JP3007463B2 - Optically active salt of 2-fluorocyclopropanecarboxylic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an optically active salt of a compound useful as a raw material for producing a quinolone derivative (Japanese Patent Application No. 2-231475) which is an excellent antibacterial agent. That is, cis-2
-With respect to salts composed of fluorocyclopropane-1-carboxylic acid and an optically active organic base, in particular (1S, 2
The present invention relates to a salt composed of S) -2-fluorocyclopropane-1-carboxylic acid and an optically active organic base.

[0002]

BACKGROUND OF THE INVENTION Stereoisomerically pure cis-2-fluorocyclopropane-1-carboxylic acid, ie, (1S, 2S) -2-
Fluorocyclopropane-1-carboxylic acid or (1R, 2R)-
Conventionally, 2-fluorocyclopropane-1-carboxylic acid has been converted from racemic cis-2-fluorocyclopropane-1-carboxylic acid to an optically active amide derivative with 1-phenylethylamine to give two diastereomers. Was separated by column chromatography, and then the amide was hydrolyzed.

This method involves the formation and cleavage of an amide bond.
The number of production steps is increased due to the need for steps, and there is a possibility that side reactions may occur in each step, and the separation and generation of by-products may become complicated. It was difficult to say that it was most suitable as an industrial production method, for example, a chromatographic treatment was required to separate the mers.

[0004]

SUMMARY OF THE INVENTION Accordingly, the present inventors have developed a stereoisomerically pure cis-2-fluorocyclopropane-1.
-A method for obtaining a carboxylic acid more easily was examined. That is, a salt of racemic cis-2-fluorocyclopropane-1-carboxylic acid and an optically active organic base is formed, and cis-2-fluorocyclopropane-1-carboxylic acid and an optically active organic base are formed from this salt. It was believed that the objective could be achieved by isolating a previously unknown stereoisomerically pure salt of the compound. As a result of diligent studies, it is composed of (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid or (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid and various optically active organic bases. The present inventors have found that a new salt meets the intended purpose and completed the present invention.

[0005]

The present invention relates to a salt of cis-2-fluorocyclopropane-1-carboxylic acid with an optically active organic base,
Further, the cis-2-fluorocyclopropane-1-carboxylic acid is (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid or (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid. Related to the above salts.

The optically active organic base has the formula (Wherein, Aryl represents a halogen atom, a nitro group, a cyano group, a carbamoyl group, an aryl group which may have an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, and R ¹ , R ² And R ³ may be the same or different and include a halogen atom, an alkyl group having 6 or less carbon atoms, a halogenoalkyl group having 6 or less carbon atoms, an alkoxy group having 6 or less carbon atoms, a nitro group, a carbamoyl group or A phenyl group which may have a cyano group, a halogen atom, an alkyl group having 6 or less carbon atoms, a halogenoalkyl group having 6 or less carbon atoms, an alkoxy group having 6 or less carbon atoms, a nitro group, a carbamoyl group or a cyano group. A benzyl group having a phenyl group, an alkyl group having 1 to 5 carbon atoms, or a hydrogen atom.) Serial relates to a salt of.

Further, when the optically active organic base is N-benzyl-
α-methylbenzylamine, (R)-(+)-N-benzyl-α
-Methylbenzylamine, 1-phenyl-2- (p-tolyl) ethylamine, (R) -1-phenyl-2- (p-tolyl) ethylamine, 1-phenylethylamine, (R)-(+)-1- Phenylethylamine, 1- (1-naphthyl) ethylamine, (S)-
(-)-1- (1-naphthyl) ethylamine or (-)-cis-2-
It relates to the above salt, which is benzylaminocyclohexanemethanol.

[0008] cis-2-fluorocyclopropane-1-carboxylic acid is a compound in which a fluorine atom and a carboxyl group are in a cis configuration on a cyclopropane ring, and there are two enantiomers. These are (1S, 2S) -2-fluorocyclopropane-1-
Carboxylic acid or (1R, 2R) -2-fluorocyclopropane-1
-Carboxylic acid. Equation 1 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid represented by the formula: The salt of (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid represented by and an optically active organic base can be obtained by the following method.

[0009] Racemic cis-2-fluorocyclopropane-1-carboxylic acid and an optically active organic base are usually dissolved in a suitable solvent and then mixed to form a diastereomer salt. Then, a salt of one cis-2-fluorocyclopropyl-1-carboxylic acid and an optically active organic base is crystallized. Once the salt once formed is further recrystallized using an appropriate solvent, the desired salt with higher purity can be obtained.

The stereoisomerically pure salt referred to in the present invention is as follows. That is, when a stereoisomer is present in the acid and the base constituting the salt, the acid and the base formed of one kind of the stereoisomer occur in combination when the stereoisomer exists in the acid and the base. Salt is called stereoisomerically pure. In other words, it indicates that both the acid and the base constituting the salt are composed of one type of stereoisomer. Here, being composed of one type of stereoisomer may be any state as long as it is recognized that it does not substantially contain another isomer.

The optically active organic base used for forming the salt includes, for example, a compound represented by the formula (Wherein, Aryl represents a halogen atom, a nitro group, a cyano group, a carbamoyl group, an aryl group which may have an alkyl group having 1 to 5 carbon atoms or an alkoxy group having 1 to 5 carbon atoms, and R ¹ , R ² And R ³ may be the same or different and include a halogen atom, an alkyl group having 6 or less carbon atoms, a halogenoalkyl group having 6 or less carbon atoms, an alkoxy group having 6 or less carbon atoms, a nitro group, a carbamoyl group or A phenyl group which may have a cyano group, a halogen atom, an alkyl group having 6 or less carbon atoms, a halogenoalkyl group having 6 or less carbon atoms, an alkoxy group having 6 or less carbon atoms, a nitro group, a carbamoyl group or a cyano group. Represents a benzyl group having a phenyl group, an alkyl group having 1 to 5 carbon atoms, or a hydrogen atom. Substituted optically active ethylamine derivatives Le group (1-aryl-ethylamine derivatives)
Can be mentioned.

Here, examples of the aryl group include a phenyl group and a naphthyl group. The aromatic ring of these aryl groups may have one or more of a halogen atom, a nitro group, a cyano group, a carbamoyl group, an alkyl group having 1 to 5 carbon atoms, or an alkoxy group having 1 to 5 carbon atoms, One or more of these substituents may be present.

Such optically active bases include N-benzyl-α-methylbenzylamine and 1-phenyl-2- (p-
Tolyl) ethylamine, 1-phenylethylamine and
1- (1-naphthyl) ethylamine can be exemplified. Of these bases, (R)-(+)-N-benzyl can form a more advantageous salt in combination with (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid. -Α-methylbenzylamine, (R) -1-phenyl-2
-(p-Tolyl) ethylamine, (R)-(+)-1-phenylethylamine and (S)-(-)-1- (1-naphthyl) ethylamine are preferred.

On the other hand, the aromatic ring of the 1-arylethylamine derivative may be not only a hydrocarbon-based aromatic ring but also an aromatic heterocyclic ring containing a sulfur atom, a nitrogen atom or an oxygen atom. For example, thiophene, benzothiophene, pyridine, quinoline, isoquinoline, furan, benzofuran and the like can be mentioned.

In addition, salt formation can be performed with an optically active organic base other than the 1-arylethylamine derivative. For example, 2-benzylaminocyclohexanemethanol may be used, and (-)-cis-2-benzylaminocyclohexanemethanol is preferable in combination with (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid.

The amount of the optically active base used is usually equal to or less than the amount of the carboxylic acid.

Various solvents can be used as a solvent for crystallization or recrystallization of the target salt.

Among them, examples of the hydrocarbon solvent include n-hexane, n-pentane, benzene, toluene,
Methanol, ethanol, propanol, isopropanol (IPA), n-
As ether solvents such as butanol, diethyl ether, tetrahydrofuran (THF), dimethoxyethane (DM
E), etc .; Halogen solvents such as chloroform, methylene chloride and ethylene chloride; amide solvents such as dimethylformamide (DMF) and dimethylacetamide
(DMAC) and the like. In addition, water, acetonitrile, acetates and the like can be mentioned. These solvents may be used alone or in combination of two or more.

Although the amount of the solvent to be used cannot be unconditionally determined, it may be about 2 to 100 times as a standard.

The temperature at which the target salt is crystallized or recrystallized is not constant, but may be a temperature condition generally used, and specifically, a temperature between ice-cooling and the boiling point of the solvent used. It should be done in.

Next, the present invention will be described in detail with reference to examples and reference examples, but the present invention is not limited to these examples.

The optical purity of (1S, 2S)-or (1R, 2R) -fluorocyclopropane-1-carboxylic acid was measured as follows. In addition, the absolute configurations of these compounds were determined in comparison with samples synthesized separately and having known absolute configurations.

Reference Example: Optical Purity Measurement Method 850 mg of diphenylphosphoric acid chloride was added to dichloromethane 6
of triethylamine 0.9 ml while stirring under ice-cooling.
300 mg of the free form of cis-2-fluorocyclopropane-1-carboxylic acid and (S) -1-phenylethylamine are sequentially added. After stirring at room temperature for 20 hours, the reaction solution is washed with water, 1N hydrochloric acid, 1N aqueous sodium hydroxide solution, and water in this order. After drying the organic layer with anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. 10 mg of the obtained amide derivative in 10 ml
5 μl of a solution dissolved in a mobile phase solvent is subjected to high performance liquid chromatography using a normal phase column to measure optical purity. High performance liquid chromatography conditions: Column; YMC SIL A-002 (4.6 mm x 15 cm) Mobile phase; n-hexane: ethyl acetate = 1: 1 (v / v) Elution rate; 1 ml / min detection; UV, 254 nm

[0024]

【Example】

Example 1 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid / (R)-(+)-N-benzyl-α-methylbenzylamine salt Cis-2-fluorocyclopropane-1-carboxylic acid 2.48
g was dissolved in 60 ml of isopropyl ether.
(R)-(+)-N-benzyl-α-methylbenzylamine 5.0
A solution of 3 g in 60 ml of isopropyl ether was added at room temperature. After the reaction solution in which crystals were precipitated was stirred at room temperature overnight, the crystals were collected by filtration.

[0025] 2.0 g of the obtained crystals were added to 95 ml of isopropyl ether, dissolved under heating and reflux, and allowed to cool at room temperature overnight. The precipitated crystals were collected by filtration and dried to give the title compound 1.11
g was obtained as colorless crystals.

Melting point: 89-91 ° C. [α] _D = 39.39 ° (c = 1.01, methanol) Elemental analysis: Calculated as C ₄ H ₅ O ₂ F.C ₁₅ H ₁₇ N (%) C 72.33 H 7.04 N 4.44 Analytical value (%) C 72.03 H 7.28 N 4.93 ¹ H-NMR (CDCl ₃ ) δ: 1.01-1.04 (m, 1H), 1.46 (d, 3H,
J = 7.2 Hz), 1.69-1.71 (m, 1H), 1.72-1.76 (m, 1
H), 3.71 (q, 2H, J = 12.5 Hz), 3.96 (q, 1H, J = 5.2 H
z), 4.63-4.77 (m, 1H), 7.18 (br, 1H), 7.22-7.40
(m, 10H)

Reference Example 1 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (1S, 2S) -2-fluorocyclopropane-1- obtained in Example 1
Carboxylic acid ・ (R)-(+)-N-benzyl-α-methylbenzylamine salt 100 mg and 1N sodium hydroxide 1.2 ml, water
After mixing with 1.0 ml, the mixture is mixed with 3 ml of chloroform.
And washed three times. Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 40 mg of the title compound as an oil.

Optical purity 90.0% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H)

Example 2 (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid / (S)-(-)-N-benzyl-α-methylbenzylamine salt Cis-2-fluorocyclopropane-1-carboxylic acid 1.64
g in 40 ml of isopropyl ether.
(S)-(-)-N-benzyl-α-methylbenzylamine 3.33
g was dissolved in 40 ml of isopropyl ether at room temperature. After the reaction solution in which crystals were precipitated was stirred at room temperature overnight, the crystals were collected by filtration.

[0030] 1.80 g of the obtained crystals were dissolved in isopropyl ether.
The solution was added to 42 ml of Teru, dissolved under heating and reflux, and left at room temperature overnight. The precipitated crystals were collected by filtration and dried to give 1.25 g of the title compound as pale red crystals.

Melting point: 84-85 ° C. [α] _D = −31.23 ° (c = 1.01, methanol) Elemental analysis: Calculated value (%) as C ₄ H ₅ O ₂ F · C ₁₅ H ₁₇ N C 72.33 H 7.04 N 4.44 Analytical value (%) C 72.24 H 7.00 N 4.44 ¹ H-NMR (CDCl ₃ ) δ: 0.86-1.17 (m, 1H), 1.47 (d, 3H,
J = 7.2 Hz), 1.57-1.90 (m, 2H), 3.63 (q, 2H, J = 1
2.5 Hz), 3.94 (q, 1H, J = 5.4 Hz), 4.21-5.13 (m, 1
H), 7.17-7.50 (m, 10H), 9.13 (br, 1H)

Reference Example 2 (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid (1R, 2R) -2-fluorocyclopropane-1 obtained in Example 2
-Carboxylic acid ・ (S)-(-)-N-benzyl-α-methylbenzylamine salt 100 mg and 1N sodium hydroxide solution 1.2 m
l and water (1.0 ml) were mixed and washed three times with chloroform (3 ml). Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 36 mg of the title compound as an oil.

Optical purity 99.0% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H)

Example 3 (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid / (S)-(+)-1-phenyl-2- (P-tolyl) ethylamine salt Cis-2-fluorocyclopropane-1-carboxylic acid 2.0 g
Was dissolved in 55 ml of diethyl ether. Next, (S)-(+)-1-phenyl-2- (P-tolyl) ethylamine
A solution of 4.06 g in 55 ml of diethyl ether was added at room temperature. The reaction solution in which the crystal was precipitated was stirred at room temperature for 1 hour and collected.

5.0 g of the obtained crystal was mixed with 110 ml of ethanol.
And dissolved under heating and reflux, and then allowed to cool at room temperature. The precipitated crystals were collected by filtration, dried, and the same procedure was repeated to give 1.17 g of the title compound as colorless crystals.

Melting point: 176-178 ° C. [α] _D = 58.70 ° (c = 1.02, methanol) Elemental analysis: Calculated value (%) as C ₄ H ₅ O ₂ F · C ₁₅ H ₁₇ N C 72.33 H 7.04 N 4.44 Analytical value (%) C 72.55 H 7.04 N 4.41 1H-NMR (CDCl ₃ , CF ₃ COOH) δ: 0.89-1.86 (m, 3H), 2.40
(s, 3H), 3.06 (d, 2H, J = 5.4 Hz), 4.17-5.11 (m, 2
H), 6.64-7.51 (m, 11H)

Reference Example 3 (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid (1R, 2R) -2-fluorocyclopropane-1- obtained in Example 3.
Carboxylic acid ・ (S)-(+)-1-phenyl-2- (P-tolyl) ethylamine 50 mg and 1.2 ml of 1N sodium hydroxide solution, water
1.0 ml, and the mixture was washed three times with 3 ml of chloroform.

Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the title compound (20 mg) as an oil.

Optical purity 100% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H)

Example 4 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid / (-)-cis-2-benzylaminocyclohexanemethanol salt (-)-Cis-2-benzylaminocyclohexanemethanol
2.1 g was dissolved in 30 ml of diethyl ether. Next, a solution of 1.0 g of cis-2-fluorocyclopropane-1-carboxylic acid dissolved in 30 ml of diethyl ether was added to this solution at room temperature. The reaction solution in which crystals were precipitated was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration.

2.3 g of the obtained crystal was mixed with acetonitrile 70
After dissolving in water under reflux, the mixture was allowed to cool at room temperature. The precipitated crystals were collected by filtration, dried, and the same operation was repeated to give 0.42 g of the title compound as colorless crystals.

Melting point: 116-117 ° C. [α] _D = 19.18 ° (c = 1.01, methanol) Elemental analysis: Calculated value (%) as C ₄ H ₅ O ₂ F · C ₁₄ H ₂₁ N C 66.85 H 8.10 N 4.33 Analytical value (%) C 66.90 H 7.73 N 4.51 1H-NMR (CDCl ₃ ) δ: 0.80-1.91 (m, 11H), 2.05-2.40
(br, 1H), 2.83-3.23 (br, 1H), 3.37-3.51 (m, 2H),
3.99 (s, 2H), 4.17-5.20 (m, 1H), 7.06-7.63 (m, 8
H)

Reference Example 4 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid obtained in Example 4.
Carboxylic acid ・ (-)-cis-2-benzylaminocyclohexanemethanol salt 50 mg and 1N sodium hydroxide solution 1.2 m
and 1.0 ml of water, and washed three times with 3 ml of chloroform. Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 20 mg of the title compound as an oil.

Optical purity 87.2% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H) Example 5 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (D)-(+) -α-phenethylamine salt Cis-2-fluorocyclopropane-1-carboxylic acid 0.7 g
Was dissolved in 5 ml of isopropyl ether. Next, a solution of 0.81 g of (R)-(+)-phenethylamine dissolved in 5 ml of isopropyl ether was added to this solution at room temperature. After the reaction solution on which the crystals were precipitated was stirred overnight at room temperature, the crystals were collected by filtration. After dissolving 1.2 g of the obtained crystals in 95 ml of tertiary butyl-methyl ether while heating under reflux, the mixture was allowed to cool at room temperature overnight. The precipitated crystals were collected by filtration, dried, and the same procedure was repeated to obtain 0.77 g of the title compound as colorless crystals.

Melting point: 75-76 ° C. [α] _D = 31.37 ° (c = 1.07, methanol) Elemental analysis: C ₄ H ₅ O ₂ F · C ₈ H ₁₁ N Calculated value (%) C 63.95 H 7.17 N 6.22 Analytical value (%) C 63.80 H 7.51 N 6.30 ¹ H-NMR (CDCl ₃ ) δ: 0.49-0.91 (m, 1H), 1.20-1.49
(m, 2H, J = 6.2 Hz), 1.57 (d, 3H), 4.00-4.99 (m, 2
H), 6.23-6.57 (br, 3H), 7.14-7.51 (m, 5H)

Reference Example 5 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (1S, 2S) -2-fluorocyclopropane-1 obtained in Example 5
-Carboxylic acid ・ (D)-(+)-α-phenethylamine salt 50 mg
And 1.2 ml of 1N sodium hydroxide solution and 1.0 ml of water, and the mixture was washed three times with 3 ml of chloroform. Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and then ethyl acetate was added.
Extracted three times with ml. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
The title compound (22 mg) was obtained as an oil.

Optical purity 90.6% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H)

Example 6 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid / (R)-(-)-1-phenyl-2- (p-tolyl) ethylamine salt Cis-2-fluorocyclopropane-1-carboxylic acid 3.12
g was dissolved in 40 ml of diethyl ether. Then add (R)-(-)-1-phenyl-2- (p-tolyl) ethylamine to this solution
A solution of 6.34 g in 160 ml of diethyl ether was added at room temperature. Crystals precipitated immediately. After stirring the mixture at room temperature for 1 hour, the crystals were collected by filtration. Dry this
9.35 g of crude crystals were obtained.

The obtained crude crystals were dissolved in 234 ml of ethanol while heating under reflux, and then allowed to cool at room temperature for 15 hours. The precipitated crystals were collected by filtration and dried to obtain 2.67 g of crystals. This crystal was recrystallized by the same operation again to obtain the title compound.
1.70 g were obtained.

Melting point: 177-179 ° C (wet at about 171 ° C) [α] _D = -64.42 ° (c = 1.01, methanol) Elemental analysis: Calculated value (%) C as C ₁₉ H ₂₂ O ₂ NF 72.36 H 7.03 N 4.44 Analytical value (%) C 72.36 H 6.78 N 4.72 ¹ H-NMR (CDCl ₃ ) δ: 0.92-1.90 (m, 3H), 2.26 (s, 3H),
2.90-3.26 (m, 2H), 4.16-4.44 and 5.0-5.17 (m,
total 3H), 6.86 and6.97 (d, J = 7 Hz, 2H), 7.32 (s, 5
H)

Reference Example 6 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid (1S, 2S) -2-fluorocyclopropane-1 obtained in Example 6.
-Carboxylic acid ・ (R)-(-)-1-phenyl-2- (p-tolyl) ethylamine 100 mg and 1N sodium hydroxide solution 1.2 m
l and 1.0 ml of water were mixed, and the mixture was washed three times with 3 ml of chloroform. Next, the aqueous layer was acidified by adding 5 ml of 1N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 37 mg of the title compound as an oil.

Optical purity 95.5% ee ¹ H-NMR (CDCl ₃ ) δ: 1.06-1.49 (m, 1H), 1.63-2.11
(m, 2H), 4.43-5.29 (m, 1H), 10.49-10.97 (br, 1H)

Example 7 (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid / (S)-(-)-1- (1-naphthyl) ethylamine salt (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid 520
mg was dissolved in 5 ml of diethyl ether. Next, to this solution was added a solution prepared by dissolving 856 mg of (S)-(-)-1- (1-naphthyl) ethylamine in 5 ml of diethyl ether at room temperature. Crystals precipitated immediately. After stirring the mixture at room temperature for 2 hours, the crystals were collected by filtration. This was dried to obtain 1.335 g of crude crystals.

The obtained crude crystals were washed with isopropyl alcohol
After dissolving in 9.5 ml with heating under reflux, the mixture was allowed to cool with stirring at room temperature for 13 hours. The precipitated crystals were collected by filtration and dried, 820 mg
Was obtained.

Melting point: 148 ° C. [α] _D = 14.25 ° (c = 1.02, methanol) Elemental analysis: Calculated value (%) as C ₁₆ H ₁₈ O ₂ NF C 69.80 H 6.59 N 5.09 Analysis value (%) C 70.10 H 6.28 N 5.31 ¹ H-NMR (CDCl ₃ ) δ: 0.08-2.30 (m, 3
H), 1.68 (d, J = 6.5 Hz, 3
H), 3.95 and 4.69 (m, total)
1H), 5.15 (q, J = 6.5H
z),

──────────────────────────────────────────────────の Continuing from the front page (72) Inventor Hirofumi Kawanishi 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Co., Ltd. 2-231475 (JP, A) JP-A-56-108737 (JP, A) "Graduate School of Organic Chemistry (2)" (1989-8-1) Kodansha Scientific, No. 665-667. (Int.Cl. ⁷ , DB name) C07C 61/15 C07C 211/27 C07B 57/00 346 CAPLUS (STN) REGISTRY (STN) WPIDS (STN)

Claims (13)

(57) [Claims] 1. A cis-2-fluorocyclopropane-1-carboxylic acid having the formula (In the formula, Aryl represents a phenyl group or a naphthyl group, R ¹ represents a hydrogen atom, R ² represents a benzyl group or a hydrogen atom, R ³ represents a halogen atom, an alkyl group having 6 or less carbon atoms, An optically active organic base represented by a halogenoalkyl group having 6 or less carbon atoms, an alkoxy group having 6 or less carbon atoms, a phenyl group which may have a nitro group, a carbamoyl group or a cyano group, or a hydrogen atom. With salt 2. Cis-2-fluorocyclopropane-1
-Salts of carboxylic acids and 2-benzylaminocyclohexanemethanol 3. The salt according to claim 2, wherein the 2-benzylaminocyclohexanemethanol is (−)-cis-2-benzylaminocyclohexanemethanol. 4. The method according to claim 1, wherein the cis-2-fluorocyclopropane-1-carboxylic acid is (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid or (1R, 2R) -2-fluorocyclopropane-1-carboxylic acid. 3. The salt according to claim 1, which is an acid. 5. The salt according to claim 1, wherein the cis-2-fluorocyclopropane-1-carboxylic acid is (1S, 2S) -2-fluorocyclopropane-1-carboxylic acid. 6. The salt according to claim 1, wherein the optically active organic base is N-benzyl-α-methylbenzylamine. 7. The salt according to claim 6, wherein the N-benzyl-α-methylbenzylamine is (R)-(+)-N-benzyl-α-methylbenzylamine. 8. The salt according to claim 1, wherein the optically active organic base is 1-phenyl-2- (p-tolyl) ethylamine. 9. The salt according to claim 8, wherein the 1-phenyl-2- (p-tolyl) ethylamine is (R) -1-phenyl-2- (p-tolyl) ethylamine. 10. The salt according to claim 1, wherein the optically active organic base is 1-phenylethylamine. 11. 1-Phenylethylamine is (R)-(+)-1
The salt according to claim 10, which is a salt with phenylethylamine. 12. An optically active organic base comprising 1- (1-naphthyl)
The salt according to claim 1, which is ethylamine. 13. The method of claim 1 wherein 1- (1-naphthyl) ethylamine is (S)
The salt according to claim 12, which is-(-)-1- (1-naphthyl) ethylamine.