JPH08169875A - Azetidinone compound and its production - Google Patents

Abstract

PURPOSE: To obtain a novel azetidinone compound which is useful as a synthetic intermediate for β-methylcarbapenem compounds having antibacterial activities from inexpensive starting materials through simple operations with good handleability. CONSTITUTION: This compound is represented by formula I [R is H, a readily removable protecting group; R<1> is an alkyl which may be substituted with (protected) OH or a halogen; R<2> is H, a (substituted) alkyl; R<3> and R<4> are each a (substituted) alkyl, a (substituted) aryl], for example, methyl N- (R)-2-[(3S, 4R)-3-[-(R)-1-t-butyldimethyl-silyloxy]-2-oxoazetidin-4-yl]propionyl}-N- isopropyldithio-carbamate. The compound of formula I is obtained by allowing a compound of formula II (Z is an eliminating group) to react with a compound of formula III in the presence of a compound of the formula: M(Hal)n (R<5> )m [M is a metal; Hal is a halogen; R<5> is a lower alkyl; a lower alkoxy, a (substituted) phenoxy, cyclopentadienyl; (m), (n) are each 0-5 where m+n is the valence of M] and a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an azetidinone compound which is a useful synthetic intermediate for a carbapenem compound, a process for producing the same, and use thereof.

[0002]

2. Description of the Related Art A general formula [V '] is used as a synthetic intermediate for carbapenem compounds.

[Chemical 10] (In the formula, R ¹ a protected unprotected alkyl group optionally substituted in good hydroxyl or halogen atom, R ²
Represents a hydrogen atom or an optionally substituted alkyl group. The carboxylic acid derivative represented by () is important, and several production methods thereof have been proposed.

Among them, Japanese Unexamined Patent Publication No. 62-252786 discloses a general formula [VIII].

[Chemical 11] [In the formula, R ¹ and R ² have the same meanings as described above, R represents a hydrogen atom or a protecting group of N which can be easily removed, and r ¹ represents two adjacent carbon atoms which may have a substituent. X is an oxygen atom, a sulfur atom or S
O, SO ₂ or Nr ² (r ² is a hydrogen atom, an alkyl group or a phenyl group), Y is an oxygen atom, a sulfur atom, or Nr ³ (r ³ is a hydrogen atom, an alkyl group or a phenyl group) .) Is shown. ] It is described that the 4-substituted azetidinone represented by the above formula is easily hydrolyzed to a carboxylic acid derivative represented by the general formula [V '].

In addition, Tetrahedron Let
t. Vol. 27 5687-5690 (1986) in general formula [IX]

[Chemical 12] (In the formula, X has the same meaning as described above, and r ⁴ and r ⁵ each represent a hydrogen atom or a methyl group.).

However, these general formulas [VIII] and [I
The 4-substituted azetidinone derivative represented by X] is manufactured using expensive boron triflate or tin triflate and is not industrially suitable.

Further, the general formula is disclosed in JP-A-63-170377.
[X]

[Chemical 13] (In the formula, r ⁶ represents a hydroxyl-protecting group, and r ⁷ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group.) The compound represented by the following formula Mg (OOCCH ₂ COOr ⁸ ) ₂ [XI] (in the formula, represents an r ⁸ carboxy protecting group) and reacted with a magnesium malonate compound to give a compound represented by the general formula [XI
I]

Embedded image (In the formula, r ⁶ and r ⁸ have the same meanings as described above.). However, even in this case, tin triflate is used for the production of the compound of the general formula [X], which is not preferable as an industrial production method.

[0007]

The present invention provides intermediates of 1β-methylcarbapenem compounds useful as antibacterial agents.

[0008]

The present inventors have completed the present invention as a result of earnestly studying an inexpensive and safe method without using expensive reagents or highly toxic reagents.

That is, the present invention has the general formula [I]

[Chemical 15] (In the formula, R is a hydrogen atom or a protecting group which can be easily removed, R ¹ is an optionally protected hydroxyl group or an alkyl group which may be substituted with a halogen atom, and R ² is a hydrogen atom or a substituted group. Optionally an alkyl group,
R ³ and R ⁴ are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. ), An azetidinone compound represented by the formula (1), a method for producing the same, and a method for using the same.

As the protecting group R for N, a protecting group generally used for protecting N can be used. Specific examples thereof include trisubstituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl, dimethylcumylsilyl, and optionally substituted benzyl groups. (Examples of the substituent include a nitro group and a lower alkoxy group.), A lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, and an optionally substituted benzyloxycarbonyl group (the substituents are a nitro group and a lower alkoxy group. And the like), and an acyl group such as an acetyl group and a benzoyl group.

As the hydroxyl-protecting group for R ¹ , a protecting group generally used for protecting a hydroxyl group can be used. Specific examples thereof include trisubstituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl, dimethylcumylsilyl, and optionally substituted benzyl groups. (Examples of the substituent include a nitro group and a lower alkoxy group.), A lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, and an optionally substituted benzyloxycarbonyl group (the substituents are a nitro group and a lower alkoxy group. And the like), an acetyl group, an acyl group such as a benzoyl group, a triphenylmethyl group, a tetrahydropyranyl group, and the like.

The alkyl group of R ² is a lower alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl, and its substituent is
Examples include lower alkoxy groups and halogen atoms.

Examples of the alkyl group for R ³ and R ⁴ include methyl, ethyl, propyl, butyl, pentyl, hexyl,
A straight chain having 1 to 20 carbon atoms such as heptyl and octyl,
Examples of the branched or cyclic alkyl group, and examples of the substituent thereof include a phenyl group, a lower alkoxy group and a halogen atom.

Examples of the aryl group of R ³ and R ⁴ include a phenyl group, a naphthyl group and an anthracenyl group.
Examples of the substituent include halogen atoms such as fluorine, chlorine and bromine, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and t-butyl, methoxy, ethoxy and propoxy. Examples include lower alkoxy groups, phenyl groups, alkylthio groups, substituted amino groups, nitro groups, cyano groups and the like.

The leaving group for Z is linear, branched or cyclic alkanoyloxy, aroyloxy optionally having a monocyclic or bicyclic heteroatom, arylalkanoyloxy, alkylsulfonyloxy, arylsulfonyloxy, carbamoyl. Oxy, alkoxycarboxy, aralkoxycarboxy, acyloxy groups such as alkoxyalkanoyloxy, alkanoylthio, acylthio groups such as aroylthio, alkylsulfinyl, sulfinyl groups such as arylsulfinyl, alkylsulfonyl, sulfonyl groups such as arylsulfonyl, fluorine,
Examples thereof include halogen atoms such as chlorine and bromine.

Examples of the base include secondary and tertiary amines and pyridines. For example, alkylamines such as dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, alkylanilines such as N-methylaniline, piperidine, and the like. Pyrrolidine, 2, 2,
Secondary amines such as heterocyclic amines such as 6,6-tetramethylpiperidine, morpholine and piperazine, alkylamines such as diisopropylethylamine, diisopropylmethylamine and triethylamine, dialkylanilines such as N, N-dimethylaniline, 1 -Ethylpiperidine, 4-methylmorpholine, 1-ethylpyrrolidine,
1,4-diazabicyclo [2,2,2] octane, 1,
Heterocyclic amines such as 8-diazabicyclo [5,4,0] -7-undecene or tertiary amines such as diamines such as N, N, N ′, N′-tetramethylethylenediamine, α, β or γ-picoline, 2,4-, 2,5
-2,6-, 3,4-, 3,5-lutidine, 2,4,
Examples thereof include alkylpyridines such as 6-collidine, dialkylaminopyridines such as dimethylaminopyridine, and pyridines such as condensed heterocyclized pyridines such as quinoline.

In the production of the compound represented by the general formula [I], the reaction includes chlorine-based solvents such as methylene chloride and chloroform, aromatic solvents such as chlorobenzene and toluene, polar solvents such as acetonitrile and propionitrile. Alternatively, in an organic solvent such as a mixed solvent thereof, an enolate is produced with a dithiocarbamate compound represented by the general formula [III] and a metal compound represented by the general formula [IV] and an amine, aniline or pyridine, and Enolate and general formula [I
I] to react with the azetidinone derivative. This reaction is both −50 ° C. to 100 ° C., especially −2 ° C., for both formation of enolate and reaction of enolate with azetidinone derivative.
It is preferably carried out at 0 ° C to 50 ° C.

The amounts of the dithiocarbamate compound represented by the general formula [III], the metal compound represented by the general formula [IV] and the base are 1 mol of the azetidinone derivative represented by the general formula [II]. 1 to 4 mol is suitable for each.

The compound represented by the general formula [I] is hydrolyzed to give the compound represented by the general formula [V].

Embedded image It can be converted into a carboxylic acid derivative represented by.

This hydrolysis reaction can be carried out by a conventional method. For example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide in a suitable solvent in the presence of hydrogen peroxide or It is carried out by using in the absence. As the solvent, for example, alcohols such as methanol and ethanol, an organic solvent such as acetone, tetrahydrofuran, dioxane and dimethylformamide, and a mixed solvent of water are used. The amount of the alkali metal hydroxide used is 1 mol of the compound represented by the general formula [I],
It is 2 to 8 mol, preferably 3 to 5 mol, and when hydrogen peroxide is used, the amount used is 3 to 10 mol, especially 4 to 8 mol. The reaction temperature is -10 to 80.
° C, especially 0-40 ° C is preferred.

In the reaction with magnesium malonate [VI], the reaction is an inert organic solvent, for example, a nitrile solvent such as acetonitrile or propionitrile, an ether,
Ether solvents such as tetrahydrofuran and dioxane,
Hydrocarbon solvents such as toluene, xylene, chlorobenzene, and cyclohexane, ethyl acetate, isopropyl acetate,
Ester solvents such as ethyl propionate and ethyl formate,
Examples thereof include ketone solvents such as acetone, diethyl ketone and methyl isobutyl ketone, and halogen solvents such as dichloromethane, chloroform and chlorobenzene.

The reaction temperature can be changed depending on the starting materials and the like, but usually -20 to 100 ° C. or the boiling temperature of the solvent is used. The reaction time varies depending on the reaction conditions (temperature, molar ratio), but is usually completed in about 1 to 30 hours. The amount of imidazole used relative to general formula [I] is 1 to 6 mol, preferably 1 to 4 mol, and magnesium malonate is 0.5 to 3 mol.

Examples of the ester residue of magnesium malonate include methyl, ethyl, isopropyl, t-butyl,
Examples thereof include allyl, benzyl, and substituted benzyl (the substituent includes nitro, methoxy, a halogen atom and the like, the number of substitutions and the position are arbitrary, but a p-nitro group is particularly preferable) and the like. After the completion of the reaction, the target product can be obtained by performing a usual post-treatment.

The starting compound represented by the general formula [III] can be produced, for example, according to the following reaction formula.

[Chemical 17] (In the formula, Hal and Halogen represent a halogen atom.) In the reaction, for example, amines represented by R ³ NH ₂ and carbon disulfide are water; a hydrocarbon solvent such as toluene and an ester system such as ethyl acetate. Solvents, halogen-based solvents such as chloroform and dichloromethane, ether-based solvents such as tetrahydrofuran, ketone-based solvents such as acetone, organic solvents such as acetonitrile; or in these mixed solvents, tertiary amines such as triethylamine; pyridine, lutidine, etc. Pyridines; R ⁴ − after reacting at −10 ° C. to 80 ° C. in the presence or absence of a base such as an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
An alkylating agent represented by Hal or R ⁴ ₂ SO ₄ in the presence or absence of a quaternary ammonium salt such as tetrabutylammonium bromide, benzyltriethylammonium chloride or a catalyst such as crown ether;
The dithiocarbamic acid ester obtained by reacting at 10 ° C. to 80 ° C. is isolated with or without isolation of R ² C.
Compound represented by H ₂ CO-Halogen and water; hydrocarbon solvent such as toluene, ester solvent such as ethyl acetate, halogen solvent such as chloroform and dichloromethane, ether solvent such as tetrahydrofuran, ketone such as acetone System solvents, organic solvents such as acetonitrile; or in mixed solvents thereof, tertiary amines such as triethylamine; pyridines such as pyridine and lutidine; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. The reaction is carried out at -30 ° C to 80 ° C in the presence of a base to obtain the compound represented by the general formula [III]. On this occasion,
Tetrabutylammonium bromide, quaternary ammonium salts such as benzyltriethylammonium chloride, crown ethers or 4- (N, N-dimethylamino)
The reaction may proceed smoothly by adding a catalytic amount of pyridine or the like.

[0025]

EXAMPLES Next, the present invention will be described in more detail by way of examples. The symbols in the examples have the following meanings. DIEA: N, N-diisopropylethylamine PNB: p-nitrobenzyl group

Example 1 Methyl N-{(R) -2-[(3S, 4R) -3-
[(R) -1-t-Butyldimethylsilyloxyethyl]
-2-oxoazetidin-4-yl] propionyl}-
N-isopropyl dithiocarbamate

Embedded image Methyl N-isopropyl-N-propionyl dithiocarbamate A solution of 0.41 g of methylene chloride in 4 ml of titanium tetrachloride 0.38 g of methylene chloride in 2 ml of −
It was added dropwise at 10 ° C. Next, at the same temperature, a solution of 0.26 g of diisopropylethylamine in 1 ml of methylene chloride was added dropwise, and then the temperature was raised to room temperature, (3R, 4R) -4.
0.29 g of -acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one was added. The reaction mixture was stirred at 20 to 25 ° C for 4 hr, poured into cold water, and the methylene chloride layer was washed with water. The methylene chloride layer was dried over anhydrous magnesium sulfate, and methylene chloride was distilled off. The residue was purified by silica gel column chromatography to obtain 0.23 g of orange crystals. ¹ H NMR (CDCl ₃ ) δ (ppm); 0.06 to 0.07 (6H, ss), 0.86 (9
H, s), 1.15 (3H, d), 1.21 (3H, d), 1.32 (6H, dd), 2.69 (3
H, s), 3.01 (1H, br), 3.03 (1H, m), 3.90 (1H, m), 4.16 (1
H, m), 4.68 (1H, m), 6.24 (1H, br)

Example 2 Ethyl N-benzyl-N-{(R) -2-[(3S,
4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} dithiocarbamate

[Chemical 19] To a solution of 14.8 g of ethyl N-benzyl-N-propionyl dithiocarbamate in 100 ml of methylene chloride, a solution of 11.0 g of titanium tetrachloride in 10 ml of methylene chloride was added dropwise at -8 ° C. Next, at the same temperature, 7.6 g of diisopropylethylamine was added dropwise, and then the temperature was returned to room temperature (3R, 4R) -4-acetoxy-3-[(R) -1-
t-Butyldimethylsilyloxyethyl] azetidine-2
8.14 g of on was added. The reaction mixture was stirred at room temperature for 3 hours, poured into cold water, and the methylene chloride layer was washed with water. The methylene chloride layer is dried over anhydrous magnesium sulfate,
The methylene chloride was distilled off. Crystals precipitated by adding n-heptane to the residue were collected by filtration and recrystallized from ethyl acetate-n-heptane to obtain 8.0 g of pale orange crystals. The mother liquor was concentrated and the residue was purified by silica gel chromatography to give a further 2.9 g. m. p. 100.5 to 103 ° C

Example 3 Methyl N-{(R) -2-[(3S, 4R) -3-
[(R) -1-t-Butyldimethylsilyloxyethyl]
-2-oxoazetidin-4-yl] propionyl}-
N-isobutyl dithiocarbamate

Embedded image To a solution of 10.1 g of methyl N-isobutyl-N-propionyldithiocarbamate in 100 ml of methylene chloride, a solution of 8.7 g of titanium tetrachloride in 10 ml of methylene chloride was added dropwise at -8 ° C. Next, at the same temperature, 5.9 g of diisopropylethylamine was added dropwise, and then the temperature was returned to room temperature (3R, 4R) -4-acetoxy-3-[(R) -1-
t-Butyldimethylsilyloxyethyl] azetidine-2
-ON 5.75 g was added. The reaction mixture was stirred at room temperature for 3 hours, poured into cold water, and the methylene chloride layer was washed with water. The methylene chloride layer is dried over anhydrous magnesium sulfate,
The methylene chloride was distilled off. Crystals precipitated by adding n-heptane to the residue were collected by filtration and recrystallized from ethyl acetate-n-heptane to obtain 4.1 g of pale orange crystals. The mother liquor was concentrated and the residue was purified by silica gel chromatography to give a further 3.5 g. m. p. 106-107.5 ° C

Example 4 Methyl N-{(R) -2-[(3S, 4R) -3-
[(R) -1-t-Butyldimethylsilyloxyethyl]
-2-oxoazetidin-4-yl] propionyl}-
N- (2-methoxyethyl) dithiocarbamate

[Chemical 21] Methyl N- (2-methoxyethyl) -N-propionyl dithiocarbamate 4.42 g methylene chloride 40 m
1.79 g of methylene chloride in 3.79 g of titanium tetrachloride
The solution of 1 was added dropwise at -5 ° C. Next, at the same temperature, 2.02 g of triethylamine was added dropwise, and then the temperature was returned to room temperature (3R, 4R) -4-acetoxy-3-[(R) -1.
-T-butyldimethylsilyloxyethyl] azetidine-
2.87 g of 2-one was added. The reaction mixture was stirred at room temperature for 1 hr, poured into cold water, and the methylene chloride layer was washed with water. The methylene chloride layer is dried over anhydrous magnesium sulfate,
The methylene chloride was distilled off. The residue was purified by silica gel chromatography and recrystallized from a mixed solvent of ethyl acetate-n-hexane to obtain 2.9 g of pale yellow crystals. m. p. 89 ~ 90 ° C

Examples 5 to 26 The corresponding N-propionyl dithiocarbamate compounds were prepared as (3R, 4R) -4-acetoxy-3-[(R) -1-
t-Butyldimethylsilyloxyethyl] azetidine-2
-On and treated in the same manner as in Examples 1 to 4, the compounds shown in Table 1 were obtained.

[Chemical formula 22]

[0031]

[Table 1]

