JPH0321025B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing 3-acetyl-2-azetidinone derivatives by reacting diketene with Schiff's base obtained from an aldehyde in the presence of imidazoles. 3-acetyl-2-azetidinone derivatives can be useful intermediates in the production of various β-lactam antibacterial agents, such as carbapenem derivatives having a 1-hydroxyethyl group at the 6-position or penem derivatives. Several methods are already known for its production, but each method requires a long number of steps, complicated reaction operations, or involves unstable intermediates. It has the following disadvantages. The present inventors have conducted intensive research to develop a new method for producing 3-acetyl-2-azetidinone derivatives that is easy to operate and has high efficiency. The present invention was completed based on the discovery that the object can be achieved by reacting in the presence of imidazoles. The method of the present invention will be explained in detail below. The production method of the present invention includes, in the presence of imidazoles,
This method involves reacting diketene with a suitable Schiff base in an inert solvent to obtain a 3-acetyl-2-azetidinone derivative. The imidazoles used in the reaction include imidazole, 4-methylimidazole, 2,
Various imidazole derivatives can be mentioned, such as imidazoles substituted with lower alkyl at the 2- or 4-position such as 4-dimethylimidazole and 2-methylimidazole.
-Methylimidazole is preferred. The imidazole can be used in a catalytic amount to a large excess amount, but it is preferable to use an amount of 0.1 to 1.5 times the molar amount of Schiff's base. Examples of inert solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane,
Halogenated hydrocarbons such as chloroform, 1,2-dichloroethane or mixtures thereof are preferred. diethyl ether, tetrahydrofuran,
Ethers such as dioxane and ethylene glycol dimethyl ether, nitriles such as acetonitrile, aliphatic hydrocarbons such as hexane, heptane, cyclohexane, and pentane, dimethylformamide, dimethyl sulfoxide, and acetic acid esters such as methyl acetate and ethyl acetate, etc. Solvents can also be used. It is possible to suppress or accelerate the reaction by cooling or heating, but the reaction temperature is -
10°C to 120°C is preferred. After completion of the reaction, the target compound of this reaction can be taken out by ordinary organic chemical techniques. By the method of the present invention, it is possible to obtain β-lactam derivatives having an acetyl group at the 3-position of the β-lactam ring. It is useful as a synthetic intermediate. For example, the compound of formula (1) obtained by the method of the present invention can be led to the compound of formula (5) by the following synthetic route. [In the formula, R represents a carboxyl group-protecting group or a cyclic alkyl group, DAM represents a di-p-anisylmethyl group, and Y represents a hydrogen atom or a hydroxyl group-protecting group. ] The reduction of the carbonyl group of the acetyl compound (1) can be carried out according to various methods generally used for reducing a carbonyl group to a hydroxyl group. Hydrolysis of the ester group of compound (2) is generally carried out according to a well-known method. For example, the reaction can be carried out by reacting compound (2) with caustic soda in a solvent such as methanol or tetrahydrofuran in the presence of water at 0 to 40°C. The method for converting carboxylic acid (3) into ester (4) can be carried out, for example, according to the method described in Tetrahedron Letters, 2293 (1982). Further, the reaction of converting the acetyl compound (1) into compound (2) can also be carried out according to the method described in the above-mentioned literature. Compound (4) can be converted to compound (5) in various ways, for example, by treatment with Ceric ammonium nitrate in acetonitrile-water at 15 to 35°C. It is possible to achieve a DAM removal reaction, and the method described in JP-A-57-11962 can be applied. In addition, the hydroxyl group of compound (4) was converted to p-
It is also possible to perform the above-mentioned DAM removal reaction after protection with various hydroxyl protecting groups such as nitrobenzyloxycarbonyl and t-butyldimethylsilyl. Compound (5) can be obtained by known methods such as the above-mentioned method.
