WO2002004401A1

WO2002004401A1 - PROCESS FOR THE PREPARATION OF β-AMINO ALCOHOLS IN SYN CONFIGURATION

Info

Publication number: WO2002004401A1
Application number: PCT/JP2001/005941
Authority: WO
Inventors: Tsutomu Inoue; Eiji Katayama; Hirohito Ooka; Daisuke Sato
Original assignee: Nippon Soda Co., Ltd.
Priority date: 2000-07-10
Filing date: 2001-07-09
Publication date: 2002-01-17
Also published as: JP5462899B2; JP2012116853A; JP5042438B2

Abstract

A process for the preparation of β-amino alcohols in syn configuration as represented by the general formula (2): RaC*H(OH)-C*H(Rb)-Rc [wherein Ra and Rc are each optionally substituted alkyl or the like; Rb is a group selected from among those represented by the formulae (3) to (6): (3)R1CO(R2)N-, (4)R1CO(R1'CO)N-, (5)R1SO2(R2)N-, and (6)R1R2N- (wherein R?1, R1', and R2¿ are each optionally substituted alkyl or the like); and C* represents an asymmetric carbon atom], which comprises reacting an a-aminocarbonyl compound of the general formula (1): R¿a?-CO-CH(Rb)-Rc with hydrogen or a hydrogen donor in the presence of a transition metal compound and a base.

Description

Specification

Method for producing S-amino alcohols having a syn configuration

The present invention uses a racemic diaminocarbonyl compound as a starting material to produce S-amino alcohols having a syn configuration useful as a synthetic intermediate for pharmaceuticals and agrochemicals, with high yield and high diastereoselectivity. Further, it relates to a technology for selectively manufacturing high-tech Nancho. Background technology:

An object of the present invention is to provide a practical method for producing optically active 3-amino alcohols having a syn configuration by using a readily available racemic aminopulponyl compound as a starting material.

The following methods are known as methods for producing optically active amino alcohols.

① Method by reaction of α- (substituted amino) aldehyde with metal reagent

Japanese Patent Laid-Open No. 50-137911 * (a n t i / s i n = 4.3 to 2.5 / 1)

J. Org.Chem., 55, 1439 (1990).

② Optically active method by diastereoselective reduction of amino ketone

Te t r ah e do r on. Le t t., 35, 547 (1994)

③ Optically active method by diastereoselective reduction of α-alkoxyimine

J. Chem. S o C em. Commun., 746 (1987)

方法 Method by diastereoselective hydrogenation of α-amino-S-keto acid

J. Am. Chem. Soc., Ill, 9134 (1989)

J. Am. Chem. Soc, 115, 144 (1993)

不 Asymmetric reduction of ketoxime

JP 10-45688

Of the above-mentioned conventional methods, methods (1) and (2) have a high anti-isomer production rate and are not suitable for the production of general syn-isomer. The methods (2) and (3) are complicated because the raw material of the optically active substance must be manufactured in advance, and the method (2) requires a substrate containing a functional group such as a lipoxyl group in the molecule. High stereo stereo selection Although it is possible to produce an optically active amino alcohol by its nature, it is difficult to produce an optically active form of a simple amino alcohol having no such functional group in the molecule.

Also, a method of obtaining an alcohol from a carbonyl compound using a hydrogenation catalyst is known, but α

Am. Chem. Soc., 1995, 117, 2675-2676), it is not known whether / 3-amino alcohols can be obtained from amino carbonyl compounds. It was not known whether the isomer or anti-isomer was produced advantageously.

For this reason, it has been desired to develop a highly versatile, high-yield, and highly selective production method for producing ^ -amino alcohols having a syn configuration from a racemic material as a raw material. . In the present invention, a syn isomer (a compound having a syn configuration), which means one of the diastereoisomers, means that when a carbon chain is placed in a zigzag left and right direction with a carbon chain as a main chain, the carbon is substituted in the up and down direction, respectively. Having a steric configuration such that the amino group and the hydroxyl group face the same plane. DISCLOSURE OF THE INVENTION:

The present inventors have conducted intensive studies on conditions for synthesizing syn isomers with superiority, and as a result, have found that a substituent of an amino group has a great effect on diastereoselectivity, and thus completed the present invention.

That is, the present invention provides the following general formula (1)

Ra-CO-CH (Rb)-R c (1)

[In the formula, Ra and Rc are the same or different and each may be an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an alkenyl which may have a substituent. And a aralkyl group which may have a substituent, an aryl group which may have a substituent, and an aryloxy group which may have a substituent, respectively.

Rb represents any one of the following general formulas (3), (4), (5), and (6).

(3) R 1 CO (R2) N—

(4) RICO (R 1 'CO) N—

(5) R 1 S 0 ₂ (R2) N—

(6) R 1 R2N-

(Wherein, Rl, Rl 'and R2 are the same or different and each represents a 7] elementary atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, May have Cycloalkyl group, cycloalkyl group optionally having substituent (s), alkenyl group optionally having substituent (s), aralkyl group optionally having substituent (s), optionally having substituent (s) An aryloxy group, an aryl group which may have a substituent or an aryloxy group which may have a substituent, and R1 and R2 or R1 and R1 ′ are bonded to form 5 to 8 A nitrogen-containing hetero ring of the member may be formed.