NMR data (CDCl ₃ ) δ (ppm) * 1 Example 7 0.06 to 0.07 (6H, ss), 0.87 (9H, s), 1.15 (3H, d), 1.21 (3
H, d), 1.34 (6H, dd), 1.42 (3H, t), 3.00 (1H, br), 3.07 (1
H, m), 3.21 (2H, q), 3.92 (1H, m), 4.18 (1H, m), 4.68 (1H,
m), 6.11 (1H, br) * 2 Example 8 0.06 to 0.07 (6H, ss), 0.86 (9H, s), 1.12 (3H, d), 1.18 (3
H, d), 1.34 (6H, dd), 2.95 (1H, m), 3.18 (1H, m), 3.88 (1
H, m), 4.15 (1H, m), 4.46 (2H, q), 4.69 (1H, m), 6.07 (1H,
br), 7.34 (5H, m) * 3 Example 9 0.07 to 0.08 (6H, ss), 0.88 (9H, s), 1.17 (3H, d), 1.22 (3
H, d), 1.1 to 2.2 (10H, m), 2.70 (3H, s), 3.02 (1H, br), 3.
06 (1H, m), 3.94 (1H, m), 4.21 (1H, m), 4.33 (1H, m), 6.05
(1H, br) * 4 Example 10 0.07 to 0.08 (6H, ss), 0.87 (9H, s), 1.19 (3H, d), 1.26 (3
H, d), 1.1 ~ 2.1 (10H, m), 3.06 (1H, m), 3.23 (1H, m), 3.9
7 (1H, m), 4.22 (1H, m), 4.39 (1H, m), 6.29 (1H, br), 7.4
~ 7.6 (5H, m) * 5 Example 16 0.07 ~ 0.08 (6H, ss), 0.87 (9H, s), 1.16 (3H, d), 1.27 (3
H, d), 1.2 to 1.4 (14H, br), 1.69 (1H, br), 2.71 (3H, s),
2.95 (1H, br), 3.40 (1H, m), 3.91 (1H, m), 3.94 (2H, m),
4.17 (1H, m), 6.11 (1H, br) * 6 Example 17 0.05 to 0.06 (6H, ss), 0.87 (9H, s), 1.15 (3H, d), 1.22 (3
H, d), 1.15 ~ 1.4 (13H, br), 1.63 (2H, m), 2.67 (3H, s),
2.94 (1H, m), 3.36 (1H, m), 3.87 (1H, m), 3.94 (2H, t), 4.
16 (1H, m), 6.28 (1H, br), * 7 Example 19 0.06 to 0.07 (6H, ss), 0.85 (9H, s), 1.16 (3H, d), 1.23 (3
H, d), 1.32 (6H, d), 2.94 (1H, m), 3.28 (1H, m), 3.8 (2H, m
m), 4.14 (1H, m), 5.07 (2H, d), 5.93 (1H, br), 7.2 (5H, m)

Example 28 (R) -2-[(3S, 4S) -3-[(R) -1-t]
-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionic acid

[Chemical formula 23] Compound of Example 2, ethyl N-benzyl-N-
{(R) -2-[(3S, 4R) -3-[(R) -1-
t-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} dithiocarbamate 4.94 g of water-methanol mixed solvent (2: 1, 60
(ml) suspension with 4.9 g of 35% hydrogen peroxide solution at 20 ° C.
At the same time, a 28% aqueous sodium hydroxide solution (5.7 g) was added dropwise while adjusting the pH to 11 to 13. After completion of the reaction, 60 ml of water was added and the mixture was washed with methylene chloride, and then a 35% hydrochloric acid aqueous solution was added for acid precipitation. The precipitated crystals were collected by filtration, washed with water, and dried well to give white crystals 2.8.
g was obtained. From NMR, IR spectrum, and HPLC, the desired (R) -2-[(3S, 4S) -3-[(R) -1-
It was confirmed to be t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionic acid.

Example 29 4-Nitrobenzyl (R) -4-{(3S, 4R)-
3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate

[Chemical formula 24] Compound of Example 2, ethyl N-benzyl-N-
{(R) -2-[(3S, 4R) -3-[(R) -1-
9.90 g of t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} dithiocarbamate and 3.40 g of imidazole were dissolved in 40 ml of acetonitrile and reacted at 40 ° C. for 6 hours. After completion of the reaction, the mixture was cooled, and triethylamine (4.05) was added to a suspension of 9.57 g of mono-p-nitrobenzyl malonate, 1.90 g of anhydrous magnesium chloride and 80 ml of acetonitrile.
was added at room temperature to prepare Mg (OCOCH ₂ COO
PNB) ₂ solution. After reacting at 50 ° C. for 6 hours, the mixture was cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.95 g of white crystals. This is the target of 4 from NMR, IR, and HPLC.
-Nitrobenzyl (R) -4-{(3S, 4R) -3
It was confirmed to be-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate.

Example 30 4-Nitrobenzyl (R) -4-{(3S, 4R)-
3-[(R) -1-hydroxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate

[Chemical 25] 2.21 g of the compound of Example 1 and 0.39 g of imidazole
Was heated to reflux in 25 ml of acetonitrile for 2.5 hours. Then, the reaction solution was cooled, and 2.86 g of mono-p-nitrobenzyl malonate and 0.59 g of magnesium chloride were added.
And 1.22 g of triethylamine were added to a suspension of 20 ml of acetonitrile at room temperature to prepare Mg (OCOCH
₂ COOPNB) ₂ solution, DIEA 0.7
6 g was added and reacted at 50 ° C. for 4 hours. After the reaction,
The mixture was cooled to room temperature, 30 ml of water was added, 35% hydrochloric acid was added to adjust the pH to 1 or less, and the mixture was reacted at 25 ° C. for 6 hours. 300 ml of ethyl acetate was added to this reaction solution, and the mixture was washed with a 5% aqueous sodium hydrogen carbonate solution, water and saturated saline. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to 30 ml. To this concentrated solution, 150 ml of n-heptane was added, and the precipitated crystals were filtered, washed with 15 ml of a mixed solution of n-heptane: ethyl acetate (2: 1) and dried to obtain 1.61 g of a white powder. This compound is the target 4-nitrobenzyl (R) -4-{(3S, 4R)-from NMR, IR and HPLC.
It was confirmed to be 3-[(R) -1-hydroxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate.

Example 31 4-nitrobenzyl (R) -4-{(3S, 4R)-
3-[(R) -1-hydroxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate

[Chemical formula 26] 4.03 g of the compound of Example 2 and 0.77 g of imidazole
Was dissolved in 50 ml of acetonitrile and heated under reflux for 4 hours. Next, the reaction solution was cooled, and 4.96 g of mono-p-nitrobenzyl malonate and 0.87 g of magnesium chloride were added.
And Mg (OCOCH) prepared by adding 1.83 g of triethylamine at room temperature to a suspension of 30 ml of acetonitrile.
₂ COOPNB) ₂ solution, 0.83 g of triethylamine was further added, and the mixture was reacted at 50 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, 60 ml of water was added, 35% hydrochloric acid was added to adjust the pH to 1 or less, and the mixture was reacted at 25 ° C. for 6 hours. The reaction solution was concentrated to about 150 ml, and 200 ml of ethyl acetate was added for extraction. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated to 50 ml. To this concentrated solution, 80 ml of n-heptane was added, and the precipitated crystals were filtered, and n-heptane: ethyl acetate (2: 1) was added.
It is washed with 20 ml of mixed solution and dried to give a white powder 2.17.
g was obtained. This compound is the target 4-nitrobenzyl (R) -4-{(3S, 4
R) -3-[(R) -1-hydroxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate was confirmed.

Reference Example 1 Methyl Nn-butyl-N-propionyl dithiocarbamate

[Chemical 27] 3.90 g of n-butylamine and 5.3 of triethylamine
8 g was dissolved in 50 ml of toluene, and 4.13 g of carbon disulfide was added dropwise at 0 ° C. After stirring for 30 minutes, 8.02 g of methyl iodide was added dropwise and stirring was continued at room temperature for 3 hours. After completion of the reaction, the organic layer was washed with water, diluted hydrochloric acid, diluted aqueous sodium hydrogen carbonate solution and saturated saline in this order, and dried over anhydrous magnesium sulfate. To this solution, 5.55 g of propionyl chloride and a catalytic amount of 4- (N, N-dimethylamino) pyridine were added, and 6.06 g of triethylamine was added dropwise at 60 ° C. After aging for another 30 minutes at the same temperature, cool to room temperature,
The organic layer was washed with water, diluted hydrochloric acid, diluted aqueous sodium hydrogen carbonate solution and saturated saline in this order, and dried over anhydrous magnesium sulfate. Toluene was distilled off under reduced pressure, and the resulting residue was purified by distillation under reduced pressure to obtain 10.1 g of an orange liquid (bp.
89-97 ° C / 1-2 mmHg).

Reference Example 2 Ethyl N-benzyl-N-propionyl dithiocarbamate

[Chemical 28] Benzylamine 4.29 g and triethylamine 4.05
g was dissolved in 30 ml of toluene, and 3.05 g of carbon disulfide was added dropwise at 10-20 ° C. After the dropping, 6.17 g of diethyl sulfuric acid was added dropwise, and the mixture was reacted at 40-50 ° C for 2 hours.
After completion of the reaction, the mixture was cooled to room temperature and washed with water, and then toluene was distilled off under reduced pressure. The obtained oily substance was dissolved again in 30 ml of toluene, 3.92 g of propionyl chloride was added at room temperature, and then 4.29 g of triethylamine was added dropwise. After reacting at room temperature for another 1 hour, the mixture was washed with water and toluene was distilled off under reduced pressure.
The obtained residue was recrystallized from n-hexane to give a yellow crystal 1.
0.0 g was obtained (mp 50-51 ° C.).

Synthesis examples including Reference Examples 1 and 2 are shown in Table 2.

[0040]

The compound of the present invention has antibacterial activity.
(R) -2-[(3S, 4S) -3-, which is useful as an intermediate for the production of β-methylcarbapenem compounds and is a general-purpose intermediate for 1β-methylcarbapenem compounds.
[(R) -1-t-butyldimethylsilyloxyethyl]
2-oxoazetidin-4-yl] propionic acid and 4
-Nitrobenzyl (R) -4-{(3S, 4R) -3
It can be easily converted into-[(R) -1-hydroxyethyl] -2-oxoazetidin-4-yl} -3-oxovalerate and the like. Further, the production of the compound of the present invention is an inexpensive raw material and is easy to handle and operate, which is advantageous as an industrial production method.

[Table 2]

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Claims (7)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R is a hydrogen atom or a protecting group which can be easily removed, R ¹ is an optionally protected hydroxyl group or an alkyl group which may be substituted with a halogen atom, and R ² is a hydrogen atom or a substituted group. Optionally an alkyl group,
R ³ and R ⁴ are the same or different and each represents an optionally substituted alkyl group or an optionally substituted aryl group. ) Azetidinone compound represented by. 2. A compound represented by the general formula [II]: (In the formula, R represents a hydrogen atom or a protecting group which can be easily removed, R ¹ represents a hydroxyl group which may be protected or an alkyl group which may be substituted with a halogen atom, and Z represents a leaving group.) And an azetidinone derivative represented by the general formula [III] (In the formula, R ² represents a hydrogen atom or an optionally substituted alkyl group, and R ³ and R ⁴ represent the same or differently substituted alkyl groups or optionally substituted aryl groups. And a dithiocarbamate compound represented by the general formula M (Hal) _n (R ⁵ ) _m [IV] (wherein M is a metal atom, Hal is a halogen atom, R
⁵ is a lower alkyl group, a lower alkoxy group, a phenoxy group, a substituted phenoxy group, or a cyclopentadienyl group, n and m are 0, 1, 2, 3, 4 or 5, and n + m is a valence of M Indicates. ) The compound represented by the general formula [I] (In the formula, R, R ¹ , R ² , R ³ and R ⁴ are the same as above.)
The manufacturing method of the azetidinone compound represented by. 3. The method according to claim 2, wherein M is Ti or Zr and m + n is 4. 4. The method according to claim 2, wherein M is Al and m + n is 3. 5. A compound represented by the general formula [I] is: (Wherein R ⁶ represents a protective group for a hydroxyl group, and R ³ and R ⁴ have the same meanings as described above), and the compound and the method for producing the same according to claim 1. 6. A compound represented by the general formula [I]: (Wherein R, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above) and hydrolyze an azetidinone compound represented by the general formula [V] (In the formula, R, R ¹ and R ² have the same meanings as described above.) A method for producing a compound represented by the formula. 7. A compound represented by the general formula [I]: (Wherein R, R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), the azetidinone compound represented by the general formula Mg (OOCCH ₂ COOR ⁷ ) ₂ [VI ] (Wherein R ⁷ represents a lower alkyl group or a carboxy protecting group), the compound is reacted with a magnesium malonate compound represented by the general formula [VII] (In the formula, R, R ¹ , R ² and R ⁷ have the same meanings as described above.)