by introducing a suitable substituent for R 3 as with the pressure of hydrogen gas. Considering practicality, this is a preferred embodiment, and a suitable reaction temperature is 70 to 90 ° C.
  • the present invention includes [Invention 1] to [Invention 6] and provides a practical method for reducing amides and lactams.
  • A represents a cyclopentadienyl (Cp) group or a 1,2,3,4,5-pentamethylcyclopentadienyl (Cp * ) group
  • M represents Fe, Ru, or Os.
  • B represents halogen, carbon monoxide, acetonitrile, phenyl isocyanide or triphenylphosphine
  • C represents a nitrogen-nitrogen (NN) or phosphorus-nitrogen (PN) bidentate ligand.
  • R 3 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic ring group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group or Represents a substituted arylsulfonyl group] or a amide represented by the general formula [3]
  • R 1 -R 2 represents that R 1 and R 2 of the amide represented by the general formula [2] are connected by a covalent bond (except when R 2 is a hydrogen atom) ⁇
  • the group 8 (VIII) transition metal complex represented by the general formula [1] is represented by the general formula [6].
  • Cp * represents a 1,2,3,4,5-pentamethylcyclopentadienyl group
  • X represents halogen or acetonitrile.
  • P—C 2 —N represents a bidentate ligand in which phosphorus and nitrogen are connected via two carbons
  • invention 5 The amide according to any one of invention 1 to invention 4, wherein the pressure of hydrogen gas (H 2 ) is 2.5 to 3.5 MPa in any one of invention 1 to invention 4. Of reducing lactic acids or lactams.
  • invention 6 The method for reducing an amide or lactam according to any one of invention 1 to invention 5, wherein the reaction temperature is 70 to 90 ° C in any one of invention 1 to invention 5.
  • the catalyst system of the present invention can be applied to the reduction of amides and lactams that are remarkably difficult to reduce, and gives the target products of the present invention alcohols and amino alcohols with high selectivity and high yield. Therefore, it becomes a substitute for the conventional stoichiometric hydride reducing agent and can be suitably used for production on a large scale.
  • reaction conditions are relatively relaxed, impurities that are difficult to separate from the target product are hardly produced as a by-product, and the purification is not burdened. Even when an optically active substrate having hydrogen at the ⁇ -position of the ester group or amide group is used, racemization does not occur throughout the reaction (see Example 7 and Example 24). Further, although this reaction is under reducing conditions, hydrogenolysis such as debenzylation does not occur at all (see Example 3).
  • the present invention is an alternative to conventional stoichiometric hydride reducing agents, and further, since the desired reduction can be carried out under relatively mild reaction conditions, a wide range of substrate applications for amides and lactams. This is a practical reduction method.
  • Lactams in the presence of a group 8 (VIII) transition metal complex represented by the general formula [1], a base and hydrogen gas, an amide represented by the general formula [2], or represented by the general formula [3] Lactams can be reduced to alcohols represented by general formula [4] or aminoalcohols represented by general formula [5], respectively.
  • a group 8 (VIII) transition metal complex represented by the general formula [1] a base and hydrogen gas
  • a of the group 8 (VIII) transition metal complex represented by the general formula [1] represents a Cp group or a Cp * group. Of these, the Cp * group is preferred.
  • M in the group 8 (VIII) transition metal complex represented by the general formula [1] represents Fe, Ru or Os. Among these, Fe and Ru are preferable, and Ru is particularly preferable.
  • B of the group 8 (VIII) transition metal complex represented by the general formula [1] represents halogen such as chlorine, bromine and iodine, carbon monoxide, acetonitrile, phenyl isocyanide or triphenylphosphine. Among them, halogen and acetonitrile are preferable, and chlorine is particularly preferable.
  • a cationic complex may be used, and such counter anions include chlorine, tetrafluoroborate (BF 4 ⁇ ), triflate ion (CF 3 SO 3 ⁇ ), hexafluorophosphate (PF 6 ⁇ ), Examples include hexafluoroantimonate (SbF 6 ⁇ ).
  • CF 3 SO 3 Among them -, PF 6 - and SbF 6 - are preferable, and CF 3 SO 3 - and PF 6 - are more preferred.
  • C in the group 8 (VIII) transition metal complex represented by the general formula [1] represents an NN or PN bidentate ligand.
  • P—C 2 —N is preferable, and Ph 2 P (CH 2 ) 2 NH 2 is particularly preferable.
  • the NN bidentate ligand is In particular, 2-pyridylmethylamine is more effective.
  • NN bidentate ligands can be produced by known methods, and many are commercially available. The PN bidentate ligand is described in Aldrichichima ACTA (USA), 2008, Vol.
  • NN and PN (PC 2 -N) bidentate ligands are shown in [Chemical Formula 8], but are not limited to these representative examples (respective representative examples) In the structural formula, any number of lower alkyl groups can be substituted on any carbon atom).
  • the abbreviations in the representative examples are as follows. Me: methyl group, Ph: phenyl group, i-Pr: isopropyl group, t-Bu: tert-butyl group, Bn: benzyl group.
  • * Represents an asymmetric carbon or axial asymmetry, and can take R or S form. When there are a plurality of *, any combination of R-form or S-form can be taken.
  • PN bidentate ligand described in the above Aldrichica ACTA can be used similarly.
  • the group 8 (VIII) transition metal complex represented by the general formula [1] is described in Organometallics (USA), 2003, Vol. 22, p. 4190-4192 and Organometallics (USA), 1997, Vol. 16, p. 1956-1961 etc.
  • the claims of the present invention are based on a two-component preparation method in which the catalyst system is derived from AMBC and a base, but the same catalytically active species due to the action with hydrogen gas (a reaction solvent may be involved). All methods by which ⁇ AMHC [wherein H represents hydride] ⁇ can be prepared in the reaction system are intended to be included in the claims of the present invention.
  • Organometallics USA), 2003, Vol. 22, p.
  • the amount of the group 8 (VIII) transition metal complex represented by the general formula [1] used is a catalytic amount relative to 1 mol of the amide represented by the general formula [2] or the lactam represented by the general formula [3]. However, usually 0.3 to 0.00001 mol is preferable, and 0.2 to 0.0001 mol is more preferable.
  • Bases include alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, tetra n-butylammonium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium Alkali metal alkoxides such as isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8 Diazabicyclo [5.4.0] undec-7-ene (DBU) an organic base such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsily
  • the amount of the base used may be 0.7 mol or more, preferably 0.8 to 20 mol, particularly 0.9, relative to 1 mol of the group 8 (VIII) transition metal complex represented by the general formula [1]. To 10 mol is more preferred.
  • the amount of hydrogen gas (H 2 ) used may be 2 mol or more per 1 mol of the amides represented by the general formula [2] or the lactams represented by the general formula [3]. An excess is preferred, and a large excess under pressure is particularly preferred.
  • the hydrogen gas pressure may be higher than atmospheric pressure, but is preferably 2 to 5 MPa, and more preferably 2.5 to 3.5 MPa in view of practicality.
  • R 1 of the amide represented by the general formula [2] represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group.
  • an alkyl group, a substituted alkyl group, an aromatic ring group, and a substituted aromatic ring group are preferable, and an alkyl group and a substituted alkyl group are particularly preferable.
  • the alkyl group can have a straight chain or branched chain structure having 1 to 18 carbon atoms, or a cyclic structure (when the number of carbon atoms is 3 or more).
  • a single bond of any two adjacent carbon atoms in the alkyl group is replaced with a double bond in any number, and the stereochemistry of the double bond is E-form, Z-form, or E-form.
  • a mixture of Z bodies can be taken.
  • the aromatic ring group is an aromatic carbon hydrogen group having 1 to 18 carbon atoms, such as phenyl group, naphthyl group, anthryl group, or pyrrolyl group, furyl group, thienyl group, indolyl group, benzofuryl group, benzothienyl group, etc.
  • An aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom can be employed.
  • the alkyl group, alkenyl group or aromatic ring group may have a substituent on an arbitrary carbon atom in any number and in any combination (substitute alkyl group, substituted alkenyl group and substituted aromatic ring group, respectively). Corresponding to).
  • substituents include fluorine, chlorine, bromine, iodine halogen atoms, azide groups, nitro groups, methyl groups, ethyl groups, propyl groups and other lower alkyl groups, fluoromethyl groups, chloromethyl groups, bromomethyl groups and other lower groups.
  • Lower alkyl groups such as haloalkyl groups, methoxy groups, ethoxy groups, propoxy groups, etc., lower haloalkoxy groups such as fluoromethoxy groups, chloromethoxy groups, bromomethoxy groups, dimethylamino groups, diethylamino groups, dipropylamino groups, etc.
  • Lower alkylthio groups such as amino group, methylthio group, ethylthio group and propylthio group, lower alkoxycarbonyl groups such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, benzyloxycarbonyl group and aminocarbonyl group (CONH 2 ) , Dimethyl Lower alkylaminocarbonyl groups such as minocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, alkynyl group, phenyl group, naphthyl group, pyrrolyl group, furyl group, thienyl group and other aromatic ring groups, phenoxy group, naphthoxy group, Aromatic ring oxy groups such as pyrrolyloxy group, furyloxy group and thienyloxy group, aliphatic heterocyclic groups such as piperidyl group, piperidino group and morpholinyl group, protected
  • “Lower” means straight or branched chain or cyclic (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms. “Protecting groups for hydroxyl groups, amino groups (including amino acids or peptide residues), thiol groups, aldehyde groups and carboxyl groups” are described in Protective Groups In Organic Synthesis, ThirdTEdition, 1999, JohnJWileyle & Sons, Inc. Can be used (two or more functional groups can be protected with one protecting group).
  • Alkynyl group “aromatic ring group”, “aromatic ring oxy group” and “aliphatic heterocyclic group” include halogen atom, azide group, nitro group, lower alkyl group, lower haloalkyl group, lower alkoxy group.
  • a protective body of thiol group, a protective body of thiol group, a protective body of aldehyde group, a protective body of carboxyl group, etc. can be substituted.
  • the present invention is a reduction reaction
  • the substituent itself may be reduced depending on the type of the substituent.
  • the desired reaction can be performed satisfactorily by adopting suitable reaction conditions.
  • R 2 of the amide represented by the general formula [2] represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group.
  • an alkyl group, a substituted alkyl group, an aromatic ring group, and a substituted aromatic ring group are preferable, and an alkyl group and a substituted alkyl group are particularly preferable.
  • the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the same as the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R 1 of the amides represented by the general formula [2]. The same.
  • R 3 of the amide represented by the general formula [2] is a hydrogen atom, alkyl group, substituted alkyl group, aromatic ring group, substituted aromatic ring group, alkoxycarbonyl group, substituted alkoxycarbonyl group, alkylsulfonyl group, substituted alkylsulfonyl Represents a group, an arylsulfonyl group or a substituted arylsulfonyl group.
  • an aromatic ring group, a substituted aromatic ring group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group and a substituted arylsulfonyl group are preferable, and in particular, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, An alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, and a substituted arylsulfonyl group are more preferable.
  • alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the same as the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R 1 of the amides represented by the general formula [2]. The same.
  • R 1 -R 2 of the lactam represented by the general formula [3] represents that R 1 and R 2 of the amide represented by the general formula [2] are covalently bonded (provided that R 2 Except when is a hydrogen atom).
  • the covalent bond is naturally between any carbon atoms of R 1 and R 2 , but may be bonded through a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom.
  • Suitable R 1 and R 2 are the same as in the case of the amides represented by the general formula [2]. It has also been clarified that the number of ring members of lactams affects the reaction rate, and the substrate is preferably a 4- to 6-membered ring compared to a 7-membered ring.
  • a compound in which the substituents R 1 and R 3 of the amide represented by the general formula [2] are combined at the same time as F as the substrate of Example 6 is also represented by the general formula [2] of the present invention. Treat as indicated amides.
  • any carbon atom of R 2 and R 3 of the amide represented by the general formula [2] may be covalently bonded (in some cases, a nitrogen atom, And may be linked via a hetero atom such as an oxygen atom or a sulfur atom), and are treated as amides represented by the general formula [2] of the present invention.
  • Reaction solvents include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, ⁇ , ⁇ , ⁇ -trifluorotoluene, xylene, ethylbenzene and mesitylene, methylene chloride Halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, diethylene glycol dimethyl ether And ethers such as anisole, and alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. Of these, alcohols are
  • the reaction solvent may be used in an amount of 0.1 L (liter) or more per 1 mol of the amide represented by the general formula [2] or the lactam represented by the general formula [3]. .2 to 20L is preferable, and 0.3 to 10L is more preferable.
  • the reaction temperature may be 50 ° C or higher, but is preferably 60 to 100 ° C, and more preferably 70 to 90 ° C in view of practicality.
  • the reaction time is not particularly limited, but is usually within 120 hours. However, since it varies depending on the catalyst system, substrate and reaction conditions, analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable that the progress of the reaction is followed by the reaction, and the point of time when the raw material has almost disappeared is the end point of the reaction.
  • the target alcohols represented by the general formula [4] or the amino alcohols represented by the general formula [5] can be obtained by performing normal operations on the reaction-terminated liquid.
  • the desired product can be purified to a high chemical purity by activated carbon treatment, distillation, recrystallization, column chromatography or the like, if necessary.
  • an amide represented by the general formula [2], or represented by the general formula [3] Lactams can be reduced to alcohols represented by general formula [4] or aminoalcohols represented by general formula [5], respectively (Aspect 1).
  • a more active catalytically active species can be prepared by a preferred combination of a group 8 (VIII) transition metal complex and a base (Aspect 2).
  • An extremely highly active catalytically active species can be prepared by a particularly more preferable combination of a group 8 (VIII) transition metal complex and a base (Aspect 3).
  • a more practical reduction method can be provided by a combination of Embodiments 1 to 3 and a suitable reaction solvent (Aspect 4).
  • a remarkably practical reduction method can be provided by a combination of modes 1 to 4 and a suitable hydrogen gas pressure (mode 5).
  • a combination of Embodiments 1 to 5 and a suitable reaction temperature can provide a very practical reduction method (Aspect 6).
  • Example 1 The experimental operation of Example 1 is shown below as a representative example.
  • reaction-terminated liquid is filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid are concentrated under reduced pressure, and semi-microdistilled to obtain the following formula: 378 mg of the amino alcohol represented by The yield was> 99%.
  • Examples 2 to 16 were the same as Example 1 except that the type of lactam, the amount of Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ], the amount of tert-butoxypotassium used and the reaction time were changed. Went to. The results of Examples 2 to 16 are summarized in Table 1.
  • the substrate F of Example 6 is a compound in which the substituents of R 1 and R 3 of the amide share a phenyl group. Further, the ⁇ -position of the ethoxycarbonyl group of the product of Example 7 was not racemized at all.
  • Example 17 to 23 The experimental operation of Example 23 is shown below as a representative example.
  • reaction-terminated liquid was filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid were concentrated under reduced pressure, and semi-microdistilled to obtain 326 mg of the aminoalcohol represented by The yield was 91%.
  • Examples 17 to 22 were carried out in the same manner as in Example 23, except that the type of lactam, the type of Cp * RuCl [bidentate ligand], and the reaction temperature were changed.
  • the results of Examples 17 to 22 are summarized in Table 2.
  • Example 24 The following formula is applied to a Schlenk tube under an argon atmosphere: Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ] 12.3 mg (0.025 mmol, 0.03 eq), tert-butoxypotassium 2.8 mg [0.025 mmol, 1.00 eq (for the ruthenium complex) Equivalent))], 5.6 mL of isopropanol, 259.7 mg (0.81 mmol, 1.00 eq) represented by the above formula was added, and freeze degassing was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder.
  • SUS stainless steel
  • the inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 3 MPa, and the mixture was stirred at 80 ° C. for 20 hours.
  • the reaction completion liquid By purifying the reaction completion liquid by silica gel column chromatography, As a result, 108.8 mg of the alcohol represented by the formula (1) was obtained. The yield was 90%. No reduction in optical purity was observed in the reduction reaction. Also, the following formula 127.2 mg of an asymmetric auxiliary group represented by the following formula was recovered. The recovery rate was 89%.
  • Example 24 The result of Example 24 is shown in the following scheme.
  • Example 25 The experimental operation of Example 25 is shown below as a representative example.
  • the inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 5 MPa, and the mixture was stirred at 100 ° C. for 90 hours.
  • the conversion of the reaction finished liquid was> 99%.
  • the reaction-terminated liquid was filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid were concentrated under reduced pressure, and semi-microdistilled to obtain 126 mg of the aminoalcohol represented by The yield was 90%.
  • Examples 26 to 31 were carried out in the same manner as in Example 25, except that the type of lactam, the amount of Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] used, and the reaction time were changed.
  • the results of Examples 25 to 31 are summarized in Table 3.
  • Example 32 to 37 The experimental operation of Example 32 is shown below as a representative example.
  • the inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 5 MPa, and the mixture was stirred at 100 ° C. for 90 hours.
  • the conversion rate of the reaction finished liquid was 100%.
  • the reaction-terminated liquid is filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid are concentrated under reduced pressure, and semi-microdistilled to obtain the following formula: The alcohol shown by was obtained. Also, the following formula Was recovered.
  • Examples 33 to 37 were carried out in the same manner as in Example 32 by changing the kind of amides, the amount of Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] used, and the reaction time.
  • the results of Examples 32 to 37 are summarized in Table 4.

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Abstract

Amides or lactams can be reduced respectively into alcohols or amino alcohols in the presence of an 8(VIII) group transition metal complex, a base and hydrogen gas (H2).  By appropriately combining an 8(VIII) group transition metal complex, a base, a reaction solvent, the hydrogen gas pressure and the reaction temperature, a highly practical reduction method can be provided.  A practical method for reducing amides and lactams which is applicable to a broad scope of substrates because of being usable as a substitute for the existing method with the use of a stoichiometric hydride reducing agent and ensuring the achievement of desired reduction under relatively mild reaction conditions.

Description

アミド類およびラクタム類の実用的な還元方法Practical methods for reducing amides and lactams
　本発明は、医農薬中間体の製造技術として重要なアミド類およびラクタム類の還元方法に関する。 The present invention relates to a method for reducing amides and lactams that are important as production techniques for pharmaceutical and agrochemical intermediates.
発明の背景Background of the Invention
　アミド類からアルコール類への還元は、アルミニウム系のヒドリド還元剤を量論的に用いる方法が多用されている（ラクタム類からアミノアルコール類への還元も同様）。一方、遷移金属を触媒とする水素ガス（Ｈ2）による還元、特に、再現性が高い均一系触媒を用いる方法は、研究が殆ど成されていない。最近、特徴的な３座のホスフィン配位子を有するルテニウム錯体を用いる均一系の水素化が報告されたが（特許文献１、非特許文献１）、高い触媒活性を発現するには高温条件を必要とし、さらにアミン類の製造をターゲットにしたものである。 For the reduction of amides to alcohols, a method using a stoichiometric amount of an aluminum-based hydride reducing agent is frequently used (the same applies to the reduction of lactams to amino alcohols). On the other hand, little research has been conducted on the reduction with hydrogen gas (H 2 ) using a transition metal as a catalyst, particularly the method using a homogeneous catalyst with high reproducibility. Recently, homogeneous hydrogenation using a ruthenium complex having a characteristic tridentate phosphine ligand has been reported (Patent Document 1, Non-Patent Document 1). Necessary and further targeted for the production of amines.
　本発明で用いる８（ＶＩＩＩ）族遷移金属錯体は、塩基および水素ガスの共存下に、ケトン類、エポキシド類、イミド類およびエステル類の還元に有効であることが報告されている（非特許文献２）。しかしながら、これらの基質に比べて還元が格段に困難なアミド類およびラクタム類への適応は一切報告されていない。 The group 8 (VIII) transition metal complex used in the present invention has been reported to be effective in the reduction of ketones, epoxides, imides and esters in the presence of a base and hydrogen gas (Non-Patent Documents). 2). However, no adaptation to amides and lactams, which are much more difficult to reduce than these substrates, has been reported.
国際公開２００３／０９３２０８号パンフレットInternational Publication 2003/093208 Pamphlet
本発明の目的は、アミド類およびラクタム類の実用的な還元方法を提供することにある。 An object of the present invention is to provide a practical method for reducing amides and lactams.
　ヒドリド還元剤を量論的に用いる方法は、該還元剤が高価で取り扱いに注意がいること、後処理が煩雑で廃棄物が多いことから大量規模での生産には不向きであった。よって、この様な問題を伴わない水素ガスを用いる還元、特に、工業化に向けたスケールアップが比較的容易に行える均一系触媒を用いる方法が強く望まれていた。 The method of using a hydride reducing agent in a stoichiometric manner is not suitable for production on a large scale because the reducing agent is expensive and careful in handling, and the post-treatment is complicated and waste is large. Accordingly, there has been a strong demand for a reduction method using hydrogen gas that does not involve such a problem, in particular, a method using a homogeneous catalyst that can be relatively easily scaled up for industrialization.
　さらに、本発明では還元が格段に困難なアミド類およびラクタム類を対象とするため、高活性な触媒を設計する必要がある。この様な場合、多くの知見があり、配位子の変更が比較的容易に行える金属錯体を選択することが得策である。本発明で用いる８（ＶＩＩＩ）族遷移金属錯体は、この様な要件を正に備えており好適である。しかしながら、該金属錯体から誘導される触媒系がアミド類およびラクタム類の還元に有効であるかは全く不明であり、この有効性を明らかにすることが本発明の課題である。また、本発明で対象とする目的生成物はアルコール類およびアミノアルコール類であり、上記の触媒系で所望の生成物が高い選択性で収率良く得られるかも全く不明であった。 Furthermore, since the present invention targets amides and lactams that are extremely difficult to reduce, it is necessary to design a highly active catalyst. In such a case, there is a lot of knowledge, and it is a good idea to select a metal complex that can change the ligand relatively easily. The group 8 (VIII) transition metal complex used in the present invention has such a requirement and is suitable. However, it is completely unknown whether the catalyst system derived from the metal complex is effective for the reduction of amides and lactams, and it is an object of the present invention to clarify this effectiveness. Moreover, the target products targeted in the present invention are alcohols and aminoalcohols, and it was completely unknown whether a desired product can be obtained with high selectivity and high yield in the above catalyst system.
　本発明者らは、上記の課題を踏まえて鋭意検討した結果、８（ＶＩＩＩ）族遷移金属錯体、塩基および水素ガスの存在下に、アミド類またはラクタム類を、それぞれアルコール類またはアミノアルコール類に還元できることを新たに見出した。 As a result of intensive studies based on the above problems, the present inventors have converted amides or lactams into alcohols or amino alcohols in the presence of a group 8 (VIII) transition metal complex, a base and hydrogen gas, respectively. I found out that it can be reduced.
