JPH0822838B2 - Optically active carboalkylated amino alcohol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel optically active carboalkylated amino alcohol.

[Structure of Invention]

The present inventors have completed the present invention as a result of extensive studies to find an optically active substance useful as a reaction reagent for asymmetric synthesis and the like.

That is, the present invention provides the following general formulas (1-1) and (1-2)
Alternatively, it relates to an optically active carboalkylated amino alcohol represented by (1-3).

(However, Ph represents a phenyl group, R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, X represents an -O- group or -S- group, and Z represents It is a metal atom.) Next, the constitution of the present invention will be explained.

Examples of the optically active carboalkylated amino alcohol of the present invention include the followings.

That is, in the general formulas (1-1) to (1-3), R is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. Further, X represents an -O- group or -S- group, and Z represents a metal atom. More specifically, R
Examples thereof include a hydrogen atom, a methyl group and an ethyl group. Examples of the metal atom represented by Z include copper, zinc, nickel, iron, cobalt, magnesium, calcium, sodium and potassium.

The optically active carboalkylated amino alcohol of the present invention can be produced, for example, by the following method.

One is the optically active form of erythro-2-amino-1,2-diphenylethanol represented by the following general formula, namely (1
S, 2R) body (2) or (1R, 2S) body (3) or threo-2-amino-1,2-diphenylethanol represented by the following general formula, which is obtained by chemically converting these This is a method in which the (1S, 2S) form (4) of is used as a starting material.

(However, Ph represents a phenyl group.) That is, after alkylation using each optically active substance, a carbomethylating agent such as ethyl bromoacetate, and a substituted carbomethylating agent such as ethyl chloropropionate, After making the ester part a metal salt such as sodium salt with sodium hydroxide or sodium hydrosulfide,
It can be a carboxylic acid or a thiocarboxylic acid or can be converted into another metal salt.

For example, the reaction formula when (1S, 2R) -2-amino-1,2-diphenylethanol is used as a starting material and ethyl bromoacetate is reacted to form a sodium salt is as follows.

(However, Ph represents a phenyl group.) In addition, erythro-2-amino-1,2-diphenylethanol as a starting material or threo-2-amino-1,2-diphenyl obtained by chemically converting erythro-2-amino-1,2-diphenylethanol The reaction may be performed using each racemic form of ethanol and then optically resolved.

However, the method is not limited to this method, and can also be synthesized by a ring-opening reaction between an optically active trans-stilbene oxide and an esterified product of glycine or an esterified product of alanine.
Further, a reaction product of trans or cis racemic stilbene oxide and glycine, alanine or a derivative thereof may be optically resolved.

〔The invention's effect〕

The novel optically active substance of the present invention is also useful as a reaction reagent for asymmetric synthesis and the like, and is particularly useful as a separating agent for racemic optical resolution.

That is, by supporting the novel substance of the present invention on a carrier such as silica gel using a silane coupling agent such as 3-glycidoxypropyltrimethoxysilane as a spacer, a separating agent for liquid chromatography can be obtained, and optical resolution is difficult. The optical resolution of the racemate, which is said to have become possible.

〔Example〕

Hereinafter, the present invention will be described in detail with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Synthesis Example 1 (1R, 2S) -2-Ethoxycarbonylmethylamino-1,2
-Synthesis of diphenylethanol.

(1R, 2S) -2-Amino-1,2-diphenylethanol 2.1
Dissolve 0 g in 30 ml methylene chloride and stir at room temperature. A solution prepared by dissolving 2.00 g of ethyl bromoacetate in 15 ml of methylene chloride was added thereto, and stirring was continued at room temperature for 7 days. Then, 1.5 ml of triethylamine is added and stirred at room temperature for 1 day. T
After confirming consumption of the raw materials by LC, methylene chloride is distilled off. 100 ml of benzene is added to the residue, and the mixture is washed once with water to remove triethylamine / hydrogen bromide, then washed with saturated saline, and the organic layer is dried with sodium sulfate.

When benzene is distilled off, crude (1R, 2S) -2-ethoxycarbonylmethylamino-1,2-diphenylethanol 2.60
g (88%) was obtained, and silica gel TLC (developing medium CH ₂ Cl ₂ / M
It was almost 1 spott at eOH = 19/1). This crude product can be used in the subsequent steps. Yield 2.20 g (75%).

 The physical properties of this compound are as follows.

Melting point; 123-125 ℃ Specific rotation; [α] ¹⁸ _D + 2.4 ° (c1.00, EtOH) Infrared absorption spectrum (IR) value (KBr); 3180,1745,765,705cm ^-1 Proton nuclear magnetic resonance Spectrum ( ¹ H-NMR) value (CDC
l ₃ ); δ1.17 (t, 3H, J = 7Hz), 2.35 (bs, 2H), 3.16 (ps
eudo s, 2H), 3.98 (q, 2H, J = 7Hz), 4.15 (d, 1H, J = 6H
z), 4.76 (d, 1H, J = 6Hz), 7.20 (s, 10H) ppm Elemental analysis value; Calculated value (C ₁₈ H ₂₁ NO ₃ ) C 72.22, H 7.07, N 4.68% Measured value C 72.43, H 7.11, N 4.47% Synthesis Example 2 (1S, 2R) -2-Ethoxycarbonylmethylamino-1,2
-Synthesis of diphenylethanol.

(1S, 2R) -2-Amino-1,2, diphenylethanol 3.1
Dissolve 5 g in 45 ml methylene chloride and stir at room temperature. To this was added 3.00 g of ethyl bromoacetate dissolved in 15 ml of methylene chloride, and the mixture was stirred at room temperature for 7 days. Further, 2.3 ml of triethylamine is added and the mixture is stirred at room temperature for 1 day. After confirming the consumption of the raw materials by TLC, the methylene chloride is distilled off. 100 ml of benzene is added to the residue, and the mixture is washed once with water to remove triethylamine / hydrogen bromide, washed with saturated saline, and the organic layer is dried with sodium sulfate.

3.41 g (77%) of crude product obtained by distilling off benzene
Recrystallization of about 300 ml of hexane gives purified (1S, 2R) -2-ethoxycarbonylmethylamino-1,2, diphenylethanol 3.25 g (73%).

 The physical properties of this compound are as follows.

Melting point; 126.5-127 ° C Specific rotation; [α] ²² _D −2.5 ° (c 1.01, EtoH) IR, ¹ H-NMR spectrum and Rf value are (1R, 2S) -2-amino-1,2, diphenyl This is completely the same as the product obtained using ethanol as a starting material (Synthesis Example 1).

Example 1 Synthesis of (1S, 2R) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt.

(1S, 2R) -2-Ethoxycarbonylmethylamino-1,2
-Suspension of 2.02 g of diphenylethanol in 20 ml of methanol, add 6.8 ml of 1N aqueous sodium hydroxide solution, and stir at room temperature for 3 days. During this time, the suspension becomes a homogeneous transparent solution. Then, methanol and water are distilled off, and 70
Vacuum drying (about 2mmHg) for 12 hours at (℃, (1S, 2R) -2-
Carboxymethylamino-1,2-diphenylethanol ・
1.92 g (97%) of monosodium salt are obtained. This crude product has only one spot at the origin in silica gel TLC (developing medium CH ₂ Cl ₂ / MeOH = 19/1) and can be used in the subsequent steps.

 The physical properties of this compound are as follows.

Melting point: 229 to 234 ° C (decomposition) Specific rotation: [α] ¹⁶ _D −3.7 ° (c 0.76, H ₂ O) IR value (KBr); 3280,1600,1415,760,700cm ^-1 Example 2 (1R , 2S) -2-Carboxymethylamino-1,2-diphenylethanol monosodium salt synthesis.

(1R, 2S) -2-Ethoxycarbonylmethylamino-1,2
-Suspension of 2.60 g of diphenylethanol in 20 ml of methanol, 8.6 ml of 1N aqueous sodium hydroxide solution is added thereto, and the mixture is stirred at room temperature for 3 days. During this time, the suspension becomes a homogeneous transparent solution. Then, methanol and water are distilled off, and 70
Vacuum drying (about 2mmHg) at ℃ for 12 hours, (1R, 2S) -2-
Carboxymethylamino-1,2-diphenylethanol ・
2.47 g (97%) of monosodium salt are obtained. This crude product is a silica gel TLC (developing medium CH ₂ Cl ₂ / MeOH = 19/1) with only 1 spot at the origin, and the IR spectrum is (1S, 2
(R) -2-Ethoxycarbonylmethylamino-1,2-diphenylethanol is exactly the same as the starting product.

 The physical properties of this compound are as follows.

Melting point: 231-235 ° C (decomposition) Specific rotation: [α] ¹⁷ _D + 3.8 ° (c 0.83, H ₂ O) Synthesis example 3 (1S, 2S) -2-ethoxycarbonylmethylamino-1,2
-Synthesis of diphenylethanol.

(1S, 2S) -2-Amino-1,2-diphenylethanol 526
Dissolve mg in 10 ml methylene chloride and stir at room temperature. Ethyl bromoacetate (412 mg) was dissolved in methylene chloride (3 ml), and the mixture was stirred at room temperature for 5 days. Then triethylamine
0.4 ml is added and the mixture is further stirred at room temperature for 1 day. After confirming the consumption of the raw materials by TLC, the methylene chloride is distilled off. To the residue was added 100 ml of benzene, washed once with water and triethylamine.
After removing the hydrobromide salt, the organic layer is washed with a saturated saline solution and dried with sodium sulfate.

The crude product obtained by distilling off benzene is
TLC (developing medium CH ₂ Cl ₂ / MeOH = 19/1) has two components (Rf = 0.57 and 0.50), and when separated by silica gel column chromatography, purified (1S, 2S) -2-ethoxycarbonylmethyl Amino-1,2-diphenylethanol
614 mg (83%) are obtained as an oil.

 The physical properties of this compound are as follows.

Specific rotation: [α] ¹⁷ _D −33.8 ° (c1.03, MeOH) IR value (neat); 3350,1740,1205,765,705 cm ^{−1 1} H-NMR value (CDCl ₃ ); δ1.20 (t , 3H, J = 7Hz), 3.02 (bs, 2H), 3.66 (d, 1H, J
= 8Hz), 4.07 (q, 2H, J = 7Hz), 4.59 (d, 1H, J = 8Hz), 7.
05 (s, 10H) ppm Elemental analysis value; Calculated value (C ₁₈ H ₂₁ NO ₃ ) C 72.22, H 7.07, N 4.68% Measured value C 72.48, H 7.21, N 4.42% Example 3 (1S, 2S)- Synthesis of 2-carboxymethylamino-1,2-diphenylethanol monosodium salt.

(1S, 2S) -2-Ethoxycarbonylmethylamino-1,2
-Dissolve 450mg of diphenylethanol in 10ml of methanol and stir 1N aqueous sodium hydroxide solution 1.6m.
Add l and stir at room temperature for 12 hours. After that, methanol and water were distilled off, and the residue was vacuum dried at 70 ° C for 12 hours (about 2 mmHg), and (1S, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt 421 mg (96%).
Is obtained. This crude product is silica gel TLC (developing medium C
With H ₂ Cl ₂ / MeOH = 19/1) there is only 1 spot at the origin,
It can be used in later steps.

 The physical properties of this compound are as follows.

Melting point; 222 to 225 ° C. (decomposition) Specific rotation; [α] ¹⁸ _D −43.3 ° (c 1.06, MeOH) IR value (KBr); 3305,1590,1415,770,700 cm ⁻¹ Application Example 1 In Example 2 Reaction of the obtained (1R, 2S) -2-carboxymethylamino-1,2-diphenylethanol monosodium salt with glycidoxypropylsilane-treated silica gel.

The monosodium salt is dissolved in 20 ml of methanol (99.5%), 7.0 g of glycidoxypropylsilane-treated silica gel [Lichrosorb Si 100.10 μm (E. Merck)] is added, and the mixture is allowed to stand at room temperature for 7 days. Filter the silica gel,
After washing with methanol, it is transferred to an aqueous solution of copper sulfate to form a copper salt. The structural formula of the obtained substance is presumed to be as follows.

(However, Ph represents a phenyl group, Y represents silica gel, and m and n are integers in which the sum of them is 3.) Using the separating agent thus obtained, various racemates are obtained. Optical resolution was performed. That is, the above separating agent was applied to a stainless steel column (25 cm × 0.46 cm) for high performance liquid chromatography.
φ) and optical resolution of various racemates was carried out at a flow rate of 1.0 ml / min (30 ° C.) using a 0.25 mM copper sulfate aqueous solution as a solvent, and good results as shown in Table 1 were obtained.

Claims (1)

[Claims] 1. An optically active carboalkylated amino alcohol represented by the following general formula (1-1), (1-2) or (1-3). (However, Ph represents a phenyl group, and R represents a hydrogen atom or an alkyl group having 1 to 10 carbon atoms.
X represents an -O- group or an -S- group, and Z represents a metal atom. )