JPH032152A - Stereo-selective production of 2-substituted-3-aminocarbonylpropionic acid - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate for an inhibiting agent for acidic protease such as renin, in high stereo-selectivity and yield, by reducing an alpha,beta-unsaturated carboxylic acid derivative in the presence of an asymmetrically hydrogenating transition metal catalyst. CONSTITUTION:The objective compound of formula II (* represents asymmetric C) can be produced by the catalytic reduction of an alpha,beta-unsaturated carboxylic acid derivative of formula I (R<1> is aryl; R<2> and R<3> are H, lower alkyl, 3-8C cycloalkyl or amino-protecting group: R<2> and R<3> may together form 2-6C alkylene, etc.; R<4> is H or lower alkyl) in the presence of an asymmetrically hydrogenating catalyst in a solvent (e.g. methanol) under 0-200atm at 0-200 deg.C in a hydrogen gas atmosphere. The catalyst is a hydrogenating catalyst containing asymmetric C in the molecule and its amount is 1/100 to 1/1000mol per 1mol of the compound of formula I.

Description

Detailed Description of the Invention [Objective] (Industrial Application Field) The present invention provides an optically active synthetic intermediate useful in the synthesis of a compound having excellent inhibitory activity against acidic proteases such as renin. Regarding manufacturing methods.

(Prior art) The three-dimensional structure of inhibitors against acidic proteases such as renin has an important influence on the strength of their activity, especially the (2R)-2-substituted-3-aminocarbonyl In analogues of propionic acid, (2R
) is known to have a strong inhibitory activity and is preferable as a medical product.

Conventionally, methods for synthesizing such asymmetric compounds include, for example, a method using an asymmetric alkylation reaction such as Evans et al.
The method disclosed in Japanese Unexamined Patent Publication No. 63-63649 is known, but it requires multiple steps.

On the other hand, as a method for synthesizing racemic compounds, for example, the method of Iizuka et al. [J, Med, Chem, 3XL701 (
1988)], but it requires a complicated process of separating enantiomers, and in many cases separation is extremely difficult, making it unsuitable for practical use.

(Problems to be Solved by the Invention) As a result of extensive research over many years on the synthesis of optically active 2-substituted-3-aminocarbonylpropionic acids, the present inventors discovered that α,β-unsaturated unsaturated When a catalytic reduction reaction is carried out using an asymmetric hydrogenation transition metal catalyst as a saturated norboxylic acid, asymmetric 2-substituted-3-aminocarbonylpropionic acids having the above-mentioned preferred absolute coordination are excellent. The present invention was completed based on the discovery that the catalyst can be obtained with high stereoselectivity and in high yield, and that the catalyst used can be reused.

〔composition〕

The general formula of the present invention [wherein R1 represents an optionally substituted aryl group, and R2 and R3 are the same or different, a hydrogen atom, a lower alkyl group, a substituted lower alkyl group (the substituted Examples of the group include an optionally protected amino group, a mono- or di-lower alkyl-substituted amino group, an optionally protected hydroxyl group, an optionally substituted aryl group, or an optionally substituted group having 3 to 8 carbon atoms. ), an optionally substituted cycloalkyl group having 3 to 8 carbon atoms or a protecting group for an amino group, or R2
and R3 together represent an alkylene group having 2 to 6 carbon atoms or an alkylene group having 2 to 6 carbon atoms interrupted by an oxygen atom, sulfur atom or nitrogen atom, and R4 is
It represents a hydrogen atom or a lower alkyl group, and wood represents an asymmetric carbon atom. The novel stereoselective method for producing 2-substituted-3-aminocarbonylpropionic acid represented by The method is characterized in that α, β-, β-carboxylic acid derivatives are reduced in the presence of an asymmetric hydrogenation transition metal catalyst.