Carbapenem derivatives such as thienamycin can be derived according to the method described in Tetrahedron Letters, 2293 (1982). As the raw material Schiff base obtained from aldehyde, Schiff bases having various substituents can be used, and derivatives having various substituents on the N-atom or 4-position of 3-acetyl-2-azetidinone can be used. can be manufactured. For example, according to the method of the present invention, the general formula [] [In the formula, R ₁ represents an arylmethyl group, a diarylmethyl group, or an aryl group, and R ₂ represents a carboxyl group, a cyclic alkyloxycarbonyl group, or an aryl group protected by a protecting group. ] By reacting the Schiff base represented by the formula with diketene, the general formula [] [In the formula, R ₁ and R ₂ have the same meanings as above. ] A β-lactam derivative represented by the following can be obtained. The Schiff base of the general formula [], which is a raw material compound, can be easily synthesized from the corresponding aldehyde and amine according to commonly used known methods. Alternatively, it can be subjected to reaction with diketene without isolation. Next, R ₁ and R ₂ in the above formula will be described in detail. In R ₁ , examples of the arylmethyl group include benzyl group, substituted benzyl group, etc., examples of the diarylmethyl group include unsubstituted or substituted diphenylmethyl group, and examples of the aryl group include phenyl group, substituted phenyl group, etc. etc. can be mentioned. Furthermore, the substituted benzyl group includes a p-methoxybenzyl group, a benzyl group substituted with a lower alkoxyl group having 1 to 3 carbon atoms such as a 2,4-dimethoxybenzyl group, and a nitro group such as a p-nitrobenzyl group. The substituted benzyl group etc., as the substituted diphenyl group and methyl group, di-p
- A diphenylmethyl group substituted with a lower alkoxyl group having 1 to 3 carbon atoms such as anisylmethyl group, and a substituted phenyl group such as a lower alkoxyl group having 1 to 3 carbon atoms such as p-methoxyphenyl group. Examples include substituted phenyl groups. In R ₂ , the protecting group for the carboxyl group is a commonly used protecting group, such as a lower alkyl group, a mono- or diaryl lower alkyl group, an aryl group, a substituted lower alkyl group, and the like. Here, examples of lower alkyl groups include linear or branched lower alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl. Examples of mono- or diaryl lower alkyl groups include benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, p-nitrobenzyl group, o-nitrobenzyl group, diphenylmethyl group, di-p-anisylmethyl group. Examples of aryl groups include unsubstituted or substituted mono- or diphenylmethyl groups with lower alkoxyl groups having 1 to 3 carbon atoms or nitro groups, such as phenyl groups, p-nitrophenyl groups, etc. Examples of substituted lower alkyl groups include phenyl groups substituted with 2,
1 or more carbon atoms substituted with halogen atoms such as 2,2-trichloroethyl group and 2-iodoethyl group
3 lower alkyl group, benzyloxymethyl group,
Examples include a lower alkyl group having 1 to 3 carbon atoms substituted with a benzyloxy group such as a methoxymethyl group or a lower alkoxyl group having 1 to 3 carbon atoms. Furthermore, in R ₂ , examples of the cyclic alkyloxycarbonyl group include a menthyloxycarbonyl group and norbornyloxycarbonyl group, and examples of the aryl group include a phenyl group and a p-methoxyphenyl group having 1 to 3 carbon atoms. Examples include phenyl groups substituted with lower alkoxyl groups. In the compound represented by the general formula [] obtained by the method of the present invention, there are two steric relationships, cis and trans, between the 3-acetyl group and _R2 , and although stereoisomers exist, trans You can get a body. Note that the acetyl group and the substituted carbons at the 3rd and 4th positions of R ₂ are asymmetric carbons, and optical isomers exist. Furthermore, the general formula obtained by the method of the present invention [] [In the formula, R ₁ has the same meaning as above. ] In the β-lactam compound represented by
The production ratio of the two optical isomers 4-(R)-derivative and 4-(S)-derivative derived from the asymmetric carbon at the 4-position of the lactam ring is based on the ratio between the menthyl group and the l-(-)-menthyl group, for example. By using an optically active menthyl group, it is possible to obtain a 4-(S)-derivative as the main product, although it varies depending on the reaction conditions, the type of R ₁ substituent, etc. As described above, the method of the present invention provides an effective 3-acetyl-2-azetidinone derivative and a method for producing the same. Next, the present invention will be further explained with reference to Examples, but the present invention is of course not limited to these in any way. In addition, in the following examples, the following abbreviations are made. l-(-)-menthyl group

[Formula]: Men di-p-anisylmethyl group

[Example 1]

Di-p-anisylmethylamine 2.43g
(10mM), n-butyl glyoxylate 1.78g
(12mM) was dissolved in toluene (95ml), azeotropically dehydrated to produce Schiff's base, and the same amount of toluene as the distilled amount was added, and 0.68g of imidazole was added.
