JPH0757756B2 - Penem derivative, production method and use thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula (I)

[Chemical formula 23] (In the formula, R is hydrogen or an allyl group,

[Chemical formula 24] Is a tetrahydrofuryl group, a 1,4-dioxanyl group,
It represents a 5-oxo-oxolanyl group, a 2-oxo-1,3-dioxolanyl group or a 1,3-dioxolanyl group. And a pharmacologically acceptable salt thereof.

The compound of the general formula (I) according to the present invention is a novel compound, has a very remarkable effect on the treatment of infectious diseases such as Gram-positive bacteria and Gram-negative bacteria, and is not limited to pharmaceuticals. It can be used extensively as an animal drug.

[0003]

It is well known that a wide variety of antibiotics have been invented and used since the invention of penicillin by Fleming and the use of penicillin as a chemotherapeutic agent by Florey et al. is there. The most widely used antibiotics in Japan in the field of antibiotics today are β-lactams, which account for more than 80% of all antibiotics.

The reason why β-lactam antibiotics are widely used is that they are highly safe in addition to their strong antibacterial activity and broad antibacterial spectrum. The widespread use of these β-lactam antibiotics is that they may be obtained by fermentation.

Β-lactam agents produced by microorganisms include penicillin, cephalosporins, nocardicin, clavulanic acid, carbapenems and the like. Although many carbapenem compounds have already been produced by actinomycetes and bacteria, the penem compound is a non-natural β-lactam and has not yet been found in nature.

The penem skeleton has the following structural formula:

[Chemical 25] The carbapenem skeleton has a methylene group at the 1-position replaced by a sulfur atom, and both have extremely similar structures. In addition, the penem skeleton of penicillin has a large strain in the ring, while the cephalosporin of cephalosporin reacts with transpeptidases involved in bacterial cell wall synthesis because stabilization is hindered by the double bond in the 6-membered ring. , Inhibit its work. From these facts, strong activity was expected in the penem skeleton.

Fact 1-thiathienamycin (S. Ohy
a et al. Antimicrob. Agents Chemo
ther. , 21, 492, 1982) and Sch
29482 (AK Gangury et al. J. Anti.
microb. Chemother. , (Suppl,
C) A strong activity is found in Volume 9, page 1, 1982) and the like.

As described above, many penem derivatives have been synthesized due to the similarities of the skeletons. For example, JP-A-54
-119486, JP-A-54-88291, JP-A-56
-25110, JP-A-57-9784 and the like.

Many syntheses of these penem derivatives have also been reported. For example, A. Longo et al. [Gazz. Ch
im, Ital. , 111, pp. 371-77, 198
1 year], V. M. Girijavallabhan et al. [Tetrahedron Letters. , 22
Vol. 3, 3485, 1981] and the like.

[0010]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have aimed to develop a new antibiotic, and have focused on β-lactam antibiotics.

Among the β-lactam antibiotics, the penem compound is generally chemically stable, though its biological evaluation is still unknown, and is more stable than carbapenem against renal dehydropeptidase I.

The present invention has been completed by conducting research to find a penem derivative which has these advantages and has a strong antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria and can be used orally. . In addition, as part of this research, the synthetic method was improved in various ways, and the penem derivative was synthesized at a lower cost.

[0013]

The present invention has the general formula (I)

[Chemical formula 26] (In the formula, R is hydrogen or an allyl group,

[Chemical 27] Is a penem derivative having the same meaning as described above or a pharmacologically acceptable salt thereof.

The penem derivative represented by the general formula (I) can be synthesized by the following method.

[Chemical 28]

[Chemical 29]

[Chemical 30]

[Chemical 31]

[Chemical 32]

(Wherein R and the group

[Chemical 33] Represents the same as defined above, R ² represents a protecting group for a carboxyl group or an allyl group, X represents a halogen, and Z represents an aryl group. )

Base

[Chemical 34] Illustrating specific compounds representing moieties,

[Chemical 35] Is mentioned.

The compound having the above-mentioned general formula (I) has optical isomers and stereoisomers based on asymmetric carbon atoms, all of which are shown by the plane formula. The range is not limited. However, preferably, the carbon atom at the 5-position of the penem skeleton is R
It is possible to select a compound having a coordination, and the carbon atom at the 6-position is the S coordination.

The 1-hydroxyethyl group which is the 6-position substituent is preferably in the R-coordinate, and the 2-position substituent is selected such that the α-position carbon is in the R-coordinate.

The above steps will be sequentially described. The first step is a step of obtaining a thiocarboxylic acid ester having the general formula (V), which comprises the azetidinone derivative of the general formula (II) or (III) and 1.5 to 2 equivalents of the thiocarboxylic acid represented by the general formula (IV). With water and alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, and ethers such as tetrahydrofuran and dioxane as solvents, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or sodium methoxide and sodium ethoxy. The reaction proceeds by adjusting the pH of the reaction solution to 8 to 10 by adding an alkali metal alkoxide such as a metal oxide. After completion of the reaction, the reaction mixture is neutralized with a dilute mineral acid, extracted with an organic solvent immiscible with water, and the organic solvent layer is washed with water. After drying with a desiccant, the target product (V) is obtained by distilling off the organic solvent. The target compound thus obtained may be used in the next step without purification, but if necessary, it can be further purified by column chromatography, preparative thin layer chromatography, recrystallization or the like. it can.

The second step is N represented by the general formula (VII).
In the step of producing a hydroxyl ester compound, a glyoxylic acid ester represented by the general formula (VI) is added to the compound having the general formula (V), an ether such as tetrahydrofuran or dioxane, or an aromatic compound such as benzene, toluene or xylene. The compound of the general formula (VII) which is the target adduct is obtained by heating under reflux in hydrocarbons. The product of this step is obtained by distilling off the solvent and is used in the next step without purification in most cases, but it can be purified by column chromatography, recrystallization or the like in some cases.

The third step is halogenation to obtain the compound of the general formula (VII
This is a step of producing a compound represented by I). In carrying out the reaction of this step, the compound represented by the general formula (VII) is diluted with an organic solvent and thionyl chloride, thionyl halide such as thionyl bromide, phosphorus oxyhalide such as phosphorus oxychloride in the presence of a base. , Phosphorus pentachloride, by contacting with a phosphorus halide. In this step, the temperature is preferably −40 ° C. to 0 ° C., and the reaction is completed within several hours.

The base used in this step is preferably an organic base such as triethylamine, diisopropylethylamine, pyridine or lutidine. The solvent may be one that does not participate in this reaction, but ether solvents such as tetrahydrofuran and dioxane, and chlorine solvents such as methylene chloride and chloroform are preferable.

After the reaction, the product of this step is obtained by diluting it with an organic solvent immiscible with water, washing it with a saturated aqueous solution of sodium hydrogencarbonate and water, adding a desiccant and drying, and distilling off the solvent. To be The product of this step is used in the next step without purification, but may be purified by a purification means such as recrystallization, column chromatography, preparative thin layer chromatography and the like. In some cases, after completion of the reaction, the insoluble matter can be filtered off and the filtrate can be concentrated for use in the next step without purification.

The fourth step is a step of producing a phosphorus-ylide compound represented by the general formula (IX).

In carrying out the reaction of this step, the reaction is carried out by mixing the compound represented by the general formula (VIII) with an organic solvent and treating with triarylphosphine such as triphenylphosphine in the presence of a base. The reaction temperature is usually room temperature to 1
As the base often used in 00, organic bases such as triethyl, diisopropylethylamine, pyridine and lutidine are preferable, and the solvent is an ether type such as tetrahydrofuran and dioxane, an aromatic hydrocarbon type such as benzene and toluene, an aliphatic type such as cyclohexane. Hydrocarbons are preferred.

After completion of the reaction, the target compound (IX) is a dilute acid,
It is obtained by successively washing with dilute alkali and water, drying with a desiccant and then concentrating. The desired compound thus obtained can be purified by a purification means such as column chromatography, recrystallization method, preparative thin layer chromatography and the like, if necessary.

On the other hand, a known compound represented by the general formula (X) (JP-A-56-25110) and the general formula

[Chemical 36] (In the formula, the group

[Chemical 37] Is represented by the general formula (IX) by mixing the acid chloride represented by the above) in a chlorine-based solvent such as methylene chloride or chloroform or an aromatic hydrocarbon solvent such as benzene, toluene or xylene. The target compound is obtained.

In carrying out this step 5, the reaction is usually suitable at 0 ° C. to room temperature, and is completed within 5 hours.
After completion of the reaction, the insoluble matter (mainly silver salt) is removed by filtration, washed with water, dried with a desiccant and then concentrated to obtain the target compound (IX).

The target compound (I
X) can be purified by the purification means shown in step 4, if necessary.

The sixth step is a step of producing a compound represented by the general formula (XI).

The method of protecting the hydroxyl group differs depending on the nature of each protecting group. For example, when a silyl-based protecting group such as t-butyldimethylsilyl group is used as the protecting group, the compound having the general formula (IX) is diluted with a solvent and contacted with tetrabutylammonium fluoride to facilitate the reaction. proceed. The reaction may be near room temperature,
The solvent used is preferably an ether organic solvent such as dioxane or tetrahydrofuran.

After the completion of the reaction, the target compound (XI) is obtained by diluting the mixture with an organic solvent immiscible with water, successively washing with a saturated aqueous solution of sodium hydrogencarbonate and water, drying with a desiccant and then concentrating. . This compound (XI) can be used as it is in the next step, but if necessary, it can be purified by a purification means such as column chromatography, recrystallization, preparative thin layer chromatography and the like.

The seventh step is a step of producing a penem derivative having the general formula (XIII), which is a step of heating and ring-closing the compound having the general formula (XI) in a solvent.

In carrying out this step, the solvent used in the reaction is not particularly limited, but aromatic hydrocarbon solvents such as benzene, toluene and xylene and ether solvents such as dioxane and diethoxyethane are suitable.

After completion of the reaction, the target compound of this step (XII
I) can be obtained by distilling off the solvent from the mixture under reduced pressure. The compound (XIII) thus obtained can be further purified by column chromatography, recrystallization and preparative thin layer chromatography, if necessary.

The eighth step is a step of producing the penem derivative having the general formula (XII), and heating and ring-closing the phosphorus-ylide compound of the general formula (IX) in the same manner as in step 7.

This step is the same as the seventh step, and after the reaction is completed,
The target compound (XII) can be obtained by concentrating.
The compound thus obtained can be purified, if necessary, by a conventional method such as column chromatography, recrystallization, preparative thin layer chromatography and the like.

The ninth step is a step of producing the penem derivative having the above-mentioned general formula (XIII).

This step can be performed in exactly the same manner as step 6 described above. Similarly to step 6, step 9 can be purified using a general purification method such as column chromatography, recrystallization and preparative thin layer chromatography.

The tenth step is a step of producing a penem derivative having the general formula (I), which is a step of removing the protecting group of the carboxyl group of the penem derivative having the general formula (XIII). The removal of the protecting group depends on its type, but it is generally removed by a method known in the art. In the case where the protecting group is an aralkyl group such as benzyl or paranitrobenzyl, a method of reacting with a catalytic reduction catalyst such as hydrogen and palladium-carbon or an alkali metal sulfide such as sodium sulfide is preferable. .

When the protecting group is an allyl group, a method using triarylphosphine or palladium tetrakistriarylphosphine is exemplified, and a method using palladium tetrakistriarylphosphine or tri-butyltin hydride is also mentioned.

The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and acetic acid. Esters such as ethyl and methyl acetate, fatty acids such as acetic acid, and mixed solvents of these organic solvents and water are preferable.

When the protecting group is an aralkyl group, after the reaction is completed, the insoluble matter is removed by filtration, water and an organic solvent immiscible with water are added, the mixture is distributed between water and the organic solvent layer, and the aqueous layer is concentrated for deprotection. The desired compound is obtained. This target compound can be further purified, if necessary, by using column chromatography, recrystallization, preparative thin layer chromatography and the like. If the allyl group is a protective group, after the reaction is complete, dilute with water and an organic solvent immiscible with water, add weak alkali such as potassium hydrogen carbonate to form a weak alkaline solution, and separate and concentrate the aqueous layer to obtain the objective. The compound is obtained. This target compound can be further purified, if necessary, by column chromatography, recrystallization, preparative thin layer chromatography and the like.

Of the above steps, in steps 1 to 10,
Although general synthetic methods for the compounds of the present invention have been described, it goes without saying that these can be used in exactly the same manner for the synthesis of optically active compounds. When an optically active substance is used as the compound having the general formula (II) or (III), the compound having the general formula

[Chemical 38]

(Wherein

[Chemical Formula 39] Has the same meaning as described above), even if the compound is a dl compound, it is racemically resolved in any of Step 2, Step 6 and Step 8 to obtain an optically active single compound. Further, the compound (II) or (III) is a dl compound and has the general formula

[Chemical 40]

(Wherein

[Chemical 41] Also has the same meaning as described above), which is an optically active single compound, it is racem-resolved at any of Steps 2, 6 and 8 to give an optically single compound. To be

The method of optical resolution is preferably a method by recrystallization, a method by column chromatography or a resolution by preparative thin layer chromatography.

In the general formula (I) of the present invention, the group R in which a hydrogen atom is present can be converted into a pharmacologically acceptable salt form, if necessary. Examples of such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium and magnesium, amino acid salts such as lysine and ammonium salts, with sodium or potassium being preferred.

Further, the penem derivative represented by the general formula (I) of the present invention shows a strong antibacterial activity even in a racemic form, but in general, the most preferable isomer among them is (5
A compound having R, 6S) coordination and further R coordination with respect to the 6-position substituent 1-hydroxyethyl group can be mentioned.

This compound of the present invention is a novel compound,
Moreover, it exhibits strong antibacterial activity. This is also clear from the comparison with the in vitro antibacterial activity of the compound separately synthesized by the present inventors. The compounds synthesized for this comparison are new and known compounds, which are described in JP-A-56
No. 25110 and JP-A-54-88291.

The compounds of the present invention have antibacterial activity which can be determined by testing them in standard in vitro dilution test methods. Staphylococcus aureus (Staphyloco) using such standard microbiological methods
ccus aureus, Micrococcus luteus, and other Gram-positive bacteria, Escherichia coli
a coli), Klebsierra niumonia (kleb)
siella pneumoiae), Serratia marcescen
s), Proteus mogany (Proteus mo)
rganii), Enterobacter cloaca (Ent)
erobacter cloacae, Alcaligenes faeca
Lis), Proteus vulgaris, and Bacteroides fragilis as anaerobes.
es fragilis), Fusobacterium barium (Fusobacterium varium) was found to show activity at a test amount of 0.025-50 μg / ml.

The compounds of the present invention do not have a very high toxicity value (LD ₅₀ ) in vivo like general penem derivatives, and they are prescribed as usual antibacterial agents for oral administration, parenteral administration and external administration. To be done.

The dose of the penem derivative of the present invention depends on many factors, but a typical daily dose is 50 mg to 5 g for a standard adult, and preferably 100 mg to a divided dose. It is 4 g. Generally, the administration will be in dosage units containing a suitable amount of active ingredient and a suitable physiologically acceptable carrier or diluent.

For oral administration, tablets or capsules can be used which contain the active ingredient together with a diluent,
For example, lactose, glucose, sucrose, mannitol, sorbitol and cellulose and a lubricant such as talc, stearic acid or a salt thereof, and the tablet may further contain a binder such as magnesium silicate, starch and the like.

Isotonic aqueous solutions or suspensions are suitable for parenteral administration, ie intramuscular and subcutaneous administration.
The compound of the present invention is used not only for humans but also for animals.

The protecting groups used in the synthesis of the compounds of the present invention may be any of those commonly used in the β-lactam art. Suitable protective groups for hydroxyl group include t-butyldimethylsilyl group, t-butoxycarbonyl group, p-nitrobenzyloxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group.

Examples of the protective group for the carboxyl group include allyl group, 2,2,2-trichloroethyl group, t-butyl group,
An allyl group is preferred, such as a p-nitrobenzyl group.

In the following formulation examples, the active ingredient is, for example, (1′R, 2 ″ R, 5R, 6S) -6-
It may be either (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt or an equivalent amount of another compound of the present invention.

Formulation Example 1 Capsule No. Component mg / capsule mg / capsule 1 Active ingredient 250 100 2 Corn starch 20 10 3 Magnesium stearate 5 2 ────────────────── — Total amount 275 112

(Production Method) The ingredients of Nos. 1 and 2 were mixed with an appropriate mixer, the ingredient of No. 3 was added and further mixed. The mixture was filled using an encapsulation machine.

Formulation Example 2 Tablet No. Component mg / tablet 1 Active ingredient 250 2 Lactose 55 3 Corn starch 40 4 Magnesium stearate 5 ──────────── Total amount 350

(Manufacturing Method) The components Nos. 1 to 3 were mixed with a suitable mixer. No. 4 ingredient was added and mixed for several minutes. The mixture was compressed to size and weight on a suitable tablet press.

Formulation Example 3 Injectable composition Component Amount in ampoule Active ingredient 1.0 g 0.5 g 0.25 g Production method

20 ml of a sterile aqueous solution of the active ingredient, 10 m
1.0 g of active ingredient in 1 or 5 ml ampoule,
It was filled and sealed so that the amount became 0.5 g or 0.25 g.

Reference Example 1 (1′R, 2 ″ R, 3S, 4R and 1′R, 2 ″)
S, 3S, 4R and 1'S, 2 "R, 3R, 4S and 1'S, 2" S, 3R, 4S) -3- (1'-ter
t-butyldimethylsilyloxyethyl) -4-
(2 ″ -Tetrahydrofuranoylthio) -2-azetidinone (2)

[0066]

[Chemical 42] (1'R, 3R, 4R and 1'S, 3R, 4S) -3-
(1-tert-butyldimethylsilyloxyethyl)
-4-Phenylsulfonyl-2-azetidinone (1)
(1.953 g, 5.29 mmol) in acetone (40
ml) and water (14 ml) was added. Tetrahydrofuran-2-thiocarboxylic acid (1.28
g, 9.68 mmol) was added and 1N at 0 ° C. with stirring.
NaOH was added dropwise to adjust the pH to 11.0. Then 1 NH
After adjusting the pH to 7.0 with Cl, the mixture was extracted with chloroform, the organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (silica gel 70 g, hexane: ethyl acetate = 5: 1) to obtain 1.139 g (60%) of the title compound (2) as a colorless oil. It was

[0067]

[Equation 1] NMR δ (CDCl ₃ ): 1.20 (1.5H, d),
1.21 (1.5H, d), 1.87-2.36 (4
H, m), 3.14-3.24 (1H, m), 3.92.
-4.20 (2H, m), 4.20-4.33 (1H,
m), 4.48 (1H, dd, J = 5Hz, 5Hz),
5.19 (0.5H, d, J = 2.3Hz), 5.23
(0.5H, d, J = 2.6Hz), 6.28 (0.5
H, br. s), 0.30 (0.5H, br.s)

Reference Example 2 (1′R, 2 ″ R, 3S, 4R and 1′R, 2 ″)
S, 3S, 4R) -3- (1′-tert-Butyldimethylsilyloxyethyl) -4- (2 ″ -tetrahydrofuranoylthio) -2-azetidinone (4)

[0069]

[Chemical 43] (1'R, 3S, 4R) -4-acetoxy-3- (1 '
-Tert-butyldimethylsilyloxyethyl) -2
-Azetidinone (3) (2.26 g, 7.9 mmol)
Tetrahydrofuran (170 ml) and water (60 m
To a mixture of l), tetrahydrofuran-2-thiocarboxylic acid (2.09 g, 15.8 mmol; 2R / 2S = 1)
/ 1 mixture). Under stirring, 1N sodium hydroxide was added dropwise to this mixture to adjust the pH to 7.3. The mixture was stirred for 15 minutes, tetrahydrofuran-2-thiocarboxylic acid (0.32 g, 2.4 mmol) was further added, and the pH was adjusted to 8.0 with 1N sodium hydroxide.

Water (50 ml) was added to the mixture, and the mixture was extracted with ethyl acetate (150 ml) three times. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained crude product was purified by silica gel chromatography to give the title compound (4) as a colorless oil (2.34 g).
(82%) was obtained.

Reference Example 3 (1′R, 2 ″ R, 3S, 4R) -3- (1′-te)
rt-Butyldimethylsilyloxyethyl) -4-
(2 ″ -Tetrahydrofuranoylthio) -2-azetidinone (5) and (1′R, 2 ″ R, 3S, 4R) —
3- (1′-tert-butyldimethylsilyloxyethyl) -4- (2 ″ -tetrahydrofuranoyl) -2
-Azetidinone (6)

(A)

[Chemical 44] (1'R, 3S, 4R) -4-acetoxy-3- (1 '
-Tert-butyldimethylsilyloxyethyl) -2
-Azetidinone (3) (3.28 g, 11.4 mmol) in tetrahydrofuran (170 ml) and water (60
ml) was added tetrahydrofuran-2-thiocarboxylic acid (1.51 g, 14.7 mmol; 2R / 2S = 3/1 mixture obtained by resolution). This mixture was treated as in Example 2 and the crude product obtained was subjected to flash chromatography (silica gel 600 g, 4 g).
% Ethyl acetate-chloroform) and the first fraction is concentrated (1′R, 2 ″ S, 3S, 4R) -3.
-(1'-tert-butyldimethylsilyloxyethyl) -4- (2 ''-tetrahydrofuranoylthio)-
1.09 g of 2-azetidinone (5) as a colorless solid
Obtained.

[0073]

[Equation 2] _{NMRδ (CDCl 3): 0.08 (} 6H, S), 0.
88 (9H, S), 1.19 (3H, d, J = 6.0H
z), 1.86-2.37 (4H, m), 3.17 (1
H, d, d), 3.91-4.12 (2H, m), 4.
21-4.32 (1H, m), 4.48 (1H, d,
d, J = 5 Hz, 5 Hz), 5.23 (1H, d, J =
2.6 Hz), 6.34 (1H, br.s)

The second fraction was concentrated (1'R, 2''R, 3
2.26 g of S, 4R) -3- (1'-tert-butyldimethylsilyloxyethyl) -4- (2 ''-tetrahydrofuranoylthio) -2-azetidinone (6) was obtained as a colorless oil.

[0075]

[Equation 3] _{NMRδ (CDCl 3): 0.08 (} 6H, S), 0.
88 (9H, S), 1.21 (3H, d, J = 6H
z), 1.83-2.38 (4H, m), 3.18 (1
H, d, d), 3.90-4.18 (2H, m), 4.
20-4.33 (1H, m), 4.48 (1H, d,
d, J = 5 Hz, 5 Hz), 5.19 (1 H, d, J =
2.6 Hz), 6.40 (1H, br.s)

(B)

[Chemical formula 45]

(1'R, 3S, 4R) -3- (1'-t
ert-Butyldimethylsilyloxyethyl) -4-phenylsulfonyl-2-azetidinone (7) (9.26)
g, 25.06 Limol) and tetrahydrofuran-2-thiocarboxylic acid (4.96 g, 37.5 mmol; mixture of 2R / 2S = 3/1 obtained by resolution) in Example 1.
The crude product obtained in the same manner as above was purified by flash chromatography (silica gel 1200 g, 4% ethyl acetate-chloroform) to give (1′R, 2 ″ S, 3).
1.67 g of S, 4R) -3- (1′-tert-butyldimethylsilyloxyethyl) -4- (2 ″ -tetrahydrofuranoylthio) -2-azetidinone (5) was obtained as a colorless solid. The spectral data of the product was completely in agreement with that obtained in Reference Example 3- (A). Also, (1′R, 2 ″ R, 3S, 4R) -3- (1′-te
rt-Butyldimethylsilyloxyethyl) -4-
5.46 g of (2 ″ -tetrahydrofuranoylthio) -2-azetidinone (6) was obtained as a colorless oily substance, and the spectral data thereof was completely in agreement with that obtained in Reference Example 3- (A).

Reference Example 4 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R,
2 ″ ″ S, 3S, 4R and 1 ″ S, 2 ″ ″ R, 3
R, 4S and 1 "S, 2""S, 3R, 4S) -1
-(1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1 ''-tert
-Butyldimethylsilyloxyethyl) -4-
(2 ″ ″-Tetrahydrofuranoylthio) -2-azetidinone (10)

(A)

[Chemical formula 46]

(1'R, 2''R, 3S, 4R and 1 '
R, 2 ″ S, 3S, 4R and 1 ′S, 2 ″ R, 3
R, 4S and 1'S, 2 "S, 3R, 4S) -3-
(1'-tert-Butyldimethylsilyloxyethyl) -4- (2 ''-tetrahydrofuranoylthio)-
2-azetidinone (2) (1.225 g, 3.41 mmol) and glyoxylic acid allyl ester (0.540)
g, 4.09 mmol) was dissolved in benzene (100 ml), and the mixture was heated under reflux for 25 hours. Azeotropic water was removed by passing through molecular sieves 4A. Benzene was distilled off under reduced pressure, and the obtained alcohol compound (8) was used without purification.

Crude alcohol compound (8) (1.61 g)
Was dissolved in tetrahydrofuran (5 ml), and 2,6-lutidine (0.48 ml) was added. Stir at −10 ° C. and add thionyl chloride (0.25 ml) to the mixture. After 20 minutes, the mixture was transferred to ice water (50 ml), and this was extracted three times with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to flash chromatography (silica gel 35 g, ethyl acetate: hexane = 1: 1).
Purified in 3), (1 ″ R, 2 ″ ″ R, 3S, 4R
And 1 ″ R, 2 ″ ″ S, 3S, 4R and 1 ″ S,
2 ″ ″ R, 3R, 4S and 1 ″ S, 2 ″ ″ S, 3
R, 4S) -1- (1′-allyloxycarbonyl-
1.242 g of 2'-chloromethyl) -3- (1'-tert-butyldimethylsilyloxyethyl) -4- (2 '''-tetrahydrofuranoylthio) -2-azetidinone (9) as a pale yellow oil. (74%) was obtained.

Chlorine compound (9) (1.242 g, 2.
52 mmol), triphenylphosphine (1.322)
g, 5.04 mmol) and 2,6-lutidine (0.3
A mixture of 24 g, 3.02 mmol) was dissolved in tetrahydrofuran (15 ml) and stirred at 55-60 ° C for 75 hours. The insoluble matter was filtered off, the filtrate was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude product was subjected to flash chromatography (silica gel 80 g, ethyl acetate: hexane = 1: 1).
Purification in 2) gave 0.854 g (47%) of the title compound (10) as a colorless oil.

(B)

[Chemical 47] (1 ″ R, 3S, 4R and 1 ″ S, 3R, 4S) −
1- (1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1'-tert
-Butyldimethylsilyloxyethyl) -4-silverthio-
2-azetidinone (11) (0.614 g) was dissolved in methylene chloride (5 ml), and methylene chloride (1 m
2-Tetrahydrofurancarboxylic acid chloride (0.117 g) dissolved in 1) was added. The mixture was stirred at 0 ° C for 15 minutes and at room temperature for 15 minutes. The insoluble material was filtered off, the filtrate was washed with saturated sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained crude product was purified by flash chromatography to give the title compound (10) as a colorless oil (0.295 g, 71%).
Obtained.

Reference Example 5 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R,
2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- (2 ″ ″-Tetrahydrofuranoylthio) -2-azetidinone (14)

[Chemical 48]

[Chemical 49]

(1'R, 2''R, 3S, 4R and 1 '
R, 2 ″ S, 3S, 4R) -3- (1′-tert-
Butyldimethylsilyloxyethyl) -4- (2 "-"
Tetrahydrofuranoylthio) -2-azetidinone (4) (2.44 g, 6.79 mmol) was used in Reference Example 3-
The same treatment as in (A) was conducted to obtain 1.21 g (30%) of the title compound (14) as a colorless amorphous substance.

Reference Example 6 (1 ″ R, 2 ″ ″ S, 3S, 4R) -1- (1 ″ —
Allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- (2 ″ ″-tetrahydrofuranoylthio) -2-azetidinone (17)

[Chemical 50]

(1'R, 2 ''S, 3S, 4R) -3-
(1'-tert-Butyldimethylsilyloxyethyl) -4- (2 ''-tetrahydrofuranoylthio)-
2-Azetidinone (5) (1.09 g, 3.03 mmol) was treated in the same manner as in Reference Example 3- (A) to give the title compound (17) as a colorless amorphous substance, 0.39 g (18).
%)Obtained.

Reference Example 7 (1 ″ R, 2 ″ ″ R, 3S, 4R) -1- (1 ″ —
Allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1 "-tert-butyldimethylsilyloxyethyl) -4- (2"'-tetrahydrofuranoylthio) -2-azetidinone (20)

[Chemical 51]

(1'R, 2''R, 3S, 4R) -3-
(1'-tert-Butyldimethylsilyloxyethyl) -4- (2 ''-tetrahydrofuranoylthio)-
2-Azetidinone (6) (4.96 g, 13.79 mmol) was treated in the same manner as in Reference Example 3- (A) to give 1.62 g (36) of the title compound (20) as a colorless amorphous.
%)Obtained.

Reference Example 8 (1 ″ R, 3 ″ ″ R, 3S, 4R and 1 ″ R,
3 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- (3 ′ ″-Tetrahydrofuranoylthio) -2-azetidinone (22)

[Chemical 52]

(1 "R, 3S, 4R) -1- (1"-
Allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1'-tert-butyldimethylsilyloxyethyl) -4-silver thio-2-azetidinone (2) (1.88 g) and 3-tetrahydrofuran Carboxylic acid chloride (0.404 g) and Reference Example 3-
The same treatment as in (B) was performed to obtain 1.048 g (73%) of the title compound (22) as a colorless amorphous substance.

Reference Example 9 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R,
2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- (2 ′ ″-Tetrahydropyranoylthio) -2-azetidinone (23)

[Chemical 53]

(1 "R, 3S, 4R) -1- (1"-
Allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1'-tert-butyldimethylsilyloxyethyl) -4-silver thio-2-azetidinone (21) (1.88 g) and 2-tetrahydro Pyrancarboxylic acid chloride (0.385 g) and Reference Example 3-
The same treatment as in (B) was performed to obtain 1.033 g (70.6%) of the title compound (23) as a pale yellow amorphous substance.

Reference Example 10 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R,
2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- ( 2 ″ -paradioxanoylthio) -2-azetidinone (24)

[Chemical 54]

(1 "R, 3S, 4R) -1- (1"-
Allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4-silver thio-2-azetidinone (21) (0.88 g) and 2- Palladioxanecarboxylic acid chloride (0.389 g) and Reference Example 3-
Treatment in the same manner as in (B) gave the title compound (24) as a pale yellow oil, 1.007 g (68.6%).

Reference Example 11 (1 ″ R, 2 ″ ″ S, 3S, 4R and 1 ″ S,
2 ″ ″ S, 3R, 4S) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- [1 ″ -tert-butyldimethylsilyloxyethyl) -4- (2 ″-(5 ″ ″-oxo)
Oxoranoylthio] -2-azetidinone (25)

[Chemical 55]

(1 ″ R, 3S, 4R and 1 ″ S, 3
R, 4S) -1- (1′-allyloxycarbonyl-
2'-Triphenylphosphoranylidenemethyl) -3-
(1 ″ -tert-butyldimethylsilyloxyethyl) -4-silver thio-2-azetidinone (11) (0.3
63 g) and (2S) -2- (5-oxo) oxolanylcarboxylic acid chloride were treated in the same manner as in Reference Example 3- (B) to obtain 0.25 g of the title compound (25).

Reference Example 12 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ S,
2 ″ ″ R, 3R, 4S) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- [2 ″ ″-(5 ″ ″-oxo) oxolanoylthio] -2-azetidinone (26)

[Chemical 56]

(1 ″ R, 3S, 4R and 1 ″ S, 3
R, 4S) -1- (1′-allyloxycarbonyl-
2'-Triphenylphosphoranylidenemethyl) -3-
(1 ″ -tert-butyldimethylsilyloxyethyl) -4-silver thio-2-azetidinone (11) (0.3
63 g) and (2R) -2- (5-oxo) oxolanylcarboxylic acid chloride were treated in the same manner as in Reference Example 3- (B) to obtain 0.162 g of the title compound (26).

Reference Example 13 (1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R,
2 ″ ″ S, 3S, 4R and 1 ″ S, 2 ″ ″ R, 3
R, 4S and 1 "S, 2""S, 3R, 4S) -1
-(1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1 ''-hydroxyethyl) -4- (2 '''-tetrahydrofuranoylthio) -2-azetidinone (27)

[Chemical 57]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R, 2 ″ ″ S, 3S, 4R and 1 ″ S,
2 ″ ″ R, 3R, 4S and 1 ″ S, 2 ″ ″ S, 3
R, 4S) -1- (1′-allyloxycarbonyl-
2'-Triphenylphosphoranylidenemethyl) -3-
(1 ″ -tert-Butyldimethylsilyloxyethyl) -4- (2 ″ ″ tetrahydrofuranoylthio)-
2-Azetidinone (10) (0.295 g, 0.41 mmol) was dissolved in tetrahydrofuran (2 ml) and a mixture of acetic acid (206 ml) and tetrahydrofuran (1 ml) was added. Then tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.23 m
1) was added, and the mixture was stirred at room temperature for 62 hours. The reaction product was diluted with ethyl acetate, washed successively with saturated sodium hydrogen carbonate and water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was subjected to flash chromatography (silica gel 10 g, ethyl acetate: hexane = 2: 1 to 1: 1).
Purification with ethyl acetate: hexane = 1: 2) gave 0.12 g (48%) of the title compound (27).

Reference Example 14 (1 "R, 2""R, 3S, 4R) -1- (1"-
Allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1 ''-hydroxyethyl)
-4- (2 ""-tetrahydrofuranoylthio) -2
-Azetidinone (28)

[Chemical 58]

(1'R, 2 ''S, 3S, 4R) -1-
(1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1 ''-tert-
Butyldimethylsilyloxyethyl) -4- (2 "-"
Tetrahydrofuranoylthio) -2-azetidinone (2
0) (1.40 g, 1.95 mmol) and acetic acid (0.9
8 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 5.9 ml) were treated in the same manner as in Reference Example 13 to give 1.03 of the title compound (28).
g (87%) were obtained.

Reference Example 15 (1 ″ R, 2 ″ ″ S, 3R, 4S and 1 ″ S,
2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -hydroxyethyl) -4-
[2 ″ ″-(5 ″ ″-oxo) oxolanoylthio] -2-azetidinone (29)

[Chemical 59]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ S, 2 ″ ″ R, 3R, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- [2 ″ ″-
(5 ″ ″-oxo) oxolanoylthio] -2-azetidinone (25) (0.25 g, 0.34 mmol),
Acetic acid (0.2 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 0.9 m
l) is operated in the same manner as in Reference Example 13 to give the title compound (29)
0.060 g was obtained.

Example 1 (1′R, 2 ″ S, 5R, 6S) -6- (1′-te)
rt-Butyldimethylsilyloxyethyl) -2-
(2 ″ -Tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (30) and (1′R, 2 ″ R,
5R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (3
1)

[Chemical 60]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R, 2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -3- (1'-tert-butyldimethylsilyloxyethyl) -4- (2 "'-tetrahydrofuranoylthio) -2-azetidinone (14) (1.
21 g, 1.69 mmol) and toluene (120 ml)
The mixture was refluxed for 16 hours, cooled and the solvent was distilled off. The resulting crude product was carefully purified by flash chromatography (silica gel 90 g, ethyl acetate: hexane = 1: 15) to give the title compound (30) 0.247 g (3
3%) was obtained. Further, 0.312 g of the title compound (31)
(42%) obtained.

Example 2 (1′R, 2 ″ S, 5R, 6S) -6- (1′-te
rt-Butyldimethylsilyloxyethyl) -2-
(2 ″ -Tetrahydrofuranyl) penem-3-carphonic acid allyl ester (30)

[Chemical formula 61]

(1 ″ R, 2 ″ ″ S, 3S, 4R) −
1- (1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1'-tert
-Butyldimethylsilyloxyethyl) -4-
A mixture of (2 ′ ″-tetrahydrofuranoylthio) -2-azetidinone (17) (0.394 g, 0.55 mol) and toluene (40 ml) was treated in the same manner as in Example 1 to give the title compound (30). 0.176 g (73%) was obtained.

Example 3 (1′R, 2 ″ R, 5R, 6S) -6- (1′-te)
rt-Butyldimethylsilyloxyethyl) -2-
(2 ″ -Tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (31)

[Chemical formula 62]

(1 "R, 2""R, 3S, 4R)-
1- (1'-allyloxycarbonyl-2'-triphenylphosphoranylidenemethyl) -3- (1'-tert
-Butyldimethylsilyloxyethyl) -4-
A mixture of (2 ′ ″-tetrahydrofuranoylthio) -2-azetidinone (20) (2.04 g, 2.84 mmol) and toluene (200 ml) was treated in the same manner as in Example 1 to give the title compound (31). 1.12 g (89.8%)
Obtained.

Example 4 (1′R, 3 ″ S, 5R, 6S) -6- (1′-te
rt-Butyldimethylsilyloxyethyl) -2-
(3 ″ -Tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (32) and (1′R, 3 ″ R,
5R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (3
3)

[Chemical formula 63]

(1 ″ R, 3 ″ ″ R, 3S, 4R and 1 ″ R, 3 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) 3- (1'-tert-butyldimethylsilyloxyethyl) -4- (3 "'-tetrahydrofuranoylthio) -2-azetidinone (22) (1.0
48 g, 1.46 mmol) and toluene (100 ml)
The mixture of the above compounds was treated in the same manner as in Example 1 to give the title compound (3
2) 0.329 g (50%), and the title compound (3
0.286 g (46%) of 3) was obtained.

Example 5 (1′R, 2 ″ S, 5R, 6S) -6- (1′-te
rt-Butyldimethylsilyloxyethyl) -2-
(2 ″ -Tetrahydropyranyl) penem-3-carboxylic acid allyl ester (34) and (1′R, 2 ″ R,
5R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid allyl ester (3
5)

[Chemical 64]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R, 2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -4- (2 "-tetrahydropyranoylthio) -3- (1" -tert-butyldimethylsilyloxyethyl) -2-azetidinone (23) (1.
033 g, 1.41 mmol) and toluene (70 ml)
The mixture of the above compounds was treated in the same manner as in Example 1 to give the title compound (3
4) 0.194 g (30.3%) and the title compound (3
5) was obtained in an amount of 0.189 g (29.5%).

Example 6 (1′R, 2 ″ S, 5R, 6S and 1′R, 2 ″)
R, 5R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (3
6)

[Chemical 65]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R, 2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -4- (2 ″ -paradioxanoylthio) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -2-azetidinone (24) (1.00
A mixture of 7 g, 1.37 mmol) and toluene (70 ml) was treated in the same manner as in Example 1 to obtain 0.496 g (79.5%) of the title compound (36).

Example 7 (1′R, 2 ″ S, 5R, 6S) -6- (1′-te)
rt-Butyldimethylsilyloxyethyl) -2-
(2 ″ -Paradioxanyl) penem-3-carboxylic acid allyl ester (37) and (1′R, 2 ″ R, 5
R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (38)

[Chemical formula 66]

The isomer mixture (1 'obtained in Example 6)
R, 2 ″ S, 5R, 6S and 1′R, 2 ″ R, 5
R, 6S) -6- (1′-tert-butyldimethylsilyloxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (36)
(0.333 g) was classified using PLC13895 (developed 5 times with chloroform) manufactured by Merck & Co., Inc., and 0.1647 g (49.5%) of the title compound (37) and 0.1544 g of the title compound (38). (46.4%) was obtained.

Example 8 (1′R, 2 ″ R, 5R, 6S) -1- (1′-te
rt-Butyldimethylsilyloxyethyl) -2-
[2 ″-(5 ″ -oxo) oxolanyl] penem-
3-carboxylic acid allyl ester (39) and (1'S,
2 "R, 5S, 6R) -6- (1'-tert-butyldimethylsilyloxyethyl) -2- [2"-
(5 ″ -oxo) oxolanyl) penem-3-carboxylic acid allyl ester (40)

[Chemical formula 67]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ S, 2 ″ ″ R, 3R, 4S) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -3- (1 ″ -tert-butyldimethylsilyloxyethyl) -4- [2 ″ ″-
(5 ″ ″-oxo) oxolanoylthio] -2-azetidinone (26) (0.162 g, 0.22 mmol)
A mixture of toluene and toluene (50 ml) was treated in the same manner as in Example 1 to obtain 23 mg (23%) of the title compound (39) and 30 mg (30%) of the title compound (40).

Example 9 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester ( 41)

[Chemical 68]

(1'R, 2 ''S, 5R, 6S) -6-
(1'-tert-Butyldimethylsilyloxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-
3-Carboxylic acid allyl ester (30) (0.176
g, 0.40 mmol), acetic acid (201 μl) and tetra-n-butylammonium fluoride (1.2 ml of a 1M solution in tetrahydrofuran) were treated in the same manner as in Reference Example 15 to give 0.105 g (86) of the title compound (41). %)Obtained.

Example 10 (1′R, 2 ″ R, 5R, 6S) -6, (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester ( 42)

[Chemical 69]

(1'R, 2''R, 5R, 6S) -6-
(1'-tert-Butyldimethylsilyloxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-
3-Carboxylic acid allyl ester (31) (1.12 g,
2.55 mmol), acetic acid (128 ml) and tetra-
n-Butylammonium fluoride (1M solution in tetrahydrofuran, 7.64 ml) was treated in the same manner as in Reference Example 15 to obtain 0.877 g of the title compound (42).

Example 11 (1′R, 3 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester ( 43)

[Chemical 70]

(1'R, 3 ''S, 5R, 6S) -6-
(1′-tert-Butyldimethylsilyloxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-
3-Carboxylic acid allyl ester (32) (0.200
g, 0.45 mmol), acetic acid (0.228 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.36 ml) were treated in the same manner as in Reference Example 15 to give the title compound (43) as 0 .131 g (89
%)Obtained.

Example 12 (1′R, 3 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester ( 44)

[Chemical 71]

(1'R, 3''R, 5R, 6S) -6-
(1′-tert-Butyldimethylsilyloxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-
3-Carboxylic acid allyl ester (33) (0.200
g, 0.45 mmol), acetic acid (0.228 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.36 ml) were treated in the same manner as in Reference Example 15 to give the title compound (44) as 0 .149 g was obtained.

Reference Example 17 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid allyl ester (45)

[Chemical 72]

(1'R, 2 ''S, 5R, 6S) -6-
(1'-tert-Butyldimethylsilyloxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-
3-Carboxylic acid allyl ester (34) (0.189
g, 0.42 mmol), acetic acid (0.21 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.25 ml) were treated in the same manner as in Reference Example 15 to give the title compound (45) as 0 .131 g (92
%)Obtained.

Example 14 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid allyl ester (46)

[Chemical formula 73]

(1'R, 2''R, 5R, 6S) -6-
(1′-tert-Butyldimethylsilyloxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-
3-Carboxylic acid allyl ester (35) (0.194
g, 0.428 mmol), acetic acid (0.21 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.28 ml) were treated in the same manner as in Reference Example 15 to give the title compound (46) as 0 .133 g (92
%)Obtained.

Example 15 (1′R, 2 ″ S, 5R, 6S and 1′R, 2 ″)
R, 5R, 6S) -6- (1'-hydroxyethyl)-
2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (47)

[Chemical 74]

(1'R, 2 ''S, 5R, 6S and 1'
R, 2 ″ R, 5R, 6S) -6- (1′-tert-
Butyldimethylsilyloxyethyl) -2- (2 "-"
(Paladioxanyl) penem-3-carboxylic acid allyl ester (36) (0.163 g, 0.358 mmol),
Acetic acid (0.179 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.
(07 ml) was treated in the same manner as in Reference Example 15 to obtain the title compound (47) (0.120 g, 98%).

Example 16 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (48) )

[Chemical 75]

(1'R, 2 ''S, 5R, 6S) -6-
(1'-tert-Butyldimethylsilyloxyethyl) -2- (2'-paradioxanyl) penem-3-carboxylic acid allyl ester (37) (0.165 g, 0.
361 mmol), acetic acid (0.18 ml) and tetra-
The n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.08 ml) was treated in the same manner as in Reference Example 15 to obtain 0.109 g (88%) of the title compound (48).

Example 17 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (49) )

[Chemical 76]

(1'R, 2''R, 5R, 6S) -6-
(1′-tert-Butyldimethylsilyloxyethyl) -2- (2 ″ -paradioxanyl) penem-3-
Carboxylic acid allyl ester (38) (0.154 g,
0.339 mmol), acetic acid (0.17 ml) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 1.02 ml) were treated in the same manner as in Reference Example 15 to give 0.111 g of the title compound (49). (95.7
%)Obtained.

Example 18 (1'R, 2 "R, 5R, 6S) -6- (1'-Hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid allyl ester (50)

[Chemical 77]

(1'R, 2''R, 5R, 6S) -6-
(1'-tert-Butyldimethylsilyloxyethyl) -2- [2 "-(5" -oxo) oxolanyl] penem-3-carboxylic acid allyl ester (39)
(23 mg, 0.05 mol), acetic acid (0.035 ml)
And tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 0.21 ml) in Reference Example 15
13 mg (76 mg) of the title compound (50)
%)Obtained.

Example 19 (1'S, 2 "R, 5S, 6R) -6- (1'-hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid allyl ester (51)

[Chemical 78]

(1'R, 2''R, 5S, 6R) -6-
(1′-tert-Butyldimethylsilyloxyethyl) -2- [2 ″-(5 ″ -oxo) oxolanyl] penem-3-carboxylic acid allyl ester (40)
(30 mg, 0.066 mmol), acetic acid (0.35 μ
1) and tetra-n-butylammonium fluoride (1M solution in tetrahydrofuran, 0.5 ml) in Reference Example 1
In the same manner as in 5, perform 15 mg (6) of the title compound (51).
7%) was obtained.

Example 20 (1'R, 2''R, 3S, 4R and 1'R, 2 '')
S, 3S, 4R and 1'S, 2 "R, 3R, 4S and 1'S, 2" S, 3R, 4S) -6- (1'-hydroxyethyl) -2- (2 "'- Tetrahydrofuranyl)
Penem-3-carboxylic acid allyl ester (52)

[Chemical 79]

(1 ″ R, 2 ″ ″ R, 3S, 4R and 1 ″ R, 2 ″ ″ S, 3S, 4R and 1 ″ S,
2 ″ ″ R, 3R, 4S and 1 ″ S, 2 ″ ″ S, 3
R, 4S) -1- (1′-allyloxycarbonyl-
2'-Triphenylphosphoranylidenemethyl) -3-
(1 ″ -hydroxyethyl) -4- (2 ″ -tetrahydrofuranoylthio) -2-azetidinone (27)
(0.666 mg, 1.10 mmol) and toluene (7
The mixture (0 ml) was treated as in Example 1 to obtain 346 mg (97%) of the title compound (52).

Example 18 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester ( 42)

[Chemical 80]

(1 "R, 2""R, 3S, 4R)-
1- (1′-allyloxycarbonyl-2′-triphenylphosphoranylidenemethyl) -3- (1 ″ -hydroxyethyl) -4- (2 ″ ″-tetrahydrofuranoylthio) -2-azetidinone (28 ) (1.03 g,
A mixture of 1.71 mmol) and toluene (100 ml) was treated as in Example 1 to give the title compound (42) at 0.
Obtained 500 g (91%).

Example 19 (1'R, 2 "S, 5R, 6S) -6- (1'-Hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid allyl ester (53) and (1'S, 2 "S, 5S, 6R) -6-
(1'-hydroxyethyl) -2- [2 "-(5""
-Oxo) oxolanyl] penem-3-carboxylic acid allyl ester (54)

[Chemical 81]

(1 ″ R, 2 ″ ″ S, 3R, 4S and 1 ″ S, 2 ″ ″ S, 3S, 4R) -1- (1′-allyloxycarbonyl-2′-triphenyl) Phosphoranilidenemethyl) -3- (1 ″ -hydroxyethyl)-
A mixture of 4- [2 ″ ″-(5 ″ ″-oxy) oxolanylthio] -2-azetidinone (29) (0.060 g) and toluene (20 ml) was treated as in Example 1 to give the title compound ( 53) and 10 mg (30%) of the title compound (54) were obtained (5%, 15%).

Example 20 (1'R, 2''R, 5R, 6S and 1'R, 2 '')
S, 5R, 6S and 1'S, 2 "R, 5S, 6R and 1'S, 2" S, 5S, 6R) -6- (1'-hydroxyethyl) -2- (2 "'- Tetrahydrofuranyl)
Penem-3-carboxylic acid potassium salt (55) and (1 '
R, 2 ″ S, 5R, 6S and 1 ′S, 2 ″ R, 5
S, 6R) -6- (1'-hydroxyethyl) -2-
(2 ″ -Tetrahydrofuranyl) penem-3-carboxylic acid potassium salt (56)

[Chemical formula 82]

(1'R, 2''R, 3S, 4R and 1 '
R, 2 ″ S, 3S, 4R and 1 ′S, 2 ″ R, 3
R, 4S and 1'S, 2 "S, 3R, 4S) -6-
(1'-Hydroxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (52) (43 mg, 0.13 mmol), triphenylphosphine (33 mg) and palladium tetrakistriphenylphosphine A mixture of (3.3 mg) was dissolved in methylene chloride (0.4 ml), and 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, with stirring at room temperature).
0.4 ml) was added. After 1 hour, the mixture was mixed with acetone (2
ml) was added and the insoluble matter was filtered off. Insoluble matter is acetone,
It was washed successively with ether and dried in a vacuum desiccator, (1'R, 2''R, 5R, 6S and 1'R,
2 ″ S, 5R, 6S and 1 ″ S, 2 ″ R, 5S, 6
R and 1'S, 2 ''S, 5S, 6R) -6- (1'-
Hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt (55)
(1′R, 2 ″ R, 5R, 6S and 1 ′S, 2 ″
23.5 mg (55.8%) of S, 5S, 6R / 1'R, 2 ''S, 5R, 6S and 1'S, 2''R, 5S, 6R = 3/1 mixture as colorless powder. )Obtained. The crystals obtained as the 2nd crystal from the filtrate were collected by filtration, dried in a vacuum desiccator (1'R, 2 "S, 5R, 6S and 1'S, 2" R, 5S, 6R). -6 mg of -6- (1'-hydroxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-3-carboxylic acid potassium salt (56) was obtained as colorless powder (93%).

Example 24 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt ( 57)

[Chemical 83]

(1'R, 2''R, 5R, 6S) -6-
(1'-hydroxyethyl) -2- (2 ''-tetrahydrofuranyl) penem-carboxylic acid allyl ester (4
2) (0.500 g, 1.54 mmol), triphenylphosphine (0.0384 g), palladium tetrakistriphenylphosphine (0.0384 g) and 2-
The ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 3.1 ml) was treated in the same manner as in Example 20 to obtain 96 mg (19.3%) of the title compound (57).

Reference Example 19 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid potassium salt (58)

[Chemical 84]

(1'R, 2 ''S, 5R, 6S) -6-
(1'-hydroxyethyl) -2- (2 ''-tetrahydropyranyl) penem-3-carboxylic acid allyl ester (45) (48.7 mg, 0.144 mmol), triphenylphosphine (1 mg), palladium tetrakis Triphenylphosphine (1 mg) and 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 0.2
8 ml) in the same manner as in Example 20 to give the title compound (5
8) was obtained (14.2 mg, 29.2%).

Reference Example 20 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid potassium salt (59)

[Chemical 85]

(1'R, 2''R, 5R, 6S) -6-
(1′-hydroxyethyl) -2- (2 ″ -tetrahydropyranyl) penem-3-carboxylic acid allyl ester (46) (43.8 mg), triphenylphosphine (1 mg), palladium tetrakistriphenylphosphine (1 mg ) And 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 0.25 ml) were treated as in Example 20 to give the title compound (59) at 13.8 m.
g (31.7%) was obtained.

Example 22 (1'R, 2 "S, 5R, 6S) -6- (1'-hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid potassium salt (6
0)

[Chemical 86]

(1'R, 2 ''S, 5R, 6S) -6-
(1'-hydroxyethyl) -2- [2 "-(5""
-Oxo) oxolanyl] penem-3-carboxylic acid allyl ester (53) (10 mg, 0.029 mmol), triphenylphosphine (0.2 mg), palladium tetrakistriphenylphosphine (0.2 mg)
And 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 0.06 ml) were treated in the same manner as in Example 20 to obtain 3 mg (30%) of the title compound (60).

Example 28 (1'R, 2 "R, 5R, 6S) -6- (1'-hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid potassium salt (6
1)

[Chemical 87]

(1'R, 2''R, 5R, 6S) -6-
(1'-hydroxyethyl) -2- [2 "-(5""
-Oxo) oxolanyl] penem-3-carboxylic acid allyl ester (50) (15 mg, 0.044 mmol), triphenylphosphine (0.2 mg), palladium tetrakistriphenylphosphine (0.2 mg)
And 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 0.1 ml) were treated in the same manner as in Example 20 to obtain 6 mg (40%) of the title compound (61).

Example 24 (1'S, 2 "R, 5S, 6R) -6- (1'-hydroxyethyl) -2- [2"-(5 "-oxo) oxolanyl] penem-3 -Carboxylic acid potassium salt (6
2)

[Chemical 88]

(1'S, 2''R, 5S, 6R) -6-
(1'-hydroxyethyl) -2- [2 "-(5""
-Oxo) oxolanyl] penem-3-carboxylic acid allyl ester (51) (4.9 mg, 0.015 mmol), triphenylphosphine (0.1 mg), palladium tetrakistriphenylphosphine (0.1 mg)
And 2-ethylhexanoic acid potassium salt (0.5 M solution in ethyl acetate, 0.004 ml) were treated in the same manner as in Example 20 to obtain 2.7 mg (55%) of the title compound (62).

Example 25 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt ( 63)

[Chemical 89]

(1'R, 2 ''S, 5R, 6S) -6-
A mixture of (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (41) (20 mg, 0.061 mmol) and palladium tetrakistriphenylphosphine (1.4 mg). Dissolved in tetrahydrofuran (0.8 mg),
Tri-n-butyltin hydride (20
μl) was added. After 25 minutes, acetic acid (4 μl) was added and the mixture was further stirred for 10 minutes. Concentrate under reduced pressure and add water (3 m
1) and ethyl acetate (2 ml) were added. With stirring, 2M potassium hydrogen carbonate was added dropwise to the mixture to adjust the pH to 8.1. The organic was extracted three times with water, and the aqueous layers were combined and washed with ethyl acetate. The aqueous layer was freeze-dried and the resulting residue was X
Purified by column chromatography using AD-2 (9 ml) to give the title compound (63) as a colorless powder.
Obtained 8 mg (44%).

Example 26 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt ( 57)

[Chemical 90]

(1'R, 2''R, 5R, 6S) -6-
(1′-hydroxyethyl) -2- (2 ″ tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (42) (0.87 mg, 2.70 mmol), palladium tetrakistriphenylphosphine (62 mg),
Tri-n-butyltin hydride (0.87 ml) and acetic acid (0.18 ml) were treated in the same manner as in Example 25 to give the title compound (57) 0.330 g (38%).

Example 27 (1′R, 3 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-3-carboxylic acid potassium salt ( 64)

[Chemical Formula 91]

(1'R, 3 ''S, 5R, 6S) -6-
(1'-Hydroxyethyl) -2- (3 ''-tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (43) (80 mg, 0.25 mmol), palladium tetrakistriphenylphosphine (5.6 mg), tri -N-Butyltin hydride (0.079 ml) and acetic acid (17 µl) were treated in the same manner as in Example 25 to obtain 51 mg (64%) of the title compound (64).

Example 28 (1'R, 3''R, 5R, 6S) -6- (1'-hydroxyethyl) -2- (3 ''-tetrahydrofuranyl) penem-3-carboxylic acid potassium salt ( 65)

[Chemical Formula 92]

(1'R, 3''R, 5R, 6S) -6-
(1'-Hydroxyethyl) -2- (3 ''-tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (44) (80 mg, 0.25 mmol), palladium tetrakistriphenylphosphine (5.6 mg), tri -N-Butyltin hydride (0.079 ml) and acetic acid (17 µl) were treated in the same manner as in Example 25 to obtain 60 mg (75%) of the title compound (65).

Example 29 (1′R, 2 ″ S, 5R, 6S and 1′R, 2 ″)
R, 5R, 6S) -6- (1'-hydroxyethyl)-
2- (2 ″ -paradioxanyl) penem-3-carboxylic acid potassium salt (66)

[Chemical formula 93]

(1'R, 2 ''S, 5R, 6S and 1'
R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (3 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester (47) (85 m
g, 0.249 mmol), palladium tetrakistriphenylphosphine (5.4 mg), tri-n-butyltin hydride (78 μl) and acetic acid (16.2 μl) were treated in the same manner as in Example 25 to give the title compound (66). ) To 14
mg (16.6%) was obtained.

Example 30 (1′R, 2 ″ S, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid potassium salt (67) )

[Chemical 94]

(1'R, 2 ''S, 5R, 6S) -6-
(1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (4
8) (108.8 mg, 0.318 mmol), palladium tetrakistriphenylphosphine (6.9 m
g), tri-n-butyltin hydride (100 μl) and acetic acid (20.7 μl) were operated as in Example 25,
77 mg (71.3%) of the title compound (67) was obtained.

Example 31 (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid potassium salt (68 )

[Chemical 95]

(1'R, 2''R, 5R, 6S) -6-
(1′-hydroxyethyl) -2- (2 ″ -paradioxanyl) penem-3-carboxylic acid allyl ester (4
9) (110.7 mg, 0.324 mmol), palladium tetrakistriphenylphosphine (7 mg), tri-n-butyltin hydride (0.101 ml) and acetic acid (21 μl) were treated in the same manner as in Example 25. 59 mg (53.4%) of compounds (68) were obtained.

Physical property data of the compounds obtained above are shown in Tables 1 to 1.
The results are shown in Table 10.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10] [Measurement of minimum inhibitory concentration (MIC)]

The minimum inhibitory concentration (MIC) of the present invention was determined by the agar plate dilution method according to the Japan Chemotherapy Society MIC measurement standard method. The inoculum was 10 ⁶ colony forming units, and the minimum concentration that inhibits growth after culturing at 37 ° C. for 18 hours was defined as μg / ml in the table.

[Therapeutic Effect in Experimental Infectious Diseases in Mice] Among the novel compounds obtained by the present invention, compound 57 was subjected to a therapeutic experiment in infected animals. ICR male mice (5 weeks old, weight 23-27 g) were used as animals, and S. aureus Smith or E. Col
i KC-14 was inoculated intraperitoneally and 2 hours later, compound 57
Was subcutaneously or orally administered, and the survival effect of the mice was observed 5 days later to compare the therapeutic effects.

(Subcutaneous administration) aureus Smit
Mice infected with h (5.7 × 10 ⁵ colony forming units) all survived in the group treated with compound 57 at 1.6 mg / kg or more. Also, E. coli
Mice infected with KC-14 3.1 × 10 ⁵ (colony forming units) were all surviving in the group administered with compound 57 at 2.6 mg / kg or more, 1.5 mg.
In the group administered with / kg, 3 out of 5 animals survived.

(Oral administration) S. aureus Smit
h mice were infected with 3.6 × 10 ⁵ (CFU / head), all of which survived in the group administered with Compound 57 at 9.6 mg / kg or more, and 5 mice in the group administered with 3.9 mg / kg Three survived. Also, E. C
oli KC-14 1.5 × 10 ⁵ (CFU / hea
12.5 m of compound 57 in mice infected by d)
All groups survived in the g / kg or higher dose groups.

For subcutaneous administration, a maximum of 50 mg / k
The maximum oral dose was 70 mg / kg. Furthermore, the minimum inhibitory concentration (MIC) of the following compounds was also measured.

Compound a: (1'R, 5R, 6S and 1'S, 5S, 6R) -2-
(2 ″ -furanyl) -6- (1′-hydroxyethyl) penem-3-carboxylic acid potassium salt

[Chemical 96]

Compound b: (1'R, 5R, 6S and 1'S, 5S, 6R) -2-
(3 ″ -furanyl) -6- (1′-hydroxyethyl) penem-3-carboxylic acid potassium salt

[Chemical 97]

Compound c: (1'R, 5R, 6S and 1'S, 5S, 6R) -6-
(1'-hydroxy) -2- (3 ''-thiophenemethyl) penem-3-carboxylic acid potassium salt

[Chemical 98]

[0187]

[Table 11]

[Table 12]

Claims (10)

[Claims] 1. A general formula: (In the formula, R is hydrogen or an allyl group; Represents a tetrahydropyranyl group. ) Or a pharmacologically acceptable salt thereof. 2. R is hydrogen, an allyl group, or --COOR
A compound according to claim 1, wherein is a carboxyl group in the form of a sodium, potassium or calcium salt. 3. The compound according to claim 1 or 2, which is an optically active substance. 4. A penem ring, wherein the carbon at the base of the hydroxy group of the 6-position hydroxyethyl group is in the R configuration and has a 5R, 6S configuration in the penem ring.
And the compound according to the third item. 5. A general formula: (In the formula, R is hydrogen or an allyl group, and Represents a tetrahydropyranyl group. In preparing a penem derivative having), or a pharmacologically acceptable salt thereof, a compound represented by the general formula: (Group in the formula: Represents the same meaning as described above, R ¹ is a hydroxyl-protecting group, R ¹ is
² is an allyl group or a carboxyl group-protecting group, and Z is an aryl group), and a phosphorus ylide compound having a general formula: (Wherein R ¹ , R ² and Represents the same meaning as described above), and then, if desired, the compound obtained is converted into a hydroxyl-protecting group R ¹
To remove the protective group R ² for the carboxyl group and restore the hydroxyl group and the carboxyl group respectively, and further to react with a pharmacologically acceptable base to form a salt thereof if necessary. A method for producing a characteristic penem derivative and a pharmacologically acceptable salt thereof. 6. A penem derivative having a general formula: ## STR3 ## wherein R represents hydrogen or an allyl group, and tetrahydropyranyl group, or a pharmacologically acceptable salt thereof. In the production, the general formula: (Wherein R ¹ , R ² , Z and the group: Has the same meaning as described above), and the protecting group R ¹ for the hydroxyl group of the phosphorus-ylide compound is removed, and the mixture is heated to give a compound represented by the general formula: (Wherein R ² and the group Represents the same meaning as described above), and further, if desired, the compound is subjected to a reaction of removing the protecting group R ² for the carboxyl group of the obtained compound and restoring the carboxyl group, and further, if necessary, a drug A method for producing a penem derivative, which comprises reacting with a physically acceptable base to form a salt thereof, and a pharmacologically acceptable salt thereof. 7. A general formula: (In the formula, R ¹ is a hydroxyl protecting group, R ² is an allyl group or a carboxyl group, Z is an aryl group, and Represents a tetrahydropyranyl group. ) With
By heating the ylide compound, a compound of the general formula: (Wherein R ¹ , R ² and the group: Represents the same meaning as described above), and if necessary, is optically resolved by one or more purification means selected from the group consisting of recrystallization, column chromatography or dispersion thin layer chromatography. And then removing the hydroxyl-protecting group R ¹ and the carboxyl-protecting group, and further reacting with a pharmacologically acceptable base, if necessary. A process for producing the optically active penem derivative described above or a pharmacologically acceptable salt thereof. 8. A general formula: (In the formula, R ¹ is a hydroxyl protecting group, R ² is an allyl group or a carboxyl group, Z is a triarylphosphonio group, and Represents a tetrahydropyranyl group. ) With
After removing the protective group R ¹ for the hydroxyl group of the ylide compound, it is optically resolved using one or more purification means selected from the group consisting of recrystallization, column chromatography or preparative thin layer chromatography, and then heated. General formula: (Wherein R ² and the group The compound having the same meaning as above), and then removing the protecting group of the carboxyl group, and further treating with a pharmacologically acceptable base, if necessary. Alternatively, a method for producing the optically active penem derivative or the salt thereof according to item 6. 9. A general formula: (In the formula, R is hydrogen or an allyl group, and Represents a tetrahydropyranyl group. The antibacterial agent which has as an active ingredient the penem derivative which has these, or its pharmacologically acceptable salt. 10. The antibacterial agent according to claim 8, wherein the daily dose contains 50 mg to 5 g of the active ingredient.