JPH089609B2 - Optically active β-amino acid derivative and its salt, and process for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to an optically active β-amino acid derivative and a salt thereof, and particularly to a novel optically active (2R, 3R, 4S, 5R) -3-
The present invention relates to an amino-2,5-dimethyl-5-pentanolide-4-carboxylic acid derivative, a salt thereof, and a method for producing the same.

[Conventional technology]

Carbapenem antibiotics typified by thienamycin and PS-5 have been drawing attention because of their strong antibacterial activity. However, on the other hand, these compounds are chemically unstable, and when administered to a living body, they have the drawbacks of being decomposed in the kidney and exhibiting nephrotoxicity.

Recently, a 1β-methylcarbapenem compound in which a methyl group has been introduced at the 1-position of the carbapenem skeleton of thienamycin is
It has been reported to have excellent properties that overcome the above drawbacks.

As a conventional synthetic method of this kind of compound, for example, the method described in Heterocycles 21:29 (1984) and Tetrahydrone Letter: 26: 583 and 587 (1985) is known.

[Problems to be solved by the invention]

However, it is extremely difficult to stereoselectively synthesize one desired stereoisomer by the above method.

[Means for solving problems]

As a result of intensive research, the present inventor has found that an optically active substance of the compound represented by the general formula I having all the chirality of the 1β-methylcarbapenem compound can be easily synthesized and completed the present invention.

An important synthetic compound of the 1β-methylcarbapenem derivative can be produced extremely efficiently from these compounds. (For example, Compound 11 whose production method is shown in Example 15 is an important intermediate for the production of 1β carbapenem compound, and from this compound, (-)-(1R , 5S, 6S) -6-[(1R) -1-Hydroxyethyl) -1-methyl-2- (2-N, N-dimethylfumino-2-iminoethyl) -1-carbapene-2-em-3- Carboxylic acids can be produced.

 The entire reaction route of the present invention is as follows.

In the above reaction route, R ¹ , R ² , and R ³ are hydrogen, and a linear / branched or cyclic C _1-10 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, pentyl). , Heptyl, cyclohexyl, etc.) aralkyl groups (eg, benzyl, phenethyl, etc.), and phenyl groups are preferred.

R ⁴ is an alcohol-derived residue used for alcoholysis of compound (9), and examples thereof include an alkyl group which is not substituted with a halogen such as methyl, ethyl and trichloroethyl groups, and an aralkyl group such as a benzyl group. To be The carbon number is preferably about 1-10.

The compound of the present invention has the following formula [In the formula, R ⁰ represents hydrogen or COOR ² , and R ⁰¹ represents hydrogen or COOR ^2.
Represents R ¹ . R ¹ and R ² are linear, branched or cyclic C _1-10
It represents an alkyl group, an aralkyl group or an aryl group] and an optically active β-amino acid derivative and a salt thereof.

The present invention includes the compounds (8) and (9) in the above reaction pathway.

When R ⁰¹ is H, the salt of the compound of the present invention includes, for example, sodium salt and potassium salt, and when R ⁰ is H, for example, hydrochloride, sulfate and the like.

The method for producing the compound of the present invention is as follows.

That is, [In the formula, R ¹ , R ² and R ³ are linear, branched or cyclic C
_1-10 alkyl group, aralkyl group or aryl group] is treated with an acid to give a compound of the following formula [Wherein R ¹ , R ² and R ³ are the same as above], and the conformation of the substituent at the 5-position is inverted by the action of a base to give a compound of the following formula [Wherein R ¹ , R ² and R ³ are the same as described above], and reacted with the following inorganics or halogenating agent [Wherein R ¹ and R ² are the same as above], and further treated with an acid To produce a compound and a salt thereof.

The compounds of formula (8) and formula (9) obtained here are
formula [In the formula, R ⁰ represents hydrogen or COOR ² , and R ⁰¹ represents hydrogen or R ¹ . R ¹ and R ² are the same as those defined above] and are novel optically active β-amino acid derivatives.

Route 2 The conversion from (3) to (5) can be carried out, for example, in a solvent such as dichloromethane, dichloroethane, chloroform, benzene, ethyl acetate, ether or THF at a temperature of 0 ° to 50 ° C. in an amount of 0.01 to 2 times the amount. It is carried out by treating with an acid such as sulfuric acid, hydrochloric acid, perchloric acid, trifluoroacetic acid or p-toluenesulfonic acid.

