JP3075558B2 - Method for producing optically active amino alcohols - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound represented by the following formula [XVI] which is useful as a therapeutic agent for HIV having a protease inhibitory activity derived from a virus.

[0002]

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Wherein Me is a methyl group and Bu-t is te
an rt-butyl group and Ph is a phenyl group).

[0004]

2. Description of the Related Art The compound [XVI] useful as an HIV protease inhibitor is disclosed in International Publication No. WO95 / 0984.
No. 3 and its production method are also described in International Publication Nos. WO 97/11937 and WO 97/1193.
No. 8 is described.

[0005] However, in these production methods, stereoselectivity was not obtained for the intermediate, and the yield of the target intermediate compound was not yet satisfactory. In addition, the reaction had to be performed by heating to 80 to 90 ° C. Furthermore, since the resulting intermediate is a 1: 1 mixture of isomers, a purification step was required for crystallization.

[0006]

DISCLOSURE OF THE INVENTION The object of the present invention is to solve the above-mentioned problems, and an object of the present invention is to provide an optically active amino alcohol compound, its enantiomer or a salt thereof in a high yield in a stereoselective manner. In addition, the present invention resides in mass production as a high-purity salt.

[0007]

Means for Solving the Problems The present inventors have solved the above problems.
As a result of intensive research to solve the problem, Mesoepoxy
Compound is composed of a proton donor and a Lewis acid.
Chiral or acetylene using mild catalysts under mild temperature conditions
Stereoselection by ring opening with a chiral amine
Optically active amino alcohol compound, its enantiomer or
Found that the salts were obtained in high yield. Also,
At this time, if a chiral proton donor is used, achiral
Ring opening of the epoxy compound with the
Amino alcohol formation also occurs with simultaneous yield
Was found. Furthermore, the amino alcohol 7
After isomerizing the 5-membered moiety to a 5-membered structure, the substituent on the nitrogen atom
R ^FourAnd / or R^FiveBy performing the removal of
The important intermediate compound [5] or its enantiomer
Alternatively, it can be used as a highly efficient and highly pure crystalline salt.
That the present invention can be mass-produced,
Was.

That is, the present invention provides (1) a compound represented by the general formula [1]:

[0009]

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(Wherein R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted Or an aralkyl group which may be substituted or R ¹ and R ¹ , or R ² and R ³ together may form an optionally substituted ring) The compound represented by the general formula [2] in the presence of a mixed catalyst comprising a Lewis acid and a proton donor:

[0011]

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(In the formula, R ⁴ and R ⁵ may be the same or different and each may be a hydrogen atom, a lower alkyl group which may be substituted, an aryl group which may be substituted, or a substituent. aralkyl group, or or an acyl group, or R ⁴ and R ⁵ and are may form a substituted together with the adjacent nitrogen atom ring, or R ⁴ and R ⁵ A compound represented by the general formula [R ^6] , which may form an imide group or an azido group containing adjacent nitrogen atoms together, and R ⁶ is a hydrogen atom or a silyl group. 3]

[0013]

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Wherein R ¹ , R ² , R ³ , R ⁴ and R
⁵ is the same as described above), a method for producing an optically active amino alcohol compound, an enantiomer thereof or a salt thereof, (2) a general formula [1 ′]

[0015]

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(Wherein R ² ′ and R ³ ′ may be the same or different and each is a hydrogen atom, an optionally substituted lower alkyl group, or an aryl group;
Or R ² ′ and R ³ ′ may form a cycloalkyl ring together with adjacent carbon atoms) in the presence of a mixed catalyst comprising a Lewis acid and a proton donor. Below, general formula [2]

[0017]

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Wherein R ⁴ , R ⁵ and R ⁶ are the same as defined above, wherein the compound represented by the general formula [3 ′]

[0019]

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(Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are as defined above), an enantiomer thereof or an enantiomer thereof or a salt thereof described above (1).
(3) General formula [1 ']

[0021]

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(Wherein R ² ′ and R ³ ′ are the same as defined above) in the presence of a mixed catalyst comprising a Lewis acid and a proton donor in the presence of a mixed catalyst of the general formula [2]

[0023]

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Wherein R ⁴ , R ⁵ and R ⁶ are the same as defined above, and reacted with a compound of the general formula [3 ′]

[0025]

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(Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are the same as those described above), an enantiomer thereof or an enantiomer thereof or a salt thereof. A general formula [4], characterized in that it isomerized into a 5-membered ring

[0027]

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(Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are the same as described above), a process for producing an optically active 1,3-dioxolan compound or an enantiomer thereof, (4) General Formula [1 ']

[0029]

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(Wherein R ² ′ and R ³ ′ are the same as those described above) in the presence of a mixed catalyst comprising a Lewis acid and a proton donor in the presence of a general catalyst [2]

[0031]

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Wherein R ⁴ , R ⁵ and R ⁶ are the same as defined above, and reacted with a compound of the general formula [3 ′]

[0033]

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(Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are as defined above), an enantiomer thereof or an enantiomer thereof or a salt thereof. Below, general formula [4]

[0035]

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Where R^Two', R^Three', R^FourAnd R^FiveIs before
Optically active 1,3-dioxo represented by
After making a run compound or its enantiomer, place it on a nitrogen atom.
Substituent R ^FourAnd / or R^FiveCharacterized by desorbing
General formula [5]

[0037]

