JP2825608B2 - Optically active threo-3-amino-2-hydroxypentanoic acid and process for producing the same - Google Patents

Description

The present invention relates to an optically active threo-3-amino-2-hydroxypentanoic acid and an optically active threo-3-amino-2.
General formula which is an intermediate for producing hydroxypentanoic acid (Wherein R represents an organic residue reductively or hydrolytically substituted with hydrogen or an amino-protecting group used in ordinary peptide synthesis) represented by the formula:
The present invention relates to protected 3-amino-2-hydroxypentanoic acid and its optically active 1- (1-naphthyl) ethylamine salt.

Further, the present invention provides a compound represented by the general formula: (Wherein R represents an organic residue which is reductively or hydrolytically substituted with hydrogen or a protecting group for an amino group used in ordinary peptide synthesis) (±) -threo-N-
Optically active 1- (1-naphthyl) ethylamine was allowed to act on protected-3-amino-2-hydroxypentanoic acid, and the resulting diastereomer salt was optically resolved by utilizing the difference in solubility. The optically active diastereomer salt is decomposed to give an optically active threo-N-protected-3-amino-
Method for producing optically active threo-N-protected-3-amino-2-hydroxypentanoic acid, characterized by collecting 2-hydroxypentanoic acid, and optically active threo-N-protected-3-ion thus collected The present invention relates to a method for producing optically active threo-3-amino-2-hydroxypentanoic acid, which comprises removing an amino-protecting group of amino-2-hydroxypentanoic acid. Furthermore, the present invention provides threo-3
-Amino-2-hydroxypentanoic acid and erythro-3-
Threo-3, wherein a mixture of amino-2-hydroxypentanoic acids is separated by utilizing the difference in solubility.
-Amino-2-hydroxypentanoic acid and erythro-3
-Amino-2-hydroxypentanoic acid.

Optically active threo-3-amino-2-hydroxypentanoic acid and optically active threo-N-protected-3-amino-2-
Hydroxypentanoic acid is a substance that has recently become increasingly important as a synthetic intermediate for the hydrolase inhibitor poststatin.

[Prior Art] A method for synthesizing 3-amino-2-hydroxypentanoic acid which is not optically active and has an unknown steric relationship between the 2-position and the 3-position is already known (Bull. Chem. Soc. Jpn., 49,3181 (19
76). ). However, 3-amino-2-hydroxypentanoic acid theoretically has four optical isomers of (2R, 3S), (2S, 3R), (2R, 3R) and (2S, 3S). ,
Conventionally, there is no known method for separating these and isolating each. Therefore, optically active threo-3-amino-2-
There is no known example of obtaining hydroxypentanoic acid.
Similarly, optically active threo-N-protected-3-amino-2-hydroxypentanoic acid also theoretically has four kinds of optical isomers, but p-methoxybenzyloxycarbonyl which is commonly used for peptide synthesis is also present. Group, a benzyloxycarbonyl group, a compound in which an amino group is protected with a t-butoxycarbonyl group, or the like,
2-hydroxypentanoic acid is not known. Therefore,
There is no known example of obtaining optically active threo-N-protected-3-amino-2-hydroxypentanoic acid.

[Problems to be Solved by the Invention] Since the hydrolase inhibitor poststatin obtained from a natural product is an optically active substance,
3-Amino-2-hydroxypentanoic acid, which is a raw material for synthesizing a structural unit of a hydrolase inhibitor, also needs to be an optically active substance. However, conventionally, optically active threo-3 was used.
The determination of the configuration of natural hydrolase inhibitors, where amino-2-hydroxypentanoic acid and optically active threo-N-protected-3-amino-2-hydroxypentanoic acid cannot be obtained. And it is difficult to produce a natural type hydrolase inhibitor.

[Means for Solving the Problems] Accordingly, the present inventors have conducted intensive studies to overcome the above problems, and as a result, first, (±) -threo-3-amino-2
It has been found that -hydroxypentanoic acid and (±) -erythro-3-amino-2-hydroxypentanoic acid can be separated by utilizing the difference in solubility. Incidentally, the confirmation of the threo form and the erythro form is carried out, for example, as shown in Reference Example, by oxazolidone conversion and the method of Shiba et al. (Bull. Chem. Soc. Jpn., 46, 3308 (19)
73). ) Can be easily distinguished by comparing the α hydrogen coupling constant in the NMR spectrum.

Then, the amino group of the (±) -threo compound is protected, and the resulting novel (±) -threo-N-protected-3-amino-2 is obtained.
-Optically active 1- (1-naphthyl) ethylamine is allowed to act on -hydroxypentanoic acid, and the resulting diastereomer salt is subjected to optical resolution utilizing the difference in solubility to obtain an optically active diastereomer salt To obtain optically active threo-N-protected-3-amino-2-hydroxypentanoic acid, and if necessary, the optically active threo-N-protected-3-amino-2-hydroxypentanoic acid. It has been found that the optically active threo-3-amino-2-hydroxypentanoic acid can be produced by removing the protecting group of the amino group.

 The present invention has been completed based on the above findings.

The present invention will be described in more detail.
Examples thereof include an organic residue which is reductively or hydrolytically substituted with hydrogen or a protecting group for an amino group used in ordinary peptide synthesis. Examples thereof include a p-methoxybenzyloxycarbonyl group and a benzyloxycarbonyl group. Group,
Although there is a t-butoxycarbonyl group and the like, a p-methoxybenzyloxycarbonyl group is preferable because it can be removed by either a method using reduction or a method using acid treatment.

In carrying out the present invention, first, 3-amino-2-hydroxypentanoic acid, which is a mixture of a threo form and an erythro form, obtained by an ordinary synthesis method, is treated with, for example, an aqueous ethanol solvent to separate the threo form and the erythro form. I do. Incidentally, the confirmation of the threo form and the erythro form can be easily distinguished by, for example, oxazolidone conversion and comparison of NMR spectra as shown in Reference Examples. Then
The (±) -threo-N-protected-3-amino-2 is a novel compound obtained by protecting the amino group of the (±) -threo compound.
Optically active 1- (1-naphthyl) ethylamine and a solvent are added to -hydroxypentanoic acid and dissolved by heating to make supersaturation. If necessary, two diastereomeric salts having a lower solubility in the solvent are used. After inoculating a small amount of the diastereomer salt of the above, the mixture is cooled to 0 ° C. to room temperature, and the hardly soluble salt precipitated is separated.

As the solvent used in the present invention, usually, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, methyl ethyl ketone, benzene, toluene, tetrahydrofuran, dioxane, isopropyl ether, hexane,
Dichloromethane, 1,2-dichloroethane, methyl acetate,
Examples thereof include a mixed solvent of ethyl acetate and a suitable combination of these organic solvents or a mixed solvent of a water-soluble organic solvent and water, and preferably alcohols such as methanol, ethanol, 1-propanol and 2-propanol. Is good. The amount of the diastereomer salt is preferably about 1 to 20 times by volume, preferably about 1 to 5 times by volume, per 1 g of the diastereomer salt.

Optically active 1- (1-naphthyl) used as a resolving agent
The molar ratio of ethylamine to (±) -threo-N-protected-3-amino-2-hydroxypentanoic acid is not particularly limited, but the former is 0.5 to 1.5 equivalents to the latter,
Preferably, 0.8 to 1.0 equivalent is used from the viewpoint of division efficiency. Since optically active 1- (1-naphthyl) ethylamine is a synthetic optical resolving agent, both enantiomers are available, and the optically active 1- (1-naphthyl) ethylamine used is used.
It is also possible to produce optically active threo-N-protected-3-amino-2-hydroxypentanoic acids having different light-emitting properties depending on the light-emitting properties of ethylamine. Here, for example, when (±) -threo-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid is used, when (−)-1- (1-naphthyl) ethylamine is used, (−) − The threo form was obtained, and (+)-1-
When (1-naphthyl) ethylamine is used, a (+)-threo compound can be obtained.

The crystals of the diastereomeric salt thus obtained are recrystallized, if necessary, and then decomposed by the action of a mineral acid such as hydrochloric acid or sulfuric acid, and the released optically active threo-N-
Protected-3-amino-2-hydroxypentanoic acid is extracted with an organic solvent such as ethyl acetate, ether, chloroform or toluene, or a diastereomer salt is treated with a water-soluble base such as sodium hydroxide, potassium hydroxide or ammonia. Then, the extracted 1- (1-naphthyl) ethylamine is extracted with an organic solvent such as ethyl acetate, ether, chloroform, toluene, etc., and then treated with a mineral acid and extracted with an organic solvent in the same manner as described above to obtain a highly purified target compound. Can be obtained.

The optically active threo-N-protection thus obtained is
3-Amino-2-hydroxypentanoic acid can be used as it is as an intermediate for peptide synthesis, but it is possible to obtain an optically active threo-3-amino-2-hydroxypentanoic acid by removing a protecting group if necessary. Can be.

[Effects of the Invention] According to the present invention, novel optically active threo-N-protected-3-amino-2-hydroxypentanoic acid and optically active threo-3-amino-2-hydroxypentane, which were conventionally difficult to produce, The acid can be obtained with high purity and high yield.

[Examples] Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto.

Example 1 (1) Threo (2R, 3S), (2S, 3R)-and erythro (2R, 3R), (2S, 3S) -3-amino-2-
Separation of hydroxypentanoic acid After heating and dissolving 4.78 g (35.9 mmol) of (2RS, 3RS) -3-amino-2-hydroxypentanoic acid in 40 ml of water, 40 ml of ethanol was added, the mixture was cooled to room temperature, and allowed to stand for 4 hours. The precipitated crystals were collected by filtration, washed three times with 3 ml of a water-ethanol (1: 1) solution, and dried to obtain threo (2R, 3S)-and (2S, 3
2.28 g of R) -3-amino-2-hydroxypentanoic acid were obtained. On the other hand, the combined filtrate and washings were treated with activated carbon, and the solvent was distilled off and dried to give erythro (2R, 3R)-and (2S,
2.45 g of 3S) -3-amino-2-hydroxypentanoic acid were obtained.

(2) Synthesis of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid threo (2R, 3S), (2S, 3R) -3- To 1.80 g (13.5 mmol) of amino-2-hydroxypentanoic acid, 4.52 g (14.9 mmol) of p-methoxybenzyl S-4,6-dimethylpyridin-2-ylthiolcarboxylate, 7.4 ml of water, 7.4 m of dioxane
l and 2.84 ml (20.3 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 19 hours. After completion of the reaction, 20 ml of water was added, and the mixture was washed twice with 30 ml of ethyl acetate, and the aqueous layer was cooled with an ice bath. The aqueous layer was adjusted to pH 2 by adding 4.5 ml of 5N hydrochloric acid, and then diluted with 20 ml of ethyl acetate.
Extracted twice with 10 ml. The oil layer was washed three times with 15 ml of 5% hydrochloric acid and three times with 15 ml of saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain threo (2R, 3S), (2
2.83 g of (S, 3R)-(p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid were obtained.

1H-NMR (CDCl3, internal standard TMS) δ (ppm): 0.98 (3H, t, J = 7.2 Hz, CH3) 1.5 to 1.78 (2H, m, CH2) 3.40 (br, OH, COOH) 3.81 (3H, s, CH3O) 4.93 to 4.0 (1H, m, NHCH) 4.24 (1H, br d, J = 1.8Hz, HOCHCOOH) 4.99,5.07 (2H, d, d, J = 11.6Hz, CH2C6H4) 5.21 (1H, d , J = 9.9Hz, NH) 6.84 to 6.91, 7.21 to 7.32 (4H, m, C6H4) Elemental analysis Calculated as C14H19NO6: C56.56, H6.44, N4.71, O32.29. Observed: C56 .69, H6.42, N4.52, O32.39. (3) Optics of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid Separation To 743.2 mg of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was added 432.0 mg of (-)-1- (1-naphthyl) ethylamine. After heating and dissolving in 2.5 ml of ethanol,
It was left at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed once with 0.2 ml of ethanol and twice with 0.3 ml, and dried to give (2R, 3S)-(-)-3- (p-methoxybenzyloxycarbonyl) amino-2. -Hydroxypentanoic acid
(-)-1- (1-naphthyl) ethylamine salt 604.3mg
I got ▲ [α] ²⁸ _D ▼ -8.0 ゜, ▲ [α] ²⁸ ₄₃₆ ▼ -16.
2 ゜ (c1.14, methanol).

490.4 mg of (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt thus obtained was heated in 1.6 ml of ethanol. After dissolution, at room temperature 1.5
Let stand for hours. The precipitated crystals were collected by filtration, and ethanol 0.2m
After washing twice with l and drying, 427.9 mg of (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt was obtained. Was. ▲ [α] ²⁴ _D ▼ −9.7 ゜, ▲
[Α] ²⁴ ₄₃₆ ▼ -20.4 ゜ (c1.00, methanol).

Example 2 (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt obtained in the same manner as in Example 1 100.1 mg 2.0 ml of 0.5N aqueous sodium hydroxide solution was added thereto, and the mixture was washed twice with 2.0 ml of chloroform, and then 2.6 ml of 0.5N hydrochloric acid.
Was adjusted to pH2. This acidic solution is treated with ethyl acetate 2.0
The mixture was extracted three times with ml, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 30.1 mg of (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid. ▲ [α] ²⁸ _D ▼ -26.1 ゜, ▲
[Α] ²⁸ ₄₃₆ ▼ -54.1 ゜ (c2.01, methanol).

Example 3 321.2 mg of (−)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (−)-1- (1-naphthyl) ethylamine salt obtained in the same manner as in Example 1. Was heated and dissolved in 1.4 ml of ethanol, and then allowed to stand at room temperature for 3.5 hours. The precipitated crystals were collected by filtration, washed three times with 0.2 ml of ethanol, and dried to obtain (-)-3-
(P-methoxybenzyloxycarbonyl) amino-2
285.2 mg of -hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt was obtained. ▲ [α] ²⁷ _D ▼ -1
0.1 ゜, ▲ [α] ²⁶ ₄₃₆ ▼ -21.5 ゜ (c1.04, methanol).

Example 4 (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentamic acid (-)-1- (1-naphthyl) ethylamine salt obtained in Example 3 28
To 1.6 mg of 0.5 mg hydrochloric acid was added 1.6 ml of acid to decompose, and ethyl acetate 3 m
Extracted three times with l. 2 ml of 0.5N hydrochloric acid and saturated saline
After washing with 4 ml, drying over anhydrous sodium sulfate and distilling off the solvent, 181.0 mg of (2R, 3S)-(−)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was obtained. . ▲ [α] ²⁷ _D ▼ -37.0 ゜, ▲
[Α] ²⁷ ₄₃₆ ▼ -78.3 ゜ (c1.81, methanol).

The protective group of the amino group of the (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid thus obtained was removed, and after the 3,5-dinitrobenzoylation, the methyl ester When the amide obtained by the conversion was analyzed by high performance liquid chromatography using an optically active substance column (OA-1000 manufactured by Sumitomo Chemical Co., Ltd.), no enantiomeric peak was observed.

Example 5 (1) Treo (2R, 3S), (2S, 3R)-and erythro (2R, 3
R), Separation of (2S, 3S) -3-amino-2-hydroxypentanoic acid 31.75 g (0.238 mol) of (2RS, 3RS) -3-amino-2-hydroxypentanoic acid was dissolved in 260 ml of water by heating, and ethanol was dissolved. 260 ml was added, the mixture was cooled to room temperature, and allowed to stand overnight. The precipitated crystals are collected by filtration, and water-ethanol (1: 1) solution 15 ml
And then dried to obtain threo (2R, 3S)-and (2S, 3R) -3-amino-2-hydroxypentanoic acid 14.
66 g were obtained. On the other hand, the filtrate and the washing solution are combined, and the solvent is distilled off and dried to obtain erythro (2R, 3R)-and (2S, 3S).
17.13 g of -3-amino-2-hydroxypentanoic acid was obtained.

14.58 g of (2RS, 3RS) -3-amino-2-hydroxypentanoic acid (threo form containing 10.7% of erythro form) (0.11 g
(0 mol), 50 ml of water and 75 ml of ethanol were added, and the mixture was suspended for 1.5 hours while heating at a bath temperature of 80 ° C., cooled to room temperature, and allowed to stand overnight. Precipitated crystals are collected by filtration, and water-ethanol (1: 1.5)
After washing twice with 10 ml of the solution and drying, threo (2R, 3
14.00 g of (S)-and (2S, 3R) -3-amino-2-hydroxypentanoic acid were obtained. On the other hand, the filtrate and the washing solution are combined, the solvent is distilled off, and the residue is dried to obtain erythro (2R, 3R)-and (2
0.58 g of (S, 3S) -3-amino-2-hydroxypentanoic acid
I got

14.58 g of (2RS, 3RS) -3-amino-2-hydroxypentanoic acid (threo form containing 10.7% of erythro form) (0.11 g
(0 mol), 110 ml of water and 110 ml of ethanol were added, and the mixture was suspended for 1.5 hours while heating at a bath temperature of 80 ° C., cooled to room temperature, and allowed to stand overnight. The precipitated crystals were collected by filtration and mixed with water-ethanol (1: 1).
1) After washing twice with 10 ml of the solution and drying, threo (2R,
13.22 g of (3S)-and (2S, 3R) -3-amino-2-hydroxypentanoic acid were obtained. mp 236-239 ° C (dec). on the other hand,
The filtrate and washings were combined, the solvent was distilled off, and the residue was dried to obtain 1.29 g of erythro (2R, 3R)-and (2S, 3S) -3-amino-2-hydroxypentanoic acid.

(2) Synthesis of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid threo (2R, 3S), (2S, 3R) -3- To 5.99 g (45.0 mmol) of amino-2-hydroxypentanoic acid, 15.07 g (49.5 mmol) of p-methoxybenzyl S-4,6-dimethylpyrimidin-2-ylthiolcarboxylate, 25 ml of water, 25 dioxane
ml and triethylamine (9.45 ml, 67.5 mmol) were added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 65 ml of water was added, and the mixture was washed twice with 100 ml of ethyl acetate, and the aqueous layer was cooled with an ice bath. The aqueous layer was adjusted to pH 2 by adding 22 ml of 5N hydrochloric acid, and extracted once with 65 ml of ethyl acetate and twice with 30 ml of ethyl acetate. Wash the oil layer with 50 ml of 5% hydrochloric acid 3
And three times with 50 ml of a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain threo (2R, 3S),
9.65 g of (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was obtained.

(3) Optical resolution of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid threo (2R, 3S), (2S, 3R) -3 5.56 g of (-)-1- (1-naphthyl) ethylamine was added to 9.65 g of-(p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid, dissolved by heating in 30 ml of ethanol, and allowed to stand at room temperature overnight. . The precipitated crystals were collected by filtration, and ethanol 5m
After washing twice twice with l, and drying (2R, 3S)-
(-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid (-)-1-
10.16 g of (1-naphthyl) ethylamine salt was obtained. ▲
[Α] ²² _D ▼ -5.9 ゜, ▲ [α] ²² ₄₃₆ ▼ -12.1. ゜ (c1.0
1, methanol).

10.16 g of the thus obtained (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt is dissolved by heating in 35 ml of ethanol. Then, it was left still at room temperature overnight. The precipitated crystals were collected by filtration, washed twice with 5 ml of ethanol, and dried to give (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1 -Naphthyl) ethylamine salt
6.83 g were obtained. ▲ [α] ²² _D ▼ -9.6 ゜, ▲ [α] ²² ₄₃₆ ▼
-20.9 ゜ (c1.01, methanol).

Example 6 6.83 g of (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt obtained in the same manner as in Example 5. Was dissolved in 29 ml of ethanol by heating, and allowed to stand at room temperature for 1 hour. The precipitated crystals were collected by filtration, and ethanol 5m
After washing three times with l, drying was performed to obtain 6.24 g of (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt. Was. ▲ [α] ²⁴ _D ▼ -10.2 ゜, ▲
[Α] ²⁴ ₄₃₆ ▼ -21.6 ゜ (c1.01, methanol). mp154.5
~ 156.5 ° C.

Example 7 (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid (-)-1- (1-naphthyl) ethylamine salt obtained in Example 6 6.
35 g of 0.5N hydrochloric acid was added to 23 g to acid-decompose, and 60 ml of ethyl acetate was added.
Extracted three times. Extract solution is 0.5N hydrochloric acid 40ml and saturated saline
After washing with 80 ml, drying over anhydrous sodium sulfate and distilling off the solvent, 3.95 g of (2R, 3S)-(-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was obtained. . ▲ [α] ²⁷ _D ▼ -37.0 ゜, ▲ [α]
²⁷ ₄₃₆ ▼ -78.3 ゜ (c1.81, methanol).

The protective group of the amino group of the (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid thus obtained was removed, and after the 3,5-dinitrobenzoylation, the methyl ester When the amide obtained by the conversion was analyzed by high performance liquid chromatography using an optically active substance column (OA-1000 manufactured by Sumitomo Chemical Co., Ltd.), no enantiomeric peak was observed.

Example 8 To 1486.8 mg of threo (2R, 3S), (2S, 3R) -3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was added 857.2 mg of (-)-1- (1-naphthyl) ethylamine. After heating and dissolving in 3.0 ml of methanol,
The mixture was allowed to stand at room temperature for 2.5 hours. The precipitated crystals were collected by filtration, washed three times with 0.4 ml of methanol, and dried to obtain (-)-3.
-(P-methoxybenzyloxycarbonyl) amino-
There was obtained 922.0 mg of 2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt. ▲ [α] ³⁰ _D ▼ -9.
8 ゜, ▲ [α] ³⁰ ₄₃₆ ▼ -20.7 ゜ (c1.02, methanol).

Example 9 (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt 92 obtained in Example 8
After 2.0 mg was dissolved in 2.3 ml of methanol by heating, the mixture was allowed to stand at room temperature for 14 hours. The precipitated crystals were collected by filtration, and 0.3 ml of methanol was added.
After washing twice and drying, (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid / (-)-1- (1-naphthyl) ethylamine salt 828.9 mg was obtained. ▲ [α] ²⁵ _D ▼ -10.5 ゜, ▲ [α] ²⁵
₄₃₆ ▼ -22.2 ゜ (c1.01, methanol). mp155.5 ~ 157.5
° C Example 10 (-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid obtained in Example 9 (-)-1- (1-naphthyl) ethylamine salt 82
To 8.5 mg, add 4.6 ml of 0.5N hydrochloric acid to acid-decompose, and add 3 m of ethyl acetate.
Extracted three times with l. 5 ml of 0.5N hydrochloric acid and saturated saline
After washing with 5 ml, drying over anhydrous sodium sulfate and distilling off the solvent, 525.6 mg of (2R, 3S)-(-)-3- (p-methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid was obtained. . ▲ [α] ²⁶ _D ▼ -37.6 ゜, ▲
[Α] ²⁶ ₄₃₆ ▼ -79.4 ゜ (c2.10, methanol).

Example 11 (2R, 3S)-(−)-3- (p−) obtained in Example 4
0.1 ml of anisole and 0.5 ml of trifluoroacetic acid were added to 86.0 mg of methoxybenzyloxycarbonyl) amino-2-hydroxypentanoic acid, and the mixture was stirred at room temperature for 30 minutes, and then the solvent was distilled off. After adding 1 ml of water and washing twice with 1 ml of ether,
By removing trifluoroacetic acid with a strongly acidic ion exchange resin, 36.0 mg of (2R, 3S)-(+)-3-amino-2-hydroxypentanoic acid was obtained. ▲ [α] ²⁵ _D ▼ 14.8 ゜, ▲
[Α] ²⁵ ₄₃₆ ▼ +27.3 ゜ (c2.09, water). mp212.0-213.0
° C (dec.).

Reference Example Synthesis of (4R, 5S), (4S, 5R) -4-ethyl-2-oxo-oxazolidine-5-carboxylic acid Poorly soluble 3-amino-2- obtained in Example 1 (1).
To 250.3 mg (0.841 mmol) of hydroxypentanoic acid was added 3.36 ml (1.68 mmol) of a 0.5N aqueous sodium hydroxide solution, and the mixture was added at room temperature.
Stir for 4.5 hours. The reaction solution was washed twice with 3 ml of ether, acidified by adding 0.6 ml (1.80 mmol) of 3N hydrochloric acid, and extracted three times with 3 ml of ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to give crude oxazolidone 68.2.
mg was obtained. A part of the crude oxazolidone was subjected to thin layer chromatography (chloroform: methanol: acetic acid = 90: 10:
Purification in 5) yielded 6.7 mg of (4R, 5S), (4S, 5R) -4-ethyl-2-oxo-oxazolidin-5-carboxylic acid.

MS m / z 160 / M + 1) + 1H-NMR (CD3 OD, internal standard TMS) δ (ppm): 0.98 (t, 3H, J = 7.4 Hz, CH3) 1.69 (dq, 2H, J = 7.4 Hz, J) = 6.2Hz, CH2) 3.78 (dt, 1H, J = 6.2Hz, J = 4.8Hz, CH) 4.68 (d, 1H, J = 4.8Hz, CH) (4R, 5R), (4S, 5S) -4 Synthesis of -ethyl-2-oxo-oxazolidine-5-carboxylic acid The readily soluble 3-amino-2- obtained in Example 1 (1)
To 148.7 mg (0.500 mmol) of hydroxypentanoic acid was added 2.0 ml (0.25 mmol) of a 0.5N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 5 hours. The reaction solution was washed twice with 2 ml of ether, acidified by adding 1.0 ml (1.00 mmol) of 1N hydrochloric acid, and the solvent was distilled off. Then, 2 ml of toluene was added, and the solvent was sufficiently distilled off to obtain a mixture of crude oxazolidone and salt. This crude oxazolidone was dissolved in a small amount of methanol and purified by thin-layer chromatography (chloroform: methanol: acetic acid = 90: 10: 5) to give (4R, 5
R), (4S, 5S) -4-Ethyl-2-oxo-oxazolidine-5-carboxylic acid, 17.7 mg.

MS m / z 160 / M + 1) + 1H-NMR (CD3 OD, internal standard TMS) δ (ppm): 0.97 (t, 3H, J = 7.4 Hz, CH3) 1.22 to 1.90 (m, 2H, CH2) 4.05 ( ddd, 1H, J = 9.0Hz, J = 9.0Hz, J = 4.5Hz, CH), 5.13
(D, 1H, J = 9.0Hz, CH)

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI // C07B 57/00 365 C07B 57/00 365 C07D 263/24 C07D 263/24 (56) References JP-A-63-63646 ( JP, A) JP-A-58-41848 (JP, A) JP-A-55-76847 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 229 / 22,227 / 20,227 / 34,269 / 08,27 1/22 C07B 57/00 C07D 263/24 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. An optically active threo-3-amino-2-hydroxypentanoic acid. 2. A compound of the general formula (+)-or (-)-which is an intermediate for producing optically active threo-3-amino-2-hydroxypentanoic acid. (Wherein R represents an organic residue reductively or hydrolytically substituted with hydrogen or an amino-protecting group used in ordinary peptide synthesis) represented by the formula:
Protected-3-amino-2-hydroxypentanoic acid. 3. An intermediate for producing an optically active threo-3-amino-2-hydroxypentanoic acid, represented by the general formula (+)-or (-)- (Wherein R represents an organic residue reductively or hydrolytically substituted with hydrogen or an amino-protecting group used in ordinary peptide synthesis) represented by the formula:
Optically active 1- (1-naphthyl) ethylamine salt of protected-3-amino-2-hydroxypentanoic acid. 4. The general formula (±) − (Wherein R represents an organic residue which is reductively or hydrolytically substituted with hydrogen or a protecting group for an amino group used in ordinary peptide synthesis) (±) -threo-N-
Optically active 1- (1-naphthyl) ethylamine was allowed to act on protected-3-amino-2-hydroxypentanoic acid, and the resulting diastereomer salt was optically resolved by utilizing the difference in solubility. The optically active diastereomer salt is decomposed to give an optically active threo-N-protected-3-amino-
A process for producing optically active threo-N-protected-3-amino-2-hydroxypentanoic acid, comprising collecting 2-hydroxypentanoic acid. 5. The general formula (±) − (Wherein R represents an organic residue which is reductively or hydrolytically substituted with hydrogen or a protecting group for an amino group used in ordinary peptide synthesis) (±) -threo-N-
Optically active 1- (1-naphthyl) ethylamine was allowed to act on protected-3-amino-2-hydroxypentanoic acid, and the resulting diastereomer salt was optically resolved by utilizing the difference in solubility. The optically active diastereomer salt is decomposed to give an optically active threo-N-protected-3-amino-
An optically active threo-3- compound comprising removing a protecting group for an amino group after collecting 2-hydroxypentanoic acid.
A method for producing amino-2-hydroxypentanoic acid. 6. A method of separating a mixture of threo-3-amino-2-hydroxypentanoic acid and erythro-3-amino-2-hydroxypentanoic acid by utilizing the difference in solubility. A method for producing amino-2-hydroxypentanoic acid and erythro-3-amino-2-hydroxypentanoic acid.