JPH0314035B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel β-lactam compound, more specifically, a compound represented by the general formula (1). (In the formula, R ₁ and R ₂ are the same or different and represent a methyl group or a hydroxymethyl group, R ₃ is a pyridyl group or a pyrimidinyl group which may be substituted with a lower alkyl group, and R ₄ is a hydrogen atom or a substituent. (optionally having a benzyl group) and salts thereof. Thienamycin (Japanese Unexamined Patent Publication No. 73191/1989), which was discovered in nature in recent years, has a strong structure, strong antibacterial activity, and
-Because it has lactamase inhibitory effect, etc.
It attracted attention, and subsequently many compounds belonging to this family have been reported. However, these are all unstable compounds and have low productivity through fermentation, so they are not put to practical use. Therefore, the present inventor conducted various researches in an attempt to synthesize compounds of this type, and as a result, the above-mentioned
The present invention was completed by successfully synthesizing a novel β-lactam compound represented by formula (1) and discovering that this compound is useful as an antibiotic. According to the present invention, the compound of formula (1) can be produced according to the following reaction formula. (However, in the ceremony

[Formula] represents a t-butyldimethylsilyl group, R ₄ ' represents a benzyl group which may have a substituent, R ₅ represents a lower alkyl group, and other symbols have the above meanings) Raw material compound () is, for example, the method of Ohno et al. [J.
Am.Chem.Soc. 103 2406 (1981)], it can be easily produced from an inexpensive dialkyl ester of 3-ketoglutaric acid. Next, each reaction in the method of the present invention will be explained in detail. ()→() Compound () is obtained by reacting compound () with 1 to 3 equivalents of t-butyldimethylsilylhalogenide, preferably chloride. Preferably, the reaction is carried out in a solvent in the presence of a base. Dimethylformamide, tetrahydrofuran, etc. can be used as the solvent, and tertiary amines such as triethylamine, n-butyllithium, etc. can be used as the base. The reaction is completed in several minutes to several hours at -30 to +20°C. ()→() Compound () is obtained by reducing compound (). The reduction is preferably carried out using a reducing agent such as an aluminum hydride metal compound, such as lithium aluminum hydride; or a borohydride metal compound, such as sodium borohydride or lithium borohydride. Conventional methods can be used for reaction, separation and purification. ()→() By reacting compound () with t-butyldimethylsilylhalogenide, compound ()
is obtained. Preferably, the reaction is carried out in a solvent in the presence of a base. As the solvent, dimethylformamide, pyridine, etc. can be used, and as the base, tertiary amine such as triethylamine, imidazole, pyridine, etc. can be used. ()→() After activating the 3rd position of compound (), halogenated trialkylsilane is applied to form 3-
After making it into a trialkylsilyl compound, the formula

The compound () can be obtained by reacting with a compound represented by the formula: (wherein R' ₁ and R' ₂ are the same or different and represent a methyl group or a protected hydroxymethyl group). In order to activate the 3-position of the compound (), for example, a method of reacting the compound () with lithium diisopropylamide in a solvent such as tetrahydrofuran at a low temperature can be used. The reaction between the activated compound () and a silyl compound such as trimethylsilyl chloride is carried out in a solvent at a low temperature, e.g. -80°C.
It takes place before and after. When the 3-trialkylsilyl compound is reacted with the compound (XII), it is preferable to carry out the reaction at a low temperature in the same manner as above. () → () Compound () is obtained by hydrolyzing compound (). For this hydrolysis, a conventional hydrolysis method can be applied, but it is preferable to use acid hydrolysis. A particularly preferred example is a method of reacting in a hydrochloric acid-methanol-water system at around 0° C. for 1 to 3 hours. ()→() Oxidation of compound () yields compound (). The oxidation is preferably carried out using an oxidizing agent such as chromic acid or pyridinium dichromate. For example, when using chromic acid as an oxidizing agent, the desired product can be obtained by reacting the compound () with 4 to 10 times the amount of chromic acid at 10 to 50°C for 1 to 30 hours in a solvent such as pyridine. generate. () → () Compound () is obtained by reacting an active derivative of malonic acid monobenzyl ester with an active derivative of compound (). As the active derivative of compound (), those used in ordinary peptide synthesis can be used, but it is particularly preferable to use imidazolide. Particularly preferred is the use of neutral magnesium salts as active derivatives of malonic acid monoesters. When using these, the compound () and, for example, 1,1'-carbonyldiimidazole are reacted in a solvent such as tetrahydrofuran, dimethylformamide, dioxane, etc., and then, for example, mono-p-nitrobenzyl ester of malonic acid is reacted. Compound () is obtained by adding magnesium salt of and reacting at -5 to 30°C for 1 to 30 hours. () → () Compound () is obtained by diazotizing compound (). As the diazotization reagent, 2-naphthylsulfonyl azide, p-toluenesulfonyl azide, methanesulfonyl azide, p-carboxybenzenesulfonyl azide, etc. can be used. The reaction is preferably carried out in the presence of a base in a solvent, and the solvent may be acetonitrile, methylene chloride, tetrahydrofuran, etc., and the base may be triethylamine, diethylamine, pyridine, etc. Reaction at -5~30℃
Progresses in 10 minutes to 1.0 hours. ()→(XI) Compound () is cyclized to obtain compound (XI) by heating to 40-100°C in a solvent in the presence of a catalyst. Benzene, toluene, etc. can be used as a solvent, and rhodium acetate, palladium acetate, copper sulfate, copper powder, etc. can be used as a catalyst. (XI)→()′ After phosphoric acid esterification or sulfonyl esterification of the 3rd position of compound (XI) to introduce a double bond between the 2nd and 3rd positions, when HSR ₃ () is applied, the compound ()′ is obtained. Examples of the phosphoric acid ester include diphenyl phosphoric ester, and examples of the sulfonyl ester include p-toluenesulfonyl ester and trifluoromethanesulfonyl ester. This esterification results in compound (XI)
and a halide corresponding to the ester, such as a chloride, in a solvent in the presence of a base. As a solvent, acetonitrile, methylene chloride, dimethylformamide,
Tetrahydrofuran and the like can be used, and diisopropylethylamine, triethylamine, 4-dimethylaminopyridine and the like can be used as the catalyst. When the compound () is reacted with the ester thus obtained, it is preferable to react in the above-mentioned solvent at -50 to +30°C for 1 to 30 hours in the presence of a base. Examples of the base used at this time include triethylamine, diisopropylethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, and the like. ()′→() Compound () in which R ₄ is a hydrogen atom can be obtained by hydrolysis or hydrogenolysis reaction of compound ()′, but it is difficult to use hydrolysis reaction, especially catalytic reduction method. is particularly preferred. Preferred catalysts used in the catalytic reduction include palladium-carbon, palladium black, platinum oxide, Raney-nickel, and the like. When producing a compound in which R ₁ or R ₂ is a hydroxymethyl group,
In the above step (→), react with a compound in which R ₁ or R ₂ is a protected hydroxymethyl group as compound (XII), and then remove the protecting group to obtain the target compound (). Compound (XII) where R ₁ = R ₂ = methyl group is also possible.
Compounds where R ₁ = R ₂ = methyl group () using
It is also possible to adopt a method of producing R 1 or R 2 and then hydroxylating either R ₁ or R ₂ . This hydroxylation can be achieved, for example, by oxidation with selenium dioxide followed by reduction with a reducing agent such as sodium borohydride. In addition, when producing a compound in which R ₁ and/or R ₂ are hydroxymethyl groups, it is preferable to protect the hydroxyl group during the reactions following this step, and in the final step ('→), the carboxylic acid group is It is preferable to eliminate the ester at the same time as the ester. A particularly preferred protecting group is a benzyloxycarbonyl group which may have a substituent. Conventional methods can be used to isolate and purify the compounds obtained by each of the above reactions from the reaction solution, but gel filtration, column chromatography, reversed-phase column chromatography, freeze-drying, etc. It is preferable to use them alone or in combination. Further, the compound of formula () can be further converted into an alkali salt, for example, an alkali metal salt such as sodium, potassium, or lithium; an alkaline earth metal salt such as calcium or magnesium; or a quaternary ammonium salt, if necessary. Table 1 shows the antibacterial activity of typical compounds of the present invention () obtained in this manner. Test compound:

【table】

【table】

【table】

[Table] Example 1 Production of (5R)-p-nitrobenzyl 6-isopropylidene-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (a) (4S)- 1-(t-butyldimethylsilyl)-
4-(methoxycarbonylmethyl)-azetidine-
Manufacture of 2-one (4S)-4-(methoxycarbonylmethyl)-azetidin-2-one (JACS 103 2405
(1981)) and 2.56 ml of triethylamine were dissolved in 30 ml of dimethylformamide, cooled to 0°C, 2.74 g of t-butyldimethylchlorosilane was added with stirring, and the mixture was further stirred for 50 minutes. After the reaction, dimethylformamide was distilled off, and the residue was dissolved in methylene chloride, washed with water, dried, and concentrated. The residue was subjected to silica gel column chromatography [solvent: n-hexane-ethyl acetate (5:
1)], 3.47g of the target product is obtained as colorless crystals.
(Yield 96.8%) was obtained. Specific optical rotation: [α] ²⁵ _D −80° (c1.0, THF) IR value: ν ^CHCl3 _nax cm ^-1 1743, 1735 PMR value: δ _CDCl3 ppm 0.20 (3H, s), 0.23 (3H, s) , 0.93 (9H, s), 2.47 (1H, dd, J=16Hz,
10Hz), 2.76 (1H, dd, J = 16Hz, 3Hz), 2.85 (1H,
dd, J=15Hz, 5Hz), 3.28(1H, dd, J=
15Hz, 6Hz), 3.68 (3H, s), 3.88 (1H, m) (b) (4R)-1-(t-butyldimethylsilyl)-
4-(2-hydroxyethyl)-azetidine-2-
on manufacturing 270 mg of lithium aluminum hydride was suspended in 70 ml of anhydrous ether, cooled to -20°C under nitrogen atmosphere, and stirred to obtain the ester compound obtained in Example 1(a).
Drop a solution of 1.42g in 70ml of anhydrous ether to -20°C.
The mixture was stirred for 10 minutes. 2N hydrochloric acid was added to the reaction solution to decompose excess reagent, followed by extraction with ether.
The extract was washed with water, dried, and then concentrated to obtain 1.23 g (yield: 97.2%) of the desired product as a colorless oil. Specific optical rotation: [α] ²⁵ _D −71.0° (c1.0, THF) IR value: ν ^CHCl3 _nax cm ^-1 3630, 3420 (shoulder), 1725 PMR value: δ _CDCl3 ppm 0.23 (6H, s), 0.96 (9H, s), 1.7 (1H, m), 1.83 (1H, br.s), 2.2 (1H, m), 2.72 (1H, dd, J=15Hz,
3Hz), 3.17 (1H, dd, J = 15Hz, 5Hz), 3.68 (1H,
m), 3.74 (2H, t, J = 7Hz) (c) 4(R)-1-(t-butyldimethylsilyl)-
Production of 4-(2-t-butyldimethylsilyloxyethyl)-azetidin-2-one 1.23 g of the alcohol obtained in Example 1(b) and 0.83 ml of triethylamine were dissolved in dimethylformamide.
The mixture was dissolved in 18 ml, cooled to 0°C, and stirred. Add 886 mg of t-butyldimethylchlorosilane to this solution,
The reaction was carried out at room temperature for 35 minutes. The solvent was distilled off from the reaction solution, and the residue was dissolved in ether, washed with water, dried, and then concentrated. The resulting residue was purified by silica gel column chromatography (solvent: methylene chloride) to obtain 1.54 g of the desired product as a colorless oil (yield: 83.4
%)was gotten. Specific optical rotation: [α] ²⁵ _D −63.0° (c1, THF) IR value: ν ^CHCl3 _nax cm ^-1 1724 PMR value: δ _CDCl3 ppm 0.03 (6H, s), 0.23 (6H, s), 0.88 (9H , s), 0.97 (9H, s), 1.64 (1H, m), 2.06 (1H, m), 2.72 (1H, dd, J=16Hz, 2Hz), 3.11 (1H, dd, J=16Hz, 5Hz) , 3.65 (1H, m), 3.68 (2H, t, J = 6Hz) (d) (4R)-1-(t-butyldimethylsilyl)-
3-isopropylidene-4-(2-t-butyldimethylsilyloxyethyl)-azetidine-2-
on manufacturing 0.207 ml of diisopropylamine and 2.5 ml of anhydrous tetrahydrofuran were placed in a side-armed flask, and the mixture was cooled to -78°C and stirred under a nitrogen atmosphere. To this was added 0.922 ml of n-butyllithium (1.6M hexane solution) and stirred for 10 minutes. Next, a solution of 1.5 ml of anhydrous tetrahydrofuran containing 112 mg of the disilyl compound obtained in Example 1(c) was added dropwise and stirred for 10 minutes. , further at −50℃
Stir for 15 minutes. The reaction solution was cooled again to −78°C,
After adding 0.045 ml of trimethylsilane chloride and stirring for 10 minutes, the mixture was stirred at -50°C for 15 minutes. The reaction solution was further cooled to -78℃, and 0.185ml of acetone was added.
After stirring for 15 minutes, 1.5 ml of saturated ammonium chloride aqueous solution was added and heated to 40°C for 20 minutes. The reaction solution was extracted with methylene chloride, and the extract was washed with water, dried, and then concentrated. When the residue was purified by silica gel column chromatography [solvent: methylene chloride-ether (15:1)], the desired product was obtained as a colorless oil.
130mg was obtained. (This contained about 25% 3-trimethylsilyl compound). IR value: ν ^CHCl3 _nax cm ^-1 1710 PMR value: δ _CDCl3 ppm 0.03 (6H, s), 0.20 (3H, s), 0.24 (3H, s), 0.83 (9H, s), 0.94 (3H, s) , 1.4~2.2 (2H, complex m) 1.72 (3H, s), 2.00 (3H, s), 3.67 (2H, t, J=7Hz), 4.20 (1H, t,
J=5Hz) (e) (4R)-3-isopropylidene-4-(2-
Production of hydroxyethyl)-azetidin-2-one

[Formula] Dissolve 1.124 g of the disilyl compound obtained in Example 1(d) (approximately 3:1 mixture of 3-isopropylidene compound and 3-trimethylsilyl compound) in 31.25 ml of methanol-water (9:1) mixture. The mixture was cooled to 0°C and stirred, 1.03 ml of concentrated hydrochloric acid was added, and the mixture was stirred at 0°C for 1.5 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and methanol was distilled off. The residue was extracted with ethyl acetate, and the extract was dried and concentrated. The residue was purified by silica gel column chromatography (solvent: ethyl acetate) to obtain 342 mg of the target product as colorless crystals (75.4% yield for Examples 1(d) and 1(e)). IR value: ν ^CHCl3 _nax cm ^-1 3440, 1730 PMR value: δ _CDCl3 ppm 1.72 (3H, s), 2.02 (3H, s), 1.5 to 2.3 (2H, complex m) 3.77 (2H, t, J= 6Hz) 4.20 (1H, dd, J = 9Hz, 2Hz) (f) Production of (4R)-3-isopropylidene-4-carboxymethyl-azetidin-2-one 66 mg of the alcohol obtained in Example 1(e) was dissolved in 0.4 ml of pyridine, and 180 mg of chromic acid was dissolved in pyridine.
3.9 ml of the solution was added and stirred at room temperature for 19 hours. The reaction solution was extracted with ethyl acetate, and the extract was diluted with saturated brine.
After washing with sodium bisulfite, drying and concentration gave a pale yellow oil. This oil was dissolved in ethyl acetate, extracted with saturated aqueous sodium bicarbonate solution, and washed with ethyl acetate. extract liquid
After acidifying with 2N hydrochloric acid, extracting with ethyl acetate,
After drying and concentration, 52 mg (yield 72.3%) of the target product was obtained as pale yellow crystals. IR value: ν ^CHCl3 _nax cm ^-1 3430, 1725, 1715 PMR value: δ _CDCl3 ppm 1.72 (3H, s), 2.00 (3H, s), 2.48 (1H, dd, J=17Hz, 10Hz), 2.90 (1H , dd, J = 17Hz, 3Hz), 4.35 (1H, dd, J = 10Hz, 3Hz), 7.50 (1H, br, s), 9.24 (1H, br, s) (g) (4R)-3-isopropylene Ridden-4-[3-
(p-nitrobenzyl)oxycarbonyl-2-
Production of [oxopropyl]-azetidin-2-one 418 mg of the carboxylic acid obtained in Example 1(f) was dissolved in 15.2 ml of tetrahydrofuran, 441.5 mg of N,N'-carbonyldiimidazole was added under a nitrogen atmosphere, and the mixture was stirred for 1 hour and 50 minutes. On the other hand, 845 mg of mono-p-nitrobenzyl malonate
was dissolved in 9 ml of anhydrous tetrahydrofuran and added with magnesium methoxide while stirring under nitrogen atmosphere.
152.6 mg was added and stirred for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the previously synthesized imidazolide solution was added to this residue, followed by stirring at room temperature for 20 hours. Concentrate the reaction solution and dissolve the residue in ethyl acetate-0.3N
After extraction with hydrochloric acid (5:1), the extract was washed with an aqueous sodium bicarbonate solution, dried, and concentrated to obtain a brown oil. When this was purified by silica gel column chromatography (solvent: ethyl acetate), 798 mg of the desired product was obtained as a pale yellow oil (yield:
93.2%) was obtained. IR value: ν ^CHCl3 _nax cm ^-1 3440, 1745, 1720 (shoulder) PMR value: δ _CDCl3 ppm 1.70 (3H, s), 2.04 (3H, s), 2.75 (1H, dd, J = 18Hz, 10Hz), 3.16 (1H, dd, J=18Hz, 3Hz), 3.58 (2H, s), 4.38 (1H, dd, J=10Hz,
3Hz), 5.26 (2H, s), 6.30 (1H, br, s), 7.52 (2H, d, J = 8Hz), 8.22 (2H, d, J
=8Hz) (h) (4R)-3-isopropylidene-4-[3-
(p-nitrobenzyl)oxycarbonyl-2-
Oxo-3-diazopropyl]-azetidine-2
- Manufacture of on 758 mg of the ketoester obtained in Example 1 (g) and 587 mg of p-toluenesulfonyl azide were dissolved in 30 ml of acetonitrile, cooled to 0°C, and 800 mg of triethylamine was added with stirring, and the mixture was dissolved at room temperature for 30 min.
Stir for a minute. The reaction solution was concentrated and the residue was purified by silica gel thin layer chromatography [solvent: n-hexane-ethyl acetate (1:1)] to obtain 572 mg (yield 70.2%) of the target product as a pale yellow semi-solid. Ta. IR value: ν ^CHCl3 _nax cm ^-1 3440, 2130, 1725 (broad) PMR value: δ _CDCl3 ppm 1.72 (3H, s), 2.01 (3H, s) 2.90 (1H, dd, J=18Hz, 10Hz) 3.50 ( 1H, dd, J = 18Hz, 3Hz) 4.36 (1H, dd, J = 9Hz, 3Hz), 5.34 (2H,
s) 6.48 (1H, br, s), 7.50 (2H, d, J=
8Hz) 8.20 (2H, d, J = 8Hz) (i) (5R) p-Nitrobenzyl 6-isopropylidene-1-azabicyclo[3.2.0]heptane-
Production of 3,7-dione-2-carboxylate 46 ml of degassed anhydrous benzene was added to 572 mg of the diazo compound obtained in Example 1(h) and 1.7 mg of rhodium acetate, and the mixture was heated under a nitrogen atmosphere at a bath temperature of 78° C. for 1 hour.
After cooling, insoluble matter was removed and the liquid was concentrated to obtain 537 mg (quantitative) of the target product in the form of light brown crystals. IR value: ν ^CHCl3 _nax cm ^-1 1750 PMR value: δ _CDCl3 ppm 1.81 (3H, s), 2.09 (3H, s) 2.40 (1H, dd, J=19Hz, 7Hz), 2.87 (1H, dd, J= 19Hz, 7Hz), 4.56 (1H, t, J = 7Hz), 4.67 (1H, s) 5.20 (1H, d, J = 14Hz), 5.36 (1H, d,
J = 14Hz), 7.51 (2H, d, J = 8Hz) 8.17 (2H, d, J
=8Hz) Example 2 (5R) p-nitrobenzyl 6-isopropylidene-3-(2-acetylaminoethylthio)-1
-Azabicyclo[3.2.0]hept-2-ene-7
-Production of -one-2-carboxylate The bicycloketone obtained in Example 1, namely (5R) p-nitrobenzyl 6-isopropylidene-1-azabicyclo[3.2.0]heptane-3,7
-Dissolve 100 mg of dione-2-carboxylate in 5.8 ml of acetonitrile, cool to 0°C, add 4 mg of 4-dimethylaminopyridine and 0.063 ml of diisopropylethylamine with stirring, react for 1 minute, and then 93.3 mg of diphenyl chloride phosphate. A solution of 1 ml of acetonitrile was added after cooling to 0°C.
After reacting for 10 minutes, it was cooled to -25℃, 0.215ml of diisopropylethylamine was added, and immediately N
- 76.4 mg of acetylcysteamine dissolved in 2 ml of acetonitrile was added, reacted at 0°C for 1 hour, and left in the refrigerator for 17 hours. Ethyl acetate was added to the reaction solution, washed with water, dried, and concentrated to obtain a red oil. This was purified by silica gel column chromatography [solvent: methylene chloride-methanol (20:1)] to obtain 85 mg (yield 65.7%) of the desired product as pale yellow crystals. Specific optical rotation: [α] ²⁴ _D −10.0° (c1.0, THF) IR value: ν ^CHCl3 _nax cm ^-1 3470, 1765, 1700, 1670 UV value: λ ^THF _nax nm 297 (ε=11320), 289 (ε=11680) 267 (ε=12990), 244 (ε=13940) PMR value: δ _CDCl3 ppm 1.82 (3H, s), 1.95 (3H, s) 2.10 (3H, s), 2.7-3.6 (6H, Complex m) 4.72 (1H, t, J = 9Hz), 5.21 (1H, d, J
= 14Hz) 5.52 (1H, d, J = 14Hz), 6.04 (1H, br,
s) 7.66 (2H, d, J = 9Hz), 8.20 (2H, d, J
=9Hz) Example 3 (5R) p-Nitrobenzyl 6-isopropylidene-3-(2-hydroxyethylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate Manufacturing of Using 131 mg of the bicycloketone obtained in Example 1 and 69.8 mg of 2-mercaptoethanol, the reaction treatment was carried out in the same manner as in Example 2, and when purified by silica gel column chromatography (solvent: ethyl acetate), colorless crystals were obtained. Target product 51mg (yield 33.2
%)was gotten. Specific optical rotation; [α] ²² _D +9.0゜ (c1.0, THF) IR value: ν ^CHCl3 _nax cm ^-1 3500 (broad), 1765, 1700 UV value: λ ^THF _nax nm 300 (ε=10530) , 266 (ε=10810) 244 (ε=12540) PMR value; δ _CDCl3 ppm 1.80 (3H, s), 2.00 (1H, br.) 2.09 (3H, s), 2.8 to 3.6 (4H, complex m) 3.72-4.00 (2H, complex m), 4.68 (1H, t, J = 8Hz), 5.20 (1H, d, J
= 14Hz) 5.50 (1H, d, J = 14Hz), 7.64 (2H, d,
J=8Hz) 8.18 (2H, d, J=8Hz) Example 4 (5R) p-Nitrobenzyl 6-isopropylidene-3-phenylthio-1-azabicyclo[3.2.0]hept-2-en-7-one -Production of 2-carboxylate Using 110 mg of the bicycloketone compound obtained in Example 1 and 82.6 mg of thiophenol, the reaction and treatment were carried out in the same manner as in Example 2, and silica gel column chromatography [solvent: methylene chloride-ethyl acetate (10:1)] When purified, 19 mg (yield 13.6%) of the desired product was obtained as a pale yellow powder. Specific optical rotation; [α] ²² _D −92.6° (c0.95, THF) IR value; ν ^CHCl3 _nax cm ^-1 1760, 1700 UV value; λ ^THF _nax nm 331 (ε=7490), 289 (ε=11930 ) 266 (ε=13090), 254 (ε=14280) PMR value; δ _CDCl3 ppm 1.68 (3H, s), 2.06 (3H, s) 2.63 (2H, d, J=9Hz), 4.54 (1H, t, J
= 8Hz) 5.25 (1H, d, J = 14Hz), 5.56 (1H, d,
J=14Hz) 7.2-7.7 (5H, m), 7.68 (2H, d, J=8Hz) 8.19 (2H, d, J=8Hz) Example 5 (5R) p-Nitrobenzyl 6-isopropylidene-3- (2-pyrimidinylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-
Production of 2-carboxylate Using 100 mg of the bicycloketone compound obtained in Example 1 and 71.8 mg of 2-mercaptopyrimidine, the reaction and treatment were carried out in the same manner as in Example 2, and when purified by silica gel column chromatography (solvent: ether), pale yellow crystals were obtained. 75 mg of the target product (yield 58.9
%)was gotten. Specific optical rotation: [α] ²⁴ _D −79.5° (c1.9, THF) IR value: ν ^CHCl3 _nax cm ^-1 1770, 1705 UV value: λ ^THF _nax nm 330 (ε=12640), 321 (ε=13500 ) 290 (ε=17400), 247 (ε=25100) PMR value: δ _CDCl3 ppm 1.80 (3H, s), 2.11 (3H, s) 3.10 (1H, dd, J=18Hz, 8Hz) 3.86 (1H, dd , J=18Hz, 11Hz) 4.80 (1H, m), 5.28 (1H, d, J=14Hz) 5.52 (1H, d, J=14Hz), 7.07 (1H, t,
J = 4Hz) 7.66 (2H, d, J = 9Hz), 8.19 (2H, d, J
= 9Hz) 8.54 (2H, d, J = 4Hz) Example 6 (5R) p-Nitrobenzyl 6-isopropylidene-3-(2-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene- 7-on-2-
Production of carboxylates Using 120 mg of the bicycloketone compound obtained in Example 1 and 91.2 mg of 2-mercaptopyrimidine, the reaction and treatment were carried out in the same manner as in Example 2, and when purified by silica gel column chromatography (solvent: ether), yellow crystals were obtained. Target product 83mg (yield 54.3
%)was gotten. Specific optical rotation; [α] ²⁴ _D −71.1° (c4.15, THF) IR value; ν ^CHCl3 _nax cm ^-1 1770, 1700 UV value; λ ^THF _nax nm 289 (ε=14050), 262.5 (ε=16600 ) 246 (ε=18600) PMR value; δ _CDCl3 ppm 1.74 (3H, s), 2.05 (3H, s) 2.90 (1H, dd, J=18Hz, 8Hz) 3.29 (1H, dd, J=18Hz, 10Hz) 4.69 (1H, dd, J = 10Hz, 8Hz) 5.30 (1H, d, J = 14Hz), 5.56 (1H, d,
J = 14Hz) 6.9 to 7.3 (1H, m) 7.35 to 7.8 (2H, complex m) 7.69 (2H, d, J = 8Hz), 8.20 (2H, d, J
= 8Hz) 8.56 (1H, br, d, J = 4Hz) Example 7 (5R) 6-isopropylidene-3-(2-acetylaminoethylthio)-1-azabicyclo[3.2.0]hept-2-ene Production of -7-one-2-carboxylic acid sodium salt 85 mg of p-nitrobenzyl ester obtained in Example 2 was dissolved in a mixture of 6 ml of dioxane and 3.1 ml of 0.1 M phosphate buffer with pH 7.6, 90 mg of 5% palladium on carbon was added, and hydrogen (1 atm) was added. The mixture was stirred under atmosphere for 3 hours. After removing the catalyst from the reaction solution and washing the solution with ethyl acetate, common salt was added to the aqueous layer to give a concentration of 5%. Add this to Diamondion HP-20 (25
ml) column, washed with water and eluted with 30% methanol water, and fractions containing the target product were collected. This was concentrated and then freeze-dried to obtain 25.9 mg (yield 40.8%) of the desired sodium salt as a pale yellow powder. Specific optical rotation; [α] ²⁴ _D −26.1° (c0.88, H ₂ O) IR value; ν ^KBr _nax cm ^-1 1770, 1650, 1600 UV value; λ ^PBS _nax (PH7.0) nm (ε) 284 (5689), 238 (12710) PMR value; δ _D2O ppm (with heavy water as 4.80) 1.93 (3H, s), 2.06 (3H, s) 2.13 (3H, s), 2.8 to 4.0 (6H, Combrex m) , 4.78 (1H, m) Example 8 (5R) 6-isopropylidene-3-(2-hydroxyethylthio)-1-azabicyclo[3.2.0]
Preparation of hept-2-en-7-one-2-carboxylic acid sodium salt. 51 mg of the p-nitrobenzyl ester compound obtained in Example 3 was mixed with 2.66 ml of dioxane at a pH of 7.2.
Dissolved in 1.86ml of 0.1M phosphate buffer, 5%
54 mg of palladium on carbon was added, and the mixture was stirred for 2 hours under a hydrogen (1 atm) atmosphere. When this was treated and purified in the same manner as in Example 7, sodium salt was obtained as a colorless powder.
8.5 mg (yield 23.2%) was obtained. Specific optical rotation; [α] ²² _D +6.89° (c0.145, H ₂ O) IR value; ν ^KBr _nax cm ^-1 1770, 1600 (broad) UV value; λ ^PBS _nax (PH7.0) nm ( ε) 285 (6740), 239 (14470) PMR value; δ _D2O (with heavy water as 4.80) ppm 1.97 (3H, s), 2.14 (3H, s) 2.95-3.40 (4H, complex m),
3.84 (2H, t, J=6Hz), 4.72 (1H,
m) Example 9 (5R) 6-isopropylidene-3-phenylthio-1-azabicyclo[3.2.0]hept-2-
Production of en-7-one-2-carboxylic acid sodium salt 19 mg of the p-nitrobenzyl ester obtained in Example 4 was dissolved in a mixture of 0.7 ml of dioxane and 0.7 ml of 0.1 M phosphate buffer at pH 7.2, 20 mg of 5% palladium on carbon was added, and hydrogen (1 atm) was added. Stirred under atmosphere for 2 hours. The solvent was removed from the reaction solution, and the solution was washed with ethyl acetate to obtain 25 ml of an aqueous solution of the desired sodium salt (OD of 7-fold dilution: 0.672). UV value; λPBS (PH7.2) max nm 280 Example 10 (5R)6-isopropylidene-3-(2-pyrimidinylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one- Production of 2-carboxylic acid 67 mg of the p-nitrobenzyl ester obtained in Example 5 was dissolved in a mixture of 4.7 ml of dioxane and 4.7 ml of 0.1M phosphate buffer at pH 7.2, 70 mg of 5% palladium on carbon was added, and hydrogen (1 atm) was added. ) Stirred under atmosphere for 3 hours. When this was treated and purified in the same manner as in Example 7, the desired carboxylic acid 29.7 was obtained as a pale yellow powder.
mg (yield 64.0%) was obtained. Specific optical rotation; [α] ²⁴ _D −194° (c1, H ₂ O) IR value; ν ^KBr _nax cm ^-1 1760, 1700, 1560, 1540 UV value; λ ^PBS _nax (PH7.0) nm (ε) 280 (11900), 243 (21300) PMR value; δ _D2O ppm (with heavy water as 4.80) 1.87 (3H, s), 2.12 (3H, s) 2.93 (1H, dd, J=18Hz, 8Hz), 3.48
(1H, dd, J = 18Hz, 10Hz) 4.79 (1H, m), 7.39 (1H, t, J =
5Hz) 8.68 (2H, d, J = 5Hz) Example 11 (5R) 6-isopropylidene-3-(2-pyridylthio)-1-azabicyclo[3.2.0]hept-
Production of 2-en-7-one-2-carboxylic acid 83 mg of the p-nitrobenzyl ester obtained in Example 6 was dissolved in a mixture of 4 ml of dioxane and 2.4 ml of 0.1 M phosphate buffer at pH 7.2, 85 mg of 5% palladium on carbon was added, and hydrogen (1 atm) was added. The mixture was stirred under atmosphere for 3 hours. When this was treated and purified in the same manner as in Example 7, the desired carboxylic acid was obtained as a pale yellow powder.
16.3 mg (yield 28.4%) was obtained. Specific optical rotation; [α] ²⁴ _D −142.2° (c0.45, H ₂ O) IR value; ν ^KBr _nax cm ^-1 1740, 1602, 1575, 1560 UV value; λ ^PBS _nax (PH7.0) nm ( ε) 291, 241 (15680) PMR value; δ _D2O ppm (with heavy water as 4.80) 1.83 (3H, s), 2.14 (3H, s) 2.76 (1H, dd, J=17Hz, 8Hz), 3.01 (1H, dd, J=17Hz, 10Hz) 4.75 (1H, m), 7.49 (1H, dd, J=
6Hz, 4Hz), 7.68 (1H, d, J = 8Hz), 7.92 (1H, m), 8.56 (1H, br.d, J =
4Hz) Example 12 (5R)p-nitrobenzyl6(z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-1-azabicyclo[3.2.0]hepta-3,7- Production of dione-2-carboxylate (a) (4R) 1-(t-butyldimethylsilyl)-
3(Z and E)-(1-methyl-2-hydroxy)
Production of ethylidene-4-(2-t-butyldimethylsilyl)oxyethyl-azetidin-2-one The isopropylidene compound (3) obtained in Example 1(d)
- 984 mg of trimethylsilyl compound (containing about 25%) was dissolved in 20 ml of dioxane, and the bath temperature was 105°C.
A solution prepared by dissolving 218 mg of selenium dioxide in 12 ml of a mixture of dioxane and water (5:1) was added dropwise to the mixture while stirring, and the mixture was stirred for 41.5 hours. During the process, after 14 hours had passed, the same amount of selenium dioxide as above in dioxane-aqueous solution was added. After the reaction, insoluble matter was removed and the liquid was concentrated, and the residue was dissolved in ethyl acetate. After washing with water, washing with a saturated aqueous solution of sodium bicarbonate, drying and concentrating, 1.0g of yellow oil was obtained.
was gotten. Dissolve this oil in methanol,
40 mg of sodium borohydride was added under ice cooling, and the mixture was stirred for 70 minutes. Concentrate the reaction solution, dissolve the residue in ethyl acetate, wash with water, dry, and concentrate to form a brown oil.
1.0g was obtained. When this was purified by silica gel column chromatography [solvent: n-hexane-ethyl acetate (6:1)], the Z-form was obtained as a colorless oil.
270 mg (yield 35.3%) and 110 mg (yield 14.4)
%)was gotten. Z-body IR value; ν ^CHCl3 _nax cm ^-1 3340 (broad), 1695 PMR value; δ _CDCl3 ppm 0.04 (6H, s), 0.26 (3H, s) 0.30 (3H, s), 0.70 (9H, s) 0.98 (9H, s), 1.72 (3H, s) 1.60 to 2.06 (2H, complex m), 3.72 (2H, t, J=6Hz), 4.25 (3H, complex m) E body IR value; ν ^CHCl3 _nax cm ^-1 1720 NMR value; δ _CDCl3 ppm 0.06 (6H, s), 0.21 (3H, s) 0.25 (3H, s), 0.90 (9H, s) 0.97 (9H, s), 1.60~2.19 (2H, m), 2.02 (3H, s), 3.77 (2H, t, J=6Hz), 4.10 (2H,
s), 4.40 (1H, m) (b) (4R) 1-(t-butyldimethylsilyl)-
3(Z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-
(2-t-butyldimethylsilyloxyethyl)-
Production of azetidin-2-one 270 mg of Z-alcohol obtained in Example 12(a)
was dissolved in 3 ml of methylene chloride, cooled to 0°C, 0.113 ml of triethylamine and 8.3 mg of 4-dimethylaminopyridine were added, and then 175 mg of formic acid p-nitrobenzyl chloride dissolved in 1 ml of methylene chloride was added, and the mixture was cooled to 0°C. for 30 minutes, followed by stirring at room temperature for 22 hours. During 1 hour and 3 hours, the reaction solution was cooled to 0°C, and triethylamine, 4-
Dimethylaminopyridine and a methylene chloride solution of formic acid p-nitrobenzyl chloride were added in twice the above amount, and after 7 hours, the same amount as above was added. After the reaction was completed, methylene chloride was added to the reaction solution, washed with water, dried, and concentrated. The yellow solid residue was subjected to silica gel column chromatography [solvent: n
-hexane-ethyl acetate (10:1)] to obtain 267 mg (yield 68.3%) of the desired product as a colorless powder. IR value; ν ^CHCl3 _nax cm ^-1 1730, 1610 PMR value; δ _CDCl3 ppm 0.04 (6H, s), 0.24 (3H, s) 0.28 (3H, s), 0.85 (9H, s) 0.96 (9H, s) , 1.83 (3H, s) 1.60-2.06 (2H, complex m), 3.72 (2H, t, J=6Hz), 4.30 (1H,
t, J = 4Hz), 5.10 (2H, s), 5.24 (2H, s), 7.55 (2H, d, J =
9Hz), 8.18 (2H, d, J = 9Hz) (c) (4R)3(Z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-(2-hydroxyethyl )-Production of azetidin-2-one 267 mg of the disilyl compound obtained in Example 12(b) was dissolved in 10 ml of a mixture of methanol and water (9:1),
The mixture was cooled to 0° C., 0.165 ml of concentrated hydrochloric acid was added, and the mixture was stirred for 15 minutes, followed by stirring for 4 hours and 30 minutes under water cooling. After adjusting the reaction solution to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate, methanol was distilled off, and the mixture was extracted with ethyl acetate. After drying the organic layer and concentrating it, the residue was washed with n-hexane to obtain the desired product as colorless crystals.
165 mg (quantitative) was obtained. PMR value; δ CDCl ₃ −CD ₃ OD (6:1) ppm 1.82 (3H, s), 1.60 to 2.15 (2H, complex m), 3.70 (2H, t, J=
6Hz), 4.25 (1H, dd, J=9Hz, 3Hz), 5.03
(2H, s), 5.29 (2H, s), 7.59 (2H,
d, J = 9Hz), 8.22 (2H, d, J =
9Hz) (d) (4R)3(Z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-carboxymethyl-azetidine-2-
on manufacturing 165 mg of the alcohol obtained in Example 12(c) was dissolved in 5 ml of pyridine, 483 mg of chromic acid dissolved in 7 ml of pyridine was added, and the mixture was stirred at room temperature for 14 hours. After adding 100 ml of water to the reaction solution, it was extracted with ethyl acetate, dried and concentrated, and the resulting residue was dissolved in ethyl acetate, and extracted with a saturated aqueous solution of sodium hydrogen carbonate. After washing this with ethyl acetate, ethyl acetate was added again, and the pH was adjusted to 1 with 0.5N hydrochloric acid. This was extracted with ethyl acetate under salting out, dried and concentrated to give the desired product as a pale yellow oil (121mg).
(Yield 70.5%) was obtained. IR value; ν ^CHCl3 _nax cm ^-1 3320 (broad), 1740, 1610 PMR value; δ _CDCl3 ppm 1.80 (3H, s), 2.23 to 3.15 (2H, complex m), 4.23 to 4.55 (1H, m), 5.02 (2H, s), 5.23 (2H, s), 7.52 (2H, d, J=9Hz), 8.19 (2H,
d, J=9Hz) (e) (4R)3(Z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-[3-(p-nitrobenzyl)oxycarbonyl- 2-oxopropyl]-azetidine-
Manufacture of 2-one 121 mg of the carboxylic acid obtained in Example 12(d) was dissolved in 3.0 ml of anhydrous tetrahydrofuran, 59.2 mg of N,N'-carbonylimidazole was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Separately, 113.6 mg of mono-p-nitrobenzyl malonic acid ester was dissolved in 2 ml of anhydrous tetrahydrofuran, and 46.7 mg of magnesium methoxide was added while stirring under a nitrogen atmosphere, followed by stirring at room temperature for 1 hour. The solvent was distilled off from the reaction solution under reduced pressure, and the previously synthesized imidazolide solution was added to this residue, followed by stirring at room temperature for 17.5 hours. The reaction solution was concentrated, the residue was dissolved in a mixture of ethyl acetate and 0.3N hydrochloric acid, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate, then dried and concentrated to give a yellow oil. When this was purified by silica gel column chromatography [solvent: chloroform-methanol (6:1)], 115 mg of the desired product was obtained as a colorless oil (yield 63.9%).
was gotten. IR value; ν ^CHCl3 _nax cm ^-1 1760, 1610 PMR value; δ _CDCl3 ppm 1.75 (3H, s), 2.79 (1H, dd, J=
8Hz, 10Hz), 3.20 (1H, dd, J=
18Hz, 3Hz), 3.60 (2H, s), 4.22
(1H, dd, J = 10Hz, 3Hz), 5.02 (2H,
s), 5.24 (4H, s), 6.85 (1H, s), 7.47
(2H, d, J = 9Hz), 7.50 (2H, d, J
=9Hz), 8.18 (4H, d, J = 9Hz) (f) (4R)3(Z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-[3-( p-nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]-
Production of azetidin-2-one β-ketoester 115 obtained in Example 12(e)
mg and 0.039 ml of p-toluenesulfonyl azide were dissolved in 3.9 ml of acetanilyl, and 0.086 ml of triethylamine was added while stirring at 0°C.
Stirred for 20 minutes. The pale yellow oil obtained by concentrating the reaction solution was subjected to silica gel column chromatography [solvent: chloroform-methanol (15:1)]
When purified, 114 mg of the target product was obtained as a colorless oil.
(Yield 94.6%) was obtained. IR value; ν ^CHCl3 _nax cm ^-1 2140, 1760, 1720 PMR value; δ _CDCl3 ppm 1.79 (3H, s), 2.97 (1H, dd, J=
18Hz, 9Hz), 3.52 (1H, dd, J=
18Hz, 3Hz), 4.42 (1H, dd, J=9Hz,
3Hz), 5.02 (2H, s), 5.23 (2H, s),
5.36 (2H, s), 6.89 (1H, s), 7.52 (4H, d, J=9Hz), 8.18 (4H,
d, J=9Hz) (g) (5R)p-nitrobenzyl 6(z)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-1-azabicyclo[3.2.0]hepta- Production of 3,7-dione-2-carboxylate 114 mg of the diazo compound obtained in Example 12(f) and 5.15 ml of anhydrous benzene degassed into 0.171 mg of rhodium acetate.
was added and heated under a nitrogen atmosphere at a bath temperature of 78°C for 1 hour and 20 minutes. After cooling, the insoluble matter was removed and the liquid was concentrated to obtain 114 mg (quantitative) of the target product as a pale yellow oil. IR value; ν ^CHCl3 _nax cm ^-1 1760, 1610 PMR value; δ _CDCl3 ppm 1.82 (3H, s), 2.43 (1H, dd, J=
18Hz, 6Hz), 2.90 (1H, dd, J=
18Hz, 6Hz), 4.59 (1H, t, J=
6Hz), 4.71 (1H, s), 5.00 (2H, s),
5.22 (4H, s), 7.48 (4H, d, J=
9Hz), 8.15 (4H, d, J = 9Hz) Example 13 (5R) p-nitrobenzyl 6 (z and E) - [1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-(2-pyrimidinylthio)-1-azabicyclo[3.2.0]hept-
Production of 2-en-7-one-2-carboxylate 114 mg of the bicycloketone obtained in Example 12 was dissolved in 4.2 ml of acetonitrile, cooled to 0°C, and 0.041 ml of diisopropylethylamine and 2.8 mg of 4-dimethylaminopyridine were added with stirring, followed by 0.046 mg of diphenyl chloride phosphate. ml of acetonitrile dissolved in 1 ml of acetonitrile, cooled to 0°C and added,
Stir for a minute. The reaction solution was cooled to -25°C, 0.177 ml of diisopropylethylamine was added, and then 49.5 mg of 2-mercaptopyrimidine was added immediately.