(10mM) and 1.01g of diketene at 50℃.
(12mM) in toluene (30ml) was added dropwise over 2 hours and stirred for 15 minutes. The reaction solution was poured into cold diluted hydrochloric acid and extracted with toluene, followed by 2N-hydrochloric acid, saturated saline,
By washing with saturated sodium bicarbonate solution and saturated brine, drying with sodium sulfate, and distilling off the solvent under reduced pressure, the obtained oil was separated and purified using silica gel column chromatography to obtain 1-
(di-p-anisylmethyl)-3-acetyl-4-
n-butyloxycarbonyl-2-azetidinone
3.86g (88%) was obtained. mp,: 92.5~94.0℃ IR ^nujol/max (cm ^-1 ): 1765, 1740, 1712, 1612,
1255, 1026, 818 NMRδ ( _CDCl3 ): 0.60−1.80 (7H, m), 2.28
(3H, S), 3.77 (6H, S), 3.77-4.15
(2H, m), 41.7 (1H, d, J=2Hz),
4.40 (1H, d, J=2Hz), 5.78 (1H, S),
6.60-7.40 (8H, m), ppm [Example 2] Di-p-anisylmethylamine 243mg (1mM),
178mg (1.2mM) of n-butyl glyoxylate was dissolved in toluene (12ml), azeotropically dehydrated to produce Schiff's base, added with the same amount of toluene as the distilled amount, and 82mg (1mM) of 4-methylimidazole was added. In addition, a solution of 101 mg (1.2 mM) of diketene in toluene (0.5 ml) was added dropwise at 50°C over 20 minutes, and the mixture was stirred for 3 hours.
The reaction solution was poured into cold dilute hydrochloric acid, extracted with toluene,
The extract was mixed with 2N hydrochloric acid, saturated saline, saturated sodium bicarbonate solution,
After washing with saturated brine and drying with Glauber's salt, the solvent was distilled off under reduced pressure, and the resulting oil was separated and purified by silica gel thin layer chromatography to obtain 1-(di-p-
(anisylmethyl)-3-acetyl-4-n-butyloxycarbonyl-2-azetidinone 240mg
(55%). IR and NMR were the same as those obtained in [Example 1]. [Example 3] Di-p-anisylmethylamine 243mg (1mM),
178mg (1.2mM) of n-butyl glyoxylate was dissolved in toluene (12ml), azeotropically dehydrated to produce Schiff base, added with the same amount of toluene as the distilled amount, and 82mg (1mM) of 2-methylimidazole was dissolved. In addition, a solution of 101 mg (1.2 mM) of diketene in toluene (0.5 ml) was added dropwise at 50°C over 20 minutes, and after stirring for 2 hours, the mixture was further stirred at 60°C for 1 hour and at 80°C for 1 hour. By performing post-treatment and separation and purification in the same manner as described in [Example 2], 24 mg of 1-(di-p-anisylmethyl)-3-acetyl-4-n-butyloxycarbonyl-2-azetidinone ( 5%). IR and NMR were the same as those obtained in [Example 1]. [Example 4] Di-p-anisylmethylamine 1.118g
(4.6mM) and 1.058g (4.6mM) of l-(-)-menthyl glyoxylate were dissolved in toluene (43ml), azeotropically dehydrated to produce Schiff base, and the same amount of toluene as the distilled amount was dissolved in toluene (43ml). In addition, imidazole 313mg
(4.6mM) and 4.646g of diketene at 50℃
(5.5mM) in toluene (14ml) was added dropwise over 2 hours and stirred. By post-treating and separating and purifying the reaction solution in the same manner as described in [Example 1], 1-(di-p-anisylmethyl)-3-acetyl-4-l-(-)-menthyloxy Carbonyl-
1.965 g (82%) of 2-azetidinone was obtained.
