JP2003160546A - METHOD FOR PRODUCING PURE TRANS-2-[(alpha-METHYLBENZYL) AMINO]CYCLOPENTANOL AS DIASTEREOMERIC ISOMER - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound of (1R,2R)-trans-2-[(R)-(α-methylbenzyl) amino]cyclopentanol succinate having high purity as a diastereomeric isomer, and to provide a new compound of (1S,2S)-trans-2-[(S)-(α-methylbenzyl) amino]cyclopentanol succinate having high purity as a diastereomeric isomer. <P>SOLUTION: This method comprises reacting a mixture of the two diastereomers of trans-2-[(R)-(α-methylbenzyl)amino]cyclopentanol represented by the formula (1) (wherein the absolute configurations of α-position are individually R configuration or S configuration) with the succinate in a solvent to generate the succinates of both the diasteromers, and crystallizing the slightly soluble salts in the mixture of the succinates of the diastreomers in the solvent, and then separating the slightly soluble salts of the succinates of the diastereomers in a solid phase from a liquid phase wherein the easily soluble salt of the succinates of the diastereomers is a main component. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a highly pure diastereoisomeric trans-2-[(α-methylbenzyl) amino] cyclopente which is useful as a chemical synthesis intermediate, particularly as a pharmaceutical synthesis intermediate. Industrial production method of tanol and novel compound (1R, 2R) -obtained by this method
Trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate and (1S, 2
S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate.

[0002]

2. Description of the Related Art As a method for producing highly pure trans-2-[(α-methylbenzyl) amino] cyclopentanol as a diastereoisomer, for example, trans-2
The diastereomeric mixture of-[(R)-(α-methylbenzyl) amino] cyclopentanol was subjected to flash column chromatography to give (1R, 2R) -trans-2-[(R)-(α-methyl Benzyl) amino] cyclopentanol, and (1S, 2S) -trans-
A method for separating two diastereomers of 2-[(R) -α-methylbenzyl] amino] cyclopentanol (LE Overman, S. Sugai, J. Org. Chem., 50, 4154).
(1985)) has been proposed. However, since this method uses column chromatography, there is a problem as a method for industrially obtaining a large amount of each diastereomer.

[0003]

Therefore, the transformer-2 is used.
Each of the diastereomers of-[(α-methylbenzyl) amino] cyclopentanol (however, the absolute configuration of the α-position is R configuration or S configuration individually) is highly pure, convenient and in high yield. Elucidation of the manufacturing method is required.

[0004]

The present inventors have found that trans-2-[(α-methylbenzyl) amino] cyclopentanol (where the absolute configuration at the α-position is R-configuration or S-configuration individually). As a result of diligently researching the industrial production method of each diastereomer of (1), trans-2-[(α-methylbenzyl) amino] cyclopentanol was treated with succinic acid in a solvent to form a succinate salt. And trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate having a specific configuration and trans-2-[(α-methylbenzyl) amino] cyclopentanol Since succinate shows different solubilities in a solvent, both succinates are separated based on the solubility behavior to give pure trans-isomers as diastereoisomers.
The present invention has been completed by discovering that 2-[(α-methylbenzyl) amino] cyclopentanol can be obtained.

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

[Chemical 2] (In the formula, the absolute configuration at the α-position is individually the R configuration or the S configuration), represented by trans-2-[(α
A mixture of two diastereomers of -methylbenzyl) amino] cyclopentanol is reacted with succinic acid in a solvent to form the succinate salt of both diastereomers,
Precipitating the sparingly soluble salt in this mixture of diastereomeric succinates from the solvent, followed by that of the solid phase diastereomeric succinate and the diastereomeric succinate The method for producing trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate, which comprises solid-liquid separation of a liquid phase containing the salt of 1) as a main component.

More specifically, the present invention relates to a mixture of both diastereomers of, for example, trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol with succinic acid. When a salt of both diastereomers is formed by reacting in a solvent, the compound (1
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate precipitates, while (1S, 2S) -trans-2- [as a readily soluble salt. Since (R)-(α-methylbenzyl) amino] cyclopentanol succinate remains in the liquid phase as an easily soluble salt, both diastereomeric succinates are separated by solid-liquid separation of both. And thus, as a diastereoisomer, highly pure trans-2-
Each diastereomer of [(α-methylbenzyl) amino] cyclopentanol succinate, where the absolute configuration at the α-position is individually the R or S configuration, can be obtained. Each of the obtained succinates can be converted into a free alcoholic form by salt removal by treatment with an acid, an alkali, an ion exchange resin or the like.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The diastereomer of trans-2-[(α-methylbenzyl) amino] cyclopentanol to be produced in the present invention includes (1
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol, (1S, 2S)
-Trans-2-[(R) -α-methylbenzyl] amino] cyclopentanol, (1R, 2R) -trans-
2-[(S) -α-methylbenzyl] amino] cyclopentanol and (1S, 2S) -trans-2-
There can be four types of [(S) -α-methylbenzyl] amino] cyclopentanol.

For example, the first two diastereomers are LE Overman, S. Sugai, J. Org. Chem., 50, 415.
4 (1985), a cyclopentene oxide is reacted with (R) -α-methylbenzylamine to obtain a mixture.

On the other hand, the other two diastereomers are:
Similarly, it is obtained as a mixture by reacting cyclopentene oxide with (S) -α-methylbenzylamine. The present invention provides a method for obtaining a single diastereomer from a mixture of two diastereomers thus obtained.

In general, the two diastereomers may have different physicochemical properties.
Overman et al. Performed chromatographic separation by taking advantage of the difference in adsorption to silica gel. However, as described above, this method is hardly an industrial method. The present inventors have noticed that the two types of diastereomers are amine compounds, and when a certain type of salt is produced, the difference in the three-dimensional structure of each diastereomer is
Focusing on the possibility that the solubility of the resulting salt will differ depending on the three-dimensional structure of the salt, we investigated the method for obtaining a single diastereomer from a mixture of two diastereomers from such an approach. Of.

As a result of earnest research, trans-2-[(α-methylbenzyl) amino] cyclopentanol was converted into its succinic acid salt by using succinic acid which was industrially available at a low cost. It has been found that a single diastereomer can be fractionally obtained from a mixture of diastereomers of different species due to the difference in solubility. That is, for example, (1R, 2R) -trans-2-[(R)
In the case of a mixture of two diastereomers of-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol , A salt-forming reaction with succinic acid in a selected solvent, followed by (1R, 2R) -trans-2- as a sparingly soluble salt in the selected solvent.
[(R)-(α-Methylbenzyl) amino] cyclopentanol succinate was precipitated, solid-liquid separated, and taken out. From the mother liquor part, the easily soluble salt (1S, 2S)
A syrupy product containing -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate as a main component was obtained.

On the other hand, (1R, 2R) -trans-2-
[(S)-(α-Methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-[(R)-
In the case of a mixture of two kinds of diastereomers with (α-methylbenzyl) amino] cyclopentanol, a salt forming reaction with succinic acid is similarly performed in a solvent selected, and subsequently it is hardly soluble in the selected solvent. As salt of (1S, 2S)-
Trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate was precipitated, solid-liquid separated, and taken out. From the mother liquor part, a syrup-like product containing (1R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate, which is an easily soluble salt, as a main component is obtained. Obtained.

The mixture of two diastereomers used for salt formation may be not only an equal mixture but also a mixture containing one of the diastereomers in excess. Separation of the two diastereomers of trans-2-[(α-methylbenzyl) amino] cyclopentanol is preferably carried out according to the following procedure and conditions.

Succinic acid is used in a solvent in an amount of 1.0 to 5.0 mol, preferably 1. 0 mol, per mol of the diastereomer mixture.
The salt is made by contacting with 0 to 2.0 moles. In this case, a salt (acid salt) formed by reacting 1 mol of amino alcohol with 1 mol of succinic acid and a salt formed by reaction of 2 mol of amino alcohol with 1 mol of succinic acid (neutral salt)
Is possible. In order to achieve the object of the present invention, formation of acidic salt is preferable. Therefore, the amount of succinic acid used is preferably 1.0 mol or more based on the diastereomer mixture. Further, although there may be several methods for contacting succinic acid and diastereomers, it is always preferable to contact them in the state of excess succinic acid. Specifically, a preferred addition method is to add the diastereomer mixture to the succinic acid solution, or to simultaneously add the succinic acid and the diastereomer mixture to the solvent while controlling the addition rate. As the solvent used for salt formation, various solvents can be used, and water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, acetonitrile and the like are preferable, and 2-propanol is preferably used. These solvents may be used alone or in combination.

As the solvent used for crystallization, various solvents can be used, water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, acetonitrile and the like are preferable, and 2-propanol is preferably used. These solvents may be used alone or in combination.

