JP3088777B2 - Novel optical resolving agent and method for producing optically active amine using the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel optical resolving agent and a novel method for producing an optically active amine using the same.

[0002]

2. Description of the Related Art As a method for obtaining an optically active amine, optical resolution is an extremely effective method and is widely used. However, conventionally used optical resolving agents for amines are expensive, only one optically active substance is inexpensive, and recovery is not easy.

For example, tartaric acid is inexpensive because the L-form is easily obtained from nature and the D-form is expensive. Mandelic acid is inconvenient for recovery. Since pantolactone is used as pantoic acid and then lactonized under acidic conditions, it is easy to recover,
Since it is soluble in water, it is necessary to concentrate it or to increase the number of extractions with an organic solvent.

[0004]

The present inventors have paid attention to the fact that optically active pantolactones of D and L can be industrially produced at low cost, and derived this to obtain an optically active amine with the above-mentioned defect improved. It was examined whether or not the optical resolving agent could be formed.

That is, a lower alkyl group or a benzyl group is added to the 2-position hydroxyl group of pantolactone, the following general formula [1 ']

Embedded image (Wherein R ¹ represents a lower alkyl group of C2 to C4, *
Represents an asymmetric carbon) and / or O-alkylpantolactone represented by the following general formula [1]:

[0006]

Embedded image

Wherein R ² represents a lower alkyl group or a benzyl group having 1 to 4 carbon atoms, and * represents an asymmetric carbon. It was thought that a more suitable pantolactone derivative could be obtained, and further, the water solubility could be reduced and the compound could be more easily recovered, and industrial optical resolution would be possible.

The optically active O-alkyl pantolactones [1 '] and [1] can be easily produced by a method newly developed by the present inventors. That is, it can be produced by reacting optically active pantolactone with an alkyl halide in the presence of a metal oxide.

Examples of the alkyl halide include methyl iodide, ethyl iodide, ethyl bromide, n-propyl iodide,
Examples thereof include n-propyl bromide and benzyl bromide. Examples of the metal oxide include silver oxide and barium oxide.

[0010] The novel optically active O-
An optically active O-alkyl pantolactone [1] containing an alkyl pantolactone [1 '] is converted into a compound represented by the following general formula [2]

Embedded image (Wherein R ′ and R ″ are different lower alkyl groups,
Which represents a phenyl group, a naphthyl group or an aralkyl group which may have 1 to 3 lower alkyl, halogen or alkoxy groups) to form two diastereomers, Optical resolution can be performed using the difference in solubility of the salt in the solvent.

Further, the optical splitting method of the present invention will be specifically described. The optically active O-alkyl pantolactone [1] is reacted with (±) -amine [2] by heating in water, or the optically active O-alkyl pantolactone [1] is heated in an aqueous alkali solution to give the lactone. Open the ring and add (±) -amine hydrochloride solution to react. After completion of the reaction, it is difficult to crystallize by cooling or concentrate, add an appropriate organic solvent, and dissolve by heating.If necessary, remove inorganic salts such as salt by filtration, and then cool or concentrate as necessary. The soluble amine salt of O-alkyl pantoic acid is selectively crystallized and solid-liquid separated.

The (±) -amine [2] used for the optically active O-alkylpantolactone [1] is
It is used in a molar ratio of 0.4-1.2, and more preferably 0.9-1.1.

If the optically active salt thus obtained is not yet optically pure, a pure salt can be easily obtained by recrystallization as required. A desired optically active amine can be obtained by adding an alkali to the obtained salt, decomposing the salt, and extracting the salt with an organic solvent. After the aqueous layer is acidified with hydrochloric acid or the like, it is lactonized by heating, and extracted with an organic solvent, whereby the optically active O-alkylpantolactone [1] can be easily recovered in good yield. Alternatively, hydrochloric acid is added to the obtained salt to decompose it, and then lactonized by heating, extracted with an organic solvent to recover the optically active O-alkylpantolactone [1], and then the aqueous layer is made alkaline. The desired optically active amine can be easily obtained by extraction with an organic solvent.

Examples of the amine [2] that can be optically resolved include 1-phenylethylamine, 1-phenylpropylamine, 1- (1-naphthyl) ethylamine and 1-methyl-3-phenylpropylamine.

By selecting a combination of these amines and optically active O-alkyl pantolactone [1] such as O-methyl pantolactone, O-ethyl pantolactone, On-propyl pantolactone and O-benzylpantolactone. Further, the optical division can be performed more efficiently.

[0016]

According to the present invention, novel optically active O-alkyl pantolactones and the like can be provided as good optical resolving agents for producing optically active amines.

[0017]

【Example】

Example 1 (-)-Pantolactone ([α] D-5
5.0 g of 0.7 ゜ (21 ° C., c2, water) is dissolved in 25 ml of N, N-dimethylformamide (hereinafter abbreviated as DMF). 8.9 g of silver oxide and 27.3 g of methyl iodide are added, and the mixture is stirred and reacted at room temperature for 1 hour. After adding 100 ml of ether, the insoluble matter is removed by filtration. The filtrate was washed with water, dried over anhydrous magnesium sulfate, concentrated, and distilled under reduced pressure to obtain 4.69 g of (+)-O-methylpantolactone. bp 53-55
° C / 3 torr. [Α] D + 49.2 ゜ (21 ° C., c
2, MeOH).

[0018]

Example 2 In Example 1, 6.58 g of ethyl iodide was used in place of methyl iodide, and the mixture was stirred and reacted at room temperature for 16 hours. Post-treatment, silica gel column chromatography purification, and distillation under reduced pressure were performed to obtain (+)-O-ethyl pantolactone 5.27.
g was obtained. bp 60-62 ° C / 3 torr. [Α] D +
51.6 ° (21 ° C., c2, MeOH).

[0019]

Example 3 (+)-On-propyl pantolactone was prepared in the same manner as in Example 2 except that 8.90 g of n-propyl iodide was used in place of ethyl iodide. 45 g were obtained. bp 71-72 ° C / 5 torr
r. [Α] D + 48.9 ゜ (21 ° C., c2, MeO
H).

[0020]

Example 4 A reaction, work-up and column chromatography purification were carried out in the same manner as in Example 2 except that 32.8 g of benzyl bromide was used in place of ethyl iodide.
7.30 g of benzyl pantolactone were obtained. This was recrystallized from ethyl acetate and n-hexane. mp42 ~
43 ° C. [Α] D + 89.9 ° (21 ° C., c2, MeO
H).

[0021]

Example 5 (+)-Pantolactone ([α] D + 5
0.3 g (21 ° C., c2, water)) of 5.0 g in DMF25
Dissolve in ml. 8.8 g of barium oxide and 27.3 g of methyl iodide are added, and the mixture is heated and stirred under reflux for 2 hours.
Water is added, extracted with methylene chloride, washed with brine, dried over anhydrous magnesium sulfate and concentrated. After silica gel column chromatography purification, distillation was performed under reduced pressure to obtain 3.54 g of (-)-O-methylpantolactone. bp 53-55 ° C / 3to
rr. [Α] D-45.6 ゜ (21 ° C., c2, MeO
H)

[0022]

Example 6 In Example 5, 12.5 g of ethyl iodide was used in place of methyl iodide, and the mixture was stirred and reacted at room temperature for 18 hours. Post-treatment and purification were carried out in the same manner as in Example 5 to give (-)-O
-2.05 g of ethyl pantolactone were obtained. bp60 ~
62 ° C / 3 torr. [Α] D-36.9 ゜ (21 ° C.,
c2, MeOH).

[0023]

Example 7 (±) -1-phenylethylamine 7.6
4 g are dissolved in 31.5 ml of 2N hydrochloric acid. (+)-O
-Methyl pantolactone ([α] D + 49.2 ゜) 9.
08 g was placed in 35 ml of a 2N aqueous solution of caustic soda, stirred and dissolved, and the pH was adjusted to 8 with 2N hydrochloric acid. Combine the two liquids and concentrate under reduced pressure to dryness. Methyl ethyl ketone (hereinafter ME
200 ml), heated to 50 ° C. and filtered.
Remove insolubles. After concentration under reduced pressure to dryness, methanol 72m
1 and 360 ml of isopropyl ether were added and dissolved by heating, followed by cooling to 5 ° C. for crystallization. The crystals were collected by filtration.
g was obtained. This was recrystallized from 13 ml of methanol and 65 ml of isopropyl ether to obtain 4.94 g of crystals of (+)-1-phenylethylamine. (+)-O-methyl pantoate. mp 136.5-138 ° C. [Α]
D + 23.7 ° (21 ° C., c2, MeOH). 4.00 g of this salt was decomposed with a 2N aqueous solution of sodium hydroxide, extracted with ether and concentrated to obtain 1.64 g of (+)-1-phenylethylamine. 98.0% ee by HPLC analysis
Met. At this time, hydrochloric acid was added to the aqueous layer to adjust the pH to 1, followed by heating under reflux for 1 hour. Extracted twice with ether and concentrated (+)-O-methylpantolactone 1.9.
2 g were recovered. [Α] D + 54.0 ° (21 ° C., c
2, MeOH). bp 53-55 ° C / 3 torr. ¹ H
-NMR (90 MHz, CDCl ₃ ): δ 4.00,
_{3.88 (each 1H, d, -CH} 2 -O-C
O), 3.64 (3H, s, MeO), 3.59 (1
H, s, MeOCH), 1.21, 1.10 (each
_{3H, s, Me 2 C <} ). IR (NaCl) ν: 28
40, 1785, 1465, 1215, 1160, 11
20,1115,995 cm ^-1 .

[0024]

Example 8 11.9 g of (±) -1- (1-naphthyl) ethylamine and 10.0 g of (+)-O-methylpantolactone ([α] D + 49.2 ゜) were put in 100 ml of water, and After heating under reflux for 5 hours, the mixture was concentrated to dryness. 80 ml of acetone and 40 ml of methanol are added and dissolved by heating, and then cooled to 5 ° C. for crystallization. The crystals were collected by filtration and 7.91
g was obtained. 54 ml of acetone and 27 m of methanol
and recrystallized with (1) to obtain crystals of (+)-1- (1-naphthyl) ethylamine. (+)-O-methyl pantoate 4.2
7 g were obtained. mp 174-176 ° C. [Α] D + 22.
3 ゜ (21 ° C., c2, MeOH). After decomposing 4.00 g of this salt with a 2N aqueous solution of sodium hydroxide, the extract was concentrated with ether and concentrated to give (+)-1- (1-naphthyl) ethylamine 1.9.
1 g was obtained. It was 96.9% ee by HPLC analysis. At this time, hydrochloric acid was added to the aqueous layer to adjust the pH to 1, followed by heating under reflux for 1 hour. Extracted twice with ether, concentrated and (+)-O-methylpantolactone 1.87
g was collected. [Α] D + 54.1 ゜.

[0025]

Example 9 10.8 g of (±) -1- (1-naphthyl) ethylamine was dissolved in 31.5 ml of 2N hydrochloric acid.
(+)-O-ethyl pantolactone ([α] D + 51.
6 ゜) 10.0 g was placed in 35 ml of a 2N aqueous solution of caustic soda, dissolved by stirring, and adjusted to pH 8 with 2N hydrochloric acid. Combine the two liquids and concentrate under reduced pressure to dryness. After adding 200 ml of MEK, the mixture is heated to 50 ° C., and filtered to remove insolubles. After concentrating to dryness under reduced pressure, 200 ml of isopropanol was added and dissolved by heating, and then cooled to 5 ° C. for crystallization. The crystals were collected by filtration to obtain 7.23 g. 170 ml of isopropanol
And recrystallized with (+)-1- (1-naphthyl) ethylamine. (+)-O-ethyl pantoic acid salt, 5.39.
g was obtained. mp 136.5-138 ° C. [Α] D + 2
3.7 ° (21 ° C., c2, MeOH). This salt 4.00
g was decomposed with a 2N aqueous solution of sodium hydroxide, extracted and concentrated with ether, and (+)-1- (1-naphthyl) ethylamine.
88 g were obtained. It was 98.0% ee by HPLC analysis. In addition, hydrochloric acid was added to the aqueous layer at this time to adjust the pH to 1, followed by heating under reflux for 1 hour. Extracted twice with ether,
It was concentrated and 1.70 g of (+)-O-ethyl pantolactone was recovered. [Α] D + 55.0 ° (21 ° C., c2, Me
OH). bp 60-62 ° C / 3 torr. ¹ H-NM
R (90 MHz, CDCl ₃ ): δ 4.20 to 3.50
_{(2H, m, MeCH 2 O} ), 4.00,3.90 (e
_{ach 1H, d, -CH 2 -O} -CO), 3.68
(1H, s, EtOCH), 1.28 (3H, t, C H
₃ CH ₂ O), 1.20, 1.10 (each 3H,
_s, Me 2 C <). IR (NaCl) ν: 2840, 1
785, 1465, 1215, 1160, 1120, 1
115,995 cm ^-1 .

[0026]

Example 10 10.4 g of (±) -1-methyl-3-phenylpropylamine was dissolved in 35 ml of 2N hydrochloric acid. (+)-On-propyl pantolactone ([α]
D + 48.9 ゜) is placed in 40 ml of a 2N aqueous solution of sodium hydroxide, stirred and dissolved, and adjusted to pH 8 with 2N hydrochloric acid. Combine the two liquids and concentrate under reduced pressure to dryness. MEK1
After adding 20 ml and heating to 50 ° C., the mixture is filtered to remove insolubles. Concentrate under reduced pressure to about 120 ml. Crystallize at 5 ° C with cooling. The crystals were collected by filtration to obtain 15.09 g. This was recrystallized with 100 ml of MEK to give (+)-1-methyl-
6.64 g of crystals of 3-phenylpropylamine. (+)-On-propyl pantoate were obtained. mp140-1
42 ° C. [Α] D + 22.2 ゜ (21 ° C., c1, MeO
H). After decomposing 4.00 g of this salt with a 2N aqueous solution of sodium hydroxide, the mixture was extracted with ether and concentrated to give (+)-1-methyl-3.
1.63 g of -phenylpropylamine were obtained. HPLC
Analysis showed 98.0% ee. At this time, hydrochloric acid was added to the aqueous layer to adjust the pH to 1, followed by heating under reflux for 1 hour. Extract twice with ether, concentrate, and add (+)-O-
1.87 g of n-propyl pantolactone was recovered.
[Α] D + 49.0 ° (21 ° C., c2, MeOH). b
p71-72 ° C / 5 torr. ¹ H-NMR (90 MH
_{z, CDCl 3): δ4.10~3.37 (} 2H, m,
EtCH ₂ O), 4.02, 3.88 (each 1
_{H, d, -CH 2 -O-} CO), 3.65 (1H, s,
_{PrOCH), 1.66 (2H, q} , CH 3 C H 2 CH
₂ O), 1.20, 1.10 (each 3H, s, M
_{e 2 C <), 0.96 (} 3H, t, C H 3 CH 2 CH 2
O). IR (NaCl) ν: 2875, 1790, 14
65, 1375, 1200, 1120, 1030, 10
15,995 cm ^-1 .

[0027]

Example 11 (±) -1-phenylpropylamine 1
0.57 g is dissolved in 39 ml of 2N hydrochloric acid. (+)-
O-benzylpantolactone ([α] D + 80.9 °)
17.22 g is put into 43 ml of a 2N aqueous solution of caustic soda, dissolved by stirring, and adjusted to pH 8 with 2N hydrochloric acid. Combine the two liquids and concentrate under reduced pressure to dryness. Add 200 ml of MEK and add 50
After heating to 0 ° C, the mixture was filtered to remove insolubles. After concentrating to dryness under reduced pressure, heat and dissolve again with 70 ml of MEK. Crystallize at 5 ° C with cooling. The crystals were collected by filtration to obtain 14.19 g. This was recrystallized with 160 ml of MEK to obtain 9.96 g of crystals of (+)-1-phenylpropylamine. (+)-O-benzylpanto acid salt. mp 122-123 ° C. [Α]
D + 36.4 ° (21 ° C., c1, MeOH). 8.00 g of this salt was decomposed with 1N-hydrochloric acid, adjusted to pH 1, and heated under reflux for 1 hour. The mixture was extracted twice with ether and concentrated, and 4.49 g of (+)-O-benzylpantolactone was recovered. This was recrystallized with a mixed solvent of ethyl acetate and n-hexane. [Α] D + 91.3 ゜ (21 ° C., c1, Me
OH). mp 42-43 ° C. ¹ H-NMR (90 MH
z, CDCl ₃ ): δ 7.37 (5H, bs, C
_{6 H 5), 5.08,4.73 (each} 1H, d,
PhCH ₂ O), 4.02, 3.85 (each 1
_{H, d, -CH 2 -O-} CO), 3.74 (1H, s,
PhCH ₂ OC H ), 1.14, 1.10 (each
_{3H, s, Me 2 C <} ). IR (NaCl) ν: 178
5,1760,1120,985 cm ^-1 . The aqueous layer was converted to caustic, extracted with ether and concentrated (+)-
1-phenylpropylamine was obtained. It was 93.6% ee by HPLC analysis.

[0028]

Example 12 6.80 g of (±) -1-methyl-3-phenylpropylamine is dissolved in 23 ml of 2N hydrochloric acid. (+)-O-benzylpantolactone ([α] D +
80.9 ゜) 10.00 g of 2N-caustic soda aqueous solution 2
After dissolving in 4 ml with stirring, the pH is adjusted to 8 with 2N hydrochloric acid. After the two liquids are combined and heated and stirred at 50 ° C. for 30 minutes,
Cryogenic crystallization at ℃. The crystals were collected by filtration and wet 14.9.
8 g were obtained. This was recrystallized with a mixed solvent of 12 ml of methanol and 36 ml of water to obtain 6.06 g of crystals of (+)-1-methyl-3-phenylpropylamine. (+)-O-benzyl pantoate. mp 147-149 ° C.
[Α] D + 45.4 ° (21 ° C., c1, MeOH). 4.00 g of this salt was decomposed with 1N-hydrochloric acid to adjust the pH to 1, followed by heating under reflux for 1 hour. Extract with ether twice, concentrate, and add (+)-O-benzylpantolactone.
19 g were recovered. [Α] D + 91.0 °. The aqueous layer was converted to caustic, extracted with ether and concentrated (+)-
1.49 g of 1-methyl-3-phenylpropylamine was obtained. The optical purity of the amine was 92.8 by HPLC analysis.
% Ee.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References Liebigs Annalender der Chemie, 1989 (1), pp. 103-104. Chem. Soc. , Chem. Commun. , 1990 (15), p. 1033-1034 Journal full Prak tische Chemie, 327 (1), p. 174-176 (1985) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 307/33 C07B 57/00 360 C07C 211/27-211/30 CA (STN) REGISTRY (STN)

Claims (3)

(57) [Claims] 1. The following general formula [1 ′] as an optical resolving agent: (Wherein R ¹ represents a lower alkyl group of C2 to C4, *
Represents an asymmetric carbon). 2. The following general formula [2]: (Wherein R ′ and R ″ are different lower alkyl groups,
When optically resolving an amine represented by a phenyl group, a naphthyl group or an aralkyl group which may have 1 to 3 lower alkyl, halogen and alkoxy groups), the following general formula [1] (Wherein, R ² represents a lower alkyl group or a benzyl group of C1 to C4, and * represents an asymmetric carbon). An optical activity characterized by using an O-alkylpantolactone represented by the following formula: Method for producing amine. (3) (±) -1-phenylethylamine,
(±) -1-phenylpropylamine, (±) -1-
In optically resolving (1-naphthyl) ethylamine or (±) -1-methyl-3-phenylpropylamine, an O-alkylpantolactone represented by the general formula [1] is used as an optical resolving agent, and the resolving agent is used. Producing two diastereomeric salts with the above-mentioned (±) -amine, and optically resolving the (±) -amine by utilizing the difference in solubility between the diastereomeric salts; Production method.