However, when R 2 is a hydrogen atom, R 1 is not an alkoxy group, a cycloalkoxy group, an aryloxy group, or an aralkyloxy group. )]

Characterized in that hydrogen or a compound that donates hydrogen is allowed to act on a racemic α-aminocarbonyl compound represented by the following formula (2) Ra-C * H (OH) -C * H (Rb) one Rc (2)

(In the formula, R a, R b and R c have the same meanings as described above, and C * represents an asymmetric carbon atom.)

This is a method for producing ^ -amino alcohols having a syn configuration represented by:

In the method for producing a ^ -amino alcohol having a syn configuration according to the present invention, the transition metal compound is preferably a homogeneous hydrogenation catalyst.

The homogeneous hydrogenation catalyst is more preferably represented by the following general formula (7)

Ma XYP xmNx n (7)

(In the formula, Ma represents a Group VIII metal atom, X and Y are the same or different and represent a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxyl group, and Px represents a phosphine ligand. , Nx represents an amine ligand, m and n represent 0 or an integer of 1 to 4).

In the method for producing / 3-amino alcohols having a syn configuration according to the present invention, the base may be represented by the following general formula (8):

Mbm'Zn '(8)

(Wherein, Mb represents an alkali metal or alkaline earth metal, Z is represents hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a mercapto group, an aromatic group, or C0 ₃ group a, m ', n 'Represents an integer of from 1 to 3.).

Further, by using an optically active transition metal compound in the present invention, an optically active / 3-amino alcohol having a syn configuration can be obtained. As the optically active transition metal compound, An optically active transition metal compound in which both P 化合物 and Nx in the general formula (7) are optically active, or one of them is optically active can be used.

In the present invention, a racemic S-amino alcohol having a syn configuration can be obtained by using an optically inactive transition metal compound. As the optically inactive transition metal complex, an optically inactive transition metal complex in which both Px and Nx in the general formula (7) are optically inactive can be used. When both PX and Nx are optically inactive, it means that these ligands are racemic, or that they are ligands having no asymmetric center. According to the present invention, an optically active amino alcohol having a syn configuration represented by the general formula (2) having a syn configuration useful as a synthetic intermediate for pharmaceutical and agricultural chemicals can be obtained with high selectivity and high yield. Can be manufactured to rate.

Hereinafter, the present invention will be described in detail. The present invention is characterized in that, as described above, hydrogen or a compound that provides hydrogen is allowed to act on the aminocarbonyl compound represented by the general formula (1) in the presence of a transition metal compound and a base. This is a method for producing 3-amino alcohols having a syn configuration represented by the general formula (2).

The starting compound of the present invention is a compound represented by the following general formula (1).

Ra-CO-CH (Rb) -R c (1)

In the formula, Ra and Rc are the same or different and each may be a linear or branched alkyl group which may have a substituent, a linear or branched alkenyl group which may have a substituent, or a substituent. A cycloalkyl group which may have a substituent, an aralkyl group which may have a substituent or an aryl group which may have a substituent.

In the general formula (1), Ra or Rc may have a substituent (linear or branched alkyl group, linear or branched alkenyl group, cycloalkyl group, aralkyl group or aryl group). There are no particular restrictions on the substitution position, the type of substituent, the number of substituents, and the like, as long as the substituent does not inhibit the reaction.

Such substituents include, for example, hydroxy, carboxyl, amino,

Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, 1; -butyl, pentyl, and hexyl;

Alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, etc. Alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl group, and a phenyl group which may have a substituent at any position of the benzene ring ,

A naphthyl group such as 1-naphthyl or 2-naphthyl group which may have a substituent at any position of the naphthalene ring;

Furan, pyran, dioxolan, dioxane, pyrrol, thiophan, imidazole, pyrazole, oxazole, isoxoxazole, triazole, thiazole, isothiazole, pyridine, pyridazine, pyrazine, benzoimidazole, benzopyrazole, benzothiazole, quinoline, etc. A heterocyclic group (these groups may have a substituent at any position); and

Examples include halogen atoms such as fluorine, chlorine, and bromine.

An alkyl group of a linear or branched alkyl group which may have the substituent may be methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-Examples include alkyl groups having 1 to 20 carbon atoms, such as pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, octadecyl, and icosyl groups.

Examples of the alkenyl group of the linear or branched alkenyl group which may have a substituent include vinyl, 1-propenyl, 2-propenyl, 1-isopropenyl, 1-butenyl, and 1-isopropyl. Examples thereof include alkenyl groups having 2 to 20 carbon atoms such as propenyl, 2-butenyl, 3-butenyl, 1,3-butenyl, 11-pentenyl, 2_pentenyl, 3-pentenyl, and 2-hexene. it can.

Examples of the cycloalkyl group of the optionally substituted cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups. .

Examples of the aralkyl group of the aralkyl group which may have a substituent include, for example, aralkyl groups having 7 to 20 carbon atoms such as benzyl, α-methylbenzyl, α, <¾-dimethylbenzyl and α-ethylbenzyl groups. Can be mentioned.

Examples of the aryl group of the aryl group which may have a substituent include aromatic hydrocarbon groups such as phenyl, 1-naphthyl and 2-naphthyl groups; Oxygen-containing heterocyclic groups such as furanyl, bilanyl, and dioxolanyl;

I-containing heterocyclic groups such as chenyl,

Piparyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, thizolyl, isothiazolyl, pyridyl, pyradadyl, pyrazinyl, benzimidazolyl, benzpyrazolyl, benzothiazolyl, quinolinolole, anthranyl, indolyl, indolyl, etc. Alternatively, an unsaturated nitrogen-containing heterocyclic group can be exemplified.

Rb represents any one of the following general formulas (3), (4), (5), and (6).

(3) Rl CO (R2) N—

(4) RI CO (R 1 'CO) N-

(5) R 1 S 0 ₂ (R2) N—

(6) R1 2N- wherein R 1, R Γ and R 2 are the same or different and each have a hydrogen atom, a formyl group, an alkyl group which may have a substituent, or a substituent. An optionally substituted alkoxy group, a cycloalkyl group optionally having a substituent, a cycloalkoxy group optionally having a substituent, an alkenyl group optionally having a substituent, Aralkyl group, an optionally substituted aralkyl group, a substituted or unsubstituted aryl group or an optionally substituted aralkyl group; R2 or R1 and R1 ′ may combine to form a 5- to 8-membered nitrogen-containing heterocycle.

However, when R 2 is a hydrogen atom, R 1 is not an alkoxy group, a cycloalkoxy group, an aryloxy group, or an aralkyloxy group.

When R 2 is a hydrogen atom, and R 1 is an alkoxy group, a cycloalkoxy group, an aryloxy group, or an aralkyloxy group, 3-amino alcohol having an anti-steric configuration which is not the object compound of the present invention is dominant. Because it is generated.

In the case where Rb is the general formula (3) RI CO (R2) N—, particularly, Rl and R2 are an alkyl group which may have a substituent, an alkoxy group which may have a substituent, and a substituent A cycloalkyl group optionally having a substituent, a cycloalkoxy group optionally having a substituent, an alkenyl group optionally having a substituent, an aralkyl group optionally having a substituent, a substituent R 1 and R 2 are bonded to each other when R 1 and R 2 are a aralkyloxy group which may have a substituent, an aryl group which may have a substituent or an aryl group which may have a substituent, or 5 To 8-member nitrogen containing When a terrorist ring is formed, the selectivity of the syn stereoisomer is high, which is preferable.

R 1, R 1 ′ and R 2 in R b are specifically a hydrogen atom,

Methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl, heptyl, etc.

~ 10 alkyl groups,

A cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

Phenyl group, 2-methylphenyl, 2-ethylphenyl, 2-isopropylphenyl, 2-t-butylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-vinylphenyl, 3-methylphenyl, 3-ethylphenyl, 3- ^ Tso Propylphenyl, 3-methoxyphenyl, 3-chlorophenyl, 3-vinylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-isopropylisopropyl, 4-t-butylphenyl, 4-vinylphenyl, cumenyl, mesityl , An xylyl group, an aryl group which may have a substituent such as 1-naphthyl, 2-naphthyl, anthryl, phananthryl, indenyl group,

Aralkyl groups having 7 to 20 carbon atoms which may have a substituent such as benzyl, 4-cyclobenzyl, and α-methylbenzyl;

Alkenyl groups having 2 to 10 carbon atoms, such as vinyl, aryl, and crotyl groups;

Carbon number of methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, t-pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, heptyloxy, etc. Examples thereof include an alkoxy group having 1 to 10 or a cycloalkoxy group having 3 to 8 carbon atoms.

Phenoxy group, 2-methyl phenoxy, 2-ethyl phenoxy, 2-isopropyl phenoxy, 2_t-butyl phenoxy, 2-methoxy phenoxy, 2-chloro phenoxy, 2-vinyl phenoxy, 3-methyl phenyl, 3-ethyl phenoxy, 3-isopropyl Phenoxy, 3-methoxyphenoxy, 3-chlorophenoxy, 3-vinylphenoxy, 4-methylphenoxy, 4-ethylphenoxy, 4 ^ T-sopropylphenoxy, 41-t-butylphenyloxy, 4-vinylphenoxy, Aralkyl groups such as 1-naphthoxy, 2-naphthoxy and other aryloxy groups, benzyloxy, 4-chlorobenzyloxy and 4-methylbenzyloxy groups And an aralkyloxy group having 7 to 20 carbon atoms which may have a substituent such as an oxy group.

Examples of the heterocycle in the case where 11 and 11 'or R1 and R2 are bonded to form a nitrogen-containing heterocycle include succinimid, maleimid, phthalimid, and 1,2-cyclohexanecarboxy. And imids such as amide, 2,4,6-trioxopiperidine, α-pyridone and the like.

More specific examples of R b include acetylamino, propionylamino, propylcarbonylamino, benzoylamino, 4-methylbenzoylamino, 2-methylbenzoylamino, 3-methoxybenzoylamino, and 2-methoxybenzoylamino. 4-Aminamino groups such as methoxybenzoylamino groups,

Diacetylamino groups such as diacetylamino, dibenzoylamino group,

N—Acetyl N—Methylamino, N—Benzoyl N—Methylamino, N—Acetyl-N—Ethylamino, N—Benzoru N—Ethylamino, N—Acetylino N—Benzylamino, N N-alkyl N —acylaamino groups, such as —benzoyl-N-benzylamino, 4 —methylbenzoylmethylamino group, etc.

N-acetyl-N-phenylamino, N-acetyl-N-4-methylphenylamino, N-acetyl-N-2-chlorophenylamino, N-acetyl-N-2,4-dichlorophenylamino, N-benzyl N- such as N-phenylamino, N-benzyl-1-N-4-methylphenylamino, N-benzylyl N-2-chlorophenylamino, N-benzyl-N-2,4-dichlorophenylamino Aryl-N-acylamino group,

N-Methoxycarbonyl-N-methylamino, N-ethoxycarbone N-methylamino, N-methoxycarbonyl-N-ethylamino, N-ethoxycarbone N-Ethylamino, N-Propoxycarbone N- N-alkoxycarbonyl-N-alkylamino groups such as propylamino, N-isopropoxycarbonyl N-methylamino, N-butoxycarbonyl N-ethylamino, Nt-butoxycarbonyl N-butoxyamino group,

N-Methoxycarbonyl N-methylamino, N-ethoxycarbonyl-1-N-methylamino, N-methoxycarbonyl-1-N-ethylamino, N-ethoxycarbonyl-2-N-ethylamino, N-propoxycarbonyl-N-propylamino, N-isopropoxycarbonyl N-methylamino, N-butoxycarbonyl N-ethylamino, N-t-butoxy N-alkoxycarbonyl N-alkylamino groups such as ponyl-N-methylamino group, Nt-butoxycarbonyl N-butoxyamino group, etc.

N-Methoxycarbonyl-1-N-phenylamino, N-ethoxycarbonyl-N-phenylamino, N-propoxycarbonyl-N-phenylamino, N-isopropoxycarbonyl-N-phenylamino, N-butoxycarbonyl-N-phenylamino N-alkoxycarbonyl-N-arylamino groups such as, N_t-butoxycarbonyl-N-phenylamino group,

N-methyl-methylsulfonylamino, N-ethyl-methylsulfonylamino, N-propyl-methyl-sulfonylamino, N-isopropyl-methylsulfonylamino, N-benzyl-methylsulfonylamino, N- Butyl monomethylsulfonylamino, N-methylethylsulfonylamino, N-ethylethylethylsulfonylamino, N-methylpropylpropylsulfonylamino, N-ethylpropylpropylsulfonylamino, N-methyl-isopropylsulfonylamino N-ethyl-isopropylsulfonylamino, N-methyl-butylsulfonylamino, N-ethyl-butylsulfonylamino, N-methyl-tert-butylsulfonylamino, N-ethyl-tert-butylsulfonylamino, N —Methyl-phenylsulfonylamino, N— Lamino, N-benzyl-phenylsulfonylamino, N-methyl-1-methylphenylsulfonylamino, N-benzyl-4-methylphenylsulfonylamino, N-ethyl-1-chlorophenylsulfonylamino An N-alkyl-alkylsulfonylamino group or an N-alkylmono-substituted phenylsulfonylamino group such as a mino, N-methyl-1,2,4-dichlorophenylsulfonylamino group,

N-Phenyl-methylsulfonylamino, N-Phenyl-ethylsulfonylamino, N-Phenyl-propylsulfonylamino, N-Phenyl-isopropylsulfonylamino, N-Phenyl-butylsulfonylamino, N —Phenyl-t-butylsulfonylamino, N-phenyl-1-phenylsulfonylamino, N-phenyl-4-methylphenylsulfonylamino, N-phenyl-2-chlorophenylsulfonylamino, N-phenyl2, N-yl-alkylsulfonylamino group or N-aryl-substituted phenylsulfonylamino group, such as 4-dichlorophenylsulfonylamino group,

Succinimidyl, maleimidyl, phthalimidyl, 3-methylphthalimidyl, 4-methylphthalimidyl, 4-n-butylphthalimidyl, 4 Imid groups such as phthalimidyl group, tetramethylphthalimidyl group, 1,2-cyclohexanecarboxamidoyl group, 2,4,6-trioxopiperidine-11-yl group, α-pyridone-11-yl group, etc. Can be mentioned.

The transition metal compound used in the present invention is preferably a homogeneous hydrogenation catalyst. As such a homogeneous hydrogenation catalyst, for example, a transition metal complex of a Group VIII element of the periodic table such as Ru, Rh, Ir, or Pt is preferable. These transition metal compounds can be synthesized and obtained by the method described in, for example, Angew. Cem. Int. Ed., 3_, 1703 (1998).

The transition metal compound is more preferably a transition metal complex represented by the general formula (7).

MaXYPxmNxn (7)

In the formula, Ma represents a Group VIII metal atom, X and Y are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group or an alkoxy group, Px represents a phosphine ligand, and Nx represents And m and n each represent 0 or an integer of 1 to 4.

In the general formula (6), Ma represents a Group VIII metal such as Ru, Rh, Ir, and Pt. Among these, a Ru complex is particularly preferable in view of the stability of the complex and availability.

In the general formula (6), X and Y are the same or different and each represent a hydrogen atom, a halogen atom such as fluorine, chlorine, or bromine, a carboxyl group, a hydroxyl group, a methoxy, ethoxy, a propoxy, an isopropoxy, or a butoxy group. Represents an anion such as an alkoxy group.

The phosphine The Px is a ligand, for example, the general formula PR _A R _B R _C with phosphorus monodentate ligand represented and _{_{_{R D R E P- W_P R F}}} 2 of phosphorus represented by R _G And the like.

In the general formula PR _A R _B R _C , R _A , R _B , and R _c are the same or different and each represent an alkyl group, a phenyl group or a cycloalkyl group which may have a substituent, And two of R _A , R _A , R _B and R _c may be taken together to form an alicyclic group which may have a substituent. When at least one of R _A , R _B , and R _c is optically active, or when all three are different substituents, the general formula PR _A R _B R _C is optically active. In addition, all of R _A , R _B , and R _c are optically inactive groups, and when at least two are the same, the general formula PR _A R _B R _C is optically inactive.

