JPH069549A - Optically active aziridine-2-carboxylic acid derivative and its production - Google Patents

Abstract

PURPOSE:To provide the new compound useful as an intermediate for synthesizing various compounds, especially agricultural chemicals, medicines, etc. CONSTITUTION:The compound of formula I (R<1-a> is H, alkyl; R<2-a> is a carboxyl- protecting group; but a case where the R<1-a> is H and R<2-a> is methyl or benzyl is excluded), e.g. N-(triphenylmethyl)-(S)-aziridine-2-carboxylic acid benzyl ester. The compound of formula I is obtained by subjecting a 2(S)- or 2(R)-, 3(R)-N- triphenylmethyl-3-haloalanine derivative of formula II (X is halogen; R<1> is H, alkyl; R<2> is a carboxyl-protecting group) to an intramolecular cyclization reaction in the presence of a weak base (e.g. KHSO3) in a nitrile solvent at room temperature to 150 deg.C. The compound of formula I can be obtained from an inexpensive raw material in a good yield.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel compounds and a process for producing 2 (S)-or 2 (R)-, 3 (S)-or 3 (R) -aziridine-2-carboxylic acid derivatives containing them. Regarding These compounds are useful as synthetic intermediates for various compounds, especially agricultural chemicals, pharmaceuticals and the like.

[0002]

2. Description of the Related Art N-triphenylmethyl- (S) -aziridine-2-carboxylic acid derivatives having a hydrogen atom at the 3-position and a benzyl group as a protective group at the 2-position are disclosed in Bull. Chem. Soc. Jpn. ，
Vol. 51, p. 1577, and that the 3-position is a hydrogen atom and the 2-carboxyl protecting group is a methyl group are described in Synth. Commun. , Volume 21, 239
P., US Pat. Nos. 4,622,418 and 4,60
It is a compound known in the literature from the specification of 3,011.

These compounds are disclosed in Organic Synthetic Chemistry, 42, 14, J. Chem. Soc. Chem. C
ommun. , 1987, p.153, Tetrahhe
It is known as a useful synthetic intermediate for various compounds as described in dron Letters, Vol. 30, p. 4073. As a conventional synthetic method of the optically active aziridine-2-carboxylic acid derivative represented by the above formula (I),
Bull. Chem. Soc. Jpn. , Volume 51, 1
577, and Bull. Chem. Soc. Jp
n. , 52, 3579, (S)-
There is a method of synthesizing from serine or (S) -threonine through several steps of benzyl esterification, N-triphenylmethylation, tosylation of a hydroxyl group, and then an intramolecular cyclization reaction in the presence of a base. However, this method is not necessarily industrially advantageous because it requires very expensive (S) -serine or (S) -threonine as a raw material. In addition, JP-A-57
The racemic aziridine-2-carboxylic acid obtained by the method disclosed in Japanese Patent Publication No. 146751 is divided into (S) -form and (R) -form by appropriate optical resolution, and then a carboxyl group and an amino group are separated. There is also a method of protecting and converting to a derivative, but this method requires handling of an unstable aziridine-2-carboxylic acid and is not an industrially advantageous method.

[0004]

DISCLOSURE OF THE INVENTION The object of the present invention is to provide novel 2 (S), 3 (R) -aridine-2-carboxylic acid derivatives and 2 (S)-or 2 (R) -containing them. , 3
The present invention provides a method for producing a (S)-or 3 (R) -aziridine-2-carboxylic acid derivative. Further, the present invention is a production process in which an objective optically active aziridine-2-carboxylic acid can be obtained starting from an inexpensive raw material, having high production efficiency and high yield, as compared with the conventional method. It is intended for the development of methods.

[0005]

According to the present invention, the following formula (II)

[0006]

[Chemical 4]

(In the above formula, R ¹ is a hydrogen atom or an alkyl group, R ² is a protective group for a carboxyl group, and X is a halogen atom). 2 (S)-or 2 ( R)-, 3 (S) or 3 (R) -N-triphenylmethyl-3-haloalanine derivative is subjected to an intramolecular cyclization reaction in the presence of a weak base in a nitrile solvent. Formula (I)

[0008]

[Chemical 5]

(Wherein R ¹ is a hydrogen atom or an alkyl group, and R ² is a protective group for a carboxyl group), 2 (S)-or 2 (R)-, 3 (S )
Alternatively, a method for producing a 3 (R) -aziridine-2-carboxylic acid derivative is provided.

Further, a compound within the scope of the above formula (I), which is represented by the following formula (Ia)

[0011]

[Chemical 6]

(In the above formula, R ^1-a is a hydrogen atom or an alkyl group, and R ^2-a is a protecting group for a carboxyl group, provided that R ^1-a is a hydrogen atom and R ^{2 is} There is also provided a novel 2 (S), 3 (R) -aziridine-2-carboxylic acid derivative represented by ^-a is a methyl group or a benzyl group).

The alkyl group referred to in R ¹ and R ^1-a used for specifying substitution in the present specification is not particularly limited in its chain length or shape (straight chain or branched chain). It is appropriately selected depending on the final target compound produced by utilizing, but usually, straight chain and branched chain compounds having 10 or less carbon atoms can be mentioned. Furthermore, considering the availability as a synthetic intermediate and the ease of producing the starting material, a lower alkyl group having 5 or less carbon atoms is preferable. Therefore, preferred specific groups for R ¹ and R ^1-a are hydrogen atom, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group. Group, tert-butyl group, n-pentyl group, iso-pentyl group and the like.

R ² and R ^2-a are a protecting group for a carboxyl group usually used in the field of amino acid derivative or peptide synthesis, and include, for example, an unsubstituted or substituted benzyl group, an aralkyl group such as diphenylmethyl group, and R Alkyl groups as defined for ¹ , in particular their lower alkyl groups may be mentioned as preferred.

The starting material of the formula (II) is prepared by a method known per se of an ester of a 3-halo-α-amino acid under ordinary amino group protecting conditions, for example, in the presence of triethylamine. , N- with chlorotriphenylmethane
It can be obtained by triphenylmethylation. Examples of the method for producing a 3-halo-α-amino acid or its ester include, for example, JP-B-58-22140 and JP-A-5-220.
It can be produced by the method described in JP-A No. 7-188548 or an improved method thereof, but the 3-halo-alanine or methylalanine derivative in which R ¹ represents a hydrogen atom or a methyl group uses an enzyme conversion method. It is possible to produce these optically active compounds at low cost from 3-halo-2-ketopropionic acid or butyric acid (International Publication WO 9
2/05268). As the halogen atom represented by X in the formula (II), fluorine, chlorine, bromine and iodine atoms can be used, but in view of easiness of raw material production and efficiency of the dehydrohalogenation reaction of the present invention, chlorine can be used. Atoms are especially preferred.

Therefore, in the method of the present invention, the amino group of (R)-or (S) -3-chloroalanine or 3-chloro-2-aminobutyric acid, which is supplied inexpensively as described above, is triphenylmethyl. It is particularly advantageous to use compounds protected with a group and to add them to a nitrile solvent such as acetonitrile with a weak base such as potassium fluoride or potassium hydrogen sulfite to carry out the intramolecular cyclization reaction.

Weak salts used to carry out intramolecular cyclization reactions
As the group, the above potassium fluoride (KF), hydrogen sulfite
Potassium (KHSO₃), NaF, AgF, K₂
SO ₃, K₂HPO_Four, K₂WO_Four, K₂S₂O_FiveToi
Inorganic salts, triethylamine, diisopropyl ether
Examples include organic tertiary amines such as chillamine.
it can. However, as a base, CsF, NaHC
O₃, Na₂CO₃, NaOH, KOH, alkyl lychee
When a strong base such as um is used, dehydrohalogenation and hydrolysis
It is not preferable because side reactions such as solution occur. Of the above weak base
The amount used is a 3-chloroalanine derivative represented by the formula (II)
An equimolar amount is sufficient, but use in excess
The reaction tends to be accelerated by. Used for reaction
The nitrile solvent used is acetonitrile or
Pionitrile, butyronitrile, valeronitrile
Other examples include nitrile solvents. Reaction temperature is from room temperature
The range of 150 ° C is preferable, and the reaction time and side reaction
In terms of response control, the boiling point of acetonitrile is 9
Around 0 ° C. is particularly preferable.

The reaction product can be obtained as a pure product by simply extracting from the reaction solution with an organic solvent such as dichloromethane, ethyl acetate or diethyl ether, drying and concentrating. If necessary, a pure product can be obtained by performing a purification operation such as a silica gel column or recrystallization.

Among the compounds of formula (I) thus obtained, the compound in which R ¹ is a hydrogen atom and R ² is a combination of a methyl group or a benzyl group is a known compound as described above, Those excluding these compounds have not been described in the prior art documents and are novel aziridine derivatives. Therefore, the present invention also provides a novel compound represented by the above formula (Ia).

[0020]

The present invention will be described in more detail based on the following examples.

Example 1 N- (triphenylmethyl)-
Synthesis of (S) -aziridine-2-carboxylate benzyl

[0022]

[Chemical 7]

114 mg (0.25 mm) of N- (triphenylmethyl) -3-chloro-L-alanine benzyl ester
ol) was dissolved in anhydrous acetonitrile (15 mL),
Add 300 mg (2.5 mmol) of potassium hydrogen sulfite and 48
The mixture was heated under reflux for an hour. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (15 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate, purified by preparative silica gel thin layer chromatography, and recrystallized from diisopropyl ether / hexane to give N- (triphenylmethyl)-(S) -aziridine-2-carboxylic acid. Benzyl acid 1
00 mg was obtained as colorless needle crystals. Yield 95%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.47 to 7.49 (m, 6H), 7.31 to 7.
39 (m, 6H), 7.18 to 7.25 (m, 8H),
5.21 (ABq, 2H), 2.28 (dd, 1H, J
= 1.5, 2.5 Hz), 1.92 (dd, 1H, J =
2.5, 6.2 Hz), 1.41 (dd, 1H, J = 1.
5, 6.2 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
4,143.6,135.8,129.3,128.
6,128.4,128.3,127.7,126.
9, 74.4, 66.7, 31.8, 28.8

IR (liquid film) ν: 3060, 3030, 1
740, 1590, 1485, 1445, 1235, 1
170,1015,745,705,695,625cm
⁻¹ Melting point: 115-116 ° C. [α] _D = −96.9 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (obtained by hydrogenation using Pd-carbon as a catalyst, L -Alanine is an optically active column [Crownpak CR (-), manufactured by Daicel Chemical Industries]
Determined by HPLC analysis using. ) (Note that the above e.
e. is the enantiomeric excess (Enantiomeric Ex
cess). )

Example 2 N- (triphenylmethyl)-
Synthesis of methyl (S) -aziridine-2-carboxylate

[0027]

[Chemical 8]

152 mg (0.4 mmol) N- (triphenylmethyl) -3-chloro-L-alanine methyl ester
Was dissolved in anhydrous acetonitrile (25 mL), potassium hydrogen sulfite (480 mg, 4.0 mmol) was added, and the mixture was heated under reflux for 54 hr. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (20 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl)-
120 mg of (S) -aziridine-2-carboxylate was obtained as colorless crystals. Yield 90%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.50 (m, 6H), 7.23 (m, 6H),
7.22 (m, 3H), 3.76 (s, 3H), 2.2
5 (dd, 1H, J = 1.4, 3.4 Hz), 1.89
(Dd, 1H, J = 3.4, 5.9 Hz), 1.41 (d
d, 1H, J = 1.4, 5.9 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 172.
0, 143.6, 129.3, 127.7, 127.
0, 74.4, 52.1, 31.7, 28.7

IR (liquid film) ν: 3060, 3030, 2
950, 1750, 1590, 1490, 1450, 1
390, 1245, 1200, 1180, 1080, 1
035,1015,745,710,630 cm ^-1 [α] _D = -73.0 (C = 1.0, CHCl ₃ ), melting point: 92-95 ° C. Optical purity:> 99% ee (catalyst Pd-carbon L-alanine obtained by hydrogenation, followed by acid hydrolysis, was used as an optically active column [Crownpak CR (-),
Manufactured by Daicel Chemical Industries, Ltd.]. )

Example 3 N- (triphenylmethyl)-
Synthesis of ethyl (S) -aziridine-2-carboxylate

[0032]

[Chemical 9]

156 mg (0.4 mmol) of N- (triphenylmethyl) -3-chloro-L-alanine ethyl ester
Was dissolved in anhydrous acetonitrile (25 mL), 480 mg (4.0 mmol) of potassium hydrogen sulfite was added, and the mixture was heated under reflux for 68 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (20 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl)-
135 mg of ethyl (S) -aziridine-2-carboxylate was obtained as a colorless oily substance. Yield 95%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.49 to 7.52 (m, 6H), 7.19 to 7.
32 (m, 9H), 4.23 (q, 2H, J = 7.3H
z), 2.25 (dd, 1H, J = 1.0, 2.5H
z), 1.87 (dd, 1H, J = 2.5, 5.1H
z), 1.39 (dd, 1H, J = 1.0, 5.1H
z), 1.29 (t, 3H, J = 7.3 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
5,143.7, 129.4, 127.6, 126.
9, 74.4, 60.9, 31.8, 28.6, 14.
Three

IR (liquid film) ν: 3060, 3030, 2
975, 1740, 1590, 1485, 1445, 1
235, 1180, 1030, 1000, 745, 70
5,630 cm ^-1 [α] _D = -75.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (determined by the same method as described in Example 2)

Example 4 N- (triphenylmethyl)-
Of (S) -aziridine-2-carboxylic acid-n-propyl
Synthesis

[0037]

[Chemical 10]

164 mg of N- (triphenylmethyl) -3-chloro-L-alanine-n-propyl ester (0.
After dissolving 4 mmol) in anhydrous acetonitrile (25 mL), 480 mg (4.0 mmol) of potassium hydrogen sulfite was added, and the mixture was heated under reflux for 63 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (20 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and purified by preparative silica gel thin layer chromatography to obtain 140 mg of N- (triphenylmethyl)-(S) -aziridine-2-carboxylic acid-n-propyl as a colorless oily substance. Got as. Yield 94%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.49 to 7.51 (m, 6H), 7.19 to 7.
29 (m, 9H), 4.14 (t, 2H, J = 6.9H
z), 2.25 (dd, 1H, J = 1.5, 3.0H
z), 1.88 (dd, 1H, J = 3.0, 6.3H
z), 1.68 (m, 2H), 1.39 (dd, 1H,
J = 1.5, 6.3 Hz), 0.96 (t, 3H, J =
7.4 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
6,143.7,129.3,127.6,126.
9, 74.3, 66.5, 31.8, 28.6, 22.
0, 10.3

IR (liquid film) ν: 3055, 3030, 2
970, 1745, 1590, 1485, 1445, 1
235, 1180, 1075, 1015, 745, 70
5,630 cm ^-1 [α] _D = -87.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (determined by the same method as described in Example 2)

Example 5 N- (triphenylmethyl)-
(S) -aziridine-2-carboxylic acid-n-butyl compound
Success

[0042]

[Chemical 11]

85 mg (0.2 mmo) of N- (triphenylmethyl) -3-chloro-L-alanine-n-butyrate
l) was dissolved in anhydrous acetonitrile (10 mL),
240 mg (2 mmol) of potassium hydrogen sulfite was added and the mixture was heated under reflux for 48 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (15 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl)-
(S) -aziridine-2-carboxylic acid-n-butyl 7
5.0 mg was obtained as a colorless oil. Yield 98%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.19 to 7.33 (m, 15H), 4.18
(T, 2H, J = 6.5 Hz), 2.25 (dd, 1H,
J = 1.5, 2.7 Hz), 1.88 (dd, 1H, J =
2.7, 6.0 Hz), 1.68 (m, 2H), 1.39
(Dd, 1H, J = 1.5, 6.0 Hz), 1.38
(M, 2H), 0.96 (t, 3H, J = 7.0 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
6,143.7,129.3,127.6,126.
9, 74.3, 64.8, 31.8, 30.7, 28.
6, 19.1, 13.7

IR (liquid film) ν: 3050, 2955, 2
930, 1745, 1590, 1485, 1445, 1
235, 1180, 1075, 1025, 1010, 7
45,705,630 cm ⁻¹ [α] _D = −79.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (determined in the same manner as in Example 2)

Example 6 N- (triphenylmethyl)-
Of (S) -aziridine-2-carboxylic acid-n-pentyl
Synthesis

[0047]

[Chemical 12]

30 mg (0.0) of N- (triphenylmethyl) -3-chloro-L-alanine-n-pentyl ester
(7 mmol) was dissolved in anhydrous acetonitrile (5 mL), and then 84 mg (0.7 mmol) of potassium hydrogen sulfite was added to the solution to give 5
The mixture was heated under reflux for 0 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (10 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and then purified by preparative silica gel thin layer chromatography to obtain 26.0 mg of N- (triphenylmethyl)-(S) -aziridine-2-carboxylic acid-n-pentyl colorless. Obtained as an oil. Yield 92
%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.1 to 7.48 (m, 15H), 4.10 (t,
2H, J = 6.8Hz), 2.18 (dd, 1H, J =
1.4, 2.9 Hz), 1.80 (dd, 1H, J = 2.
9,5.9 Hz), 1.60 (m, 2H), 1.32 (d
d, 1H, J = 1.4, 5.9 Hz), 1.28 (m, 4
H), 0.84 (t, 3H, J = 6.9 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
6,143.7,129.3,127.6,126.
9, 74.2, 65.1, 31.8, 28.6, 28.
4, 28.0, 22.3, 13.9

IR (liquid film) ν: 3055, 3030, 2
980, 1745, 1590, 1485, 1445, 1
235, 1180, 1030, 1015, 745, 70
5,630 cm ^-1 [α] _D = -67.5 (C = 0.4, CHCl ₃ ) Optical purity:> 99% ee (determined by the same method as described in Example 2)

Example 7 N- (triphenylmethyl)-
Of (S) -aziridine-2-carboxylic acid-isopropyl
Synthesis

[0052]

[Chemical 13]

39 mg (0.0) of N- (triphenylmethyl) -3-chloro-L-alanine-isopropyl ester
96 mmol) was dissolved in anhydrous acetonitrile (7 mL), and then 120 mg (1 mmol) of potassium hydrogen sulfite was added.
The mixture was heated under reflux for an hour. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (10 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and then purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl).
34.5 mg of-(S) -aziridine-2-carboxylic acid-isopropyl was obtained as a colorless oily substance. Yield 97%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.20 to 7.51 (m, 15H), 5.13
(M, 1H), 2.24 (dd, 1H, J = 1.5,
2.9 Hz), 1.84 (dd, 1H, J = 2.9, 5.
9Hz), 1.37 (dd, 1H, J = 1.5, 5.9H
z), 1.27 (dd, 6H, J = 6.3, 9.2 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
4, 144.0, 129.7, 127.9, 127.
2, 76.6, 68.6, 32.2, 28.8, 22.
1,22.0

IR (liquid film) ν: 3060, 2980, 2
930, 1745, 1595, 1490, 1445, 1
385, 1245, 1195, 1110, 1090, 1
015,730,710,630 cm ^-1 [α] _D = -65.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (determined in the same manner as in Example 2)

Example 8 N- (triphenylmethyl)-
(S) -aziridine-2-carboxylic acid-isobutyl
Success

[0057]

[Chemical 14]

50 mg (0.12) of N- (triphenylmethyl) -3-chloro-L-alanine-isobutyl ester
mmol) was dissolved in anhydrous acetonitrile (10 mL), 144 mg (1.2 mmol) of potassium hydrogen sulfite was added, and the mixture was heated under reflux for 81 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (15 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and then purified by preparative silica gel thin layer chromatography to obtain 44.3 mg of N- (triphenylmethyl)-(S) -aziridine-2-carboxylic acid-isobutyl as a colorless oily substance. Got as. Yield 96%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.19 to 7.52 (m, 15H), 3.97
(D, 2H, J = 6.8 Hz), 2.25 (dd, 1H,
J = 1.5, 2.5 Hz), 1.98 (m, 1H), 1.
88 (dd, 1H, J = 2.5, 6.8Hz), 1.40
(Dd, 1H, J = 1.5, 6.8Hz), 0.952
(Dd, 6H, J = 2.4, 6.9 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
6,143.7,129.3,127.6,126.
9, 74.3, 71.0, 31.8, 28.6, 27.
8, 19.1

IR (liquid film) ν: 3060, 2960, 2
870, 1745, 1595, 1485, 1445, 1
405, 1385, 1225, 1180, 1080, 1
030,985,765,745,705,630 cm ^-1 [α] _D = -65.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (similar to the method described in Example 2 Decided)

Example 9 N- (triphenylmethyl)-
(2S, 3R) -3-Methyl-aziridine-2-carbo
Synthesis of acid methyl ester

[0062]

[Chemical 15]

N- (triphenylmethyl)-(2R, 3
S) -2-Amino-3-chlorobutyric acid methyl ester 10
5 mg (0.27 mmol) of anhydrous acetonitrile (15 mL)
Dissolved in 325 mg of potassium hydrogen sulfite (2.7 mg).
mmol) was added and the mixture was heated under reflux for 63 hours. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (20 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and then purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl)-(2S, 3R) -3-methyl-aziridine-2-carboxylic acid methyl ester 94. 0.5 mg was obtained as a colorless oil. Yield 98%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.19 to 7.53 (m, 15H), 3.74
(S, 3H), 1.88 (d, 1H, J = 6.8Hz),
1.63 (dq, 1H, J = 5.3, 6.8 Hz), 1.
37 (d, 3H, J = 5.3 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 170.
7, 143.9, 129.4, 127.6, 126.
8, 75.0, 51.8, 35.9, 34.8, 13.
Three

IR (liquid film) ν: 3060, 3020, 2
940, 1745, 1595, 1490, 1445, 1
380, 1230, 1195, 1175, 1120, 1
050,1030,765,745,705,630cm
^-1 [α] _D = -61.0 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (optical activity of L-α-aminobutyric acid obtained by the same operation as in Example 2) Determined by HPLC analysis using various columns.)

Example 10 N- (triphenylmethyl)
Synthesis of benzyl-(R) -aziridine-2-carboxylate

[0067]

[Chemical 16]

114 mg (0.25 mm) of N- (triphenylmethyl) -3-chloro-D-alanine benzyl ester
ol) was dissolved in anhydrous acetonitrile (15 mL),
Add 300 mg (2.5 mmol) of potassium hydrogen sulfite and 48
The mixture was heated under reflux for an hour. After cooling to room temperature, 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to stop the reaction, and the mixture was extracted with dichloromethane (15 mL × 2 times). The organic layer was dried over anhydrous magnesium sulfate and then purified by preparative silica gel thin layer chromatography to obtain N- (triphenylmethyl).
Benzyl 102- (R) -aziridine-2-carboxylate
mg was obtained as colorless crystals. Yield 97%.

¹ H-NMR (CDCl ₃ , 400 MHz)
δ: 7.47 to 7.49 (m, 6H), 7.31 to 7.
39 (m, 6H), 7.18 to 7.25 (m, 8H),
5.20 (ABq, 2H), 2.28 (dd, 1H, J
= 1.5, 2.5 Hz), 1.93 (dd, 1H, J =
2.5, 6.2 Hz), 1.41 (dd, 1H, J = 1.
5, 6.2 Hz) ¹³ C-NMR (CDCl ₃ , 100 MHz) δ: 171.
4,143.6,135.8,129.3,128.
6,128.4,128.3,127.7,126.
9, 74.3, 66.7, 31.8, 28.8

IR (liquid film) ν: 3060, 3030, 1
740, 1590, 1485, 1445, 1235, 1
170,1015,745,705,695,625cm
⁻¹ Melting point: 113-115 ° C. [α] _D = + 96.3 (C = 1.0, CHCl ₃ ) Optical purity:> 99% ee (D-alanine obtained by the same method as described in Example 1) Determined from)

In Examples 11 to 13 below, the reaction time was shortened as compared with Examples 1 to 10 only to see the effect of the kind of the weak base, so the yield was low. However, if the reaction time is lengthened, the reaction proceeds quantitatively. The theoretical yields are also given in the following examples.

Example 11 N- (triphenylmethyl)
-(S) -aziridine-2-carboxylate-benzyl combination
Success

[0073]

[Chemical 17]

45.6 mg (0.1%) of N- (triphenylmethyl) -3-chloro-L-alanine-benzyl ester
1 mmol of various weak bases was added to 5 mmol) and the reaction was carried out in 5 mL of anhydrous acetonitrile under heating under reflux for 20 hours. Post-treatment and extraction were carried out in the same manner as described in Example 1. Each weak base used in Table 1 and the resulting N- (triphenylmethyl)-
The yield of (S) -aziridine-2-carboxylate-benzyl is shown.

Table 1 ─────────────────────────────────── Base yield (%) From the recovered raw materials Theoretical yield (%) of ─────────────────────────────────── KF 37 69 ────── ────────────────────────────── AgF 37 57 ───────────────── ────────────────── KHSO ₃ 34 100 ───────────────────────────── ─────── K ₂ SO ₃ 33 100 ─────────────────────────────────── K _{2 HPO 4 29 100 ─────────────────────────────────── K 2 WO} 4 _{7 100 ─────────────────────────────────── K 2 S 2 O} 5 32 100 ───── ────────────────────────────── Triethylamine 34 100 ───────────────── ────────────────── Diisopropylethylamine 24 100 ──────────────────────────── ───────

Example 12 N- (triphenylmethyl)
-(S) -aziridine-2-carboxylate-benzyl combination
Success

[0077]

[Chemical 18]

45.6 mg (0.1%) of N- (triphenylmethyl) -3-chloro-L-alanine-benzyl ester
120 mg (1 mmol) of potassium hydrogen sulfite was added to (5 mmol), and the reaction was carried out in 5 mL of each nitrile under heating under reflux for 20 hours. Post-treatment and extraction were carried out in the same manner as described in Example 1. Table 2 shows the solvent used and the yield of the obtained N- (triphenylmethyl)-(S) -aziridine-2-carboxylate-benzyl.

Table 2 ──────────────────────────────── Solvent yield (%) Theoretical yield from the recovered raw materials Rate (%) ──────────────────────────────── Acetonitrile 34 100 ──────────── ───────────────────── Propionitrile 36 100 ───────────────────────── ──────── Butyronitrile 29 100 ──────────────────────────────── Valeronitrile 26 100 ─── ─────────────────────────────

Example 13 N- (triphenylmethyl)
-(S) -aziridine-2-carboxylate-benzyl combination
Success

[0081]

[Chemical 19]

N- (triphenylmethyl) -3-chloro-L-alanine-benzyl ester 45.6 mg (0.1
Each equivalent amount of potassium hydrogen sulfite was added to (mmol) and reacted in 5 mL of acetonitrile under heating under reflux for 20 hours. Post-treatment and extraction were carried out in the same manner as described in Example 1. Table 3 shows the equivalent amount of potassium hydrogen sulfite used and the yield of the obtained N- (triphenylmethyl)-(S) -aziridine-2-carboxylate-benzyl.

Table 3 ──────────────────────────────── KHSO ₃ equivalent Yield (%) From the raw material recovered Theoretical yield (%) of ──────────────────────────────── 2 20 100 ───────── ──────────────────────── 5 36 100 ──────────────────────── ───────── 10 34 100 ──────────────────────────────── 15 33 100 100 ─── ───────────────────────────── 20 32 100 ─────────────────── ────────────── 30 30 100 100 ─────────────────────── ────────

[0084]

INDUSTRIAL APPLICABILITY The compound of the present invention is a useful synthetic intermediate of an optically active α-amino acid and was expected to be industrially used. However, there was no general-purpose manufacturing method for this, and sufficient results were not achieved. According to the invention, in particular cheaply supplied (D)-or (L) -3-chloroalanine,
Alternatively, it is possible to synthesize an objective optically active aziridine-2-carboxylic acid derivative containing a novel compound with good yield in a low yield by using an inexpensive weak base in 3 steps from 3-chloro-2-aminobutyric acid. The industrial and inexpensive manufacturing method of can be provided.

Claims (2)

[Claims] 1. The following formula (Ia): (In the above formula, R ^1-a is a hydrogen atom or an alkyl group,
R ^2-a is a protective group for a carboxyl group, provided that R ^1-a is a hydrogen atom and R ^2-a is a methyl group or a benzyl group) 2 (S ),
3 (R) -aziridine-2-carboxylic acid derivative. 2. The following formula (II): (In the above formula, R ¹ is a hydrogen atom or an alkyl group,
² is a protecting group for a carboxyl group, and X is a halogen atom) 2 (S)-or 2 (R)
-, 3 (S) or 3 (R) -N-triphenylmethyl-3-haloalanine derivative is subjected to an intramolecular cyclization reaction in the presence of a weak base in a nitrile solvent. I) [Chemical Formula 3] (In the above formula, R ¹ is a hydrogen atom or an alkyl group, and R ² is a protective group for a carboxyl group), 2 (S)-or 2 (R)-, 3 (S) or 3 (R)
-Method for producing aziridine-2-carboxylic acid derivative.