JP2002193901A - Method of optical resolution of (1s*,4r*)-4-amino-2- cyclopentene-1-carboxylic esters - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple method of obtaining high purity (1S,4R)-4-amino-2- cyclopentene-1-carboxylic esters or (1R,4S)-4-amino-2-cyclopentene-1-carboxylic esters in high yield. SOLUTION: The method of optical resolution of a (1S*,4R*)-4-amino-2- cyclopentene-1-carboxylic ester is characterized by reacting a (1S*,4R*)-4- amino-2-cyclopentene-1-carboxylic ester with a 2-hydroxycarboxylic acid of high optical activity or a sulfonic acid of high optical activity in the presence of a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to (1S ^* , 4R
^* ) It relates to an optical resolution method for 4-amino-2-cyclopentene-1-carboxylic acid esters. (1S, 4R) -4-amino-2-cyclopentene-1-carboxylic acid esters or (1R, 4S)-obtained by the present invention.
4-Amino-2-cyclopentene-1-carboxylic esters are useful as synthetic intermediates for pharmaceuticals such as anti-influenza drugs.

[0002]

2. Description of the Related Art Conventionally, (1S, 4R) -4-amino-2
As a method for preparing -cyclopentene-1-carboxylic acid esters, optically active 2-azabicyclo [2.2.1] is used.
A method is known in which hept-5-en-3-one [hereinafter, 2-azabicyclo [2.2.1] hept-5-en-3-one may be abbreviated as ABH] is alcoholyzed. (See WO 99/33781).

[0003]

In the above-mentioned method, it is necessary to use optically active ABH as a raw material. Optical activity A
As a method for producing BH, for example, a method of optically resolving (±) -ABH using a microorganism or an enzyme (Japanese Patent No. 2648)
No. 013) is known, but in this method,
Special microorganisms or enzymes are required, and there are problems such as low reactor efficiency due to low substrate concentration during the reaction and long reaction time. Therefore, the above-mentioned method is not easy to obtain optically active ABH as a raw material, and cannot be said to be an industrially advantageous method for producing optically active ACC.

However, the object of the present invention is (1S, 4
R) -4-Amino-2-cyclopentene-1-carboxylic acid esters or (1R, 4S) -4-amino-2-
High purity cyclopentene-1-carboxylic acid ester,
An object of the present invention is to provide a method for obtaining a compound in a high yield and easily.

[0005]

According to the present invention, the above object is achieved by the general formula (1)

[0006]

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(In the formula, R ¹ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted aryl group or an optionally substituted aralkyl group.) (1S ^* , 4R
^* )-4-Amino-2-cyclopentene-1-carboxylic acid esters [hereinafter referred to as (±) -ACCs (1)
To the general formula (3) in the presence of a solvent.

[0008]

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[0009] (In the formula, * represents an asymmetric carbon atom, ^{R 2}
And R ³ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an aryl group which may have a substituent or an aralkyl group which may have a substituent, or R ⁴ may be a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, an aryl group which may have a substituent, or a substituent; Represents an aralkyl group which may have ) [Hereinafter may be referred to as optically active 2-hydroxycarboxylic acids (3)] or a general formula (4)

[0010]

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Wherein * represents an asymmetric carbon atom;
⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom,
Alkyl group, cycloalkyl group, bicycloalkyl group,
Represents an alkenyl group, an alkynyl group, an alkoxyl group, an aryl group or an aralkyl group which may have a substituent, or forms a ring together with a carbon atom to which they are bonded, or R ⁵ , R ⁶ and R ⁷
Two of which together with the carbon atom to which they are attached may form a ring. ) [Hereinafter referred to as an optically active sulfonic acid (4)
[±] -ACCs (1).

In a preferred embodiment, (±) -AC
Class C (1) is represented by the general formula (2)

[0013]

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(Wherein R ¹ is as defined above, and X represents a halogen atom, a carboxylic acid residue or a sulfonic acid residue.) (1S ^* , 4R ^* )-4
-Amino-2-cyclopentene-1-carboxylic acid ester [hereinafter, this may be referred to as (±) -ACC salt (2)] with a base.

In the above formula, R ¹ , R ² , R ³ , R ⁴ ,
Examples of the alkyl group represented by R ⁵ , R ⁶ and R ⁷ include, for example, a methyl group, an ethyl group, an n-propyl group,
i-propyl group, n-butyl group and the like; alkenyl group includes, for example, vinyl group, allyl group, 1-propenyl group; and alkynyl group includes, for example, ethynyl group, 2-propynyl group and the like. No. R
¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Examples of the aryl group represented by each include a phenyl group and a naphthyl group, and examples of the aralkyl group include a benzyl group and a phenethyl group. Aryl groups and aralkyl groups may have a substituent on their aromatic ring, such substituents include
For example, halogen atoms such as chlorine atom, bromine atom and iodine atom; alkyl groups such as methyl group, ethyl group and n-propyl group; aryl groups such as naphthyl group and p-methylphenyl group; methoxy group, ethoxy group and n -An alkoxyl group such as a propoxy group; a nitro group.

The ring which R ² and R ³ may form together with the carbon atom to which they are bonded includes, for example, a cyclopentane ring, a cyclohexane ring and the like.

Examples of the cycloalkyl group represented by R ¹ , R ⁵ , R ⁶ and R ⁷ include, for example, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group and the like, and a bicyclo group represented by R ⁵ , R ⁶ and R ⁷ respectively. Examples of the alkyl group include a 7,7-dimethylbicyclo [2.2.1] hepta-2-one-1-yl group, an isopinocampheyl group, and the like.

The acyl group represented by R ⁴ includes, for example, a formyl group, an acetyl group, a propionyl group, a benzoyl group and the like.

Examples of the alkoxyl group represented by R ⁵ , R ⁶ and R ⁷ include, for example, a methoxy group, an ethoxy group and an n-propoxy group. R ⁵ , R ⁶
And The ring which may have formed together with the carbon atom to which R ⁷ is bonded, for example, 7,7-dimethyl-bicyclo [2.2.1] heptane ring, include such norbornane ring, R ^5, Examples of the ring which two of R ⁶ and R ⁷ may form together with the carbon atom to which they are bonded include a cyclopentane ring and a cyclohexane ring.

Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the carboxylic acid residue include an acetic acid residue, a propionic acid residue, an oxalic acid residue and a formic acid residue. And sulfonic acid residues, for example, p-toluenesulfonic acid residue,
Methanesulfonic acid residue, trifluoromethanesulfonic acid residue, sulfuric acid residue and the like can be mentioned.

The reaction in the present invention is carried out in advance by using (±) -AC
The (±) -ACCs (1) prepared by allowing a base to act on the C salt (2) were added with the optically active 2 in the presence of a solvent.
May be carried out by adding hydroxycarboxylic acids (3) or optically active sulfonic acids (4), but (±)
-From the viewpoint of the stability of ACCs (1), a base is present in a system in which an optically active 2-hydroxycarboxylic acid (3) or an optically active sulfonic acid (4) and a (±) -ACC salt (2) and a solvent are present. And the (±) -ACCs (1) generated by the reaction of the (±) -ACC salt (2) with the base are immediately reacted with the optically active 2-hydroxycarboxylic acids (3) or the optically active sulfonic acids (4). It is preferable to perform the above.

As the base, any of an inorganic base and an organic base can be used. Examples of the inorganic base include hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate and calcium carbonate; hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate. Examples of the organic base include pyridine, imidazole, triethylamine and the like. These bases are previously prepared as optically active 2-
It may be used as a salt of the hydroxycarboxylic acid (3) or the optically active sulfonic acid (4).

The amount of the base used is (±) -ACC salt (2)
Is preferably in the range of 0.25 to 1.5 times the molar amount of
More preferably, it is in the range of 5- to 1.0-fold molar.

The method for producing the (±) -ACCs (1) and the (±) -ACC salt (2) used in the present invention is not particularly limited. The hydrochloride can be produced by treating (±) -ABH with a hydrogen chloride alcohol solution (WO 99/337).
81 publication).

The amount of the optically active 2-hydroxycarboxylic acid (3) or the optically active sulfonic acid (4) used is as follows:
(±) -ACCs (1) or (±) -ACC salts (2)
Is preferably in the range of 0.3 to 1.5 times the molar amount to 0.4 to 1.5 times in terms of economy and ease of post-treatment.
More preferably, it is in the range of 1.0 mole.