In the above general formulas (I) and (II), the "optionally substituted aryl group" in the definition of R1, R2 and R3 refers to 1 to 4 selected from the following on the ring of the aryl group. Indicates an aryl group that may have a substituent. Examples of the aryl group include aromatic hydrocarbon groups having 6 to 10 carbon atoms such as phenyl and naphthyl, preferably phenyl, 1-naphthyl and 2-naphthyl.
It is a naphthyl group. Substituents on the ring include amino group; nitro group; cyano group: carboxy group optionally substituted with lower alkyl group described below or halogeno lower alkyl group described later; carbamoyl group: fluorine, chlorine, bromine, iodine, etc. Halogen atom; lower alkyl group as described below; lower alkoxy group such as methoxy, ethoxy, propoxy; trifluoromethyl, trichloromethyl, tribromomethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, 2-bromoethyl, 2-chloroethyl , 2-
Fluoroethyl, 2,2-dibromoethyl, 2,2,2
-trifluoroethyl, 2,2,2-trichloroethyl, n-trifluoropropyl, 2-trifluoromethylbutyl, 4-trifluoromethylpentyl, 3-trifluoromethylpentyl, 2-trifluoromethylpentyl, 3, 1 carbon number such as 3-trifluorodimethylbutyl
to 6 linear or branched halogeno lower alkyl groups; include the above-mentioned aliphatic acyl groups and alkylenedioxy groups having 1 to 4 carbon atoms such as methylenedioxy, ethylenedioxy, and propylenedioxy; It is preferably a lower alkyl group, a halogen atom, or a halogeno-lower alkyl group.

Specific examples of the "optionally substituted aryl group" include aryl groups such as phenyl, 1-naphthyl, and 2-naphthyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, and 2-fluorophenyl; Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-difluorophenyl, 2゜5-difluorophenyl, 2,6-difluorophenyl, 2.4- Difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2,4-
Dichlorophenyl, 2,3. Lotrifluorophenyl, 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5. rottrifluorophenyl, 2.4. Lotrifluorophenyl, 2,3,6-
Substituted with halogen atoms such as tribromophenyl, 2,3.4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2.4,6-trichlorophenyl Aryl group; 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-dichloromethylphenyl, 4-
Trichloromethylphenyl, 2-tribromomethylphenyl, 3-dibromomethylphenyl, 4-dibromomethylphenyl, 3,5-bistrifluoromethylphenyl, 2,5-bistrifluoromethylphenyl, 2,6-
Bistrifluoromethylphenyl, 2,4-bistrifluoromethylphenyl, 3,5-bistribromomethylphenyl, 2,5-bisdibromomethylphenyl, 2.
6-bisdichloromethylmethylphenyl, 2,4-bisdichloromethylphenyl, 2,3,6-tristrifluoromethylphenyl, 2,3,4-tristrifluoromethylphenyl, 3,4,5-tristrifluoro Methylphenyl, 2,5,6-tristrifluoromethylphenyl, 2,4,6-tristrifluoromethylphenyl, 2,3,6-tristribromomethylphenyl,
2.3,4-trisdibromomethylphenyl, 3,4,
Aryl group substituted with a halogeno lower alkyl group such as 5-tristribromomethylphenyl, 2,5,6-trisdichloromethylmethylphenyl, 2,4,6-trisdichloromethylphenyl; 2-methylphenyl ,3
-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl,
2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5 dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dibutylphenyl, 2,6-dipropylmethylphenyl,
2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,
5-trimethylphenyl, 2,5,6-trimethylphenyl, 2.4,6-trimethylphenyl, 2,3,6-
Lower alkyl groups such as tributylphenyl, 2,3,4-tripentylphenyl, 3,4.5-tributylphenyl, 2,5,6-triprobylmethylphenyl, 2,4,6-triprobylphenyl Substituted aryl group; 2-methoxyphenyl, 3-methoxyphenyl, 4
-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentoxyphenyl, 3.5-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-
Dimethoxyphenyl, 3,5-dibutoxyphenyl, 2
, 5-dinitrophenyl, 2,6-dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl, 2,3,
6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,
5,6-trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2
, 3,4-tripentoxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,4,6-triproxyphenyl. Aryl group; 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 3,
5-diaminophenyl, 2,5-diaminophenyl, 2
, 6-diaminophenyl, 2,4-diaminophenyl; 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 3
, 5-dinitrophenyl, 2,5-dinitrophenyl,
Aryl group substituted with nitro group such as 2.6-dinitrophenyl, 2,4-dinitrophenyl; 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,
Aryl groups substituted with cyano groups such as 3,5-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 2,4-dicyanophenyl; 2-acetylphenyl, 3-acetylphenyl, 4 -acetylphenyl, 3,5-diacetylphenyl, 2,5-diacetylphenyl, 2,6-diacetylphenyl, 2,4-
Aryl groups substituted with aliphatic acyl groups such as diacetylphenyl, 2,3゜6-tripropionylphenyl; 2-carboxyphenyl, 3-carboxyphenyl,
Aryl group substituted with a carboxy group such as 4-carboxyphenyl; 2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 3,5
-Aryl group substituted with a carbamoyl group such as dicarbamoylphenyl, 2,5-dicarbamoylphenyl, 2゜6-dicarbamoylphenyl, 2,4-dicarbamoylphenyl; 3,4-methylenedioxyphenyl Aryl groups substituted with alkylenedioxy groups such as

