JP2002155035A - 3-amino-1-indanol, method for synthesizing the same and optical isomer separating agent comprising the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound which is expected to be a synthetic intermediate for medicines and agrochemicals, a separating agent for chromatography, or an optically resolving agent for racemates. SOLUTION: This 3-amino-1-indanol represented by formula (I) (OH and NH2 are arranged in the cis-or trans-configuration, and the 3-amino-1-indanol may be a racemate or an optically active isomer), a method for synthesizing the same, an optically active isomer of the 3-amino-1-indanol, and a method for optically resolving the 3-amino-1-indanol, and an optical isomer separating agent containing the optically active isomer as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel substance 3-
Amino-1-indanol and its synthesis method, and 3-
The present invention relates to an optically active form of amino-1-indanol, an optical resolution method thereof, and an optical isomer separating agent containing the optically active form as an active ingredient.

[0002]

2. Description of the Related Art Aminoindanol is an important intermediate of various fine chemical derivatives including physiologically active substances such as medical and agricultural chemicals. For example, cis-1-amino-2-indanol is
J. Med. Chem., 35, 2525 (1992), J. Med. Chem., 35, 1702 (1992)
2), J. Med. Chem, 35, 1685 (1992) and the like disclose that it is an effective intermediate for the production of anti-HVM drugs.

[0003] Optically active aminoindanols are effective as a separating agent for optically active carboxylic acids (chiral acids). For example, Japanese Patent Publication No. 11-511742 discloses 1-aminoindan-2-ol. A chiral acid separation process is disclosed.

[0004] 3-Amino-1-indanol is also a compound expected as an intermediate for synthesis of medical and agricultural chemicals, or as a chromatographic separating agent or a racemic optical resolving agent, but there has been no example of successful synthesis. The establishment of a synthesis method has been strongly desired.

[0005]

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that 3-amino-1-indanol which is a novel substance, and 3-amino-1-indanol which is easily available using raw materials. Method for synthesizing -1-indanol, effective method for resolving the obtained 3-amino-1-indanol, and separation for optical isomers using the optically active form of 3-amino-1-indanol as an active ingredient An agent was found, and the present invention was completed.

That is, the present invention provides a compound represented by the formula (I):
Provide amino-1-indanol.

[0007]

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(In the formula, the OH group and the NH ₂ group have a cis configuration or a trans configuration, and may be a racemate or an optically active compound.) The present invention provides a compound represented by the formula (II)

[0009]

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The amino group of β-phenyl-β-alanine represented by the formula (III)

[0011]

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[In the formula, A represents an RCO- or ROCO- group. Here, R is an alkyl group or an aryl group having 1 to 30 carbon atoms. And a compound represented by the formula
Formula (IV) is obtained by Friedel-Crafts acylation.

[0013]

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(Wherein A has the same meaning as described above), and the protecting group of this compound is removed and reduced. Method for synthesizing 3-amino-1-indanol,
A diastereomer salt formed after reacting a mixture of an optically active form of -amino-1-indanol and an optically active form of 3-amino-1-indanol represented by the above formula (I) with an optically active carboxylic acid For isolating 3-amino-1-indanol, and an optical isomer containing an optically active form of 3-amino-1-indanol represented by the above formula (I) as an active ingredient. Provide a separating agent.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION
Amino-1-indanol is a cis or trans form,
Alternatively, it may be racemic or optically active.

Β-phenyl-β-alanine (II) as a starting material can be synthesized from benzaldehyde, malonic acid and ammonium acetate by a known method. The obtained β-phenyl-β-alanine (II) is a protecting group for an amino group such as acetic anhydride, benzoyl chloride, 9-fluorenylmethyl chloroformate, benzyloxycarbonyl chloride, and di-t-butyl dicarbonate. Using a compound having a group that can be used, the amino group is protected with a protecting group to obtain a compound (III). As the amino-protecting group, an acetyl group and a benzoyl group are preferable, and an acetyl group is more preferable. Next, a compound having an indane skeleton represented by the formula (IV) can be obtained by performing a Friedel-Crafts acylation reaction of the compound (III). The Friedel-Crafts acylation is carried out, for example, by first adding PCl ₅ to the compound (III) and reacting it in a solvent such as ethyl ether or THF, and then further in a solvent such as methylene chloride at 0 to 5 ° C. The reaction is carried out by adding AlCl ₃ at a temperature of. The outline of the reaction so far is shown in the following reaction formula.

[0017]

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(Wherein A has the same meaning as described above;
Represents an acetyl group, and Ph represents a phenyl group. Subsequently, by removing and reducing the protecting group of the obtained compound (IV), 3-amino-1-indanol can be obtained. However, the method of removing and reducing the protecting group of compound (IV) can be used. The ratio of the trans form and the cis form can be changed, and the trans form and the cis form can be selectively synthesized. Hereinafter, the method for synthesizing the trans and cis isomers will be described in detail.

First, (±) -trans-3-amino-1-indanol (racemic) (I-
The outline of the synthesis method 1) is shown below.

[0020]

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(In the formula, A has the same meaning as described above.) That is, the compound (IV) obtained above is heated under reflux under acidic conditions to remove the protecting group and remove the hydrochloride (V). And the carbonyl group is further reduced to obtain the 3-amino-1-indanol represented by the formula (I) preferentially in the trans form at a ratio of trans: cis = 3: 1. it can. The reduction from the carbonyl group to the hydroxyl group can be performed by using a metal hydride reagent such as sodium borohydride.

By purifying the mixture (I) of the trans-form and the cis-form obtained above, (±) -trans-3
-Amino-1-indanol (racemate) (I-1) can be obtained. As a purification method, for example, a method of forming a salt of the mixture (I) with a 2-arylcarboxylic acid such as 2-naphthylacetic acid, heating the mixture to reflux in a solvent such as methylene chloride, and leaving it at room temperature is preferable. Used for According to this method, only the trans-form salt can be selectively crystallized. Subsequently, an alkali aqueous solution selected from sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like is allowed to act thereon, followed by extraction with a suitable organic solvent, whereby the trans form ( I-1) can be obtained.

Next, (±) -cis-3 from compound (IV)
The outline of the method for synthesizing -amino-1-indanol (racemic) (I-2) is shown below.

[0024]

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(Wherein, A has the same meaning as described above;
Represents an acetyl group, and Et represents an ethyl group. That is, by dissolving the compound (IV) in an appropriate organic solvent and performing a reduction reaction using, for example, borohydride,
The cis form of (±) -N-acyl-3-aminoindan-1-ol (VI) can be preferentially obtained in a ratio of cis: trans = 3: 1. The reaction solvent at this time is preferably tetrahydrofuran (THF). The reaction temperature is preferably from -100 to -50C. Next, the obtained mixture (VI) of the cis-form and the trans-form is purified by chromatography, recrystallization and the like to give (±) -cis-N-acyl-
3-aminoindan-1-ol (VII) is obtained.

The obtained (±) -cis-N-acyl-3-
The aminoindan-1-ol (VII) is heated under reflux in a suitable basic organic solvent and then extracted with a suitable organic solvent to give (±) -cis-3-amino-1-indanol (racemic) (I -2) can be obtained. At this time, the basic organic solvent is preferably a sodium hydroxide-ethanol mixed solvent, and the extraction solvent is preferably methylene chloride.

The optical resolution of the racemic 3-amino-1-indanol can be carried out by a diastereomer salt method using an optically active carboxylic acid. The optically active carboxylic acid to be used is not particularly limited, but dibenzoyltartaric acid is preferably used because an optically active substance can be obtained efficiently.

The solvent used for optical resolution is not particularly limited, but a mixed solvent of water and ethanol is preferred. The crystallization temperature is in the range of 0 to 60C, preferably 10 to 40C. If necessary, the crystallized diastereomer salt can be recrystallized to obtain a crystalline diastereomer salt having higher optical purity.

3-amino-1 obtained as described above
-The optically active form of indanol is an optical isomer separating agent,
Particularly, it is useful as a racemic optical resolution agent of an optically active carboxylic acid.

To optically resolve an optically active carboxylic acid using an optically active form of 3-amino-1-indanol,
An optically active carboxylic acid can be obtained by mixing an optically active form of 3-amino-1-indanol and a racemic optically active carboxylic acid in a suitable solvent, and then precipitating a diastereomer salt. it can. In particular, a carboxylic acid having an aryl group at the 2-position can be preferably optically resolved.

[0031]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be specifically described below with reference to embodiments. Note that the present invention is not limited by these examples.

Example 1 [Synthesis of trans-3-amino-1-indanol] (1) Synthesis of (±) -β-phenyl-β-alanine (II) 115 g (1.08 mol) of benzaldehyde, 113 g of malonic acid ( 1.08 mol), ammonium acetate 16
7 g (2.16 mol) was added to 270 mL of ethanol, and the mixture was stirred under heating and reflux for 5 hours. The precipitated white crystals were filtered, and the filtrate was mixed with a water-ethanol mixed solvent (1: 4,
Recrystallization from 2.5 L) gave 85.14 g of the title compound (II) as white crystals (yield 48%).

(2) Synthesis of (±)-(N-acetyl) -β-phenyl-β-alanine (III) 50 g (0.33 mol) of compound (II) obtained in (1)
Was dissolved in 200 mL of water in which 13.32 g (0.32 mol) of NaOH was dissolved, and 78 g of acetic anhydride (0.7 g) was dissolved.
7 mol), and the mixture was stirred at room temperature for 4 hours. The precipitated white crystals were filtered, washed well with water, and dried by heating under vacuum to obtain 55.85 g of the title compound (III) (89% yield).

(3) Synthesis of (±)-(N-acetyl) -3-aminoindan-1-one (IV)
55.00 g (0.27 m) of the compound (III) obtained in (2)
ol) and 55.31 g (0.27 mol) of PCl ₅ , and 160 mL of ethyl ether and 40 mL of THF were added thereto.
After stirring at 0 ° C. for 30 minutes, the mixture was stirred at room temperature for 5 hours. Subsequently, the solvent was distilled off under reduced pressure, and ethyl ether (3 ×
(100 mL), and ethyl ether was again distilled off under reduced pressure, followed by vacuum drying. 300 mL of methylene chloride
177 g of AlCl ₃ while stirring at 0 ° C.
(1.35 mol) was added slowly. After further stirring at room temperature for 2.5 hours, the reaction solution was poured into a 2 L Erlenmeyer flask containing 1 L of ice, and after confirming that AlCl ₃ was completely reacted, extraction was performed with methylene chloride (4 × 400 mL). . The organic layer was dried over sodium sulfide, the desiccant was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 48.70 g of the title crude product (IV). This was separated and purified by silica gel column chromatography (ethyl acetate), and further ethyl acetate (300 mL)
From the title compound (IV).
24 g were obtained (76% yield).

Melting point 155-158 ° C. ¹ H-NMR (CDCl ₃ ) δ = 2.055 (s, 3H), 2.468 (d
d, 1H, J = 3.3,19.2), 3.216 (dd, 1H, J = 7.8,19.2), 5.681 (d
t, 1H, J = 3.3,7.8), 5.956 (s, 1H), 7.453-7.754 (m, 4H) (4) Synthesis of (±) -3-aminoindan-1-one hydrochloride (V) (3) 18.26 g (0.097 m) of the compound (IV) obtained in
ol) was added to 300 mL of a 1N aqueous hydrochloric acid solution, and the mixture was stirred under reflux with heating for 5 hours. After confirming that the reaction was completed, the solvent was distilled off under reduced pressure and dried under vacuum to obtain 17.51 g of the title compound (V).

257 ° C. ¹ H-NMR (D ₂ O) δ = 2.826-2.900 (m, 1H), 3.353
(dd, 1H), 5.158-5.184 (m, 1H), 7.686-7.941 (m, 4H) IR (KBr) 3450, 3000, 2900, 1730, 1600, 1490,
1370, 1290, 1260, 780 cm ^-1 (5) Synthesis of (±) -trans-3-amino-1-indanol (I-1) 17.51 g of the compound (V) obtained in (4) was dissolved in ethanol 4
Dissolve in 50 mL, cool to 0 ° C. and NaBH ₄ 2.76
g (0.072 mol) was gradually added, and the mixture was stirred overnight.
Most of the solvent was distilled off under reduced pressure, 100 mL of water was added, and the mixture was extracted with methylene chloride (5 × 200 mL). The organic layer was dried over sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain (±) -3-amino-1.
7.38 g of indanol (I) were obtained. Further, the aqueous layer was distilled off under reduced pressure, and after vacuum drying, 200 mL of ethanol was added.
After cooling to 0 ° C., 1.22 g of NaBH ₄ (0.072 mol
After l) was added, the mixture was stirred overnight. Subsequently, most of the solvent was distilled off under reduced pressure, 100 mL of water was added, and the mixture was dried over sodium chloride. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain (±) -3-amino acid 5.97 g of 1-indanol (I) was obtained, and a total of 13.35 g (0.0
89 mol) of (±) -3-amino-1-indanol (I) (a mixture of trans-form: cis-form = 3: 1) was obtained. To this, 17.5 g of 2-naphthylacetic acid (0.094
mol), 1 L of chloroform was added, and the mixture was stirred under heating and reflux for several minutes, and then left at room temperature. The precipitated white salt was separated by filtration and vacuum-dried. The solution was made basic by adding 100 mL of a 1N aqueous solution of NaOH thereto, and extracted with methylene chloride (5 × 300 mL). The organic layer was dried over sodium sulfate. The desiccant was filtered off, dried in vacuo, and recrystallized from benzene-petroleum ether (5: 1, 300 mL) to give the title compound (±) as white crystals.
7.02 g of-(I-1) was obtained (49% in two steps).

Melting point 108-110 ° C. ¹ H-NMR (D ₂ O) δ = 1.583 (brs, 3H), 2.056 (d
t, 1H, J = 6.3,13.7), 2.461 (ddd, 1H, J = 3.0,6.3,13.7), 4.
641 (t, 1H, J = 6.3), 5.336 (dd, 1H, J = 3.0,6.3), 7.306-7.4
26 (m, 4H) IR (KBr) 3350, 3300, 3125 (br), 2925, 2700, 165
0, 1320, 1300, 1040,990, 780 cm ^-1 (6) Optical resolution of (±) -trans-3-amino-1-indanol (I-1) Compound (±)-(I) obtained by (5) -1) 7.52 g
(0.05 mol) and 19.25 g (0.051 mol) of L-(+)-dibenzoyltartaric acid were dissolved by heating in a mixed solvent of water and ethanol (1: 1, 630 mL) and left at room temperature. The precipitated crystals were filtered, recrystallized three times from a mixed solvent of water and ethanol (1: 1, 150 mL), filtered, dried in vacuo, and optically pure (1S, 3).
S) -Trans-3-amino-1-indanol-L-
(+)-Dibenzoyl tartrate (5.30 g) was obtained.
The solution was made basic by adding 50 mL of a 1N aqueous NaOH solution, and extracted with methylene chloride (4 × 200 mL). After the organic layer was dried over sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum. This was recrystallized from benzene-hexane (1: 1, 40 mL) to obtain 1.10 g of (1R, 3R) -trans-3-amino-1-indanol (I-1) as colorless crystals. Rate 29%, optical purity 99% ee or more).

Melting point: 112 to 113.5 ° C. [α] = 39.3 (c = 1.00, ethanol) On the other hand, the filtrate of the first recrystallization was concentrated under reduced pressure, and then 1N Na
The solution was made basic with 50 mL of an aqueous OH solution and extracted with methylene chloride (4 × 200 mL). The organic layer was dried over sodium sulfate, and after removing the desiccant by filtration, the solvent was distilled off under reduced pressure and dried under vacuum. To this, 7.20 g (0.019 mol) of D-(-)-dibenzoyltartaric acid was added, and the mixture was recrystallized three times using a mixed solvent of water and ethanol to obtain optically pure (1R, 3R)-. Trans-3-amino-1-indanol-D-(-)-dibenzoyl tartrate (3.15 g) was obtained. The solution was made basic by adding 50 mL of a 1N aqueous NaOH solution, and extracted with methylene chloride (4 × 200 mL). After the organic layer was dried over sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum. This is benzene-hexane (1: 1, 40 m
By recrystallization from (L), colorless crystals (1S, 3
S) -trans-3-amino-1-indanol (I-
1) 1.43 g was obtained (yield 38%, optical purity 99% e.
e. or more).

Melting point: 113.5 to 114 ° C. [α] = 38.1 (c = 1.00, ethanol) The optical purity was determined by HPLC under the following conditions. Column: CROWNPAK CR (manufactured by Daicel Chemical Industries, Ltd.) Flow rate: 0.5 mL / min Detection Wavelength: 200 nm Developing solvent: pH 2 HClO ₄ aqueous peak: before (1S, 3S) - (I -1), after (1R, 3
R)-(I-1) Example 2 [Synthesis of cis-3-amino-1-indanol] (1) (±) -cis-N-acetyl-3-amino-1-amino
Synthesis of indanol (VII) 8.0 g (0.0%) of compound (IV) obtained in (3) of Example 1
42 mol) was dissolved in 100 mL of THF and cooled to −78 ° C., followed by 42 mL of 1.01 M BH ₃ / THF.
(0.042 mol) was added slowly, and the mixture was stirred overnight. 1
The reaction was stopped by adding an aqueous solution of N hydrochloric acid, followed by extraction with methylene chloride. The organic layer was dried over sodium sulfate, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain (±) -N-acetyl-3-amino-1-indanol (cis-form: trans-form). = 3: 1 mixture) (VI)
6.54 g were obtained. Further purification was performed by silica gel column chromatography (eluate, ethyl acetate) to obtain 3.33 g of white crystals. Subsequently, this was added to ethyl acetate (90 m
L) and recrystallized twice from the title compound (±)-(VII)
1.45 g were obtained (two-step yield 18%).

Melting point 170-172 ° C. ¹ H-NMR (CDCl ₃ ) δ = 1.80 (dt, 1H, J = 5.7,8.
1), 2.01 (s, 3H), 2.57 (d, 1H, J = 6.3), 2.92 (ddd, 1H, J = 6.
6,7.5,13.8), 5.15 (dd, 1H, J = 6.3,13.1), 5.30 (dd, 1H, J =
7.5,13,5), 7.32-7.46 (m, 4H) IR (KBr) 3400, 3300, 1640, 1550, 1280, 1060,
990, 780, 760 cm ^-1 (2) Synthesis of (±) -cis-3-amino-1-indanol (I-2) 4.09 g of (±)-(VII) obtained in (1) (0. 021
mol) was dissolved in a 1N sodium hydroxide solution-ethanol mixed solvent (100 mL: 10 mL) with heating, and the mixture was heated under reflux for 6 days. After cooling to room temperature, methylene chloride (4 ×
200 mL). The organic layer was dried over sodium sulfide, the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was dried under vacuum to obtain 2.41 g of the title compound (±)-(I-2) (yield 75%). .

Melting point 67-75 ° C. ¹ H-NMR (CDCl ₃ ) δ = 1.64 (dt, 1H, J = 6.6, 1.
2), 2.13 (br s, 3H), 2.81 (dt, 1H, J = 6.6,13.2), 4.24 (t,
1H, J = 6.3), 5.05 (t, 1H, J = 6.0), 7.302-7.443 (m, 4H) IR (KBr) 3350, 1580, 1460, 1340, 1050, 770,
740 cm ^-1 (3) Optical resolution of (±) -cis-3-amino-1-indanol (I-2) The compound (±)-(I-2) obtained in (2) was converted to the following HPL
Optical division was performed under the condition C. Column: CROWNPAK CR (+) (manufactured by Daicel Chemical Industries, Ltd.) Flow rate: 1.0 mL / min Detection wavelength: 220 nm Developing solvent: pH 1.9 HClO ₄ aqueous solution Temperature: 10 ° C. -2) and the subsequent component-(I
After concentration, each fraction is made basic by adding a 10% aqueous solution of caustic soda, and then extracted with chloroform to obtain the desired optically active component- (I-2) (yield 2).
8%, optical purity 97.3% ee) and the component after optical activity-
(I-2) (18% yield, optical purity 95% ee) was obtained. The optical purity was determined under the same conditions as in Example 1.

Optically active component-IR of the component (I-2), ¹ H
-The measurement results of NMR and CD are shown below. FIG. 1 shows the CD spectrum of the optically active component- (I-2).

IR (neat) 3350, 1645, 1580, 1455, 1
325, 1090, 1045, 760, 735cm -1 1 H-NMR (300MHz) (CDCl 3) δ = 1.63 (ddd, 1
H, J = 6.6,6.6,6.6Hz), 2.43 (bs, 3H + H 2 O), 2.73 (ddd, 1H, J =
6.6,6.6,6.6Hz), 4.21 (dd, 1H, J = 6.6,6.6Hz), 5.02 (dd, 1
H, J = 6.6,6.6Hz), 7.2-7.5 (m, 4H) ppm CD (CHCl ₃ , 5.4 × 10 ^-4 M) -5.6mdeg (285nm),
-5.0 mdeg (296 nm) Application example (1S, 3S) -trans-3-amino-1-indanol obtained in (6) of Example 1, and shown in Table 1 for comparison (1S, 2S) -Trans-1-amino-2-
Using indanol and (1S, 2S) -trans-2-amino-1-indanol as separating agents, the racemates of compounds 1 and 2 shown in Table 1 were optically resolved by diastereomeric crystallization. .

That is, in the case of the separating agent of the present invention, equimolar amounts of the separating agent and the racemate of the compound to be separated were dissolved in acetonitrile and cooled to 4 ° C. to precipitate crystals. In the case of the comparative separating agent, an equimolar amount of the separating agent and the racemate of the compound to be separated are dissolved by heating in a mixed solvent of water and ethanol (1: 1) and left at 26 ° C. to form crystals. Was deposited. Table 1 shows the results.

[0045]

[Table 1]

From the results shown in Table 1, it can be seen that the separating agent of the present invention can separate the racemate of the compound to be separated more efficiently than the comparative separating agent.

[0047]

Industrial Applicability The novel 3-amino-1-indanol of the present invention is a very important compound as an intermediate for the synthesis of medical and agricultural chemicals, especially pharmaceuticals. Further, optically active 3-amino-1-indanol can be widely used as a separating agent for optically active carboxylic acids.

[Brief description of the drawings]

FIG. 1 is a CD spectrum of an optically active component- (I-2) obtained in (3) of Example 2.

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Claims (5)

[Claims] 1. A 3-amino-1-indanol represented by the formula (I). Embedded image (In the formula, the OH group and the NH ₂ group have a cis configuration or a trans configuration, and may be a racemic form or an optically active form.) 2. A compound of the formula (II) The amino group of β-phenyl-β-alanine represented by the formula (III) is protected by a protecting group. [In the formula, A represents an RCO- or ROCO- group. Here, R is an alkyl group or an aryl group having 1 to 30 carbon atoms. To obtain a compound represented by the formula: Friedel-Cr
Formula (IV) by afts acylation (Wherein A has the same meaning as described above), and the protecting group of the compound is further removed and reduced. A method for synthesizing indanol. 3. The 3-amino-1-indanol according to claim 1, which is an optically active substance. 4. The method of claim 3, wherein the mixture of the optically active substance of 3-amino-1-indanol according to claim 1 is reacted with an optically active carboxylic acid, and the resulting diastereomeric salt is separated. -1- Optical resolution method of indanol. 5. A separating agent for optical isomers comprising the optically active 3-amino-1-indanol according to claim 1 as an active ingredient.