JPH047739B2 - - Google Patents

Description

[Detailed Description of the Invention] [Object of the Invention] The present invention relates to the general formula (In the formula, R ¹ is a phenyl group or a lower alkyl group, R ² is a benzyl group, and R ³ is a protecting group.) and a method for producing the same.

[Industrial application field]

The β-aminothiol ester of the present invention represented by the general formula () can be converted into a carbapenem β-lactam antibiotic such as thienamycin. Carbapenem β-lactam antibiotics exhibit excellent antibacterial activity against almost all bacteria, including Bacillus aeruginosa, and their strength is much greater than that of conventional drugs, and they also have excellent β-lactamase stability. Therefore, they are a group of substances that have great expectations as the next generation of β-lactam antibiotics.

[Technical background]

Currently, carbapenem β-lactam antibiotics have low productivity through fermentation, and industrially they have to rely on chemical synthesis. This can be said to be completely different from conventional penicillin and cephalosporin antibiotics.

To date, various carbapenem β-lactam antibiotics are in the clinical stage, but the synthetic intermediates that form the basis of these compounds are based on the general formula It is a well-known fact among those skilled in the art that it is a β-lactam represented by the formula (wherein R ₂ and R ³ have the same meanings as above).

The β-aminothiol ester of the present invention represented by the general formula () forms a β-lactam ring,
By protecting the hydroxyl group and further deprotecting the protecting group, the optically active β-lactam represented by the above general formula ( (See reference example).

[Conventional technology]

Conventionally, methods for producing β-lactams represented by the above general formula () include 1) constructing a monocyclic β-lactam ring having a side chain at the 4-position using asymmetric synthesis using optically active amino acids or enzymes; 2) Using special means to selectively construct asymmetric carbons corresponding to the 3-, 4-, and 1'-positions to form a β-lactam ring. Method and 3) A method of constructing a monocyclic β-lactam having a side chain at the 3-position from L-threonine, optically active penicillin, etc. and then introducing a side chain at the 4-position is known [Masayuki Shibuya, Synthetic Organic Chemistry] Association journal, 41 , 62
(1983)].

[Problems to be Solved by the Invention] However, method 1) above is relatively difficult to introduce a side chain into the 3-position, is unsuitable for large-scale synthesis, and is difficult to adopt as an industrial production method. Furthermore, although method 2) is an industrially adopted method, it has the disadvantage that the manufacturing process is long and includes optical resolution. Furthermore, the method 3) has the disadvantage that although the desired product can be obtained as an optically active substance, the number of manufacturing steps is long.

The present inventors discovered a β-aminothiol ester represented by the above general formula () and an industrial production method useful for synthesizing the β-lactam represented by the above general formula () in a short and simple process, and accomplished the present invention. completed.

[Summary of the invention]

The β-aminothiol ester of the present invention represented by the above general formula () in the presence of a tertiary amine,
general formula (In the formula, R ¹ represents the same meaning as above.) β-hydroxythiol ester represented by the general formula (In the formula, R and R' are an alkyl group or a cycloalkyl group, and can be combined to form a ring together with bonded boron.) Then, the resulting reaction mixture is general formula (In the formula, R ₂ and R ³ have the same meanings as above.) It is produced by reacting an imine represented by the formula, followed by treatment with hydrogen peroxide.

The β-hydroxythiol ester represented by the general formula () is a compound that can be easily obtained by protecting the hydroxyl group of β-hydroxycarboxylic acid, followed by dehydration condensation with the corresponding mercaptan, and then deprotection ( (See reference example below). As the β-hydroxythiol ester represented by the general formula (), for example, S-phenyl-3
(R)-hydroxybutanethioate, S-t-butyl-3(R)-hydroxybutanethioate, S
-Ethyl-3(R)-hydroxybutanethioate, S-sec-butyl-3(R)-hydroxybutanethioate, S-n-propyl-3(R)-hydroxybutanethioate, S-isopropyl-3
(R)-Hydroxybutanethioate and the like can be used. On the other hand, boron compounds represented by the general formula () are industrially easily available, such as 9-borabicyclo[3.3.1]nonyltrifluoromethanesulfonate, dicyclopentyltrifluoromethanesulfonyloxyboron, di-n
-butyltrifluoromethanesulfonyloxyboron, etc. can be used.

The reaction between the β-hydroxythiol ester represented by the general formula () and the boron compound represented by the general formula () needs to be carried out in the presence of a tertiary amine. Tertiary amines include diisopropylethamine, triethylamine,
Examples include trimethylamine and tributylamine, but it is preferable to use diisopropylethylamine in order to carry out the reaction efficiently.

This reaction is carried out in a solvent. Examples of solvents include halogenated hydrocarbon solvents such as methylene chloride, chloroform, and 1,2-dichloroethylene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and dimethoxyethane (DMF);
Aromatic hydrocarbons such as toluene and xylene can be used.

The reaction normally proceeds smoothly at a temperature ranging from -78°C to room temperature. The reaction mixture obtained by the above reaction is reacted with the imine represented by the above general formula (). Examples of the imine represented by the general formula () include N-3-benzyloxypropylidenebenzylamine, N-3-tetrahydropyranyloxypropylidenebenzylamine, and N-3-t-butyldimethylsilyloxypropylidenebenzylamine. , N-3-triethylsilyloxypropylidenebenzylamine, etc. are used.

The solvent used in the reaction with the imine is the same as the solvent used in the reaction between the β-hydroxythiol ester and the boron compound.

The reaction proceeds easily between -78°C and room temperature.

In the present invention, a β-aminothiol ester represented by the above general formula () is obtained by reacting an imine and then treating it with hydrogen peroxide. A 30% aqueous solution of hydrogen peroxide is usually used. The amount of hydrogen peroxide used is 1 to 50 equivalents based on the β-hydroxythiol ester. During the hydrogen peroxide treatment, it is desirable to cool the reaction solution to -25°C to room temperature.

Hereinafter, the present invention will be further explained in detail with reference to Reference Examples and Examples.

Reference example 1 Methyl 3-hydroxybutyrate 5.91g (50mmol),
Dissolve 3.74 g (55 mol) of imidazole in 20 ml of DMF and add t-butyldimethylsilyl chloride.
8.29 g (55 mmol) was added in several portions. After stirring at room temperature for 30 minutes, ice water was added and extracted three times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This concentrated liquid was distilled (62-68℃/
5 mmHg), 10.51 g of methyl (-)-3-t-butyldimethylsilyloxybutyrate was obtained. Yield 91%.

TLC: 0.4 (hexane: diethyl ether 20:
1).

IR: (neat) 1735cm ^-1 . NMR: δ0.03, 0.06 (each 3H; s), 0.85 (9H; s), 1.20 (3H; d J = 5), 2.42 (2H; m), 3.75 (3H ;s), 4.25(1H;m). MS: 115, 133, 159 [M-(Me+COOMe)], 175 [M-Bu], 217 [M-Me]. [α] ²⁰ _D −31.75° (c=1.94, CHCl ₃ ). Reference example 2 Dissolve 3.58 g (15.4 mmol) of methyl (-)-3-t-butyldimethylsilyloxybutyrate in 30 ml of methanol and add 30 ml of 1N potassium hydroxide.
Stirred for 15 hours. Most of the methanol is distilled off,
Extracted with diethyl ether acidified with 1N hydrochloric acid. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 3.18 g of (-)-3-t-butyldimethylsilyloxybutyric acid.

Yield 95%.

TLC: 0.2 (hexane: diethyl ether 20:
1).

IR: (neat) 1710 cm ^-1 . NMR: δ0.09, (6H; s), 0.88 (9H; s),
1.20 (3H; dJ=6), 2.46 (2H; dJ=6),
4.27 (1H; dt J=6,6). MS: 110, 137, 197, 218 [M]. [α] ²⁰ _D −12.50° (c=0.96.chloroform), Reference example 3 (-)-3-t-Butyldimethylsilyloxybutyric acid 3.18g (19.2mmol), thiophenol 2.26ml
(22 mmol) was dissolved in 100 ml of methine chloride and 4.53 g (22 mmol) of N,N'-dicyclohexylcarbodiimide was added thereto. After stirring at room temperature for 2 hours, it was filtered, and the filtrate was concentrated and distilled (110-116
℃/0.3mmHg), (-)-3-t
-Butyldimethylsilyloxybutyric acid phenylthioester 5.00g (yield 83%) was obtained.

TLC: 0.3 (hexane: diethyl ether 20:
1).

IR (neat) 1710cm ^-1 . NMR: δ0.07 (6H; s), 0.91 (9H; s), 1.22
(3H; d J=5), 2.61, 2.87 (each 1H;
dd J=15.7), 4.34 (1H, m), 7.41 (5H;
s). MS: 115, 159 [M-(Me+COSPh)], 253 [M
-Bu], 295 [M-Me]. [α] ²⁰ _D −65.91° (c=0.98, CHCl ₃ ). Reference example 4 (-)-3-t-Butyldimethylsilyloxybutyric acid 218mg (1mmol), t-butylmercaptan
Dissolve 0.11 ml (1 mmol) in 5 ml of methylene chloride to obtain 206 mg of N,N'-dicyclohexylbodiimide.
(1 mmol) and 5 mg of N,N-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 3 days. Reaction solution, 10
silica gel column chromatography (C-
200; developing solvent methylene chloride), (-)-
3-t-butyldimethylsilyloxybutyric acid-t-
231 mg of butyl thioester was obtained. Yield 80%.

TLC: 0.5 (hexane: diethyl ether 20:
1).

IR: (neat) 1685 cm ^-1 . NMR: δ0.04 (6H; s), 0.84 (9H; s), 1.16
(3H; d J=6), 1.41 (9H:s), 2.38,
2.66 (each 1H; dd J=15.7) 4.26 (1H,
m). MS: 119, 135, 159, 177, 233 [M-Bu], 275
[M-Me]. [α] ²⁰ _D −47.65° (c=0.94, CHCl ₃ ). Reference example 5 (-)-3-t-Butyldimethylsilyloxybutyric acid phenylthioester 3.26g (10.4mmol)
Add 50 ml of acetic acid:THF:water (3:1:1) to
Stirred at 50°C for 24 hours. By concentrating and distilling this (128-130℃/0.8mmHg), (-)
-3-hydroxybutyric acid phenylthioester
Obtained 1.91 g, yield 94%.

TLC: 0.35 (hexane: diethyl ether 1:
1).

IR: (neat) 3440, 1705 cm ^-1 . NMR: δ1.20 (3H; d J=6), 2.82 (2H; d
J=6), 3.0 (1H; br.s), 4.22 (1H; m),
7.36 (5H; s). MS: 110 [PhSH], 137 [COSPh], 196 (M). [α] ²⁰ _D −42.25° (c=1.42, CHCl ₃ ). Reference example 6 (-)-3-Hydroxybutyric acid-t-butylthioester 1.55g (5.3mmol) and 25ml acetic acid:
Dissolve in THF:water (3:1:1) at 50-55℃.
Stirred for two days. Concentrate the reaction solution under reduced pressure to 40g
The product was purified by silica gel column chromatography (developing solvent: hexane: diethyl ether 2:1) to obtain 755 mg (4.28 mmol) of (-)-3-hydroxybutyric acid-t-butyl thioester. Yield 80
%.

TLC: 0.45 (hexane: diethyl ether 1:
1).

IR: (neat) 3430, 1680 cm ^-1 . NMR: δ1.19 (3H; d J = 6), 1.44 (9H;
s), 2.57 (2H; d J=5), 3.4 (1H; br.
s), 4.18 (1H; m). MS: 98, 120, 143, 148, 177 [M+1]. [α] ²⁰ _D −41.83° (c=1.96, chloroform). Example 1 3-Benzyloxypropionaldehyde 820
mg (5.0 mmol), benzylamine 0.55 ml (5.0 m−
1 g of magnesium sulfate was added to 10 ml of diethyl ether and stirred for 30 minutes. The reaction solution was filtered and washed with benzene, and the filtrate was concentrated. This imine was used in the following reaction without further purification.

Dissolve 806 mg (4.11 mmol) of (-)-3-hydroxybutyric acid phenyl thioester in 16 ml of methylene chloride at -70°C and diisopropylethylamine 1.50 mg.
ml (8.6 mmol), 9-BBN triflate 2.27 g
(8.4 mmol) was added. After heating at the same temperature for 30 minutes, raising the temperature to -35°C over 15 minutes, and stirring at -35° to -20°C for 1 hour, 20ml of the methylene chloride solution of imine prepared previously was added thereto. The temperature was raised from -20°C to 5°C over 1.5 hours, and the mixture was further stirred at room temperature for 1.5 hours.
Add 20 ml of phosphate buffer (PH7.0), 20 ml of methanol, and 10 ml of 35% hydrogen peroxide to an ice bath at the same temperature.
After stirring for 10 minutes at room temperature, diluted with methylene chloride.
The extract was extracted twice, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 70g of the concentrated solution was subjected to silica gel column chromatography.
(C-300; developing solvent hexane: diethyl ether 3:2), further purified with 100 g (developing solvent hexane: diethyl ether 2:1 → 1:2), and the raw material (-)-3-hydroxybutyric acid phenylthioester 304 mg and 672 mg of 3-benzylamino-5-benzyloxy-2-(1-hydroxyethyl)pentanoic acid phenylthioester were obtained.

Yield 36% (58% yield based on raw material consumption) TLC: 0.28 (Hexane: Diethyl ether 1:
1).

IR: (neat) 3350, 1705 cm ^-1 . NMR: δ1.24 (3H; d J = 6), 2.0 (2H,
m), 2.98 (1H; ddJ=3,6), 3.1−3.7
(5H; m), 3.68, 3.87 (each 1H; d J=
13), 4.4 (1H; m), 4.38 (2H; s), 7.20,
7.23 (10H: each s), 7.33 (5H; s). MS: 145, 160, 189, 200, 254, 311, 340 [M
-SPh], 358 [M- _PhCH2 ]. Example 2 3-benzyloxypropionaldehyde
1.642g (10.0mmol), benzylamine 1.09ml
(10.0 mmol) and 2 g of magnesium sulfate were added to 20 ml of diethyl ether and stirred for 30 minutes. The reaction solution was filtered, washed with benzene, and the filtrate was concentrated. This imine was used in the following reaction without further purification. Dissolve 1.492 g (8.46 mmol) of (-)-3-hydroxybutyric acid t-butyl thioester in 40 ml of methylene chloride, and add 3.13 ml (18 mmol) of diisopropylethylamine and 4.59 g (17 mmol) of 9-BBN triflate at -70°C. Ta. 40 minutes at the same temperature,
After stirring at -25°C to -10°C for 1 hour, 40 ml of the previously prepared imine solution in methylene chloride was added thereto, followed by stirring at -10°C to 15°C for 4 hours. 60ml of phosphate buffer (PH7.0), 60ml of methanol in an ice bath, 31
Add 30 ml of % hydrogen peroxide and incubate in an ice bath for 20 minutes at room temperature.
Stirred for 40 minutes. This reaction solution was diluted with methylene chloride.
The extract was extracted twice, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Separated using 150g of silica gel column chromatography (C-300; developing solvent: diethyl ether:hexane 2:1), 3
-benzylamino-5-benzyloxy-2-
838 mg of (1-hydroxyethyl)pentanoic acid t-butylthioester was obtained.

TLC: 0.34 (hexane: diethyl ether 1:
1).

IR: (neat) 3400, 1680 cm ^-1 . NMR: δ1.25 (3H; d J = 6), 1.43 (9H;
s), 2.0 (2H; m), 2.78 (1H; dd J=3,
8), 3.1-3.9 (7H; m), 4.28 (1H; m),
4.42 (2H; s), 7.21 (5H; s), 2.23 (5H;
s). MS: 254, 294, 328, 338 [M-PhCH ₂ ], 372
[M-Bu], 430 [M+1]. Reference example 7 3-benzylamino-5-benzyloxy-2
Dissolve 752 mg (1.67 mmol) of -(1-hydroxyethyl)pentanoic acid phenylthioester in 10 ml of THF and add 448 mg of t-butoxypotassium.
(4.0 mmol), add 5 ml of THF suspension with 0.2 ml of water,
Furthermore, 0.6 ml of water was added. After stirring at room temperature for 6 hours, the mixture was neutralized with 1N hydrochloric acid, and the reaction solution was extracted six times with ethyl acetate while salting out, and the organic layer was concentrated. Dissolve the concentrate in 150 ml of acetonitrile and add 2,2-
Add 440 mg (2.0 mmol) of dipyridyl disulfide, and add triphenyl phosphin under heating to reflux.
A solution of 525 mg (2.0 mmol) in 30 ml of acetonitrile
The mixture was added dropwise over 20 minutes, and the mixture was further heated under reflux for 3 hours.
After concentrating the reaction solution, a fraction of the target product containing 2-pyridothione was obtained using 60 g of silica gel column chromatography (developing solvent: diethyl ether), and this fraction was mixed with 1N sodium hydroxide, water, and saturated saline. By washing, drying over anhydrous sodium sulfate, and concentrating, 410 mg of 1-benzyl-4-(2-benzyloxyethyl)-3-(1-hydroxyethyl)-2-azetidinone was obtained. Yield 72%.

TLC: 0.25 (diethyl ether).

IR: (chloroform) 3460, 1735 cm ^-1 . NMR: δ1.23 (3H; d J = 6), 1.8 (3H;
m), 2.87 (8/9H; dd J=6.3), 3, 14
(1/9H; m), 3.3-3.7 (3H; m), 3.8-4.2
(2H; m), 4.32, 4.35 (2H; each s), 4.56
(1H; d J = 15), 7.23, 7.26 (10H; each
s).

MS: 91, 146, 160, 199, 201, 277, 311. Reference example 8 3-benzylamino-5-benzyloxy-2
838 mg of -(1-hydroxyethyl)pentanoic acid t-butyl thioester (containing mainly benzyl alkyl as an impurity) was dissolved in 20 ml of THF, 1 ml of 4N potassium hydroxide was added thereto, and the mixture was stirred at 45°C for 2 days. The reaction solution was neutralized with 1N hydrochloric acid, extracted six times with ethyl acetate while salting out, and the organic layer was concentrated. Dissolve the concentrate in 150ml of acetonitrile,
2,2-dipyridyl disulfide 440mg (2.0m-
mol), triphenylfuosufine 525mg
(2.0 mmol) was added, and the mixture was heated under reflux for 6 hours. After concentrating the reaction solution, 60 g of silica gel column chromatography (developing solvent: diethyl ether)
to obtain a fraction of the target product containing 2-pyridothione,
This fraction was washed with 1N sodium hydroxide, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1-bendi-4-(2-benzyloxyethyl)-3-(1-hydroxyethyl )−
51 mg of 2-azetidinone was obtained. Various spectral data of this substance are 1-benzyl-4 obtained in Reference Example 7.
-(2-benzyloxyethyl)-3-(1-hydroxyethyl)-2-azetidinone.

Reference example 9 Dissolve 100 mg (0.3 mmol) of 1-benzyl-4-(2-benzyloxyethyl)3-(1-hydroxyethyl)-2-azetidinone in 5 ml of methylene chloride and add 0.06 ml of 2,6-lutidine.
(0.5 mmol) and 0.09 ml (0.4 mmol) of t-butyldimethylsilyl triflate were added in an ice bath, and after stirring at room temperature for 5 minutes, ice water was added and extracted twice with methylene chloride. After adding sodium hydrogen sulfate to the extract and removing lutidine, it was concentrated and purified by silica gel column chromatography (C-300; 10 g developing solvent: hexane: diethyl ether 1:1) to obtain 1-benzyl-4-(2- Benzyloxyethyl)-3-(1-t-butyldimethylsilyloxyethyl)-2-azetidinone 128 mg (yield 89%)
I got it.

TLC: 0.45 (hexane: diethyl ether 1:
1).

IR: (chloroform) 174cm ^-1 . NMR: δ0.04, 0.08 (each 3H; s), 0.84
(9H; s), 1.14 (3H; d J=6), 1.8
(2H; m), 2.82 (8/9H; dd J=2,6),
3.15 (1/9H; m), 3.35 (2H; m), 3.67
(1H; m), 4.0-4.6 (3H; m), 4.43 (2H;
s), 7.24, 7.27 (10H; eachs). MS: 91, 290, 396 [M-Bu], 438 [M-Me]. Reference example 10 120mg of sodium and liquid ammonia at -70℃
I added about 5 ml. Add 3-(1-t
-butyldimethylsilyloxyethyl)-4-(2
-Hydroxyethyl)-2-azetidinone 99mg
(0.28 mmol) in diethyl ether and stirred at -70 to -50°C for 1 hour. Added a saturated ammonium chloride aqueous solution and allowed to stand at 0°C. Extracted with dichloromethane. The extract was diluted with saturated brine. After washing and drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. 10g silica gel column chromatography (C-300; developing solvent diethyl ether→
By purification with diethyl ether:methanol (20:1), 59 mg of 3-(1-t-butyldimethylsilyloxyethyl)-4-(2-hydroxyethyl)-2-azetidinone was obtained in a yield of 76%.

TLC: 0.17 (diethyl ether).

IR: (chloroform) 3440, 1750 cm ^-1 . NMR: δ0.12 (6H; s), 0.92 (9H; s), 1.27
(3H; d J=6), 1.88 (2H; m), 2.55
(1H; br.s), 2.91 (1H; m), 3.74 (3H; m),
4.17 (1H; m), 6.4 (1H; br.s). MS: 75, 216 [M-Bu], 258 [M-Me]. 3-(1-t-butyldimethylsilyloxyethyl)-4-(2-hydroxyethyl)-2-azetidinone, 2,2-dimethoxypropane, BF ₃ .
Conversion to 7-(1-t-butyldimethylsilyloxyethyl)-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one by OEt ₂ followed by tetrabutylammonium fluoride. The literature (FA
Bouffard, DBR Johnston, and B.G.
Christensin, J.Org.Chem., 45 1130 (1980)) Known substance 7-(1-hydroxyethyl)-2,2
-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one. Comparison of NMR spectra shows that 7-(1-hydroxyethyl)-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one is a mixture of two stereoisomers. Divided. (Ratio approximately 9:1). The main product is 6 which can be derived into carbapenem antibiotics including thienamycin.
(R),7(S)-(1(R)-hydroxyethyl)-
2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one, and the by-product is 6(R),7(R)-(1(R)-hydroxyethyl)- It was 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one.

Reference example 11 The diastereomer mixture obtained in Reference Example 10 was separated by silica gel column chromatography, and the obtained 3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-4(R)-(2 -Hydroxyethyl)-2-azetidinone 95 mg (0.35 mmol) 1.5
chromic acid 150mg pyridine dissolved in ml pyridine
This was added to 1.5 ml of Sarett's reagent under an ice bath.
After stirring overnight at room temperature, inorganic salts were removed by 10 g of silica gel column chromatography (developing solvent: ethyl acetate), pyridine was removed by azeotropy with toluene, and 5 g of silica gel column chromatography (developing solvent: diethyl ether) was removed. )
to obtain 76 mg of 3(S)-[1(R)-t-butyldimethylsilyloxyethyl]-4(R)carboxymethyl-2-azetinone. Yield 76%.
Analytical samples were recrystallized from diethyl ether.

TLC: 0.2 (diethyl ether). mp: 151-154℃ (decomposition). IR: (chloroform) 3310, 1750, 1730 cm ^-1 . NMR: δ0.08 (6H; s), 0.82 (9H; s), 1.21
(3H; d J=7), (2.3~3.0 (3H; m),
3.9 (1H; m), 4.16 (2H; m), 7.0 (1H; br.
s); 8.1 (1H; br.s). MS: 186, 230 [M-Bu], 272 [M-Me]. Anal: Calculated values C ₁₃ H ₂₅ O ₄ NSi C54.32%, H8.77%, N4.87%. Actual values: C54.07%, H8.72%, N4.80%. [α] ²⁰ _D +16.19° (c=1.00, chloroform). Reference example 12 4(R)-carboxymethyl-3(S)-[1(R)
-t-butyldimethylsilyloxyethyl]-2
- Dissolve 56 mg (0.20 mmol) of azetidinone and 27 mg (0.25 mmol) of benzyl alcohol in 3 ml of methylene chloride, add 52 mg (0.25 mmol) of N,N'-dicyclohexylcarbodiimide and one teaspoon of N,N-
Dimethylaminopyridine was added and stirred at room temperature for 2 hours. The reaction solution was concentrated, and 10 g of silica gel column chromatography (C-300; developing solvent
59 mg of 4(R)-benzyloxymethyl-3
(S)[1(R)-t-butyldimethylsilyloxyethyl]-2-azetidinone was obtained. Yield 80%.
Samples for analysis were obtained by recrystallization from diethyl ether, hexane.

TLC: 0.26 (diethyl ether:hexane 2:
1). mp: 93.5-94.5℃ IR: (Chloroform) 3450, 1765, 1735 cm ^-1 . NMR: δ0.07 (6H; s), 0.88 (9H; s), 1.21
(3H; d J=7), 2.5-2.9 (3H; m), 4.0
(1H; m), 4.2 (2H; m), 5.18 (2H; s),
5.95 (1H; br.s), 7.37 (5H; s). MS: 232, 276, 320 [M-Bu]. Anal: Calculated value C ₂₀ M ₃₁ O ₄ NSi C63.63%, H8.28%, N3.71%, actual value C63.61%, H8.24%, N3.71%. [α] ²⁰ _D +16.59° (c=1, chloroform). Reference example 13 4(R)-benzyloxymethyl-3(S)-[1
(R)-t-butyldimethylsilyloxyethyl]
Acetic acid in 2-azetidinone 57mg (0.15mmol):
Add 2ml of THF:water (3:1:1) and heat at 50-60℃.
Stirred for 30 hours. The reaction solution was concentrated under reduced pressure at low temperature.
silica gel column chromatography (C-
200; Purified with 4(R) (developing solvent ethyl acetate)
35 mg of -benzyloxymethyl-3(S)-[1(R)-hydroxyethyl]-2-azetidinone was obtained.
Yield 89%.

[α] ²⁰ _D +9.84° (c=2.1, chloroform). This one is based on the literature (DGMelillo, T.Liu, K.
Ryan, M. Sletzinger and I. Shinkai
Tetrahedron Lett. 22 913 (1981)) The spectral data corresponded completely with the data except for the optical rotation. In addition, this substance has been led to thienamycin according to the above-mentioned literature.

Optical rotation is determined from the literature (N.Ikota, O.Yoshino and
K.Koga Chem.Pharm.Bull 30 1929 (1982)) stated value [α] ²⁰ _D +9.9° (c = 2, 3, chloroform)
shows good agreement.

Claims (1)

[Claims] 1. General formula β-aminothiol ester represented by (wherein R ¹ is a phenyl group or a lower alkyl group,
R ² is a benzyl group and R ³ is a protecting group. ). 2 In the presence of a tertiary amine, the general formula β-Hydroxythiol ester represented by and the general formula The reaction mixture is then reacted with a boron compound represented by the general formula The general formula consists of reacting the imine represented by and then treating with hydrogen peroxide. A method for ^producing a β ^- aminothiol ^ester represented by , or a cycloalkyl group, which together can form a ring with the bound boron).