JPH0358339B2 - - Google Patents

Description

[Detailed Description of the Invention] [Object of the Invention] The present invention provides a novel general formula (wherein R ¹ is an alkyl group or an aryl group).

[Industrial application field]

The β-hydroxythiol 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, it is a group of substances that has great expectations as a next-generation β-lactam antibiotic.

[Technical background]

Carbapenem β-lactam antibiotics have low productivity through fermentation, and currently have to rely on chemical synthesis for industrial purposes. This can be said to be completely different from conventional penicin 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 are protecting groups).

The β-hydroxythiol ester of the present invention represented by the above general formula () undergoes aldol condensation with imine, formation of a β-lactam ring, protection of hydroxyl group,
Furthermore, by deprotecting the protecting group, the optically active β-lactam represented by the general formula () can be obtained in a short step, and it was therefore found to be a useful synthetic intermediate (see Reference Examples below). .

[Conventional technology]

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

[Problem that the invention seeks to solve]

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 employ 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) above has the disadvantage that although the desired product can be obtained in the form of an optically active substance, the number of manufacturing steps is long.

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

[Summary of the invention]

The β-hydroxythiol ester of the present invention represented by the general formula () can be produced according to the following reaction formula.

(In the formula, R ¹ is an alkyl group or an aryl group,
R ⁴ is a hydroxyl protecting group. ) [First step] In this step, the hydroxyl group of the β-hydroxy ester represented by the general formula () is protected to produce the β-alkoxy ester represented by the general formula (). The β-hydroxy ester represented by the general formula (), which is a raw material for this step, is produced at an extremely low cost on an industrial scale by microbial oxidation of butanoic acid.

When protecting the hydroxyl group in this step, t-
Butyldimethylsilyether, tetrahydropyranyl ether, etc. are used. In the case of t-butyldimethylsilyether, protection proceeds easily under the conditions of t-butyldimethylsilyl chloride-imidazole in dimethylformamide (DMF). In the case of tetrahydropyranyl ether, the hydroxyl group can be protected under the conditions of dihydropyran-p-toluenesulfonic acid in methylene chloride.

The reaction proceeds easily at 0°C to room temperature.

[Second process]

In this step, the β-alkoxy ester represented by the general formula () obtained in the first step is hydrolyzed to produce the β-alkoxycarboxylic acid represented by the general formula (). The hydrolysis in this step can be carried out in a hydrous alcoholic solvent such as aqueous methanol or aqueous ethanol, and with a base such as potassium hydroxide or sodium hydroxide.

The reaction proceeds easily at 0°C to room temperature.

[Third step]

This step is to produce a β-alkoxythiol ester represented by the general formula () by dehydrating and condensing the β-alkoxycarboxylic acid represented by the general formula () obtained in the second step with an aryl or alkyl mercaptan. It is.
The dehydration condensation in this step must be carried out in the presence of a catalytic amount of 4-dimethylaminopyridine and a dehydrating agent. DCC (dicyclohexylcarbodiimide) or the like can be used as a dehydrating agent. Examples of the thiol used in this step include benzenethiol, t-butylmercaptan, ethanethiol, sec-butylmercaptan, n-propylmercaptan, and isopropylmercaptan.

Note that this reaction uses halogenated hydrocarbons such as methylene chloride and chloroform as a solvent.

The reaction proceeds easily at 0°C to 40°C.

[Fourth step]

This step is carried out by deprotecting the β-alkoxythiol ester represented by the general formula () obtained in the third step.
A β-hydroxythiol ester represented by the following formula is produced. Regardless of whether the protecting group for the hydroxyl group is t-butyldimethylsilyl ether or tetrahydropyranyl ether, acetic acid-water-
Deprotection can be carried out under the conditions of tetrahydrofuran.

The reaction proceeds easily between room temperature and 70°C.

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

Reference example 1 Methyl 3-hydroxybutyrate 5.91g (50mmol),
3.74 g (55 mmol) of imidazole was dissolved in 20 ml of DMF, and 8.29 g (55 mmol) of t-butyldimethylsilyl chloride 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-butyldimethylsilioloxybutyrate was obtained. Yield 91%.

TLC: 0.4 (hexane: diethyl ether 20:1) IR: (neat) 1735 cm ^-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 (3HH; 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 was distilled off, acidified with 1N hydrochloric acid, and extracted with diethyl ether. 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-Butylmethylsilyloxybutyric acid 3.18g (19.2mmol), thiophenol 2.26ml
(22 mmol) was dissolved in 100 ml of methylene chloride and added with N,N-dicyclohexylcarbodiimide.
4.53g (22mmol) was added. After stirring at room temperature for 2 hours, it was filtered, and the filtrate was concentrated and distilled (110-116
℃/0.3mmHg), (-)-3-
5.00 g (yield: 83%) of t-butyldimethylsilioxybutyric acid phenylthioester was obtained.

TLC: 0.3 (hexane:diethyl ether 20:1). IR: (neat) 1710 cm ^-1 . NMR: δ0.07 (6H; s), 0.91 (9H; s), 1.22
(3H; dJ=5), 2.61, 2.87 (each 1H; ddJ=
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 218 mg (1 mmol), t-butyl mercaptan
Dissolve 0.11 ml (1 mmol) in 5 ml of methylene chloride and add N,N-dicyclohexylcarbodiimide.
206 mg (1 mmol) and 5 mg of N,N-dimethylaminopyridine were added and stirred at room temperature for 3 days. The reaction solution was subjected to 10 g of silica gel column chromatography (c-200: developing solvent methylene chloride) to obtain 231 mg of (-)-3-t-butyldimethylsilyloxybutyrate-t-butylthioester.
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; dJ=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 ). Example 1 (−)-3-t-Butylmethylsilyloxybutyric acid phenylthioester 3.26 g (10.4 mmol),
Add 50 ml of acetic acid:THF:water (3:1:1),
The mixture was stirred at ℃ 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 ). Example 2 (-)-3-Hydroxybutyric acid-t-butylthioester 1.55g (5.33mmol) was mixed with 25ml of acetic acid:
Dissolve in THF:water (3:1:1) at 50-55℃.
It was stirred for two days. The reaction solution was concentrated under reduced pressure for 40 minutes.
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-butylthioester.
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° (cp1.96, chloroform). Reference example 5 3-Benzyloxypropionaldehyde 820
mg (5.0 mmol), benzylamine 0.55 ml (5.0 m
mol), 1 g of magnesium sulfate was added to 10 ml of diethyl ether, and the mixture was 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 and heat diisopropylethylamine at -70°C.
1.50ml (8.6mmol), 9-BBN triflate 2.27
g (8.4 mmol) was added. -35 for 30 minutes at the same temperature
After raising the temperature to .degree. C. over 15 minutes and stirring for 1 hour at -35.degree. C. to -20.degree. C., 20 ml of the methylene chloride solution of the imine prepared previously was added thereto. -20℃ to 50℃
The temperature was raised over 1.5 hours until the temperature reached 1.5 hours, and the mixture was further stirred at room temperature for 1.5 hours. Phosphate buffer (PH7.0) under ice bath
Add 20 ml of methanol, 20 ml of methanol, and 10 ml of 31% hydrogen peroxide solution, stir at the same temperature for 15 minutes, then at room temperature for 10 minutes, then extract twice with methylene chloride, wash the extract with saturated brine, and add anhydrous sulfuric acid. After drying with sodium, it was concentrated under reduced pressure. The concentrated solution was subjected to silica gel column chromatography (70 g (c-300; developing solvent: hexane: diethyl ether 3:2), and further 100 g (developing solvent: hexane: diethyl ether 2:1 →
1:2) and the raw materials (-)-3-hydroxybutyric acid phenylthioester 304mg, 3-benzylamino-5-benzyloxy-2-(1-hydroxyethyl)pentanoic acid phenylthioester
Obtained 672 mg. Yield 36% (yield based on raw material consumption)
58%) TLC: 0.28 (hexane: diethyl ether 1:
1). IR: (neat) 3350, 1705 cm ^-1 . NMR: δ1.24 (3H; d J = 6), 2.0 (2H; s),
2.98 (1H; dd J=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 _] . Reference example 6 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 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. 60 ml of phosphate buffer (PH7.0), 60 ml of methanol in an ice bath,
30 ml of 31% hydrogen peroxide solution was added, and the mixture was stirred in an ice bath for 20 minutes and at room temperature for 40 minutes. This reaction solution was extracted twice with methylene chloride, and the extract was 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- containing mainly benzyl alcohol as an impurity.
838 mg of 2-(1-hydroxyethyl)pentanoic acid t-butylthioester was obtained.

TCL: 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), 7.23 (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 phenyl thioester in 10 ml of THF and add 448 mg (4.0 mmol) of t-butoxypotassium.
A suspension of 0.2 ml of water in 5 ml of THF was added, and then 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. 150% concentrate
ml acetonitrile, add 440 mg (2.0 mmol) of 2,2-dipyridyl disulfide, and add 525 mg (2.0 mmol) of triphenylphosphine under heating under reflux.
mol) in acetonitrile was added dropwise over 20 minutes, and the mixture was further heated under reflux for 3 hours. After concentrating the reaction solution, 2-
1-Benzyl-4-(2-benzyl 410 mg of oxyethyl)-3-(1-hydroxyethyl)-2-azetidinone was obtained. Yield 72%.

TCL: 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 (mainly containing benzyl alcohol 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, and the organic layer was concentrated. Dissolve the concentrate in 150ml of acetonitrile,
2,2-dipyridyl disulfide 440mg (2.0m
mol), triphenylphosphine 525mg (2.0m
mol) was added thereto, and the mixture was heated under reflux for 6 hours. After concentrating the reaction solution, 2-
1-Benzyl-4-(2-benzyl 51 mg of oxyethyl)-3-(1-hydroxyethyl)-2-azetidinone was obtained. Various spectral data of this substance are 1-benzyl-4-(2) obtained in Reference Example 7.
-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 (0.5 mmol) of 2,6-lutidine to this solution.
mmol) and t-butyldimethylsilyl triflate (0.09 ml, 0.4 mmol) were added in an ice bath, and after stirring at room temperature for 5 minutes, ice water was added, and the mixture was 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; 10g developing solvent: hexane:diethyl ether 1:1). 128 mg (yield: 89%) of benzyloxyethyl)-3-(1-t-butyldimethylsilyloxyethyl)-2-azetidinone was obtained.

TLC: 0.45 (hexane: diethyl ether 1:
1). IR: (chloroform) 1740 cm ^-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;
each s). 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 for 1 hour at -70°C to -50°C. Added a saturated aqueous ammonium chloride solution and allowed to stand at 0°C. Extracted with dichloromethane. The mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 10g silica gel column chromatography (c-300; developing solvent diethyl ether→
By purifying with diethyl ether:ethanol (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 with 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, DBRJohnston, and B.G.
Christensen, J.Org.Chem., 45 , 1130 (1980))
7-(1-hydroxyethyl)-, a known substance
This led to 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octan-8-one.

From comparison of NMR spectra, 7-(1-hydroxyethyl)-2,2-dimethyl-3-oxa-
1-azabicyclo[42.0]octan-8-one was found to be a mixture of two stereoisomers (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-products are 6(R), 7(R)-[1(R)-hydroxyethyl]-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)
-Dissolve 95 mg (0.35 mmol) of 2-azetidinone in 1.5 ml of pyridine, 150 mg of chromic acid and 1.5 ml of pyridine.
This was added to the Sarett reagent prepared 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)-carboxylmethyl-2-azetidinone. 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 value C ₁₃ H ₂₅ O ₄ NSi
C54.23%, 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-azetidinone 56 mg (0.20 mmol), benzyl alcohol 27 mg (0.25 mmol) were dissolved in 3 ml of methylene chloride, N,N'-dicyclohexylcarbodiimide 52 mg (0.25 mmol) and one teaspoon of N, N-dimethylaminopyridine was added and stirred at room temperature for 2 hours. The reaction solution was concentrated and purified by 10 g of silica gel column chromatography (C-300, developing solvent: hexane:diethyl ether 1:2) to produce 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 H ₃₁ O ₄ NSi
C63.63%; H8.23%; 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-butyldimethylsilioxyethyl]-2-
Azetidinone 57mg (0.15mmol) acetic acid: THF:
2 ml of water (3:1:1) was added and stirred at 50°C to 60°C for 30 hours. The reaction solution was concentrated under reduced pressure at low temperature and subjected to 5 g silica gel column chromatography (c-
200; Purified with ethyl acetate (developing solvent) and purified with 4(R)-
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 (D.G.Melillo, T.Liu, K.
Ryan M. Sletzinger and I. Shinkai
Except for the optical rotation, it completely matched the spectral data described in Tetrahedron Lett. 22 , 913 (1981). In addition, this substance has been led to thienamycin according to the above-mentioned literature.

The optical rotation is calculated from the literature (N.Ikota, O.Yoshino and
This shows good agreement with the value [α] ²⁰ _D +9.9° (c=2.3 chloroform) described in K. koga Chem. Pharm, Bull 30 , 1929 (1982)).

Claims (1)

[Claims] 1. General formula β-hydroxythiol ester represented by (wherein R ¹ is an alkyl group or an aryl group).