JPH07133258A - 2,5-pyrrolidine dione derivative - Google Patents

Abstract

PURPOSE:To obtain the subject inexpensive compound useful as a synthetic intermediate for (R)-3-pyrrolidinol of a synthetic raw material of a carbapenum derivative exhibiting excellent antibacterial activity and comprising a mixture of specific stereoisomers. CONSTITUTION:The objective compound comprises a mixture of (3S,4 S)-2,5-pyrrolidine dione derivative of formula I [R<1> is H or an aralkyl; R<2> is a 1-3C alkyl; X is a halogen; (S) is S-configuration] with (3S,4R)-2,5-pyrrolidine dione derivative of formula II [(R) is R-configuration], e.g. (3S,4R)- and (3S,4S)-3- acetoxy-l-benzyl-4-bromo-2,5-pyrrolidine dione. The objective compound is obtained by reacting a compound of formula III or a compound of formula IV (R<3> is a 1-4C alkyl) with a hydrogen halide in the presence of a lower aliphatic acid followed by further adding a dehydrating condensation agent, e.g. an acid anhydride to perform intramolecular cyclization.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 2,5-pyrrolidinedione derivative represented by the formula (I) which is useful as a synthetic intermediate of optically active 3-pyrrolidinol (VIII).

[0002]

2. Description of the Related Art Julie et al. Have described a method for producing (S) -3-pyrrolidinol using (S) -1-benzyl-3-hydroxy-2,5-pyrrolidinedione as an intermediate, which is synthesized from L-malic acid. Reported [see SYNTHETIC COMMUNICATIONS, Volume 15 (No. 7), pp. 587-598 (1985)]. On the other hand, in JP-A-2-191278, (S) -3-acetoxy-1-benzyl-2,5-pyrrolidinedione synthesized from acetyl-L-malic anhydride is used as an intermediate (S)-. A method of making 3-pyrrolidinol is disclosed.

[0003]

The optically active 1-benzyl-3-hydroxy-2,5-pyrrolidinedione and the optically active 3-acetoxy-1-benzyl-2,5-pyrrolidinedione are as described above. Known as an important synthetic intermediate of optically active 3-pyrrolidinol,
In all of the conventional production methods, expensive optically active malic acid is used as a starting material. In particular, (R) -3-pyrrolidinol
(VIII) is a very expensive non-natural type D-
Since malic acid must be used as a starting material, it is unlikely to be an economical manufacturing method.

Therefore, an object of the present invention is to provide an optically active (R)
Inexpensive synthetic intermediate (I) of 3-pyrrolidinol (VIII)
To provide.

[0005]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have conducted earnest research on a method for producing optically active 3-pyrrolidinol utilizing an inexpensive asymmetric source. As a result, the compound (R) -1-benzyl-3-hydroxy-2,5-pyrrolidinedione, which is conveniently derived from optically active tartaric acid and is a synthetic intermediate of (R) -3-pyrrolidinol (VIII), The present invention has been completed by discovering a novel compound (I) which can be easily converted into the compound (II) and the compound (R) -3-acetoxy-1-benzyl-2,5-pyrrolidinedione (III).

The novel 2,5-pyrrolidinedione derivative (I) of the present invention has the general formula

[0007]

[Chemical 2]

[In the formula, R ¹ represents a hydrogen atom or an aralkyl group, R ² represents an alkyl group having 1 to 3 carbon atoms, X represents a halogen atom, (S) represents an S-coordinate,
(R) represents the R configuration]. 1, 2, 3, 4, 5 in the above formula
Is a number added to clearly indicate the position of the substituent on the pyrrolidine ring.

In the above general formula, R ¹ represents a hydrogen atom or a benzyl group which may have 1 or 2 substituents selected from the following on the ring of the phenyl group. The substituent on the ring is a nitro group, a methoxy group, a methyl group, a bromine atom,
Among them, a benzyl group is preferable among the aralkyl groups.

In the above general formula, R ² may be an alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group or a propyl group, preferably a methyl group.

In the above general formula, X represents a halogen atom, for example, a chlorine atom or a bromine atom.

3-acyloxy-4-halogeno-2,5
-Pyrrolidinedione has two asymmetric carbons at the 3- and 4-positions, and has an absolute configuration of (3S, 4S), (3S, 4R), (3
R, 4S) and (3R, 4R), there are a total of four stereoisomers, but in the present invention, (3S, 4S) and (3S, 4
R) is a mixture.

The compound (I) of the present invention has the general formula

[0014]

[Chemical 3]

[In the formula, R ¹ and (R) have the same meanings as described above. ] The compound (V) represented by

[0016]

[Chemical 4]

[In the formula, R ¹ and (R) have the same meanings as described above, and R ³ represents an alkyl group having 1 to 4 carbon atoms. The alkyl group of R ³ is methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, t
-Butyl group is exemplified, and methyl group is preferable. ] It can synthesize | combine by making the compound (VI) shown by these and hydrogen halide act in the presence of a lower fatty acid.

This reaction is roughly divided into a two-step reaction including a substitution reaction with a halogen anion (first step) and a subsequent intramolecular cyclization reaction (second step).

[0019]

[Chemical 5]

When the compound (V) is used as a starting material, a small amount of water, preferably about 1 molar equivalent, is added to the reaction mixture in advance in order to suppress side reactions.

The hydrogen halide used in the first step includes hydrogen chloride and hydrogen bromide, preferably hydrogen bromide.

The lower fatty acid is acetic acid.

This reaction is usually carried out in a solution of hydrogen halide in acetic acid. The amount of hydrogen halide used is 1 molar equivalent or more, preferably 4 to 8 molar equivalents, relative to the substrate.

The reaction temperature is room temperature to 100 ° C., preferably
It is performed at 40 ° C to 60 ° C.

The substitution reaction with a halogen anion is usually completed in several hours, depending on the reaction temperature, and after the substitution reaction is completed,
The reaction mixture can be used for the next intramolecular cyclization reaction without purification.

The intramolecular cyclization reaction of the second step is promoted by adding about 1 to 3 molar equivalents of the dehydration condensing agent to the reaction solution of the first step. It takes 10 to several tens of hours until the intramolecular cyclization reaction is completed.

Examples of such dehydration condensing agents include acid anhydrides such as acetic anhydride, propanoic anhydride, butanoic acid anhydride, benzoic acid anhydride and trifluoroacetic acid anhydride; acetyl chloride, acetyl bromide, propanoic acid chloride, butanoic acid. Chloride,
Acid halides such as benzoyl chloride, methyl chlorocarbonate, and ethyl chlorocarbonate; N, N'-dicyclohexylimide, diphenylphosphoric acid azide, diethylphosphoric acid cyanide, and the like are preferable, and acid anhydride is preferable, and more preferable is anhydrous. It is acetic acid.

[0028]

[Chemical 6]

The hydrogen halide used in the first step includes hydrogen chloride and hydrogen bromide, preferably hydrogen bromide.

The lower fatty acid includes acetic acid, propionic acid and butyric acid, preferably acetic acid.

This reaction is usually carried out in a lower fatty acid solution of hydrogen halide. The amount of hydrogen halide used is 1 molar equivalent or more, preferably 4 to 8 molar equivalents, relative to the substrate.

When (VI) is used as a starting material, the reaction temperature is room temperature to 100 ° C, preferably 40 ° C to 60 ° C.
Done in.

The substitution reaction with a halogen anion is usually completed in several hours, depending on the reaction temperature, and after the substitution reaction is completed,
The reaction mixture can be used for the next intramolecular cyclization reaction without purification.

The intramolecular cyclization reaction of the second step is promoted by adding about 1 to 3 molar equivalents of the dehydration condensing agent to the reaction solution of the first step. It takes 10 to several tens of hours until the intramolecular cyclization reaction is completed.

Examples of such dehydration condensing agents include acid anhydrides such as acetic anhydride, propanoic anhydride, butanoic acid anhydride, benzoic acid anhydride, trifluoroacetic acid anhydride; acetyl chloride, acetyl bromide, propanoic acid chloride, butanoic acid. Chloride,
Acid halides such as benzoyl chloride, methyl chlorocarbonate, and ethyl chlorocarbonate; N, N'-dicyclohexylimide, diphenylphosphoric acid azide, diethylphosphoric acid cyanide, and the like are preferable, and acid anhydride is preferable, and more preferable is anhydrous. It is acetic acid.

The method for separating the compound (I) from the reaction mixture obtained under the present reaction conditions is not particularly limited, and it can be carried out by extraction operation or the like, and can be subjected to the next step without purification. If necessary, it can be purified by column chromatography.

Compound (I) produced under the above reaction conditions
Is a mixture of two stereoisomers of the (3S, 4S) isomer and the (3S, 4R) isomer, but the carbon steric to which the acyloxy group is bound is the starting material (V) and It retains the solid of (VI) almost completely.

The compounds (V) and (VI), which are the starting materials for the above reaction, are synthesized from diacetyl-L-tartaric anhydride according to the following reaction formula.

[0039]

[Chemical 7]

[Wherein R ¹ , R ³ and (R) have the same meanings as described above] The novel compound (I) of the present invention (R ¹ = benzyl group, R ² =
A methyl group, X = bromine atom) can be derived to compound (II) and compound (III) useful as a synthetic intermediate of 3-pyrrolidinol according to the following reaction formula.

[0041]

[Chemical 8]

The compound (VII) can be obtained by subjecting the compound (I) to solvolysis under acidic conditions. As a preferable reaction condition, methanol, ethanol or water is added to the reaction mixture of the previous step in which the compound (I) is synthesized, and the mixture is stirred at room temperature to reflux temperature for several hours to several tens hours.

The hydrogenolysis reaction of compound (I) and compound (VII) is carried out by treatment with an active metal or hydrogenation reaction using a noble metal catalyst such as palladium or nickel.

As the active metal used in the hydrogenolysis reaction, zinc can be mentioned.

In the case of hydrogenolysis reaction with zinc, zinc is used in an amount of 2 to 3 equivalents with respect to the substrate. The reaction is carried out at 60 ° C. to 70 ° C. in a mixed solvent of water-organic solvent, usually 2-3
Finish in time. Acetone as the preferred organic solvent,
1,2-dimethoxyethane, tetrahydrofuran, N,
Examples thereof include N-dimethylformamide.

The hydrocracking reaction by catalytic hydrogenation is 1 to 4
It is carried out at room temperature under atmospheric hydrogen pressure. Useful catalysts include palladium / carbon, Raney nickel and the like.

As the solvent, a mixed solvent of water and an organic solvent is preferable, and as the organic solvent, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and ketones such as acetone are preferable.

The mixing ratio of water and organic solvent is 1:10 to 1: 1.
And preferably 1: 3 to 1: 2.

A base such as magnesium oxide or sodium acetate may be added to the reaction mixture in order to neutralize the hydrogen halide produced during the reaction. The addition amount of the base is 1 equivalent to the hydrogen halide.

The method for separating and purifying Compound (II) or Compound (III) from the reaction mixture is not particularly limited, and column chromatography, recrystallization and the like can be performed.

[0051]

INDUSTRIAL APPLICABILITY Compound (I) obtained from naturally occurring inexpensive L-tartaric acid is (R) -1-benzyl-3-hydroxy-2,5-pyrrolidinedione (II) having a very high optical purity. ) And (R) -3-acetoxy-1
It can be easily converted to -benzyl-2,5-pyrrolidinedione (III) and has high industrial utility value.

The compound (II) or compound (III) having the (R) coordination can be prepared by the two steps of (R) -3-pyrrolidinol (VI).
II) can be guided to [SYNTHETIC COMMUNICATIONS], Volume 15 (No. 7), 5
87-598 (1985)]. The hydrochloride (IX) of (VIII) is a raw material for synthesizing a carbapenem derivative (XIV) showing extremely excellent antibacterial activity, and is disclosed in JP-A-60-84258.
It can be led to (XIV) according to the method described in the publication.

[0053]

[Chemical 9]

The present invention will be specifically described below with reference to examples.

[0055]

【Example】

Example 1 (3S, 4R) and (3S, 4S) -3-acetoxy-1-benzyl-4-bromo-2,5-pyrrolidinedione

[0056]

[Chemical 10]

A mixture of methyl N-benzyl-L-tartaramidate (2.53 g, 10 mmol) and 30% hydrobromic acid acetic acid solution (12 ml, HBr: 60 mmol) was stirred at 50 ° C. for 6.5 hours. did. After the reaction mixture was once cooled to room temperature, acetic anhydride (2.83 ml, 3
0 mmol) was added and stirring was continued at 50 ° C. for 16 hours again. After completion of the reaction, the reaction mixture was poured into ice water (10 ml) and extracted twice with toluene (25 ml).
The organic layers were combined, washed with 20% brine (7.5 ml), dried (anhydrous sodium sulfate), and the solvent was evaporated under reduced pressure. Rover column (Merck Si6
0, eluent: hexane / ethyl acetate = 3/1), and the title compound consisting of two isomers (isomer ratio: isomer a / isomer b = 3/2 from ¹ H-NMR analysis). (2.92 g, yield 89%) was obtained as a colorless transparent oil. (Is isomer a a (3S, 4R) form (3S, 4S)
Body or not identified) Physical property value of isomer mixture IR (neat) cm ⁻¹ : 1755, 1720, 139
5,1222,1167 ¹ H-NMR (CDCl ₃ ) δ
ppm isomer a: 2.20 (3H, s), 4.69 (1H,
d, J = 4.6 Hz), 4.72 (1H, d, J = 1)
4.3 Hz), 4.78 (1H, d, J = 14.3H)
z), 5.50 (1H, d, J = 4.6 Hz), 7.3
~ 7.4 (5H, m) isomer b: 2.25 (3H, s), 4.73 (1H,
d, J = 14.1 Hz), 4.75 (1H, d, J = 1)
4.1Hz), 4.90 (1H, d, J = 7.3H)
z), 5.52 (1H, d, J = 7.3 Hz), 7.3
~ 7.4 (5H, m) High resolution FAB-MS [m / z, (C ₁₃ H ₁₂ BrNO ₄
+ H) ⁺ Main single chemical species] Calculated: 326.0028 Found: 326.0034 Example 2 (3S, 4R) and (3S, 4S) -3-acetoxy-4-bromo-2,5. -Pyrrolidinedione

[0058]

[Chemical 11]

O, O'-diacetyl-L-tartaramic acid (1.399 g, 6 mmol), 30% hydrobromic acid acetic acid solution (7.2 ml, HBr: 36 mmol) and water (108).
mg, 6 mmol) at 50 ° C. for 7.
Stir for 5 hours. The reaction mixture was once cooled to room temperature, acetic anhydride (1.13 ml, 12 mmol) was added, and the mixture was stirred again at 50 ° C. for 18 hr. After the reaction was completed, the reaction solution was poured into ice water (21 ml) and washed with ethyl acetate (20 m).
Extraction was carried out twice in l). Match the organic layer, 20%
The extract was washed with brine (5 ml), dried (anhydrous sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was separated and purified by a Rover column (Si60 manufactured by Merck & Co., eluent: hexane / ethyl acetate = 3/1) to give two isomers ( ¹ H-
From NMR analysis, isomer ratio: isomer A / isomer B = 6 /
The title compound consisting of 5) (0.871 g, yield 61%)
Was obtained as a colorless transparent oil. (Isomer A is (3S,
4R) form or (3S, 4S) form or not identified) Physical properties of isomer mixture IR (neat) cm ^-1 : 3250,1800,173
5,1375,1220,1180 ¹ H-NMR (CD ₃ OD) δ ppm Isomer A: 2.20 (3H, s), 4.98 (1H,
d, J = 7 Hz), 5.68 (1H, d, J = 7 Hz) Isomer B: 2.17 (3H, s), 5.11 (1H,
d, J = 5 Hz), 5.65 (1 H, d, J = 5 Hz) Elemental analysis value (as C ₆ H ₆ BrNO ₄ ) Calculated value: C, 30.53; H, 2.56; Br, 33.
85; N, 5.93 Found: C, 30.46; H, 2.83; Br, 33.
76; N, 6.13 Reference Example 1 (3R, 4S) and (3S, 4S) -1-benzyl-
3-bromo-4-hydroxy-2,5-pyrrolidinedione

[0060]

[Chemical 12]

A mixture of methyl N-benzyl-L-tartrate amidate (6.46 g, 25 mmol) and 30% hydrobromic acetic acid solution (29.9 ml, HBr, 150 mmol) was stirred at 50 ° C. for 5 hours. did. After the reaction mixture was once cooled to room temperature, acetic anhydride (7.1 ml, 7 ml
5 mmol) was added and stirring was continued again at 50 ° C. for 20 hours. Then, to the reaction mixture, methanol (30 m
1) was added, and the mixture was stirred at room temperature for 42 hours and further at 45 ° C. for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to about 20 ml, water (20 ml) was added, and toluene (30 ml) was added.
Was extracted twice. Combine the organic layers and water (15 ml)
The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Rover column (Merck Si
60, eluent: hexane / ethyl acetate = 2/1) to separate and purify to obtain high polarity isomer (1.38 g) and low polarity isomer (3.87 g) as colorless crystals. Yield 74% Highly polar isomer Melting point: 126.5-128.0 ° C (recrystallized from diethyl ether) IR (KBr) cm ^-1 : 3432,1693,113
5,747,720 ¹ H-NMR (CDCl ₃ ) δppm 2.95 (1H,
d, J = 6.7 Hz, OH), 4.65 (1H, t, J
= 6.7 Hz), 4.70 (1H, d, J = 14.3H)
z), 4.73 (1H, d, J = 14.3 Hz), 4.
80 (1H, d, J = 6.7 Hz), 7.28 to 7.3
7 (5H, m) Elemental analysis value (as C ₁₁ H ₁₀ BrNO ₃ ) Calculated value: C, 46.50; H, 5.79; Br, 28.
12; N, 4.93 Found: C, 46.27; H, 3.80; Br, 27.
88; N, 4.89 low polar isomer Melting point: 97.5-98.5 ° C (recrystallized from diethyl ether-hexane) IR (KBr) cm ^-1 : 3447, 3319, 171
3,1696,1176 1 NMR (CDCl ₃ ) δppm: 3.13 (1H,
d, J = 4 Hz, OH), 4.58 (1H, d, J = 5
Hz), 4.70 (1H, d, J = 14Hz), 4.7
3 (1H, d, J = 14Hz), 4.76 (1H, d
d, J = 4,5 Hz), 7.28 to 7.37 (5H,
m) Elemental analysis (C ₁₁ H ₁₀ as BrNO ₃₎ Calculated: C, 46.50; H, 5.79 ; Br, 28.
12; N, 4.93 Found: C, 46.60; H, 3.50; Br, 27.
96; N, 4.96 Reference Example 2 (R) -3-acetoxy-1-benzyl-2,5-pyrrolidinedione

[0062]

[Chemical 13]

