JPS6134408B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to aminoalcohol derivatives. Specifically, the present invention relates to novel amino alcohol derivatives useful as ligands in asymmetric alkylation of carbonyl compounds. Conventionally, many attempts have been made to produce optically active alcohols by asymmetric alkylation of carbonyl compounds, but generally only very low optical purity has been obtained. The present inventors previously discovered the formula () as a ligand for asymmetric alkylation of carbonyl compounds. It has been found that 2-hydroxymethyl-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine represented by is excellent. (Refer to the specifications of Japanese Patent Application Nos. 53-11171 and 53-62584) Therefore, in view of these points, the present inventors conducted intensive research to develop a new ligand, and as a result, the general formula () (In the formula, R ¹ and R ² represent a lower alkyl group, and the other represents a hydrogen atom.) It was discovered that an asymmetric amino alcohol derivative represented by the following formula could be used as a ligand, and the present invention was achieved. That is, the gist of the present invention is that the general formula ()
It consists of amino alcohol derivatives shown in The present invention will be explained in detail below. In the general formula () of the amino alcohol derivative according to the present invention, R ¹ or R ² is, for example, methyl, ethyl, n-propyl, isopropyl, n-
It is a lower alkyl group having 1 to 6 carbon atoms such as butyl, isobutyl, sec-butyl, t-butyl, etc., and the other one represents a hydrogen atom. As the amino alcohol derivative according to the present invention, for example, 2-(1-hydroxy--methylethyl)-1-[(1-methylpyrrolidin-2-yl)
methyl]pyrrolidine, 2-(1-ethyl-1-hydroxypropyl)-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine, 2-(1-
Hydroxy-1-propylbutyl)-1-[(1-
Methylpyrrolidin-2-yl)methyl]pyrrolidine, 2-(1-butyl-1-hydroxypentyl)-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine, 2-hydroxymethyl-1-
Examples include [(1-ethylpyrrolidin-2-yl)methyl]pyrrolidine, 2-hydroxymethyl-1-[(1-neopentylpyrrolidin-2-yl)methyl]pyrrolidine, and the like. The amino alcohol derivative according to the present invention can be produced, for example, as described below. First, for those in which R ¹ is a lower alkyl group, the formula () 2-hydroxymethyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidine represented by the general formula () (In the formula, R ¹ represents a lower alkyl group.) It can be produced by reacting a carboxylic acid chloride represented by the following in a conventional manner and then reducing it with lithium aluminum hydride. In addition, for those in which R ² is a lower alkyl group, the formula () (In the formula, Z represents a benzyloxycarbonyl group.) N- ⁽ N ^- benzyloxycarbonylprolyl)proline methyl ester represented by It can be produced by reacting a Grignard reagent represented by (representing an alkyl group) by a conventional method, and then reducing it with lithium aluminum hydride. The compounds according to the present invention are useful as ligands in the asymmetric alkylation of carbonyl compounds. When used as a ligand in asymmetric alkylation, the 2-position and
The carbon atom at the 2' position must be an asymmetric carbon. Further, as a ligand for asymmetric alkylation, alkali metal salts of the amino alcohol derivative according to the present invention, such as lithium salt, sodium salt, and potassium salt, are also used. The alkali metal salt of an amino alcohol derivative can be produced, for example, by reacting the amino alcohol derivative with an alkyl lithium or the like. Asymmetric alkylation of a carbonyl compound using an amino alcohol derivative as a ligand may be carried out as described below. Carbonyl compounds to be asymmetrically alkylated are ketones and aldehydes, with particular preference being given to aldehydes. Examples of aldehydes include aliphatic aldehydes such as acetaldehyde, propionaldehyde, n-butyraldehyde, isobutyraldehyde, and n-amyl aldehyde, aromatic aldehydes such as benzaldehyde and tolualdehyde, other hydrocarbon aldehydes, nicotinic aldehyde, furfuryl aldehyde, etc. and aldehydes having a substituent such as alkoxy or dialkylamino which does not react with the alkylating agent. Among these aldehydes, aliphatic aldehydes or aromatic aldehydes represented by the general formula () R ³ CHO () (in the formula, R ³ represents an alkyl group or an aryl group) are generally used. Further, as the ketone, alkyl ketones and aryl ketones such as acetophenone, cyclohexylmethyl ketone, and cyclohexyl phenyl ketone are used. As an alkylating agent that performs asymmetric alkylation,
Examples include alkyllithium and dialkylmagnesium. Alkyl lithium is usually represented by the general formula () R ⁴ Li () (wherein R ⁴ represents an alkyl group). Examples of these alkyllithiums include methyllithium, ethyllithium, n-propyllithium, isopropyllithium, n-butyllithium, and isobutyllithium. As the dialkylmagnesium, one represented by the general formula () R ⁵ ₂ Mg () (in the formula, R ⁵ represents an alkyl group) is used. Examples of these dialkylmagnesiums include dimethylmagnesium, diethylmagnesium, di-n-propylmagnesium, diisopropylmagnesium, di-n-butylmagnesium, diisobutylmagnesium, di-sec-butylmagnesium, dihexylmagnesium, and the like. When a carbonyl compound and an alkylating agent are reacted, a solvent inert to the reaction is usually present. Such inert solvents include hexane,
Examples include hydrocarbons such as heptane, octane, benzene, and toluene, and ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, tetrahydropyran, dimethyl ether, methyl ethyl ether, dimethoxyethane, and dimethoxymethane. Preferably when using an alkyl lithium as the alkylating agent,
Toluene is used when dialkylmagnesium is used as an ether or alkylating agent.
Of course, two or more of these inert solvents may be used in combination. The amount of these inert solvents is usually 10 to 1000 ml, preferably 50 to 500 ml, per 1 g of carbonyl compound.
It is about ml. When a carbonyl compound and an alkylating agent are reacted, the alkylating agent is required to be used in an amount equal to or more than the same molar amount as the carbonyl compound, and is usually used in an amount of about 1.2 to 20 times the amount. In particular, it is preferable to use about 2 to 10 times the amount by mole. The amount of the amino alcohol derivative according to the present invention to be present as a ligand is usually about 1 to 20 moles, preferably about 2 to 10 moles, relative to the carbonyl compound. During the reaction, it is preferable to mix the alkali metal salt of the amino alcohol derivative and the alkylating agent in advance in the inert solvent. It is desirable that the reaction temperature is low, and usually
The temperature is 0 to -200°C, preferably -50 to -150°C.
If the reaction temperature is too high, optical purity will decrease. The reaction time varies depending on various other conditions, but is usually about 30 minutes to 2 hours. After the reaction, water and acid are added to stop the reaction, and the desired alcohol is isolated using appropriate methods such as extraction, solvent distillation, filtration recrystallization, distillation, and chromatography according to conventional methods of organic chemistry. can do. The correlation between the asymmetricity of the amino alcohol derivative according to the present invention and the asymmetricity of the alcohol produced is as follows:
Since it varies depending on various other conditions, it may be appropriately selected and used depending on the type of target compound. According to the asymmetric alkylation of carbonyl compounds using aminoalcohol derivatives as ligands according to the present invention, both production yield and optical purity are high;
Optically active alcohols can be produced from carbonyl compounds. Reference examples, manufacturing examples, and application examples are listed below.
The present invention will be explained in more detail, but the present invention is not limited by the following examples unless it exceeds the gist thereof. Reference example 1 (s)-N-benzyloxycarbonylproline dicyclohexylamine salt (21.5g, 50m
A solution of dicyclohexylcarbodiimide (10.4 g, 50 mmol) in chloroform (50 ml) was added to a solution of (s)-proline methyl ester hydrochloride (8.3 g, 50 mmol) in chloroform (150 ml) at 0°C under an argon atmosphere. Stirring was continued for 3 hours at 0° C. and overnight at room temperature. After treatment by a conventional method, (2S.2'S)-N-(N-benzyloxycarbonylprolyl)proline methyl ester (hereinafter abbreviated as 〓) was obtained in a yield of 92% (16.5 g). mp69−71℃ [α] ²⁸ _D −83.45° (C2.10, CH ₂ Cl ₂ ) Reference example 2 Add 25 ml of 30% hydrogen bromide-acetic acid solution to a solution of 〓 (21.6 g, 60 mmol) in acetic acid (170 ml). The mixture was added and stirred for 1 hour. Acetic acid was distilled off under reduced pressure at room temperature by azeotroping with heptane, the residue was washed three times with 100 ml of ethyl ether (hereinafter referred to as ether), and the solvent was distilled off under reduced pressure. Tetrahydrofuran (below) is added to the residue.
Add 16 ml of lithium aluminum hydride (hereinafter abbreviated as _LiAlH4 ) (17 g,
450 mmol) was gradually added. Stir overnight at room temperature, then heat to reflux for 3 hours. Post-treatment by a conventional method gave 2-hydroxymethyl-1-[(pyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓) in a 62% yield (6.72 g) as a colorless oil. . bp 115°C (0.9mmHg) [α] ²⁸ _D -52.8° (C1.01, EtOH) IR spectrum (neat) 3330, 1400, 1065,
1045cm ^-1 NMR spectrum (CDCl ₃ ) δ 3.80 (s, 2H),
3.45 (d, 2H), 3.34−2.15 (m, 8H), 2.09
(m, 8H) Elemental analysis agrees with the calculated value of C ₁₀ H ₂₀ ON ₂ Production Example 1 Add methylmagnesium bromide (93m
mol) in THF (10 ml) was added, and the mixture was stirred at 0°C for 1 hour. The reaction mixture was added to a cold aqueous ammonium chloride solution, the organic layer was extracted with ether, the ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was dissolved in THF (50 ml) and _LiAlH4
A suspension of (9.79 g, 258 mmol) in THF (200 ml) was added at 0° C. and then heated under reflux for 3 hours. An aqueous sodium sulfate solution was added dropwise to the reaction mixture, cooled to 0°C, and a white precipitate was filtered off. The filtrate was dried over anhydrous potassium carbonate, the solvent removed, and distilled.
(2S・2′S)-2-(1-hydroxy-1-methylethyl)-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) is 77
% yield (6.62 g) as a colorless oil. bp85℃ (1mmHg) [α] ¹⁹ _D -50.8゜(C1, EtOH) IR spectrum (neat) 3350, 2930, 2860,
2775, 1445, 1360, 1175, 1130, 935cm ^-1 NMR spectrum (CDCl ₃ ) δ 1.10 (s, 6H),
1.23-2.15 (m, 8H), 2.22-3.45 (m, 9H),
2.30 (s, 3H) Elemental analysis agrees with the calculated value of C ₁₃ H ₂₆ ON ₂ Production example 2 〓 (18 g, 50 mmol) in THF (60 ml) solution and ethylmagnesium bromide (127 mmol) in THF
(150 ml) solution was reacted and post-treated in the same manner as in Preparation Example 1. However, when treating with LiAlH ₄ , the amount of THF to dissolve the residue is 100 ml, and the amount of LiAlH ₄ is 11.4 g (300 ml).
mol) in THF (250 ml), and instead of distillation, it was separated by chromatography on an alumina column (developing solvent: methylene chloride-ethyl acetate). As a result, the yield of (2S・2′S)-2-(1-ethyl-1-hydroxypropyl)-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) Obtained at 56% (12.7g). bp95℃ (1mmHg) [α] ²² _D -88.7゜(C1, EtOH) IR spectrum (neat) 3400, 2950, 2860,
2775, 1450, 1355, 1205, 1160, 1130, 1070,
1040, 955 cm ^-1 NMR spectrum (CDCl ₃ ) δ 0.65−1.15 (m,
6H), 1.15-2.0 (m, 12H), 2.0-3.95 (m,
9H), 2.35 (s, 3H) Elemental analysis agrees with the calculated value of C ₁₅ H ₃₀ ON ₂ Production Example 3 Produced in the same manner as Production Example 2 except that ethylmagnesium bromide was replaced with n-propylmagnesium bromide ( 2S・2′S)-2-(1-hydroxy-1-propylbutyl)-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) was obtained in a yield of 33%. Ta. bp110℃ (0.7mmHg) [α] ²⁶ _D -70.3゜(C1, EtOH) IR spectrum (neat) 3360, 3125, 2930,
2840, 2770, 1430, 1125, 1035, 990cm ^-1 NMR spectrum (CCl ₄ ) δ 0.7−2.05 (m,
22H), 2.05-3.60 (m, 8H), 2.37 (s,
3H), 4.45 (exchanged with s, 1H, D ₂ O) Elemental analysis agrees with the calculated value of C ₁₇ H ₃₄ ON ₂ Production Example 4 In Production Example 2, ethylmagnesium bromide was converted to n-butylmagnesium bromide. (2S・2′S)-2-(1-butyl-
1-Hydroxypentyl)-1-[(1-methylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) was obtained in a yield of 21%. bp120℃ (0.8mmHg) [α] ²⁴ _D -60.6゜(C1, EtOH) IR spectrum (neat) 3180, 2950, 2860,
2775, 1455, 1445, 1370, 1355, 1205, 1130,
1040cm ^-1 NMR spectrum ( _CDCl3 ) δ 0.63−1.08 (m,
6H), 1.08-2.05 (m, 20H), 2.05-3.24
(m, 9H), 2.50 (s, 3H) Elemental analysis agrees with the calculated value of C ₁₉ H ₃₈ ON ₂ Production example 5 〓 (5.52 g, 30 mmol) of acetonitrile (50
acetyl chloride (2.59 g, 33 ml) solution at 0°C.
mol) in acetonitrile (10 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure,
The residue was treated with 10% sodium hydroxide solution (20ml) and extracted with ether. The ether layer was dried over anhydrous potassium carbonate, and the solvent was distilled off. residue
LiAlH ₄ (2.0 g,
53 mmol) in THF (50 ml) and heated under reflux for 1 hour. Post-processed in the same manner as in Production Example 1 to obtain 2-
Hydroxymethyl-1-[(1-ethylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) was obtained as a colorless oil in a yield of 70% (4.45 g). bp102℃ (0.8mmHg) [α] ²⁶ _D -103.2゜(C1, EtOH) IR spectrum (neat) 3360, 2950, 2875,
2775, 1450, 1345, 1205, 1155, 1105, 1080,
1050, 910 cm ^-1 NMR spectrum (CCl ₄ ) δ 1.06 (t, J=6
Hz, 3H), 1.35-3.60 (m, 20H), 4.44 (s,
1H, D ₂ O) Elemental analysis agrees with the calculated value of C ₁₂ H ₂₄ ON ₂ Production Example 6 In Production Example 5, except that acetyl chloride was replaced with pivaloyl chloride, (2S. 2′S)−
2-Hydroxymethyl-1-[(1-neopentylpyrrolidin-2-yl)methyl]pyrrolidine (hereinafter abbreviated as 〓〓) was obtained in a yield of 72%. bp114°C (0.6mmHg) [α] ³² _D -163° (C1.02, EtOH) IR spectrum (neat) 3400, 2945, 2860,
2780, 1470, 1450, 1390, 1355, 1195, 1110,
1035cm ¹ NMR spectrum (CCl ₄ ) δ 1.83 (s, 9H), 1.4
-2.8 (m, 18H), 2.8-3.6 (m, 3H) Elemental analysis is consistent with the calculated value of C ₁₅ H ₃₀ ON ₂ Application example Using the amino alcohol derivative produced in the production example as a ligand, asymmetric alkylation is included. I went there. When alkyl lithium is used as an alkylating agent, an amino alcohol derivative (4.05 m
mol) in ether (18 ml) at 0°C under an argon atmosphere, stirred for 30 minutes, cooled to -123°C, added a solution of benzaldehyde (1 mmol) in ether (2 ml), Stirred at -123°C for 1 hour. The reaction was stopped by adding 3N hydrochloric acid, and the product was extracted with ether.
The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was separated by chromatography on a thin layer of silica gel (developing solvent: methylene chloride).
After further distillation, the product was analyzed for NMR spectroscopy and IR spectroscopy.
Identification was made by spectrum, and optical purity was determined from optical rotation. When dialkylmagnesium is used as an alkylating agent, amino alcohol derivatives (4m
mol) in ether (7 ml) at 0°C was added n-butyllithium (4 mmol) and then dialkylmagnesium (4 mmol). The solvent was distilled off under reduced pressure, triene (18 ml) was added, the mixture was cooled to -110°C, a solution of benzaldehyde (1 mmol) in toluene (2 ml) was added dropwise, and the mixture was stirred at -110°C for 1 hour. After the reaction, post-treatment was carried out in the same manner as when using alkyl lithium. The results are summarized in Table 1.

【table】

[Table] In the table, Me represents a methyl group and Bu represents a butyl group. This table shows that the asymmetric alkylation can be controlled by changing various conditions.

Claims (1)

[Claims] 1 General formula () (In the formula, R ¹ or R ² represents a lower alkyl group, and the other represents a hydrogen atom.) An amino alcohol derivative represented by the following.