　先ず、８（ＶＩＩＩ）族遷移金属錯体としては、“シクロペンタジエニル（Ｃｐ）基または１，２，３，４，５－ペンタメチルシクロペンタジエニル（Ｃｐ*）基、ハロゲン、一酸化炭素、アセトニトリル、フェニルイソシアニドまたはトリフェニルホスフィン、および、窒素－窒素（Ｎ－Ｎ）またはリン－窒素（Ｐ－Ｎ）の二座配位子を有する、Ｆｅ、ＲｕまたはＯｓ錯体”を用いることができ、“Ｃｐ*基、ハロゲンまたはアセトニトリル、および、リンと窒素が２つの炭素を介して結ばれた二座配位子（Ｐ－Ｃ2－Ｎ）を有する、Ｒｕ錯体”が好ましく、特に“Ｃｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］（Ｐｈ；フェニル基）”がより好ましいことを新たに明らかにした。 First, group 8 (VIII) transition metal complexes include “cyclopentadienyl (Cp) group or 1,2,3,4,5-pentamethylcyclopentadienyl (Cp * ) group, halogen, carbon monoxide”. Fe, Ru or Os complexes having a bidentate ligand of acetonitrile, phenyl isocyanide or triphenylphosphine, and nitrogen-nitrogen (NN) or phosphorus-nitrogen (PN) "Ru complexes with a Cp * group, halogen or acetonitrile, and a bidentate ligand (PC 2 -N) in which phosphorus and nitrogen are connected via two carbons" are preferred, especially "Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ] (Ph; phenyl group) ”was newly clarified.
　次に、塩基としては、アルカリ金属の水酸化物またはアルコキシドが好ましく、特にアルカリ金属のアルコキシドがより好ましいことを新たに明らかにした。 Next, it has been newly clarified that as the base, an alkali metal hydroxide or alkoxide is preferable, and an alkali metal alkoxide is particularly preferable.
　また、反応溶媒としては、立体的に嵩高い第３級アルコールであるｔｅｒｔ－ブタノールを用いることにより、アミド結合の加アルコール分解等の副反応を制御することができ、目的生成物を高い選択性で得ることができる。 Further, by using tert-butanol, which is a sterically bulky tertiary alcohol, as a reaction solvent, side reactions such as alcoholysis of an amide bond can be controlled, and the target product can be selected with high selectivity. Can be obtained at
　さらに、水素ガスの圧力としては、窒素上の置換基であるＲ3に好適な電子求引性基を導入することにより、従来技術に比べて比較的低い水素圧でも反応がスムーズに進行することを見出した。実用性を考慮すると好ましい態様であり、係る好適な水素ガスの圧力は、２．５から３．５ＭＰａである。 Furthermore, as for the pressure of hydrogen gas, by introducing an electron withdrawing group suitable for R 3 which is a substituent on nitrogen, the reaction proceeds smoothly even at a relatively low hydrogen pressure compared to the prior art. I found. Considering practicality, this is a preferred embodiment, and the pressure of such a suitable hydrogen gas is 2.5 to 3.5 MPa.
　最後に、反応温度としては、水素ガスの圧力と同様、Ｒ3に好適な置換基を導入することにより、従来技術に比べて相当低い温度でも反応がスムーズに進行することを見出した。実用性を考慮すると好ましい態様であり、係る好適な反応温度は、７０から９０℃である。 Finally, as the reaction temperature, it was found that the reaction proceeds smoothly even at a considerably lower temperature than in the prior art by introducing a suitable substituent for R 3 as with the pressure of hydrogen gas. Considering practicality, this is a preferred embodiment, and a suitable reaction temperature is 70 to 90 ° C.
　この様に、アミド類およびラクタム類の実用的な還元方法として有用な方法を見出し、本発明に到達した。 Thus, a useful method was found as a practical method for reducing amides and lactams, and the present invention was achieved.
　すなわち、本発明は［発明１］から［発明６］を含み、アミド類およびラクタム類の実用的な還元方法を提供する。 That is, the present invention includes [Invention 1] to [Invention 6] and provides a practical method for reducing amides and lactams.
［発明１］
一般式［１］
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ａはシクロペンタジエニル（Ｃｐ）基または１，２，３，４，５－ペンタメチルシクロペンタジエニル（Ｃｐ*）基を表し、ＭはＦｅ、ＲｕまたはＯｓを表す。さらに、Ｂはハロゲン、一酸化炭素、アセトニトリル、フェニルイソシアニドまたはトリフェニルホスフィンを表し、Ｃは窒素－窒素（Ｎ－Ｎ）またはリン－窒素（Ｐ－Ｎ）の二座配位子を表す］で示される８（ＶＩＩＩ）族遷移金属錯体、塩基および水素ガス（Ｈ2）の存在下に、一般式［２］
Figure JPOXMLDOC01-appb-C000009
 ［式中、Ｒ1はアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基を表し、Ｒ2は水素原子、アルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、Ｒ3は水素原子、アルキル基、置換アルキル基、芳香環基、置換芳香環基、アルコキシカルボニル基、置換アルコキシカルボニル基、アルキルスルホニル基、置換アルキルスルホニル基、アリールスルホニル基または置換アリールスルホニル基を表す］で示されるアミド類、または一般式［３］
Figure JPOXMLDOC01-appb-C000010
 ｛式中、Ｒ1－Ｒ2は一般式［２］で示されるアミド類のＲ1とＲ2が共有結合で結ばれていることを表す（但し、Ｒ2が水素原子の場合を除く）｝で示されるラクタム類を、それぞれ一般式［４］
Figure JPOXMLDOC01-appb-C000011
 ｛式中、Ｒ1は一般式［２］で示されるアミド類のＲ1と同じである｝で示されるアルコール類、または一般式［５］
Figure JPOXMLDOC01-appb-C000012
 ｛式中、Ｒ1－Ｒ2は一般式［２］で示されるアミド類のＲ1とＲ2が共有結合で結ばれていることを表し（但し、Ｒ2が水素原子の場合を除く）、Ｒ3は一般式［２］で示されるアミド類のＲ3と同じである｝で示されるアミノアルコール類に還元する方法。 [Invention 1]
General formula [1]
Figure JPOXMLDOC01-appb-C000008
 [Wherein, A represents a cyclopentadienyl (Cp) group or a 1,2,3,4,5-pentamethylcyclopentadienyl (Cp * ) group, and M represents Fe, Ru, or Os. Further, B represents halogen, carbon monoxide, acetonitrile, phenyl isocyanide or triphenylphosphine, and C represents a nitrogen-nitrogen (NN) or phosphorus-nitrogen (PN) bidentate ligand. In the presence of the indicated group 8 (VIII) transition metal complex, base and hydrogen gas (H 2 ), the general formula [2]
Figure JPOXMLDOC01-appb-C000009
 [Wherein R 1 represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, and R 2 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted group. Represents an aromatic ring group, R 3 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic ring group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group or Represents a substituted arylsulfonyl group] or a amide represented by the general formula [3]
Figure JPOXMLDOC01-appb-C000010
 {In the formula, R 1 -R 2 represents that R 1 and R 2 of the amide represented by the general formula [2] are connected by a covalent bond (except when R 2 is a hydrogen atom) }, Each of the lactams represented by the general formula [4]
Figure JPOXMLDOC01-appb-C000011
 {Wherein, R 1 is the same as R 1 of amides of the general formula [2]} alcohols represented by or general formula [5]
Figure JPOXMLDOC01-appb-C000012
 {In the formula, R 1 -R 2 represents that R 1 and R 2 of the amide represented by the general formula [2] are connected by a covalent bond (except when R 2 is a hydrogen atom) , R 3 is the same as R 3 of the amide represented by the general formula [2]}.
　［発明２］
発明１において、一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体が一般式［６］
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｃｐ*は１，２，３，４，５－ペンタメチルシクロペンタジエニル基を表し、Ｘはハロゲンまたはアセトニトリルを表す。さらに、Ｐ－Ｃ2－Ｎはリンと窒素が２つの炭素を介して結ばれた二座配位子であることを表す］で示される８（ＶＩＩＩ）族遷移金属錯体であり、さらに塩基がアルカリ金属の水酸化物またはアルコキシドであることを特徴とする、発明１に記載のアミド類またはラクタム類の還元方法。 [Invention 2]
In the invention 1, the group 8 (VIII) transition metal complex represented by the general formula [1] is represented by the general formula [6].
Figure JPOXMLDOC01-appb-C000013
 [Wherein Cp * represents a 1,2,3,4,5-pentamethylcyclopentadienyl group, and X represents halogen or acetonitrile. Further, P—C 2 —N represents a bidentate ligand in which phosphorus and nitrogen are connected via two carbons], and is a group 8 (VIII) transition metal complex represented by The method for reducing an amide or lactam according to the invention 1, which is an alkali metal hydroxide or alkoxide.
［発明３］
発明２において、一般式［６］で示される８（ＶＩＩＩ）族遷移金属錯体が式［７］
Figure JPOXMLDOC01-appb-C000014
 ［式中、Ｃｐ*は１，２，３，４，５－ペンタメチルシクロペンタジエニル基を表し、Ｐｈはフェニル基を表す］で示される８（ＶＩＩＩ）族遷移金属錯体であり、さらに塩基がアルカリ金属のアルコキシドであることを特徴とする、発明２に記載のアミド類またはラクタム類の還元方法。 [Invention 3]
In Invention 2, the group 8 (VIII) transition metal complex represented by the general formula [6] is represented by the formula [7].
Figure JPOXMLDOC01-appb-C000014
 [Wherein Cp * represents a 1,2,3,4,5-pentamethylcyclopentadienyl group and Ph represents a phenyl group], which is a group 8 (VIII) transition metal complex represented by The method for reducing amides or lactams according to the invention 2, characterized in that is an alkoxide of an alkali metal.
　［発明４］
発明１及至発明３の何れか１つにおいて、反応溶媒がｔｅｒｔ－ブタノールであることを特徴とする、発明１及至発明３の何れか１つに記載のアミド類またはラクタム類の還元方法。 [Invention 4]
The method for reducing amides or lactams according to any one of inventions 1 to 3, wherein the reaction solvent is tert-butanol in any one of inventions 1 to 3.
　［発明５］
発明１及至発明４の何れか１つにおいて、水素ガス（Ｈ2）の圧力が２．５から３．５ＭＰａであることを特徴とする、発明１及至発明４の何れか１つに記載のアミド類またはラクタム類の還元方法。 [Invention 5]
The amide according to any one of invention 1 to invention 4, wherein the pressure of hydrogen gas (H 2 ) is 2.5 to 3.5 MPa in any one of invention 1 to invention 4. Of reducing lactic acids or lactams.
　［発明６］
発明１及至発明５の何れか１つにおいて、反応温度が７０から９０℃であることを特徴とする、発明１及至発明５の何れか１つに記載のアミド類またはラクタム類の還元方法。 [Invention 6]
The method for reducing an amide or lactam according to any one of invention 1 to invention 5, wherein the reaction temperature is 70 to 90 ° C in any one of invention 1 to invention 5.
詳細な説明Detailed description
　本発明の触媒系は、還元が格段に困難なアミド類およびラクタム類の還元にも適応でき、本発明の目的生成物であるアルコール類およびアミノアルコール類を高い選択性で収率良く与える。よって、従来の量論的なヒドリド還元剤の代替となり、大量規模での生産にも好適に利用できる。 The catalyst system of the present invention can be applied to the reduction of amides and lactams that are remarkably difficult to reduce, and gives the target products of the present invention alcohols and amino alcohols with high selectivity and high yield. Therefore, it becomes a substitute for the conventional stoichiometric hydride reducing agent and can be suitably used for production on a large scale.
　しかも、反応条件が比較的緩和なため、目的生成物との分離の難しい不純物を殆ど副生せず、精製に負荷が掛からない。また、エステル基やアミド基のα位に水素を有する光学活性な基質を用いても、反応を通してラセミ化は起こらない（実施例７および実施例２４を参照）。さらに、本反応は還元条件であるにも拘らず、脱ベンジル化等の加水素分解も全く起こらない（実施例３を参照）。 Moreover, since the reaction conditions are relatively relaxed, impurities that are difficult to separate from the target product are hardly produced as a by-product, and the purification is not burdened. Even when an optically active substrate having hydrogen at the α-position of the ester group or amide group is used, racemization does not occur throughout the reaction (see Example 7 and Example 24). Further, although this reaction is under reducing conditions, hydrogenolysis such as debenzylation does not occur at all (see Example 3).
　この様に、本発明は、従来の量論的なヒドリド還元剤の代替となり、さらに所望の還元が比較的緩和な反応条件下で実施できるため、基質適用範囲の広い、アミド類およびラクタム類の実用的な還元方法である。 Thus, the present invention is an alternative to conventional stoichiometric hydride reducing agents, and further, since the desired reduction can be carried out under relatively mild reaction conditions, a wide range of substrate applications for amides and lactams. This is a practical reduction method.
　本発明のアミド類およびラクタム類の実用的な還元方法について詳細に説明する。 The practical reduction method of the amides and lactams of the present invention will be described in detail.
　本発明では、一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体、塩基および水素ガスの存在下に、一般式［２］で示されるアミド類、または一般式［３］で示されるラクタム類を、それぞれ一般式［４］で示されるアルコール類、または一般式［５］で示されるアミノアルコール類に還元することができる。 In the present invention, in the presence of a group 8 (VIII) transition metal complex represented by the general formula [1], a base and hydrogen gas, an amide represented by the general formula [2], or represented by the general formula [3] Lactams can be reduced to alcohols represented by general formula [4] or aminoalcohols represented by general formula [5], respectively.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体のＡは、Ｃｐ基またはＣｐ*基を表す。その中でもＣｐ*基が好ましい。 A of the group 8 (VIII) transition metal complex represented by the general formula [1] represents a Cp group or a Cp * group. Of these, the Cp * group is preferred.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体のＭは、Ｆｅ、ＲｕまたはＯｓを表す。その中でもＦｅおよびＲｕが好ましく、特にＲｕがより好ましい。 M in the group 8 (VIII) transition metal complex represented by the general formula [1] represents Fe, Ru or Os. Among these, Fe and Ru are preferable, and Ru is particularly preferable.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体のＢは、塩素、臭素、ヨウ素等のハロゲン、一酸化炭素、アセトニトリル、フェニルイソシアニドまたはトリフェニルホスフィンを表す。その中でもハロゲンおよびアセトニトリルが好ましく、特に塩素がより好ましい。Ｂの種類によってはカチオン性錯体を採ることもあり、係るカウンターアニオンは、塩素、テトラフルオロボラート（ＢＦ4 -）、トリフラートイオン（ＣＦ3ＳＯ3 -）、ヘキサフルオロホスフェート（ＰＦ6 -）、ヘキサフルオロアンチモネート（ＳｂＦ6 -）等が挙げられる。その中でもＣＦ3ＳＯ3 -、ＰＦ6 -およびＳｂＦ6 -が好ましく、特にＣＦ3ＳＯ3 -およびＰＦ6 -がより好ましい。 B of the group 8 (VIII) transition metal complex represented by the general formula [1] represents halogen such as chlorine, bromine and iodine, carbon monoxide, acetonitrile, phenyl isocyanide or triphenylphosphine. Among them, halogen and acetonitrile are preferable, and chlorine is particularly preferable. Depending on the type of B, a cationic complex may be used, and such counter anions include chlorine, tetrafluoroborate (BF 4 − ), triflate ion (CF 3 SO 3 − ), hexafluorophosphate (PF 6 − ), Examples include hexafluoroantimonate (SbF 6 − ). CF 3 SO 3 Among them -, PF 6 - and SbF 6 - are preferable, and CF 3 SO 3 - and PF 6 - are more preferred.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体のＣは、Ｎ－ＮまたはＰ－Ｎの二座配位子を表す。その中でもＰ－Ｃ2－Ｎが好ましく、特にＰｈ2Ｐ（ＣＨ2）2ＮＨ2がより好ましい。また、一般式［２］で示されるアミド類、またはＲ3が芳香環基または置換芳香環基である一般式［３］で示されるラクタム類の還元では、Ｎ－Ｎ二座配位子が効果的であり、特に２－ピリジルメチルアミンがより効果的である。Ｎ－Ｎ二座配位子は、公知の方法により製造でき、また多くが市販されている。Ｐ－Ｎ二座配位子は、Ａｌｄｒｉｃｈｉｍｉｃａ ＡＣＴＡ（米国），２００８年，第４１巻，第１号，ｐ．１５－２６等により製造できる。代表的なＮ－ＮおよびＰ－Ｎ（Ｐ－Ｃ2－Ｎ）の二座配位子を［化８］に示すが、これらの代表例に限定されるものではない（代表例のそれぞれの構造式において、任意の炭素原子上に、任意の数で、低級アルキル基が置換できる）。なお、代表例における略記号は次の通りとする。Ｍｅ；メチル基、Ｐｈ；フェニル基、ｉ－Ｐｒ；イソプロピル基、ｔ－Ｂｕ；ｔｅｒｔ－ブチル基、Ｂｎ；ベンジル基。＊は不斉炭素または軸不斉を表し、Ｒ体またはＳ体を採ることができる。＊が複数ある場合には、Ｒ体またはＳ体の任意の組み合わせを採ることができる。 C in the group 8 (VIII) transition metal complex represented by the general formula [1] represents an NN or PN bidentate ligand. Among them, P—C 2 —N is preferable, and Ph 2 P (CH 2 ) 2 NH 2 is particularly preferable. In the reduction of the amide represented by the general formula [2] or the lactam represented by the general formula [3] in which R 3 is an aromatic ring group or a substituted aromatic ring group, the NN bidentate ligand is In particular, 2-pyridylmethylamine is more effective. NN bidentate ligands can be produced by known methods, and many are commercially available. The PN bidentate ligand is described in Aldrichichima ACTA (USA), 2008, Vol. 41, No. 1, p. 15-26 or the like. Representative NN and PN (PC 2 -N) bidentate ligands are shown in [Chemical Formula 8], but are not limited to these representative examples (respective representative examples) In the structural formula, any number of lower alkyl groups can be substituted on any carbon atom). The abbreviations in the representative examples are as follows. Me: methyl group, Ph: phenyl group, i-Pr: isopropyl group, t-Bu: tert-butyl group, Bn: benzyl group. * Represents an asymmetric carbon or axial asymmetry, and can take R or S form. When there are a plurality of *, any combination of R-form or S-form can be taken.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　また、上記のＡｌｄｒｉｃｈｉｍｉｃａ ＡＣＴＡに記載されたＰ－Ｎ二座配位子も同様に用いることができる。 Also, the PN bidentate ligand described in the above Aldrichica ACTA can be used similarly.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体は、Ｏｒｇａｎｏｍｅｔａｌｌｉｃｓ（米国），２００３年，２２巻，ｐ．４１９０－４１９２およびＯｒｇａｎｏｍｅｔａｌｌｉｃｓ（米国），１９９７年，第１６巻，ｐ．１９５６－１９６１等により製造できる。本発明の請求項は、触媒系がＡＭＢＣと塩基から誘導される２成分調製法を基に記載しているが、水素ガスとの作用（反応溶媒が関与することもある）により同じ触媒活性種｛ＡＭＨＣ［式中、Ｈはヒドリドを表す］｝が反応系内で調製できる全ての方法が本発明の請求項に含まれるものとする。具体的に補足すると、２成分調製法｛Ｃｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］、塩基／水素ガス（反応溶媒が関与することもある）｝で調製される触媒活性種のＣｐ*ＲｕＨ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］は、３成分調製法｛Ｃｐ*ＲｕＣｌ（ｃｏｄ）（ｃｏｄ；１，５－シクロオクタジエン）、Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2、塩基／水素ガス（反応溶媒が関与することもある）｝でも同様に調製することができる。さらに、Ｏｒｇａｎｏｍｅｔａｌｌｉｃｓ（米国），２００３年，２２巻，ｐ．４１９０－４１９２で報告されている様に、同じ触媒活性種｛Ｃｐ*ＲｕＨ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］｝は、イソプロピルアルコール中でＣｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］と塩基からも同様に調製できる。予め調製した触媒活性種を用いて水素ガスの存在下に（必要に応じて塩基の共在下に）反応を行うこともできる。具体例以外でもこの様な関係にある全ての調製方法が、本発明の請求項には含まれていることを意味する。 The group 8 (VIII) transition metal complex represented by the general formula [1] is described in Organometallics (USA), 2003, Vol. 22, p. 4190-4192 and Organometallics (USA), 1997, Vol. 16, p. 1956-1961 etc. The claims of the present invention are based on a two-component preparation method in which the catalyst system is derived from AMBC and a base, but the same catalytically active species due to the action with hydrogen gas (a reaction solvent may be involved). All methods by which {AMHC [wherein H represents hydride]} can be prepared in the reaction system are intended to be included in the claims of the present invention. Specifically supplemented, a catalytically active species prepared by a two-component preparation method {Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ], base / hydrogen gas (which may involve a reaction solvent)} Cp * RuH [Ph 2 P (CH 2 ) 2 NH 2 ] is a three-component preparation method {Cp * RuCl (cod) (cod; 1,5-cyclooctadiene), Ph 2 P (CH 2 ) 2 NH 2 , Base / hydrogen gas (reaction solvent may be involved)} can be similarly prepared. Furthermore, Organometallics (USA), 2003, Vol. 22, p. The same catalytically active species {Cp * RuH [Ph 2 P (CH 2 ) 2 NH 2 ]} is reported in Cp * RuCl [Ph 2 P (CH 2 ) 2 in isopropyl alcohol, as reported in 4190-4192. It can be similarly prepared from NH 2 ] and a base. The reaction can also be carried out in the presence of hydrogen gas (if necessary, in the presence of a base) using a catalytically active species prepared in advance. All preparation methods having such a relationship other than the specific examples are included in the claims of the present invention.
　一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体の使用量は、一般式［２］で示されるアミド類、または一般式［３］で示されるラクタム類１モルに対して触媒量を用いれば良いが、通常は０．３から０．００００１モルが好ましく、特に０．２から０．０００１モルがより好ましい。 The amount of the group 8 (VIII) transition metal complex represented by the general formula [1] used is a catalytic amount relative to 1 mol of the amide represented by the general formula [2] or the lactam represented by the general formula [3]. However, usually 0.3 to 0.00001 mol is preferable, and 0.2 to 0.0001 mol is more preferable.
　塩基は、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等のアルカリ金属の炭酸水素塩、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等のアルカリ金属の炭酸塩、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等のアルカリ金属の水酸化物、水酸化テトラｎ－ブチルアンモニウム、リチウムメトキシド、ナトリウムメトキシド、カリウムメトキシド、リチウムエトキシド、ナトリウムエトキシド、カリウムエトキシド、リチウムイソプロポキシド、ナトリウムイソプロポキシド、カリウムイソプロポキシド、リチウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド等のアルカリ金属のアルコキシド、トリエチルアミン、ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］ウンデセ－７－エン（ＤＢＵ）等の有機塩基、リチウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド等が挙げられる。その中でもアルカリ金属の水酸化物およびアルコキシドが好ましく、特にアルカリ金属のアルコキシドがより好ましい。 Bases include alkali metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, Alkali metal hydroxides such as potassium hydroxide, tetra n-butylammonium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium Alkali metal alkoxides such as isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8 Diazabicyclo [5.4.0] undec-7-ene (DBU) an organic base such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide. Of these, alkali metal hydroxides and alkoxides are preferable, and alkali metal alkoxides are more preferable.
　塩基の使用量は、一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体１モルに対して０．７モル以上を用いれば良く、０．８から２０モルが好ましく、特に０．９から１０モルがより好ましい。 The amount of the base used may be 0.7 mol or more, preferably 0.8 to 20 mol, particularly 0.9, relative to 1 mol of the group 8 (VIII) transition metal complex represented by the general formula [1]. To 10 mol is more preferred.
　水素ガス（Ｈ2）の使用量は、一般式［２］で示されるアミド類、または一般式［３］で示されるラクタム類１モルに対して２モル以上を用いれば良いが、通常は大過剰が好ましく、特に加圧下での大過剰がより好ましい。係る水素ガスの圧力は、大気圧より高い条件で行えば良いが、２から５ＭＰａが好ましく、実用性を考慮すると特に２．５から３．５ＭＰａがより好ましい。 The amount of hydrogen gas (H 2 ) used may be 2 mol or more per 1 mol of the amides represented by the general formula [2] or the lactams represented by the general formula [3]. An excess is preferred, and a large excess under pressure is particularly preferred. The hydrogen gas pressure may be higher than atmospheric pressure, but is preferably 2 to 5 MPa, and more preferably 2.5 to 3.5 MPa in view of practicality.
　一般式［２］で示されるアミド類のＲ1は、アルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基を表す。その中でもアルキル基、置換アルキル基、芳香環基および置換芳香環基が好ましく、特にアルキル基および置換アルキル基がより好ましい。 R 1 of the amide represented by the general formula [2] represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group. Among these, an alkyl group, a substituted alkyl group, an aromatic ring group, and a substituted aromatic ring group are preferable, and an alkyl group and a substituted alkyl group are particularly preferable.
　アルキル基は、炭素数が１から１８の、直鎖または枝分れの鎖式、または環式（炭素数が３以上の場合）を採ることができる。アルケニル基は、該アルキル基の、任意の隣り合う２つの炭素原子の単結合が二重結合に、任意の数で置き換わり、該二重結合の立体化学はＥ体、Ｚ体、またはＥ体とＺ体の混合物を採ることができる。芳香環基は、炭素数が１から１８の、フェニル基、ナフチル基、アントリル基等の芳香族炭素水素基、またはピロリル基、フリル基、チエニル基、インドリル基、ベンゾフリル基、ベンゾチエニル基等の窒素原子、酸素原子または硫黄原子等のヘテロ原子を含む芳香族複素環基を採ることができる。 The alkyl group can have a straight chain or branched chain structure having 1 to 18 carbon atoms, or a cyclic structure (when the number of carbon atoms is 3 or more). In the alkenyl group, a single bond of any two adjacent carbon atoms in the alkyl group is replaced with a double bond in any number, and the stereochemistry of the double bond is E-form, Z-form, or E-form. A mixture of Z bodies can be taken. The aromatic ring group is an aromatic carbon hydrogen group having 1 to 18 carbon atoms, such as phenyl group, naphthyl group, anthryl group, or pyrrolyl group, furyl group, thienyl group, indolyl group, benzofuryl group, benzothienyl group, etc. An aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom can be employed.
　該アルキル基、アルケニル基または芳香環基は、任意の炭素原子上に、任意の数でさらに任意の組み合わせで、置換基を有することもできる（それぞれ置換アルキル基、置換アルケニル基および置換芳香環基に対応する）。係る置換基としては、フッ素、塩素、臭素、ヨウ素のハロゲン原子、アジド基、ニトロ基、メチル基、エチル基、プロピル基等の低級アルキル基、フルオロメチル基、クロロメチル基、ブロモメチル基等の低級ハロアルキル基、メトキシ基、エトキシ基、プロポキシ基等の低級アルコキシ基、フルオロメトキシ基、クロロメトキシ基、ブロモメトキシ基等の低級ハロアルコキシ基、ジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基等の低級アルキルアミノ基、メチルチオ基、エチルチオ基、プロピルチオ基等の低級アルキルチオ基、シアノ基、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基等の低級アルコキシカルボニル基、ベンジルオキシカルボニル基、アミノカルボニル基（ＣＯＮＨ2）、ジメチルアミノカルボニル基、ジエチルアミノカルボニル基、ジプロピルアミノカルボニル基等の低級アルキルアミノカルボニル基、アルキニル基、フェニル基、ナフチル基、ピロリル基、フリル基、チエニル基等の芳香環基、フェノキシ基、ナフトキシ基、ピロリルオキシ基、フリルオキシ基、チエニルオキシ基等の芳香環オキシ基、ピペリジル基、ピペリジノ基、モルホリニル基等の脂肪族複素環基、ヒドロキシル基の保護体、アミノ基（アミノ酸またはペプチド残基も含む）の保護体、チオール基の保護体、アルデヒド基の保護体、カルボキシル基の保護体等が挙げられる。 The alkyl group, alkenyl group or aromatic ring group may have a substituent on an arbitrary carbon atom in any number and in any combination (substitute alkyl group, substituted alkenyl group and substituted aromatic ring group, respectively). Corresponding to). Examples of such substituents include fluorine, chlorine, bromine, iodine halogen atoms, azide groups, nitro groups, methyl groups, ethyl groups, propyl groups and other lower alkyl groups, fluoromethyl groups, chloromethyl groups, bromomethyl groups and other lower groups. Lower alkyl groups such as haloalkyl groups, methoxy groups, ethoxy groups, propoxy groups, etc., lower haloalkoxy groups such as fluoromethoxy groups, chloromethoxy groups, bromomethoxy groups, dimethylamino groups, diethylamino groups, dipropylamino groups, etc. Lower alkylthio groups such as amino group, methylthio group, ethylthio group and propylthio group, lower alkoxycarbonyl groups such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, benzyloxycarbonyl group and aminocarbonyl group (CONH 2 ) , Dimethyl Lower alkylaminocarbonyl groups such as minocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, alkynyl group, phenyl group, naphthyl group, pyrrolyl group, furyl group, thienyl group and other aromatic ring groups, phenoxy group, naphthoxy group, Aromatic ring oxy groups such as pyrrolyloxy group, furyloxy group and thienyloxy group, aliphatic heterocyclic groups such as piperidyl group, piperidino group and morpholinyl group, protected hydroxyl groups, amino groups (including amino acids or peptide residues) , A thiol group protector, an aldehyde group protector, a carboxyl group protector, and the like.
なお、本明細書において、次の各用語は、それぞれ次に掲げる意味で用いられる。"低級"とは、炭素数が１から６の、直鎖または枝分れの鎖式、または環式（炭素数３以上の場合）を意味する。"ヒドロキシル基、アミノ基（アミノ酸またはペプチド残基も含む）、チオール基、アルデヒド基およびカルボキシル基の保護基"としては、Ｐｒｏｔｅｃｔｉｖｅ Ｇｒｏｕｐｓ ｉｎ Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ，Ｔｈｉｒｄ Ｅｄｉｔｉｏｎ，１９９９，Ｊｏｈｎ Ｗｉｌｅｙ ＆ Ｓｏｎｓ，Ｉｎｃ．に記載された保護基等を用いることができる（２つ以上の官能基を１つの保護基で保護することもできる）。 In the present specification, the following terms are used in the following meanings. “Lower” means straight or branched chain or cyclic (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms. “Protecting groups for hydroxyl groups, amino groups (including amino acids or peptide residues), thiol groups, aldehyde groups and carboxyl groups” are described in Protective Groups In Organic Synthesis, ThirdＴEdition, 1999, JohnＪWileyｌｅ & Sons, Inc. Can be used (two or more functional groups can be protected with one protecting group).
また、"アルキニル基"、"芳香環基"、"芳香環オキシ基"および"脂肪族複素環基"には、ハロゲン原子、アジド基、ニトロ基、低級アルキル基、低級ハロアルキル基、低級アルコキシ基、低級ハロアルコキシ基、低級アルキルアミノ基、低級アルキルチオ基、シアノ基、低級アルコキシカルボニル基、アミノカルボニル基、低級アルキルアミノカルボニル基、ヒドロキシル基の保護体、アミノ基（アミノ酸またはペプチド残基も含む）の保護体、チオール基の保護体、アルデヒド基の保護体、カルボキシル基の保護体等が置換することもできる。 “Alkynyl group”, “aromatic ring group”, “aromatic ring oxy group” and “aliphatic heterocyclic group” include halogen atom, azide group, nitro group, lower alkyl group, lower haloalkyl group, lower alkoxy group. , Lower haloalkoxy group, lower alkylamino group, lower alkylthio group, cyano group, lower alkoxycarbonyl group, aminocarbonyl group, lower alkylaminocarbonyl group, protected hydroxyl group, amino group (including amino acid or peptide residue) A protective body of thiol group, a protective body of thiol group, a protective body of aldehyde group, a protective body of carboxyl group, etc. can be substituted.
　本発明は還元反応であるため、置換基の種類によっては置換基自体が還元される場合もある。しかしながら、好適な反応条件を採用することにより所望の反応を良好に行うことができる。 Since the present invention is a reduction reaction, the substituent itself may be reduced depending on the type of the substituent. However, the desired reaction can be performed satisfactorily by adopting suitable reaction conditions.
　一般式［２］で示されるアミド類のＲ2は、水素原子、アルキル基、置換アルキル基、芳香環基または置換芳香環基を表す。その中でもアルキル基、置換アルキル基、芳香環基および置換芳香環基が好ましく、特にアルキル基および置換アルキル基がより好ましい。該アルキル基、置換アルキル基、芳香環基および置換芳香環基は、一般式［２］で示されるアミド類のＲ1に記載したアルキル基、置換アルキル基、芳香環基および置換芳香環基と同じである。 R 2 of the amide represented by the general formula [2] represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. Among these, an alkyl group, a substituted alkyl group, an aromatic ring group, and a substituted aromatic ring group are preferable, and an alkyl group and a substituted alkyl group are particularly preferable. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the same as the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R 1 of the amides represented by the general formula [2]. The same.
　一般式［２］で示されるアミド類のＲ3は、水素原子、アルキル基、置換アルキル基、芳香環基、置換芳香環基、アルコキシカルボニル基、置換アルコキシカルボニル基、アルキルスルホニル基、置換アルキルスルホニル基、アリールスルホニル基または置換アリールスルホニル基を表す。その中でも芳香環基、置換芳香環基、アルコキシカルボニル基、置換アルコキシカルボニル基、アルキルスルホニル基、置換アルキルスルホニル基、アリールスルホニル基および置換アリールスルホニル基が好ましく、特にアルコキシカルボニル基、置換アルコキシカルボニル基、アルキルスルホニル基、置換アルキルスルホニル基、アリールスルホニル基および置換アリールスルホニル基がより好ましい。該アルキル基、置換アルキル基、芳香環基および置換芳香環基は、一般式［２］で示されるアミド類のＲ1に記載したアルキル基、置換アルキル基、芳香環基および置換芳香環基と同じである。アルコキシカルボニル基（ＣＯ2Ｒ）のアルキル基（Ｒ）、置換アルコキシカルボニル基（ＣＯ2Ｒ’）の置換アルキル基（Ｒ’）、アルキルスルホニル基（ＳＯ2Ｒ）のアルキル基（Ｒ）、置換アルキルスルホニル基（ＳＯ2Ｒ’）の置換アルキル基（Ｒ’）、アリールスルホニル基（ＳＯ2Ａｒ）の芳香環基（Ａｒ）および置換アリールスルホニル基（ＳＯ2Ａｒ’）の置換芳香環基（Ａｒ’）は、一般式［２］で示されるアミド類のＲ1に記載したアルキル基、置換アルキル基、芳香環基および置換芳香環基と同じである。 R 3 of the amide represented by the general formula [2] is a hydrogen atom, alkyl group, substituted alkyl group, aromatic ring group, substituted aromatic ring group, alkoxycarbonyl group, substituted alkoxycarbonyl group, alkylsulfonyl group, substituted alkylsulfonyl Represents a group, an arylsulfonyl group or a substituted arylsulfonyl group. Among them, an aromatic ring group, a substituted aromatic ring group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group and a substituted arylsulfonyl group are preferable, and in particular, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, An alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, and a substituted arylsulfonyl group are more preferable. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the same as the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R 1 of the amides represented by the general formula [2]. The same. Alkyl alkoxycarbonyl group (CO 2 R) (R) , a substituted alkoxycarbonyl group (CO 2 R ') substituted alkyl group (R'), the alkyl group of an alkylsulfonyl group (SO 2 R) (R) , a substituted an alkylsulfonyl group (SO 2 R ') substituted alkyl group (R'), substituted aromatic Hajime Tamaki arylsulfonyl group (SO 2 Ar) aromatic Hajime Tamaki (Ar) and substituted arylsulfonyl group (SO 2 Ar ') ( Ar ′) is the same as the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R 1 of the amide represented by the general formula [2].
　Ｒ3に好適な電子求引性基を導入すると所望の還元反応が比較的緩和な条件で進行することを明らかにした。その効果は“メシル基＞メトキシカルボニル基＞パラトルエンスルホニル基～ｔｅｒｔ－ブトキシカルボニル基＞ベンジルオキシカルボニル基”の順であり、この順に好ましい置換基の態様と言える。 It was clarified that when a suitable electron withdrawing group is introduced into R 3 , the desired reduction reaction proceeds under relatively mild conditions. The effect is in the order of “mesyl group> methoxycarbonyl group> paratoluenesulfonyl group to tert-butoxycarbonyl group> benzyloxycarbonyl group”.
　一般式［３］で示されるラクタム類のＲ1－Ｒ2は、一般式［２］で示されるアミド類のＲ1とＲ2が共有結合で結ばれていることを表す（但し、Ｒ2が水素原子の場合を除く）。該共有結合は、Ｒ1とＲ2の任意の炭素原子同士間は当然であるが、窒素原子、酸素原子または硫黄原子等のヘテロ原子を介して結ばれることもある。好適なＲ1およびＲ2は、一般式［２］で示されるアミド類の場合と同じである。また、ラクタム類の環員数が反応速度に影響を与えることも明らかにしており、基質としては、７員環に比べて４から６員環が好ましい。 R 1 -R 2 of the lactam represented by the general formula [3] represents that R 1 and R 2 of the amide represented by the general formula [2] are covalently bonded (provided that R 2 Except when is a hydrogen atom). The covalent bond is naturally between any carbon atoms of R 1 and R 2 , but may be bonded through a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom. Suitable R 1 and R 2 are the same as in the case of the amides represented by the general formula [2]. It has also been clarified that the number of ring members of lactams affects the reaction rate, and the substrate is preferably a 4- to 6-membered ring compared to a 7-membered ring.
　また、実施例６の基質であるＦの様に、一般式［２］で示されるアミド類のＲ1とＲ3の置換基が同時に兼ね合わさった化合物も、本発明の一般式［２］で示されるアミド類として扱う。さらに、実施例２４の基質の様に、一般式［２］で示されるアミド類のＲ2とＲ3の任意の炭素原子同士が共有結合で結ばれることもあり（場合によっては、窒素原子、酸素原子または硫黄原子等のヘテロ原子を介して結ばれることもある）、本発明の一般式［２］で示されるアミド類として扱う。 Further, a compound in which the substituents R 1 and R 3 of the amide represented by the general formula [2] are combined at the same time as F as the substrate of Example 6 is also represented by the general formula [2] of the present invention. Treat as indicated amides. Furthermore, as in the substrate of Example 24, any carbon atom of R 2 and R 3 of the amide represented by the general formula [2] may be covalently bonded (in some cases, a nitrogen atom, And may be linked via a hetero atom such as an oxygen atom or a sulfur atom), and are treated as amides represented by the general formula [2] of the present invention.
　反応溶媒は、ｎ－ヘキサン、シクロヘキサン、ｎ－ヘプタン等の脂肪族炭化水素系、ベンゼン、トルエン、α，α，α－トリフルオロトルエン、キシレン、エチルベンゼン、メシチレン等の芳香族炭化水素系、塩化メチレン、クロロホルム、１，２－ジクロロエタン等のハロゲン化炭化水素系、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、テトラヒドロフラン、２－メチルテトラヒドロフラン、ｔｅｒｔ－ブチルメチルエーテル、ジイソプロピルエーテル、ジエチレングリコールジメチルエーテル、アニソール等のエーテル系、メタノール、エタノール、ｎ－プロパノール、イソプロパノール、ｎ－ブタノール、ｔｅｒｔ－ブタノール等のアルコール系等が挙げられる。その中でもアルコール系が好ましく、特にｔｅｒｔ－ブタノールがより好ましい。これらの反応溶媒は、単独または組み合わせて用いることができる。 Reaction solvents include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene, α, α, α-trifluorotoluene, xylene, ethylbenzene and mesitylene, methylene chloride Halogenated hydrocarbons such as chloroform and 1,2-dichloroethane, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, diisopropyl ether, diethylene glycol dimethyl ether And ethers such as anisole, and alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. Of these, alcohols are preferred, and tert-butanol is more preferred. These reaction solvents can be used alone or in combination.
　アルコール系の反応溶媒を用いると所望の還元反応がスムーズに進行するが、立体的な嵩高さが期待できないメタノールではアミド結合の加アルコール分解も起こる（実施例１と同様の反応をメタノール中で行うと３４モル％副生）。イソプロパノールやｔｅｒｔ－ブタノール中で行うと、この副反応は効果的に制御できる（イソプロパノール；１８モル％副生、ｔｅｒｔ－ブタノール；副生せず）。この様に、アルコール系の中でも立体的な嵩高さが期待できる第３アルコールが極めて効果的である。 When an alcohol-based reaction solvent is used, the desired reduction reaction proceeds smoothly. However, in the case where methanol cannot be expected to be sterically bulky, amide bond alcoholysis also occurs (the same reaction as in Example 1 is performed in methanol). And 34 mol% by-product). When performed in isopropanol or tert-butanol, this side reaction can be effectively controlled (isopropanol; 18 mol% by-product, tert-butanol; no by-product). Thus, the tertiary alcohol that can be expected to be three-dimensionally bulky among alcohols is extremely effective.
　反応溶媒の使用量は、一般式［２］で示されるアミド類、または一般式［３］で示されるラクタム類１モルに対して０．１Ｌ（リットル）以上を用いれば良いが、通常は０．２から２０Ｌが好ましく、特に０．３から１０Ｌがより好ましい。 The reaction solvent may be used in an amount of 0.1 L (liter) or more per 1 mol of the amide represented by the general formula [2] or the lactam represented by the general formula [3]. .2 to 20L is preferable, and 0.3 to 10L is more preferable.
　反応温度は、５０℃以上で行えば良いが、６０から１００℃が好ましく、実用性を考慮すると特に７０から９０℃がより好ましい。 The reaction temperature may be 50 ° C or higher, but is preferably 60 to 100 ° C, and more preferably 70 to 90 ° C in view of practicality.
　反応時間は、特に制限はないが、通常は１２０時間以内であるが、触媒系、基質および反応条件により異なるため、ガスクロマトグラフィー、薄層クロマトグラフィー、液体クロマトグラフィー、核磁気共鳴等の分析手段により反応の進行状況を追跡し、原料が殆ど消失した時点を反応の終点とすることが好ましい。 The reaction time is not particularly limited, but is usually within 120 hours. However, since it varies depending on the catalyst system, substrate and reaction conditions, analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, nuclear magnetic resonance, etc. It is preferable that the progress of the reaction is followed by the reaction, and the point of time when the raw material has almost disappeared is the end point of the reaction.
　後処理は、反応終了液に対して通常の操作を行うことにより、目的とする一般式［４］で示されるアルコール類、または一般式［５］で示されるアミノアルコール類を得ることができる。目的物は、必要に応じて、活性炭処理、蒸留、再結晶、カラムクロマトグラフィー等により、高い化学純度に精製することができる。　本発明では、一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体、塩基および水素ガスの存在下に、一般式［２］で示されるアミド類、または一般式［３］で示されるラクタム類を、それぞれ一般式［４］で示されるアルコール類、または一般式［５］で示されるアミノアルコール類に還元することができる（態様１）。 In the post-treatment, the target alcohols represented by the general formula [4] or the amino alcohols represented by the general formula [5] can be obtained by performing normal operations on the reaction-terminated liquid. The desired product can be purified to a high chemical purity by activated carbon treatment, distillation, recrystallization, column chromatography or the like, if necessary. In the present invention, in the presence of a group 8 (VIII) transition metal complex represented by the general formula [1], a base and hydrogen gas, an amide represented by the general formula [2], or represented by the general formula [3] Lactams can be reduced to alcohols represented by general formula [4] or aminoalcohols represented by general formula [5], respectively (Aspect 1).
　８（ＶＩＩＩ）族遷移金属錯体と塩基の、好ましい同士の組み合わせにより、さらに高活性な触媒活性種を調製することができる（態様２）。 A more active catalytically active species can be prepared by a preferred combination of a group 8 (VIII) transition metal complex and a base (Aspect 2).
　８（ＶＩＩＩ）族遷移金属錯体と塩基の、特により好ましい同士の組み合わせにより、極めて高活性な触媒活性種を調製することができる（態様３）。 An extremely highly active catalytically active species can be prepared by a particularly more preferable combination of a group 8 (VIII) transition metal complex and a base (Aspect 3).
　態様１から３と好適な反応溶媒の組み合わせにより、さらに実用的な還元方法を提供できる（態様４）。 A more practical reduction method can be provided by a combination of Embodiments 1 to 3 and a suitable reaction solvent (Aspect 4).
　態様１から４と好適な水素ガスの圧力の組み合わせにより、格段に実用的な還元方法を提供できる（態様５）。 A remarkably practical reduction method can be provided by a combination of modes 1 to 4 and a suitable hydrogen gas pressure (mode 5).
　態様１から５と好適な反応温度の組み合わせにより、極めて実用的な還元方法を提供できる（態様６）。 A combination of Embodiments 1 to 5 and a suitable reaction temperature can provide a very practical reduction method (Aspect 6).
　［実施例］
　実施例により本発明の実施の形態を具体的に説明するが、本発明はこれらの実施例に限定されるものではない。なお、実施例における略記号は次の通りとする。Ｃｐ*；１，２，３，４，５－ペンタメチルシクロペンタジエニル基、Ｐｈ；フェニル基、ｔｅｒｔ；第３級、Ｂｕ；ブチル基、Ｂｏｃ；ｔｅｒｔ－ブトキシカルボニル基、Ｍｅ；メチル基、Ｃｂｚ；ベンジルオキシカルボニル基、Ｍｓ；メシル基、Ｔｓ；パラトルエンスルホニル基、Ｂｎ；ベンジル基、Ｅｔ；エチル基。 [Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. The abbreviations in the examples are as follows. Cp * : 1,2,3,4,5-pentamethylcyclopentadienyl group, Ph: phenyl group, tert: tertiary, Bu: butyl group, Boc: tert-butoxycarbonyl group, Me: methyl group, Cbz: benzyloxycarbonyl group, Ms: mesyl group, Ts: paratoluenesulfonyl group, Bn: benzyl group, Et: ethyl group.
　［実施例１から１６］
　実施例１の実験操作を代表例として下に示す。 [Examples 1 to 16]
The experimental operation of Example 1 is shown below as a representative example.
アルゴン雰囲気下、シュレンク管に、下記式
Figure JPOXMLDOC01-appb-C000016
 で示されるＣｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］２０．０ｍｇ（０．０４ｍｍｏｌ，０．０２ｅｑ）、ｔｅｒｔ－ブトキシカリウム４．５ｍｇ［０．０４ｍｍｏｌ，１．００ｅｑ（ルテニウム錯体に対する当量）］、ｔｅｒｔ－ブタノール１０ｍＬと、下記式
Figure JPOXMLDOC01-appb-C000017
 で示されるラクタム類３７０ｍｇ（２．００ｍｍｏｌ，１．００ｅｑ）を加え、凍結脱気を３回繰り返した。アルゴン雰囲気下、得られた溶液をカニュラーにより、ガラス製内筒を有するステンレス鋼（ＳＵＳ）製耐圧反応容器に移した。反応容器内を水素ガスで５回置換し、水素圧を３ＭＰａに設定し、８０℃で３６時間攪拌した。反応終了液をシリカゲル濾過し、酢酸エチルで洗浄し、濾液と洗浄液を減圧濃縮し、セミミクロ蒸留することにより、下記式
Figure JPOXMLDOC01-appb-C000018
 で示されるアミノアルコール類を３７８ｍｇ得た。収率は＞９９％であった。 The following formula is applied to a Schlenk tube under an argon atmosphere:
Figure JPOXMLDOC01-appb-C000016
 Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ] 20.0 mg (0.04 mmol, 0.02 eq), tert-butoxy potassium 4.5 mg [0.04 mmol, 1.00 eq (for ruthenium complex) Equivalent)], tert-butanol 10 mL,
Figure JPOXMLDOC01-appb-C000017
 370 mg (2.00 mmol, 1.00 eq) of the lactam represented by the above was added, and freeze degassing was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder. The inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 3 MPa, and the mixture was stirred at 80 ° C. for 36 hours. The reaction-terminated liquid is filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid are concentrated under reduced pressure, and semi-microdistilled to obtain the following formula:
Figure JPOXMLDOC01-appb-C000018
 378 mg of the amino alcohol represented by The yield was> 99%.
　実施例２から１６は、ラクタム類の種類、Ｃｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］の使用量、ｔｅｒｔ－ブトキシカリウムの使用量および反応時間を変えて、実施例１と同様に行った。実施例２から１６の結果を表１に纏めた。 Examples 2 to 16 were the same as Example 1 except that the type of lactam, the amount of Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ], the amount of tert-butoxypotassium used and the reaction time were changed. Went to. The results of Examples 2 to 16 are summarized in Table 1.
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
　実施例６の基質Ｆは、アミド類のＲ1とＲ3の置換基がフェニル基を共有した化合物である。また、実施例７の生成物の、エトキシカルボニル基のα位は全くラセミ化していなかった。 The substrate F of Example 6 is a compound in which the substituents of R 1 and R 3 of the amide share a phenyl group. Further, the α-position of the ethoxycarbonyl group of the product of Example 7 was not racemized at all.
　［実施例１７から２３］
　実施例２３の実験操作を代表例として下に示す。 [Examples 17 to 23]
The experimental operation of Example 23 is shown below as a representative example.
　アルゴン雰囲気下、シュレンク管に、下記式
Figure JPOXMLDOC01-appb-C000020
 で示されるＣｐ*ＲｕＣｌ［Ｃ5Ｈ4ＮＣＨ2ＮＨ2］７６．０ｍｇ（０．２０ｍｍｏｌ，０．１０ｅｑ）、ナトリウムメトキシド３２．４ｍｇ［０．６０ｍｍｏｌ，３．００ｅｑ（ルテニウム錯体に対する当量）］、ｔｅｒｔ－ブタノール２ｍＬと、下記式
Figure JPOXMLDOC01-appb-C000021
 で示されるラクタム類３５０ｍｇ（２．００ｍｍｏｌ，１．００ｅｑ）を加え、凍結脱気を３回繰り返した。アルゴン雰囲気下、得られた溶液をカニュラーにより、ガラス製内筒を有するステンレス鋼（ＳＵＳ）製耐圧反応容器に移した。反応容器内を水素ガスで５回置換し、水素圧を５ＭＰａに設定し、１００℃で９０時間攪拌した。反応終了液をシリカゲル濾過し、酢酸エチルで洗浄し、濾液と洗浄液を減圧濃縮し、セミミクロ蒸留することにより、下記式
Figure JPOXMLDOC01-appb-C000022
 で示されるアミノアルコール類を３２６ｍｇ得た。収率は９１％であった。 The following formula is applied to a Schlenk tube under an argon atmosphere:
Figure JPOXMLDOC01-appb-C000020
 Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] 76.0 mg (0.20 mmol, 0.10 eq), sodium methoxide 32.4 mg [0.60 mmol, 3.00 eq (equivalent to the ruthenium complex)] , Tert-butanol 2mL and the following formula
Figure JPOXMLDOC01-appb-C000021
 Was added 350 mg (2.00 mmol, 1.00 eq), and freeze deaeration was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder. The inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 5 MPa, and the mixture was stirred at 100 ° C. for 90 hours. The reaction-terminated liquid was filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid were concentrated under reduced pressure, and semi-microdistilled to obtain
Figure JPOXMLDOC01-appb-C000022
 326 mg of the aminoalcohol represented by The yield was 91%.
　実施例１７から２２は、ラクタム類の種類、Ｃｐ*ＲｕＣｌ［二座配位子］の種類および反応温度を変えて、実施例２３と同様に行った。実施例１７から２２の結果を表２に纏めた。 Examples 17 to 22 were carried out in the same manner as in Example 23, except that the type of lactam, the type of Cp * RuCl [bidentate ligand], and the reaction temperature were changed. The results of Examples 17 to 22 are summarized in Table 2.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
　［実施例２４］
　アルゴン雰囲気下、シュレンク管に、下記式
Figure JPOXMLDOC01-appb-C000024
 で示されるＣｐ*ＲｕＣｌ［Ｐｈ2Ｐ（ＣＨ2）2ＮＨ2］１２．３ｍｇ（０．０２５ｍｍｏｌ，０．０３ｅｑ）、ｔｅｒｔ－ブトキシカリウム２．８ｍｇ［０．０２５ｍｍｏｌ，１．００ｅｑ（ルテニウム錯体に対する当量）］、イソプロパノール５．６ｍＬと、下記式
Figure JPOXMLDOC01-appb-C000025
 で示されるアミド類２５９．７ｍｇ（０．８１ｍｍｏｌ，１．００ｅｑ）を加え、凍結脱気を３回繰り返した。アルゴン雰囲気下、得られた溶液をカニュラーにより、ガラス製内筒を有するステンレス鋼（ＳＵＳ）製耐圧反応容器に移した。反応容器内を水素ガスで５回置換し、水素圧を３ＭＰａに設定し、８０℃で２０時間攪拌した。反応終了液をシリカゲルカラムクロマトグラフィーで精製することにより、下記式
Figure JPOXMLDOC01-appb-C000026
 で示されるアルコール類を１０８．８ｍｇ得た。収率は９０％であった。還元反応において光学純度の低下は全く認められなかった。また、下記式
Figure JPOXMLDOC01-appb-C000027
 で示される不斉補助基を１２７．２ｍｇ回収した。回収率は８９％であった。 [Example 24]
The following formula is applied to a Schlenk tube under an argon atmosphere:
Figure JPOXMLDOC01-appb-C000024
 Cp * RuCl [Ph 2 P (CH 2 ) 2 NH 2 ] 12.3 mg (0.025 mmol, 0.03 eq), tert-butoxypotassium 2.8 mg [0.025 mmol, 1.00 eq (for the ruthenium complex) Equivalent))], 5.6 mL of isopropanol,
Figure JPOXMLDOC01-appb-C000025
 259.7 mg (0.81 mmol, 1.00 eq) represented by the above formula was added, and freeze degassing was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder. The inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 3 MPa, and the mixture was stirred at 80 ° C. for 20 hours. By purifying the reaction completion liquid by silica gel column chromatography,
Figure JPOXMLDOC01-appb-C000026
 As a result, 108.8 mg of the alcohol represented by the formula (1) was obtained. The yield was 90%. No reduction in optical purity was observed in the reduction reaction. Also, the following formula
Figure JPOXMLDOC01-appb-C000027
 127.2 mg of an asymmetric auxiliary group represented by the following formula was recovered. The recovery rate was 89%.
　実施例２４の結果を下のスキームに示す。 The result of Example 24 is shown in the following scheme.
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　［実施例２５から３１］
　実施例２５の実験操作を代表例として下に示す。 [Examples 25 to 31]
The experimental operation of Example 25 is shown below as a representative example.
　アルゴン雰囲気下、シュレンク管に、下記式
Figure JPOXMLDOC01-appb-C000029
 で示されるＣｐ*ＲｕＣｌ［Ｃ5Ｈ4ＮＣＨ2ＮＨ2］２２．８ｍｇ（０．０６ｍｍｏｌ，０．１０ｅｑ）、ナトリウムメトキシド９．７ｍｇ［０．１８ｍｍｏｌ，３．００ｅｑ（ルテニウム錯体に対する当量）］、ｔｅｒｔ－ブタノール０．６ｍＬと、下記式
Figure JPOXMLDOC01-appb-C000030
 で示されるラクタム類１３８ｍｇ（０．６０ｍｍｏｌ，１．００ｅｑ）を加え、凍結脱気を３回繰り返した。アルゴン雰囲気下、得られた溶液をカニュラーにより、ガラス製内筒を有するステンレス鋼（ＳＵＳ）製耐圧反応容器に移した。反応容器内を水素ガスで５回置換し、水素圧を５ＭＰａに設定し、１００℃で９０時間攪拌した。反応終了液の変換率は＞９９％であった。反応終了液をシリカゲル濾過し、酢酸エチルで洗浄し、濾液と洗浄液を減圧濃縮し、セミミクロ蒸留することにより、下記式
Figure JPOXMLDOC01-appb-C000031
 で示されるアミノアルコール類を１２６ｍｇ得た。収率は９０％であった。 The following formula is applied to a Schlenk tube under an argon atmosphere:
Figure JPOXMLDOC01-appb-C000029
 Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] 22.8 mg (0.06 mmol, 0.10 eq), sodium methoxide 9.7 mg [0.18 mmol, 3.00 eq (equivalent to ruthenium complex)] , Tert-butanol 0.6mL and the following formula
Figure JPOXMLDOC01-appb-C000030
 138 mg (0.60 mmol, 1.00 eq) represented by the above formula was added, and freeze deaeration was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder. The inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 5 MPa, and the mixture was stirred at 100 ° C. for 90 hours. The conversion of the reaction finished liquid was> 99%. The reaction-terminated liquid was filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid were concentrated under reduced pressure, and semi-microdistilled to obtain
Figure JPOXMLDOC01-appb-C000031
 126 mg of the aminoalcohol represented by The yield was 90%.
　実施例２６から３１は、ラクタム類の種類、Ｃｐ*ＲｕＣｌ［Ｃ5Ｈ4ＮＣＨ2ＮＨ2］の使用量および反応時間を変えて、実施例２５と同様に行った。実施例２５から３１の結果を表３に纏めた。 Examples 26 to 31 were carried out in the same manner as in Example 25, except that the type of lactam, the amount of Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] used, and the reaction time were changed. The results of Examples 25 to 31 are summarized in Table 3.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
　［実施例３２から３７］
　実施例３２の実験操作を代表例として下に示す。 [Examples 32 to 37]
The experimental operation of Example 32 is shown below as a representative example.
　アルゴン雰囲気下、シュレンク管に、下記式
Figure JPOXMLDOC01-appb-C000033
 で示されるＣｐ*ＲｕＣｌ［Ｃ5Ｈ4ＮＣＨ2ＮＨ2］２２．８ｍｇ（０．０６ｍｍｏｌ，０．１０ｅｑ）、ナトリウムメトキシド９．７ｍｇ［０．１８ｍｍｏｌ，３．００ｅｑ（ルテニウム錯体に対する当量）］、ｔｅｒｔ－ブタノール０．６ｍＬと、下記式
Figure JPOXMLDOC01-appb-C000034
 で示されるアミド類１１８ｍｇ（０．６０ｍｍｏｌ，１．００ｅｑ）を加え、凍結脱気を３回繰り返した。アルゴン雰囲気下、得られた溶液をカニュラーにより、ガラス製内筒を有するステンレス鋼（ＳＵＳ）製耐圧反応容器に移した。反応容器内を水素ガスで５回置換し、水素圧を５ＭＰａに設定し、１００℃で９０時間攪拌した。反応終了液の変換率は１００％であった。反応終了液をシリカゲル濾過し、酢酸エチルで洗浄し、濾液と洗浄液を減圧濃縮し、セミミクロ蒸留することにより、下記式
Figure JPOXMLDOC01-appb-C000035
 で示されるアルコール類を得た。また、下記式
Figure JPOXMLDOC01-appb-C000036
 で示されるアミン類を回収した。 The following formula is applied to a Schlenk tube under an argon atmosphere:
Figure JPOXMLDOC01-appb-C000033
 Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] 22.8 mg (0.06 mmol, 0.10 eq), sodium methoxide 9.7 mg [0.18 mmol, 3.00 eq (equivalent to ruthenium complex)] , Tert-butanol 0.6mL and the following formula
Figure JPOXMLDOC01-appb-C000034
 Was added 118 mg (0.60 mmol, 1.00 eq), and freeze degassing was repeated three times. Under an argon atmosphere, the resulting solution was transferred by cannula to a pressure resistant reaction vessel made of stainless steel (SUS) having a glass inner cylinder. The inside of the reaction vessel was replaced with hydrogen gas five times, the hydrogen pressure was set to 5 MPa, and the mixture was stirred at 100 ° C. for 90 hours. The conversion rate of the reaction finished liquid was 100%. The reaction-terminated liquid is filtered through silica gel, washed with ethyl acetate, the filtrate and the washing liquid are concentrated under reduced pressure, and semi-microdistilled to obtain the following formula:
Figure JPOXMLDOC01-appb-C000035
 The alcohol shown by was obtained. Also, the following formula
Figure JPOXMLDOC01-appb-C000036
 Was recovered.
　実施例３３から３７は、アミド類の種類、Ｃｐ*ＲｕＣｌ［Ｃ5Ｈ4ＮＣＨ2ＮＨ2］の使用量および反応時間を変えて、実施例３２と同様に行った。実施例３２から３７の結果を表４に纏めた。 Examples 33 to 37 were carried out in the same manner as in Example 32 by changing the kind of amides, the amount of Cp * RuCl [C 5 H 4 NCH 2 NH 2 ] used, and the reaction time. The results of Examples 32 to 37 are summarized in Table 4.
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037

Claims (6)

  1. 一般式［１］
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ａはシクロペンタジエニル（Ｃｐ）基または１，２，３，４，５－ペンタメチルシクロペンタジエニル（Ｃｐ*）基を表し、ＭはＦｅ、ＲｕまたはＯｓを表す。さらに、Ｂはハロゲン、一酸化炭素、アセトニトリル、フェニルイソシアニドまたはトリフェニルホスフィンを表し、Ｃは窒素－窒素（Ｎ－Ｎ）またはリン－窒素（Ｐ－Ｎ）の二座配位子を表す］で示される８（ＶＩＩＩ）族遷移金属錯体、塩基および水素ガス（Ｈ2）の存在下に、一般式［２］
    Figure JPOXMLDOC01-appb-C000002
     ［式中、Ｒ1はアルキル基、置換アルキル基、アルケニル基、置換アルケニル基、芳香環基または置換芳香環基を表し、Ｒ2は水素原子、アルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、Ｒ3は水素原子、アルキル基、置換アルキル基、芳香環基、置換芳香環基、アルコキシカルボニル基、置換アルコキシカルボニル基、アルキルスルホニル基、置換アルキルスルホニル基、アリールスルホニル基または置換アリールスルホニル基を表す］で示されるアミド類、または一般式［３］
    Figure JPOXMLDOC01-appb-C000003
     ｛式中、Ｒ1－Ｒ2は一般式［２］で示されるアミド類のＲ1とＲ2が共有結合で結ばれていることを表す（但し、Ｒ2が水素原子の場合を除く）｝で示されるラクタム類を、それぞれ一般式［４］
    Figure JPOXMLDOC01-appb-C000004
     ｛式中、Ｒ1は一般式［２］で示されるアミド類のＲ1と同じである｝で示されるアルコール類、または一般式［５］
    Figure JPOXMLDOC01-appb-C000005
     ｛式中、Ｒ1－Ｒ2は一般式［２］で示されるアミド類のＲ1とＲ2が共有結合で結ばれていることを表し（但し、Ｒ2が水素原子の場合を除く）、Ｒ3は一般式［２］で示されるアミド類のＲ3と同じである｝で示されるアミノアルコール類に還元する方法。     General formula [1]
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, A represents a cyclopentadienyl (Cp) group or a 1,2,3,4,5-pentamethylcyclopentadienyl (Cp * ) group, and M represents Fe, Ru, or Os. Further, B represents halogen, carbon monoxide, acetonitrile, phenyl isocyanide or triphenylphosphine, and C represents a nitrogen-nitrogen (NN) or phosphorus-nitrogen (PN) bidentate ligand. In the presence of the indicated group 8 (VIII) transition metal complex, base and hydrogen gas (H 2 ), the general formula [2]
    Figure JPOXMLDOC01-appb-C000002
     [Wherein R 1 represents an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aromatic ring group or a substituted aromatic ring group, and R 2 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted group. Represents an aromatic ring group, R 3 represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group, a substituted aromatic ring group, an alkoxycarbonyl group, a substituted alkoxycarbonyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group or Represents a substituted arylsulfonyl group] or a amide represented by the general formula [3]
    Figure JPOXMLDOC01-appb-C000003
     {In the formula, R 1 -R 2 represents that R 1 and R 2 of the amide represented by the general formula [2] are connected by a covalent bond (except when R 2 is a hydrogen atom) }, Each of the lactams represented by the general formula [4]
    Figure JPOXMLDOC01-appb-C000004
     {Wherein, R 1 is the same as R 1 of amides of the general formula [2]} alcohols represented by or general formula [5]
    Figure JPOXMLDOC01-appb-C000005
     {In the formula, R 1 -R 2 represents that R 1 and R 2 of the amide represented by the general formula [2] are connected by a covalent bond (except when R 2 is a hydrogen atom) , R 3 is the same as R 3 of the amide represented by the general formula [2]}.
  2. 請求項１において、一般式［１］で示される８（ＶＩＩＩ）族遷移金属錯体が一般式［６］
    Figure JPOXMLDOC01-appb-C000006
     ［式中、Ｃｐ*は１，２，３，４，５－ペンタメチルシクロペンタジエニル基を表し、Ｘはハロゲンまたはアセトニトリルを表す。さらに、Ｐ－Ｃ2－Ｎはリンと窒素が２つの炭素を介して結ばれた二座配位子であることを表す］で示される８（ＶＩＩＩ）族遷移金属錯体であり、さらに塩基がアルカリ金属の水酸化物またはアルコキシドであることを特徴とする、請求項１に記載のアミド類またはラクタム類の還元方法。     In Claim 1, 8 (VIII) group transition metal complex shown by General formula [1] is General formula [6].
    Figure JPOXMLDOC01-appb-C000006
     [Wherein Cp * represents a 1,2,3,4,5-pentamethylcyclopentadienyl group, and X represents halogen or acetonitrile. Further, P—C 2 —N represents a bidentate ligand in which phosphorus and nitrogen are connected via two carbons], and is a group 8 (VIII) transition metal complex represented by The method for reducing amides or lactams according to claim 1, which is an alkali metal hydroxide or alkoxide.
  3. 請求項２において、一般式［６］で示される８（ＶＩＩＩ）族遷移金属錯体が式［７］
    Figure JPOXMLDOC01-appb-C000007
     ［式中、Ｃｐ*は１，２，３，４，５－ペンタメチルシクロペンタジエニル基を表し、Ｐｈはフェニル基を表す］で示される８（ＶＩＩＩ）族遷移金属錯体であり、さらに塩基がアルカリ金属のアルコキシドであることを特徴とする、請求項２に記載のアミド類またはラクタム類の還元方法。     In Claim 2, the group 8 (VIII) transition metal complex represented by the general formula [6] is represented by the formula [7].
    Figure JPOXMLDOC01-appb-C000007
     [Wherein Cp * represents a 1,2,3,4,5-pentamethylcyclopentadienyl group and Ph represents a phenyl group], which is a group 8 (VIII) transition metal complex represented by The method for reducing amides or lactams according to claim 2, wherein is an alkoxide of an alkali metal.
  4. 請求項１及至請求項３の何れか１項において、反応溶媒がｔｅｒｔ－ブタノールであることを特徴とする、請求項１及至請求項３の何れか１項に記載のアミド類またはラクタム類の還元方法。 The reduction of amides or lactams according to any one of claims 1 to 3, wherein the reaction solvent is tert-butanol in any one of claims 1 to 3. Method.
  5. 請求項１及至請求項４の何れか１項において、水素ガス（Ｈ2）の圧力が２．５から３．５ＭＰａであることを特徴とする、請求項１及至請求項４の何れか１項に記載のアミド類またはラクタム類の還元方法。 5. The method according to claim 1, wherein the pressure of hydrogen gas (H 2 ) is 2.5 to 3.5 MPa in any one of claims 1 to 4. The method for reducing an amide or lactam described in 1.
  6. 請求項１及至請求項５の何れか１項において、反応温度が７０から９０℃であることを特徴とする、請求項１及至請求項５の何れか１項に記載のアミド類またはラクタム類の還元方法。 The amide or lactam according to any one of claims 1 to 5, characterized in that the reaction temperature is 70 to 90 ° C in any one of claims 1 to 5. Reduction method.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103058897A (en) * 2012-12-27 2013-04-24 苏州大学 Method for preparing chiral beta-hydroxy sulfonamide
EP2734299A4 (en) * 2011-07-18 2016-05-11 Univ Alberta Catalysts and processes for the hydrogenation of amides
CN114853624A (en) * 2021-04-07 2022-08-05 青岛贞开生物医药技术有限公司 Preparation method of 4-amino-1-butanol and N-protected derivative thereof

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JP5628613B2 (en) 2010-09-21 2014-11-19 高砂香料工業株式会社 Method for producing alcohol and / or amine from amide compound

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Title
ITO MASATO ET AL., YUKI GOSEI KAGAKU KYOKAISHI, vol. 66, 12 November 2008 (2008-11-12), pages 1042 - 1048 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2734299A4 (en) * 2011-07-18 2016-05-11 Univ Alberta Catalysts and processes for the hydrogenation of amides
US9745332B2 (en) 2011-07-18 2017-08-29 The Governors Of The Univerity Of Alberta Catalysts and processes for the hydrogenation of amides
CN103058897A (en) * 2012-12-27 2013-04-24 苏州大学 Method for preparing chiral beta-hydroxy sulfonamide
CN114853624A (en) * 2021-04-07 2022-08-05 青岛贞开生物医药技术有限公司 Preparation method of 4-amino-1-butanol and N-protected derivative thereof

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