N-benzyl-O, O'-diacetyl-L
Tartaric amic acid (970 mg, 3 mmol) and 30% hydrobromic acid acetic acid solution (3.6 ml, HBr: 18 mmol)
And a mixture of water (54 mg, 3 mmol) was added to 5
The mixture was stirred at 0 ° C for 21.5 hours. After the reaction mixture was once cooled to room temperature, acetic anhydride (0.87 ml, 6 mmo
1) was added, and the mixture was stirred again at 50 ° C. for 5.5 hours. After completion of the reaction, the reaction solution was poured into ice water (20 ml) and extracted twice with toluene (20 ml). The organic layers were combined, dried (anhydrous sodium sulfate), and the solvent was evaporated under reduced pressure to give a crude product of the compound of Example 1. Subsequently, the crude product was dissolved in 67% aqueous dioxane solution, 5% palladium carbon (90 mg) was added, and hydrogen pressure was applied (2 atm).
Stir vigorously for 30 minutes at room temperature. After filtering the catalyst, the filtrate was concentrated to about 10 ml, extracted twice with toluene (20 ml), and the organic layer was concentrated under reduced pressure. The residue was purified using a reverse phase column (eluent: acetonitrile / water = 40/60) to obtain the title compound (493 mg, total yield 66%). In addition, HPLC [column: Chiralcel OJ (manufactured by Daicel Chemical Industries, φ4.6 × 250 mm); mobile phase: hexane / isopropyl alcohol = 2/1; flow rate: 0.6
ml / min; detection wavelength: 225 nm; retention time:
As a result of measuring the optical purity using the (R) form 38 min and the (S) form 41 min], it was 99% ee. Melting point: 59-60 ° C IR (nujol) cm ^-1 : 1758, 1706, 14
29, 1405, 1225 ¹ H-NMR (CDCl ₃ ) δppm: 2.16 (3H,
s), 2.67 (1H, dd, J = 5.0, 18.3H)
z), 3.17 (1H, dd, J = 8.8, 18.3H)
z), 4.69 (1H, d, J = 14.1 Hz), 4.
72 (1H, d, J = 14.1 Hz), 5.45 (1
H, dd, J = 5.0, 8.8 Hz), 7.26 to 7.
40 (5H, m) Reference Example 3 (R) -1-benzyl-3-hydroxy-2,5-pyrrolidinedione

[0064]

[Chemical 14]

A crude product (6.72 g) obtained by reacting methyl N-benzyl-L-tartrate amidate (6.46 g, 25 mmol) in the same manner as in Example 2 was added to a 75% aqueous methanol solution (150 ml). 5% palladium carbon (0.67 g) was added, and the mixture was vigorously stirred under hydrogen pressure (2 atm) at room temperature for 1 hour. After filtering the catalyst, the filtrate is about 4
It was concentrated to 0 ml and extracted twice with ethyl acetate (40 ml). Combine the organic layers and wash with water (20 ml),
The solvent was distilled off under reduced pressure. The obtained crude crystals were mixed with toluene (2
Recrystallization from 4 ml) gave the title compound (3.24 g, total yield 63%). In addition, HPLC [column: Chiralpak AS (manufactured by Daicel Chemical Industries, φ4.6 × 250 m
m); mobile phase: hexane / isopropyl alcohol = 6
/ 1; Flow rate: 0.6 ml / min; Detection wavelength: 225n
m; retention time: (R) body 31 min, (S) body 28
min] was used to measure the optical purity, and the result was 99% ee.
Met.