(The production ratio of 4-(S) form and 4-(R) form obtained by NMR was 3:2.) Furthermore, 1-(di-
p-anisylmethyl)-3-acetyl-4-l-
(−)-Menthyloxycarbonyl-2-azetidinone can be separated into the 4-(S) form by fractional recrystallization with n-hexane-carbon tetrachloride solvent, and (3S,4S)-1 -(di-p-anisylmethyl)-3-acetyl-4-l-(-)-menthyloxycarbonyl-2-azetidinone was obtained. mp: 99-100℃ IR ^nujol/max (cm ^-1 ): 1763, 1739, 1712, 1613,
1510, 1242, 1033 _, 818 NMRδ ( _C6D6 ): 0.50-1.95 (19H, m), 1.94
(3H, S), 3.33 (6H, S), 4.00 (1H, d,
J=2Hz), 4.75 (1H, d, J=2Hz),
4.40-5.05 (1H, m), 5.90 (1H, S), 6.60
~7.60 (8H, m) ppm Also, by crystallizing the liquid with n-hexane-carbon tetrachloride solvent, (3R,4R)-1-
(di-p-anisylmethyl)-3-acetyl-4-
l-(-)-menthyloxycarbonyl-2-azetidinone was obtained. mp: 123~125℃ IR ^nujol/max (cm ^-1 ): 1770, 1740, 1713, 1606,
1506, 1241, 1202, 1028 _, 822 NMR δ ( _C6D6 ): 0.50-1.95 (19H, m), 1.93
(3H, S), 3.28 (3H, S), 3.30 (3H,
S), 4.12 (1H, d, J = 2Hz), 4.75 (1H,
d, J=2Hz), 4.40-4.85 (1H, m),
5.94 (1H, S), 6.50-7.50 (8H, m), pp
m. [Example 5] Di-p-anisylmethylamine 243mg (1mM),
178mg (1.2mM) of n-butyl glyoxylate was dissolved in toluene (7ml), azeotropically dehydrated to produce Schiff's base, added with the same amount of toluene as the distilled amount, and added with 34mg (0.5mM) of imidazole. A solution of 101 mg (1.2 mM) of diketene in toluene (5.5 ml) was added dropwise over 2 hours at °C, and the mixture was further stirred for 1.3 hours. The reaction solution was post-treated and separated and purified in the same manner as described in [Example 2] to obtain 356 mg of 1-(di-p-anisylmethyl)-3-acetyl-4-n-butyloxycarbonyl-2-azetidinone ( 81%). (IR and NMR were the same as those obtained in [Example 1].) [Example 6] Di-p-anisylmethylamine 243mg (1mM),
178 mg (1.2 mM) of n-butyl glyoxylate was dissolved in toluene (7 ml), azeotropically dehydrated to produce Schiff base, added with the same amount of toluene as the distilled amount, and 7 mg (0.1 mM) of imidazole. 50℃
Diketene 101mg (1.2mM) in toluene (5.5ml)
The solution was added dropwise over 2 hours and stirred for 3 hours. The reaction solution was post-treated in the same manner as described in [Example 2],
By separating and purifying, 263 mg (60%) of 1-(di-p-anisylmethyl)-3-acetyl-4-n-butyloxycarbonyl-2-azetidinone was obtained.
