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WO2011062280A1 - Procédé de production d'un alcool optiquement actif - Google Patents

Procédé de production d'un alcool optiquement actif Download PDF

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Publication number
WO2011062280A1
WO2011062280A1 PCT/JP2010/070745 JP2010070745W WO2011062280A1 WO 2011062280 A1 WO2011062280 A1 WO 2011062280A1 JP 2010070745 W JP2010070745 W JP 2010070745W WO 2011062280 A1 WO2011062280 A1 WO 2011062280A1
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Prior art keywords
group
compound
optically active
atom
active alcohol
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Japanese (ja)
Inventor
一彰 石原
学 波多野
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Nagoya University NUC
Sekisui Medical Co Ltd
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Nagoya University NUC
Sekisui Medical Co Ltd
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Priority to JP2011541985A priority Critical patent/JP5750667B2/ja
Publication of WO2011062280A1 publication Critical patent/WO2011062280A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a method for producing an optically active alcohol in which an organic zinc compound and a carbonyl compound are reacted using a phosphoramide compound.
  • Physiologically active substances often have optically active substances having asymmetric carbon atoms. For this reason, it is important to obtain an optically active substance having the desired absolute configuration.
  • a method of obtaining an optically active substance a method of synthesizing a racemic mixture and then separating the optically active substance by optical resolution or the like can be mentioned. However, this method is inefficient because it requires a chemical conversion step using an optical resolution agent or an enzyme. Thus, development of asymmetric synthesis methods that can selectively obtain optically active substances has been underway.
  • Non-Patent Document 1 and Patent Document 1 disclose a method for synthesizing a highly enantioselective tertiary alcohol using a phosphoramide compound (L) as a catalyst and an organozinc compound as an organometallic nucleophile ( See the scheme below).
  • Non-Patent Document 2 discloses a method for obtaining diethyl zinc (Et 2 Zn) from ZnCl 2 , NaOMe, and EtMgCl.
  • Non-Patent Document 2 discloses a method in which diethyl zinc and a carbonyl compound are reacted to obtain an optically active alcohol.
  • Non-Patent Document 2 merely discloses the synthesis of an optically active alcohol by primary alkylation.
  • a side reaction may occur along with the addition reaction.
  • a reduction reaction may occur as a side reaction.
  • an aldol reaction may occur as a side reaction in addition to the reduction reaction.
  • a bulky alkylation reaction such as secondary alkylation
  • the production of a reduced product by this side reaction becomes a problem. Therefore, in the bulky alkylation reaction such as secondary alkylation, development of a method capable of suppressing side reactions and obtaining an optically active alcohol with high enantioselectivity is desired.
  • An object of the present invention is to provide a production method capable of suppressing side reactions and obtaining an optically active alcohol by highly enantioselective secondary alkylation.
  • the present invention (A) a zinc halide, metal alkoxide, and RMgY (R; 2 grade hydrocarbon group, Y; halogen atom) by reacting, and obtaining the organic zinc compound ZnR 2, (B) formula A step of reacting a carbonyl compound with the organozinc compound in the presence of the phosphoramide compound represented by (1) (hereinafter referred to as “compound (1)”), in the step (A),
  • compound (1) a method for producing an optically active alcohol that is 1.8 equivalents or less with respect to 1 equivalent of the zinc halide.
  • R 1 to R 5 are each independently a monovalent hydrocarbon group.
  • R 2 and R 3 are each bonded to a phosphorus atom directly or via an atom other than a carbon atom.
  • X is an oxygen atom or a sulfur atom.
  • A is a methylene group or a carbonyl group.
  • an optically active alcohol can be obtained with high enantioselectivity through secondary alkylation while suppressing side reactions.
  • an aldehyde as the carbonyl compound
  • an optically active alcohol can be obtained with high yield and high enantioselectivity.
  • optically active alcohols having various structures can be obtained from a carbonyl compound by wide alkylation that does not depend on a commercially available organozinc compound. Therefore, if the optically active alcohol synthesized according to the present invention is used as a synthetic intermediate for pharmaceuticals or agricultural chemicals (for example, a synthetic intermediate for clemastine frequently used as an antihistamine), the intended pharmaceutical or agricultural chemical can be produced with high efficiency. Can be manufactured.
  • Step (A) In step (A), zinc halide, metal alkoxide, and RMgY obtained by reacting the organic zinc compound ZnR 2 (R; halogen atoms; secondary hydrocarbon group, Y).
  • zinc halide there is no limitation in particular in the kind of said zinc halide. Any of F, Cl, Br, and I may be sufficient as the halogen atom contained in the said zinc halide.
  • zinc chloride ZnCl 2
  • ZnCl 2 zinc chloride
  • the type of metal alkoxide is not particularly limited.
  • the metal contained in the metal alkoxide include Li, Na, K, Mg, and Al.
  • the number of carbon atoms of the alkoxide contained in the metal alkoxide is usually 1 to 8, preferably 1 to 6, and more preferably 1 to 4.
  • Specific examples of the alkoxide include methoxide, ethoxide, propoxide, and butoxide.
  • Specific examples of the metal alkoxide include sodium methoxide (NaOMe) and sodium ethoxide (NaOEt).
  • the amount of the metal alkoxide is not particularly limited as long as the organozinc compound can be obtained.
  • the amount of the metal alkoxide is usually 1.5 equivalents or more, preferably 2 to 3 equivalents, more preferably 2.3 to 2.7 equivalents relative to 1 equivalent of the zinc halide (in the present specification, “equivalent” means “mol equivalent.” In this specification, either “equivalent” or “mol equivalent” is used.) It is preferable for the amount of the metal alkoxide to be in the above range since the enantioselectivity of the reaction can be increased.
  • RMgY is a compound generally known as a Grignard reagent.
  • Y is a halogen atom (F, Cl, Br or I), usually Cl or Br, and preferably Cl.
  • R is a secondary hydrocarbon group. This R constitutes an organic group (R) in the obtained organozinc compound (ZnR 2 ).
  • the type and structure of the secondary hydrocarbon group are not particularly limited.
  • the secondary hydrocarbon group may have a chain structure or a cyclic structure (for example, a cycloalkyl group).
  • the secondary hydrocarbon group is usually a saturated hydrocarbon group, but may contain an unsaturated bond.
  • the secondary hydrocarbon group may have one or more other substituents.
  • the secondary hydrocarbon group may have a substituent containing an atom other than a carbon atom and a hydrogen atom as a substituent.
  • the secondary hydrocarbon group may contain one or more atoms other than carbon atoms and hydrogen atoms in a chain structure or a cyclic structure. Examples of the atoms other than the carbon atom and hydrogen atom include one or more of an oxygen atom, a nitrogen atom, and a sulfur atom.
  • the carbon number of the secondary hydrocarbon group is not particularly limited.
  • the secondary hydrocarbon group usually has 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms.
  • Specific examples of the secondary hydrocarbon group include secondary chain alkyl groups (such as i-propyl group and sec-butyl group) and cyclic alkyl groups (such as cyclopentyl group and cyclohexyl group).
  • the organic zinc compound (ZnR 2 ; in the present specification, the organic zinc compound may be expressed as “R 2 Zn”, which has the same meaning as “ZnR 2 ”).
  • the organic group (R) in the organozinc compound is derived from the organic group (R) of the RMgY. Two organic groups (R) exist in the organozinc compound. Each organic group (R) is usually the same organic group, but may be a different organic group.
  • the amount of the RMgY is 1.8 equivalents or less, preferably 1.0 to 1.8 equivalents, more preferably 1.2 to 1.7 equivalents relative to 1 equivalent of the zinc halide. is there. It is preferable for the amount of RMgY to be in the above range since the enantioselectivity of the alkylation reaction can be increased. In particular, when the optically active alcohol is produced by continuously performing the step (B) from the step (A), it is preferable because the enantioselectivity can be increased.
  • step (A) when the remaining RMgY reacts with the generated organic zinc compound, a zinc ate complex ([R 3 Zn] ⁇ [MgX] + ) may be formed.
  • the complex is remarkably highly active, and the presence of this highly active complex is considered to be a factor that reduces the enantioselectivity of the alkylation reaction.
  • step (B) when the step (B) is carried out continuously from the step (A), there is a high possibility that the complex is present in the reaction system, and as a result, the enantioselectivity may be further lowered.
  • the amount of the three components is not particularly limited as long as the amount of RMgY is within the above range.
  • specific amounts of the three components are (1 equivalent), (1.5 equivalents or more), and (1.8 equivalents). Or less), preferably (1 equivalent), (2-3 equivalents), and (1.0-1.8 equivalents), more preferably (1 equivalent), (2.3-2.7 equivalents), and ( 1.2 to 1.7 equivalents).
  • the amount of the three components there is a case where the zinc halide, the metal alkoxide, and the RMgY are (1 equivalent), (2.5 equivalents), and (1.6 equivalents), respectively. be able to.
  • the amounts of the zinc halide, the metal alkoxide, and the RMgY are respectively set in order to bring the amount of the organozinc compound in the step (B) into a specific range. It can be a specific range.
  • the amount of the three components is (2.5 to 3.5 equivalents) with respect to 1 equivalent of the carbonyl compound in step (B), respectively. (6 to 9 equivalents) and (4 to 5.6 equivalents), and more preferred examples are (2.5 to 3 equivalents), (7 to 8 equivalents), and (4 to 4.8 equivalents). Can be mentioned.
  • the zinc halide, the metal alkoxide, and the RMgY are respectively (3 equivalents), (7.5 equivalents), and (4) with respect to 1 equivalent of the carbonyl compound. .8 equivalents).
  • enantioselectivity can be enhanced by setting the amount of RMgY within the above range. Therefore, in the present invention, usually, after determining the amount of the RMgY relative to the zinc halide, the amount of the metal alkoxide relative to the zinc halide is determined (of course, the method of determining the respective components is not limited to this method). .
  • Step (A) is usually performed by adding the zinc halide and the metal alkoxide to a solvent, and then adding the RMgY.
  • Step (A) is usually performed in a solvent.
  • the type of the solvent There is no particular limitation on the type of the solvent. Examples of the solvent include known solvents (for example, ether solvents) used in Grignard reaction. The said solvent may be only 1 type and 2 or more types of mixed solvents may be sufficient as it.
  • the reaction temperature is usually about 0 to 20 ° C. You may change reaction temperature suitably in a process (A).
  • the reaction time is usually about 1 to 3 hours.
  • Step (A) may have other steps as necessary.
  • the other step include a step of distilling off the solvent after completion of the reaction by an appropriate method such as distillation under reduced pressure.
  • a high concentration or solvent-free organic zinc compound can be obtained by distilling off the solvent by an appropriate method such as distillation under reduced pressure.
  • the organozinc compound that is liquid in a high concentration or no solvent state can also serve as a reaction solvent by itself. Therefore, if this organozinc compound is used, the step (B) can be carried out without adding a special solvent. As a result, the yield can be increased and industrially advantageous.
  • organic zinc compounds having various secondary hydrocarbon groups can be obtained by the step (A).
  • an organic zinc compound having a secondary hydrocarbon group that is not commercially available can also be obtained by the step (A).
  • optically active alcohols having various structures can be obtained.
  • R 1 to R 5 are each independently a monovalent hydrocarbon group.
  • the monovalent hydrocarbon group refers to a group in which one hydrogen atom is removed from the carbon atom of the hydrocarbon.
  • Examples of the monovalent hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an arylalkyl group, and an arylalkenyl group.
  • alkyl group and the like The number of carbon atoms of the alkyl group, alkenyl group, and alkynyl group (hereinafter collectively referred to as “alkyl group and the like”) is not particularly limited.
  • the alkyl group generally has 1 to 12, preferably 1 to 10, more preferably 1 to 8, more preferably 1 to 6, and particularly preferably 1 to 4 carbon atoms.
  • the carbon number of the alkenyl group and alkynyl group is usually 2 to 12, preferably 2 to 10, more preferably 2 to 8, more preferably 2 to 6, and particularly preferably 2 to 4.
  • the carbon number of the alkyl group or the like is usually 4 to 12, preferably 4 to 10, more preferably 5 to 8, and more preferably 6 to 8.
  • the structure of the alkyl group and the like is not particularly limited.
  • the alkyl group or the like may be linear or have a side chain.
  • the alkyl group or the like may have a chain structure or a cyclic structure (a cycloalkyl group, a cycloalkenyl group, and a cycloalkynyl group).
  • the alkyl group or the like may have one or more other substituents.
  • the alkyl group or the like may have a substituent containing an atom other than a carbon atom and a hydrogen atom as a substituent.
  • atoms other than a carbon atom and a hydrogen atom may contain 1 or 2 or more atoms other than a carbon atom and a hydrogen atom in a chain structure or a cyclic structure.
  • the atoms other than the carbon atom and hydrogen atom include one or more of an oxygen atom, a nitrogen atom, and a sulfur atom.
  • alkyl group examples include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, pentyl group, Examples include isopentyl group, neopentyl group, hexyl group, heptyl group, octyl group, and 2-ethylhexyl group.
  • Specific examples of the cycloalkyl group include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a 2-methylcyclohexyl group.
  • alkenyl group examples include a vinyl group, an allyl group, and an isopropenyl group.
  • Specific examples of the cycloalkenyl group include a cyclohexenyl group.
  • aryl group etc. The number of carbon atoms of the aryl group, arylalkyl group, and arylalkenyl group (hereinafter collectively referred to as “aryl group etc.”) is not particularly limited.
  • the aryl group or the like usually has 6 to 15, preferably 6 to 12, and more preferably 6 to 10 carbon atoms.
  • the aryl group or the like may have one or more other substituents.
  • the aromatic ring contained in the aryl group or the like may have one or more other substituents.
  • the position of this substituent may be any of o-, m-, and p-.
  • Specific examples of the substituent include, for example, a halogen atom (one or more of F, Cl, Br, and I), an alkyl group, an alkenyl group, a nitro group, an amino group, a hydroxyl group, and an alkoxy group. Or 2 or more types are mentioned.
  • the position of the substituent may be any of o-, m-, and p-.
  • alkyl group and alkenyl group as the substituent include one or more of an alkyl group and an alkenyl group having 1 to 6, preferably 1 to 4 carbon atoms.
  • Specific examples of the alkyl group and alkenyl group include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, and t-butyl group. 1 type (s) or 2 or more types.
  • the alkyl group and alkenyl group may further have other substituents, and may be a halogenated alkyl group or a halogenated alkenyl group.
  • a halogen atom one or more of F, Cl, Br and I, etc.
  • alkoxy group as the substituent examples include an alkoxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms.
  • Specific examples of the alkoxy group include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group and t-butoxy group.
  • the aromatic ring contained in the aryl group or the like may have one or more heteroatoms (oxygen atom, nitrogen atom, and sulfur atom).
  • the aromatic ring contained in the aryl group or the like is an aromatic heterocyclic ring (furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, pyrazole, imidazole, triazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, quinoline, isoquinoline, And pyrimidine etc.).
  • aryl group examples include a phenyl group, a tolyl group, an ethylphenyl group, a xylyl group, a cumenyl group, a mesityl group, a methoxyphenyl group (o-, m-, and p-), and an ethoxyphenyl group (o -, M-, and p-), naphthyl groups (such as 1-naphthyl group and 2-naphthyl group), and biphenyl groups.
  • arylalkyl group examples include a benzyl group, a methoxybenzyl group (o-, m-, and p-), an ethoxybenzyl group (o-, m-, and p-), and a phenethyl group.
  • arylalkenyl group examples include a styryl group and a cinnamyl group.
  • R 2 and R 3 are each directly bonded to a phosphorus atom or bonded to a phosphorus atom via an atom other than a carbon atom (hereinafter, this bond is referred to as “indirect bond”).
  • this bond is referred to as “indirect bond”.
  • an oxygen atom, a nitrogen atom, and a sulfur atom are mentioned, for example.
  • More specific examples of the indirect bond include an “R 2 (or R 3 ) —OP” structure and an “R 2 (or R 3 ) —N (E) —P” structure.
  • both R 2 and R 3 may be directly bonded to the phosphorus atom or indirectly bonded, and one of R 2 and R 3 is directly bonded to the phosphorus atom and the other is indirectly bonded. May be.
  • R 2 and R 3 are indirectly bonded (for example, when bonded via an oxygen atom)
  • specific examples of R 2 and R 3 are, for example, independently 3 or more carbon atoms, preferably Can be a monovalent hydrocarbon group having 4 or more carbon atoms, more preferably 4 to 10 carbon atoms.
  • the “E” may be a hydrogen atom or another monovalent hydrocarbon group.
  • the other monovalent hydrocarbon group may be the same group as R 2 (or R 3 ), or may be a different group.
  • the explanation of R 1 to R 5 is appropriate for the structure and content of the other monovalent hydrocarbon group.
  • the nitrogen atom has two monovalent hydrocarbon groups, at least one of them may correspond to R 2 (or R 3 ).
  • the other monovalent hydrocarbon group include an alkyl group having 1 to 5 carbon atoms, an alkenyl group, and an alkynyl group. More specific examples of the other monovalent hydrocarbon group include a methyl group, an ethyl group, an n-propyl group, and an i-propyl group.
  • R 4 and R 5 may combine with each other to form a ring.
  • the number of ring members is not particularly limited.
  • the number of ring members is usually a 4- to 10-membered ring including the nitrogen atom to which R 4 and R 5 are bonded, preferably 5 to It can be an 8-membered ring.
  • the ring may contain a hetero atom (oxygen atom, nitrogen atom, sulfur atom, etc.) in the structure.
  • the ring may have other substituents.
  • the ring may have an unsaturated bond in the structure.
  • Specific examples of the ring formed by combining R 4 and R 5 with each other are shown below.
  • Specific examples of the ring include a 5-membered ring structure formed by a tetramethylene group, a 6-membered ring structure formed by a pentamethylene group, a 7-membered ring structure formed by a hexamethylene group, and a heptamethylene group.
  • R 1 to R 5 may all be the same group or may be partially or all different groups.
  • R 2 and R 3 may be the same group or different groups.
  • R 1 to R 3 may all be the same group.
  • R 2 and R 3 may be the same group, and R 1 may be a different group.
  • R 4 and R 5 may be the same group or different groups.
  • R 1 to R 5 There is no particular limitation on the specific structure of R 1 to R 5 .
  • specific structures of R 1 to R 5 for example, the structures exemplified above can be appropriately combined as necessary.
  • R 1 can be, for example, an alkyl group, an arylalkyl group, or an arylalkenyl group.
  • alkyl group include the alkyl groups described above, particularly methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, and t- It can be a butyl group.
  • the arylalkyl group can be, for example, the arylalkyl group described above, in particular, a benzyl group, and an o-, m-, and p-alkoxybenzyl group (such as a methoxybenzyl group and an ethoxybenzyl group).
  • R 1 is an alkyl group, an aryl group, an arylalkyl group, or an arylalkenyl group, and can be a group different from either or both of R 2 and R 3 .
  • R 2 and R 3 can each independently be an aryl group or a cycloalkyl group, for example.
  • the aryl group can be a phenyl group or a group represented by any of the following formulas (4a) to (4e).
  • a phenyl group or a group represented by the formula (4a) or (4b) can be preferably used.
  • R 10 is a monovalent hydrocarbon group.
  • R 11 is a hydrogen atom or a monovalent hydrocarbon group.
  • explanations of R 1 to R 5 are appropriate.
  • R 10 and R 11 may be bonded to each other to form a ring.
  • the ring may be a saturated ring or an unsaturated ring.
  • the ring structure include an alicyclic structure having usually 4 to 8, more preferably 5 to 8, and more preferably 6 to 8 carbon atoms.
  • Specific examples of the ring include a cyclohexane structure.
  • Specific examples of the group represented by the formula (4a) in which R 10 and R 11 are bonded to each other to form a ring include a 1,2,3,4-tetrahydronaphthyl group and derivatives thereof. .
  • the aryl group and the cycloalkyl group may have one or more other substituents.
  • the phenyl group and the aromatic rings of the formulas (4a) to (4e) may have one or more other substituents.
  • the position of this substituent may be either m- or p-.
  • Specific examples of the substituent include one or more of a halogen atom, an alkyl group, an alkenyl group, a nitro group, an amino group, a hydroxyl group, and an alkoxy group.
  • X is an oxygen atom or a sulfur atom. Usually, “X” is an oxygen atom. “A” is a methylene group or a carbonyl group. Usually, “A” is a methylene group.
  • Specific examples of the compound (1) include compounds represented by the following general formula.
  • R 1 ′ is an alkyl group or arylalkyl group having 2 or more carbon atoms, preferably 3 or more carbon atoms, more preferably 3 to 10 carbon atoms, and is a group different from R 2 ′ and R 3 ′ .
  • R 2 ′ and R 3 ′ are the same or different cycloalkyl group, aryl group, arylalkyl group, or arylalkenyl group.
  • R 4 ′ is an alkyl group, an alkenyl group, or an alkynyl group. The description of R 1 to R 4 is appropriate for R 1 ′ to R 4 ′ .
  • the method for obtaining the compound (1) is not particularly limited.
  • Compound (1) can be obtained, for example, by the method described in Non-Patent Document 1 or Patent Document 1.
  • the carbonyl compound may be an aldehyde (R 6 —CHO) or a ketone (R 7 —CO—R 8 ).
  • the carbonyl compound may be any of an aromatic carbonyl compound, an aliphatic carbonyl compound, and an alicyclic carbonyl compound. It is preferable to use an aldehyde as the carbonyl compound because an optically active alcohol can be obtained with high yield and high enantioselectivity.
  • R 6 to R 8 are monovalent hydrocarbon groups (provided that R 8 is a monovalent hydrocarbon group different from R 7 ).
  • the monovalent hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an arylalkyl group, and an arylalkenyl group.
  • the description of R 1 to R 5 is appropriate for the type and structure of the monovalent hydrocarbon group.
  • R 7 can be a methyl group or an ethyl group.
  • R 8 can be a phenyl group or a substituted phenyl group.
  • substituent of the substituted phenyl group include a halogen atom, a halogenated alkyl group, and a nitro group, which are groups having electron withdrawing properties.
  • the halogen atom include one or more of a fluorine atom, a chlorine atom, and a bromine atom.
  • halogenated alkyl group part or all of the hydrogen atoms of the alkyl group (for example, methyl group and ethyl group) are replaced with halogen atoms (one or more of fluorine, chlorine, and bromine atoms). Any group may be used.
  • halogenated alkyl group include a trifluoromethyl group (CF 3 —) and a trichloromethyl group (CCl 3 —).
  • step (B) the carbonyl compound is reacted with the organozinc compound in the presence of compound (1).
  • “in the presence” means that the compound (1) may be present in at least a part of the reaction process, and is not always required in all stages of the reaction process. That is, in the present invention, if compound (1) is added to the reaction system, even if any change occurs in the reaction process, the requirement “in the presence” is satisfied.
  • a complex is formed between the compound (1) and the organozinc compound (see Patent Document 1 and Non-Patent Document 1).
  • the description of the complex formation is an inventor's guess as described in Patent Document 1. Therefore, the description of the complex formation does not explain the contents of the present invention. It is not an explanation to define.)
  • the amount of the organozinc compound is not particularly limited.
  • the amount of the organozinc compound can usually be 1 to 5 equivalents, preferably 1 to 4 equivalents, and more preferably 1 to 3 equivalents with respect to 1 equivalent of the carbonyl compound.
  • the amount of compound (1) is not particularly limited.
  • the amount of the compound (1) is usually 0.1 to 20 mol%, preferably 0.5 to 15 mol%, more preferably 1 to 15 mol%, more preferably 5 to 15 mol%, based on the carbonyl compound. it can.
  • the reaction time is usually 1 to 48 hours, preferably 1 to 24 hours.
  • the reaction temperature is usually ⁇ 20 to 70 ° C., preferably 10 to 50 ° C., more preferably 15 to 40 ° C.
  • Step (B) may be performed in the presence of a solvent or may be performed in the absence of a solvent.
  • it can be appropriately selected to perform step (B) in the presence or absence of a solvent.
  • the organic zinc compound which is liquid in a high concentration or no solvent state can also serve as a solvent. Therefore, it is possible to proceed the reaction by adding the compound (1) and the carbonyl compound without adding a special solvent. By not using a solvent, it is possible to reduce the cost of the solvent itself, to avoid dangers such as toxicity and flammability that the solvent may have, and to reduce the equipment size by compressing the reaction capacity, etc. Have
  • the step (B) can be performed in the presence of a solvent.
  • the solvent include hexane, heptane, and toluene.
  • the said solvent may be only 1 type and 2 or more types of mixed solvents may be sufficient as it.
  • the said solvent may contain alcohol (methanol, ethanol, etc.) further for a yield improvement.
  • the obtained organozinc compound may be isolated and then added to the reaction system to perform the step (B).
  • step (A) and step (B) need not be completely separated.
  • Step (A) and step (B) can be performed continuously.
  • the compound (1) and the carbonyl compound can be subsequently added to the reaction system to carry out the step (B).
  • the step (A) and the step (B) can be performed in one reaction tank.
  • Compound (1) may be present in the reaction system in the step (B). Therefore, the phosphoramide compound (1) does not always need to be added to the reaction system after the step (A). For example, compound (1) can be added to the reaction system at the stage of step (A) to obtain the organozinc compound, and then the carbonyl compound can be added to the reaction system. Of course, after obtaining the organozinc compound by the step (A), the compound (1) and the carbonyl compound may be added to the reaction system.
  • a titanium additive (Ti (Oi—Pr) 4 or the like) may not be used as a reaction accelerator.
  • Ti Ti (Oi—Pr) 4 or the like
  • an equimolar to excess amount of titanium additive relative to the carbonyl compound has been used as a reaction accelerator.
  • the titanium additive has a strong hygroscopic decomposability and is not easy to handle.
  • a method for producing an optically active alcohol can be easily performed.
  • the above titanium additive may be used.
  • the amount of the titanium additive used is 2 equivalents or less, preferably 1 equivalent or less, more preferably 0.5 equivalents or less, more preferably 0.3 equivalents or less, particularly preferably 0 to 1 equivalent of the carbonyl compound. .1 equivalent or less.
  • Step (B) can be performed in the absence or presence of an amine compound.
  • the present invention is preferable because an optically active alcohol can be obtained with high yield and high enantioselectivity even in the absence of an amine compound.
  • the amine compound include monoamine, diamine, triamine, tetraamine (such as porphyrin), and polyamine.
  • the amine compound may be any of primary amines, secondary amines, and tertiary amines.
  • the amine compound may have a chain structure or a cyclic structure (alicyclic amine or aromatic amine).
  • the amine compound may be linear or may have a side chain.
  • a preferred example of the amine compound is TMEAD (tetramethylethylenediamine).
  • the type and structure of the optically active alcohol obtained by the present invention are not particularly limited. As described above, in the present invention, organic zinc compounds having various secondary hydrocarbon groups can be obtained by the step (A). As a result, in the present invention, optically active alcohols of various types and structures can be produced. When the carbonyl compound is a ketone, the optically active alcohol is an optically active tertiary alcohol. On the other hand, when the carbonyl compound is an aldehyde, the optically active alcohol is an optically active secondary alcohol.
  • steps may be included as necessary.
  • the other steps include optical resolution for separating only the optically active substance and physical operation steps such as product concentration, purification, and isolation.
  • a suspension was prepared by adding Et 2 O (5 ml) at room temperature under a nitrogen atmosphere to a dedicated container capable of centrifugation and centrifugation containing ZnCl 2 (682 mg, 5 mmol) and NaOMe (540 mg, 10 mmol). The suspension was stirred at room temperature for 20 minutes. The suspension was cooled to 0 ° C., and i-PrMgCl (2.0 M Et 2 O solution, 4 ml, 8 mmol) was slowly added dropwise over 10 minutes. After the addition, the suspension was warmed to room temperature. The suspension was then stirred at room temperature for 2 hours and centrifuged (4000 rpm, 10 minutes). From this supernatant, an i-Pr 2 Zn solution (0.44M Et 2 O solution) was taken out.
  • i-Pr 2 Zn (3.4 ml, 1.5 mmol) obtained in the above step was added to a Schlenk reaction tube containing the phosphoramide compound (1b) (17.8 mg, 0.05 mmol) at room temperature. It was. Thereafter, Et 2 O was distilled off almost completely from the resulting solution by distillation under reduced pressure to obtain i-Pr 2 Zn reagent (including phosphoramide compound (1b)). The reagent is almost solvent-free.
  • Benzaldehyde (0.5 mmol) was added to the i-Pr 2 Zn reagent and stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC, the solution was cooled to 0 ° C. Thereafter, ethyl acetate (5 ml) and saturated aqueous ammonium chloride solution (10 ml) were added in this order, and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (15 ml ⁇ 3), and the extracted organic layer was washed with a saturated aqueous sodium chloride solution (10 ml) and dried over magnesium sulfate. Filtration was performed using “Celite”, and the solvent was distilled off under reduced pressure.
  • Entry 1 is a result of using an organozinc compound obtained with a mixing ratio described in Non-Patent Document 2 targeting a secondary alkyl group. From Table 1, it can be seen that entry 1 has a good yield, but the enantiomeric excess is low (3%) and the enantioselectivity is not sufficient. On the other hand, entries 2 to 5 all have a high enantiomeric excess and are excellent in enantioselectivity. Although entry 2 has a slightly lower yield than entry 1 (reduced products are generated by side reactions), it can be seen that entries 2-5 are still in high yield.
  • optically active secondary alcohols having similar side chain structures can also be obtained with high yield and high enantioselectivity.
  • R and R ' optically active secondary alcohols having similar side chain structures
  • the present invention is useful for synthesizing optically active alcohols from carbonyl compounds with high enantioselectivity.
  • the synthesized optically active alcohol is useful as pharmaceuticals, agricultural chemicals, etc. or synthetic intermediates thereof.
  • a pharmaceutical for example, clemastine frequently used as an antihistamine

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Abstract

La présente invention concerne un procédé d'obtention d'un alcool optiquement actif faisant appel à une alkylation secondaire hautement énantiosélective, cela s'accompagnant d'une suppression des réactions parasites. L'invention concerne, plus précisément, un procédé de production d'un alcool optiquement actif comprenant (A) une étape consistant à obtenir un composé de zinc organique par réaction d'un halogénure de zinc, d'un alcoxyde métallique et de RMgY (où R représente un groupe hydrocarbure secondaire et Y représente un atome d'halogène) et (B) une étape consistant à faire réagir un composé carbonyle avec le composé de zinc organique en présence d'un composé de phosphoroamide (1). Lors de l'étape (A), la quantité de RMgY n'est pas supérieure à 1,8 équivalents pour un équivalent d'halogénure de zinc. (Dans la formule (1), R1 à R5 représentent chacun, indépendamment les uns des autres, un groupe hydrocarbure monovalent et R2 et R3 sont chacun liés à un atome de phosphore directement ou par l'intermédiaire d'un atome autre qu'un atome de carbone; X représente un atome d'oxygène ou un atome de soufre; et A représente un groupe méthylène ou un groupe carbonyle.)
PCT/JP2010/070745 2009-11-20 2010-11-19 Procédé de production d'un alcool optiquement actif Ceased WO2011062280A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2008111371A1 (fr) * 2007-03-09 2008-09-18 National University Corporation Nagoya University Composé de phosphoramide, procédé de fabrication de celui-ci, ligand, complexe, catalyseur et procédé de fabrication d'un alcool optiquement actif

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008111371A1 (fr) * 2007-03-09 2008-09-18 National University Corporation Nagoya University Composé de phosphoramide, procédé de fabrication de celui-ci, ligand, complexe, catalyseur et procédé de fabrication d'un alcool optiquement actif

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MANABU HATANO ET AL.: "Highly Alkyl-Selective Addition to Ketones with Magnesium Ate Complexes Derived from Grignard Reagents", ORGANIC LETTERS, vol. 7, no. 4, 2005, pages 573 - 576 *
MANABU HATANO ET AL.: "Highly Efficient Alkylation to Ketones and Aldimines with Grignard Reagents Catalyzed by Zinc(II) Chloride", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 128, 2006, pages 9998 - 9999 *
TOMOKAZU MIZUNO ET AL.: "Catalytic Enantioselective Synthesis of Tertiary Alcohols with Grignard Reagents", 89TH ANNUAL MEETING OF CHEMICAL SOCIETY OF JAPAN IN SPRING KOEN YOKOSHU II, THE CHEMICAL SOCIETY OF JAPAN, - 13 March 2009 (2009-03-13), pages 1137 *

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