In the general formula _{_{_{R D R E P- W- PR F}}} R G, R Dゝ_E R _F, R _G are the same or different from Represents an alkyl group, a phenyl group or a cycloalkyl group which may have a substituent, and may have a substituent when R _D and R _E or R _F and R _G are taken together. Good alicyclic groups may be formed. W represents a hydrocarbon group having 1 to 5 carbon atoms, a cyclohydrocarbon group, an aryl group, an unsaturated hydrocarbon group, or the like.

Examples of monodentate phosphine ligands represented by the general formula PR _A R _B R _C is, for example, trimethyl chill phosphine, tri E chill phosphine, tributyl phosphine, triphenyl phosphine, cyclohexyl phosphine to tricyclo, tri (p- tolyl ) Phosphine, diphenylmethylphosphine, dimethylphenylphosphine, isopropylmethylphosphine, cyclohexyl (0-anisyl) monomethylphosphine, 1- [2- (diphenylphosphino) fluorocenyl] ethyl methyl ether, 2 Tertiary phosphines such as — (diphenylphosphino) 1-2′-methoxy-1, 2-binaphthyl and the like are preferred. Further, a phosphine ligand in which R _A , R _B , and R _c are composed of three different substituents can be used.

The above-mentioned general formula 1 ₁₃ 1 _£ ^ ^—1 ^ _? 1 ^> 1. Is an example of an optically active bidentate phosphine ligand such as bisdiphenylphosphinomethane, bisdiphenylphosphinoethane, bisdiphenylphosphinopropane, bisdiphenyl. Suitable examples include bidentate tertiary phosphine compounds such as phosphinobutane, bisdimethylphosphinoethane, and bisdimethylphosphinopropane.

In addition, available bidentate phosphine ligands include, for example, BI NAP: 2,2'-bis- (diphenylphosphino) -11, Γ-binaphthyl, an alkyl group and a aryl group on the naphthyl ring of BI NAP. BI NAP derivative having a substituent, for example, H ₈ BI NAP, BI NAP-induced body 1-5 pieces have a substituent of an alkyl group such as a benzene ring bonded to the phosphorus atom such as BI NAP, for example, Xy 1 y 1 —BI NAP: 2, 2 ′ —bis- (di-1,5-xylylphosphino) -1,1, Γ—binaphthyl, and BI CHEP _: 2, 2 ′ —bis- (dicyclohexylphosphino) 1,6,6 ′ —Dimethyl-1,1,1-biphenyl, BPPFA: 1— [Γ, 2-bis (diphenylphosphine) fuerocenyl] ethyldiamine, CH I RAPHOS: 2,3-bis (diphenylphosphine) butane, CYCPHOS: 1-cyclohexyl-1,2-bis-1 (diff Diphenylphosphino) ethane, DEGPHOS: mono-substituted-3,4-bis- (diphenylphosphino) pyrrolidine, DI OP: 2,3-0-isopropylidene-1,2,3-dihydroxy-1,4, bis (diph Enylphosphino) Butane, DI PAMP: 1, 2-bis [(0-methoxyphenyl) phenylphosphino] ethane, DuPHOS: (substituted 1,2_bis (phosphorano) benzene), NORPHOS: 5,6-bis (diphenylphosphino) 1-2— Norbornene, PNNP: N, N, 1-bis- (diphenylphosphino) 1-N, N, 1-bis [1-phenylethyl] ethylenediamine, PROPHO S: 1,2-bis- (diphenylphosphino) propane, SKEWPH0S: 2,4-bis (diphenylphosphino) pentane and the like. BI NAP derivatives having a fluorine substituent can also be used. Of course, the phosphine ligand that can be used in the present invention is not limited thereto as long as it can form a metal complex stably.

The amine ligand Nx, formula NRHR! Monodentate ligand and one nitrogen represented by RJ general formula _{_{_{R K R L N- X- NR M}}} R N diamine ligand represented by like Can be mentioned.

In the general formula NR _H RIRJ, R _H , R or Rj are the same or different and represent 7j element, an alkyl group, an aryl group, or an unsaturated hydrocarbon group, and two of R _H and Rj are the same. An alicyclic group which may have a substituent may be formed. Further, at least one of R _H and R _: Rj may be an optically active group.

In the general formula _{_{_{R K R L N- X- NR M}}} R N, R K, R have R _M, R _N, taken identical or different from, 7Jc group, an alkyl group, Ariru group or unsaturated hydrocarbon group the stands may be formed R _K and R _L or R _M and R _N are together a connexion which may have a substituent alicyclic group.

X represents an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group, an aryl group, an unsaturated hydrocarbon group, or the like.

Examples of the monoamine ligand represented by the general formula NR _H RiR j include methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, cyclopentylamine, cyclohexylamine, benzylamine, dimethylamine, getylamine, zipamine. Monoamine compounds such as dihexylamine, dicyclopentylamine, dicyclohexylamine, dibenzylamine, diphenylamine, phenylethylamine, proline and piperidine can be exemplified. Further, examples of the optically active monoamine ligand include optically active monoamine compounds such as optically active phenylethylamine, naphthylethylamine, cyclohexylamine, and cycloheptylethylenediamine.

Examples of the general formula diamine ligand represented by _{_{_{R K R L N- X- NR M}}} R N, Mechirenjia Min, Echirenjiamin, 1, 2-Jiaminopuropan, propylene Jian, 1, 3-diamine Nopropane, 1,4-diaminobutane, 2,3-diaminobutane, 1,2-cyclopentanediamine, 1,2-cyclohexanediamine, N-methylethylenediamine, N, N'-dimethylethylenediamine , N, N, N′—trimethylethylenediamine, N, N, Ν ′, Ν′—tetramethylethylenediamine, ο-phenylenediamine, ρ-phenylenediamine and the like.

Optically active diamine ligands include optically active 1,2-diphenylethylenediamine, 1,2-cyclohexanediamine, 1,2-cycloheptanediamine, 2,3-dimethylbutandiamine, 1-Methyl_2,2-diphenylethylenediamine, 1-butyl-2,2-diphenylethylenediamine, 1-isopropyl-1,2,2-diphenylethylenediamine, 1-methyl-1,2,2-diphenylethylenediamine 2-di (P-methoxyphenyl) ethylenediamine, 1-isobutyl-1,2,2-di (p-methoxyphenyl) ethylenediamine, 1-isopropyl-1,2,2-di (P-methoxyphenyl) ethylenediamine, 1-Benzyl-1,2,2-di (p-methoxyphenyl) ethylenediamine, 1-methyl-1,2,2-dinaphthylethylenediamine, 1_isobutyl-2,2-dinaphthylethylenediamine Min, 1-isopropyl-2, can be exemplified 2-Jinafuchi ethylene diamine and the like.

The optically active diamine compound is not limited to the exemplified optically active diamine derivatives, and optically active propanediamine, butanediamine, phenylenediamine, cyclohexanediamine derivatives and the like can also be used. The amine ligand that can be used in the present invention is not limited to these as long as it can form a metal complex stably.

In the present invention, the amount of the homogeneous hydrogenation catalyst used depends on the type of the reaction substrate, the reaction vessel and the economical efficiency, etc., but is usually 1100-1 / molar ratio with respect to the carbonyl compound as the reaction substrate. 10,000,000, preferably 1/200 to: L / 100,000.

The base used in the present invention is a compound represented by the general formula (8),

Mbm'Z n '(8)

In the formula, M b represents an alkali metal or an alkaline earth metal,

Z is an alkoxy group having 1 to 6 carbon atoms such as methoxy, ethoxy, and propoxy;

Aryl groups such as phenyl and naphthyl,

Or human Dorokishi group, a mercapto group, a C0 ₃ group, m 'and n' represent an integer of 1 to 3.

Examples of the _{base, KOH, KOCH 3, KOCH (} CH 3) 2, KOC (CH 3) 3, KC 10 H 8, NaOH, NaOCH 3, L i OH, L i OCH 3, L i OCH (CH 3) _{_{_{2 Mg (OC 2 H 5)}}} 2, Na SH, the _{_{_{K 2 C0 3, C s 2}}} C 0 3 or the like can be exemplified. In the present invention, a quaternary ammonium salt can be similarly used as the base.

The amount of the base to be used is generally 0.5 to 100 equivalents, preferably 2 to 40 equivalents, relative to the Group VIII transition metal complex.

The reaction is carried out by dissolving the α-aminocarbonyl compound represented by the general formula (1) as a substrate in an inert solvent, and reacting with hydrogen or hydrogen in the presence of a predetermined amount of a transition metal complex and a base. This is done by applying an object.

The solvent that can be used for the reaction is not particularly limited as long as it is inert and solubilizes the reaction raw material (substrate) and the catalyst system. Such solvents include, for example, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as pentane, hexane and octane; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; Ethers, ethers such as tetrahydrofuran, alcohols such as methanol, ethanol, 2-propanol, butanol, benzyl alcohol, acetonitrile, DMF (Ν, Ν-dimethylformamide), メチル -methylpyrrolidone, pyridine, Organic solvents containing a heteroatom such as DMSO (dimethyl sulfoxide) can be mentioned.

Among the above, in the present invention, alcohol-based solvents are particularly preferred because the product is an alcohol. These solvents can be used alone or as a mixed solvent thereof.

The amount of the solvent used is determined based on the solubility of the reaction substrate, the economic efficiency, and the like. For example, in the case of using 2-propanol, the concentration of the substrate can be as low as 1% or less and in a state close to no solvent containing only the substrate. Preferably, the concentration is 20 to 50% by weight. it can.

The reaction is carried out in the presence of hydrogen gas or a compound donating hydrogen. When hydrogen gas is used, it is desirable that the hydrogen pressure in the system is 1 to 200 atm, preferably 3 to 100 atm. Compounds that donate hydrogen include hydride complexes and hydrogen storage alloys.

The reaction temperature is −30 to 100 ° C., preferably 15 to 100 ° C. in consideration of the reaction rate and the like. It can be carried out even at around room temperature of 25 to 40 ° C. The reaction depends on the reaction substrate concentration, temperature, It usually takes several minutes to 10 hours, depending on the reaction conditions such as pressure.

When the optically active amino alcohol represented by the general formula (2) is industrially mass-produced, the reaction may be of a batch type or a continuous type.

In the present invention, the raw material represented by the general formula (1)

Ra-CO-CH (Rb) -Rc (1)

R of the compound represented by

(3) r 1 CO (2) N-

(4) r 1 CO (R 1 'CO) N—

(Here, rl represents an alkoxy group, a cycloalkoxy group, an alkenyloxy group, an aralkyloxy group, or an aryloxy group, and R2 and Rl 'are the same as described above.) —After the formation of the amino alcohol, the ring-closing reaction may further proceed to form an oxazolidinone derivative.

When the oxazolidinone derivative is produced, it can be treated with an acid or a base to obtain a syn configuration / 3-amino alcohol.

The following table shows examples of the compound represented by the general formula (2) and the compound represented by the general formula (1), which is a starting material, which can be produced by the present invention.

In the table, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ph represents a phenyl group.

Table 1

Table 1 (continued)

Table 1 (continued)

Table 1 (continued)

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. In addition, the apparatus used for the measurement of the physical property in each Example is as follows. Nuclear magnetic resonance: iH NMR Varian GEMINI-300 (300MHz)

Optical rotation: JASCO DIP- 360

High-speed liquid mouth chromatography: Shimadzu LC-10Advp & SPD-lOAvp

Gas chromatography: Shimadzu Corporation GC-17A & C-E7A Plus Example 1

Synthesis of Syn-1-2-phthalimidyl-1-Phenol-1-propanol

40 ml of 2-propanol in a 10 Om1 autoclave, [(PPh ₃ ) ₂ ] Ru (II) Cl ₂ [N¾C¾C¾N¾], 3.8 mg (0.005 mmol), 1 N—tBu 0 2— 0.25 ml of a propanol solution and 1.40 g (5.0 mmol) of 2-phthalimidylpropiophenone were placed in an argon atmosphere, and hydrogen was injected up to 10 atm. After stirring at 30 ° C for 18 hours, the reaction mixture was applied to a silica gel short column (eluent = Jethyl ether), and the eluate was concentrated under reduced pressure to give 2-phthalimidoyl-1-phenyl-propanol 1 43 g were obtained. The formation ratio of diastereoisomers (diastereomers) and their relative configurations can be determined from the chemical shift value of the terminal methyl group in ¹ H—N MR spectrum analysis (Japanese Patent Laid-Open No. 50-137911: Syn isomer <5 = 1). 47, anti-isomer 5 = 1.40). The diastereomer ratio was 35: 1.1 (diastereoisomer excess: 94% de), and the main product was the syn isomer. Example 2

Synthesis of optically active 2-phthalimidoyl-1-phenyl-1-propanol

2-propanol 10 ml, toluene 4 ml 1, [(S) -Xylylbinap] Eu (II) Cl ₂ [(S, S) DPEN] 5.6 mg (0.005 t) in a 100 ml autoclave 2.0 ml of 5N-tBuOK / 2-propanol solution and 1.40 g (5.0 mmol) of 2-phthalimidylpropiophenone were placed in a metal autoclave under an atmosphere of argon, and hydrogen was added to the autoclave. Pressurized to 0 atm. After stirring at 25 ° C for 18 hours, the reaction mixture was applied to a silica gel short column (eluent-getyl ether), and the eluate was concentrated under reduced pressure to give 2-phthalimidoyl-1-phenyl-. 1-propanol l.llg (yield 7 9%). According to ¹ H-NMR spectrum in the same manner as in Example 1, the ratio of syn isomer: anti isomer was 22.6: 1 (92% de).

The main product of these diastereomers was separated by silica gel column chromatography (eluent: hexane Z: ethyl acetate = 82). Since the optical rotation was [a] _D ³¹ = + 43.3 ° (c = l.00, acetone), it was confirmed that the main product was a compound having the title structure (J. Prakt. Chem., 2, 307 (1990).). When this was measured by HPLC, the excess of the optically active substance was 96% ee (column: Daicel Chiralcel 0J, mobile phase; hexane: ethanol = 15: 1).

Example 3

Synthesis of optically active 1-phenyl-2- (N-methyl-N-benzoylamino) 1-propanol [(S) -Xylylbinap] Bu (II) Cl ₂ [(S, S) DPEN] under argon atmosphere In a simple autoclave (volume: 100 ml) containing 0.5 ml (0.0005 bandol) of 0.001N isopropanol solution, add 1 ml of isopropanol and 0.25 ml (0.125 liter) of 0.5N-tBuOK / 2-propanol solution. The mixture was added and stirred for 10 minutes. 1-Phenyl-2- (N-methyl-N-benzoylamino) propan-1-one

(1.34 g; 5. Olmmol) in isopropanol (5 ml) was added and hydrogen was injected at 12 atm.

After stirring at 25 ° C for 18 hours, the reaction mixture was applied to a silica gel short column (eluent-ethyl ether), and the eluate was concentrated under reduced pressure to give 1-phenyl-2- (N-methyl-N-benzoylamino).

4.98 g (99% yield) of 1-propanol was obtained. — As a result of NMR spectrum analysis, only the syn isomer was formed (syn isomer (5 = 1.47, anti isomer S = 1.40). The optical purity was measured by HP LC to be 98% ee (column: Daicel Chiralcel 0J, mobile phase; hexane: ethanol

= 3: 1).

Example 4

Synthesis of optically active-syn-1-phenyl-2- (N-methyl-N-benzoylamino) -4-methylpentan-1-ol

Under an argon atmosphere, 1-phenyl-2- (N-methyl-N-benzoylamino) -4-methylpentan-1-one (150 mg; 0.485 oi: ^ [P (3,5-xylyl) ₃ ] ₂ Eu (II ) Cl ₂ [(S, S) -DPEN] 0.5N-tBuOK in a simple autoclave (capacity 100m 1) containing 5.4mg (0.005 tmol) of isopropanol solution 5ml 0.5 ml (0.125 mmol) of a 2-propanol solution was added, and hydrogen was injected at 10 atm. After stirring at 25 for 65 hours, the reaction mixture was applied to a silica gel short column (eluent = getyl ether). The eluate was concentrated under reduced pressure to obtain 86.7 mg of 1-phenyl-2- (N-methylbenzoylamino) -4-methylpentan-1-ol (57% yield). The diastereomer ratio can be determined from the chemical shift value of the N-methyl group in the ¹ H-N MR spectrum (syn isomer S = 3.12 ppm, anti isomer S = 2.66 ppm), and only the syn isomer is formed. I was As a result of measuring the optical purity by HPLC, it was 84¾ee (column: Daicel Chiralcel 0J, mobile phase; hexane: ethanol = 40: 1).

Reference example 1

Synthesis of optically active-trans-3,4-dimethyl-5-phenyl-2-oxazolidinone

Under an argon atmosphere, 2- (N- (t-butoxycarbonyl) -N-methylamino) propiophenone (590 mg; 2.24 mmol) and [(S) -Xylylbinap] Ru (II) Cl ₂ [(S, S) DPEN] (12.5 mg; 0.1 mmol) was dissolved in 5 ml of isopropanol. This solution and 1. 1 ml (0.56 liters) of 0.5N-tBuOKZ2-propanol solution were put into a simple autoclave (100 ml capacity, and hydrogen was injected at 12 atm. After stirring at room temperature for 16 hours, The reaction solution was filtered through celite and concentrated under reduced pressure to give 3,4-dimethyl-5-phenyl-2-oxoxolidinone (374 mg; 1.96 bandol) .The diastereomer ratio was — 4 in the NMR spectrum. The optical shift was determined from the chemical shift value of the methyl group (anti-isomer S = 1.38 ppm, syn-isomer S = 0.56 ppm), and only the anti-isomer (> 99% de). As a result of measurement by chromatography (column: GL Sciences Inc. CP CHRASIL-DEX CB 0 O. 25 * 25m), it was found to be 99% ee.

According to the present invention, S-amino alcohols having a syn-configuration useful as a synthetic intermediate for pharmaceuticals and agrochemicals can be produced in a highly selective, high yield, and industrially advantageous manner in both racemic and optically active forms. Can be.

Claims

The scope of the claims

1. General formula (1)

Ra -CO-CH (Rb) -R c (1)

[In the formula, Ra and Rc are the same or different and each may be an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an alkenyl which may have a substituent. And an aralkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aralkyl group which may have a substituent.

Rb represents any one of the following general formulas (3), (4), (5), and (6).

(3) R 1 CO (R2) N—

(4) RI CO (R Γ CO) Ν-

_{(5) Rl S0 2 (R2} ) N -

(6) R1R2N-

(Here, Rl, Rl 'and R2 are the same or different and each have a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, An optionally substituted cycloalkyl group, an optionally substituted cycloalkoxy group, an optionally substituted alkenyl group, an optionally substituted alkenyloxy group, An aralkyl group which may have a aralkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aralkyl group which may have a substituent; R1 and R2 or R1 and R1 'may combine to form a 5- to 8-membered nitrogen-containing heterocycle, provided that when R2 is a hydrogen atom, R1 is an alkoxy group, a cycloalkoxy group, Aryloxy group, Aralquilo There is no death group.)]

Wherein a racemized α-aminocarbonyl compound represented by the formula is reacted with hydrogen or a compound that donates hydrogen in the presence of a transition metal compound and a base.

Ra-C * H (OH) -C * H (Rb) — Rc (2)

A method for producing an amino alcohol having a syn configuration represented by the formula: The method for producing a ^ -amino alcohol having a syn configuration according to claim 1 or 2, wherein the transition metal compound is a homogeneous hydrogenation catalyst.

2. The homogeneous hydrogenation catalyst has the general formula (7)

Ma XYP xmNx n (7)

(In the formula, Ma represents a Group VIII metal atom,

X and Y are the same or different and each represent 7] an atom, a halogen atom, a carboxyl group, a hydroxyl group or an alkoxyl group,

Px represents a phosphine ligand,

Nx represents an amine ligand,

m and n represent 0 or an integer of 1 to 4. )

Is a transition metal complex represented by

A method for producing a / 3-amino alcohol having the syn configuration according to claim 1.

4. The base has the general formula (8)

Mbm'Zn '(8)

(Wherein, Mb represents an alkali metal or an alkaline earth metal, Z represents a hydroxy group, an alkoxy group having 1 to 6 carbon atoms, a mercapto group, an aromatic group, or a CO ₃ group, m ′, n 'Represents an integer of 1 to 3.)

The method for producing an amino alcohol having the syn configuration according to claim 1, which is a compound represented by the formula:

5. The method for producing an optically active amino alcohol having a syn configuration according to claim 1, wherein the transition metal compound is an optically active transition metal compound.

6. The optical activity having a syn configuration according to claim 1, wherein at least one of the ligands PX and N x constituting the transition metal compound is an optically active substance. / 3—Amino alcohol production method.

7. The method for producing a racemic amino alcohol having a syn configuration according to claim 1, wherein the transition metal compound is optically inactive.

8. The racemic S-amino alcohol having a syn configuration according to claim 1, wherein both the ligands PX and NX constituting the transition metal compound are optically inactive. Manufacturing method.