As the solvent, a solvent used in ordinary organic reactions can be used as long as it does not adversely affect the reaction in the present invention. Preferred solvents include, for example, alcohols such as methanol, ethanol, n-propanol and i-propanol; nitriles such as acetonitrile, propionitrile and benznitrile; aromatic hydrocarbons such as toluene, xylene and cumene; acetone. And ketones such as methyl ethyl ketone and methyl isopropyl ketone. These solvents may be used alone or as a mixture of two or more. The amount of the solvent used is preferably in the range of 1 to 50 times the weight of (±) -ACCs (1) or (±) -ACC salt (2), and 1 to 10 times the weight from the viewpoint of economy. Is more preferable.

The reaction temperature varies depending on the type of substrate and solvent used, but is preferably in the range of room temperature to 120 ° C., more preferably in the range of 25 to 70 ° C.
Although the reaction time varies depending on the type of the substrate and the solvent used, it is preferably about 5 minutes to 5 hours, more preferably about 5 minutes to 2 hours.

In the above reaction, the optical activity 2
-When the hydroxycarboxylic acid (3) or the optically active sulfonic acid (4) is in the (R) -form, (1S, 4R)-
ACCs and [(1R, 4S) -ACCs corresponding to [(1
(S, 4R) -ACCs (R) -optical resolving agent] salt and [(1R, 4S) -ACCs (R) -optical resolving agent] salt are obtained, and optically active 2-hydroxycarboxylic acids used When (3) or the optically active sulfonic acid (4) is in the (S) -form, [(1S, 4R) -ACCs · (S) -optical resolving agent] salt and [(1R, 4S) -ACC Kind
(S) -optical resolution agent].

The above diastereomer salt can be prepared, for example, by cooling the reaction solution to a crystallization temperature to make it supersaturated, and making use of the difference in solubility of the diastereomer salt in the solvent to one of the more insoluble diastereomer salts. Can be optically separated from each other by preferentially crystallization. The crystallization temperature varies depending on the type and amount of the solvent used, the reaction temperature, and the like, but is preferably in the range of -10C to 30C from the viewpoint of economy.

When crystallizing one diastereomer salt, it is preferable to add a very small amount of the diastereomer salt to be crystallized to the reaction solution as seed crystals. The precipitated diastereomer salt can be isolated by a usual method such as filtration and centrifugation.

The obtained diastereomer salt is reacted with a base such as triethylamine, sodium hydroxide or potassium hydroxide to give the free (1S, 4
Although R) -ACCs or (1R, 4S) -ACCs can be used, they can also be used as such as synthetic intermediates of pharmaceuticals such as anti-influenza drugs without such operations.

[0032]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 A 1 L four-necked flask equipped with a thermometer and a stirrer was charged with 200 g of (1S ^* , 4R ^* )-4-amino-1-methoxycarbonyl-2-cyclopentene hydrochloride.
(1.13 mol), 540 g of acetonitrile and 60 g of methanol were charged. After the internal temperature was raised to 50 ° C., 98.4 g of sodium (R) -mandelicate (0.5%) was added.
7 mol) over 30 minutes. After stirring for 30 minutes, the resulting solid was filtered using a glass filter. The filtrate was gradually cooled to 3 ° C. while stirring, and then precipitated (1).
S, 4R) -4-Amino-1-methoxycarbonyl-2
The crystals of -cyclopentene. (R) -mandelic acid salt were filtered. The obtained crystals were subjected to high performance liquid chromatography (H
PLC) analysis revealed that the optical purity was 92.1% ee. The yield of crystals after drying was 82.6 g (0.28 m
ol) and the yield was 24.8% (based on the racemate).

Example 2 200 g of (1S ^* , 4R ^* )-4-amino-1-methoxycarbonyl-2-cyclopentene hydrochloride was placed in a 1 L four-necked flask equipped with a thermometer and a stirrer.
(1.13 mol), 540 g of acetonitrile, 60 g of methanol and 85.7 g of (R) -mandelic acid (0.
57 mol). After raising the internal temperature to 50 ° C,
57.0 g (0.57 mol) of triethylamine in 30
We put in over a minute. After stirring for 30 minutes, the mixture was gradually cooled to 3 ° C. with stirring to precipitate (1S, 4R) -4-amino-1-methoxycarbonyl-2-cyclopentene.
The crystals of (R) -mandelic acid salt were filtered. When the obtained crystals were analyzed by HPLC, the optical purity was 92.3% ee.
Met. The yield of crystals after drying was 81.9 g (0.28 g).
mol), and the yield was 24.8% (based on the racemate).

Example 3 In Example 1, (R) -sodium mandelate 9
The same operation was performed except that 98.4 g (0.57 mol) of sodium (S) -mandelate was used instead of 8.4 g (0.57 mol). Obtained (1R, 4S)-
HPLC analysis of crystals of 4-amino-1-methoxycarbonyl-2-cyclopentene. (S) -mandelic acid salt revealed that the optical purity was 91.8% ee. The yield of the crystals after drying was 83.6 g (0.29 mol), and the yield was 25.7% (based on the racemate).

Example 4 In Example 2, 85.7 g of (R) -mandelic acid was used.
(S) -mandelic acid 8 instead of (0.57 mol)
The same operation was performed except that 5.7 g (0.57 mol) was used. The resulting (1R, 4S) -4-amino-1-
HPLC analysis of the crystals of methoxycarbonyl-2-cyclopentene. (S) -mandelic acid salt revealed that the optical purity was 92.8% ee. The yield of crystals after drying is 8
3.3 g (0.28 mol), the yield was 24.8%
(Based on racemic 100%).

Example 5 In Example 1, (R) -sodium mandelate 9
144.9 g (0.57 mol) of sodium (S) -camphorsulfonate instead of 8.4 g (0.57 mol)
The same operation was performed except that 1) was used. (1
S, 4R) -4-Amino-1-methoxycarbonyl-2
HPLC analysis of crystals of -cyclopentene. (S) -camphorsulfonate revealed that the optical purity was 65.5%.
ee. The yield of crystals after drying was 33.6 g (0.
09 mol), and the yield was 8.0% (based on the racemate).

Example 6 In Example 2, 85.7 g of (R) -mandelic acid was used.
The same operation was performed except that 142.7 g (0.57 mol) of (S) -camphorsulfonic acid monohydrate was used instead of (0.57 mol). Obtained (1S, 4R)
The crystals of -4-amino-1-methoxycarbonyl-2-cyclopentene. (S) -camphorsulfonate were converted to HP
As a result of LC analysis, the optical purity was 72.8% ee. The yield of the crystals after drying was 41.1 g (0.11 mol).
l) with a yield of 9.7% (based on the racemate)
Met.

[0039]

According to the present invention, (1S, 4R) -4-
Amino-2-cyclopentene-1-carboxylic acid esters or (1R, 4S) -4-amino-2-cyclopentene-1-carboxylic acid esters can be easily produced with high purity, high yield, and high yield.

Claims (2)

[Claims] 1. A compound of the general formula (1) (In the formula, R ¹ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group which may have a substituent, or an aralkyl group which may have a substituent.) (1S ^* , 4R ^* )-4-Amino-2-cyclopentene-1-carboxylic acid ester is converted to a compound of the general formula (3) in the presence of a solvent. (In the formula, * represents an asymmetric carbon atom, and R ² and R ³ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an optionally substituted aryl group or a substituent. R ⁴ may represent a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, an acyl group, or may represent a aralkyl group which may be possessed, or may form a ring together with a carbon atom to which they are bonded. Represents an aryl group which may have a substituent or an aralkyl group which may have a substituent.)
-Hydroxycarboxylic acids or the general formula (4) (In the formula, * represents an asymmetric carbon atom, and R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom, an alkyl group, a cycloalkyl group, a bicycloalkyl group, an alkenyl group, an alkynyl group, an alkoxyl group, Represents an aryl group which may have a group or an aralkyl group which may have a substituent, or forms a ring together with the carbon atom to which they are bonded, or R ⁵ , R ^{5 6} and R ⁷ may be combined with the carbon atom to which they are attached to form a ring.) ^* , 4R ^* ) Optical resolution of 4-amino-2-cyclopentene-1-carboxylic acid esters. 2. The method according to claim 1, wherein (1S ^* , 4R)
^* ) 4-Amino-2-cyclopentene-1-carboxylic acid ester is represented by the general formula (2): (Wherein, R ¹ represents an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an optionally substituted aryl group or an optionally substituted aralkyl group, and X represents a halogen atom , Represents a carboxylic acid residue or a sulfonic acid residue.) (1S ^* , 4R ^* )
The optical resolution method according to claim 1, which is prepared by allowing a base to act on a salt of -4-amino-2-cyclopentene-1-carboxylic acid esters.