I got it. (IR and NMR were the same as those obtained in [Example 1].) The following compounds can be obtained by the same method as shown in [Example 1]. In addition, in the column of "raw material compound", "amount" indicates the amount of the corresponding amine (R ₁ -NH ₂ ) and aldehyde (R ₂ -CHO) used to generate Schiff's base.

【table】

[Example 15]

[Men(d) represents a d-(+)-menthyl group. ] Di-p-anisylmethylamine (243 mg), d-(+)-menthyl glyoxylate (230 mg), diketene (101 mg), and imidazole (75 mg) were used to react according to the method of Example 1. After post-treatment, 4391 mg of 1-(di-p-anisylmethyl)-3-acetyl-4-d-menthyloxycarbonyl-2-azetidinone) was obtained. The ratio of 4S and 4R isomers in high performance liquid chromatography (HPLC) is approximately 2.
It was against 3. Note that the MNR showed a spectrum similar to that obtained in Example 1. [Example 16] 243mg (1mM) of di-p-anisylmethylamine and 265mg (1mM) of 1-(±)-(2,4-dichlorophenyl)-ethylglyoxylate were dissolved in dry toluene (12ml) and dried azeotropically. Add the same amount of dry toluene as the distilled amount to generate a base, add 68 mg (1 mM) of imidazole, and add diketene (101
mg) diluted with 42 ml of dry toluene at 50°C.
The mixture was added dropwise over 20 minutes and stirred at the same temperature for 1 hour. Two isomers were obtained by adding brine to the reaction solution, extracting with toluene, washing with water, drying with mirabilite, distilling off the solvent, and purifying the residue by silica gel chromatography.
I got 393mg and 93mg. Their IR and NMR data were as follows. Isomer 1 IR ^CHCl3/max (cm ^-1 ); 1755, 1715, 1602, 1453,
1353, 1168, 1022 NMRδ (C ₆ D ₆ ): 1.12 (3H, dJ=6.6Hz) 1.92 (3H,
s), 3.87 (1H, dJ=, 2.2Hz) 4.75 (1H,
dJ=2.2Hz) ppm Isomer 2 IR ^CHCl3/max (cm ^-1 ); 1758, 1715, 1605, 1352 NMRδ (C ₆ D ₆ ): 1.14 (3H, dJ=6.4Hz), 1.89 (3H, s) , 3.92 (1H, dJ=2.4Hz), 4.81 (1H, dJ=2.4Hz) ppm [Example 17] a Di-p-anisylmethylamine (243 mg) R-
(+)-1-Phenylethyl glyoxylate (196 mg) was dissolved in toluene (12 ml), azeotropically dehydrated to produce Schiff's base, added with the same amount of toluene as the distilled amount, and imidazole (68 mg). and 50
A solution of diketene (101 mg) in toluene (2 ml) was added dropwise over 20 minutes at °C, and the mixture was stirred at the same temperature for 1 hour. (3S,
4S)-1-(di-p-anisylmethyl)-3-acetyl-4-(R-(+)-phenylethyloxycarbonyl)-2-azetidinone (334 mg) and (3R,
4R) body (118 mg) was obtained. The IR and NMR data of the (3S, 4S) body were as follows. IR ^CHCl ₃ ^/max (cm ^-1 ): 1753, 1713, 1600, 1345,
1163, 1018 NMRδ (C ₆ D ₆ ): 1.21 (3H, dJ=6.6Hz), 1.84
(3H, s), 3.94 (1H, dJ=2.2Hz), 4.78
(dJ=2.2Hz), IR and NMR data of P・p・m・(3R,4R) body were as follows. IR, ^CHCl ₃ ^/max (cm ^-1 ): 1757, 1715, 1600, 1165 NMR, δ (C ₆ D ₆ ): 1.16 (3H, dJ=6.6Hz), 1.79
(3H, s), 3.80 (1H, dJ=2.2Hz), 4.76
(1H, dJ=2.2Hz)p・p・m・b Example using S-(-)-1-phenylethylglyoxylate instead of R-(+)-1-phenylethylglyoxylate By carrying out the reaction in the same manner as in 9 a), (3S,4S)-1-(di-p-
anisylmethyl)-3-acetyl-4-(S-(-)
-1-phenylethyloxycarbonyl)-2-
A mixture of azetidinone and (3R,4R) isomers was obtained.
NMR was similar to that obtained for the R-(-)-isomer.
NMR analysis showed that the ratio of (3S, 4S) and (3R, 4R) isomers was 1:3. The following compounds were obtained in the same manner as in [Example 1]. In the table, "amount of glyoxylate" and "amount of amine" refer to the corresponding glyoxylate (OHC-COOR ₃ ) and amine (R ₁ -NH ₂ ) used to generate Schiff's base, respectively. indicates the amount of

【table】

【table】

[Reference example 2]

(3S,4S,5R)-1-(di-p-anisylmethyl)
-3-(1-hydroxyethyl)-4-l-(-)-
Menthyloxycarbonyl-2-azetidinone (30 mg) was dissolved in tetrahydrofuran (0.9 ml) and methanol (0.45 ml), and after dropwise addition of 1N sodium hydroxide (0.06 ml), the mixture was stirred at room temperature for 4 hours.
The reaction mixture was neutralized with 1N hydrochloric acid, concentrated, diluted with ether, added with 1N sodium hydroxide (0.1 ml), and extracted with water. 1N-hydrochloric acid (0.12 ml) was added dropwise to the extracted aqueous layer, and after extraction with ether, the extract was washed with water, dried with sodium sulfate, and the solvent was distilled off to obtain (3S,
4S,5R)-1-(di-p-anisylmethyl)-3-
(1-hydroxyethyl)-4-carboxyl-2
-Azetidinone (22 mg) was obtained. IR ^nujol/max (cm ^-1 ): 3250, 1750, 1723, 1515,
1305, 1250, 1177, 1030, 835NMRδ ( _CDCl3 ): 1.22 (3H, dJ=6
Hz), 3.18 (1H, m), 3.72 (6H, s), 4.10 (1H,
dJ=2Hz), 5.75 (1H, s) ppm [Reference example 3] (3-a) Step (3S,4S,5R)-1-(di-p-anisylmethyl)-3-(1-hydroxy)-4-carboxyl-2-azetidinone (4.0g), potassium acetate (1.0g) Lead tetraacetate (5.3 g) was added in several portions to a dimethylformamide (20 ml) solution at 40°C, and the mixture was stirred for 1 hour. After adding ethylene glycol and stirring for several minutes, the reaction solution was diluted with saturated brine and ethyl acetate, filtered to remove insoluble matter, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and then the solvent was distilled off. By isolating and purifying the obtained residue by silica gel column chromatography, (3R, 4R, 5R)
-1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-2-azetidinone (3.23 g) was obtained. IR ^CHCl3/max (cm ^-1 ): 1752, 1357, 1302, 1242,
1174, 1028, 953 NMRδ (CDCl ₃ ): 1.26 (3H, dJ=6.5Hz), 1.90
(3H, s), 3.07 (1H, broad, dJ=6.5
Hz), 3.78 (6H, s), 4.07 (1H, m), 5.83
(1H, broad, s) 5.88 (1H, broad, s)
ppm Specific power [α] ^22/D +26.0° (c=0.04, CHCl ₃ ) (3-b) Step (3R,4R,5R)-1-(di-p-anisylmethyl)-3-(1 A solution of -hydroxyethyl)-4-acetoxy-2-azetidinone (1.0 g) in methylene chloride (5 ml) was cooled with ice, 4-dimethylaminopyridine (0.61 g) was added, and p-nitrobenzylchloroformate (0.77 g) of methylene chloride (5
ml) solution was added dropwise, and after stirring for 1 hour, toluene (25
ml) was added. Remove the precipitate and drain the liquid.
