JPH05255243A - Aziridine-2-carboxylic acid derivative and its production - Google Patents

Abstract

PURPOSE:To provide the new (S)-aziridine-2-carboxylic acid derivative capable of being readily produced, regarded as the active derivative of the alpha-amine acid, and having a high industrial application value. CONSTITUTION:An (S)-aziridine-2-carboxylic acid derivative of formula I (R is lower alkyl), e.g. (S)-N-(isoptopyloxycarbonyl)aziridine-2-carboxylic acid isopropyl ester. The compound of formula I or its R-isomer is obtained in the form of a compound of formula IV by reacting an (S)- or (R)-aziridine-2- carboxylic acid derivative of formula II (R<1>, R<2> are independently alkyl or aralkyl) as a raw material with a tetraalkyl titanate of formula III (R<3> is alkyl, aralkyl) to transesterify R<1> and R<2> with R<3> while the steric configuration of the raw material is maintained.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel compounds and a process for producing (S)-and (R) -aziridine-2-carboxylic acid derivatives containing them.

[0002]

PRIOR ART The following formula

[0003]

[Chemical 5]

The (S) -aziridine-2-carboxylic acid derivative in which R ³ is a benzyl group is disclosed in Bull. Chem. Soc. Japan.
51, page 1577, and is a known compound. Further, (S)-and (R) -aziridine-2-carboxylic acid derivatives in which a carboxyl group and an amino group are protected are described in Biopolymers, Volume 20, 1811.
As described in the page, it is known as various useful synthetic intermediate raw materials.

As a conventional method for producing (S)-and (R) -aziridine-2-carboxylic acid derivatives in which a carboxyl group and an amino group are protected, Bull. Chem. Soc.
, 51, 1577, L-.
There is a method of obtaining serine through several reaction steps. In this method, the carboxyl group of L-serine is first protected as an ester and reacted, so that the protecting group on the carboxyl side of the final product aziridine-2-carboxylic acid derivative is defined in the first reaction. ..

A method for producing a racemic aziridine-2-carboxylic acid is disclosed in JP-A-57-146751.
As disclosed in the publication, there is a method of treating a racemate of β-chloroalanine in the presence of an alkali. The racemic compound obtained by this method is subjected to (S)-
There is also a method of protecting a carboxyl group and an amino group and converting the derivative into a derivative after separation into the isomer and the (R) -isomer, but in this method, it is necessary to handle an unstable aziridine-2-carboxylic acid. Not an advantageous method.

[0007]

The object of the present invention is to provide novel (S) -aziridine-2-carboxylic acid derivatives and to provide optically active aziridine-2-containing them.
A method for producing a carboxylic acid derivative is provided.

[0008]

According to the present invention, the following general formula (I)

[0009]

[Chemical 6]

There is provided a (S) -aziridine-2-carboxylic acid derivative represented by the formula (wherein R is a lower alkyl group). The “lower alkyl group” referred to in the present specification includes
A straight chain or a branched chain having 6 or less carbon atoms is included, and specific examples thereof include a methyl group, an ethyl group, an isopropyl group, a butyl group and the like. Further, the present invention provides the following general formula (II)

[0011]

[Chemical 7]

(In the above formula, R ¹ and R ² are independently an alkyl group or an aralkyl group, and R ¹ and R ² may be the same group or different groups from each other). With the optically active aziridine-2-carboxylic acid derivative as a starting material, the protecting group of amino group and carboxyl group is converted into another protecting group while maintaining the three-dimensional structure of the starting material. The following general formula (III) containing (S) -aziridine-2-carboxylic acid derivative

[0013]

[Chemical 8]

There is also provided a method for producing a (S)-or (R) -aziridine-2-carboxylic acid derivative represented by the above formula (wherein R ³ is an alkyl group or an aralkyl group). The compound of the present invention can be regarded as an active derivative of α-amino acid and was expected to be industrially used. However, there was no general-purpose manufacturing method, and sufficient results were not obtained. As a result of intensive studies to solve these problems, the present inventors have found that the method for producing the (S)-and (R) -aziridine-2-carboxylic acid derivative represented by the general formula (III) and the general formula The compound of (I) was found and the present invention was completed.

In the method of the present invention, the optically active aziridine-2-carboxylic acid derivative represented by the general formula (II) is converted into the following general formula (IV)

[0016]

[Chemical 9]

(Wherein R ³ is an alkyl group or an aralkyl group) is reacted with a tetraalkyl titanate to give a protective group for the amino group and the carboxyl group of the raw material while maintaining the configuration of the raw material. Is converted into another protecting group by transesterification. The (S)-and (R) -aziridine-2-carboxylic acid derivatives in which R ¹ and R ² in the general formula (II), which are the starting materials, are benzyl groups can be produced by the above-mentioned documents and the like. .. It is a feature of the production method of the present invention that R ¹ and R ² can both be converted to R ³ from these compounds while maintaining the configuration thereof, and isomers can be selectively formed by selecting raw materials. is there.

When the aziridine-2-carboxylic acid derivative of the general formula (II) is reacted with the tetraalkyl titanate of the general formula (IV), a solvent is not necessarily required, but stirring is facilitated to facilitate the reaction. The use of a solvent is preferred to proceed. When a solvent is used, any solvent may be used as long as it dissolves the aziridine-2-carboxylic acid derivative (II) and tetraalkyl titanate (IV) and does not react with these compounds. Examples of such a solvent include aromatic hydrocarbons such as toluene and benzene, halogenated solvents such as chloroform and dichloromethane, and ethers such as diethyl ether and tetrahydrofuran.

The tetraalkyl titanate represented by the general formula (IV) may be used in an amount of 2 molar equivalents with respect to the aziridine-2-carboxylic acid derivative as the raw material represented by the general formula (II), but an excess amount may be used. The reaction tends to be accelerated by using The reaction temperature is preferably in the range of -20 ° C to 100 ° C. From the viewpoint of reaction time and suppression of side reactions, the range of 0 ° C to 70 ° C is particularly preferable. Since the reaction proceeds even at room temperature without the need for special heating or cooling equipment,
It is recommended to carry out at this temperature, but when the reaction is slow, it is preferable to slightly heat from the viewpoint of reaction time.

Tetraalkyl titanate can be easily prepared from an alcohol corresponding to titanium tetrachloride, but if it is commercially available, it may be used. It is also possible to generate a desired tetraalkyl titanate in equilibrium by using an excessive amount of alcohol corresponding to the alkoxyl group of tetraalkyl titanate and adding commercially available tetraalkyl titanate, for example, tetraisopropyl titanate. It is also an embodiment of the present invention to add a raw material aziridine-2-carboxylic acid derivative into this system, and it has an advantage that the preparation of tetraalkyl titanate and the subsequent reaction can be performed by one apparatus.

[0021]

The present invention will be described in more detail based on the following examples. Example 1: (S) -N- (isopropyloxycarbonyl
L) Synthesis of aziridin-2-carboxylate isopropyl

[0022]

[Chemical 10]

[0023] (S) - N - (benzyloxycarbonyl) aziridine-2-carboxylic acid benzyl (29.5%
(Wt / wt) including monoethyl ester) 138mg
Tetrahydrofuran (2.9 ml) (0.477 mmol)
Tetraisopropyl titanate (0.4
99 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 20 hours. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (3 ml), and the insoluble matter was removed by suction filtration. The filtrate was extracted with chloroform (50 ml × 1 time, 20 ml × 2 times), the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 153.7 mg of a colorless oily substance. It was separated by column chromatography, (S) - N - was obtained (isopropyloxy carbonyl) aziridine-2-carboxylic acid isopropyl 45.9mg as a colorless oil. The yield of the compound was 45%.

The nuclear magnetic resonance spectrum of the compound is shown below.
The results of ( ¹ H NMR) analysis, infrared absorption spectrum analysis and optical rotation analysis are shown. For the structure of the compound,
The absolute configuration was confirmed by nuclear magnetic resonance spectral analysis by further cleavage into the derivative by cleavage of the aziridine ring by reduction. (Physical and chemical properties) Colorless oily substance ¹ H NMR (CDCl ₃ , 270 MHz): δ = 5.08 (sep, 1H, J = 6.3 Hz),
4.94 (sep, 1H, J = 6.3Hz), 3.02 (dd, 1H, J = 3.3, 5.3H
z), 2.54 (dd, 1H, J = 1.3, 3.3Hz), 2.41 (dd, 1H, J = 1.
3, 5.3Hz), 1.30 (d, 3H, J = 5.0Hz), 1.28 (d, 3H, J = 6.3
Hz), 1.28 (d, 3H, J = 6.3Hz), 1.25 (d, 3H, J = 6.3Hz) IR (liquid film) 3000, 1735, 1470, 1370, 1310, 1230, 119
0, 1100, 1010, 905 cm ^-1 [α] _D- 33.3 (c = 1.00, C
HCl ₃ ) Example 2: (S) -N- (isopropyloxycarbonione
L) Synthesis of aziridin-2-carboxylate isopropyl

[0025]

[Chemical 11]

[0026] (S) - N - (benzyloxycarbonyl) aziridine-2-carboxylic acid benzyl ester (2
Includes 9.5% (wt / wt) monoethyl ester) 1
39.3 mg (0.471) was dissolved in chloroform (3 ml), tetraisopropyl titanate (2.5 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 31 hours. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (3 ml), and the insoluble matter was removed by suction filtration. The filtrate is chloroform (20 ml
The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Obtained colorless oily substance 193.
3 mg was separated by column chromatography, and (S)-
N- (isopropyloxycarbonyl) aziridine-2
81.6 mg of isopropyl carboxylate were obtained as colorless oil. The yield of the compound was 79%.

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

[0028]

[Chemical 12]

[0029] (S) - N - (benzyloxycarbonyl) aziridine-2-carboxylic acid benzyl (29.5%
(Contains (wt / wt) monoethyl ester) 49.7 mg
(0.168 mmol) was dissolved in chloroform (3 ml), tetraethyl titanate (1.3 mmol) was added, and the mixture was stirred at 34 ° C. for 23 hours under a nitrogen atmosphere. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (3 ml), and the insoluble matter was removed by suction filtration. The filtrate is chloroform (30 ml x 3).
The organic layer was dried over anhydrous sodium sulfate. The colorless oil 51.7mg obtained by concentration under reduced pressure and column chromatography separation, (S) - as a colorless oily substance (ethoxycarbonyl) aziridine-2-carboxylate 29.0 mg (0.155 mmol) - N Obtained. The yield of the compound was 90%.

The nuclear magnetic resonance spectrum of the compound is shown below.
The results of ( ¹ H NMR) analysis, infrared absorption spectrum analysis and optical rotation analysis are shown. For the structure of the compound,
The absolute configuration was confirmed by nuclear magnetic resonance spectral analysis by further cleavage into the derivative by cleavage of the aziridine ring by reduction. (Physical and chemical properties) Colorless oily substance ¹ H NMR (CDCl ₃ , 270 MHz): δ = 4.20 (m, 4H), 3.08 (dd, 1
H, J = 1.3, 3.0Hz), 2.57 (dd, 1H, J = 3.1, 5.4Hz), 2.46
(dd, 1H, J = 1.3, 5.3Hz), 1.31 (t, 3H, J = 7.1Hz), 1.28
(t, 3H, J = 7.3Hz) IR (liquid film) 3000, 1722, 1460, 1400, 1380, 1320, 129
0, 1220, 1185, 1140, 1100, 1040, 1025 cm ^-1 Example 4: (S) -N- (methoxycarbonyl) aziri
Synthesis of methyl gin-2-carboxylate

[0031]

[Chemical 13]

[0032] (S) - N - (benzyloxycarbonyl) aziridine-2-carboxylic acid benzyl (23.8 percent
(Wt / wt) including monoethyl ester) 143mg
(0.488 mmol) was dissolved in a mixed solvent of chloroform (3 ml) and methanol (0.9 ml), tetraisopropyl titanate (1.0 mmol) was added, and the mixture was stirred at 60 ° C. for 24 hours in a nitrogen atmosphere. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (1 ml), and the insoluble matter was removed by suction filtration. The filtrate was extracted with chloroform (20 ml × 3 times), and the organic layer was dried over anhydrous sodium sulfate. Reduced pressure colorless oil 148mg obtained by concentration and column chromatography separation, (S) - N - was obtained (methoxycarbonyl) aziridine-2-carboxylate 12.4mg as a colorless oil. The yield of the compound was 16%.

The nuclear magnetic resonance spectrum of the compound is shown below.
The results of ( ¹ H NMR) analysis, infrared absorption spectrum analysis and optical rotation analysis are shown. For the structure of the compound,
The absolute configuration was confirmed by nuclear magnetic resonance spectral analysis by further cleavage into the derivative by cleavage of the aziridine ring by reduction. (Physical and chemical properties) Colorless oily substance ¹ H NMR (CDCl ₃ , 270 MHz) δ = 3.79 (s, 3H), 3.76 (s, 3
H), 3.11 (dd, 1H, J = 3.3, 5.1Hz), 2.58 (dd, 1H, J = 1.3,
3.3Hz), 2.49 (dd, 1H, J = 1.3, 5.3Hz) IR (liquid film) 2980, 1745, 1730, 1440, 1388, 1330, 130
0, 1230, 1200, 1190, 1025, 795 cm ^-1 [α] _D- 57.0 (c = 0.58, CHCl ₃ ) Example 5: (S) -N- (n-butoxycarbonyl) a
Synthesis of n-butyl dilysine-2-carboxylate

[0034]

[Chemical 14]

[0035] (S) - N - (benzyloxycarbonyl) aziridine-2-carboxylic acid benzyl (23.8 percent
(Wt / wt) including monoethyl ester) 144mg
(0.491 mmol) was dissolved in a mixed solvent of chloroform (3 ml) and 1-butanol (3 ml), tetraisopropyl titanate (1.0 mmol) was added, and the mixture was stirred at 45 ° C. for 25 hours in a nitrogen atmosphere. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (3 ml), and the insoluble matter was removed by suction filtration. The filtrate was extracted with dichloromethane (20 ml × 3 times), and the organic layer was dried over anhydrous sodium sulfate. The colorless oil 218mg obtained by azeotroping with vacuum concentration and benzene (for excess 1-butanol removed) by column chromatography separation, (S) - N - ( n- butoxycarbonyl) aziridine-2 106 mg of n-butyl carboxylate was obtained as a colorless oily substance. The yield of the compound was 89%.

The nuclear magnetic resonance spectrum of the compound is shown below.
The results of ( ¹ H NMR) analysis, infrared absorption spectrum analysis and optical rotation analysis are shown. For the structure of the compound,
The absolute configuration was confirmed by nuclear magnetic resonance spectral analysis by further cleavage into the derivative by cleavage of the aziridine ring by reduction. (Physical and chemical properties) Colorless oily substance ¹ H NMR (CDCl ₃ , 270 MHz): δ = 4.05-4.25 (m, 4H), 3.08
(dd, 1H, J = 3.3, 5.3Hz), 2.57 (dd, 1H, J = 1.3, 3.3Hz),
2.46 (dd, 1H, J = 1.3,5.3Hz), 1.57-1.71 (m, 4H), 1.29
-1.47 (m, 4H), 0.95 (t, 3H, J = 7.3Hz), 0.93 (t, 3H, J =
7.5Hz) IR (liquid film) 2953, 2940, 1745, 1738, 1730, 1320, 131
8, 1290, 1215, 1180cm ^-1 [α] _D −36.4 (c = 0.93, C
HCl ₃₎ Example 6: (S) -N- (n- butoxycarbonyl) A
From n-butyl dilysine-2-carboxylate to (S) -N-
(N-Ethoxycarbonyl) aziridine-2-carvone
Synthesis of ethyl acidate

[0037]

[Chemical 15]

[0038] (S) - N - (n- butoxycarbonyl)
N-Butyl aziridinecarboxylate 62.8 mg (0.25
(7 mmol) was dissolved in chloroform (3 ml), tetraethyl titanate (0.57 mmol) was added, and the mixture was stirred at 45 ° C. for 26 hours in a nitrogen atmosphere. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (3 ml), and the insoluble matter was removed by suction filtration. The filtrate was extracted with chloroform (20 ml × 3 times), and the organic layer was dried over anhydrous sodium sulfate. 52 mg of a colorless oily substance obtained by concentration under reduced pressure and azeotropic distillation with benzene was separated by column chromatography to obtain (S)-
11.3 mg of ethyl N- (ethoxycarbonyl) aziridine-2-carboxylate was obtained as a colorless oily substance. The yield of the compound was 24%.

Example 7: (S) -N- (n-butoxyca)
Rubonyl) aziridine-2-carboxylate from n-butyl
(S) -N- (benzyloxycarbonyl) -2-azide
Synthesis of benzyl lysinecarboxylate

[0040]

[Chemical 16]

[0041] (S) - N - (n- butoxycarbonyl)
Aziridine-2-carboxylate n-butyl 55.1 mg
(0.227 mmol) and benzyl alcohol (0.25 m
(1, 2.42 mmol) was dissolved in chloroform (3 ml), tetraisopropyl titanate (0.42 mmol) was added, and the mixture was stirred at 44 ° C. for 24.5 hours in a nitrogen atmosphere. The reaction was stopped by adding a saturated aqueous solution of sodium hydrogen carbonate (5 ml), and the insoluble matter was removed by suction filtration. The filtrate was concentrated under reduced pressure to obtain 73.2 mg of a colorless oily substance. And column chromatography separation, (S) - N - (benzyloxy-carbonyl) aziridine-2-carboxylic acid benzyl 6.9mg as a colorless oil. The yield of the compound was 10%.

[0042]

The present invention provides a novel (S) -aziridine-
The present invention provides a method for simply producing a 2-carboxylic acid derivative and an optically active aziridine-2-carboxylic acid derivative containing them, and these compounds are useful as raw materials for synthetic intermediates.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsuyuki Ogura 2-6-10-403 Tsudanuma, Narashino-shi, Chiba (72) Inventor Yasuo Kato 1618 Ida, Nakahara-ku, Kawasaki-shi, Kanagawa Nippon Steel Corporation Tip Inside the Technical Research Laboratory (72) Inventor Kenji Fukumoto 1618 Ida, Nakahara-ku, Kawasaki-shi, Kanagawa Nippon Steel Corporation Advanced Technology Research Laboratories

Claims (2)

[Claims] 1. A general formula: (S) -aziridine-2-carboxylic acid derivative represented by the formula (wherein R is a lower alkyl group). 2. A general formula: (In the above formula, R ¹ and R ² are independently an alkyl group or an aralkyl group), using a (S)-or (R) -aziridine-2-carboxylic acid derivative as a starting material, a compound of the general formula: Chemical 3] (In the above formula, R ³ is an alkyl group or an aralkyl group)
A tetraalkyl titanate represented by the following formula is used to transesterify R ¹ and R ² into R ³ while maintaining the configuration of the above-mentioned raw material. (In the above formula, R ³ is an alkyl group or an aralkyl group)
A method for producing an (S)-or (R) -aziridine-2-carboxylic acid derivative represented by: