JPH045037B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing penem derivatives ().

(In the formula, R ¹ represents a hydroxyl group-protecting group, R ² represents a linear or branched lower alkyl group substituted with a fluorine atom, and R ³ represents a carboxy group-protecting group.

With the remarkable increase in the number of resistant bacteria in recent years, a chemotherapeutic agent with a broad antibacterial spectrum and strong antibacterial activity against resistant bacteria is desired. The present inventors have conducted intensive research over many years to synthesize a novel penem derivative having the above-mentioned activity, and as a result, the general formula () (in the formula,
R ² has the same meaning as described above, and R ¹ and R ³ represent a hydrogen atom. ) was found to have excellent antibacterial activity against a wide range of pathogenic bacteria. This time, the inventors investigated various methods of synthesizing these compounds, and synthesized synthetic intermediates of these compounds, which are general formulas () (in the formula, R ¹ is a protecting group for the hydroxyl group, R ²
represents a linear or branched lower alkyl group substituted with a fluorine atom, and R ³ represents a protecting group for a carboxy group. ) and completed the present invention by discovering a new and simple method for producing penem derivatives having the following. Its production method is based on the general formula () (in the formula, R ¹ is a hydroxyl-protecting group, R ² is a linear or branched lower alkyl group substituted with a fluorine atom, and R ³ is a carboxyl-protecting group). , X represents an oxygen atom or a sulfur atom) is reacted with trivalent phosphorus, and a compound having the general formula () (in the formula, R ¹ is a hydroxyl protecting group and R ² is a straight chain substituted with a fluorine atom) is reacted with trivalent phosphorus. or a branched lower alkyl group, R ³ represents a protecting group for a carboxy group)
This is a method for obtaining penem carboxylic acid ester having This method efficiently synthesizes the general formula in shorter steps than conventional methods of synthesizing penem derivatives, such as those disclosed in J.Am.Chem.Soc. This method is excellent in that it can synthesize compounds having ().

The present invention is a method for synthesizing a novel penem derivative having the general formula ().

In the formula, examples of the protecting group for the hydroxyl group represented by R ¹ include p-nitrobenzyloxycarbonyl, o-
Benzyloxycarbonyl groups such as nitrobenzyloxycarbonyl, benzyloxycarbonyl; trimethylsilyl, triethylsilyl, tert
- trialkylsilyl groups such as butyldimethylsilyl; lower alkanoyl groups such as acetyl, propionyl, butyryl, chloroacetyl; methoxymethyl, ethoxymethyl, 1-methyl-1-
Methoxyethyl, 2-methoxyethoxymethyl,
Alkoxyalkyl groups such as 2,2,2-trichloroethoxymethyl; ethoxycarbonyl, propoxycarbonyl, isobutoxycarbonyl,
Examples include alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. Preferred are p-nitrobenzyloxycarbonyl group, triethylsilyl group or tert-butyldimethylsilyl group. The linear or branched lower alkyl group substituted with a fluorine atom represented by R ² is, for example, 2-fluoroethyl, 3-fluoropropyl, 1-fluoro-2-propyl, 4
-fluorobutyl, 1,3-difluoro-2-propyl, and 2,2,2-trifluoroethyl. Preferably 2-fluoroethyl,
3-fluoropropyl or 1-fluoro-2-
It is a propyl group, particularly preferably a 2-fluoroethyl group. Examples of the protecting group for the carboxy group represented by R ³ include methyl, ethyl, propyl,
Alkyl groups such as isopropyl, butyl, isobutyl, tert-butyl; allyl groups such as allyl, 2-chloroallyl, 2-methyl-2-propenyl; methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, Examples include alkoxymethyl groups such as isobutoxymethyl, and benzyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, and p-nitrobenzyl. Among the carboxyl protecting groups represented by R ³ , those that easily return to carboxylic acid in vivo include acetoxymethyl,
Acyloxymethyl groups such as propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl; 1-
Alkoxycarbonyloxyethyl groups such as methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl; Phthalidyl group; (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl group can be mentioned. Allyl, p-nitrobenzyl, (2-oxo-5-methyl-1,
3-dioxolen-4-yl)methyl group.

Note that the compound having the general formula () has optical isomers based on an asymmetric carbon atom, and all of these isomers are shown in a single formula. Among these isomers, preferred are (5R,
6S) and 6-[1-(R)] coordination compounds.

Penem derivatives with general formula () are novel general formula () (In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and X represents an oxygen atom or a sulfur atom.)
It can be obtained by cyclizing a compound having 2 to 4 equivalents of a trivalent organic phosphorus compound in a solvent. The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction, but chloroform, halogenated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran and dioxane, ethyl acetate, butyl acetate, etc. , aromatic hydrocarbons such as benzene, toluene, and xylene, dialkylacetamides such as dimethylformamide and dimethylacetamide, acetonitrile, dimesulfoxide, etc., and mixed solvents thereof may also be used. Preferred are benzenetoluene, xylene, and the like.

As trivalent organic phosphorus compounds, trialkyl phosphites, cyclic and/or alicyclic trialkyl phosphites, triaryl phosphites, mixed alkylaryl phosphites, triamide phosphites, and the like can be used. Preferred is trialkyl phosphite.

The reaction temperature is not particularly limited and is usually carried out at 20° to 200°C, preferably 50° to 150°C. The time required for the reaction varies depending on the type of compound having the general formula () and the reaction temperature, but is from 2 hours to 4 days.
After completion of the reaction, the penem derivative (2) is isolated from the reaction mixture according to a conventional method. For example, after removing insoluble matter from the reaction mixture, if necessary, the reaction mixture is washed with water, dried, and the solvent and reagents are distilled off, and the resulting target compound is purified, if necessary, by recrystallization, thin layer chromatography, column chromatography, or the like.

Hydroxyl group protecting group R ¹ and carboxy group protecting group of penem derivative () obtained by the present invention
Penem derivatives exhibiting strong antibacterial activity can be obtained by removing R ³ by a conventional method, for example, the method described in JP-A No. 57-2289. Also, general formula ()
The compound in which R ¹ is a hydrogen atom and R ³ returns to a carboxylic acid in vivo can be used as an oral antibacterial agent in its ester form.

The compound having the general formula () used in the present invention can be produced by the method shown below.

Compound () can be obtained by reacting acetoxyazetidinone () disclosed in JP-A-54-88291 with carbon disulfide and fluorine-substituted alkyl mercaptan to obtain compound (), and then reacting with alkoxyoxalyl chloride.

Also, UK Patent Application GB2042514,
(1980) can be used to produce compound () (X=0) according to the method of BG Christensen et al. (Tetrahedron lettlers 3535 (1982)).

Example 1 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid allyl ester (3S,4R)-N-allyloxyoxalyl-3
-[1-(R)-tert-butyldimethylsilyloxyethyl)-4[(2-fluoroethylthio)carbonothioylthio]azetidin-2-one 112mg
A solution of 3 ml of toluene containing 77μ of triethyl phosphite was stirred at 75° to 80°C under a nitrogen atmosphere for 20 hours, the solvent and volatile substances were distilled off under reduced pressure, and the residue was transferred to a Lorber column (Silica gel size A manufactured by Merck; developing solvent , benzene-ethyl acetate (30:1)) yielded 32 mg of the target compound with a mp of 63° to 5°C.
was gotten.

Infrared absorption spectrum ν ^Liq _nax cm ^-1 : 1760, 1675 Ultraviolet absorption spectrum λ ^EtOH _nax nm : 260, 334 Nuclear magnetic resonance absorption spectrum δ _ppn CDCl ₃ (60M
Hz); 0.90 (9H, s), 1.25 (3H, d, J = 6.0Hz),
3.22 (2H, dt, J = 18.0, 6.0Hz), 3.67 (1H,
dd, J = 4.0, 2.0Hz), 4.60 (2H, dt, J =
46.0, 6.0Hz), 4.0~4.48 (1H, m), 4.66
(2H, d, J = 6.0Hz), 5.57 (1H, d, J =
2.0Hz), 5.12-6.22 (3H, m) Example 2 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-tert-butyldimethylsilyloxyethyl]penem-3-carboxylic acid p-nitrobenzyl ester (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[1-(R )-tert-butylmethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidine-2
A solution of 129 mg of -one and 75 μ of triethyl phosphite in 3 ml of toluene was stirred at 75° to 80°C for 19 hours under a nitrogen stream, and the solvent and volatile substances were distilled off under reduced pressure.
Transfer the residue to a Rover column (Merck silica gel)
sizeA; developing agent benzene-ethyl acetate (25:1))
18 mg of the target compound was obtained.

Infrared absorption spectrum ν ^Liq _nax : 1790, 1690,
1605 Nuclear magnetic resonance spectrum (CDCl ₃ ) δ _ppn : 0.90 (9H, s), 1.35 (3H, d, J = 6.0Hz),
3.32 (2H, dt, J = 19.0, 6.0Hz), 3.80 (1H,
dd, J=4.0, 2.0Hz), 4.00~4.60 (1H, m),
4.70 (2H, dt, J=47.0, 6.0Hz), 5.25, 5.50
(2H, AB-quartet, J=144.0Hz), 5.72
(1H, d, J = 2.0Hz), 7.68, 8.24 (4H,
_A2B2 , _J =9.0Hz) Example 3 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid allyl ester 1) Preparation of starting materials (3S,4R)-3-[1-(R)-tert-butyldimethyl A methylene chloride solution (40 ml) of 3.84 g of silyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidin-2-one was cooled to 0-5°C, and calcium carbonate
4.00g and allyloxyoxalyl chloride 1.78
A solution of 2.1 ml of diisopropylethylamine in 5 ml of methylene chloride was added thereto, and the mixture was stirred at 0-5° C. for about 30 minutes.
The reaction solution was diluted with 300 ml of chloroform, washed twice with cold water, dried over anhydrous magnesium sulfate, filtered, and adjusted to volume with chloroform to obtain (3S,4R)-N-allyloxyoxalyl-3-. [1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidine-
A 370 ml solution of 2-one was obtained.

2-A) The above-mentioned (3S,4R)-N-allyloxyoxalyl-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio ] After adding 3.43 ml of triethyl phosphite to 370 ml of chloroform solution of azetidin-2-one, approx.
The mixture was heated under reflux under a nitrogen stream for 16 hours. The solvent and volatile substances were distilled off under reduced pressure, and the residue was purified by column chromatography using silica gel (developing agent: benzene-ethyl acetate 30:1 and benzene-ethyl acetate 5:1) to give benzene-ethyl acetate 30 2.66 g of the target compound was obtained as colorless crystals from the eluted portion of :1. This product matched those previously obtained in Example 1 in its infrared absorption spectrum, ultraviolet absorption spectrum, and nuclear magnetic resonance spectrum.
Also, from the eluate of benzene-ethyl acetate 5:1, (3S,4R)-N-[(allyloxycarbonyl)triethoxyphosphoranylidenemethyl]
-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidin-2-one 0.491 g (infrared absorption spectrum: ν ^Liq _nax ; 1750, 1635cm ^-1 , thin layer chromatography (Merck, silica gel 60F-
254):Developing solution benzene-ethyl acetate 5:1R _f
= 0.26) was obtained. Even if 0.49 g of this product was heated under reflux in 50 ml of chloroform for 18 hours, the target compound could not be obtained.
Add 125 mg of hydroquinone under nitrogen stream.
After heating at ℃ for 7 hours, the solvent was distilled off, and column chromatography using silica gel (developing agent, benzene-ethyl acetate)
Purification with 30:1) yielded 161 mg of the target compound and (5S,6S)-2-(2-fluoroethylthio)-6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carvone. Acid allyl ester (5R form: 5S form = 4:1)
was gotten.

2-B) (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl-4-[(2-
(3S,4R)-N-allyloxyoxalyl-3-[1-(R)-tert-] prepared in the same manner as in 1) from 6.0 g of fluoroethylthio)carbonothioylthio]azetidin-2-one
Butyldimethylsilyloxyethyl]-4-
A solution of 470 ml of chloroform of [(2-fluoroethylthio)carbonothioylthio]azetidin-2-one was heated to reflux in a nitrogen stream, and a solution of 5.36 ml of triethyl phosphite in 130 ml of chloroform was heated for about 4 hours. It dripped slowly. After the dropwise addition was completed, the mixture was refluxed for about 16 hours. The solvent and volatile substances were distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (developing agent, benzene-ethyl acetate 30:
Purification in step 1) yielded 4.963 g of the target compound as colorless crystals. This product has the same infrared absorption spectrum as that obtained in Example 1,
The ultraviolet absorption spectra and nuclear magnetic resonance spectra were consistent.

2-C) (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2
(3S,4R)-N-allyloxyoxalyl-3-[1-(R)-tert-] prepared from 384 mg of -fluoroethylthio)carbonothioylthio]azetidin-2-one in the same manner as in 1).
Butyldimethylsilyloxyethyl]-4-
Add 236μ of trimethyl phosphite to 300ml of a chloroform solution of [(2-fluoroethylthio)carbonothioylthio]azetidin-2-one.
10 ml of chloroform solution was added thereto, and the mixture was heated under reflux for 18 hours in a nitrogen stream. The solvent and volatile substances were distilled off under reduced pressure, and the residue was purified in the same manner as in 2-B) to obtain 207 mg of the target compound as colorless crystals. This item was prepared in Example 1 first.
The infrared absorption spectrum, ultraviolet absorption spectrum, and nuclear magnetic resonance spectrum were consistent with those obtained in .

2-D) (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2
(3S,4R)-N-allyloxyoxalyl-3-[1-(R)-tert-] prepared from 384 mg of -fluoroethylthio)carbonothioylthio]azetidin-2-one in the same manner as in 1).
Butyldimethylsilyloxyethyl]-4-
Add tri-n-butyl phosphite to 30 ml of a chloroform solution of [(2-fluoroethylthio)carbonothioylthio]azetidin-2-one.
A 10 ml solution of 541μ in chloroform was added, and the mixture was heated under reflux for 18 hours in a nitrogen stream. The solvent and volatile substances were distilled off under reduced pressure, and the residue was converted to 2-B)
Purification was performed in the same manner as above to obtain 211 mg of the target compound as colorless crystals. This product has the same infrared absorption spectrum as that obtained in Example 1,
The ultraviolet absorption spectra and nuclear magnetic resonance spectra were consistent.

2-E) (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2
-Fluoroethylthio)carbonothioylthio]azetidin-2-one prepared in the same manner as in 1) from 959 mg (3S,4R)-N-allyloxyoxalyl-3-[1-(R)-tert-
Butyldimethylsilyloxyethyl]-4-
To a 70 ml chloroform solution of [(2-fluoroethylthio)carbonothioylthio]azetidin-2-one was added a 25 ml chloroform solution of 1.14 ml tri-iso-propyl phosphite, and the mixture was refluxed in a nitrogen stream for 18 hours. The solvent and volatile substances were distilled off under reduced pressure, and the residue was purified in the same manner as in 2-B) to obtain 350 mg of the target compound as colorless crystals. This product matched those previously obtained in Example 1 in its infrared absorption spectrum, ultraviolet absorption spectrum, and nuclear magnetic resonance spectrum.

Example 4 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p-
Nitrobenzyl ester 1) Preparation of starting materials (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidine- A methylene chloride solution (24 ml) containing 2.3 g of 2-one was cooled to 0-5°C, and calcium carbonate was added.
Add 2.4 g of p-nitrobenzyloxyoxalyl chloride and 1.75 g of p-nitrobenzyloxyoxalyl chloride in 6 ml of methylene chloride, and add 1.25 ml of diisopropylethylamine.
Add 6 ml of methylene chloride solution and heat at 0-5°C.
Stirred for 30 minutes. The reaction solution was diluted with 150 ml of chloroform, washed twice with cold water, dried over anhydrous magnesium sulfate, filtered, and adjusted to volume with chloroform to give (3S,4R)-N-p-
Nitrobenzyloxyoxalyl-3-[1-
180 ml of (R)-tert-butyldimethylsilyloxyethyl]-4-(2-fluoroethylthio)carbonothioylthio]azetidin-2-one
A solution was obtained.

2-A) The above (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[1-(R)-tert
-butyldimethylsilyloxyethyl]-4
- 180 ml of a chloroform solution of [(2-fluoroethylthio)carbonothioylthio]azetidin-2-one was heated to reflux under a nitrogen stream,
60ml of triethyl phosphite 2.06ml in that solution
The chloroform solution was added dropwise over about 4 hours, and the mixture was refluxed for about 16 hours after the addition. The solvent and volatile substances were distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (developing agent,
When purified with benzene-ethyl acetate 30:1 and benzene-ethyl acetate 5:1), the target compound was obtained from the benzene-ethyl acetate 30:1 eluate.
1.68 g was obtained as colorless crystals. This product matched those previously obtained in Example 2 in its infrared absorption spectrum and nuclear magnetic resonance spectrum. Furthermore, from the eluate of benzene-ethyl acetate 5:1, (3S,4R)-N-[(p-nitrobenzyloxycarbonyl)triethoxyphosphoranylidenemethyl]-3-[1-(R)-tert
-butyldimethylsilyloxyethyl]-4
-[(2-Fluoroethylthio)carbonothioylthio]azetidin-2-one 519 mg (Infrared absorption spectrum: ν ^Liq _nax : 1750, 1630 cm
^-1 , Thin layer chromatography (manufactured by Merck & Co., Ltd.,
Silica gel 60F-254): developing solution benzene ethyl acetate 5:1 R _f =0.30) was obtained. Even if 100 mg of this product was heated under reflux for 16 hours in 20 ml of chloroform, the target compound could not be obtained. However, 190 mg of this product was added with 3 mg of hydroquinone in dry xylene (12 ml) and heated at 125°C under a nitrogen atmosphere for 7 hours.
After heating for an hour, the solvent was distilled off, and column chromatography using silica gel (developing agent, benzene-ethyl acetate 30:
Purification by step 1) yields 70 mg of the target compound and (5R,6S)-2-(2-fluoroethylthio).
-6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p-nitrobenzyl ester (5R form: 5S
body = 3.5:1) was obtained.

2-B) (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2
-Fluoroethylthio)carbonothioylthio]azetidin-2-one (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[1-
A 70 ml solution of (R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]azetidin-2-one in chloroform was heated to reflux under a nitrogen stream, and the solution was A solution of 1.14 ml of tri-iso-propyl phosphate in 25 ml of chloroform is approx.
It was dropped for about 2.5 hours and refluxed for about 17 hours after dropping. The solvent and volatile substances were distilled off under reduced pressure, and the residue was subjected to column chromatography using silica gel (developing agent, benzene-ethyl acetate).
30:1) yielded 109 mg of the target compound as colorless crystals. This product matched those previously obtained in Example 2 in its infrared absorption spectrum and nuclear magnetic resonance spectrum.

Reference Example 1 (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4[(2-fluoroethylthio)carbonothioylthio]azetidin-2-one Method A (Steps Method) 2-fluoroethylthioacetate (268mg)
was dissolved in 4 ml of anhydrous methanol and cooled to about -15°C. In a nitrogen stream, a methanol solution (4 ml) of 0.5 M sodium methoxide was added dropwise, stirred for about 5 minutes, and carbon disulfide (132 μ) was added to give a solution of about -
Stirred at 15°C for about 15 minutes. (3R, 4R) −3−
[1-(R)-tert-butyldimethylsilyloxyethyl)-4-acetoxyazetidine-2-
Add on (604 mg) and heat at -15° to -10°C for 2.5 hours.
After further stirring for 15 minutes at 0° to 5°C, acetic acid (0.21
ml) and extracted with ethyl acetate and brine. After washing with brine, drying with anhydrous magnesium sulfate and distilling off the solvent, the residue was purified by column chromatography using silica gel (developing agent: benzene-ethyl acetate 10:1), with a melting point of 106-107°C. Target compound with (345
mg) and the raw material compound (3S,4R)-3-[1
-(R)-tert-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-one (131 mg) was obtained.

Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3050,
1765, 1725 Nuclear magnetic resonance absorption spectrum δ _ppn CDCl ₃ (60M
Hz): 0.89 (9H, s), 1.21 (3H, d, J = 6.0Hz),
3.20 (1H, t, J = 2.0Hz), 3.68 (2H, dt, J
=21.0, 6.0Hz), 4.00~4.50 (1H, m), 4.59
(2H, dt, J = 47.0, 6.0Hz), 5.65 (1H, d,
J=2.0Hz), 6.65 (1H, br) Method B (coexistence method) 2-Fluoroethylthioacetate (268mg)
and carbon disulfide (132 μ) were dissolved in anhydrous methanol (4 ml) and cooled to about -15°C. In a nitrogen stream, a 0.5M methanol solution (4 ml) of sodium methoxide was slowly added dropwise over about 15 minutes, and the mixture was stirred at about -15°C for 30 minutes. (3R, 4R) −3
-[1-(R)-tert-butyldimethylsilyloxyethyl)-4-acetoxyazetidine-2
-on (604 mg) was added and heated to -15° to -10°C for about 1 hour.
After stirring for a period of time, crystals of the target compound begin to precipitate. The reaction solution was left as it was in a freezer at about -20°C overnight, and then treated and purified in the same manner as in Method A to obtain the target compound (536 mg).

Reference example 2 (3S,4R)-N-allyloxyoxalyl-3
-[1-(R)-tert-butyldimethylsilyloxyethyl]-4[(2-fluoroethylthio)
Carbonothioylthio]azetidin-2-one (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioylthio]acetidine A methylene chloride solution (3 ml) of 100 mg of -2-one and 36μ of triethylamine was cooled to 0-5°C.
A 0.5 ml methylene chloride solution containing 39 mg of allyloxyoxalyl chloride was added, and the mixture was stirred at 0-5°C for about 30 minutes. The reaction solution was diluted with 30 ml of methylene chloride, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 116 mg of the target compound having an mp of 58°-60°C.

Infrared absorption spectrum ν ^Nujol _nax cm ^-1 : 1810,
1745, 1695 Nuclear magnetic resonance absorption spectrum δ _ppn CDCl ₃ (60M
Hz); 0.85 (9H, s), 1.22 (3H, d, J = 6.0Hz),
3.41~4.05 (3H, m), 4.60 (2H, dt, J=
47.0, 6.0Hz), 4.35 (1H, m), 4.75 (2H, d,
J=6.0Hz), 5.11~6.22 (3H, m), 6.70 (1H,
d, J=4.0Hz) Reference example 3 (3S,4R)-N-p-nitrobenzyloxyoxalyl-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoro Ethylthio)carbonothioylthio]azetidin-2-one (3S,4R)-3-[1-(R)-tert-butyldimethylsilyloxyethyl]-4-[(2-fluoroethylthio)carbonothioyl A methylene chloride solution (3 ml) of 100 mg of [thio]azetidin-2-one and 36μ of triethylamine was cooled to 0-5°C.
p-Nitrobenzyloxyoxalyl chloride
Add 63.5 mg of 0.5 ml methylene chloride solution and mix at 0-5°C.
Stir for about 30 minutes and process in the same manner as in Example 1.
129 mg of the target compound was obtained.

Infrared absorption spectrum ν ^Liq _nax cm ^-1 : 1815,
1770, 1710 Reference example 4 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-hydroxyethyl)penem-
3-Carboxylic acid p-nitrobenzyl ester (5R,6S)-2-(2-fluoroethylthio)-
A solution of 6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid p-nitrobenzyl ester (82 mg) in tetrahydrofuran (2 ml), acetic acid (86μ) and tetrabutylammonium fluoride (1) Add maltetrahydrofuran solution (0.604 ml) and stir overnight at room temperature.
Stir for 10 hours on a 30 °C oil bath. After diluting the reaction solution with ethyl acetate, it was sequentially washed with saturated brine, 5% sodium bicarbonate solution, and saturated brine, and the solvent was distilled off. : ethyl acetate = 65:35) to obtain the target compound (40 mg).

Melting point 168-170℃ Ultraviolet absorption spectrum λ ^EtOH _nax nm: 261, 339 Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ _ppn : 1.18 (3H, d, J = 6.0Hz), 2.9-3.7 (2H,
m), 3.86 (1H, dd, J=6.0, 2.0Hz), 3.8~
4.15 (1H, m), 4.66 (2H, dt, J = 47.0, 6.0
Hz), 5.19 (1H, d, J = 4.0Hz), 5.30, 5.48
(2H, AB-q, J=14.0Hz), 5.77 (1H, d,
J = 2.0Hz), 7.72, 8.25 (4H, A ₂ B ₂ , J = 9.0
Hz) Reference example 5 (5R,6S)-2-(2-fluoroethylthio)-
6-[1-(R)-hydroxyethyl)penem-
Sodium 3-carboxylate (5R,6S)-2-(2-fluoroethylthio)-
6-(1-(R)-hydroxyethyl)penem-3
-Carboxylic acid p-nitrobenzyl ester (39
mg) in tetrahydrofuran (3 ml), phosphate buffer (PH = 7.1, 3 ml) and 10% palladium on carbon (78 mg) were added, and the mixture was heated at room temperature under a hydrogen stream.
Stir for 2.5 hours. After removing the catalyst, the mixture is washed with ethyl acetate, and the aqueous layer is concentrated under reduced pressure to about 2 ml.
This was applied to a column of Diaion HP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.), and the portion eluted with 5% acetone water was concentrated under reduced pressure and lyophilized to obtain the target compound (17 mg) as a white powder.

Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3425,
1765, 1600 Ultraviolet absorption spectrum λ ^H2O _nax nm: 252.5, 321.5 Nuclear magnetic resonance spectrum (D ₂ O) δ _ppn : 1.30 (3H, d, J = 6.0Hz), 2.9-3.5 (2H,
m), 3.90 (1H, dd, J=6.0, 2.0Hz), 4.0~
4.45 (1H, m), 4.70 (2H, dt, J = 47.0, 6.0
Hz), 5.69 (1H, d, J = 2.0Hz) Reference example 6 (5R, 6S)-2-(2-fluoroethylthio)-
6-[1-(R)-hydroxyethyl)penem-
Sodium 3-carboxylate (5R,6S)-2-(2-fluoroethylthio)-
To a solution of 64 mg of 6-[1-(R)-tert-butyldimethylsilyloxyethyl)penem-3-carboxylic acid allyl ester in 1.6 ml of tetrahydrofuran, add 82μ of acetic acid and 0.57 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. , stir at room temperature for 18 hours. After diluting the reaction solution with ethyl acetate, it was washed successively with saturated brine, 5% sodium bicarbonate solution, and saturated brine, and dried over anhydrous magnesium sulfate. When the solvent is distilled off, (5R, 6S)-2-(2-
43 mg of allyl fluoroethylthio-6-[1-(R)-hydroxyethyl]penem-3-carboxylic acid ester was obtained.

Next, 43 mg of (5R,6S)-2-(2-fluoroethylthio)-6-[1-(R)-hydroxyethyl]penem-3-carboxylic acid allyl ester was dissolved in 1 ml of methylene chloride, and 2-ethylhexane was added. A solution of 23 mg of sodium chloride in 0.5 ml of ethyl acetate was added, followed by 5 mg of triphenylphosphine and 5 mg of tetrakis(triphenylphosphine)palladium, and the solution was stirred for about 1 hour in a nitrogen stream. This reaction solution was diluted with 10 ml of ethyl acetate, and water (5 ml
The aqueous layer was concentrated under reduced pressure to about 2 ml.
This was applied to a column of Diaion HP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.), and the portion eluted with 5% acetone water was concentrated under reduced pressure and lyophilized to obtain 24 mg of the target compound as a white powder. This product matched those obtained in Reference Example 5 above in its infrared absorption spectrum, ultraviolet absorption spectrum, and nuclear magnetic resonance absorption spectrum.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydroxyl group-protecting group, R ² is a linear or branched lower alkyl group substituted with a fluorine atom, R ³ is a carboxy group-protecting group, and X is an oxygen atom or a sulfur atom. A trivalent organic phosphorus compound is reacted with a compound having the general formula A method for producing a penem derivative having the formula (wherein R ¹ , R ² and R ³ have the same meanings as described above).