Washed sequentially with 2N hydrochloric acid and saturated saline, dried with mirabilite,
The solvent was distilled off. By isolating and purifying the obtained residue by silica gel column chromatography, (3R,
4R,5R)-1-(di-p-anisylmethyl)-3
-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (1.2 g) was obtained. IR ^neat/max (cm ^-1 ): 1770, 1740, 1610, 1583,
1020, 850, 818, 735 NMRδ (CHCl ₃ ): 1.42 (3H, dJ=6Hz), 1.85
(3H, s), 3.28 (1H, dJ=6Hz), 3.73
(6H, s), 5.22 (2H, s), 5.87 (1H,
s), 6.11 (1H, s) ppm Specific light intensity [α] ^22/D +40.5° (c=0.38, CHCl ₃ ) [Reference example 4] (4-a) Step (3R,4R,5R)-1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (0.75g) A 10% water-acetonitrile (5 ml) solution of Ceric ammonium nitrate (1.59 g) was added dropwise to a 10% water-acetonitrile (5 ml) solution at room temperature.
Stir for 30 minutes. After adding an aqueous solution (1.5 ml) of sodium sulfite (0.05 g) and stirring, the reaction solution was diluted with saturated brine and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and saturated brine, dried with mirabilite, and the solvent was distilled off. The residue was isolated and purified by silica gel column chromatography to obtain (3R,
4R,5R)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2
-Azetidinone (0.42g) was obtained. IR ^neat/max (cm ^-1 ): 3300, 1774, 1745, 1602,
1344, 1258, 1029, 843 NMRδ (CDCl ₃ ): 1.45 (3H, dJ=6.0Hz), 2.09
(3H, s), 3.37 (1H, ddJ=1.2 and 6.0
Hz), 5.25 (2H, s), 5.87 (1H, dJ=1.2
Hz), 6.96 (1H, broad, s) ppm Specific light intensity [α] ^22/D +36.6° (c = 0.09, CHCl ₃ ) (4-b) Step 5% palladium on carbon (300 mg) was added to ethanol (5 ml) ) - The mixture was stirred in water (5 ml) under a hydrogen atmosphere for 30 minutes and washed with water. The quality obtained,
Add a solution of (3R,4R,5R)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone (3.00g) in ethanol (30ml), and under hydrogen atmosphere for 2 hours. Stirred. The reaction solution was filtered through Celite, the solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain (3R,4R,5R)-3-(1-hydroxyethyl)-4-acetoxy-2-azetidinone (0.900g). I got it. IR ^CHCl3/max (cm ^-1 ): 2980, 1760, 1362, 1220,
1025 NMRδ ( _CDCl3 ): 1.30 (3H, dJ=6Hz), 2.12
(3H, s), 3.17 (1H, ddJ=2 and 5
Hz), 3.4-3.8 (1H, broad, s), 4.17
(1H, dqJ = 5 and 6Hz), 5.83 (1H, dJ
= 2Hz), 7.37 (1H, broad, s) ppm

Claims (1)

[Claims] 1. Diketene and general formula [] [In the formula, R ₁ represents an arylmethyl group, a diarylmethyl group, or an aryl group, and R ₂ represents a carboxyl group, a cyclic alkyloxycarbonyl group, or an aryl group protected by a protecting group. ] A general formula characterized by reacting a Schiff base represented by [] in the presence of an imidazole. [In the formula, R ₁ and R ₂ have the same meanings as above. ] A method for producing a 3-acetyl-2-azetidinone derivative represented by: