JP2002308836A - Method for purifying optically active 1-(fluorophenyl) ethylamine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for purifying optically active 1-(fluorophenyl) ethylamines of formula 1 (wherein n is 1-5 and a fluorine atom or fluorine atoms may be in any substituting position except the case where n is 1 and the fluorine atom is in the ortho-position; R is an optically active α-arylethyl group of C*HMeAr; Ar is a phenyl group or a 1- or 2-naphthyl group; and *is an asymmetric carbon) which are important intermediates of pharmaceuticals and agricultural chemicals with good industrial efficiency in high optical purity. SOLUTION: The optically active 1-(fluorophenyl)ethylamines of formula 1 are converted to the salts of an inorganic acid or an organic acid, and then purified by recrystallization.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a purification method for obtaining optically active 1- (fluorophenyl) ethylamine, which is an important intermediate of pharmaceuticals and agricultural chemicals, with high optical purity.

[0002]

BACKGROUND OF THE INVENTION Optically active 1- (fluorophenyl) ethylamine is an important intermediate for pharmaceuticals and pesticides.

A method for producing an optically active para-fluoro form (4-fluoro form) is described in Tetrahedron, 56, 6651-66.
55 (2000), J. Chem. Soc., Perkin Trans. 2, 1339-13.
48 (2000), J. Chem. Soc., Perkin Trans. 2, 95-99
In (1978), (S) -3 ', 4'-methylenedioxyma
ndelic acid, (S) -2-naphthylglycolic acid, (+)-tart
Optical resolution by aric acid has been reported. However, in these methods, a special resolving agent is required and the resolving efficiency is not always high, so that it is not efficient as an industrial production method. No other methods for synthesizing optically active compounds have been reported.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a synthetic intermediate of optically active 1- (fluorophenyl) ethylamine by converting it into a salt of an inorganic acid or an organic acid and purifying it by recrystallization. -(Fluorophenyl) ethylamine.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have found that optical activity 1-
By synthesizing the intermediate of (fluorophenyl) ethylamine into an inorganic or organic acid salt and purifying it by recrystallization,
It was revealed that 1- (fluorophenyl) ethylamine having high optical purity was obtained.

That is, the present invention provides a compound represented by the general formula [1]:

[0007]

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[In the formula, n represents 1 to 5, and takes an arbitrary substitution position. However, n is 1 and the ortho position is excluded. R is C *
Represents an optically active α-arylethyl group represented by HMeAr, Ar represents a phenyl group or 1 or 2-naphthyl group, and * represents an asymmetric carbon].
-A refining method characterized in that-(fluorophenyl) ethylamines are converted into salts of inorganic acids or organic acids and recrystallized.

Further, the present invention provides a compound represented by the general formula [1]:

[0010]

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[In the formula, n represents 1 to 5, and takes an arbitrary substitution position. However, n is 1 and the ortho position is excluded. R is C *
Represents an optically active α-arylethyl group represented by HMeAr, Ar represents a phenyl group or 1 or 2-naphthyl group, and * represents an asymmetric carbon].
-(Fluorophenyl) ethylamines are salts of inorganic or organic acids.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a method for purifying optically active 1- (fluorophenyl) ethylamine of the present invention will be described in detail.

The optically active 1- (fluorophenyl) ethylamines represented by the general formula [1] of the present invention include those represented by the general formula [2]

[0014]

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[In the formula, n represents 1 to 5, and takes an arbitrary substitution position. Provided that n is 1 and the ortho position is excluded, and the general formula [3]

[0016]

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[Wherein, Ar represents a phenyl group or 1 or 2-naphthyl group, and * represents an asymmetric carbon] The general formula obtained by dehydrating and condensing an optically active primary amine represented by the following formula: [4]

[0018]

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[In the formula, n represents 1 to 5, and takes an arbitrary substitution position. However, n is 1 and the ortho position is excluded. Ar represents a phenyl group or a 1- or 2-naphthyl group, and * represents an asymmetric carbon.] The optically active imine represented by the formula: can be produced by asymmetric reduction using a hydride reducing agent. The following three compounds can be mentioned.
Among them, the N-α-phenylethyl compound (1-a) is more preferable.

[0020]

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* Represents an asymmetric carbon, and the stereochemistry of 1-a, 1-b and 1-c is RR, SR or RS
(The absolute configuration shown before the hyphen represents the absolute configuration on the 1- (fluorophenyl) ethyl group side, and the absolute configuration shown after the hyphen is a chiral auxiliary. represents an absolute configuration on the α-arylethyl group side, usually using an R-form or S-form chiral auxiliary having 98% ee or more), and a diastereomer excess of 10% de or more can be used. .

The inorganic acids used in the present invention include carbonic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, boric acid, perchloric acid and the like. Among them, hydrochloric acid and hydrobromic acid are more preferred.

The organic acids used in the present invention include acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, hexanoic acid, heptanoic acid, cyclohexanecarboxylic acid, octanoic acid, phenylacetic acid, and 3-phenylpropionic acid. Aliphatic carboxylic acids such as acids, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, fluoroacetic acid, difluoroacetic acid,
Haloalkylcarboxylic acids such as trifluoroacetic acid, bromoacetic acid, iodoacetic acid, 2-chloropropionic acid, 3-chloropropionic acid, acrylic acid, crotonic acid, citraconic acid, maleic acid, fumaric acid, cis or trans
-Unsaturated carboxylic acids such as cinnamic acid, benzoic acid, o, m
Or p-toluic acid, o, m or p-fluorobenzoic acid, o, m or p-chlorobenzoic acid, o, m or p-bromobenzoic acid, o, m or p-iodobenzoic acid, o, m or p-hydroxybenzoic acid, o, m or p-anisic acid, o, m or p-aminobenzoic acid,
o, m or p-nitrobenzoic acid, o, m or p-cyanobenzoic acid, o, m or p-benzenedicarboxylic acid (phthalic acid, isophthalic acid, terephthalic acid), α, β or γ-picolinic acid, , 6-pyridinedicarboxylic acid,
Aromatic carboxylic acids such as 1- or 2-naphthoic acid, sulfonic acids such as methanesulfonic acid, chloromethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-phenolsulfonic acid, lactic acid, apple Acid, tartaric acid, dibenzoyltartaric acid, 2
-Phenylpropionic acid, mandelic acid, camphoric acid,
Optically active carboxylic acids such as cis-2-benzamidocyclohexanecarboxylic acid; phenylethanesulfonic acid;
Optically active sulfonic acids such as 0-camphorsulfonic acid,
Optically active phosphoric acids such as 2,2 '-(1,1'-binaphthyl) phosphoric acid, optically active amino acids such as 4-aminobutyric acid, phenylglycine, aspartic acid, pyroglutamic acid, N-acetyl-3,5- Dibromo-tyrosine, N-
Optically active N-acyl amino acids such as acyl-phenylalanine, N-acyl-aspartic acid, N-acylglutamic acid, N-acylproline (N-acyl groups include acetyl, benzyloxycarbonyl, benzoyl, benzenesulfonyl Group, p-toluenesulfonyl group, etc.) and other organic acids include formic acid, oxalic acid, malonic acid, succinic acid, adipic acid, pimelic acid,
Examples include cyanoacetic acid, citric acid, glycolic acid, glyoxylic acid, pyruvic acid, levulinic acid, oxaloacetic acid, mercaptoacetic acid, phenoxyacetic acid, picric acid and the like. Optically active carboxylic acids, optically active sulfonic acids, optically active phosphoric acids, optically active amino acids and optically active N-acyl amino acids have optical isomers, and both optical isomers can be used. Among them, phthalic acid is more preferred.

The amount of the acid used in the present invention is as follows.
It may be used in an amount of 0.3 molar equivalent or more, and preferably 0.3 to 5 molar equivalents, based on the optically active 1- (fluorophenyl) ethylamine represented by the general formula [1].
0.3-3 molar equivalents are more preferred.

The method for preparing the salt of the present invention comprises the steps of:
It may be determined appropriately according to the combination of (fluorophenyl) ethylamines and an acid. Usually, the optically active amines and the acid are directly added to a recrystallization solvent and mixed, or each solution is prepared in advance and the solutions are mixed. Can be prepared.

The recrystallization solvent used in the present invention includes:
There is no particular limitation as long as it does not react with the optically active 1- (fluorophenyl) ethylamines, acids or salts thereof, and the diastereomer excess before purification or the target diastereomer excess after purification and It may be appropriately determined according to the recovery rate and the like.

Examples of the recrystallization solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, c-hexane and n-heptane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene and mesitylene; Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether and 1,4-dioxane, acetone, methyl ethyl ketone,
Ketones such as methyl isobutyl ketone, ethyl acetate, ester such as n-butyl acetate, acetonitrile, nitrile such as propionitrile, methanol, ethanol,
Examples thereof include alcohols such as n-propanol, i-propanol and n-butanol, and water. Among them, n-hexane, n-heptane, toluene, methylene chloride, t-butyl methyl ether, acetone, ethyl acetate, acetonitrile, methanol, ethanol, n-
Propanol and i-propanol are more preferred. These solvents can be used alone or in combination.

The amount of the recrystallization solvent used in the present invention is not particularly limited as long as the salt before purification is completely or partially dissolved when heated, and the diastereomer excess before purification is used. The ratio may be determined as appropriate depending on the ratio, the target diastereomeric excess after purification, the recovery ratio, and the like. Usually, it is sufficient to use 1 volume or more of the salt of the optically active 1- (fluorophenyl) ethylamine represented by the general formula [1], preferably 1 to 100 volumes,
1-50 volumes are more preferred.

In the recrystallization operation of the present invention, by adding a seed crystal, crystals can be deposited smoothly and efficiently. The amount of the seed crystal used is preferably 1/10 to 1/10000 weight, more preferably 1/20 to 1/5000 weight, based on the salt before purification.

The temperature conditions for the recrystallization operation of the present invention can be appropriately determined depending on the boiling point and the freezing point of the solvent used. Usually, the temperature before room temperature (25 ° C.) is about the boiling point of the recrystallization solvent. Is dissolved, and crystals can be precipitated at -40 to 80 ° C.

In the present invention, since the diastereomer excess of the precipitated crystals is improved, the precipitated crystals are recovered by filtration or the like to obtain highly pure salts of 1- (fluorophenyl) ethylamines. Can be. Further, by repeating the recrystallization operation, a product having a higher purity can be obtained. The obtained salt is used as it is or after being converted to a free base with an alkaline aqueous solution,
By subjecting to hydrogenolysis, the desired 1- (fluorophenyl) ethylamine having a high optical purity can be obtained without racemization. The optically active amine can be recovered as a free base by neutralizing with an alkaline aqueous solution and extracting with an organic solvent). Further, the obtained crude product of the optically active amine can be purified, if necessary, by activated carbon, distillation, recrystallization, column chromatography or the like.

[0032]

EXAMPLES Hereinafter, embodiments of the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

% De,% ee in Examples and Reference Examples
Represents a diastereomeric excess and an enantiomeric excess, respectively, and represents chiral GC (CP-Chirasil-
Dex CB).

[Example 1] Recrystallization purification using hydrochloride salt of SS-para-1-a In 3 ml of methanol, optically active 1- (fluorophenyl) ethylamines (SS-para-1-a, Diastereomer ratio / SS form: RS form = 93: 7) 1.00
g (4.11 mmol, 1 eq) and 37% hydrochloric acid 0.4
ml (4.87 mmol, 1.18 eq).
The mixture was stirred at ℃ for 30 minutes and concentrated under reduced pressure. The residue contains i-
5 ml of propanol and 3 ml of n-heptane were added, dissolved by heating, and stirred for 18 hours while cooling to room temperature. The precipitated crystals were filtered, washed with a small amount of n-heptane, dried under vacuum, and then 0.85 g of crystals having the structure shown below and mother liquor.
0.26 g was obtained. Each de is 0.5N-Na
It was made into a free base with an aqueous OH solution and subjected to chiral GC analysis. As a result, 95.8% de (major form was SS form), 47.
It was 6% de (the major body was an SS body).

[0035]

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¹ H-NMR (TMS, CDCl ₃ ):
91 (d, 6.6 Hz, 6H), 3.75-4.00
(M, 2H), 7.00-7.80 (Ar-H, 9
H), 10.52 (br, 2H).

Example 2 Purification of recrystallization of SS-para-1-a with hydrobromide In 3 ml of methanol, optically active 1- (fluorophenyl) ethylamines (SS-para-1) were added. -A, diastereomer ratio / SS form: RS form = 93: 7) 1.01
g (4.14 mmol, 1 eq) and 47% hydrobromic acid
0.5 ml (4.30 mmol, 1.04 eq) was added, the mixture was stirred at 80 ° C. for 30 minutes, and concentrated under reduced pressure. To the residue, 8 ml of i-propanol and 3 ml of n-heptane were added, dissolved by heating, and stirred for 66 hours while cooling to room temperature. The precipitated crystals were filtered, washed with a small amount of n-heptane, dried in vacuo, and then 0.91 g of crystals having the structure shown below.
And 0.28 g of mother liquor were obtained. Each de is 0.5
When the free base was prepared with an aqueous solution of N-NaOH and chiral GC analysis was performed, 98.4% de (major form was SS)
Body), 37.0% de (major body is S-S body).

[0038]

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¹ H-NMR (TMS, CDCl ₃ ):
98 (d, 6.8 Hz, 6H), 3.80-4.10
(M, 2H), 7.00-7.80 (Ar-H, 9
H), 10.01 (br, 2H).

Example 3 Purification of recrystallization of SS-meta-1-a with phthalic acid salt A mixture of 3 ml of i-propanol and 3 ml of n-heptane was added with an optically active 1- (fluorophenyl) ethylamine. (SS-Meta-1-a, diastereomer ratio / S
-S form: RS form = 86: 14) 1.00 g (4.1)
2 mmol, 1 eq) and phthalic acid 0.68 g (4.0
9 mmol, 0.99 eq), stirred at 80 ° C. for 30 minutes, and concentrated under reduced pressure. 17.5 ml of i-propanol was added to the residue, dissolved with heating, and stirred for 18 hours while cooling to room temperature. The precipitated crystals were filtered, washed with a small amount of n-heptane, and dried under vacuum to obtain 1.32 g of crystals having the structure shown below and 0.47 g of mother liquor. Each de is made a free base with 0.5N-NaOH aqueous solution,
Chiral GC analysis revealed that 99.2% de (major body was S-S body) and 46.0% de (major body was R-S body).
Body).

[0041]

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¹ H-NMR (TMS, CDCl ₃ ):
78 (d, 7.0 Hz, 3H), 1.80 (d, 7.0
Hz, 3H), 4.05 (m, 2H), 7.04-7.
70 (Ar-H, 11H), 8.45-8.58 (Ar
-H, 2H), 10.48 (br, 3H).

Example 4 Recrystallization Purification of SS-3,5-1-a with Phthalates In a mixed solution of 5 ml of i-propanol and 6 ml of methanol, optically active 1- (fluorophenyl) ethylamine was added. (SS-3,5-1-a, diastereomer ratio / S
-S form: RS form = 87: 13) 1.01 g (3.8)
5 mmol, 1 eq) and phthalic acid 0.64 g (3.8
3 mmol, 0.99 eq) was added thereto, dissolved by heating, and stirred for 19 hours while cooling to room temperature. The precipitated crystals were collected by filtration, washed with a small amount of n-heptane, and dried under vacuum to obtain 1.05 g of crystals having the structure shown below and 0.54 g of mother liquor. Each de was converted to a free base with a 0.5N-NaOH aqueous solution, and subjected to chiral GC analysis.
The de (major body was S-S body) and 9.1% de (major body was R-S body).

[0044]

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¹ H-NMR (TMS, CDCl ₃ ):
77 (d, 6.6 Hz, 3H), 1.81 (d, 6.6
Hz, 3H), 4.03 (q, 6.6 Hz, 1H),
4.10 (q, 6.6 Hz, 1H), 6.75-7.7
0 (Ar-H, 10H), 8.45-8.58 (Ar-
H, 2H), 10.79 (br, 3H).

[Reference Example 1] / Purified SS-para-1
Conversion of -a • hydrochloride to optically active 1- (para-fluorophenyl) ethylamine SS-para-1-a • hydrochloride purified in Example 1 (9
5.8% de) 309 mg (1.10 mmol, 1e)
q) was dissolved in 1.5 ml of methanol, 5.6 mg of 5% palladium / activated carbon (containing 50% by weight of water) (0.05% by weight as Pd) was added, and the hydrogen pressure was set to 0.5 MPa. Stir for 15 hours. The reaction-terminated liquid was filtered through celite, concentrated and dried in vacuo to obtain (S) -1- (para-fluorophenyl) ethylamine hydrochloride. To this hydrochloride were added 10 ml of t-butyl methyl ether and 0.5 ml of t-butyl methyl ether.
10 ml of an aqueous solution of N-NaOH was added, and the mixture was stirred at room temperature for 30 minutes. After static separation, the recovered aqueous layer was extracted with 5 ml of t-butyl methyl ether. After drying with sodium, filtration, concentration and vacuum drying, a crude product of (S) -1- (para-fluorophenyl) ethylamine having the structure shown below was obtained.
The conversion and the optical purity of the crude product were> 99% and 95.6% ee, respectively, by chiral GC analysis.

[0047]

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¹ H-NMR (TMS, CDCl ₃ ):
39 (d, 6.6 Hz, 3H), 2.10 (br, 2
H), 4.11 (q, 6.6 Hz, 1H), 7.12-
7.38 (Ar-H, 4H).

Reference Example 2 / Purified SS-Meta-1
Conversion of -a-phthalate to optically active 1- (meta-fluorophenyl) ethylamine SS-meta-1-a-phthalate purified in Example 3 (99.2% de) 615 mg (1 .50 mmol, 1
eq) was dissolved in 4.0 ml of methanol, 7.3 mg (0.03% by weight as Pd) of 5% palladium / activated carbon (containing 50% by weight of water) was added, and the hydrogen pressure was set to 0.5 MPa. Stir for 14 hours. The reaction-terminated liquid was filtered through celite, concentrated, and dried in vacuo.
Fluorophenyl) ethylamine phthalate was obtained.
This phthalate is added to t-butyl methyl ether 10m
l and 10 ml of 0.5N-NaOH aqueous solution were added, and the mixture was stirred at room temperature for 30 minutes. After static separation, the recovered aqueous layer was extracted with 5 ml of t-butyl methyl ether, and the combined organic layer was washed with saturated saline. And dried over anhydrous sodium sulfate,
After filtration, concentration and vacuum drying, (S) -1 having the structure shown in the following formula
A crude product of-(meta-fluorophenyl) ethylamine was obtained. The conversion and the optical purity of the crude product were 99.5% and 99.1% ee, respectively, by chiral GC analysis.

[0050]

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¹ H-NMR (TMS, CDCl ₃ ):
40 (d, 6.6 Hz, 3H), 2.80 (br, 2
H), 4.10 (q, 6.6 Hz, 1H), 6.86-
7.42 (Ar-H, 4H).

[0052]

The optically active 1- (fluorophenyl) ethylamine, which is an important intermediate of pharmaceuticals and agricultural chemicals, can be industrially and efficiently purified to high optical purity.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Katsu Kuriyama 2805 Imafukunakadai, Kawagoe-shi, Saitama Prefecture Central Chemical Glass Co., Ltd. (72) Inventor Masatomi Kanai 2805 Imafukunakadai, Kawagoe-shi, Saitama Central Glass F-term in Chemical Research Laboratories Co., Ltd. (Reference) 4H006 AA02 AC83 AD33 BE01

Claims (8)

[Claims] 1. A compound of the general formula [1] [In the formula, n represents 1 to 5, and takes an arbitrary substitution position.
However, n is 1 and the ortho position is excluded. R represents an optically active α-arylethyl group represented by C * HMeAr; Ar represents a phenyl group or 1 or 2-naphthyl group;
Represents an asymmetric carbon.] An optically active 1- (fluorophenyl) ethylamine represented by the formula (1) is converted into a salt of an inorganic acid or an organic acid and recrystallized and purified. 2. The method according to claim 1, wherein the inorganic acid comprises hydrochloric acid or hydrobromic acid. 3. The method according to claim 1, wherein the organic acid comprises phthalic acid. 4. The purification method according to claim 1, wherein the stereochemistry of * in the general formula [1] is R-form or S-form. 5. A compound of the general formula [1] [In the formula, n represents 1 to 5, and takes an arbitrary substitution position.
However, n is 1 and the ortho position is excluded. R represents an optically active α-arylethyl group represented by C * HMeAr; Ar represents a phenyl group or 1 or 2-naphthyl group;
Represents an asymmetric carbon.] An inorganic or organic acid salt of an optically active 1- (fluorophenyl) ethylamine represented by the formula: 6. The salt according to claim 5, wherein the inorganic acid comprises hydrochloric acid or hydrobromic acid. 7. The salt according to claim 5, wherein the organic acid comprises phthalic acid. 8. The salt according to claim 5, wherein the stereochemistry of * in the general formula [1] is R-form or S-form.