When the mixture of (3) and (4) is reacted under the same conditions, the mixture of (5) and (6) is obtained. Separation and purification of (5) from this mixture can be easily performed by column chromatography.

Route 3 (5) to (7) can be converted into methanol in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, potassium t-butoxide. , Lower alcohols such as ethanol and t-butanol, water-containing acetone, acetonitrile, THF and other solvents at 25 °
It is carried out by treating at a temperature of 100 ° C. for 10 minutes to 24 hours. When the mixture of (5) and (6) is treated in the same manner, a mixture of (7) and unreacted (6) is obtained. Separation and purification of (7) from this mixture can be easily performed by column chromatography or the like.

Route 4 The conversion from (7) to (8) can be carried out, for example, by a method commonly used for converting a dithioacetal to a carbonyl compound (see, for example, “Protective by Greene,“ Protective ”).
Group in Organic Synthesis "129-139
Method described on page). Typically, a small amount to 70% of water is added in a solvent such as acetone, acetonitrile, THF, alcohol such as methanol,
A combination of inorganic salts such as CuCl ₂ and CuO, AgNO ₃ and Ag ₂ O, HgCl ₂ and HgO, or bromine, N-bromosuccinimide, N-chlorosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin And a halogenating agent such as the above at a temperature of 0 ° to 100 ° C. for 5 minutes to 24 hours.

Route 5 Conversion from (8) to (9) is carried out by treatment with an acid such as hydrochloric acid or sulfuric acid in an aqueous solution at a temperature of 20 ° to 100 ° C. for 1 to 48 hours.

Route 6 The conversion from (9) to (10) is carried out by, for example, converting (9) into an alcohol such as methanol, ethanol, benzyl alcohol, phenol, or 2,2,2-trichloroethanol.
It is carried out by treating at a temperature of ° to 100 ° C for 1 to 24 hours.

In the representation of the desired product (10) the ester moiety R ⁴
Is the same as the alcohol R ⁵ OH used in the conversion of (9) to (10).

Route 7 (10) is converted to (11) by, for example, converting (10) into a base such as triethylamine, pyridine, dimethylaniline or 4-dimethylaminopyridine, or methanol, ethanol or the like in the presence of ethylene oxide or propylene oxide. 20 ° in a solvent such as alcohol or acetonitrile
Dicyclohexylcarbodiimide (D
CC) and processing.

The conversion (path 1) of (3) and (4) from (1) and (2) is performed as follows, for example. That is,
(R) -3-Hydroxybutyric acid ester (1) (wherein the ester moiety R ¹ is the same as defined above) is converted to ether, THF, 1,2-
-78 ° in a dry solvent such as dimethoxyethane or dioxane
To a temperature of 0 ° C., lithium diisopropylamide, lithium bis (trimethylsilyl) amide, lithium N-
t-Butylcyclohexylamide, lithium 2,2,6,6-
From two of the lithiating agents such as tetramethylpiperidide
After treating with 2.5 times amount for 10 minutes to 5 hours, 1 equivalent of compound (2) (wherein R ² and R ³ are the same as defined above) prepared by the method described below was used for the reaction such as THF. The solution dissolved in the same solvent is treated at a temperature of -78 ° to 0 ° C for 10 minutes to 5 hours.

The product is a mixture of two isomers of (3) and (4), and these two compounds can be separated by column chromatography. However, since it is possible to easily separate and purify only the desired isomer also in the step (7) or (8) of the subsequent step, (3) and (4) are not separated but the following mixture is left as it is. It can be used in the process.

The compound (2) can be synthesized as follows.

The compound (2) can be produced from (12) via (13) and (14) in 3 steps. First, the conversion of (12) to (13) is performed by converting compound (12) (wherein R ³ is the same as above) into n-butyl at a temperature of −78 ° to 30 ° C. in a dry solvent such as ether or THF. After treatment with 1 to 1.2 times the amount of a lithium agent such as lithium or lithium diisopropylamide for 1 to 48 hours, then pyruvaldehyde acetal CH ₃ COCH (OR ⁵ ) ₂ [wherein R ⁵ has 1 to 10 carbon atoms] Represents an alkyl group]
It is carried out by treating 1.5-fold amount and a temperature of -78 ° C to 30 ° C for 1 to 48 hours.

From (13) to (14), the conversion is from 1 to 80% water containing alcohol such as methanol and ethanol, acetone, THF,
By treating in a solvent such as dioxane in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid at 0 ° to 60 ° C for 10 minutes to 48 hours. Done. Further, (13) is dissolved in a solvent such as dichloromethane, chloroform, benzene, ethyl acetate, ether and the like, and the above acid is added at 1 to 60 at 0 ° C to room temperature.
% Aqueous solution with stirring for 10 minutes to 48 hours.

The conversion of (14) to (2) is carried out by a conventional method using hexamethyldisilazane and n-butyllithium, ether, TH
A solution of lithium bis (trimethylsilyl) amide prepared by treatment in a solvent such as F, hexane or pentane at a temperature of −78 ° C. to 25 ° C. for 10 minutes to 24 hours was added at −78 ° C. to 30 ° C.
Treat with 1 equivalent of (14) at a temperature of ℃ for 10 minutes to 24 hours. Next, 1 to 2 times the amount of chlorotrimethylsilane was added, and the mixture was stirred at a temperature of −78 ° to 40 ° C. for 30 minutes to 48 hours,
It is carried out by treating with 1 to 1.5 times amount of R ² OCOCl (wherein R ² is the same as defined above) and a temperature of −78 ° C. to 30 ° C. for 10 minutes to 48 hours.

The desired (2) can also be obtained by using ² to 3 times the amount of R ² OCOCl without adding the above chlorotrimethyldilane.

Hereinafter, the present invention will be specifically described with reference to Examples.
It is not limited by these examples.

Reference Example 1 2- (1,3-dithiane-2-ylidene) propanal dimethyl acetal ^{[13; R 3 = - (CH} 2) 3 -, R 5 = CH 3 ] Using 2-trimethylsilyl-1,3 of Dithiane 35.2 g anhydrous TH
The solution dissolved in 400 ml of F was cooled to −78 ° C., and an n-butyllithium (0.195 mol) -hexane solution was added dropwise thereto under an argon stream so as not to exceed −60 ° C. After the dropping, the temperature was slowly raised to 0 ° C. over 4 hours. The reaction solution was cooled to −78 ° C. again, and 23.54 ml of pyruvic aldehyde dimethyl acetal was slowly added dropwise so that the temperature did not exceed −60 ° C. After stirring at the same temperature for 1 hour, the mixture was left at room temperature overnight.
Pour the reaction mixture into a mixture of 300 ml of methylene chloride and 300 ml of water,
After shaking well, the methylene chloride layer was separated, dried (MgSO ₄ ) and concentrated under reduced pressure. When the residue is distilled under reduced pressure, the target product is 35.7g.
was gotten.

bp.105-110 ° C / 0.1mmHg ¹ H-NMR (CDCl ₃ ) δ 1.68 (3H, s), 2.08 (2H, m), 2.79 (4
H, m), 3.20 (6H, s), 5.21 (1H, s) Reference Example 2 2- (1,3-dithian-2-ylidene) propanal [1
4; Production of R ₃ =-(CH ₂ ) _3- ] 2- (1,3-dithian-2-ylidene) propanal dimethyl acetal [13; R ³ =-(CH ₂ ) _3- , R ⁵ = CH ₃ ]
19.0 g was dissolved in 80 ml of chloroform, 40 ml of a 1: 1 mixed solution of trifluoroacetic acid and water was added thereto under ice cooling, and the mixture was stirred at the same temperature for 2 hours. The chloroform layer was separated, washed successively with water, aqueous sodium hydrogen carbonate and water, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to give 13.1 g of the desired product.

mp.80-82 ℃ Elemental analysis value C ₇ H ₁₀ OS ₂ theoretical value: C, 48.24; H, 5.78; S, 36.79 Experimental value: C, 48.13; H, 5.49; S, 36.55 ¹ H-NMR (CDCl ₃ ) δ1.23 (3H, s), 2.16 (2H, m), 2.92 (4
H, m), 9.96 (1H, s) Reference Example 3 N-methoxycarbonyl 2- (1,3-dithian-2-ylidene) propanimine [2; R ² = CH ₃ , R ³ =-(CH ₂ ).
_3- ] of 1,1,1,3,3,3-hexamethyldisilazane 9.8 ml
The solution dissolved in 50 ml of F was cooled to -78 ° C, and 1.5 Mn-
30 ml of a butyllithium-hexane solution was added dropwise. After stirring for 1 hour at the same temperature, 2- (1,3-dithiane-2-ylidene) propanal ^{[14; R 3 = - (CH} 2) 3 - ] 7.37g of anhydrous TH
The solution dissolved in F30 ml was slowly added dropwise so as not to exceed -60 ° C. After further stirring at -78 ° C for 1 hour, 6.44 ml of chlorotrimethylsilane was added and the temperature was gradually raised to room temperature.
Then, the reaction solution was ice-cooled and methyl chloroformate 3.92 was added.
After slowly dropping ml, the mixture was left in the refrigerator overnight. The reaction solution was concentrated to dryness under reduced pressure, the residue was extracted with methylene chloride, and the extract was concentrated under reduced pressure to obtain 8.92 g of the target crystal.

Mp.89-91 ° C. Elemental analysis C ₉ H ₁₃ NO ₂ S ₂ and a theoretical: C, 46.73; H, 5.66 ; N, 6.05; S, 27.72 Found: C, 46.60; H, 5.42 ; N, 5.97 _{; S, 28.00 IR (CH 2} Cl 2) 1700,1565cm -1 1 H-NMR (CDCl 3) δ2.07 (3H, s), 2.10 (2H, m), 3.07 (4
H, m), 3.87 (3H, s), 9.34 (1H, s) Reference Example 4 Methyl 4- (1,3-dithian-2-ylidene) -2-
(R)-(1- (R) -hydroxyethyl) -3- (R,
S) -Methoxycarbonylaminopentanoate [3; R ^{1
_{= R 2 = CH 3, R}} 3 = - (CH 2) 3 - ] and ^{[4; R 1 = R 2 =} CH 3,
_{^{R 3 = - (CH 2)}} 3 - lithium diisopropylamide 0 adjusted according to a conventional method from preparation n- butyllithium and diisopropylamine].
A solution of 042 mol of anhydrous THF (100 ml) was cooled to −78 ° C., and 2.36 g of methyl (R) -3-hydroxybutyrate was added dropwise thereto under an argon stream. After stirring at the same temperature for 1 hour, N-methoxycarbonyl 2- (1,3-dithian-2-ylidene) propanimine [2, R ² = CH ₃ , R ³ =-(CH ₂ ) _3- ] 4.6.
A solution prepared by dissolving 2 g in 100 ml of anhydrous THF was slowly added dropwise.
After stirring for another hour at -78 ° C, 2.4 ml of acetic acid was added,
The reaction solution was poured into 100 ml of water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄ ), evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. From the eluate of benzene-ethyl acetate 7: 1, [4; R ¹ = R ² = CH ₃ , R ³
= − (CH ₂ ) ₃ −] 1.89 g ¹ H-NMR (CDCl ₃ ) δ1.22 (3H, d, J = 7.0Hz), 1.62 (3H,
s), 2.02 (2H, m), 2.47 (1H, m), 2.82 (4H, m), 3.56 (3
H, s), 3.61 (3H, s), 3.82 (1H, m) 5.27 (1H, dd, J = 9.0,
Was obtained 4.74g as an oil 6.0Hz), 5.96 (1H, d , J = 9.0Hz) and ^{[3, R 1 = R 2 =} CH 3, R 3 = - - (CH 2) 3 ]. ¹ H-NMR (CDCl ₃ ) δ1.15 (3H, d, J = 6.7Hz), 1.76 (3H,
s), 2.02 (2H, m), 2.76 (3H, m), 3.57 (3H, s), 3.58 (3
H, s), 3.85 (1H, m), 5.45 (1H, t, J = 9.0Hz), 5.96 (1H,
d, J = 9 Hz) Example 1 (3R, 4S, 5R, 6R) -3,6-dimethyl-5-methoxycarbonyl-4-methoxycarbonylaminotetrahydropyran-2-spiro-2 '-(1', 3 ′ -Dithian) [5; R ^{1
_{= R 2 = CH 3, R}} 3 = - (CH 2) 3 - preparation of methyl 4- (1,3-dithiane-2-ylidene) of] -2-
(R)-(1- (R) -Hydroxyethyl) -3-
(S) -methoxycarbonylaminopentanoate [3,
R ¹ = R ² = CH ₃ , R ³ = − (CH ₂ ) ₃ −] 3.49 g was added to methylene chloride 10
Dissolve in 0 ml, 0.1M HCl-methylene chloride solution 10 ml
Was added and the mixture was stirred for 2 hours under ice cooling. After the reaction, the mixture was washed with aqueous sodium hydrogen carbonate and evaporated under reduced pressure. The residue was crystallized in isopropyl ether to obtain 3.20 g of the desired product.

mp.72-74 ℃ ▲ [α] _{^{29 D ▼ + 166 ° (C1.0}} , MoOH) IR (CH 2 Cl 2) 3450,1730,1512cm -1 1 H-NMR (CDCl 3) δ1.19 (3H, d, J = 6.9Hz), 1.34 (3H, d, J
= 6.6Hz), 1.87-2.10 (2H, m), 2.63 (2H, m), 2.65 (1
H, dq, J = 11.5,6.9Hz), 2.90 (1H, m), 2.94 (1H, dd, J =
4.8,3.8Hz), 3.49 (1H, m), 3.66 (3H, s), 3.73 (3H,
s), 4.00 (1H, m), 4.44 (1H, m), 4.88 (1H, d, J = 9.8H
z) Example 2 (3R, 4S, 5S, 6R) -3,6-Dimethyl-5-methoxycarbonyl-4-methoxycarbonylaminotetrahydropyran-2-spiro-2 '-(1', 3'-dithiane) 〔7; R ¹
= R ² = CH ₃ , R ³ =-(CH ₂ ) _3- ] (3R, 4S, 5R, 6R) -3,6-Dimethyl-5-methoxycarbonyl-4-methoxycarbonylaminotetrahydropyran-2 -Spiro-2 '-(1', 3'-dithiane) [5;
_{^{R 1 = R 2 = CH 3}} , R 3 = - (CH 2) 3 - ] 1.75g anhydrous methanol
It was dissolved in 100 ml, 1M sodium methylate-methanol solution (10.5 ml) was added thereto, and the mixture was heated under reflux for 3 hours. After cooling, ml of acetic acid was added and the solvent was distilled off under reduced pressure. The residue was dissolved in 50 ml of methylene chloride and 20 ml of water, the methylene chloride layer was washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was crystallized in isopropyl ether to obtain 1.36 g of the desired product.

mp.155-156 ° C ▲ [α] ²⁹ _D ▼ + 114 ° (C1.0, MeOH) Elemental analysis value C ₁₄ H ₂₃ NO ₅ S ₂ Theoretical value: C, 48.12; H, 6.63; N, 4.01; S , 18.35 Experimental value: C, 48.04; H, 6.62; N, 4.01; S, 18.14 IR (CH ₂ Cl ₂ ) 3440,1740,1515 cm ^{-1 1} H-NMR (CDCl ₃ ) δ1.21 (3H, d, J = 6.8Hz), 1.29 (3H, d, J
= 6.15Hz), 1.80-2.12 (3H, m), 2.41 (1H, dd, J = 10.3,
10.8Hz), 2.65 (2H, m), 2.94 (1H, m), 3,48 (1H, m), 3.
70 (6H, s), 4.05 (1H, ddd, J = 10.4,10.5,10.8Hz), 4.32
(1H, dq, J = 10.3,6.15Hz), 4.65 (1H, d, J = 10.4Hz) Example 3 (2R, 3R, 4S, 5R) -2,5-dimethyl-3-methoxycarbonylamino-5 - pentanolide-4-carboxylic acid methyl ester; preparation of ^{[8 R 1 = R 2 = CH} 3 ] (3R, 4S, 5S, 6R ) -3,6- dimethyl-5-methoxycarbonyl-4-methoxycarbonylamino-tetrahydronaphthalene Pyran-2-spiro-2 '-(1', 3'-dithiane) [7; R ¹
= R ² = CH ₃ , R ³ = − (CH ₂ ) ₃ −] 1.70 g was dissolved in 50 ml of acetone, and cupric chloride dihydrate 1.66 g and cupric oxide 1.5
5 g was added and the mixture was heated with stirring under reflux for 2 hours. The reaction solution was ice-cooled, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography, and 1.01 g of the desired crystal was obtained from the chloroform-methanol 15: 1 eluate.

mp.135-137 ℃ ▲ [α] ²⁹ _D ▼ + 31.4 ° (C1.1, CHCl ₃ ) Elemental analysis value C ₁₁ H ₁₇ NO ₆ Theoretical value: C, 50.96; H, 6.61; N, 5.40 Experiment Value: C, 50.70; H, 6.31; N, 5,32 IR (CH ₂ Cl ₂ ) 3440,1740,1515 cm ^{−1 1} H-NMR (CDCl ₃ ) δ1.38 (3H, d, J = 6.2 Hz) , 1.39 (3H, d, J
= 7.1Hz), 2.67 (1H, m), 2.84 (1H, dd, J = 10.5,10.9H
z), 3.75 (6H, s), 3.93 (1H, ddd, J = 10.9,10.7,9.1H
z), 4.54 (1H, dq, J = 10.5,6.2Hz) Reference Example 5 N-benzyloxycarbonyl 2 (1,3-dithiane-2)
- ylidene) propane imine _{^{[2; R 2 = CH 2 C}} 6 H 5, R 3 = -
Production of (CH ₂ ) ₃ −] In the same manner as in Reference Example 3, benzyl chloroformate was used in place of methyl chloroformate to carry out the reaction, and the desired product was obtained in good yield.

_{mp.85-88 ℃ IR (CH 2 Cl 2} ) 1705,1565cm -1 1 H-NMR (CDCl 3) 2.07 (3H, s), 2.20 (2H, m), 3.05 (4H,
m), 5.28 (2H, s), 7.43 (5H, s), 9.34 (1H, s) Reference Example 6 Methyl 3- (R, S) -benzyloxycarbonylamino-4- (1,3-dithiane-2) -Yliden) -2- (R)
- (1-(R) - hydroxyethyl) - pentanoate _{^{[3; R 1 = CH 3,}} R 2 = CH 2 C 6 H 5, R 3 = - (CH 2) 3 - ] and [4; R ¹ = Production of CH ₃ , R ² = CH ₂ C ₆ H ₅ , R ³ =-(CH ₂ ) _3- ] In the same manner as in Reference Example 4, N-methoxycarbonyl 2-
(1,3-dithian-2-ylidene) propanimine [2, R
^{_{2 = CH 3, R 3 =}} - (CH 2) 3 - N- benzyloxycarbonyl instead of 2- (1,3-dithiane-2-ylidene) propane imine _{^{[2, R 2 = CH 2 C}} 6 H _When the reaction was carried out using ₅ , R ³ =-(CH ₂ ) _3- ], the desired product was obtained as an oil.

IR (CH ₂ Cl ₂ ) 3440,1725,1500 cm ⁻¹ Example 4 (3R, 4S, 5R, 6R)-and (3R, 4R, 5R, 6R) -4-benzyloxycarbonylamino-3,6-dimethyl -5-methoxycarbonyl-tetrahydropyran-2-spiro-
2 '- (1', 3'-dithiane) _{^{[5; R 1 = CH 3,}} R 2 = CH 2 C 6
H ₅ , R ³ =-(CH ₂ ) _3- ] and [6; R ⁴ = CH ₃ , R ² = CH ₂ C
Production of ₆ H ₅ , R ³ =-(CH ₂ ) _3- ] Methyl 3- (R, S) -benzyloxycarbonylamino-4- (1,3-dithian-2-ylidene obtained in Reference Example 6 ) -2- (R)-(1- (R) -Hydroxyethyl) -pentanoate (6.5 g) was dissolved in 200 ml of methylene chloride, to which 0.1 ml of a 5.2M hydrogen chloride-dioxane solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with multi-layered water, concentrated under reduced pressure, and the oily residue was purified by silica gel column chromatography. From benzene-ethyl acetate 15: 1 elution part [6, R ¹ = CH ₃ , R ² = CH ₂ C ₆ H ₅ , R ³ =-(CH ₂ ) _3- ]
1.63 g ¹ H-NMR (CDCl ₃ ) δ1.17 (3H, d, J = 6.9Hz), 1.33 (3H, d, J
= 6.6Hz), 1.86-2.08 (2H, m), 2.56-2.69 (3H, m), 2.
88 (1H, m), 2.95 (1H, dd, J = 3.4,4.8Hz), 3.47 (1H,
m), 3.68 (3H, s), 4.03 (1H, m), 4.43 (1H, m), 5.08 (2
H, s), 7.34 (5H, m), and [5, R ¹ = CH ₃ , R ² = CH ₂ C ₆ H ₅ , R ³ = − (CH ₂ ) ₃ −]
4.15 g was obtained.

_{IR (CH 2 Cl 2) 3400,1735,1720} (Sh), 1510cm -1 1 H-NMR (CDCl 3) δ1.17 (3H, d, J = 7.2Hz), 1.38 (3H, d, J
= 6.6Hz), 1.80-2.07 (2H, m), 2.60 (3H, m), 2.85 (1
H, m), 3.00 (1H, m), 3.53 (1H, m), 3.72 (3H, s), 4.18
(1H, m), 4.29 (1H, m), 5.10 (2H, dd, J = 12.2,18.2H
z), 7.35 (5H, m) Example 5 (3R, 4S, 5S, 6R) -4-Benzyloxycarbonylamino-3,6-dimethyl-5-methoxycarbonyl-tetrahydropyran-2-spiro-2'- (1 ', 3'-dithiane) _{^{[7; R 1 = CH 3,}} R 2 = CH 2 C 6 H 5, R 3 = - (CH 2) 3 - ] in the same manner as in example 2, ( 3R, 4S, 5R, 6R) -4-Benzyloxycarbonylamino-3,6-dimethyl-5-methoxycarbonyl-tetrahydropyran-2-spiro-
2 '- (1', 3'-dithiane) _{^{[5, R 1 = CH 3,}} R 2 = CH 2 C 6
^{_{H 5, R 3 = - (}} CH 2) 3 - a] the desired product is reacted with sodium methylate in 85% yield.

 The physical properties of this crystal were as follows.

mp.145-146 ℃ ▲ [α] _{^{29 D ▼ + 81.7 ° (C0.85}} , MeOH) IR (CH 2 Cl 2) 3440,1740,1515cm -1 1 H-NMR (CDCl 3) δ1.21 ( 3H, d, J = 6.8Hz), 1.28 (3H, d, J
= 6.2Hz), 1.75-2.11 (3H, m), 2.39 (1H, dd, J = 10.6,1
0.8Hz), 2.65 (2H, m), 2.92 (1H, m), 3.47 (1H, m), 3.6
0 (3H, s), 4.08 (1H, ddd, J = 9.6,10.8,11.1Hz), 4.32
(1H, m), 4.63 (1H, d, J = 9.6Hz), 5.07 (2H, dd, J = 16.
0,12.3Hz), 7.35 (5H, m) Example 6 (2R, 3R, 4S, 5R) -3-Benzyloxycarbonylamino-2,5-dimethyl-5-pentanolide-4-carboxylic acid methyl ester [8 ; R ¹ = in the same manner as ^{_{CH 3, R 2 = CH 2}} C 6 prepared in example 3 of H _5], (3R, 4S, 5S, 6R) -4- benzyloxycarbonylamino-3,6-dimethyl - 5-methoxycarbonyl-tetrahydropyran-2-spiro-
2 '- (1', 3'-dithiane) _{^{[7, R 1 = CH 3,}} R 2 = CH 2 C 6
^{_{H 5, R 3 = - (}} CH 2) 3 - ] of the desired product was obtained in 86% yield from.

mp-143-145 ° C ▲ [α] ²⁹ _D ▼ + 22.4 ° (C1.35, CHCl ₃ ) Elemental analysis value C ₁₇ H ₂₁ NO ₆ Theoretical value: C, 60.88; H, 6.31; N, 4.18 Experiment Value: C, 60.67; H, 6.05; N, 4.31 IR (CH ₂ Cl ₂ ) 3440,1740,1515 cm ^{-1 1} H-NMR (CDCl ₃ ) δ1.37 (3H, d, J = 6.1Hz), 1.39 (3H, d, J
= 6.9Hz), 2.66 (1H, m), 2.83 (1H, t, J = 10.9Hz), 3.63
(3H, s), 3.92 (1H, ddd, J = 11.0,10.9,9.0Hz), 4.53 (1
H, m), 4.89 (1H, d, J = 9.0Hz), 5.10 (2H, s), 7.35 (5H,
m) Example 7 Preparation of (2R, 3R, 4S, 5R) -3-Amino-2,5-dimethyl-5-pentanolide-4-carboxylic acid (9) (2R, 3R, 4S, 5R) -3- 670m of benzyloxycarbonylamino-2,5-dimethyl-5-pentanolide-4-carboxylic acid methyl ester _{^{[8, R 1 = CH 3,}} R 2 = CH 2 C 6 H 5 ]
A mixture of g and concentrated hydrochloric acid 15 ml was stirred overnight. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was placed in a vacuum desiccator at 50 ° C.
430 mg of the desired hydrochloride crystals when dried at
was gotten.

mp.160-163 ℃ (decomposition) Elemental analysis C ₈ H ₁₄ NO ₄ theory as Cl: C, 42.96; H, 6.31; N, 6.26 Found: C, 42.86; H, 6.60 ; N, 5.98 Reference Example 7 Methyl (2R, 3R, 4S, 5R) -3-Amino-4-carboxy-5-hydroxy-2-methyl-hexanoate (10; R
⁴ = CH ₃₎ preparation of (2R, 3R, 4S, 5R ) -3- amino-2,5-dimethyl-5-
430 mg of pentanolide-4-carboxylic acid (9) hydrochloride was dissolved in anhydrous methanol and left overnight. The solvent was distilled off under reduced pressure to obtain the desired hydrochloride. This substance is ¹ H-NM
The following peaks were shown in the R spectrum.

¹ H-NMR (CDCl ₃ -DMsod ₆ ) δ1.35 (3H, d, J = 6.2Hz), 1.4
2 (3H, d, J = 7.0Hz), 2.56 (1H, m), 3.22 (1H, m), 3.72
(3H, s), 4.10 (1H, m), 4.45 (1H, m) Reference Example 8 Methyl 2 (R)-[(3S, 4R) -3- (1 (R) -hydroxyethyl) -2-oxoazetidine 4-yl] propanoate _{^{(1, R 4 = CH 3}} ) the production of methyl (2R, 3R, 4S, 5R ) -3- amino-4-carboxy-5-hydroxy-2-methyl - hexanoate (1
510 mg of the hydrochloride salt of (0) was dissolved in 30 ml of anhydrous methanol, 1 ml of propene oxide was added thereto, and the mixture was heated under reflux for 10 minutes.
After allowing to cool, add 450 mg of DCC to this solution and stir for 4 hours.
Heated to 50 ° C. The solvent was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give benzene-ethyl acetate (1:
1) 310 mg of the desired product was obtained from the elution part.

 The physical properties of this result were as follows.

Mp.102-104 ° C. Elemental analysis C ₆ H ₁₅ NO ₄ and a theoretical: C, 53.72; H, 7.51 ; N, 6.96 Found: C, 53.44; H, 7.27 ; N, 6.93 ▲ [α] ²⁴ _D ▼ −44.7 ° (C0.45, CHCl ₃ ) IR (CH ₂ Cl ₂ ) 3410,1768,1735cm ^{−1 1} H-NMR (CDCl ₃ ) δ1.27 (3H, d, J = 7.1Hz), 1.31 ( 3H, d, J
= 6.3Hz), 2.67 (1H, m), 2.98 (1H, dd, J = 2.1,7.0Hz),
3.72 (3H, s), 3.77 (1H, dd, J = 2.1,7.7Hz), 4.16 (1H,
m) 6.09 (1H, broad s) Reference example 9 In the same manner as in Reference Example 4, R ¹ is a t-butyl group, i-
A reaction was performed using a propyl group and a β-naphthyl group, and a methyl group and a benzyl group as R ² to obtain a compound (3). Table 1 shows the above reaction examples and results.

The structure of the product was confirmed by leading to compound 9 according to routes 2-5, respectively.

Claims (4)

[Claims] 1. The following equation [In the formula, R ⁰ represents hydrogen or COOR ² , and R ⁰¹ represents hydrogen or COOR ^2.
Represents R ¹ . R ¹ and R ² are linear, branched or cyclic C _1-10
Represents an alkyl group, an aralkyl group or an aryl group] and an optically active β-amino acid derivative and a salt thereof. 2. The following equation [In the formula, R ¹ , R ² and R ³ are linear, branched or cyclic C
_1-10 alkyl group, aralkyl group or aryl group] is reacted with an inorganic salt or a halogenating agent in the presence of water to give a compound represented by the formula: [Wherein R ¹ and R ² are the same as above], and further treated with an acid And a method for producing the salt thereof. 3. The following equation [In the formula, R ¹ , R ² and R ³ are linear, branched or cyclic C
_1-10 alkyl group, aralkyl group or aryl group] is reacted with a base to invert the conformation of the substituent at the 5-position to give a compound of the following formula [Wherein R ¹ , R ² and R ³ are the same as above] and then reacted with an inorganic salt or a halogenating agent to obtain a compound represented by the formula: [Wherein R ¹ and R ² are the same as above], and further treated with an acid And a method for producing the salt thereof. 4. The following equation [In the formula, R ¹ , R ² and R ³ are linear, branched or cyclic C
_1-10 alkyl group, aralkyl group or aryl group] is treated with an acid to give a compound of the following formula [Wherein R ¹ , R ² and R ³ are the same as defined above], and then the base is allowed to act to invert the conformation of the substituent at the 5-position to give a compound of the following formula [Wherein R ¹ , R ² and R ³ are the same as above], and further reacted with an inorganic salt or a halogenating agent, [Wherein R ¹ and R ² are the same as above], and further treated with an acid And a method for producing the salt thereof.