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(Wherein R ² ′ and R ³ ′ are the same as described above), a method for producing an optically active amino alcohol compound having 1,3-dioxolane, an enantiomer thereof or a salt thereof, ) When the proton donor is (R) -1,1 ′
-Bi-2-naphthol, (S) -1,1'-bi-2-naphthol, catechol, and 4-tert-butylcatechol, wherein the Lewis acid is titanium tetraisopropoxide, Titanium chloride,
Tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, aluminum bromide, alkyl aluminum, alkyl aluminum chloride, aluminum alkoxide, magnesium chloride, zirconocene,
Zirconium tetrapropoxide, zirconium chloride,
Zirconium sulfate, zirconium fluoride, boron bromide,
The method according to (1) or (2), which is at least one selected from boron chloride and boron fluoride,
(6) at least a proton donor selected from (R) -1,1′-bi-2-naphthol, (S) -1,1′-bi-2-naphthol, catechol, and 4-tert-butylcatechol; A Lewis acid of titanium tetraisopropoxide, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, aluminum bromide, alkyl aluminum, alkyl chloride Aluminum, aluminum alkoxide, magnesium chloride, zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride, boron bromide, boron chloride,
And (7) the method of (3), wherein the proton donor is (R)
-1,1'-bi-2-naphthol, (S) -1,1'-
Bi-2-naphthol, catechol, and 4-tert
-Butyl catechol, wherein the Lewis acid is titanium tetraisopropoxide, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, bromide Aluminum, alkyl aluminum, alkyl aluminum chloride, aluminum alkoxide, magnesium chloride, zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride,
The production method of the above (4), which is at least one selected from boron bromide, boron chloride, and boron fluoride,
(8) The above wherein the proton donor is (R) -1,1′-bi-2-naphthol or (S) -1,1′-bi-2-naphthol, and the Lewis acid is titanium tetraisopropoxide. (9) the method according to (1) or (2), wherein the proton donor is (R) -1,1′-bi-2-naphthol or (S) -1,1′-bi-2-naphthol; (3) The method of (3) above, wherein the Lewis acid is titanium tetraisopropoxide, and (10) the proton donor is (R) -1,1′-bi-2-naphthol or (S) —
The present invention relates to the method for producing (4), wherein 1,1′-bi-2-naphthol is used and the Lewis acid is titanium tetraisopropoxide.

[0039]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, each group means the following. "Lower alkyl group" means, for example, an alkyl group having 1 to 6 carbon atoms, which may be linear or branched, and specifically, a methyl group, an ethyl group, a propyl group,
Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl and the like. It is preferably a lower alkyl group having 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. .

"Lower alkyl group which may be substituted"
Is, for example, 1 wherein the lower alkyl group does not affect the reaction.
The above substituents may be substituted, and specific substituents include a halogen atom (chlorine, bromine, fluorine, iodine, etc.), a hydroxyl group, an amino group, a nitro group, an alkylamino group [carbon number Primary alkylamino groups (methylamino group, ethylamino group, etc.), secondary alkylamino groups having 2-6 carbon atoms (dimethylamino group, diethylamino group, etc.)], cyano group, 3-7 carbon atoms. A cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclohexyl group, etc.), a lower alkoxy group having 1 to 6 carbon atoms (methoxy group, ethoxy group, etc.), an acyloxy group (acetoxy group,
Benzoyloxy group, etc.), aralkyloxy group (benzyloxy group, etc.), lower alkoxycarbonyl group having 2 to 6 carbon atoms (methoxycarbonyl group, ethoxycarbonyl group, etc.). Preferred are a hydroxyl group, a halogen atom, an amino group, a nitro group, an aralkyloxy group, a lower alkoxy group having 1 to 6 carbon atoms, and an acyloxy group, and particularly preferred are a hydroxyl group, an acyloxy group, a halogen atom, and 1 to 6 carbon atoms. Is a lower alkoxy group.
The substitution position and the number of substituents with respect to the lower alkyl group are not particularly limited, and are preferably 1 to 3 substituents, particularly preferably 1 to 2 substituents.

Specific examples of the “optionally substituted lower alkyl group” for R ² , R ³ , R ² ′ and R ³ ′ include methyl, ethyl, propyl, isopropyl, butyl, Isobutyl group, sec-butyl group, te
rt-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group and the like, preferably methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, and te
It is an rt-butyl group, more preferably a methyl group.

The "aryl group" is, for example, a phenyl group,
It refers to a naphthyl group, a biphenyl group and the like, and is preferably a phenyl group.

The “optionally substituted aryl group” is, for example, a group in which the above-mentioned aryl group may be substituted with one or more substituents which do not affect the reaction. Lower alkyl groups (methyl group, ethyl group, propyl group, etc.) of formulas 1 to 6, hydroxyl groups, halogen atoms (chlorine, bromine, fluorine, iodine, etc.), amino groups, nitro groups,
An alkylamino group [a primary alkylamino group having 1 to 6 carbon atoms (such as an ethylamino group), a secondary alkylamino group having 2 to 6 carbon atoms (such as a dimethylamino group)], a cyano group, and a cycloalkyl group having a carbon number of 3 to 7; Alkyl group (cyclohexyl group and the like), lower alkoxy group having 1 to 6 carbon atoms (methoxy group and ethoxy group and the like), acyloxy group (alkanoyloxy group having 2 to 6 carbon atoms such as acetyloxy group and propionyloxy group), carbon And lower alkoxycarbonyl groups of formulas 2 to 6 (such as methoxycarbonyl groups). Preferably a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, a halogen atom,
An amino group, a nitro group, a lower alkoxy group having 1 to 6 carbon atoms, and an acyloxy group having 1 to 6 carbon atoms,
Particularly preferred are a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group, an acyloxy group having 1 to 6 carbon atoms, a halogen atom and a lower alkoxy group having 1 to 6 carbon atoms. The substitution position and the number of substituents on the aryl group are not particularly limited, and are preferably 1 to
Tri-substituted, particularly preferably 1-2 substituted.

The "aralkyl group" means that the aryl group is a phenyl group and the alkyl group is, for example, one having 1 to carbon atoms.
An arylalkyl group that is six alkyl groups,
Specific examples include a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group, a phenylhexyl group and the like, and a benzyl group is preferable.

The "optionally substituted aralkyl group" means that the hydrogen on the alkyl group and / or the aryl ring of the aralkyl group may be substituted with one or more substituents which do not affect the reaction. And the alkyl group moiety is preferably on the carbon adjacent to the aryl ring. Specific examples of the substituent at the alkyl group site include a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group) and a cycloalkyl group having 3 to 7 carbon atoms (eg, cyclohexyl). And preferably a lower alkyl group having 1 to 6 carbon atoms. Examples of the substituent on the aryl ring include a lower alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group), a hydroxyl group, a halogen atom (eg, chlorine, bromine, fluorine, iodine), an amino group, and a nitro group. An alkylamino group [a primary alkylamino group having 1 to 6 carbon atoms (e.g., ethylamino group), a secondary alkylamino group having 2 to 6 carbon atoms (e.g., dimethylamino group)], a cyano group, a carbon atom having 3 to 6 carbon atoms. 7 cycloalkyl groups (such as cyclohexyl), having 1 to 1 carbon atoms
6 lower alkoxy groups (methoxy group, ethoxy group, propoxy group, etc.), acyloxy group (acetyloxy group,
And a C2-C6 alkoxycarbonyl group (e.g., a methoxycarbonyl group), preferably a C1-C6 lower alkyl group, a hydroxyl group, a halogen atom, an amino group, a nitro group. , Carbon number 1-6
Lower alkoxy groups, acyloxy groups and the like, particularly preferably a lower alkyl group having 1 to 6 carbon atoms, a hydroxyl group,
An acyloxy group, a halogen atom, and a lower alkoxy group having 1 to 6 carbon atoms. The substitution position and number of substituents on the alkyl moiety and the aryl ring of the aralkyl group are not particularly limited, and are preferably 1 to 3 substituents, particularly preferably 1 to 2 substituents.

Specific examples of the “optionally substituted aralkyl group” for R ⁴ and R ⁵ include a benzyl group, 1-
Examples include a phenethyl group, a diphenylmethyl group, a 2,2-diphenylethyl group, a trityl group, a fluorenyl group, a dibenzosuberanyl group, and the like, and preferably a benzyl group and a 1-phenethyl group.

The "acyl group" specifically includes an acetyl group, a propionyl group, a butyryl group, a pivaloyl group, a benzoyl group and the like, and a benzoyl group is preferable.

The “silyl group” specifically includes a trimethylsilyl group, a tert-butyldimethylsilyl group,
An ert-butyldiphenylsilyl group is mentioned, and a trimethylsilyl group is preferable.

The “ring” in the “optionally substituted ring” in “R ¹ and R ^{1 of} each other may form a ring that may be substituted together” is Specifically, it refers to cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene and the like having a meso structure, and preferably cyclopentane and cyclohexane. As long as the meso structure is maintained, these rings
It may have an optional substituent. Examples of the substituent include the substituents described above for the “optionally substituted aryl group”, preferably a lower alkyl group having 1 to 6 carbon atoms, and particularly preferably a methyl group. The substitution position and number are not particularly limited, and are preferably 1 to 3 substituents, particularly preferably 1 to 2 substituents. Specific examples of preferable “optionally substituted ring” include 4,4-dimethylcyclopentane.

The “ring” in the “optionally substituted ring” in “R ² and R ³ may together form an optionally substituted ring” is a cycloalkyl ring And refers to, for example, a cycloalkyl ring having 3 to 7 carbon atoms, specifically, a cyclopropyl ring, a cyclobutyl ring,
Examples include a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, a cyclooctyl ring, a perhydronaphthyl ring, and the like. Preferably, it has 3 carbon atoms such as a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring and a cyclohexyl ring.
~ 6 cycloalkyl rings. Examples of the substituent include the substituents described above for the “optionally substituted aryl group”, preferably a lower alkyl group having 1 to 6 carbon atoms, and particularly preferably a methyl group. The substitution position and number are not particularly limited, and are preferably 1 to 3 substituents, particularly preferably 1 to 2 substituents.

As the “ring” in the “optionally substituted ring” in “R ⁴ and R ⁵ may form a ring which may be substituted together with an adjacent nitrogen atom” Is specifically pyrrolidine, piperidine,
Morpholine, 2,5-diphenylpyrrolidine, 2,6-
And diphenylpiperidine.
-Diphenylpyrrolidine.

The “imide group” in “R ⁴ and R ⁵ may be combined to form an imide group containing adjacent nitrogen atoms” is specifically a succinimide group,
Examples thereof include a maleic imide group and a phthalimide group, and a phthalimide group is preferred.

The “azide group” in “R ⁴ and R ⁵ may be combined to form an azide group containing adjacent nitrogen atoms” is, for example, a trialkylsilyl azide. Contains trimethylsilyl azide, te
rt-butyldimethylsilyl azide, preferably trimethylsilyl azide.

The “cycloalkyl ring” in “R ² ′ and R ³ ′ may be combined with adjacent carbon atoms to form a cycloalkyl ring” is, for example, a group having 3 to 10 carbon atoms.
And specifically include a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, a cyclohexyl ring, a cycloheptyl ring, a cyclooctyl ring, a perhydronaphthyl ring and the like. Preferred cycloalkyl rings are cycloalkyl rings having 3 to 6 carbon atoms, such as a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring.

Specific examples of the “proton donor” include, for example, catechols (catechol, 3,5-di-tert)
-Butylcatechol, 3-methylcatechol, 4-nitrocatechol, 4-tert-butylcatechol, etc.),
Phenols ((R) -1,1′-bi-2-naphthol, (S) -1,1′-bi-2-naphthol, phenol, 2,2′-biphenol, etc.), and organic acids (acetic acid, formic acid) , Propionic acid, oxalic acid, malonic acid, etc.), alcohols [diisopropyl tartrate, diethyl tartrate, (+)-trans-α, α '-(2,2-
Dimethyl-1,3-dioxolan-4,5-diyl) bis (diphenylmethanol), (−)-trans-
α, α '-(2,2-dimethyl-1,3-dioxolan-4,5-diyl) bis (diphenylmethanol) and the like]
And the like. These "proton donors" can be used alone or in combination of two or more. Preferred “proton donors” are phenols, more preferably (R) -1,1′-bi-2-naphthol and (S) -1,1′-bi-2-naphthol.

Specific examples of “Lewis acid” include, for example, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, magnesium chloride, and alkoxytitanium (methoxytitanium, ethoxytitanium, Titanium tetraisopropoxide, etc.), cerium chloride, samarium iodide, samarium chloride, europium chloride, ytterbium chloride, boron bromide, boron chloride, boron fluoride,
Aluminum chloride, aluminum bromide, alkyl aluminum (trimethyl aluminum, triethyl aluminum, tributyl aluminum, etc.), alkyl aluminum chloride (diethyl aluminum chloride, ethyl aluminum dichloride, etc.), aluminum alkoxide (aluminum methoxide, aluminum ethoxide, aluminum isopropoxide) Etc.), zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride, and the like. Preferred "Lewis acids" are alkoxytitanium, and more preferred are titanium tetraisopropoxide. These “Lewis acids” can be used alone or in combination of two or more.

The type of the “salt” is not particularly limited, and examples thereof include inorganic acid salts (hydrochloride, hydrobromide, sulfate, phosphate, etc.) and organic acid salts (formate, acetate, and the like). Benzoate, trifluoroacetate, maleate, tartrate, etc.), sulfonate (methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), amino acid salt (arginine, aspartic acid, glutamic acid) Pharmaceutically acceptable salts thereof.

Next, methods for producing compounds including the compounds represented by formulas [3 '] and [5], which are important intermediates of the present invention, will be described in detail.

[0059]

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(Wherein R ¹ , R ² , R ³ , R ² ′, R ³ ′,
R ⁴ , R ⁵ and R ⁶ are the same as described above.

<General Production Method> Step 1 and Step 1 '(Epoxy Ring-Opening Reaction with Amine) Compound [1] or [1'] obtained by a known method is mixed with a Lewis acid and a proton donor in an appropriate solvent. By opening the epoxy ring of the compound [1] or [1 ′] with the compound represented by the general formula [2] in the presence of a mixed catalyst consisting of: [3] or [3 ′] Alternatively, an enantiomer thereof is obtained. Here, one or both of the compound [2] and the proton donor are chiral compounds.

As the “compound represented by the general formula [2]”, specifically, aralkylamines represented by benzylamines [benzylamine, diphenylmethylamine,
1,1-diphenylethylamine, 1-methyl-1-phenethylamine, (R) -1-phenethylamine,
(S) -1-phenethylamine, (R) -1- (1-naphthyl) ethylamine, (S) -1- (1-naphthyl)
Ethylamine, (R) -phenylglycinol, (S)
-Phenylglycinol, tritylamine, fluorenylamine, dibenzosuberanylamine, etc.), alkylamines (methylamine, ethylamine, propylamine,
tert-butylamine, etc.), amino acid derivatives [(R)
-Phenylglycine methyl ester, (S) -phenylglycine methyl ester, (R) -serine methyl ester, (S) -serine methyl ester, etc.], aromatic amines (aniline, 1-naphthylamine, 2-naphthylamine, etc.), 2 Secondary amines (dibenzylamine, morpholine, piperidine, pyrrolidine, etc.), imides (succinimide, maleic imide, phthalimide, etc.), silyl azides (trimethylsilyl azide, tert-butyldimethylsilyl azide, etc.) and the like, preferably benzylamine And more preferably (R) -1-phenethylamine and (S) -1-phenethylamine.

Suitable solvents used for the reaction include alcohol solvents (methanol, ethanol, n-
Propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert-butyl alcohol, etc.), hydrocarbon solvents (benzene, toluene, hexane, xylene, pentane, hexapentane, cyclohexane, heptane, etc.), ether solvents (diethyl ether, 1 , 2
-Dimethoxyethane, tetrahydrofuran, diglyme, etc.), halogenated solvents (dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.), polar solvents (N, N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, water, etc.) These may be used alone or in combination of two or more. Preferred solvents are hydrocarbon solvents and water, more preferably toluene, heptane, water, and mixtures thereof.

Examples of the proton donor include catechols (catechol, 3,5-di-tert-butylcatechol, 3-methylcatechol, 4-nitrocatechol, 4-tert-butylcatechol, etc.), phenols [( R) -1,1′-Bi-2-naphthol, (S) —
1,1′-bi-2-naphthol, phenol, 2,2 ′
-Biphenols, etc.), organic acids (acetic acid, formic acid, propionic acid, oxalic acid, malonic acid, etc.), alcohols (diisopropyl tartrate, diethyl tartrate,
(+)-Trans-α, α ′-(2,2-dimethyl-
1,3-dioxolan-4,5-diyl) bis (diphenylmethanol), (−)-trans-α, α′-
(2,2-dimethyl-1,3-dioxolane-4,5-
Diyl) bis (diphenylmethanol), etc., preferably phenols, and more preferably (R) -1,1′-bi-2-naphthol, and (S)
-1,1'-bi-2-naphthol.

Examples of the Lewis acid include titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide,
Zinc iodide, magnesium chloride, alkoxytitanium (methoxytitanium, ethoxytitanium, titanium tetraisopropoxide, etc.), cerium chloride, samarium iodide,
Samarium chloride, europium chloride, ytterbium chloride, boron bromide, boron chloride, boron fluoride, aluminum chloride, aluminum bromide, alkyl aluminum (trimethyl aluminum, triethyl aluminum,
Trialkylaluminum, alkylaluminum chloride (diethylaluminum chloride, ethylaluminum dichloride, etc.), aluminum alkoxide (aluminum methoxide, aluminum ethoxide, aluminum isopropoxide, etc.), zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, Zirconium fluoride and the like can be mentioned, preferably alkoxytitanium, and more preferably titanium tetraisopropoxide.

Preferred examples of the mixed catalyst comprising a Lewis acid and a proton donor include a combination of optically active 1,1'-bi-2-naphthol and titanium tetraisopropoxide.

The reaction temperature is 0-100 ° C., preferably 20-50 ° C. The reaction time is about 10 to 50 hours, preferably about 15 to 24 hours.

Second Step (Isomerization of 7-Membered Ring to 5-Membered Ring) In this step, the compound [3 '] or the 7-membered ring portion of its enantiomer is more thermodynamically dissolved in an appropriate solvent in the presence of an acid. Stable 5
This is a reaction for obtaining a chiral compound [4] or an enantiomer thereof by isomerization into a membered ring structure.

Suitable solvents include, for example, hydrocarbon solvents (benzene, toluene, hexane, xylene, etc.),
Ether solvents (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, 2,2-dimethoxypropane, etc.), halogen solvents (dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.), ester solvents (Ethyl acetate, methyl acetate, butyl acetate, etc.), polar solvents (N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc.), and mixed solvents thereof, and the like, with acetone being preferred.

Examples of the acid include inorganic acids (sulfuric acid, hydrochloric acid, nitric acid, etc.), organic acids (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonic acid, benzenesulfonic acid, Camphorsulfonic acid and the like), preferably an organic acid, and more preferably methanesulfonic acid.

The reaction temperature is suitably from 0 to 100 ° C., preferably from 20 to 50 ° C. Reaction time is 1 to
Five hours is preferred.

Third Step (Deprotection of Amino Protecting Group) In this step, the compound [4] obtained in the second step is removed under a suitable condition by removing the substituents R ⁴ and / or R ⁵ on the nitrogen atom. A chiral compound [5] or an enantiomer thereof and a salt thereof.

The removal conditions are appropriately selected according to the type of the substituent on the nitrogen atom. For example, when R ⁴ is a 1-phenethyl group and R ⁵ is hydrogen, a hydrogen source is used in a suitable solvent in the presence of a suitable catalyst. The substituent on the nitrogen atom is removed by catalytic reduction in the presence. At this time, an appropriate acid may be added to accelerate the reaction and take out the product as a salt.

Suitable catalysts include, for example, palladium-based catalysts, platinum-based catalysts, rhodium-based catalysts and ruthenium-based catalysts, preferably palladium-based catalysts, and more preferably palladium-carbon.

The hydrogen source includes, for example, hydrogen gas, ammonium formate, formic acid, cyclohexadiene, etc., preferably hydrogen gas.

Suitable solvents include, for example, alcohol solvents (methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert-butyl alcohol, etc.) and hydrocarbon solvents (benzene, toluene, hexane, etc.). Xylene, etc.), ether solvents (diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, diglyme, etc.), halogen solvents (dichloromethane, chloroform, carbon tetrachloride,
1,2-dichloroethane, etc.), ester solvents (ethyl acetate, methyl acetate, butyl acetate, etc.), polar solvents (N, N
-Dimethylformamide, formic acid, acetic acid, water and the like), and a mixed solvent thereof, and the like, preferably an alcoholic solvent, and more preferably isopropyl alcohol.

Suitable acids include, for example, inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic acids (formic acid, acetic acid, benzoic acid, trifluoroacetic acid, maleic acid, tartaric acid, etc.), sulfonic acid (Methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), amino acids (arginine, asparagine, glutamic acid, etc.) and the like,
It is preferably an organic acid, and more preferably benzoic acid.

The reaction temperature is from 0 to 100 ° C.
Preferably, it is 20 to 60 ° C. The reaction time is 5-1
5 hours.

[0079]

The present invention will be specifically described below with reference to examples. However, the present invention is not limited by these examples. In addition, if an Example is shown by a flow, it is as follows.

[0080]

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(In the formula, Ph is a phenyl group, Me is a methyl group, and R ⁴ , R ⁵ and R ⁶ are the same as described above.)

Example 1 (Production of Compound [3 '] (Step 1')) (S) -1,1'-Bi-2-naphthol (1.89 g)
Heptane-toluene [9: 1 (volume ratio), 350 m
l] was added, and titanium tetraisopropoxide (Ti (OPr ⁱ ) ₄ , 1.95 ml) was added under a nitrogen stream, followed by stirring at room temperature for 10 minutes. Under stirring, (R) -1-phenethylamine (compound [2]; 85 ml) and water (0.
5 ml), and 4,4- obtained by known methods.
Dimethyl-3,5,8-trioxabicyclo- [5.
1.0] octane (compound [1 ']; 100 g) was sequentially added, and the mixture was stirred at 40 ° C for 24 hours. Toluene was poured into the reaction solution, and the mixture was stirred at 40 ° C. for 1 hour. Thereafter, the mixture was cooled to 10 ° C. or lower over 1 hour, and further stirred for 1 hour. The crystals in the reaction solution are collected by filtration, washed with heptane-toluene [2: 1 (volume ratio)], and then (5R, 6S) -2,2-dimethyl-6-[(R) -1-phenethylamino] -1,3-dioxepan-5-ol (compound [3 ′]; 159 g,
Yield 91%) as yellow crystals. mp.108-109 ° C δ 1H-NMR (CDCl3,300MHz): 7.33-7.22 (m, 5H), 3.95 (q,
1H, J = 6.5Hz), 3.75 (dd, 1H, J = 1.8,12.1Hz), 3.74 (dd,
1H, J = 2.0,12.5Hz), 3.52 (dd, 1H, J = 5.5,12.5Hz), 3.48
(ddd, 1H, J = 0.5,5.9,12.1Hz), 3.37 (dt, 1H, J = 1.4,5.6Hz),
2.44 (brs, 1H), 2.34 (dt, 1H, J = 1.7,5.5Hz), 1.34 (d, 3H
, J = 6.5Hz), 1.34 (s, 3H), 1.31 (s, 3H) .IR (KBr): 3406, 2590, 1452, 1374, 1219, 1072, 1052,
841, 758, 696 cm -1 [α] D25 +91.0 ゜ (c1.00, MeOH)

Example 2 (S) -1,1′-Bi-2-naphthol (426 mg)
(60 ml) was added to the mixture, and titanium tetraisopropoxide [Ti (OPr ⁱ ) ₄ , 4
39 μl] and stirred at room temperature for 10 minutes. Under stirring,
Benzylamine (21.6 ml), water (225 μl),
And 4,4-dimethyl- obtained by a known method.
3,5,8-Trioxabicyclo [5.1.0] octane (compound [1 ′]; 30 g) was sequentially added, and the mixture was stirred at 40 ° C. for 24 hours. 1N NaOH (30 ml) was added to the reaction solution.
After refluxing (90 ° C.) for 1 hour, the aqueous layer was removed at 50 ° C., and activated carbon (0.9 g) was added to the obtained organic layer, followed by azeotropic dehydration at normal pressure. After filtering off the activated carbon, the filtrate was concentrated under reduced pressure to give crude (5R, 6S) -2,2-dimethyl-6-benzylamino-1,3-dioxepane-5-.
All (50 g, 88% ee) was obtained as a yellow oil,
Used for the next step without purification. Data was obtained from some of the products generated by column chromatography. δ 1H-NMR (CDCl3, 300MHz): 7.33-7.23 (m, 5H), 3.92 (d,
1H, J = 13.2Hz), 3.78 (d, 1H, J = 13.2Hz), 3.80-3.76 (m, 2
H), 3.59-3.49 (m, 3H), 2.56 (m, 1H), 2.04 (brs, 1H), 1.3
3 (s, 3H), 1.32 (s, 3H) .IR (CHCl3): 3416, 2941, 1454, 1372, 1219, 1159, 10
47, 842, 739,699 cm -1 [α] D + 50.6 ゜ (c0.5, MeOH)

Example 3 As in Example 2, (S) -1,1′-bi-2-naphthol (19.9 mg), toluene (2 ml), titanium tetraisopropoxide [Ti (OPr ⁱ ) ₄ , 10μ
l], diphenylmethylamine (1.2 ml), water (1
0 μl) and 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane (compound [1 ′]; 1.0 g), and purified by column chromatography. As a result, (5R, 6S) -2,
2-dimethyl-6-benzhydrylamino-1,3-dioxepan-5-ol (2.21 g, 97% yield, 9
0% ee) was obtained as a colorless wax. δ 1H-NMR (CDCl3, 300MHz): 7.44-7.17 (m, 10H), 5.00
(s, 1H), 4.02 (ddd, 1H, J = 3.0,14.4,17.1Hz), 3.82 (d, 1H,
J = 11.4Hz), 3.77 (dd, 1H, J = 1.8,13.2Hz), 3.60-3.51 (m, 3
H), 2.54 (dt, 1H, J = 1.2,4.5), 1.82 (brs, 1H), 1.32 (s, 3
H), 1.31 (s, 3H) .IR (CHCl3) 3345, 2954, 1450, 1373, 1218, 1156, 105
0, 848, 744, 698 cm -1 [α] D + 42.8 ゜ (c0.5, MeOH)

Example 4 3,5-di-tert-butylcatechol (617 m
g), heptane (2 ml) was added thereto, and titanium tetraisopropoxide [Ti (OPr ⁱ ) ₄ ,
818 μl] and stirred at room temperature for 20 minutes. Under stirring, (R) -1-phenethylamine (1.79 ml),
Water (20 μl) and 4,4-dimethyl-3,5,8-trioxabicyclo [5.1.0] octane obtained by a known method (compound [1 ′]; 2.0 g)
Were sequentially added, and the mixture was stirred at room temperature for 20 hours. Heptane (4.6 ml) was added, the mixture was stirred for 1 hour under ice-cooling, and the resulting crystals were collected by filtration to give (5R, 6S) -2,2.
-Dimethyl-6-[(R) -1-phenethylamino]-
1,3-dioxepan-5-ol (compound [3 ′];
2.14 g, yield 57%).

Example 5 In the same manner as in Example 2, (S) -1,1'-bi-2-
Naphthol (9.9 mg), heptane-toluene [9:
1 (volume ratio), 3.5 ml), titanium tetraisopropoxide [Ti (OPr ⁱ ) ₄ , 10.2 μl],
(S) -1-phenethylamine (0.85 ml), water (20 μl), and 4,4-dimethyl-3,5,8-
By using trioxabicyclo [5.1.0] octane (compound [1 ′]; 1.0 g), crude (5R,
6S) -2,2-Dimethyl-6-[(S) -1-phenethylamine] -1,3-dioxepan-5-ol (1.8 g, 97.6% de) was obtained as a yellow oil.

Example 6 In the same manner as in Example 2, (S) -1,1'-bi-2-
Naphthol (284 mg), heptane-toluene [9:
1 (volume ratio), 105 ml), titanium tetraisopropoxide [Ti (OPr ⁱ ) ₄ , 293 μl],
(±) -1-phenethylamine (25.5 ml), water (300 μl), and 4,4-dimethyl-3,5,8
By using trioxabicyclo [5.1.0] octane (compound [1 ']; 30 g), crude (5R, 6
S) -2,2-Dimethyl-6- (1-phenethylamino) -1,3-dioxepan-5-ol (55 g,
1: 1 diastereomer mixture) was obtained as a yellow oil and used in the next step without purification.

Example 7 (Production of compound [4] (second step)) (5R, 6S) -2,2-dimethyl-6-[(R) -1-phenethylamino] obtained in Example 1 After acetone (200 ml) and 2,2-dimethoxypropane (4.63 ml) were added to -1,3-dioxepan-5-ol (100.0 g), the mixture was cooled in an ice bath under a nitrogen stream. Under stirring, methanesulfonic acid (29.3 ml) was added dropwise so as to keep the internal temperature at 25 ° C or lower. After washing with acetone (1.0 ml), the ice bath was removed and the mixture was stirred at room temperature. After 3 hours, potassium carbonate (62.
5 g) / water (300 ml) solution and add
After stirring for minutes, the reaction solution was extracted with toluene. The organic layer was concentrated under reduced pressure to give crude (2S) -2-[(R) -1-
Phenethylamino] -2-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol (compound [4]; 107.4 g) was obtained as a colorless oil.
Used for the next step without purification. δ 1H-NMR (CDCl3, 300MHz): 7.34-7.20 (m, 5H), 4.15 (q,
1H, J = 7.0Hz), 3.97 (dd, 1H, J = 1.0,7.0Hz), 3.87 (q, 1H, J =
(7.0Hz), 3.74-3.69 (m, 2H), 3.48 (dd, 1H, J = 2.0, 11.0Hz),
2.45 (m, 1H), 2.34 (brs, 1H), 1.38 (d, 3H, J = 7.0Hz), 1.33 (s, 3H), 1.31 (s, 3H).

Example 8 In the same manner as in Example 7, the crude (5) obtained in Example 2 was obtained.
R, 6S) -2,2-dimethyl-6-benzylamino-
1,3-dioxepan-5-ol (50 g, 88% e
e), acetone (100 ml), 2,2-dimethoxypropane (2.4 ml), methanesulfonic acid (15.4 m)
l) and potassium carbonate (32.9 g) / water (150
ml) solution to give crude (2S) -2-benzylamino-2-[(4R) -2,2-dimethyl-1,
[3-Dioxolan-4-yl] ethanol (compound [4]; 52 g) was obtained as a yellow oily substance and used in the next step without purification. δ 1H-NMR (CDCl3, 300MHz): 7.34-7.26 (m, 5H), 4.20 (q,
1H, J = 6.6,13.3Hz), 4.05 (t, 1H, J = 7.8Hz), 3.90 (d, 1H, J = 1
(3.3Hz), 3.80-3.69 (m, 3H), 3.36 (d, 1H, J = 11.3Hz), 2.70
(brt, 1H, J = 3.6Hz), 2.22 (brs, 1H), 1.38 (s, 3H), 1.34 (s,
3H).

Example 9 In the same manner as in Example 7, the crude (5) obtained in Example 6 was obtained.
R, 6S) -2,2-dimethyl-6- (1-phenethylamino) -1,3-dioxepan-5-ol (55
g, a 1: 1 mixture of diastereomers), acetone (1
00 ml), 2,2-dimethoxypropane (2.4 m
l), methanesulfonic acid (15.4 ml), potassium carbonate (32.9 g) / water (150 ml) solution to give crude (2S) -2- (1-phenethylamino)-
2-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol (compound [4]; 57 g,
1: 1 diastereomer mixture) was obtained as a yellow oil and used in the next step without purification.

Example 10 (Production of compound [5] (third step)) 5% palladium carbon (10.0 g) was suspended in an isopropyl alcohol solution, and the crude (2S)-obtained in Example 7 was suspended.
2-[(R) -1-phenethylamino] -2-[(4
R) -2,2-Dimethyl-1,3-dioxolan-4-
Yl] ethanol (107.4 g) and benzoic acid (46.0 g). The mixture was stirred at 60 ° C. under a stream of hydrogen for 9 hours. Thereafter, the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and isopropyl alcohol was added to the residue (53%).
ml) and stirred at 70 ° C. to dissolve the crystals. N at 65 ° C
-Heptane (526 ml) was added dropwise, and the mixture was cooled to 5 ° C or lower, and further stirred for 1 hour. After filtration and washing with a 1% by weight isopropyl alcohol / n-heptane solution,
By drying, (2S) -2-amino-2-[(4
R) -2,2-Dimethyl-1,3-dioxolan-4-
[Il] ethanol benzoate (90.8 g, yield 85% from compound [3 ']) was obtained as colorless crystals. mp.112-113 ° C δ 1H-NMR (CDCl3,300MHz): 7.99 (m, 2H), 7.44 (m, 1H),
7.34 (m, 2H), 6.33 (brs, 3H), 4.18 (td, 1H, J = 6.2,7.7Hz),
4.01 (dd, 1H, J = 2.2,8.4Hz), 3.78 (dd, 1H, J = 3.7,12.5Hz),
3.70 (dd, 1H, J = 5.9,8.8Hz), 3.63 (dd, 1H, J = 6.2,12.5Hz),
1.32 (s, 3H), 1.24 (s, 3H) .IR (CHCl3): 2983, 1610, 1517, 1393, 1214, 1080, 104
8, 849, 711, 377 cm -1 (α) D20 +2.5 ゜ (c1.00, CHCl3).

Example 11 In the same manner as in Example 10, 5% palladium on carbon (5.
0g), the crude (2S) -2-benzylamino-2-[(4R) -2,2-dimethyl-1,3- obtained in Example 8.
Dioxolan-4-yl] ethanol (compound [4];
52g) and benzoic acid (24.2 g) to give (2S) -2-amino-2-[(4R) -2,
2-Dimethyl-1,3-dioxolan-4-yl] ethanol benzoate (47.2 g, yield 84% from compound [3 '], 89% ee) was obtained as yellow crystals. (Α) D + 2.2 ° (c1.00, CHCl3).

Example 12 In the same manner as in Example 10, 5% palladium on carbon (5.
0g), the crude (2S) -2- (1-phenethylamino) -2-[(4R) -2,2-dimethyl-1,3-dioxolan-4-yl] ethanol obtained in Example 9 (compound [4]; 57g, a mixture of 1: 1 diastereomers) and benzoic acid (24.2g) to give (2S) -2-amino-2-[(4R) -2,2-
Dimethyl-1,3-dioxolan-4-yl] ethanol benzoate (46.0 g, yield 8 from compound [3 ']
2%, 90% ee) were obtained as yellow crystals. (Α) D +2.3 ゜ (c1.00, CHCl3).

The yield of compound [3 '], which did not exceed 40% in the prior art, was improved to 40% or more (57 to 97%) in Examples 1 to 4. The reaction is also carried out at room temperature to 40.
It proceeded under a mild temperature condition of ° C. Furthermore, by converting the compound [5] into a benzoate, it was possible to obtain a crystal in good yield (82-85% yield from the compound [3 ']).

[0095]

As is apparent from the above, according to the present invention, an intermediate compound of a desired HIV protease inhibitor can be produced very efficiently and stereoselectively as compared with the conventional method. Further, the method for synthesizing the stereoselective optically active amino alcohol according to the present invention is a very useful method that can be used not only for producing the present intermediate compound but also for producing various compounds.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Katsuichi Sagawa, 1-1, Murasakicho, Takatsuki-shi, Osaka Japan Tobacco Inc. Pharmaceutical Research Institute, Inc. (56) References WO 97/119938 (WO, A1) German Patent Application 4333686 (DE, A1) (58) Fields investigated (Int. Cl. ⁷ , DB Name) C07D 321/00-321/06 C07D 317/00-317/28 CAPLUS (STN) REGISTRY (STN)

Claims (10)

(57) [Claims] 1. A compound of the general formula [1] (Wherein, R ¹ , R ² and R ³ may be the same or different and each may be a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group or an optionally substituted An aralkyl group, or R ¹ and R ¹ , or R ² and R ^{3 of} each other may form a ring which may be substituted together), In the presence of a mixed catalyst comprising a Lewis acid and a proton donor, a compound of the general formula [2] (Wherein, R ⁴ and R ⁵ may be the same or different, and each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, Or an acyl group,
Or R ⁴ and R ⁵ may be combined with an adjacent nitrogen atom to form an optionally substituted ring, or R ⁴ and R ⁵ are united to contain an adjacent nitrogen atom. Which may form an imide group or an azido group, and R ⁶ is a hydrogen atom or a silyl group). (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as described above), a method for producing an optically active amino alcohol compound, an enantiomer thereof, or a salt thereof. 2. A compound of the general formula [1 '] (Wherein R ² ′ and R ³ ′ may be the same or different and are each a hydrogen atom, an optionally substituted lower alkyl group or an aryl group, or R ² ′ and R ³ ′ May form a cycloalkyl ring together with an adjacent carbon atom) in the presence of a mixed catalyst comprising a Lewis acid and a proton donor in the presence of a mixed catalyst of the general formula [2] Formula 5 (Wherein R ⁴ , R ⁵ and R ⁶ are the same as described above), characterized by reacting a compound represented by the general formula [3 ′]: (Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are the same as described above), an enantiomer thereof or a salt thereof is obtained. . 3. A compound of the general formula [1 ′] (Wherein R ² ′ and R ³ ′ are the same as defined above) in the presence of a mixed catalyst comprising a Lewis acid and a proton donor in a mesoepoxide compound represented by the general formula [2] (Wherein R ⁴ , R ⁵ and R ⁶ are the same as described above), and reacted with a compound of the general formula [3 ′]. (Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are the same as described above), an enantiomer thereof or a salt thereof, which is prepared in the presence of an acid. A compound represented by the general formula [4]: (Wherein R ² ′, R ³ ′, R ⁴ and R ⁵ are the same as described above) or a method for producing an optically active 1,3-dioxolan compound or an enantiomer thereof. 4. A compound of the general formula [1 '](Where R^Two'And R^Three'Is the same as above)
Acid and proton donation to mesoepoxide compounds
Formula (2) in the presence of a mixed catalyst consisting of(Where R^Four, R^FiveAnd R⁶Is the same as above)
The compound represented by the general formula [3 '](Where R^Two', R^Three', R^FourAnd R^FiveIs the same as above
Optically active amino alcohol compound represented by
Enantiomers or their salts, which are
Formula [4](Where R^Two', R^Three', R^FourAnd R^FiveIs the same as above
Optically active 1,3-dioxolane compounds represented by
Or its enantiomer, followed by a substituent R on the nitrogen atom ^FourAnd
And / or R^FiveA general formula characterized by desorbing
[5](Where R^Two'And R^Three'Is the same as above)
Active aminoalcohol having 1,3-dioxolane
And a method for producing the enantiomers, enantiomers or salts thereof. 5. The proton donor is selected from (R) -1,1′-bi-2-naphthol, (S) -1,1′-bi-2-naphthol, catechol, and 4-tert-butylcatechol. Wherein the Lewis acid is titanium tetraisopropoxide, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, aluminum bromide, alkyl aluminum, At least one selected from alkylaluminum chloride, aluminum alkoxide, magnesium chloride, zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride, boron bromide, boron chloride, and boron fluoride
The method according to claim 1 or 2, which is a seed. 6. The proton donor is selected from (R) -1,1′-bi-2-naphthol, (S) -1,1′-bi-2-naphthol, catechol, and 4-tert-butylcatechol. Wherein the Lewis acid is titanium tetraisopropoxide, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, aluminum bromide, alkyl aluminum, At least one selected from alkylaluminum chloride, aluminum alkoxide, magnesium chloride, zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride, boron bromide, boron chloride, and boron fluoride
4. The method according to claim 3, which is a seed. 7. The proton donor is selected from (R) -1,1′-bi-2-naphthol, (S) -1,1′-bi-2-naphthol, catechol, and 4-tert-butylcatechol. Wherein the Lewis acid is titanium tetraisopropoxide, titanium tetrachloride, tin chloride, copper chloride, iron chloride, zinc chloride, zinc bromide, zinc iodide, aluminum chloride, aluminum bromide, alkyl aluminum, At least one selected from alkylaluminum chloride, aluminum alkoxide, magnesium chloride, zirconocene, zirconium tetrapropoxide, zirconium chloride, zirconium sulfate, zirconium fluoride, boron bromide, boron chloride, and boron fluoride
5. The method according to claim 4, which is a seed. 8. The proton donor is (R) -1,1′-bi-2-naphthol or (S) -1,1′-bi-2-naphthol, and the Lewis acid is titanium tetraisopropoxide. The production method according to claim 1 or 2, wherein 9. The proton donor is (R) -1,1′-bi-2-naphthol or (S) -1,1′-bi-2-naphthol, and the Lewis acid is titanium tetraisopropoxide. The method according to claim 3. 10. The method according to claim 1, wherein the proton donor is (R) -1,1′-
Bi-2-naphthol or (S) -1,1′-bi-2-
The production method according to claim 4, wherein the production method is naphthol, and the Lewis acid is titanium tetraisopropoxide.