JPH0656837A - Process for producing β-lactam derivative - Google Patents

Abstract

(57) [Summary] [Structure] General formula [II] [Wherein R ¹ is an optionally protected hydroxy-substituted lower alkyl group; R ² is an ester residue or the like; R ³ is a lower alkyl group or the like; X is a methylene group which may be substituted with a lower alkyl group or the like; Y represents a halogen atom; Z represents an oxygen atom or a sulfur atom. ] The bicycloalkane compound represented by the formula [I] embedded image is subjected to elimination reaction of the groups Y and —ZR ³ to form a double bond. [However, the symbols have the same meanings as described above. ]-
Manufacturing method of lactam derivative. [Effect] A β-lactam derivative [I] useful as a synthetic intermediate for various β-lactam antibacterial agents can be efficiently obtained by a simple operation.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel process for producing a β-lactam derivative useful as a synthetic intermediate for antibacterial drugs.

[0002]

2. Description of the Related Art Various β-lactam type antibacterial agents are known, such as penem or carbapenem derivatives, cephems, carbacephems or oxacephems.

As a method for synthesizing these compounds, for example, Journal of the Chemical Society, Chemical Communication (J. Chem. Soc.,
Chem. Commun. ) Pp. 185 and 1084 (1980), 4-allylazetidinone derivatives were used as the corresponding phosphorane compounds and then ring-closed to give 7-oxo-1-azabicyclo [3.2.0] hept-2-ene. It has been reported that 2-carboxylate is produced and then reacted with a thiol compound to produce a carbapenem derivative.

The Journal of the Chemical Society, Perkin Transaction 1 (J.C.
hem. Soc. , Perkin Trans. 1) 2
Pp. 268 (1979), 4-allyloxyazetidinone derivatives are ozone-oxidized to give the corresponding phosphorane compounds, which are ring-closed to give 1-oxa-1-dethiaceph-3-.
A method of producing em-4-carboxylate and then hydrolyzing it to produce an oxacephem derivative has been reported.

Further, the above-mentioned Journal of the Chemical Society, Chemical Communication (J. Chem. Soc., Chem. Commu
n. ), P. 185 (1980), 1-azabicyclo [3.2.0] heptane type compound having a halogen atom at the 3-position is 1,5-diazabicyclo [5.4.0] undec-5-ene (DBU). ) To produce the corresponding 1-azabicyclo [3.2.0] hept-2-ene type compound.

However, conventionally, from the 1-azabicyclo [3.2.0] heptane type compound having an aralkyloxy group (or an aralkylthio group) and a halogen atom as substituents at the 2- and 3-positions, respectively, the corresponding 1- There is no known method for producing an azabicyclo [3.2.0] hept-2-ene type compound.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel method for producing a β-lactam derivative useful as a synthetic intermediate for a β-lactam type antibacterial agent.

[0008]

According to the present invention, the general formula [I]

[0009]

[Chemical 9]

(Wherein R ¹ is a hydroxy-substituted lower alkyl group which may be protected; R ² is a hydrogen atom or an ester residue; X is a methylene group which may be substituted with a lower alkyl group or a formula: --A A group represented by —CH ₂ —A
Represents a sulfur atom, an oxygen atom or a methylene group. ), A β-lactam derivative or a salt thereof is represented by the general formula [I
I]

[0011]

[Chemical 10]

(Wherein R ³ is a lower alkyl group or a substituted or unsubstituted aryl group; Y is a halogen atom; Z is an oxygen atom or a sulfur atom, and other symbols have the same meanings as described above). bicycloalkane compound or a salt thereof, is subjected to elimination reaction of the groups Y and -ZR ³ to form a double bond, the product optionally may be prepared by a salt thereof.

In the present invention, a specific example of the group R ¹ is an optionally protected 1-hydroxyethyl group. As the protective group for the hydroxy group, any group that can be easily removed by a conventional method such as hydrolysis, acid treatment or reduction can be used. Examples of such a hydroxy-protecting group include a lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, a substituted or unsubstituted phenyl lower alkyl group (eg, a benzyl group which may be substituted with a nitro group or a lower alkoxy group). , A tri-lower alkylsilyl group, a substituted or unsubstituted phenyl lower alkoxycarbonyl group (for example, a benzyloxycarbonyl group which may be substituted with a nitro group or a lower alkoxy group), and the like.

Examples of the ester residue represented by R ² include an ester residue that is metabolized and hydrolyzed in vivo, or an ester residue that can serve as a protecting group for a carboxyl group.

Examples of the ester residue which is metabolized and hydrolyzed in the living body include, for example, formulas -Q-OCOR and -Q-OC.
O ₂ R or -Q-O-R (in the formula, Q represents a lower alkylene group, R represents a lower alkyl group, a cycloalkyl group, a lower alkenoyl group, a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group.) A group represented by

On the other hand, examples of the ester residue which can be a protective group for the carboxyl group include lower alkyl groups such as methyl group and ethyl group, lower alkenyl groups such as allyl group, halogeno lower alkyl groups such as trifluoromethyl group and nitro. Examples thereof include lower alkoxybenzhydryl groups such as benzyl group and p-methoxybenzhydryl group.

R ³ is preferably a lower alkyl group such as a methyl group or an ethyl group, or a substituted or unsubstituted aryl group such as a phenyl group.

Specific examples of the group X include a methylene group which may be substituted with a lower alkyl group such as a methylene group, an ethylidene group and a propylidene group, or a group represented by the formula -A-CH _2- Is a sulfur atom, an oxygen atom or a methylene group, with a methylene group and an ethylidene group being particularly preferred.

Further, a specific example of Y is a bromine atom.

In the above reaction, the compound [II]
Can also be used in the form of a salt, and specific examples of such a salt include alkali metal salts such as sodium salt and quaternary ammonium salts.

In the method of the present invention, the reaction of subjecting the compound [II] to the elimination reaction of the groups Y and --ZR ³ to form a double bond (hereinafter simply referred to as a double bond forming reaction) is carried out according to the type of Z. It can be carried out according to

For example, in the general formula [II], a compound in which Z is an oxygen atom, that is, [II-a]

[0023]

[Chemical 11]

(Wherein R ³¹ represents a lower alkyl group or a substituted or unsubstituted aryl group, and other symbols have the same meanings as described above), the double bond formation reaction of the compound represented by It can be suitably carried out in the presence.

In the compound [II-a], as the group R ³¹ , any of the groups mentioned in the description of R ³ can be used, and a lower alkyl group is particularly preferable.

Specific examples of the acylating agent include halides of lower aliphatic carboxylic acids having 1 to 6 carbon atoms such as acetic acid, propionic acid, pivalic acid (2,2-dimethylpropanoic acid),
Alternatively, halides of aromatic carboxylic acids such as benzoic acid can be preferably used, and iodides of these carboxylic acids can be preferably used, with acetic acid iodides being particularly preferred. These acylating agents may be produced outside the reaction system and added to the reaction system, or they may be produced inside the reaction system before use. For example, when carboxylic acid iodide is used as the acylating agent, the corresponding carboxylic acid chloride or carboxylic acid bromide is reacted with alkali metal iodide such as sodium iodide or potassium iodide in the system to produce the corresponding carboxylic acid iodide. It can be used.

The amount of the acylating agent used depends on the amount of the compound [II-
It is preferable to use 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, based on a]. On the other hand, for example, when carboxylic acid iodide is generated and reacted in the reaction system, carboxylic acid chloride or carboxylic acid bromide is used as a compound [II-
It is preferable to use 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, and 1 to 10 molar equivalents, especially 1 to 3 molar equivalents, of alkali metal iodide to a].

The reaction is preferably carried out under cooling to the reflux temperature of the solvent, especially at 0 ° C to 25 ° C.

On the other hand, in the general formula [II], a compound in which Z is a sulfur atom, that is, the general formula [II-b]

[0030]

[Chemical 12]

(However, R ³² represents a lower alkyl group or a substituted or unsubstituted aryl group, and other symbols have the same meanings as described above.) It can be suitably carried out below.

In the compound [II-b], as the group R ³² , any of the groups mentioned in the description of R ³ can be used, and a substituted or unsubstituted aryl group is particularly preferable.

Examples of the oxidizing agent include hydrogen peroxide, performic acid, peracetic acid, perbenzoic acid, metachloroperbenzoic acid, and other peracids, and manganese dioxide, lead tetraacetate, ruthenium tetroxide, and other metal salts. Mention may be made in particular of perbenzoic acid or metachloroperbenzoic acid.

The oxidizing agent is used in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound [II-b].

This reaction is preferably carried out under cooling to the reflux temperature of the solvent, especially at 0 ° C to 25 ° C.

The above double bond forming reaction can be preferably carried out in a solvent. As the solvent, any solvent can be used as long as it is inert to these reactions, and for example, toluene, benzene, dichloromethane, chloroform, ethyl acetate, acetonitrile, dimethylformamide and the like can be used.

The compound [I] thus obtained can be appropriately converted into a penem-type or cephem-type antibacterial agent by a method known per se. For example, Journal of
The Chemical Society, Chemical Communication (J. Chem. Soc., Chem. Commu
n. ) According to the method described on page 185 (1980), compound [I] or a salt thereof and general formula [V]

[0038]

[Chemical 13]

(Wherein R ⁴ represents an organic group) is reacted with a thiol compound represented by the formula (1), the resulting product is reacted with an oxidizing agent (eg iodobenzene dichloride), and then a base (eg 1,5 -Diazabicyclo [5.4.
0] undeca-5-ene) and R ¹ is a protected hydroxy-substituted lower alkyl group, or / and R
^{When 2} is an ester residue, the compound of the general formula [VI] can be prepared by a known method such as removing a protecting group for the hydroxy-substituted lower alkyl group and / or an ester residue, if desired.

[0040]

[Chemical 14]

(However, the symbols have the same meanings as described above.)
Can be converted to a β-lactam type antibacterial agent represented by In the compound [VI], as the organic group represented by R ⁴ , a group used in a known carbapenem or cephem antibacterial agent can be used.

Of the starting compound [II] used in the present invention, the compound [II-a] in which Z is an oxygen atom is represented by the general formula [III]

[0043]

[Chemical 15]

(However, the symbols have the same meanings as described above.)
The azetidinone compound represented by or a salt thereof, in a solvent,
It can be produced by intramolecular ring closure in the presence of a halogenating agent. As the halogenating agent, halogen or N-halogenosuccinimide, particularly bromine or N-bromosuccinimide can be preferably mentioned. When N-halogenosuccinimide is used as the halogenating agent,
It is preferable to use 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents, based on the azetidinone compound [III]. On the other hand, when halogen is used, the azetidinone compound [I
II] to 1 to 5 molar equivalents, preferably 1 to 1.5
It is better to use molar equivalents. When halogen is used, it is preferable to carry out the reaction in the presence of an alkali metal hydrogen carbonate or an alkali metal carbonate such as sodium hydrogen carbonate, sodium carbonate or potassium carbonate. These alkali metal hydrogen carbonates or alkali metal carbonates are used in an amount of 1 to 5 mol equivalents, preferably 1 to 2 mol equivalents, based on the azetidinone compound [III].

As the solvent, a conventional inert solvent such as acetonitrile, dimethylformamide, tetrahydrofuran, dichloromethane or chloroform can be used. This reaction is preferably carried out under cooling-refluxing temperature of the solvent, especially at -10 ° C to 25 ° C.

On the other hand, in the raw material [II], the compound [II-b] in which Z is a sulfur atom is prepared by reacting the compound [II-a] obtained above with a general formula [II-a] in the presence of a Lewis acid. I
V]

[0047]

[Chemical 16]

(However, the symbols have the same meanings as described above.)
It can be produced by reacting with a mercaptan compound represented by.

As the Lewis acid, titanium tetrachloride, tin tetrachloride, boron trifluoride ether complex and the like can be used, and the amount thereof is 1 to the compound [II-a].
It is preferable to use 5 molar equivalents, preferably 1 to 2 molar equivalents. As the solvent, any conventional inert solvent such as dichloromethane, acetonitrile or tetrahydrofuran can be used. This reaction suitably proceeds under cooling to room temperature, especially at -78 ° C to 20 ° C.

In the method of the present invention, the starting compound [II] or [III] may have an optical isomer based on the asymmetric carbon. However, when an optically active compound is used as the starting material, the reaction retains the three-dimensional structure. It is also possible to proceed as it is and convert to compound [I] or [II] without epimerization.

The starting material compound [II
I] can be produced according to a conventional method, for example, as follows. That is, the general formula [VII]

[0052]

[Chemical 17]

(However, the symbols have the same meanings as described above.)
The azetidinonecarboxylic acid derivative represented by is reacted with ethyl mercaptan in the presence of a condensing agent (carbonyldiimidazole, etc.) in a solvent (acetonitrile, dichloromethane, etc.) to give an ethylthioester, and then the amide in β-lactam. Is protected with a suitable protecting group (eg t-butyldimethylsilyl group). Then, in the presence of triethylsilane, in a solvent (dichloromethane or the like), catalytic reduction is performed with palladium-carbon to give an aldehyde of the general formula [VIII]

[0054]

[Chemical 18]

(However, the symbols have the same meanings as described above.)
A compound represented by a base (for example, sodium hydride,
The azetidinone compound [III] can be produced by reacting in a solvent (ethyl ether, tetrahydrofuran, dimethylformamide, etc.) in the presence of (n-butyllithium, etc.) and finally removing the protecting group of the amide.

In the present specification, examples of the lower alkyl group, lower alkylene group, lower alkenyl group and lower alkoxy group include those having 1 to 6 carbon atoms, and the lower alkanoyl group has 2 to 8 carbon atoms. Examples of the lower alkenoyl group include those having 3 to 8 carbon atoms.

[0057]

【Example】

Example 1 (1) To a suspension of 38 mg of sodium hydride (26%) in 1 ml of tetrahydrofuran, a solution of 0.24 g of ethyl diethylphosphonoethoxyacetic acid ethyl ester in 1 ml of tetrahydrofuran was added under ice cooling. After stirring at room temperature for 1 hour and cooling with ice, (3S, 4S) -1-t-butyldimethylsilyl-
Obtained from 0.45 g of 3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-ethylthiocarbonylethyl] -2-azetidinone according to the production method of Reference Examples 2 and 3. (3S, 4S) -1-
t-Butyldimethylsilyl-3-[(1R) -1-t-
Butyldimethylsilyloxyethyl] -4-[(1R)
A solution of -1-formylethyl] -2-azetidinone in 5 ml of tetrahydrofuran is added. After stirring at the same temperature for 2 hours,
Neutralize with acetic acid. The reaction solution is concentrated, and ethyl acetate is added to the residue. The obtained organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to give (3S, 4S) -1-t-butyldimethylsilyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R). 0.37 g of-(1-ethoxy-1-ethoxycarbonyl) -1-buten-3-yl] -2-azetidinone is obtained.

IR (film) cm ⁻¹ : 1745, 17
25,1650 NMR (CDCl ₃ ) δ: 0.06 (s, 3H), 0.
09 (s, 3H), 0.19 (s, 3H), 0.21
(S, 3H), 0.89 (s, 9H), 0.94 (s,
9H), 1.08 (d, 3H, J = 7.0Hz), 1.
25 (d, 3H, J = 6.2 Hz), 1.30 (t, 6)
H, J = 7.0 Hz), 2.92 (dd, 1H, J =
6.6, 2.2 Hz), 3.1-3.3 (m, 1H),
3.5-3.6 (m, 1H), 3.8-4.0 (m, 2)
H), 3.7-4.0 (m, 1H), 4.22 (q, 2)
H, J = 7.0 Hz), 5.15 + 6.13 (d + d,
1H, J = 7.4 Hz) Mass (m / z): 498 (M ⁺ -15), 456
(M ⁺ -57) (2) (3S, 4S) -1-t-butyldimethylsilyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R)-(1 -Ethoxy-1-ethoxycarbonyl) -1-buten-3-yl] -2-azetidinone (1.45 g) in tetrahydrofuran (3 ml) under ice-cooling (3 ml) and acetic acid (3 ml) and tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.8 ml).
Add.

After stirring at room temperature for 14 hours, the reaction solution is diluted with dichloromethane, washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography,
(3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R)-(1-ethoxy-1-ethoxycarbonyl) -1-butene-3-
Ill] -2-azetidinone (0.93 g) is obtained.

IR (film) cm ^-1 : 3100, 17
61, 1725 NMR (CDCl ₃ ) δ: 0.01 (s, 6H), 0.
80 (s, 9H), 1.03 (d, 3H, J = 7.0H
z), 1.04 (d, 3H, J = 7.0 Hz), 1.1
9-1.28 (m, 6H), 2.8-2.9 (m, 1
H), 2.8-3.0 (m, 1H), 3.49 (dd,
1H, J = 8.0, 2.0 Hz), 3.6-4.0
(M, 2H), 4.0-4.3 (m, 3H), 5.93
(D, 1H, J = 10.2 Hz), 5.95 (bs, 1
H) Mass (m / z): 342 (M ⁺ -57) (3) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R)-
To a solution of 2 g of (1-ethoxy-1-ethoxycarbonyl) -1-buten-3-yl] -2-azetidinone in 20 ml of acetonitrile, 980 mg of N-bromosuccinimide is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. The solvent was evaporated, the residue was purified by silica gel column chromatography, and (1S, 5R, 6S) -2-bromo-6-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
2.02 g of 3-ethoxy-1-methylcarbapenamu-3-carboxylic acid ethyl ester are obtained.

IR (film) cm ^-1 : 1782,17
70 NMR (CDCl ₃ ) δ: 0.07 (s, 6H), 0.
88 (s, 9H), 1.1-1.4 (m, 12H),
2.6-2.8 (m, 1H), 3.13 + 3.20 (d
d + t, 1H, J = 5.4, 3.1Hz + J = 3.8H
z), 3.68 + 4.11 (d + d, 1H, J = 11.1.
3 Hz + 10.8 Hz), 3.8-4.4 (m, 5H) Mass (m / z): 422 (M ⁺ + 2-57), 42
0 (M ⁺ -57) (4) (1S, 5R, 6S) -2-Bromo-6-
[(1R) -1-t-butyldimethylsilyloxyethyl] -3-ethoxy-1-methylcarbapenam-3-carboxylic acid ethyl ester 500 mg and thiophenol 0.107 ml in a dichloromethane 10 ml solution under a nitrogen stream, Add 0.115 ml titanium tetrachloride at 70 ° C. After stirring at the same temperature for 3 hours, pour into saturated aqueous sodium hydrogen carbonate. The organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to obtain (1S, 5R,
0.3 g of 6S) -2-Bromo-6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-3-phenylthiocarbapenam-3-carboxylic acid ethyl ester is obtained.

NMR (CDCl ₃ ) δ: 0.05 (s,
6H), 0.87 (s, 9H), 1.13 (t, 3H,
J = 7.2 Hz), 1.17 (d, 3H, J = 6.2H)
z), 1.27 (d, 3H, J = 7.0 Hz), 2.9
-3.2 (m, 2H), 3.8-4.3 (m, 4H),
4.33 (d, 1H, J = 11.2 Hz), 7.2-
7.4 (m, 2H), 7.5-7.7 (m, 2H) Mass (m / z): 526, 484 (5) (1S, 5R, 6S) -2-Bromo-6-
[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-3-phenylthiocarbapenamu-3
-To a solution of 100 mg of carboxylic acid ethyl ester in 5 ml of dichloromethane was added 32 mg of perbenzoic acid under ice cooling,
Stir for 10 minutes at the same temperature. 5 ml of saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was stirred at room temperature for 2.5 hours, and then the organic layer was separated. The obtained organic layer is washed with water and dried, and the solvent is distilled off. The residue was purified by preparative thin layer chromatography, (1S, 5
65 mg of R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid ethyl ester are obtained.

NMR (CDCl ₃ ) δ: 0.00 (s,
3H), 0.80 (s, 3H), 0.88 (s, 9
H), 1.11 (d, 3H, J = 8Hz), 1.2-
1.6 (m, 6H), 3.1-3.3 (m, 2H),
4.1-4.4 (m, 4H), 6.33 (d, 1H, J
= 4 Hz) Mass (m / z): 353 (M ⁺ ) Example 2 (1S, 5R, 6S) -2-Bromo-6-[(1R)-
1-t-butyldimethylsilyloxyethyl] -3-ethoxy-1-methylcarbapenamu-3-carboxylic acid ethyl ester 108 mg in acetonitrile 5 ml solution,
Under ice cooling, sodium iodide 75 mg and acetyl chloride 3
Add 4 mg and stir at the same temperature for 2 hours.

The reaction solution is diluted with chloroform, washed with water and dried, and then the solvent is distilled off. The residue was purified by preparative thin layer chromatography to give (1S, 5R, 6S) -6-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
51 mg of 1-methylcarbapene-2-em-3-carboxylic acid ethyl ester are obtained.

This product has the same physical properties as the product of Example 1.

Example 3 (1) To a solution of 2.3 g of diethylphosphonoethoxy acetic acid allyl ester in 40 ml of tetrahydrofuran was added 349 mg of sodium hydride (60%) under ice cooling. After stirring at the same temperature for 1 hour, the mixture was cooled to -10 ° C, and
4S) -1-t-butyldimethylsilyl-3-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
3.48 g of 4-[(1R) -1-formylethyl] -2-azetidinone are added. After stirring at -10 ° C for 30 minutes, an aqueous citric acid solution is added, and the mixture is extracted with ethyl acetate.
The obtained organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography,
(3S, 4S) -1-t-Butyldimethylsilyl-3-
[(1R) -1-t-Butyldimethylsilyloxyethyl] -4-[(3R)-(1-allyloxycarbonyl-1-ethoxy) -1-buten-3-yl] -2-azetidinone 1.88 g To get

NMR (CDCl ₃ ) δ: 0.06 (s,
3H), 0.09 (s, 3H), 0.12 (s, 3
H), 0.19 (s, 3H), 0.89 (s, 9H),
0.94 (s, 9H), 1.09 (d, 3H, J = 7.
0 Hz), 1.25 (d, 3H, J = 6.1 Hz),
1.30 (t, 3H, J = 7.0 Hz), 2.92 (d
d, 1H, J = 6.8, 2.5 Hz), 3.13-3.
23 (m, 1H), 3.55 (dd, 1H, J = 2.
5, 4.2 Hz), 3.75-4.14 (m, 3H),
4.58 (dt, 2H, J = 5.7, 1.3Hz),
5.22-5.38 (m, 2H), 5.84-6.04
(M, 1H), 6.17 (d, 1H, J = 9.3 Hz) Mass (m / z): 526 (M ⁺ +1), 510 (M
⁺ -15), 468 (M ⁺ -57) (2) (3S, 4S) -1-t-butyldimethylsilyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4- [ (3R)-(1-allyloxycarbonyl-1-ethoxy) -1-buten-3-yl] -2
-Azetidinone 1.74 g tetrahydrofuran 7 ml
Under ice cooling, 5 ml of acetic acid and tetrabutylammonium fluoride (1M tetrahydrofuran solution) were added to the solution.
Add 6 ml. After stirring at room temperature for 5 hours, the reaction solution is diluted with ethyl acetate, washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography, (3
S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R)-(1-allyloxycarbonyl-1-ethoxy) -1-butene-3-
Il] -2-azetidinone (1.17 g) is obtained.

IR (KBr) cm ^-1 : 3150, 309
0,1759,1715,1650 NMR (CDC
l ₃ ) δ: 0.05 (s, 6H), 0.87 (s, 9)
H), 1.09 (d, 3H, J = 6.6 Hz), 1.1
2 (d, 3H, J = 6.2 Hz), 1.29 (t, 3
H, J = 7.0 Hz), 2.84-3.00 (m, 2
H), 3.56 (dd, 1H, J = 8.0, 2.0H
z), 3.76-4.02 (m, 2H) 4.11-4.
28 (m, 1H), 4.66 (dt, 2H, J = 5.
7, 1.3 Hz), 5.23-5.39 (m, 2H),
5.85-6.04 (m, 2H), 6.03 (d, 1
H, J = 10.2 Hz) Mass (m / z): 396 (M ⁺ -15), 354.
342, 228, 159, 113, 73 Elemental analysis Calculated value (%) C, 61.26; H, 9.
08; N, 3.40 Found (%) C, 61.27; H, 9.19; N,
3.55 (3) (3S, 4S) -3-[(1R) -t-butyldimethylsilyloxyethyl] -4-[(3R)-(1-
To a solution of 0.50 g of allyloxycarbonyl-1-ethoxy) -1-buten-3-yl] -2-azetidinone in 0.5 ml of acetonitrile, 328 mg of N-bromosuccinimide is added under ice cooling. After stirring at the same temperature for 1 hour, an aqueous sodium thiosulfate solution is added, and the mixture is extracted with ethyl acetate.
The obtained organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography,
(1S, 5R, 6S) -2-Bromo-6-[(1R)-
521 mg of allyl ester of 1-t-butyldimethylsilyloxyethyl] -3-ethoxy-1-methylcarbapenamu-3-carboxylic acid are obtained.

NMR (CDCl ₃ ) δ: 0.06 (s,
3H), 0.07 (s, 3H), 0.88 (s, 9
H), 1.16 (d, 3H, J = 6.3 Hz), 1.2
0 (t, 3H, J = 7.1 Hz), 1.23 (d, 3)
H, J = 7.0 Hz), 2.63-2.80 (m, 1
H), 3.20 (t, 1H, J = 3.7 Hz), 3.8
0-4.09 (m, 3H), 4.18 (d, 1H, J =
11.4 Hz), 4.15-4.31 (m, 1H),
4.61-4.86 (m, 2H), 5.24-5.42
(M, 2H), 5.86-6.02 (m, 1H) Mass (m / z): 476, 474, 434, 432 (4) (1S, 5R, 6S) -2-Bromo-6- [ (1
R) -1-t-Butyldimethylsilyloxyethyl]-
3-Ethoxy-1-methylcarbapenamu-3-carboxylic acid allyl ester 300 mg and thiophenol 0.1
To a solution of 9 ml of dichloromethane in 7 ml, 0.2 ml of titanium tetrachloride is added under ice cooling and a nitrogen stream.

After stirring at the same temperature for 2 hours, the mixture is left in the refrigerator overnight. Saturated sodium hydrogen carbonate solution is added, and filtration is performed on Celite 503 (trade name, manufactured by Katayama Kagaku Co.). Wash the organic layer of the filtrate with water,
After drying, the solvent is distilled off. The residue was purified by silica gel column chromatography to give (1S, 5R, 6S) -2.
-Bromo-6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methyl-3-phenylthiocarbapenamu-3-carboxylic acid allyl ester 203 mg
To get

IR (film) cm ^-1 : 3060, 17
77, 1740, 1472, 1250 NMR (CDCl
₃ ) δ: 0.00 (s, 3H), 0.06 (s, 3)
H), 0.87 (s, 9H), 1.17 (d, 3H, J
= 6.2 Hz), 1.28 (d, 3H, J = 7.0H
z), 2.97-3.20 (m, 2H), 3.93-
4.14 (m, 2H), 4.35 (d, 1H, J = 1
1.1 Hz), 4.64 (dt, 2H, J = 5.7,
1.3 Hz), 5.14-5.26 (m, 2H), 5.
70-5.87 (m, 1H), 7.27-7.63
(M, 5H) Mass (m / z): 556, 554, 498, 49
7,446,444,402,400,356,35
4,288,286 (5) (1S, 5R, 6S) -2-Bromo-6-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
1-Methyl-3-phenylthiocarbapenamu-3-carboxylic acid allyl ester 50 mg dichloromethane 2 ml
Under ice cooling, 16 mg of metachloroperbenzoic acid was added to the solution, and the mixture was stirred at the same temperature for 30 minutes. 3 ml of saturated aqueous sodium hydrogen carbonate was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer is washed with water and dried, and the solvent is distilled off. The residue was purified by preparative thin layer chromatography to give (1S, 5R, 6S) -6-
[(1R) -1-t-Butyldimethylsilyloxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid allyl ester is obtained.

NMR (CDCl ₃ ) δ: 0.00 (s,
3H), 0.88 (s, 9H), 1.12 (d, 3H,
J = 7.4 Hz), 1.25 (d, 3H, J = 6.1H)
z), 3.12-3.30 (m, 2H), 4.18-
4.30 (m, 2H), 4.64-4.80 (m, 2)
H), 5.23-5.44 (m, 2H), 5.86-
6.05 (m, 1H), 6.37 (d, 1H, J = 2.
7 Hz) Mass (m / z): 350 (M ⁺ -15), 340,
308 (M ⁺ -57) Example 4 (1) A solution of 2.4 g of diethylphosphonoethoxyacetic acid in 10 ml of tetrahydrofuran was cooled to -40 ° C, and n-
Add 14 ml of butyl lithium (1.6 M hexane solution). The temperature is raised to -20 ° C and cooled again to -50 ° C.
(3S, 4S) -1-t-Butyldimethylsilyl-3-
After adding a solution of 2.1 g of [(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-formylethyl] -2-azetidinone in 10 ml of tetrahydrofuran and heating to 0 ° C., Pour into ethyl acetate-citric acid aqueous solution. The aqueous layer is extracted with ethyl acetate, the combined organic layers are dried and the solvent is evaporated. The residue was purified by silica gel column chromatography to give (3S, 4S) -1-
t-Butyldimethylsilyl-3-[(1R) -1-t-
Butyldimethylsilyloxyethyl] -4-[(3R)
-(1-carboxyl-1-ethoxy) -1-butene-
2.1 g of 3-yl] -2-azetidinone are obtained.

NMR (CDCl ₃ ) δ: 0.0-0.3
(M, 12H), 0.9-1.1 (m, 18H), 1.
2-1.5 (m, 9H), 2.9-4.3 (m, 7)
H), 5.2-6.4 (m, 1H) Mass (m / z): 428 (M ⁺ -57) (2) (3S, 4S) -1-t-butyldimethylsilyl-3-[( 1R) -1-t-butyldimethylsilyloxyethyl] -4-[(3R)-(1-carboxyl-1
0.2 ml of acetic acid and 0.3 ml of tetrabutylammonium fluoride (1M tetrahydrofuran solution) were added to a solution of 100 mg of -ethoxy) -1-buten-3-yl] -2-azetidinone in 1 ml of tetrahydrofuran,
After stirring at room temperature for 14 hours, the reaction solution is concentrated. Ethyl acetate is added to the residue, the obtained organic layer is washed with water, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography to give (3S, 4S) -3-[(1R) -1-t.
-Butyldimethylsilyloxyethyl] -4-[(3
40 mg of R)-(1-carboxyl-1-ethoxy) -1-buten-3-yl] -2-azetidinone are obtained.

NMR (CDCl ₃ ) δ: 0.01 (s,
6H), 0.81 (s, 9H), 1.0-1.4 (m,
9H), 2.9-3.1 (m, 2H), 3.4-4.2.
(M, 5H), 6.07 (d, 1H, J = 10.3H
z), 6.13 (bs, 1H) Mass (m / z): 314 (M ⁺ -57) (3) (3S, 4S) -3-[(1R) -t-butyldimethylsilyloxyethyl]- 4-[(3R)-(1-
Carboxyl-1-ethoxy) -1-buten-3-yl] -2-azetidinone 20 mg acetonitrile 0.
10 mg of N-bromosuccinimide is added to the 5 ml solution, and the mixture is stirred at room temperature for 15 minutes. The solvent was evaporated, the residue was purified by silica gel column chromatography, and (1
S, 5R, 6S) -2-Bromo-6-[(1R) -1-
7 mg of t-butyldimethylsilyloxyethyl] -3-ethoxy-1-methylcarbapenamu-3-carboxylic acid are obtained.

NMR (CDCl ₃ ) δ: 0.06 (s,
3H), 0.07 (s, 3H), 0.88 (s, 9
H), 1.1-1.4 (m, 9H), 2.4-3.1.
(M, 1H), 3.2-3.3 (m, 2H), 3.7-
4.3 (m, 6H) Mass (m / z): 392 (M ⁺ -57) (4) (1S, 5R, 6S) -2-Bromo-6-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
By treating 3-ethoxy-1-methylcarbapenam-3-carboxylic acid in the same manner as in Example 2, (1S, 5
R, 6S) -6-[(1R) -1-t-butyldimethylsilyloxyethyl] -1-methylcarbapene-2-em-3-carboxylic acid is obtained.

Reference Example 1 (3S, 4S) -3-[(1R) -t-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxylethyl] -2-azetidinone 50 g in 600 ml of acetonitrile. Then, under a nitrogen stream, at room temperature, 28.2 g of carbonyldiimidazole is added and stirred for 30 minutes.
Thereafter, 12.3 ml of ethyl mercaptan is added, and the mixture is stirred at room temperature overnight. The reaction solution is concentrated, ethyl acetate is added to the residue, washed with water and dried, and then the solvent is distilled off. The obtained crystal is n
-Wash with hexane, dry, (3S, 4S) -3-
53 g of [(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-ethylthiocarbonylethyl] -2-azetidinone are obtained.

M. p. : 122-123 ° C IR (KBr) cm ^-1 : 3130, 3060, 175
8, 1687 NMR (CDCl ₃ ) δ: 0.07 (s, 6H), 0.
72 (s, 9H), 1.12 (d, 3H, J = 6.3H
z), 1.24 (d, 3H, J = 6.8 Hz), 1.2
6 (t, 3H, J = 7.4 Hz), 2.7-2.9
(M, 1H), 2.88 (q, 2H, J = 7.4H
z), 2.99 (dd, 1H, J = 3.6, 2.4H
z), 3.87 (dd, 1H, J = 4.9, 2.2H)
z), 4.1-4.3 (m, 1H), 5.88 (s, 1)
H) Reference Example 2 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-ethylthiocarbonylethyl] -2-azetidinone 3.0 g
And 2,6-lutidine 1.25 ml dichloromethane 3
2.5 ml of t-butyldimethylsilyl trifluoromethanesulfonate was added to the 0 ml solution under ice cooling. 2 at room temperature
After stirring for an hour, the reaction solution is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to give (3S, 4S) -1-t-butyldimethylsilyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R). 3.7 g of -1-ethylthiocarbonylethyl] -2-azetidinone are obtained.

NMR (CDCl ₃ ) δ: 0.05 (s,
3H), 0.08 (s, 3H), 0.23 (s, 3
H), 0.29 (s, 3H), 0.88 (s, 9H),
1.20-1.27 (m, 9H), 2.88 (q, 2
H, J = 6.6 Hz), 3.33 (dd, 1H, J =
7.2, 2.4 Hz), 3.65 (dd, 1H, J =
3.8, 2.6 Hz), 4.00 (quintet, 1
H, J = 7.2 Hz) Reference Example 3 (3S, 4S) -1-t-butyldimethylsilyl-3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-ethylthiocarbonylethyl] -2-azetidinone 0.5 g, 10% palladium-
To a mixture of 0.25 g carbon and 5 ml dichloromethane,
0.53 ml of triethylsilane is added under ice cooling. After stirring at the same temperature for 30 minutes, the catalyst is filtered off and the filtrate is concentrated. Ethyl acetate was added to the residue, and the obtained organic layer was washed with water,
After drying, the solvent was distilled off to give (3S, 4S) -1-t-butyldimethylsilyl-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1. −
0.79 g of formylethyl] -2-azetidinone (containing excess triethylsilane) is obtained.

NMR (CDCl ₃ ) δ: 0.06 (s,
3H), 0.09 (s, 3H), 0.19 (s, 3
H), 0.28 (s, 3H), 0.88 (s, 9H),
0.10 (s, 9H), 1.14 (d, 3H, J = 6.
2Hz), 1.24 (d, 3H, J = 6.0Hz),
2.76-2.82 (m, 1H), 2.96 (dd, 1
H, J = 7.7, 2.6 Hz), 3.81 (t, 1H,
J = 2.6 Hz), 4.05 (quintet, 1H,
J = 6.2 Hz), 9.80 (d, 1H, J = 1.4H
z)

[0080]

INDUSTRIAL APPLICABILITY According to the present invention, a β-lactam derivative [I], which is useful as a synthetic intermediate for penem-based and cephem-based antibacterial agents, can be easily obtained by a conventional method. It can be efficiently obtained from [III] in 2 to 3 steps. In addition, conventionally, in order to synthesize a penem-based and cephem-based β-lactam derivative from a 4-allylazetidinone derivative or a 4-allyloxyazetidinone derivative, the allyl group is ozone-oxidized to an aldehyde, and then Wittig is intramolecularly synthesized. Although it was necessary to react, according to the present invention, since it is not necessary to use such harmful and dangerous ozone, the method of the present invention is a synthetic intermediate for penem-based and cephem-based β-lactam antibacterial agents. It can be an industrially excellent manufacturing method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 501/04 9284-4C 501/08 9284-4C

Claims (5)

[Claims] 1. A compound represented by the general formula [II]: (Wherein R ¹ is an optionally protected hydroxy-substituted lower alkyl group; R ² is a hydrogen atom or an ester residue; R
³ is a lower alkyl group or a substituted or unsubstituted aryl group; X is a methylene group optionally substituted with a lower alkyl group or a group represented by the formula: -A-CH _2- ; A is a sulfur atom, an oxygen atom or methylene Group; Y is a halogen atom;
Z represents an oxygen atom or a sulfur atom. ) A bicycloalkane compound or a salt thereof represented by the groups Y and —ZR ³
The compound of the general formula [I] embedded image characterized by forming a double bond by the elimination reaction of (However, the symbols have the same meanings as described above.)
-A method for producing a lactam derivative or a salt thereof. 2. In the general formula [II], when Z is an oxygen atom, in the presence of an acylating agent, and when Z is a sulfur atom, in the presence of an oxidizing agent, the groups Y and -ZR ³ are removed. The method according to claim 1, wherein a separation reaction is carried out. 3. A compound represented by the general formula [III]: (Wherein R ¹ is an optionally protected hydroxy-substituted lower alkyl group; R ² is a hydrogen atom or an ester residue; R
³¹ is a lower alkyl group or a substituted or unsubstituted aryl group; X is a methylene group optionally substituted with a lower alkyl group or a group represented by the formula: -A-CH _2- ; A is a sulfur atom, an oxygen atom or methylene Represents a group. ), Or a salt thereof, is subjected to intramolecular ring closure in the presence of a halogenating agent to obtain a compound of the general formula [II-a] (Wherein Y represents a halogen atom and other symbols have the same meanings as described above), and the bicycloalkane compound or a salt thereof is treated with a group Y and an —OR ³¹ in the presence of an acylating agent.
3. The method according to claim 2, wherein the elimination reaction is performed. 4. A compound represented by the general formula [III]: (Wherein R ¹ is an optionally protected hydroxy-substituted lower alkyl group; R ² is a hydrogen atom or an ester residue; R
³¹ is a lower alkyl group or a substituted or unsubstituted aryl group; X is a methylene group optionally substituted with a lower alkyl group or a group represented by the formula: -A-CH _2- ; A is a sulfur atom, an oxygen atom or methylene Represents a group. ), Or a salt thereof, is subjected to intramolecular ring closure in the presence of a halogenating agent to obtain the compound of the general formula [II-a] (Wherein Y represents a halogen atom and other symbols have the same meanings as described above), and a bicycloalkane compound represented by the formula [IV] (Provided that R ³² represents a lower alkyl group or a substituted or unsubstituted aryl group) and is reacted with a thiol compound represented by the general formula [II-b] (Where the symbols have the same meanings as described above), and the compound [II-b] is subjected to elimination reaction of the group Y and -SR ³² in the presence of an oxidizing agent. The method according to claim 2, which is characterized in that: 5. The process according to claim 1, 2, 3 or 4, wherein R ¹ is an optionally protected 1-hydroxyethyl group and X is an ethylidene group.