"Lower alkyl group" in the definition of R2, R3 and R4
For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, S-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl,
Neopentyl, n-hexyl, 4-methylpentyl, 3
-Methylpentyl, 2-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, ■, 1-dimethylbutyl, L, 2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl represents a straight or branched alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms.

The "protecting group" of "optionally protected amino group" and "protecting group of amino group" in the definition of R2 and R3 are:
One or two protecting groups selected from the group of protecting groups shown below are shown, and the protecting groups are not limited as long as they are normally used as protecting groups for amino groups, but preferably, for example,
Formyl, acetyl, propionyl, butyryl, imbutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, lauroyl, myristoyl,
Alkylcarbonyl groups such as tridecanoyl, balmitoyl, and stearoyl; halogenated aliphatic acyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; lower alkoxyaliphatic acyl groups such as methoxyacetyl; (E)- Aliphatic acyl groups such as unsaturated aliphatic acyl groups such as 2-methyl-2-butenoyl; arylcarbonyl groups such as benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, etc. halogenated arylcarbonyl groups such as 2,4.6-trimethylbenzoyl, lower alkylated arylcarbonyl groups such as 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, etc. Aromatic acyl groups such as nitrated arylcarbonyl groups such as benzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl; methoxycarbonyl; Lower alkoxycarbonyl groups such as ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,
Alkoxycarbonyl groups such as lower alkoxycarbonyl groups substituted with halogen or tri-lower alkylsilyl groups such as 2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl such as vinyloxycarbonyl and allyloxycarbonyl Group; benzyloxycarbonyl, 4-
Even if the aryl ring is substituted with one or two lower alkoxy or nitro groups, such as methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, and 4-nitrobenzyloxycarbonyl. Good aralkyloxycarbonyl group; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
Substituted with a tri-lower alkylsilyl group such as methyldiisopropylsilyl, methyldi-butylsilyl, triisopropylsilyl, or one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl silyl groups such as tri-lower alkylsilyl groups, or benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl,
triphenylmethyl, α-naphthyldiphenylmethyl,
Lower alkyl group substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2
, 4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 1 to 3 aryl rings substituted with lower alkyl, lower alkoxy, nitro, halogen, or cyano groups such as 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl, and piperonyl; It is an aralkyl group such as a lower alkyl group substituted with an aryl group, and more preferably an aliphatic acyl group or an aromatic acyl group.

The "mono- or di-lower alkyl-substituted amino group" in the definition of R2 and R3 refers to methylamino, ethylamino, dimethylamino, diethylamino, propylamino,
Examples include amino groups mono- or di-substituted with an alkyl group having 1 to 6 carbon atoms such as butylamino,
Preferably, it is an amino group in which an alkyl group having 1 to 4 carbon atoms is mono- or di-substituted.

Examples of the protecting group for the "optionally protected hydroxyl group" in the definitions of R2 and R3 include the aliphatic acyl group; the aromatic acyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2- tetrahydropyranyl or tetrahydrothiopyranyl groups such as yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; Tetrahydrofuranyl or tetrahydrothiofuranyl groups such as thiofuran-2-yl; said silyl groups; methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t -Lower alkoxymethyl groups such as butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl, halogenated lower groups such as 2,2.2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl Alkoxymethyl groups such as alkoxymethyl; lower alkoxylated ethyl groups such as 1-ethoxyethyl, ■-methyl-1-methoxyethyl, ■-(isopropoxy)ethyl, and halogenated groups such as 2,2.2-trichloroethyl. Substituted ethyl groups such as ethyl groups and arylzelenylated ethyl groups such as 2-(phenylzelenyl)ethyl; the aralkyl groups; the alkoxycarbonyl groups; the alkenyloxycarbonyl groups; and the aralkyloxycarbonyl groups.

[Optionally substituted cycloalkyl group having 3 to 8 carbon atoms] in the definitions of R2 and R3 refers to a saturated cyclic group having 3 to 8 shells such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 1 to 4 substituents selected from the substituents described in the above "optionally substituted aryl group" are substituted on the ring of the hydrocarbon group (preferably a 5- to 7-membered saturated cyclic hydrocarbon group). Indicates an optional group.

The "alkylene group having 2 to 6 carbon atoms" represented by R2 and R3 together includes, for example, ethylene, trimethylene,
Examples include alkylene groups having 2 to 6 carbon atoms such as tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, and hexamethylene, with preference given to ethylene and trimethylene. Or tetramethylene.

The "alkylene group having 2 to 6 carbon atoms interrupted by an oxygen atom, sulfur atom, or nitrogen atom" represented by R2 and R3 together includes, for example, methyleneoxymethylene, methyleneaminomethylene, methylenethiomethylene, ethyleneoxy Methylene, ethylene aminomethylene, ethylene thiomethylene, trimethylene oxymethylene, trimethylene amino methylene, trimethylene thiomethylene, ethylene oxyethylene, ethylene amino ethylene, ethylene thioethylene, tetramethylene oxymethylene, tetramethylene amino methylene, tetramethylene thiomethylene Methylene, trimethyleneoxyethylene, trimethyleneaminoethylene, trimethylenethioethylene, pentamethyleneoxymethylene, pentamethyleneaminomethylene, pentamethylenethiomethylene, tetramethyleneoxyethylene, tetramethyleneaminoethylene, tetramethylenethioethylene, trimethyleneoxy Examples include alkylene groups having 2 to 6 carbon atoms interrupted by an oxygen atom, sulfur atom, or nitrogen atom, such as trimethylene, trimethyleneaminotrimethylene, and trimethylenethiotrimethylene; may be substituted with the lower alkyl group, and as a result, R2 and R3 are
together with adjacent nitrogen atoms represents a saturated heterocyclic group such as, for example, piperazinyl, morpholino, 2,6-dimethylmorpholino, 2-methylmorpholino, thiomorpholino, N-methylpiperazinyl, piperidino, pyrrolidino .

[Asymmetric hydrogenation transition metal catalyst] used in the method of the present invention
As long as it is a hydrogenation catalyst having an asymmetric carbon atom in the molecule of the catalyst, there is no particular limitation, but for example, a hydrogenation catalyst having the general formula Ru(X 1) 2 (binap) having ruthenium as a transition metal , [Ru (
X ”)2 (binap) ]””Y- or Ru2
(X2)4(binap)2 ・Z [In the formula, Ru represents a ruthenium atom, and Xl may be a halogen atom such as chlorine, bromine, or iodine, or a halogen atom such as acetoxy or trifluoroacetoxy. represents an aliphatic acyloxy group, X2 represents a group similar to the halogen atom in Xl, and binap represents a group having (wherein R6 is an optionally substituted aryl group, an optionally substituted Straight chain or branched lower alkyl group or optionally substituted carbon number 3 to 8
cycloalkyl group. ) and has molecular asymmetry.

Y- represents an acidic anion such as perchlorate ion or trifluoroborate ion, and Z represents trimethylamine,
Indicates tertiary organic amine compounds such as triethylamine and pyridine. ] The asymmetric hydrogenation catalyst can be mentioned.

In the present invention, compound (1) is dissolved in a solvent, freeze-degassed, an asymmetric hydrogenated transition gold RfIIA medium is added to this solution, and the solution is further freeze-degassed, and then placed in an autoclave under a hydrogen gas atmosphere. Stir with M! This is achieved by giving back.

The solvent used is not particularly limited as long as it does not inhibit the reaction, but preferably alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene, toluene, and xylene, ether, Examples include ethers such as dimethoxyethane, diethylene glycol dimethyl ether, and tetrahydrofuran; halogenated hydrocarbons such as dichloromethane and chloroform, and mixed solvents thereof; more preferably alcohols or alcohols and other solvents mentioned above. It is a mixed solvent with

The transition metal catalyst for asymmetric hydrogenation to be used is not particularly limited as long as it is a compound as defined above, but preferably, in the formulas (III) and (TV), (1) R6 is a substituted The amount of the transition metal catalyst for asymmetric hydrogenation can be exemplified by compounds in which compound (2) R6, which is an aryl group that may be , by using 1/100 to 1/1000 mol based on the compound having general formula (I).

The steric configuration at the 2-position of the compound (II) of the present invention is selectively determined by the chirality of the transition metal catalyst for asymmetric hydrogenation. For example, in order to synthesize the compound (TI) of the present invention (2R) using the starting compound (I), (S)-bin
ap (IV) may be used.

The reaction pressure is usually 0 to 200 atm, preferably 1 to 50 atm.

The reaction temperature is usually 0°C to 200°C, preferably 20°C to 100°C.

The reaction time mainly varies depending on the reaction pressure, reaction temperature, raw material compound, and type of solvent used, but is usually 12 hours to 200 hours.

After completion of the reaction, the target compound (II) for one reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that is immiscible with water to the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

The α,β-unsaturated carboxylic acids (I), which are the raw material compounds for the method of the present invention, are known compounds (Japanese Patent Application Laid-open No. 18636-1989).
For example, the method of Horning et al. [E, C, Horning, J, ArM, Che
n+, So6. , Atsushi 5147 (1952)].

On the other hand, asymmetric hydrogenation transition metal catalysts, for example, Noyori et al. [J
, Org, Chem,, 5L 629 (198
6), J. Am.

Chem, Soc, 108.7117-7119
(1986) and J. Am.

Chem, Soc, 109.5856 (198
7)], using an optically active ruthenium compound as a raw material, the organic acid salt was mixed with methanol, ethanol,
In an alcoholic solvent such as t-butanol, 20
After reacting for 3 to 15 hours at a temperature of ~110°C, the solvent was distilled off and the reactants such as ether, tetrahydrofuran, etc.
It can be obtained by extraction with a solvent such as chloride or an alcohol such as methanol, ethanol, or t-butanol, followed by drying, and further, a purified product can be obtained by recrystallization.

After completion of the reaction, removal of the protecting group varies depending on the type of protecting group, but is generally carried out as follows by methods well known in the art.