The solvent used for salt formation and the solvent used for crystallization may be the same or different in kind and composition. When the solubility of the salt in the solvent used for salt formation is high, it is possible to perform crystallization and solid-liquid separation after replacing the solvent with a low solubility after salt formation, and the solubility of the salt in the solvent used for salt formation is low. In the case of crystallization after substitution with a solvent having high solubility after salt formation,
Solid-liquid separation is also possible.

Before crystallization, it is preferred that both diastereomeric succinates are completely dissolved. For complete dissolution, the amount of solvent used and the dissolution temperature can be appropriately selected. Although depending on the solvent used, when the amount of the solvent is large, the purity of the diastereomer is improved, but the yield is lowered, and when the amount of the solvent is small, the purity of the diastereomer is generally lowered.

Crystallization of the sparingly soluble salt from a homogeneous solution of the succinate salt of the mixture of diastereomers is possible in the usual way. When the concentration of the sparingly soluble salt is less than the saturation solubility (so-called supersaturation), crystallization is unlikely to occur, and when rapid crystallization occurs, the purity of the desired diastereomer in the crystal decreases. In this case, it is effective to add crystals having high diastereomeric purity as seed crystals in advance and start crystallization.

The solid-liquid separation temperature affects the yield of each diastereomer and the purity of the diastereomer. Solid-liquid separation at high temperature generally improves diastereomer purity but decreases yield, and solid-liquid separation at low temperature generally improves yield but diastereomer purity. Is.

The diastereomeric purity of the succinate of each diastereomer can be selected according to the purpose of use. If a salt of high diastereomeric purity, or a diastereoisomerically pure salt is desired, it can be obtained by recrystallization. Various solvents can be used as the solvent for recrystallization, but water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, acetonitrile and the like are preferable, and 2-propanol is preferably used. These solvents may be used alone or in combination.

The diastereomeric purity of the succinate salt of each diastereomer can be analyzed and determined by treating it under the conditions described below.

The diastereomeric succinate thus obtained may be subjected to a salt-removing method by an appropriate method, that is, a method using an acid, an alkali or an ion exchange resin. For example, if the diastereomeric succinate is demineralized by adding an alkaline solution and then extracted with an organic solvent such as dichloromethane, the desired free diastereomer is extracted into the organic layer. The desired diastereomer compound can be obtained by concentrating. The alkali used is preferably one having a basicity greater than that of the amino alcohol,
Either an organic base or an inorganic base can be used. However, it is preferable to use an inorganic base because the subsequent steps are easy. The inorganic base used is preferably potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate.

Each diastereomer obtained in the present invention is
It is also possible to use it as it is depending on the application. Also,
By removing the α-methylbenzyl group, it is possible to derive an enantiomer having a corresponding configuration.
For example, (1R, 2R) -trans-2-[(R)-(α
-Methylbenzyl) amino] cyclopentanol, or (1R, 2R) -trans-2-[(S)-(α-
Methylbenzyl) amino] cyclopentanol is (1
It can be derived to (R, 2R) -trans-2-aminocyclopentanol. On the other hand, (1S, 2S) -trans-2-
[(R)-(α-methylbenzyl) amino] cyclopentanol, or (1S, 2S) -trans-2-
[(R)-(α-Methylbenzyl) amino] cyclopentanol can be derived to (1S, 2S) -trans-2-aminocyclopentanol. These enantiomers are useful as chemical synthetic intermediates, especially as pharmaceutical synthetic intermediates.

[0024]

EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.
The diastereomeric ratio in this example was determined under the following liquid chromatography conditions. Column: CAPCEL PACK C-18 (4.6 mm x 150 mm) (manufactured by Shiseido) Mobile phase: Solution A; 1% (w / v) ammonium acetate aqueous solution (pH adjusted to 4.7 by adding acetic acid) Solution B: acetonitrile A solution : Solution B = 90:10 (v / v) Flow rate: 1.0 ml / min Detection: UV 254 nm Temperature: 40 ° C

Example 1 A 100 ml four-neck reaction flask was equipped with a reflux condenser and a thermometer and charged with 8 ml of 2-propanol. Then, 0.67 g (5.65 mmol) of succinic acid was added, and the mixture was heated with stirring to completely dissolve it at 50 ° C. (1
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S)
1.16 g of a diastereomeric mixture of -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol (diastereomeric ratio = 54.5: 45.5)
A solution in which (5.65 mmol) was dissolved in 2-propanol (6 ml) was prepared. The 2-propanol solution of the diastereomer mixture was added dropwise to the 2-propanol solution of succinic acid at 65 to 70 ° C. The pH of the obtained pale yellow transparent solution was 4-5. No precipitation of crystals was observed even after stirring for 20 minutes while allowing to cool, but crystals were precipitated when cooled with ice water. The precipitated crystals were filtered under reduced pressure at an internal temperature of 5 ° C, and the crystals were washed with 2-propanol (1 ml). The wet crystals were dried under reduced pressure to give white crystals of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate (0.65 g, yield: 35.5).
%) Was obtained. (1R, 2R) -trans-2-of this salt
[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-[(R)
The diastereomeric ratio of-(α-methylbenzyl) amino] cyclopentanol was 71.8: 28.2. On the other hand, the mother liquor after crystallization was concentrated to give a slightly tan syrup 1.
16 g (yield: 63.4%) was obtained.

Example 2 0.62 g of the succinate obtained in Example 1 was recrystallized from 2-propanol (4 ml) to give white crystals of trans-2-[(R)-(α-methylbenzyl) amino. ] 0.09 g of cyclopentanol succinate was obtained. This salt of (1R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1
The diastereomeric ratio of S, 2S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol was 90.3: 9.7. The mother liquor after recrystallization was concentrated to obtain white crystals of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate (0.60 g). 2-Propanol (2 ml) of this salt
Recrystallized from trans-2-[(R)-
(Α-Methylbenzyl) amino] cyclopentanol
0.16 g of succinate was obtained. (1R, 2R) -of this salt
Diazones of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol Stereoisomer ratio is 92.4: 7.6
Met. The recrystallization mother liquor was concentrated to obtain 0.29 g of slightly yellow semi-crystal.

EXAMPLE 3 1.16 g (3.59 mmol) of syrup of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate obtained in Example 1 was used. 0.29 g (0.90 mmol) of semi-crystal of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate obtained in Example 2 was combined and taken up in water (6 ml). Dissolved. At room temperature, 5.1 g of a 2N aqueous sodium hydroxide solution (1
0.2 mmol) was added to adjust the pH to 10-11. It was extracted with dichloromethane (10 ml) and the aqueous layer was further extracted with dichloromethane (5 ml). The extract layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a pale yellow syrup-like trans-
2-[(R)-(α-methylbenzyl) amino] cyclopentanol (yield: 70.0%) was obtained. (1R, 2
R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S)-
The diastereomeric ratio of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol is 44.
It was 2: 55.8.

Example 4 A 200 ml four-neck reaction flask was equipped with a reflux condenser and a thermometer and charged with 30 ml of 2-propanol.
5.33 g (45.2 mmol) of succinic acid was added, and the mixture was heated to 65 ° C. with stirring, and succinic acid was dissolved. (1
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S)
8.34 g of a diastereomeric mixture of -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol (diastereomeric ratio = 50.0: 50.0)
(34.3 mmol) was dissolved in 2-propanol (10 ml) at room temperature, and this solution was added dropwise at 45-60 ° C to the above solution of succinic acid in 2-propanol. The mixture was stirred while allowing it to cool, and cooled to room temperature. Although no precipitation of crystals was observed, the crystals of the succinate obtained in Example 2 were [(1R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol. , (1
S, 2S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol having a diastereomeric ratio of 92.4: 7.6] was added as a seed crystal at room temperature. After stirring for 10 minutes, precipitation of crystals started. After stirring at room temperature for 30 minutes, the mixture was cooled and stirred at 5 ° C. for 1 hour. The precipitated crystals were filtered under reduced pressure to give crystals
Wash with propanol (4 ml). The wet crystals were dried under reduced pressure to obtain 5.60 g (yield: 41.4%) of white crystals of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate. It was (1 of this salt
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2
The diastereomeric ratio of (S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol was 98.3: 1.7. The mother liquor after concentration under reduced pressure was concentrated to give a light yellow syrup trans-2-[(R)-(α-
Methylbenzyl) amino] cyclopentanol succinate 6.5 g (yield: 58.6%) was obtained. (1 of this salt
R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2
The diastereomeric ratio of (S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol was 18.9: 81.1.

Example 5 Trans-2-[(R)-(α-obtained in Example 4)
3.68 g of methylbenzyl) amino] cyclopentanol succinate was recrystallized from 2-propanol (10 ml) to give white crystals of trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol. Obtained 3.26 g of succinate (recrystallization yield: 88.6%). This salt of (1R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S,
The diastereomeric ratio of 2S) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol is> 99.5: <0.5 and is pure as diastereoisomer (1R , 2R) -trans-2-[(R)-
(Α-Methylbenzyl) amino] cyclopentanol
It was a succinate. Melting point: 127-130 ° C. IR
(KBr, cm ^-1 ): 3406, 2966, 2832, ¹
700, 1647.

Example 6 The diastereomerically pure (1R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate obtained in Example 5 1.0 g (3.09 mmol) was dissolved in water (5 ml), and at room temperature, 3.25 g (6.5 mmo of 2N sodium hydroxide aqueous solution).
l) was added dropwise and the pH was adjusted to 10. It was extracted twice with dichloromethane (10 ml), and the extract layer was saturated brine (5
ml) and dried over sodium sulfate. The dichloromethane solution was concentrated under reduced pressure to give a colorless transparent liquid (1R, 2
R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol 0.62 g (yield: 9
8.4%). It was crystallized when left at room temperature. Melting point: 74-76 ° C. (1R, 2R) -Trans-
2-[(R)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S) -trans-2-
The diastereomeric ratio of [(R)-(α-methylbenzyl) amino] cyclopentanol is> 99.5: <0.5, indicating the diastereomerically pure (1R, 2R)
It was -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol.

Example 7 A 200 ml four-neck reaction flask was equipped with a reflux condenser and a thermometer and charged with 30 ml of 2-propanol.
5.33 g (45.2 mmol) of succinic acid was added, and the mixture was heated to 65 ° C. with stirring, and succinic acid was dissolved. (1
R, 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol and (1S, 2S)
8.34 g of a diastereomeric mixture of -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol (diastereomeric ratio = 50.0: 50.0)
(34.3 mmol) was dissolved in 2-propanol (10 ml) at room temperature and this solution was added dropwise at 50-60 ° C to the above solution of succinic acid in 2-propanol. The mixture was stirred while allowing it to cool, and cooled to room temperature. Although no precipitation of crystals was observed, crystals of succinate [(1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol and (1R, 2R)- The diastereomeric ratio of trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol is 93.2: 6.8.
Was added as a seed crystal, and the mixture was stirred at room temperature, and crystal precipitation started after about 5 minutes. Room temperature 30
The mixture was stirred, cooled, and stirred at 5 ° C. for 1 hour. The precipitated crystals were filtered under reduced pressure, and the crystals were mixed with 2-propanol (4 ml).
Washed with. The wet crystals were dried under reduced pressure to give 6.7 g of white crystals of trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate (yield:
42.2%). (1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol of this salt and (1R, 2R) -trans-2-
The diastereomeric ratio of [(S)-(α-methylbenzyl) amino] cyclopentanol was 98.0: 2.7. The mother liquor after concentration under reduced pressure was concentrated to give a pale yellow syrup trans-2-[(S)-(α-methylbenzyl) amino].
Cyclopentanol succinate 6.3 g (yield: 57.
8%). (1S, 2S) -trans-2 of this salt
-[(S)-(α-methylbenzyl) amino] cyclopentanol and (1R, 2R) -trans-2-
The diastereomeric ratio of [(S)-(α-methylbenzyl) amino] cyclopentanol was 19.1: 80.9.

Example 8 Trans-2-[(S)-(α-obtained in Example 7)
3.68 g of methylbenzyl) amino] cyclopentanol succinate was recrystallized from 2-propanol (10 ml) to give white crystals of trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol. Obtained 3.16 g of succinate (recrystallization yield: 85.9%). (1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol of this salt and (1R,
The diastereomeric ratio of 2R) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol is> 99.5: <0.5, indicating the diastereomerically pure (1S , 2S) -trans-2-[(S)-
(Α-Methylbenzyl) amino] cyclopentanol
It was a succinate. Melting point: 127-130 ° C. IR
(KBr, cm ^-1 ): 3406, 2966, 2832, ¹
700, 1647.

Example 9 The diastereoisomerically pure (1S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate obtained in Example 8 1.0 g (3.09 mmol) The same treatment as in Example 6 was carried out to give (1S, 2S) -trans-2-[(S) as a colorless transparent liquid.
-(Α-Methylbenzyl) amino] cyclopentanol was quantitatively obtained. (1S, 2S) -Trans-2-
[(S)-(α-methylbenzyl) amino] cyclopentanol and (1R, 2R) -trans-2-[(S)
The diastereomeric ratio of-([alpha] -methylbenzyl) amino] cyclopentanol is> 99.5: <0.5, indicating the diastereomerically pure (1S, 2S) -trans-2-[(S )-(Α-Methylbenzyl) amino] cyclopentanol.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Maki Okawa             29 Shinmachi, Yashio City, Saitama Prefecture Tama Chemical Industry Co., Ltd.             Inside the company F-term (reference) 4H006 AA02 AB84 AC83 AD15 AD17                       AD33 BB14 BB15 BB21 BB31                       BD10 BD60 BE10 BE12 BJ20                       BJ50 BN20 BU42

Claims (18)

[Claims] 1. The following general formula (1): (In the formula, the absolute configuration at the α-position is individually the R configuration or the S configuration), represented by trans-2-[(α
A mixture of two diastereomers of -methylbenzyl) amino] cyclopentanol is reacted with succinic acid in a solvent to form the succinate salt of both diastereomers,
Precipitating the sparingly soluble salt in this mixture of diastereomeric succinates from the solvent, followed by that of the solid phase diastereomeric succinate and the diastereomeric succinate A method for producing trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate, which comprises solid-liquid separation of a liquid phase containing the salt of 1) as a main component. 2. Formation of succinate, precipitation of a sparingly soluble salt,
And solid-liquid separation with water, methanol, ethanol, 1-
Characterized in that it is carried out in a solvent selected from the group consisting of propanol, 2-propanol, tetrahydrofuran, acetonitrile and mixtures of two or more thereof.
The manufacturing method according to claim 1. 3. Formation of succinate, precipitation of a sparingly soluble salt,
The solid-liquid separation is performed in 2-propanol, and the production method according to claim 1 or 2, characterized in that. 4. The diastereomeric mixture of trans-2-[(α-methylbenzyl) amino] cyclopentanol used is trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol. Which is a diastereomeric mixture of
[(Α-Methylbenzyl) amino] cyclopentanol succinate is (1R, 2R) -trans-2-
[(R)-(α-methylbenzyl) amino] cyclopentanol succinate.
The manufacturing method according to any one of 1 to 3. 5. The diastereomer mixture of trans-2-[(α-methylbenzyl) amino] cyclopentanol used is trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol. Which is a diastereomeric mixture of
[(Α-Methylbenzyl) amino] cyclopentanol succinate is (1S, 2S) -trans-2-
[(S)-(α-methylbenzyl) amino] cyclopentanol succinate.
The manufacturing method according to any one of 1 to 3. 6. Trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is added to water, methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran, acetonitrile and two or more thereof. Recrystallization using a solvent selected from the group consisting of a mixture, a method for producing diastereoisomerically pure trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate . 7. The production method according to claim 6, wherein the recrystallization is performed in 2-propanol. 8. Trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is (1
The method according to claim 6 or 7, which is R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate. 9. Trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is (1
The production method according to claim 6 or 7, which is S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate. 10. Trans-2-[(α-comprising comprising treating trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate under basic conditions.
A method for producing methylbenzyl) amino] cyclopentanol. 11. A diastereomerically pure trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate comprising treating the diastereomerically pure diastereomerically pure succinate. Transformer-2
A method for producing [[(α-methylbenzyl) amino] cyclopentanol. 12. The method according to claim 10 or 11, wherein the base used is selected from the group consisting of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogen carbonate and sodium hydrogen carbonate. 13. Trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is (1
13. The method according to claim 10, which is R, 2R) -trans-2-[(R)-(α-methylbenzyl) amino] cyclopentanol succinate. 14. Trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is (1
13. The method according to claim 10, which is S, 2S) -trans-2-[(S)-(α-methylbenzyl) amino] cyclopentanol succinate. 15. The diastereomerically pure trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is converted into (1R, 2R) -trans-2-[(R)-( α-methylbenzyl) amino] cyclopentanol succinate,
The manufacturing method according to claim 11. 16. A diastereomerically pure trans-2-[(α-methylbenzyl) amino] cyclopentanol succinate is converted into (1S, 2S) -trans-2-[(S)-( α-methylbenzyl) amino] cyclopentanol succinate,
The manufacturing method according to claim 11. 17. (1R, 2R) -trans-2-
[(R)-(α-methylbenzyl) amino] cyclopentanol succinate. 18. (1S, 2S) -trans-2-
[(S)-(α-methylbenzyl) amino] cyclopentanol succinate.