Melting point: 101 to 103 ° C. IR (KBr) cm ⁻¹ : 3367, 1697, 143
4,1179 ¹ H-NMR (CDCl ₃ ) δppm: 2.68 (1H,
dd, J = 4.9, 18.2 Hz), 3.09 (1H,
dd, J = 8.5, 18.2 Hz), 3.19 (1H,
br-d, J = 2.8 Hz, OH), 4.56 to 4.6.
4 (1H, m), 4.66 (2H, s), 7.26-
7.38 (5H, m) Reference Example 4 N-benzyl-O, O'-diacetyl-L-tartaric acid

[0067]

[Chemical 15]

Diacetyl-L-tartaric anhydride (6.485)
g, 30 mmol) in dichloromethane (45 ml) under ice-cooling, benzylamine (3.28 ml, 30 mm
Ol) in dichloromethane (6.5 ml) was added dropwise over 30 minutes, and stirring was continued at room temperature for 30 minutes. Methanol (20 ml) was added to dissolve the precipitated crystals, and the solvent was evaporated under reduced pressure to give the title compound (10.04 g).

Melting point: 131.5 to 132.0 ° C. (recrystallized from water) IR (KBr) cm ⁻¹ : 3500 to 2400, 177
6,1764, 1732, 1635, 1215, 120
_{^{1 1 H-NMR (CD 3}} OD) δppm: 1.97 (3H,
s), 2.16 (3H, s), 4.29 (1H, d
d, J = 4,15 Hz), 4.51 (1H, dd, J =
5,15Hz), 5.60 (1H, d, J = 3Hz),
5.67 (1H, d, J = 3Hz), 7.21 to 7.3
2 (5H, m) Elemental analysis value (as C ₁₅ H ₁₇ NO ₇ ) Calculated value: C, 55.73; H, 5.30; N, 4.33 Actual value: C, 55.73; H, 5 .37; N, 4.36 Reference Example 5 Methyl N-benzyl-L-tartaramidate

[0070]

[Chemical 16]

N-benzyl-O, O'-diacetyl-L
-Tartaric amic acid (32.3 g, 0.10 mol) 1.
After being dissolved in a 3N HCl methanol solution (440 ml),
Stirred at room temperature for 16 hours. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain the title compound (25.8 g).

Melting point: 124.5-125.0 ° C. (recrystallized from water) IR (KBr) cm ⁻¹ : 3358, 1728, 166
0,1288,1122,1067 ¹ H-NMR (CD ₃ OD) δppm: 3.77 (3H,
s), 4.43 (1H, d, J = 15Hz), 4.47
(1H, d, J = 2Hz), 4.48 (1H, d, J =
15 Hz), 4.61 (1H, d, J = 2 Hz), 7.
20~7.33 (5H, m) Elemental analysis (C ₁₂ H ₁₅ NO ₅₎ Calculated value: C, 56.91; H, 5.97 ; N, 5.53 Found: C, 56.92 H, 5.88; N, 5.55 Reference Example 6 O, O'-diacetyl-L-tartaric amic acid

[0073]

[Chemical 17]

Ammonium acetate (2.428 g, 31.
Diacetyl-L-tartaric anhydride (6.485 g, 30 mm) was added to a suspension of 5 mmol) in acetonitrile (65 ml).
ol) was added and the mixture was stirred at room temperature for 6 hours, and then the precipitated crystals were filtered. After washing the crystals with a small amount of cold acetonitrile,
It was dried under vacuum to obtain the title compound (5.825 g).

Melting point: 185 to 187 ° C. (decomposition; recrystallization from water) IR (KBr) cm ⁻¹ : 3500 to 2300,176
1,1725,1681,1212 ¹ H-NMR (CD ₃ OD) δppm: 2.12 (3H,
s), 2.15 (3H, s) 5.60 (1H, d, J =
3 Hz), 5.63 (1 H, d, J = 3 Hz) Elemental analysis value (as C ₈ H ₁₁ NO ₇ ) Calculated value: C, 56.91; H, 5.97; N, 5.53 Measured value: C, 56.92; H, 5.88; N, 5.55.

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom or an aralkyl group, and R ^1
2 represents a lower alkyl group having 1 to 3 carbon atoms, X represents a halogen atom, (S) represents S coordination, and (R) represents R coordination], 2,5-pyrrolidine Dione derivative.