When a tri-lower alkylsilyl group is used as a protecting group for an amino group and/or a hydroxyl group, it is usually removed by treatment with a compound that generates a fluorine anion, such as tetrabutylammonium fluoride. The reaction solvent is not particularly limited as long as it does not inhibit the reaction, but ethers such as tetrahydrofuran and dioxane are preferred.

Although the reaction temperature and reaction time are not particularly limited, the reaction is usually carried out at room temperature for 10 to 18 hours.

When the protecting group for an amino group and/or a hydroxyl group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group, it can be removed by treatment with an acid or base in the presence of an aqueous solvent. As acids, hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid are used, and as bases, there are no particular limitations as long as they do not affect other parts of the compound, but sodium carbonate and carbonate are preferably used. It is carried out using an alkali metal carbonate such as potassium, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or concentrated ammonia-nia-methanol. Note that isomerization may occur during hydrolysis with a base. The solvent used is not particularly limited as long as it is used in normal hydrolysis reactions, and water or water and methanol, ethanol, n
- Mixed solvents with organic solvents such as alcohols such as propatool or ethers such as tetrahydrofuran and dioxane are suitable. The reaction temperature and reaction time vary depending on the starting materials and the base used, etc., and are not particularly limited, but in order to suppress side reactions, they are usually 0°C to 1°C.
At 50°C, for 1 to 10 hours.

When the protecting group for an amino group and/or a hydroxyl group is an aralkyl group or an aralkyloxycarbonyl group, a method for removing it by performing catalytic reduction at room temperature using a catalyst such as platinum or palladium on carbon or an oxidizing agent. It is preferable to use a method for removing it.

The solvent used in the removal by reduction is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol, and isopropanol, ethers such as diethyl ether, tetrahydrofuran, and dioxane, Aromatic hydrocarbons such as toluene, benzene, and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, fatty acids such as acetic acid, or these organic solvents and water. A mixed solvent with is suitable.

The catalyst used is not particularly limited as long as it is normally used in catalytic reduction reactions, but palladium on carbon, Raney nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine- Rhodium chloride and palladium-barium sulfate are used. The pressure is not particularly limited, but the pressure is usually 1 to 10 atm. The reaction temperature and reaction time vary depending on the starting materials and the type of catalyst, but are usually 0°C to 100"C, 5
It can be carried out from minutes to 24 hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but preferably a water-containing organic solvent. Preferably, such organic solvents include ketones such as acetone, methylene chloride,
chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,
Mention may be made of amides such as hexamethylphosphorotriamide and sulfoxides such as dimethyl sulfoxide. The oxidizing agent used is not particularly limited as long as it is a compound normally used for oxidation, but potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), and 2,3-dichloro- 5
, 6-dicyano-p-benzoquinone (DDQ) is used.

Although the reaction temperature and reaction time vary depending on the starting materials and the type of catalyst, the reaction is usually carried out at 0°C to 150°C for 10 minutes to 24 hours.

When the protecting group for the amino group and/or hydroxyl group is an alkenyloxycarbonyl group, the conditions for the removal reaction when the protecting group for the amino group is usually an aliphatic acyl group, an aromatic acyl group, or a lower alkoxycarbonyl group. In the same manner, chicks can be removed by treatment with a base. In the case of allyloxycarbonyl, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is particularly convenient and can be carried out with fewer side reactions.

When the protecting group for the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrofuranyl group, or a substituted ethyl group, it can be removed by treatment with an acid in a normal solvent. The acid used is
Preferred are hydrochloric acid, acetic acid, sulfuric acid, p-toluenesulfonic acid or acetic acid.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water may be used. suitable. The reaction temperature and reaction time vary depending on the starting materials and the type of acid used, but are usually 0°C to 50°C.
The duration ranges from 10 minutes to 18 hours.

The above reaction for removing the protecting group for the amino group and/or hydroxyl group can be carried out sequentially in any desired order.

The present invention will be explained in more detail below with reference to Examples and Reference Examples.

In the following examples, the enantiomeric excess is calculated using an optical isomer separation column (CHIRALCEL) after converting the carboxylic acid synthesized by this asymmetric hydrogenation reaction into a methyl ester.
QC), using hexane=2-propertool, U
It was determined by detecting at a V wavelength of 254 nm.

Example 1 100 mg (0.31 mmol) of E-2-(1-naphthylmethylene)-3-(morpholinocarbonyl)propionic acid was dissolved in 2 ml of anhydrous methanol and freeze-degassed three times. Under an argon gas atmosphere, Ru (O
Ac) 2 [(S)-binap] 2 mg (2,
38
Stirred at 0'C for 48 hours. After 48 hours, the solvent was distilled off under reduced pressure, and the residue was methylated with a diazomethane-ether solution, and then loaded on a silica gel column chromatography (ether:hexane=4:I) to obtain the title optically active compound as a colorless compound. 57 mg (54%) as amorphous
Obtained.

Asymmetric synthesis was possible with stereoselectivity compared to conventional methods.

Mass spectrum (m/e): 341 (M, 129
゜tR value (column: CHIRALCEL QC (Dai
cel) Solvent: hexane = 2-propertool = 50:5
0 elution rate: 1.5 ml/mj-n): (2R) form:
12.93 min.

(2S) Rest: 20.70 min.

On methyl ester E-2-benzylidene-3-(morpholinocarbonyl)
200 III g (0.73 mmol) of propionic acid were dissolved in 3 ml of absolute methanol and freeze-degassed three times. Under argon gas atmosphere, Ru(OAc)2[
(S)-binap] 2 mg (2,38X 10”)
mol) was added, freeze-degassing was repeated three times, and the solution was transferred to a stainless steel autoclave using a cannula, 2 atmospheres of hydrogen pressure was applied, and the mixture was stirred at 50° C. for 48 hours. After 48 hours, the solvent was distilled off under reduced pressure, and the residue was methylated with a diazomethane-ether solution, followed by silica gel column chromatography (ether:hexane=
4:1) to obtain 127 mg (60%) of the title optically active compound as white crystals.

Asymmetric synthesis was possible with stereoselectivity compared to conventional methods.

Melting point: 66-68°C Mass spectrum (m/e): 291 (M, 129
゜tRf Direct (Column: CHIRALCEL QC (Da
icel) Solvent: Hexane = 2-propertool = 30 near 0 Elution rate: 1. Oml/+n1n): (2R) body: 11.90 min.

(2S) Body: 15.60 min.

Zoo mg (0-64 mmol) of 2-(R)-benzyl-3-benzylmethylaminocarbo E-2-benzylidene-3-(morpholinocarbonyl)propionic acid,
It was dissolved in 3 ml of anhydrous methanol and freeze-degassed three times. Ru (OAc) z under argon gas atmosphere
[(S)-binapJ2 mg (2,38X 10-
6 mol) was added and freeze-degassed three times, and the solution was transferred to a stainless steel autoclave using a cannula and heated to 48°C at 50°C under 2 atmospheres of hydrogen pressure.
Stir for hours. After 48 hours, the solvent was distilled off under reduced pressure and purified to obtain 121 mg (60 mg) of the title optically active compound.

Asymmetric synthesis was possible with stereoselectivity compared to conventional methods.

Melting point: 119-121°C Mass spectrum (m/e): 311 (M”), 12
0.91゜ Reference diethyl succinate 16.15 g (92.7 mmol)
and 14.50 g (92.8 mmol) of 1-naphthaldehyde were dissolved in 1.60 ml of absolute ethanol,
Add 5.35 g of sodium hydride under water cooling,
The mixture was heated to reflux for 0 minutes.

