JPH0710883A - Production of gamma-lactam derivative - Google Patents

Abstract

PURPOSE:To carry out the ring enlarging reaction of the beta-lactam ring and simply and readily obtain the subject compound useful as an antimicrobial agent or its synthetic raw material by removing a carboxylic acid-protecting group in a specific beta-lactam derivative. CONSTITUTION:A carboxylic acid-protecting group R<1> of a beta-lactam derivative expressed by formula I [R<1> and R<2> are protecting group of carboxylic acid; the dotted line indicates the presence or absence) of bond; when the bond is absent, R<3> and R<4> are methyl and when the bond is present, R<3> is tetrahydrofuryl or tetrahydrofurylmethyl and R<4> is absent] to afford the objective compound expressed by formula II. Specifically, e.g. when R<1> is trichloroethvl, zinc dust is reacted therewith in a solvent such as THF. Furthermore, the compound expressed by formula I is obtained by using, e.g. (1'R,2'R,3S,4R)3-(1'-tert- butyldimethylsilyloxyethyl)-4-(2'-tetrahydrofurylca.rbonylthio)azetidi none expressed by formula III as a starting raw material.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a novel γ-lactam derivative obtained by a ring expansion reaction of a β-lactam ring.

[0002]

2. Description of the Related Art Currently, β-lactam compounds are used as antibacterial agents.
It is a very important compound, but the emergence of resistant bacteria
There is. Therefore, in order to obtain an effective antibacterial agent against this resistant bacterium
Various developments have been made from β-lactam compounds
However, among them, similar structure compounds of β-lactam compound
Since then, γ-lactam compounds have been attracting attention, and their synthesis and antibacterial
The activity was evaluated and those showing antibacterial activity were reported.
(Tetrahedron,45(1989)
p. 4537-4550). In addition, a γ-lactam compound
The synthetic method of J. Chem. Soc. Chem.
Commun. , (1988) p. 110-111 etc.
As illustrated, by ring expansion from a β-lactam compound.
Method, or J. Chem. Soc. , Pe
rkin Trans. ，I(1986) p. 2195
-At the 3rd position of azetidinone as illustrated in 2198 etc.
Methods such as utilizing the transfer reaction of compounds with azido groups are known.
Has been. Other synthetic methods include, for example, The Jo
urn of of Antibiotics,44
[1] (1991) p. 1-24. Shi
However, conventional methods for synthesizing γ-lactam compounds are complicated.
And the number of γ-lactam compounds obtained is small.
Γ-lactam compounds with sufficient antibacterial activity have not yet been found.
It has not been served. Meanwhile, Sheehan et al.
The protecting group for the carboxylic acid at the 6-position of the ring is a benzyl group and the protecting group at the 2-position is
The protecting group for rubonic acid is a trichloroethyl group, and a di-
Hydrogenolysis of a compound having a methyl group under Pd / C catalyst
By deprotecting the carboxylic acid at the 6-position, β
-Reporting to give lactam compounds (JO
rg. Chem. ，42[25] (1977) p. 40
45-4048), which decomposes into a γ-lactam compound
I have not reported anything to do. Under such circumstances, a simple γ-
It has been earnestly desired to provide a synthetic method for lactam compounds.

[0003]

The present invention provides a simple and easy method for producing a γ-lactam derivative useful as an antibacterial agent or a raw material for its synthesis.

[0004]

The present invention provides the formula (I):

[Chemical 3] (In the formula, R ¹ and R ² represent the same or different carboxylic acid protecting groups, the dotted line indicates the presence or absence of a bond, and when the bond does not exist, R ³ and R ⁴ represent a methyl group. And when a bond is present, R ³ represents a tetrahydrofuryl group or a tetrahydrofurylmethyl group,
R ⁴ is absent) by removing the protecting group R ¹ of the carboxylic acid of the compound represented by formula (II) obtained with the decomposition of the β-lactam ring:

[Chemical 4] (In the formula, R ² , R ³ , R ⁴ and the dotted line have the meanings described above).

The γ-lactam derivative represented by the formula (II) has the formula (III): by removing the protecting group R ² of the carboxylic acid.

[Chemical 5] (Wherein R ³ , R ⁴ and the dotted line have the above-mentioned meanings, Z
Represents a hydrogen atom or an alkali metal such as sodium or potassium) and can be converted into a γ-lactam derivative.

The γ-lactam derivative represented by the formula (II) has the formula (IV):

[Chemical 6] (In the formula, R ⁵ represents a hydrogen atom, a furylmethyl group or a benzyl group) to react with an amine represented by the formula (V):

[Chemical 7] (Wherein R ² , R ³ , R ⁴ , R ⁵ and the dotted line have the above-mentioned meanings), and a γ-lactam derivative represented by the formula (V) can be obtained. - lactam derivatives of the formula by removing the protecting group R ² in the carboxylic (VI):

[Chemical 8] (In the formula, R ³ , R ⁴ , R ⁵ , Z and the dotted line have the above-mentioned meanings), and can be converted into a γ-lactam derivative.

In the γ-lactam derivative of the present invention, R
¹ may be any carboxylic acid protecting group that does not affect the γ-lactam ring, R ² , R ³ and R ⁴ , and examples thereof include an allyl group, a trichloroethyl group, a methyl group,
Examples thereof include a benzyl group and a tert-butyl group. Protecting group of a carboxylic acid represented by R ^2, when the compound of interest is a γ- lactam derivative represented by the formula (III) may be those which can be removed under the same conditions as R ^1, such as allyl Group, trichloroethyl group, methyl group,
Examples thereof include a benzyl group and a tert-butyl group, but when the target compound is a γ-lactam derivative represented by the formula (II), a protecting group that is not affected by the removal conditions of R ¹ Must be For example, when the carboxylic acid protecting group represented by R ¹ is a trichloroethyl group, a benzyl group, an allyl group, or the like, and when the carboxylic acid protecting group represented by R ¹ is a methyl group, a benzyl group Etc. are preferred.

The reaction for converting the β-lactam derivative represented by the formula (I) into the γ-lactam derivative represented by the formula (II) can be carried out by a known deprotection method of carboxylic acid, and is particularly limited. Instead, the reaction reagent may be appropriately selected and performed depending on the type of the β-lactam derivative that is the starting material. Examples of the reaction reagent include zinc dust when the carboxylic acid protecting group represented by R ¹ is a trichloroethyl group, iodotrimethylsilane when it is a methyl group or a benzyl group, and tetrakistris when it is an allyl group. A transesterification reaction using a palladium catalyst such as phenylphosphine palladium and an allyl group acceptor such as 2-ethylhexanoic acid or a salt thereof, or trifluoroacetic acid in the case of a tert-butyl group can be used. The solvent used in the reaction depends on the type of β-lactam derivative and the reagent used,
It may be appropriately selected, for example, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and diethyl ether, ethyl acetate, dimethylformamide, dimethylsulfoxide, water or a mixture thereof. The dose of the reagent is exemplified and can be appropriately selected depending on the type of reaction, and is used in a large excess from 5 mol%. The reaction temperature is represented by the formula (I)
It depends on the kind of the protecting group of the carboxylic acid of the compound represented by
~ Room temperature.

The γ-lactam derivative represented by the formula (II) includes hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran and diethyl ether, ethyl acetate and dimethylformamide, By reacting an amine represented by the formula (IV) in the presence of a base in a solvent such as dimethyl sulfoxide, water or a mixture thereof,
It can be converted into a γ-lactam derivative represented by the formula (V). Examples of the base used in this reaction include pyridine, dimethylaminopyridine, triethylamine and the like, and as a condensing agent, bromotris-pyrrolidinophosphonium hexafluorophosphate, N, N′-dicyclohexylcarbodiimide (DCC), N-ethyl. Examples include -N'-diethylaminoethylcarbodiimide, N-ethyl-N'-dimethylaminopropylcarbodiimide, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and acid addition salts thereof. To be done. In the reaction, usually 100 to 150 mol% of the amine (IV) and 100 to 150 mol% of the condensing agent are used with respect to the γ-lactam derivative (II), and the base is appropriately selected in dose and kind depending on the condensing agent used. It is usually selected and used in an amount of 0 to 150 mol%. The reaction temperature is generally in the range of -20 ° C to 50 ° C, preferably 0 ° C to room temperature.

The γ-lactam derivatives represented by the formulas (II) and (V) can be converted into the γ-lactam derivatives represented by the formulas (III) and (VI) by deprotection of the carboxylic acid, respectively. it can. The deprotection method can be carried out by a known method, for example, the above-mentioned formula (I)
The β-lactam derivative represented by the formula (II) can be converted into the γ-lactam derivative represented by the formula (II) by the method exemplified in the reaction.

[0011]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Reference Example 1 Synthesis of (2'R, 4R) -3-ethylidene-4- (2'-tetrahydrofurylcarbonylthio) -1-tert-butyldimethylsilylazetidinone (2):

[Chemical 9] (1'R, 2'R, 3S, 4R) -3- (1'-ter
t-butyldimethylsilyloxyethyl) -4- (2 '
-Tetrahydrofurylcarbonylthio) azetidinone (1) in a solution of 70.0 g in methanol under ice-cooling 4NH
160 ml of Cl / dioxane solution was added and stirred for 2.5 hours. This solution was poured into an aqueous solution of NaHCO ₃ (50 g) (500 ml) and extracted with ethyl acetate. Anhydrous M
After drying with gSO ₄ , the solvent was distilled off, and the residue containing the desired product 4
0.1 g was obtained. This was dissolved in 320 ml of methylene chloride and tert-butyldimethylsilyl chloride 3
2 mg and triethylamine (29 ml) were added, and the mixture was stirred at room temperature for 9 hours. The mixture was poured into water and extracted with ethyl acetate, and the obtained organic layer was washed with KHSO ₄ solution, NaHCO ₃ aqueous solution, and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 62.1 g of a residue containing the desired product. The compound thus obtained was converted into methylene chloride (170 m
l) and dissolved in methanesulfonyl chloride (1
3.1 ml) and triethylamine (23.6 ml) were sequentially added. After 20 minutes, the mixture was diluted with ethyl acetate, and the organic layer was washed with KHSO ₄ solution, NaHCO ₃ aqueous solution, and saturated saline. After washing with anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography to obtain 29.5 g of the objective compound (2).

NMR (CDCl ₃ / TMS, δpp
m): 0.21 (s, 3H), 0.26 (s, 3H),
0.921 (s, 9H), 1.69 (d, 3H, J = 7
Hz), 1.90-2.40 (m, 4H), 3.90-
4.15 (m, 2H), 4.50 (dd, 1H, J = 4
Hz, 8 Hz), 5.90 (s, 1H), 6.19
(Q, 1H, J = 6Hz)

Reference Example 2 (2'R, 4R) -3- (2,2,2-trichloroethoxycarbonylmethylene) -4- (2'-tetrahydrofurylcarbonylthio) -1-tert-butyldimethylsilylazetidinone Synthesis of (3):

[Chemical 10] To a solution of 50.3 g of the compound (2) obtained in Reference Example 1 in ether (500 ml) was added 0.25M phosphate buffer (500 ml), NaIO ₄ (97 g), OsO.
₄ (2.5 g) were added sequentially. After stirring at room temperature for 2.5 hours, the aqueous layer was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 34.9 g of 48.9 g of the resulting residue, which was added to this methylene chloride (204 ml) solution at room temperature with triphenyl ether. Phosphoranilidene acetic acid 2,2,2-trichloroethyl ester (46.1 g) was added, and the mixture was stirred for 1 hour.
After evaporating the solvent, the residue was purified by silica gel column chromatography to obtain 16.7 g of the target compound (3) as a mixture of two isomers.

NMR (CDCl ₃ / TMS, δpp
m): Isomer A 0.26 (s, 3H), 0.29 (s, 3H), 0.9
9 (s, 9H), 1.90-2.40 (m, 4H),
3.90-4.20 (m, 2H), 4.45-4.55
(M, 1H), 4.85 (d, 1H, J = 2Hz),
5.81 (d, 1H, J = 1 Hz), 6.03 (d, 1
H, J = 1 Hz) NMR (CDCl ₃ / TMS, δppm): Isomer B 0.25 (s, 3H), 0.29 (s, 3H), 0.9
8 (s, 9H), 1.85-2.00 (m, 2H),
2.10-2.40 (m, 2H), 3.90-4.00
(M, 2H), 3.50-3.60 (m, 1H), 4,
67 (d, 1H, J = 12 Hz), 4.86 (d, 1)
H, J = 12 Hz) 6.15 (d, 1H, J = 2H
z), 6.38 (d, 1H, J = 2Hz)

Reference Example 3 (2'R, 4R) -3- (2,2,2-trichloroethoxycarbonylmethyl) -4- (2'-tetrahydrofurylcarbonylthio) -1-tert-butyldimethylsilylazetidinone Synthesis of (4):

[Chemical 11] Tellurium powder (350 mg), NaBH ₄ (240 mg)
After heating the ethanol suspension of above under reflux for 15 minutes, -50
After cooling to 0 ° C., an ethanol solution of acetic acid (320 μl) was added, followed by an ethanol solution of 540 mg of the compound (3) obtained in Reference Example 2. After stirring for 15 minutes at the same temperature, pH
The phosphate buffer of 7 was added, and the aqueous layer was further extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to obtain the target compound (4) 23
8 mg was obtained. (Yield: 43%)

NMR (CDCl ₃ / TMS, δpp
m): as a mixture of two isomers [0.23 (s), 0.24 (s), 0.25 (s),
0.26 (s); 6H], 1.85-2.30 (m, 4
H), 2.73-3.10 (m, 2H), 3.90-
4.25 (m, 3H), 4.40-4.50 (m, 1
H), [4.71 (s), 4,75 (d, J = 3H
z); 2H], [5.10 (d, J = 2 Hz), 5.5.
3 (d, J = 7 Hz); 1H]

Reference Example 4 Synthesis of (2'R, 4R) -3- (2,2,2-trichloroethoxycarbonylmethyl) -4- (2'-tetrahydrofurylcarbonylthio) azetidinone (5)

[Chemical 12] A solution of 2.0 g of the compound (4) obtained in Reference Example 3 in acetonitrile (40 ml) was added to an aqueous HF solution (48%, 2.6%).
ml) was added at room temperature and stirred for 35 minutes. Na in the reaction solution
After adding HCO ₃ aqueous solution, it was extracted with methylene chloride.
The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel chromatography to obtain 1250 mg of the target compound (5). (yield:
81%)

NMR (CDCl ₃ / TMS, δpp
m): 1.90-2.10 (m, 3H), 2.20-2.40 as a mixture of two isomers.
(M, 1H) 2.85-3.15 (m, 2H), [3.
50-3.60 (m), 3.90-4.20 (m); 3
H], 4.40-4.50 (m, 1H), 4.70-
4.85 (m, 2H), [5.02 (d, J = 2H
z), 5.41 (d, J = 5HZ); 1H], [6.3.
0 (br.s), 6.40 (br.s); 1H]

Reference Example 5 (5R, 6R, 2'R) -6- (2,2,2-trichloroethyloxycarbonylmethyl) -2- (2, -tetrahydrofuryl) penem-carboxylic acid allyl ester (6) Synthesis of:

[Chemical 13] A compound (5) obtained in Reference Example 4 (534 mg) in a methylene chloride solution (1.6 ml) was added to allyl oxalyl chloride (247 µl) and triethylamine (28) at -20 ° C.
5 μl) was added. Immediately, an aqueous KHSO ₄ solution was added to the reaction solution, the organic layer was washed with water, and then dried over anhydrous sodium sulfate. 26 ml of xylene was added to the residue obtained by distilling off the solvent.
Triethyl phosphite (440 μl) was added, and the mixture was heated under reflux for 1 hr. The solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 95 mg of the target compound (6). (Yield: 15%)

IR (neat, cm ^-1 ): 1790,
1755, 1706, 1319 NMR (CDCl _{3 /} TMS, δppm): 1.80-
2.10 (m, 3H), 2.40-2.55 (m, 1
H), 3.10-3.35 (m, 2H), 3.80-
4.05 (m, 2H), 6.20-6.30 (m, 1
H), 4.60-5.90 (m, 4H), 5.25-
5.45 (m, 3H), 5.75 (m, 1H, J = 4H
z), 5.85-6.05 (m, 1H)

Reference Example 6 Synthesis of (2'R, 4R) -3- (allyloxycarbonylmethylene) -4- (2'-tetrahydrofurylcarbonylthio) -1-tert-butyldimethylsilylazetidinone (7):

[Chemical 14] The target compound (7) was synthesized in the same manner as in Reference Example 2 using 31.5 g of the compound (2) obtained in Reference Example 1.
Obtained 9.93 g. (Yield: 26%)

IR (neat, Cm ^-1 ): 1759,
1726, 1698 NMR (CDCl _{3 /} TMS, δppm): 0.24
(S, 3H), 0.28 (s, 3H), 0.98 (s,
9H), 1.84-2.00 (m, 2H), 2.11-
2.32 (m, 2H), 3.88-4.06 (m, 2)
H), 4.48-4.64 (m, 3H), 5.21-
5.34 (m, 2H), 5.81-5.98 (m, 1
H), 6.14 (s, 1H), 6.26 (s, 1H)

Reference Example 7 Synthesis of (2'R, 4R) -3- (allyloxycarbonylmethyl) -4- (2'-tetrahydrofurylcarbonylthio) -1-tert-butyldimethylsilylazetidinone (8):

[Chemical 15] The target compound (8) 6.94 was synthesized in the same manner as in Reference Example 3 using 9.93 mg of the compound (7) obtained in Reference Example 6.
g was obtained. (Yield: 88%)

IR (neat, cm ^-1 ): 1760,
1694 NMR (CDCl ₃ / TMS, δppm): [0.18-0.28 (s); 6H], 0.96 (s, as a mixture of two isomers.
9H), 1.82-2.32 (m, 4H), 2.60-
2.98 (m, 2H), [3.51 to 3.61 (m),
3.89-4.21 (m); 3H], 4.40-4.6.
2 (m, 3H), 5.15-5.37 (m, 2H),
[5.12 (d, J = 2.6 Hz), 5.52 (d, J
= 5.3 Hz); 1H], 5.81-6.00 (m, 1
H)

Reference Example 8 Synthesis of (2'R, 4R) -3- (allyloxycarbonylmethyl) -4- (2'-tetrahydrofurylcarbonylthio) azetidinone (9):

[Chemical 16] The target compound (9) was synthesized in the same manner as in Reference Example 4 using 3.94 g of the compound (8) obtained in Reference Example 7.
58 g were obtained. (Yield: 90%)

IR (neat, cm ^-1 ): 3283,
1774, 1734, 1684 NMR (CDCl ₃ / TMS, δppm): 1.86-2.35 (m, 4H), 2.69-3.00 as a mixture of two isomers.
(M, 2H), [3,48-3.56 (m), 3.90
-4.17 (m); 3H], 4.47 (dd, 1H, J
= 8.6 Hz, 4.6 Hz), 4.61 (d, 2H, J
= 5.3 Hz), 5.24 (d, 1H, J = 10.6H)
z), 5.33 (d, 1H, J = 17.2 Hz),
[4.99 (d, J = 10.6 Hz), 5.42 (d,
J = 5.3 Hz) 1H], 5.82-6.00 (m, 1
H), [6.23 (br.s), 6.35 (br.
s), 1H]

Reference Example 9 Synthesis of (2'R, 5R) -6-allyloxycarbonylmethyl-2- (2'-tetrahydrofuryl) penem-carboxylic acid allyl ester (10) and (11):

[Chemical 17] Compound (9) obtained in Reference Example 8 To a solution of 897 mg of methylene chloride (1.6 ml) was added allyl oxalyl chloride (533 µl) and triethylamine (61) at -20 ° C.
8 μl) was added. After stirring at the same temperature for 1 hour, the mixture was diluted with ethyl acetate and washed with an aqueous NaHCO ₃ solution and saturated saline. After drying over anhydrous sodium sulfate, the solvent was distilled off. Xylene (60 ml) and triethylphosphite (1.29 ml) were added to the obtained residue, and the mixture was heated under reflux for 3 hours.
The solvent was distilled off and the obtained residue was purified by silica gel chromatography to obtain the target compounds (10) and (11) 3.
Obtained 00 mg. (Yield: 24%)

Compound (10) IR (neat, cm ^-1 ): (5R, 6R) form 1790, 1731, 1703 NMR (CDCl ₃ / TMS, δppm): (5R, 6)
R) form 1.75-2.09 (m, 3H), 2.39-2.55
(M, 1H), 2.97 (dd, 1H, J = 4.6H
z, 17.2 Hz), 3.14 (dd, 1H, J = 1
1.9 Hz, 17.2 Hz), 3.80-4.04
(M, 2H), 4.15-4.24 (m, 1H), 4.
57-4.87 (m, 4H), 5.22-5.45
(M, 5H), 5.74 (d, 1H, J = 4.0H
z), 5.81-6.02 (m, 2H) compound (11) IR (neat, cm ^-1 ): (5R, 6S) body 1792, 1736, 1706 NMR (CDCl ₃ / TMS, δppm): ( 5R, 6
S) body 1.89-2.10 (m, 2H), 1.70-1.89
(M, 1H), 2.36-2.51 (m, 1H), 2.
80 (dd, 1H, J = 4.6Hz, 17.8Hz),
2.98 (dd, 1H, J = 11.2Hz, 17.8H
z), 3.79-4.09 (m, 3H), 4.55-
4.90 (m, 4H), 5.21-5.49 (m, 6
H), 5.81-6.04 (m, 2H)

Example 1 (5R, 6R, 2'R) -2-allyloxycarbonyl-8-oxo-3- (2'-tetrahydrofuryl) -1
-Aza-4-thiabicyclo [3.3.0] oct-2-
Synthesis of ene-6-carboxylic acid (12):

[Chemical 18] (5R, 6R, 2′R) -6- (2,2,2-trichloroethyloxycarbonylmethyl) -2- (2′-tetrahydrofuryl) penem-carboxylic acid allyl ester (6) 40 mg (0.085 mmol) In tetrahydrofuran solution (1 ml) of 1M KH ₂ PO ₄ (1 m
1) was added, and zinc dust (400 mg) was added thereto. Four
After stirring vigorously for 5 minutes at room temperature, 50% acetic acid-water (3 ml) was added, the insoluble matter was filtered off, and the product was directly purified by HPLC to obtain 4.6 mg of the title compound (12). (yield:
16%)

IR (film, cm ^-1 ): 1732
1716, 1374, 1325, 1259, 1188 NMR (CDCl _{3 /} TMS, δppm): 1.70-
2.10 (m, 3H), 2.35-2.50 (m, 1
H), 2.80-3.00 (m, 1H), 3.00-
3.15 (m, 1H), 3.60-4.10 (m, 3
H), 4.65-4.80 (m, 2H), 5.25-
5.50 (m, 3H), 5.90-6.50 (m, 2
H)

Example 2 (5R, 6R, 2'R) -2-allyloxycarbonyl-6-benzylaminocarbonyl-8-oxo-3-
Synthesis of (2'-tetrahydrofuryl) -1-aza-4-thiabicyclo [3.3.0] oct-2-ene (13):

[Chemical 19] 7 mg (0.02) of the compound (12) obtained in Example 1
mmol) in methylene chloride solution (0.2 ml) at room temperature in N-ethyl-N'-diethylaminoethylcarbodiimide hydrochloride (4.3 mg), benzylamine (2.5 m).
g), N-hydroxybenzotriazole (2.5 m
g) were sequentially added and stirred for 30 minutes. The mixture was diluted with ethyl acetate, washed successively with saturated KHSO ₄ , saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (13) (8 mg). (yield:
93%)

IR (film, cm ^-1 ): 3304,
2924, 1719, 1654, 1369, 1324,
1260, 1183 NMR (CDCl _{3 /} TMS, δppm): 1.65
2.10 (m, 3H), 2.30-2.45 (m, 1
H), 2.72 (dd, J = 16 Hz, 9 Hz), 3.
06 (dd, J = 16 Hz, 9 Hz), 3.49 (d
t, J = 9 Hz, 6 Hz), 3.80 (dd, J = 13)
Hz, 7 Hz), 3.93 (dd, J = 15 Hz, 7H
z), 4.44-4.50 (m, 2H), 4.62-
4.78 (m, 2H), 5.23-5.43 (m, 3
H), 5.85-6.03 (m, 3H), 6.10-
6.20 (1H)

Example 3 (5R, 6R, 2'R) -6-Benzylaminocarbonyl-8-oxo-3- (2'-tetrahydrofuryl)-
1-aza-4-thiabicyclo [3.3.0] oct-2
-Synthesis of sodium ene-2-carboxylate (14):

[Chemical 20] 9 mg (0.02) of the compound (13) obtained in Example 2
tetrahydrofuran solution (200 μl)
2-ethylhexanoic acid sodium salt (3 mg),
Triphenylphosphine (2 mg) and tetrakistriphenylphosphine palladium (2 mg) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the aqueous layer was washed with ethyl acetate. The obtained aqueous layer was freeze-dried to obtain 5 mg of the title compound (14).
(Yield: 56%)

IR (film, cm ^-1 ): 170
0,1676,1560,1400 NMR (CDCl ₃ / TMS, δppm): 1.80
-2.20 (m, 3H), 2.20-2.35 (m, 1)
H), 2.89 (dd, 1H, J = 17Hz, 9H
z), 3.09 (dd, 1H, J = 16Hz, 9H
z), 3.80-4.00 (m, 3H), 4.43.
(S, 2H), 5.33 (t, J = 7Hz), 6.05
(D, 1H, J = 7Hz)

Example 4 (5R, 6R) -2-Benzyloxycarbonyl-8-
Synthesis of oxo-3,3-dimethyl-1-aza-4-thiabicyclo [3.3.0] octane-6-carboxylic acid (16):

[Chemical 21] Under an argon atmosphere, (5R, 6R) -6-methoxycarbonylmethyl-7-oxo-3,3-dimethyl-1-aza-4-thiabicyclo [3.2.0] heptane-2-carboxylic acid benzyl ester (15 ) 363 mg (1 m
mol) in chloroform (10 ml) was added with iodotrimethylsilane (171 μl) at room temperature and stirred for 90 minutes. After diluting with ethyl acetate, the mixture was extracted with saturated aqueous sodium hydrogen carbonate. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid, extracted with methylene chloride three times, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (16) 1
60 mg was obtained. (Yield: 46%)

IR (film, cm ^-1 ): 2756,
1732 NMR (CDCl _{3 /} TMS, δppm): 1.41
(S, 3H), 1.56 (s, 3H), 2.85 (d
d, 1H, J = 17 Hz, 10 Hz), 3.09 (d
d, 1H, J = 17 Hz, 10 Hz), 4.64 (s,
1H), 5.20 (q, 2H, J = 17Hz, 12H
z), 5.73 (d, 1H, J = 7 Hz), 7.37
(S, 5H)

Example 5 (5R, 6R) -8-oxo-3,3-dimethyl-1-
Aza-4-thiabicyclo [3.3.0] octane-2,
Synthesis of 6-dicarboxylic acid (17):

[Chemical formula 22] Under an argon atmosphere, at 0 ° C., 45 mg (0.13 mmol) of the compound (16) obtained in Example 4 was dissolved in methylene chloride (1 ml), and anisole (81 μm) was added thereto.
1) and aluminum chloride (100 mg) dissolved in nitromethane (2 ml) were sequentially added. After stirring at room temperature for another 2 hours, the mixture was diluted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid and then extracted with saturated aqueous sodium hydrogen carbonate. Water layer is diluted with diluted hydrochloric acid
After adjusting to H2, the mixture was extracted with ethyl acetate three times, and the obtained organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 20 mg of the title compound (17). (Yield: 5
9%)

NMR (CDCl ₃ / TMS, δppm) 1.47 (s, 3H), 1.50 (s, 3H), 2.7
0 (dd, 1H, J = 16Hz, 11Hz), 2.90
(Dd, 1H, J = 16Hz, 11Hz), 4.35
(S, 1H), 5.54 (d, J = 7Hz)

Example 6 (5R, 6R) -6-Benzylaminocarbonyl-8-
Synthesis of oxo-3,3-dimethyl-1-aza-4-thiabicyclo [3.3.0] octane-2-carboxylic acid benzyl ester (18):

[Chemical formula 23] 70 mg of the compound (16) obtained in Example 4 under ice cooling
(0.20 mmol) and benzylamine (21 mg)
In methylene chloride (1 ml) solution of N-ethyl-N'-
Dimethylaminopropyl carbodiimide hydrochloride 42m
g was added. After stirring for 10 minutes, the mixture was further stirred at room temperature for 90 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated potassium bisulfate and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 63 mg of the title compound (18). (Yield: 72%)

IR (film, cm ^-1 ): 1712,
1684, 1274 NMR (CDCl _{3 /} TMS, δppm): 1.39.
(S, 3H), 1.52 (s, 3H), 2.70 (d
d, 1H, J = 16 Hz, 11 Hz), 3.10-3.
30 (m, 2H), 4.40-4.50 (m, 2H),
4.63 (s, 1H), 5.20 (s, 2H), 5.6
8 (d, 1H, J = 7 Hz), 6.85 (br.s, 1
H), 7.25-7.40 (m, 10H)

Example 7 (5R, 6R) -6-Benzylaminocarbonyl-8-
Synthesis of oxo-3,3-dimethyl-1-aza-4-thiabicyclo [3.3.0] octane-2-carboxylic acid (19):

[Chemical formula 24] 35 mg (0.0) of the compound (18) obtained in Example 6
8 mmol) was used and reacted in the same manner as in Example 5 to obtain 17 mg of the title compound (19). (Yield: 61%)

IR (film, cm ^-1 ): 3294,
1732, 1683, 1635 NMR (CDCl _{3 /} TMS, δppm): 1.46.
(S, 3H), 1.50 (s, 3H), 2.70 (d
d, 1H, J = 16Hz, 9Hz), 2.87 (dd,
1H, J = 16Hz, 9Hz), 4.31 (d, 2H,
J = 5 Hz), 4.34 (s, 1H), 7.20-7.
55 (m, 5H)

Example 8 (5R, 6R) -6-carbamoyl-8-oxo-3,
3-Dimethyl-1-aza-4-thiabicyclo [3.3.
0] octane-2-carboxylic acid benzyl ester (2
Synthesis of 0):

[Chemical 25] Compound (16) 20 obtained in Example 4 at −20 ° C.
mg (0.06 mmol) of methylene chloride (0.3 m
l) To the solution, 32 mg of bromotris-pyrrolidinophosphonium hexafluorophosphate and 200 μl (0.28 mmol) of a DMF solution of ammonia were sequentially added. After stirring at room temperature for 5 hours, the reaction solution was diluted with ethyl acetate, washed with saturated potassium bisulfate and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 17 mg of the title compound (20).
(Yield: 85%)

IR (film, cm ^-1 ): 1734
1684, 1188 NMR (CDCl _{3 /} TMS, δppm) 1.41
(S, 3H), 1.54 (s, 3H), 2.71 (q,
1H, J = 22Hz, 14Hz), 3.10-3.25.
(M, 2H), 4.64 (s, 1H), 5.20 (s,
2H), 5.66 (d, 1H, J = 6Hz), 7.37
(S, 5H)

Example 9 (5R, 6R) -6- (2-furylmethyl) aminocarbonyl-8-oxo-3,3-dimethyl-1-aza-4
-Synthesis of thiabicyclo [3.3.0] octane-2-carboxylic acid benzyl ester (21):

[Chemical formula 26] 420 mg of the compound (16) obtained in Example 4 (1.
20 mmol) and 117 mg of furfurylamine as an amine to carry out a reaction in the same manner as in Example 6,
304 mg of the title compound (21) was obtained. (Yield: 59
%)

IR (film, cm ^-1 ): 3298,
1744, 1710, 1543, 1374 NMR (CDCl _{3 /} TMS, δppm) 1.39
(S, 3H), 1.52 (s, 3H), 2.65 (d
d, 1H, J = 14 Hz, 2 Hz), 3.07-3.2
7 (m, 2H), 4.47 (ABdq, 2H, J = 25
Hz, 15Hz, 5Hz), 4.63 (s, 1H),
5.19 (s, 2H), 5.65 (d, 1H, J = 6H
z), 5.89 (br.s, 1H), 6.24-6.2.
5 (m, 1H), 6.32-6.65 (m, 1H),
7.38 (s, 6H)

Example 10 (5R, 6R) -6- (2-Furylmethyl) aminocarbonyl-8-oxo-3,3-dimethyl-1-aza-4
-Synthesis of thiabicyclo [3.3.0] octane-2-carboxylic acid (22):

[Chemical 27] 97 mg (0.2) of the compound (21) obtained in Example 9
(3 mmol) was used and reacted in the same manner as in Example 5 to obtain 66 mg of the title compound (22). (Yield: 86%)

NMR (DMSO-d6 / TMS, δpp
m): 1.46 (s, 3H), 1.49 (s, 3H),
2.67 (dd, 1H, J = 17Hz, 10Hz),
2.79 (dd, 1H, J = 16Hz, 7Hz), 4.
29 (d, 2H, J = 6 Hz), 4.33 (s, 1
H), 5.49 (d, 1H, J = 6 Hz), 6.24
(D, 1H, J = 2 Hz), 6.38-6.39 (m,
1H), 7.58 (s, 1H), 8.70 (br.t,
1H)

Example 11 (5R, 6R, 2'R) -8-oxo-3- (2'-tetrahydrofuryl) -1-aza-4-thiabicyclo [3.3.0] oct-2-ene- Synthesis of sodium 2,6-dicarboxylate (23):

[28] (5R, 6R, 2'R) -6-allyloxycarbonylmethyl-2- (2'-tetrahydrofuryl) penem-carboxylic acid allyl ester (10) 100 mg (0.2
6 mmol) in ethyl acetate: methylene chloride (3: 1) solution (2 ml), 2-ethylhexanoic acid sodium salt (92 mg), triphenylphosphine (6.4 m).
g) and tetrakistriphenylphosphine palladium (6.4 mg) were sequentially added, and the mixture was stirred at room temperature for 20 minutes.
After distilling off the solvent, acetonitrile: water (3: 1) 1.2
97 ml of a fraction containing the title compound (23), which was dissolved in ml, filtered to remove insoluble matter, and purified directly by HPLC.
Got

IR (film, cm ^-1 ): 3456,
1690, 1596, 1397 NMR (CDCl _{3 /} TMS, δppm): 1.90-
2.20 (m, 2H), 2.10-2.20 (m, 1
H), 2.87 (dd, 1H, J = 16Hz, 9H
z), 2.98 (dd, 1H, J = 18Hz, 10H
z), 3.70-4.00 (m, 3H), 5.32.
(T, 1H, J = 6 Hz), 6.03 (d, 1H, J =
7Hz)

Example 12 (5R, 6S, 2'R) -8-oxo-3- (2'-tetrahydrofuryl) -1-aza-4-thiabicyclo [3.3.0] oct-2-ene- Synthesis of sodium 2,6-dicarboxylate (24):

[29] (5R, 6S, 2'R) -6-allyloxycarbonylmethyl-2- (2'-tetrahydrofuryl) penem-carboxylic acid allyl ester (11) 89 mg (0.23
was used in the same reaction as in Example 11 to obtain 96 mg of a fraction containing the title compound (24).

IR (film, cm ^-1 ): 1718,
1581, 1196 NMR (CDCl _{3 /} TMS, δppm): 1.90-
2.20 (m, 2H), 2.40-2.60 (m, 1
H), 3.00 (d, 1H, J = 2Hz), 3.03
(D, 1H, J = 4 Hz), 5.44 (t, 1H, J =
7Hz), 6.24 (d, 1H, J = 7Hz)

[0054]

INDUSTRIAL APPLICABILITY According to the present invention, γ-lactam derivative which is expected to have excellent antibacterial activity and γ which is useful as an intermediate thereof
-Lactam derivatives can be produced very simply and easily.

Claims (2)

[Claims] 1. Formula (I): (In the formula, R ¹ and R ² represent the same or different carboxylic acid protecting groups, the dotted line indicates the presence or absence of a bond, and when the bond does not exist, R ³ and R ⁴ represent a methyl group. And when a bond is present, R ³ represents a tetrahydrofuryl group or a tetrahydrofurylmethyl group,
R ⁴ does not exist) in the β-lactam derivative represented by the formula (II), wherein the protecting group for the carboxylic acid represented by R ¹ is removed: (In the formula, R ² , R ³ , R ⁴ and the dotted lines have the above-mentioned meanings) A method for producing a γ-lactam derivative. 2. The protecting group for carboxylic acid represented by R ¹ is allyl group, trichloroethyl group or methyl group,
And a carboxylic acid protecting group represented by R ² is a benzyl group,
The production method according to claim 1, which is an allyl group or a trichloroethyl group.