JP5750667B2 - Method for producing optically active alcohol - Google Patents

Description

  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.

  As an alcohol synthesis method, an alkyl addition reaction in which a carbonyl compound (aldehyde and ketone) is reacted with an organometallic nucleophile is known.

  Many physiologically active substances 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. As 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.

A method is known in which an optically active alcohol is obtained by reacting a carbonyl compound with an organometallic nucleophile. For example, 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.

International Publication WO2008 / 111371

Org. Lett. 2007, 9 (22), 4535-4538 J. Am. Chem. Soc. 2008, 130, 2771

  If an organic zinc compound having various organic groups is used, various optically active alcohols can be obtained by alkylation of the carbonyl compound. However, the types of commercially available organozinc compounds are limited. On the other hand, Non-Patent Document 2 merely discloses the synthesis of an optically active alcohol by primary alkylation.

  In the alkylation reaction of the carbonyl compound, a side reaction may occur together with the addition reaction. For example, in the alkylation reaction of an aldehyde compound, a reduction reaction may occur as a side reaction. In the alkylation reaction of a ketone compound, an aldol reaction may occur as a side reaction in addition to the reduction reaction. In particular, in 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 the side reaction 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), The amount of the metal alkoxide is 2.3 to 2.7 equivalents relative to 1 equivalent of the zinc halide, and the amount of RMgY is 1 . It is a manufacturing method of the optically active alcohol which is 8 equivalent or less.

In formula (1), R ^{1 to} R ⁵ are each independently a monovalent hydrocarbon group . R ⁴ and R ⁵ may combine with each other to form a ring. X is an oxygen atom or a sulfur atom. A is a methylene group or a carbonyl group.

  According to the present invention, an optically active alcohol can be obtained with high enantioselectivity by suppressing secondary reactions and secondary alkylation. In particular, by using an aldehyde as the carbonyl compound, an optically active alcohol can be obtained with high yield and high enantioselectivity. According to the present invention, 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.

(1) 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).

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. As the zinc halide, zinc chloride (ZnCl ₂ ) is usually used.

  There is no limitation in particular in the kind of said metal alkoxide. Examples of the metal contained in the metal alkoxide include Li, Na, K, Mg, and Al. Carbon number of the alkoxide contained in the said metal alkoxide is 1-8 normally, Preferably it is 1-6, More preferably, it is 1-4. 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 above Symbol metal alkoxide 2. 3 to 2.7 equivalents (in the present specification, the term “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.

The above 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 ).

  As long as the organozinc compound can be obtained, 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. For example, 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 number of carbon atoms of the secondary hydrocarbon group is not particularly limited. The carbon number of the secondary hydrocarbon group is usually 3 to 10, preferably 3 to 8. 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).

Kind and structure of 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 ”). There is no particular limitation. As described above, 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.

  In the step (A), 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 with respect 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.

The reason for this is estimated as follows. In the 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. In particular, 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. On the other hand, by setting the amount of RMgY within the above range, it is considered that the formation of the zinc ate complex can be suppressed, and as a result, the enantioselectivity can be enhanced. Therefore, this description is not an explanation that defines the contents of the present invention.)

In step (A), the amount of the three components is not particularly limited as long as the amount of RMgY is within the above range. In step (A), the three components (the zinc halide, the metal alkoxide, and the RMgY) Specifically as the amount of, (1 eq), (2.3 to 2.7 eq), and ( 1.8 equivalents or less), preferably (1 equivalent), ( 2.3 to 2.7 equivalents), and (1.0 to 1.8 equivalents), more preferably (1 equivalent), ( 2.3 to 2.3 equivalents). 2.7 equivalents), and (1.2 to 1.7 equivalents). As a preferable example of 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.

  When performing the step (B) continuously from the step (A), the amounts of the zinc halide, metal alkoxide, and RMgY are respectively set in order to set the amount of the organozinc compound in the step (B) within a specific range. It can be a specific range. As a preferable example of the amount of the three components, the amount of the zinc halide, metal alkoxide, and RMgY 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 include (2.5 to 3 equivalents), (7 to 8 equivalents), and (4 to 4.8 equivalents). Can be mentioned. As a suitable example of the amount of the three components, 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).

  In the present invention, as described above, the 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). .

  The specific contents and reaction conditions of the step (A) are not particularly limited as long as the organozinc compound can be obtained. 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. 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.

  The step (A) may have other steps as necessary. Examples of 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. When the obtained organic zinc compound is liquid, the organic zinc compound in a high concentration or no solvent state 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.

  In the present invention, organozinc compounds having various secondary hydrocarbon groups can be obtained by the step (A). For example, an organic zinc compound having a secondary hydrocarbon group that is not commercially available can also be obtained by the step (A). As a result, in the present invention, optically active alcohols having various structures can be obtained.

(2) Process (B)
In the step (B), the carbonyl compound and the organozinc compound are reacted in the presence of the compound (1).

In formula (1), R ^{1 to} R ⁵ are each independently a monovalent hydrocarbon group. In this specification, 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.

  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. Carbon number of the said alkyl group is 1-12 normally, Preferably it is 1-10, More preferably, it is 1-8, More preferably, it is 1-6, Most preferably, it is 1-4. Moreover, carbon number of the said alkenyl group and alkynyl group is 2-12 normally, Preferably it is 2-10, More preferably, it is 2-8, More preferably, it is 2-6, Most preferably, it is 2-4. When the said alkyl group etc. are cyclic structures, carbon number, such as the said alkyl group, is 4-12 normally, Preferably it is 4-10, More preferably, it is 5-8, More preferably, it is 6-8.

  There is no particular limitation on the structure of the alkyl group or the like. 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. For example, 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. Moreover, the said alkyl group etc. 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. 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.

  Specific examples of the alkyl group 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. Examples of the alkenyl group include a vinyl group, an allyl group, and an isopropenyl group. Specific examples of the cycloalkenyl group include a cyclohexenyl group.

  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. Carbon number, such as said aryl group, is 6-15 normally, Preferably it is 6-12, More preferably, it is 6-10.

  The structure of the aryl group or the like is not particularly limited. The aryl group or the like may have one or more other substituents. For example, 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. When these substituents are located on the aromatic ring, the position of the substituent may be any of o-, m-, and p-.

Examples of the alkyl group and alkenyl group as the substituent include one or more of an alkyl group and an alkenyl group having 1 to 6 carbon atoms, 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. For example, as the alkyl group, a group in which part or all of the hydrogen atoms of a methyl group and an ethyl group are substituted with a halogen atom (such as one or more of F, Cl, Br, and I) (CF _3- , CCl ₃ − and the like).

  Examples of the alkoxy group as the substituent 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 is an aromatic heterocycle (furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, pyrazole, imidazole, triazole, isoxazole, oxazole, isothiazole, thiazole, pyridine, quinoline, isoquinoline, And pyrimidine etc.).

  Specific examples of the aryl group 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-), a naphthyl group (1-naphthyl group, 2-naphthyl group, etc.), a biphenyl group, etc. are mentioned. Specific examples of the arylalkyl group include a benzyl group, a methoxybenzyl group (o-, m-, and p-), an ethoxybenzyl group (o-, m-, and p-), and a phenethyl group. Specific examples of the arylalkenyl group include a styryl group and a cinnamyl group.

In formula (1), R ⁴ and R ⁵ may combine with each other to form a ring. There is no particular limitation on the structure of the ring. For example, the number of ring members is not particularly limited. When R ⁴ and R ⁵ are bonded to each other to form a ring, 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 5 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. An 8-membered ring structure formed by Moreover, as a structure containing a hetero atom in a ring structure, the structure (morpholyl group) containing an oxygen atom is mentioned, for example.

R ^{1 to} R ⁵ may all be the same group or may be partially or all different groups. For example, R ² and R ³ may be the same group or different groups. R ^{1 to} R ³ may all be the same group. Among R ^{1 to} R ³ , 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.

There is no particular limitation on the specific structure of R ^{1 to} R ⁵ . As specific structures of R ^{1 to} R ⁵ , for example, the structures exemplified above can be appropriately combined and employed as necessary.

R ¹ can be, for example, an alkyl group, an arylalkyl group, or an arylalkenyl group. Examples of the 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. Examples of the arylalkyl group include the arylalkyl groups described above, in particular, a benzyl group, and o-, m-, and p-alkoxybenzyl groups (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. In the formula (4a), R ¹⁰ is a monovalent hydrocarbon group. R ¹¹ is a hydrogen atom or a monovalent hydrocarbon group. Regarding the contents of the monovalent hydrocarbon group, explanations of R ^{1 to} R ⁵ are appropriate.

When R ¹⁰ and R ¹¹ are both monovalent hydrocarbon groups, R ¹⁰ and R ¹¹ may be bonded to each other to form a ring. There is no particular limitation on the structure of the ring. The ring may be a saturated ring or an unsaturated ring. Examples of the ring structure include an alicyclic structure having usually 4 to 8, more preferably 5 to 8, 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. For example, 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-. However, among the aromatic rings of the formulas (4a) to (4e), there is only one substituent at the o-position of the aromatic ring bonded to the phosphorus atom (direct bond or indirect bond). For example, there is only one (R ⁶ ) substituent at the o-position of the aromatic ring of formula (4a). 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.

  In formula (1), “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.

In the above formula, “X” is an oxygen atom or a sulfur atom. “A” is a methylene group or a carbonyl group. R ^{1 ′} is an alkyl group or arylalkyl group having 2 or more carbon atoms, preferably 3 or more, more preferably 3 to 10 carbon atoms, and 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. Note that R ^{1 '~R 4',} the description of R 1 to R ⁴ are valid.

  There is no limitation in particular in the method of obtaining a compound (1). Compound (1) can be obtained, for example, by the method described in Non-Patent Document 1 or Patent Document 1.

There is no limitation in particular in the kind and structure of the said carbonyl compound. 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.

In the above formula, R ^{6 to} R ⁸ are monovalent hydrocarbon groups (provided that R ⁸ is a monovalent hydrocarbon group different from R ⁷ ). 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. The description of R ^{1 to} R ⁵ is appropriate for the type and structure of the monovalent hydrocarbon group.

In the above formula, R ⁷ can be a methyl group or an ethyl group. R ⁸ can be a phenyl group or a substituted phenyl group. Examples of the 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. Examples of the halogen atom include one or more of a fluorine atom, a chlorine atom, and a bromine atom. In the 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. Examples of the halogenated alkyl group include a trifluoromethyl group (CF ₃ —) and a trichloromethyl group (CCl ₃ —).

  In the step (B), the carbonyl compound and the organozinc compound are reacted in the presence of the compound (1). Here, “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. For example, after adding the compound (1) to the reaction system, 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.)

  In the step (B), the amount of the organozinc compound is not particularly limited. For example, the amount of the organozinc compound is usually 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.

  In the step (B), the amount of the 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% with respect to the carbonyl compound. it can.

  There is no limitation in particular in the reaction conditions of a process (B). The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours. Moreover, reaction temperature is -20-70 degreeC normally, Preferably it is 10-50 degreeC, More preferably, it is 15-40 degreeC.

  Step (B) may be performed in the presence of a solvent or may be performed in the absence of a solvent. In the present invention, considering the properties of the raw materials and the cost of each step, it can be appropriately selected to perform step (B) in the presence or absence of a solvent.

  When the step (B) is carried out in the absence of a solvent, an optically active alcohol can be obtained in a high yield, and it is also industrially advantageous as described later, which is preferable. As described above, 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

  On the other hand, considering the properties (solubility, etc.) of the carbonyl compound and the organozinc compound, the step (B) can be performed in the presence of a solvent. Examples of 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. In addition, the said solvent may contain alcohol (methanol, ethanol, etc.) further for a yield improvement.

(3) Others In the present invention, after the step (A) is performed, the obtained organozinc compound may be isolated and then added to the reaction system to perform the step (B). However, in the present invention, step (A) and step (B) need not be completely separated. Step (A) and step (B) can be performed continuously. For example, after obtaining the organozinc compound by the step (A), without isolating it, the compound (1) and the carbonyl compound can be subsequently added to the reaction system to carry out the step (B). According to this method, the step (A) and the step (B) can be performed in one reaction tank.

  The 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.

In the present invention, a titanium additive (Ti (Oi-Pr) ₄ or the like) may not be used as a reaction accelerator. Conventionally, as a reaction accelerator, an equimolar amount to an excess amount of a titanium additive with respect to the carbonyl compound has been used. However, the titanium additive has a strong hygroscopic decomposability and is not easy to handle. In the present invention, since it is not necessary to use a titanium additive, a method for producing an optically active alcohol can be easily performed. Of course, in the present invention, the above titanium additive may be used. However, 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. Examples of 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).

  There are no particular limitations on the type and structure of the optically active alcohol obtained by the present invention. 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.

  In this invention, you may have another process as needed. Examples of the other steps include optical resolution for separating only the optically active substance and physical operation steps such as product concentration, purification, and isolation.

  Hereinafter, the present invention will be described specifically by way of examples. In addition, this invention is not restricted to the form shown in the Example. The embodiment of the present invention can be variously modified within the scope of the present invention depending on the purpose and application.

(1) Synthesis of optically active alcohol from aldehyde (I)
An optically active secondary alcohol was synthesized from an aldehyde using diisopropyl zinc (i-Pr ₂ Zn) by the following method.

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). An i-Pr ₂ Zn solution (0.44M Et ₂ O solution) was taken out from the supernatant.

Under a nitrogen atmosphere, 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. Then, by vacuum distillation, and evaporated almost completely Et ₂ O from the resulting solution to give _i-Pr 2 Zn reagent (phosphoramide compound containing (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. The obtained concentrated liquid was purified through silica gel column chromatography (hexane / Et ₂ O = 10 / 1-2 / 1) to obtain an optically active secondary alcohol (entry 3; yield 93%). Furthermore, the enantiomeric excess of the product was determined by gas chromatography packed in a chiral column (entry 3; 91% ee (S)).

An i-Pr ₂ Zn solution was obtained by the same method as above except that the amount of i-PrMgCl was changed to 1.9 mol equivalent, and an optically active secondary alcohol was obtained by the same method as above. (Entry 1). An optically active secondary alcohol was obtained in the same manner as described above except that the i-Pr ₂ Zn solution was used instead of the i-Pr ₂ Zn reagent (entry 2). An optically active secondary alcohol was obtained by the same method as above except that the amount of NaOMe was 2.5 mol equivalent (entry 4). An optically active secondary alcohol was obtained by the same method as above except that the amount of NaOMe was 2.5 mol equivalent and the phosphoramide compound (1a) was used as the compound (1) (entry 5). The results (yield and enantiomeric excess) are shown in Table 1.

  Entry 1 is the 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, in entries 2 to 5, it can be seen that the enantiomeric excess is high and the enantioselectivity is excellent. Although entry 2 has a slightly lower yield than entry 1 (reduced products are produced by side reactions), entries 2 to 5 are still in high yield.

(2) Synthesis of optically active alcohol from aldehyde (II)
Optically active secondary alcohols shown in Table 2 were synthesized by the same method as in (1) above, except that the aldehydes and organic zinc compounds shown in Table 2 were used as aldehydes and organic zinc compounds. The synthesis scheme and results (yield and enantiomeric excess) are shown in Table 2.

  From Table 2, as a result of performing various secondary alkylation (isopropylation, sec-butylation, cyclopentylation, cyclohexylation) using various aldehydes (aliphatic aldehyde, aromatic aldehyde, alicyclic aldehyde), In either case, an optically active secondary alcohol could be obtained with high yield and high enantioselectivity.

  In particular, entries 13, 20 and 22 show that optically active secondary alcohols having similar side chain (R and R ') structures can also be obtained with high yield and high enantioselectivity. Usually, in the synthesis of optically active alcohols by asymmetric reduction of ketones, it is difficult to distinguish enantioselectivity because it is difficult to distinguish side chains. However, according to this experimental example, it can be seen that such an alcohol can be obtained with high yield and high enantioselectivity.

(3) Synthesis of optically active alcohol from ketone The above (1) except that 3,5-bis (trifluoromethyl) acetophenone is used in place of benzaldehyde and the reaction time and reaction temperature are set to the time and temperature described below. ) To obtain an optically active tertiary alcohol (“cat” is the above phosphoramide compound (1a)). The synthesis scheme is as follows. The results (yield and enantiomeric excess) are shown below.

  In this experimental example, like the aldehyde, all showed high enantioselectivity. Further, although the yield was lower than that of aldehyde, the product (aldol form) by the side reaction was a trace amount, and raw material recovery was observed. From this experimental example, it can be seen that, in the synthesis of a tertiary alcohol from a ketone, excellent enantioselectivity is exhibited and side reactions can be suppressed.

  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. For example, by using the optically active alcohol synthesized according to the present invention, it is possible to synthesize a pharmaceutical (for example, clemastine frequently used as an antihistamine) by omitting the optical resolution step that has been essential in the past.

Claims (9)

(A) a step of reacting zinc halide, metal alkoxide, and RMgY (R; secondary hydrocarbon group, Y: halogen atom) to obtain an organic zinc compound ZnR ₂ ;
(B) reacting a carbonyl compound with the organozinc compound in the presence of the phosphoramide compound represented by the formula (1),
In the step (A), the amount of the metal alkoxide is 2.3 to 2.7 equivalents relative to 1 equivalent of the zinc halide, and the amount of RMgY is 1 . The manufacturing method of the optically active alcohol which is 8 equivalent or less.

(In Formula (1), R ^{1 to} R ⁵ are each independently a monovalent hydrocarbon group. R ⁴ and R ⁵ may be bonded to each other to form a ring. X is an oxygen atom. Or a sulfur atom, and A is a methylene group or a carbonyl group.)   The method for producing an optically active alcohol according to claim 1, wherein the carbonyl compound is an aldehyde compound.   3. The method for producing an optically active alcohol according to claim 1, wherein R is a secondary alkyl group or a cycloalkyl group.   The process for producing an optically active alcohol according to any one of claims 1 to 3, wherein in the step (B), the amount of the organic zinc compound is 1 to 5 equivalents relative to the carbonyl compound.   The method for producing an optically active alcohol according to any one of claims 1 to 4, wherein the step (A) and the step (B) are performed continuously.   6. The method for producing an optically active alcohol according to claim 1, wherein in step (A), the amount of RMgY is 1.0 to 1.8 equivalents relative to 1 equivalent of the zinc halide. 7. The method for producing an optically active alcohol according to claim 1, wherein R ² and R ³ are a phenyl group or a naphthyl group.   The method for producing an optically active alcohol according to claim 1, wherein the step (B) is performed in the absence of a solvent or in the presence of a solvent.   The method for producing an optically active alcohol according to any one of claims 1 to 8, wherein the step (B) is performed in the absence or presence of an amine compound.