Furthermore, 115 ml of IN aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off under reduced pressure, water was added to perform ether extraction. The aqueous layer was made acidic with concentrated hydrochloric acid, and then extracted with ether. The organic layer was dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. Benzene was added to the residue, and the precipitated crystals were collected by filtration to obtain 15.3 g of 2-(1-naphthylmethylene)succinic acid.

150 ml of acetic anhydride was added to 14.0 g of 2-(1-naphthylmethylene)succinic acid and heated at 60°C for 1 hour. After distilling off the solvent under reduced pressure, benzene:hexane=1 is added to the residue.
: Add a mixed solution of 1, collect the precipitated crystals by filtration, and add 2-(1-
8.78 g of succinic anhydride (naphthylmethylene) was obtained.

5.00 g (21.0 mmol) of this 2-(1-naphthylmethylene)succinic anhydride was then dissolved in 150 ml of methylene chloride, and 2.56 ml of morpholine
(21.2 mmol) was added and stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was crystallized from a mixed solvent of ethyl acetate:benzene:hexane=1:1:1, and further recrystallized from ethyl acetate to obtain the title compound as white crystals. .93 g (2 melting points obtained 87 phantom 214
5-147℃ Elemental analysis value: Calculated value as C19H19NO4 C Near 0
．． 14. H:5-89. N: 4.31°Actual measurement value C:
69.40. H:6.08. N: 4.42° Mass spectrometry spectrum (m/e): 325 (M+), 238
．． 165° According to the method of honing, etc., (F,)
-Benzylidene succinic anhydride was synthesized.

This (E)-benzylidene succinic anhydride 568 mg (
3.02 mmol) was dissolved in 15 ml of methylene chloride, and further 0.4 ml (3.31 mmol) of morpholine was added, and after stirring at room temperature for 1 hour, the mixture was heated for 2 hours with constant flow.

Ethyl acetate was added, and the mixture was washed successively with normal hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl acetate.
650 mg (73%) of the title compound was obtained as white crystals.

Melting point: 123-1.24℃ Elemental analysis value: Calculated value as C15H17NO4 C: 65
,44. H:6.22. N: 5.09° Actual value C:
65.07. H:6.27. N: 5-21° Mass spectrometry spectrum (m/e): 275 (M+), 188
．． 116°, after stirring at room temperature for 1 hour, 2 o'clock+? The mixture was heated to reflux.

Ethyl acetate was added, and the mixture was washed successively with 2N hydrochloric acid and saturated brine, and then dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was recrystallized from isopropyl ether to obtain 3.1 g (6.0 g) of the title compound as a white product.
3%) obtained.

Melting point: 115-117℃ Elemental analysis value: Calculated value as C19H19NO3 C Near 3
．． 77, H:6.19. N: 4.53° Actual value C near 3.90. H:6.29. N: 4.51° Mass spectrometry spectrum (I!l/e): 308 (M+).

Patent applicant: Sankyo Co., Ltd. Agent: Patent Attorney Akio Ohno

Claims (1)

[Claims] General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 represents an optionally substituted aryl group, R^2 and R^3 are Same or different hydrogen atoms, lower alkyl groups, substituted lower alkyl groups (such substituents include optionally protected amino groups, mono- or di-lower alkyl substituted amino groups, optionally protected hydroxyl groups) , an optionally substituted aryl group or an optionally substituted cycloalkyl group having 3 to 8 carbon atoms), an optionally substituted cycloalkyl group having 3 to 8 carbon atoms, or an amino group or R^2 and R^3 taken together represent an alkylene group having 2 to 6 carbon atoms, or an alkylene group having 2 to 6 carbon atoms interrupted by an oxygen atom, sulfur atom, or nitrogen atom. It represents an alkylene group, and R^4 represents a hydrogen atom or a lower alkyl group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ( In the formula, R^1, R^2, R^3, and R^4 have the same meanings as above, and * indicates an asymmetric carbon atom.) Optically active 2-substituted-3-amino Stereoselective method for producing carbonylpropionic acid.