Stirred at ℃ for 30 minutes and stored in refrigerator for 13 hours. After adding ethyl acetate to the reaction solution, the mixture was washed with saturated brine, dried, and concentrated to obtain a brown oil. This was subjected to silica gel column chromatography [solvent: chloroform-methanol (30:
1)] and further separated by silica gel column chromatography [solvent: n-hexane-ethyl acetate (1:3)] to give 5.8 mg of Z form (yield 4.3%) and E form as a colorless oil. 22mg (yield
16.5%) was obtained. Z-form Specific rotation: [α] ²³ _D −79.0° (c0.29, THF) IR value: ν ^CHCl3 _nax cm ^-1 3280 (broad), 1760, 1610 PMR value: δ _CDCl3 ppm 1.85 (3H, s) , 3.18 (1H, dd, J=
18Hz, 9Hz), 3.92 (1H, dd, J=
18Hz, 10Hz), 4.82 (1H, m), 5.04 (2H, s), 5.25 (2H, s), 5.27 (1H, d, J = 14Hz), 5.53 (1H,
d, J = 14Hz), 7.05 (1H, t, J =
5Hz), 7.50 (2H, d, J=9Hz), 7.62 (2H,
d, J = 9Hz), 8.19 (4H, d, J =
9Hz), 8.55 (2H, d, J = 5Hz) E-form Specific rotation; [α] ²³ _D −27.0° (c1, THF) IR value; ν ^CHCl3 _nax cm ^-1 1770, 1720 (shoulder), 1610 PMR Value; δ _CDCl3 ppm 2.10 (3H, s), 3.18 (1H, dd, J=
18Hz, 9Hz), 3.82 (1H, dd, J=
18Hz, 10Hz), 4.70 (2H, s), 4.70~4.90 (1H, m), 5.22 (2H, s), 5.26 (1H, d, J=
14Hz), 5.52 (1H, d, J = 14Hz), 7.02 (1H,
t, J = 5Hz), 7.45 (2H, d, J =
9Hz), 7.62 (2H, d, J = 9Hz), 8.18 (4H,
d, J = 9Hz), 8.45 (2H, d, J =
5Hz) Example 14 (5R)6(z)-(1-methyl-2-hydroxyethylidene)-3-(2-pyrimidinylthio)-1
-Azabicyclo[3.2.0]hept-2-ene-7
Production of -one-2-carboxylic acid 5.4 mg of p-nitrobenzyl ester obtained in Example 13 was dissolved in a mixture of 0.5 ml of dioxane and 0.3 ml of 0.1 M phosphate buffer at pH 7.0, 8 mg of 5% palladium-carbon was added, and hydrogen (1 The mixture was stirred at room temperature for 2 hours under an atmosphere (atmospheric pressure). After the reaction, remove the catalyst,
When the solution is washed with ethyl acetate, an aqueous solution of the target substance is obtained.
3.0 ml was obtained. UV value; λ ^PBS _nax (PH7.0) nm 242 Example 15 (5R)6(E)-(1-methyl-2-hydroxyethylidene)-3-(2-pyrimidinylthio)-1
-Azabicyclo[3.2.0]hept-2-ene-7
Production of -one-2-carboxylic acid 82.7 mg of p-nitrobenzyl ester obtained in Example 13 was dissolved in a mixture of 3.5 ml of dioxane and 3.5 ml of phosphate buffer of pH 7.0, and 5% palladium on carbon was added.
83 mg was added, and the mixture was stirred for 2 hours under a hydrogen (1 atm) atmosphere. This was treated and purified in the same manner as in Example 7 to obtain 25.3 mg (yield: 60.7%) of the desired product as a colorless powder. Specific optical rotation; [α] ¹⁸ _D −186.7° (c0.375, H ₂ O) IR value; ν ^KBr _nax cm ^-1 3430 (broad), 1740, 1610, 1560 UV value; λ ^H2O _nax nm (ε) 239.5 (18200) PMR value; δ _D2O ppm ( _D2O is 4.80) 2.08 (3H, s), 3.08 (1H, dd, J=
18Hz, 9Hz), 3.45 (1H, dd, J=
18Hz, 10Hz), 4.29 (2H, s), 5.0 (1H, m), 7.42 (1H,
t, J = 5Hz), 8.70 (2H, d, J =
5Hz) Example 16 (5R)p-nitrobenzyl6(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-1-azabicyclo[3.2.0]hepta-3,7- Production of dione-2-carboxylate (a) 4(R)1-(t-butyldimethylsilyl)-
3(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-
(2-t-butyldimethylsilyloxyethyl)-
Production of azetidin-2-one 309 mg of E-alcohol obtained in Example 12(a)
was dissolved in 5 ml of methylene chloride and added to 0.0 mL under nitrogen atmosphere.
142 mg of 4-dimethylaminopyridine after cooling to ℃.
Then, 250 mg of formic acid p-nitrobenzyl chloride dissolved in 2 ml of methylene chloride was added, and the mixture was stirred for 6 hours under ice cooling. When 3.5 hours and 5 hours had elapsed, the same amounts of 4-dimethylaminopyridine and a methylene chloride solution of formic acid p-nitrobenzyl chloride as above were added. Methylene chloride was added to the reaction solution, washed with water, dried, and concentrated to obtain 1.0 g of a yellow oil. This was purified by silica gel column chromatography [solvent: ethyl acetate-n-hexane (2:5)] to obtain 390 mg (yield: 87.2%) of the desired product as a yellow oil. IR value; ν ^CHCl3 _nax cm ^-1 1750, 1735, 1610, 1530 PMR value; δ _CDCl3 ppm 0.03 (6H, s), 0.22 (3H, s), 0.25 (3H, s), 0.84 (9H, s), 0.98 (9H, s), 1.81~2.13 (2H, m), 2.05 (3H, s), 3.68 (2H, t, J=
6Hz), 4.32 (1H, t, J=4Hz), 4.62 (2H,
s), 5.24 (2H, s), 7.50 (2H, d, J=
9Hz), 8.19 (2H, d, J = 9Hz) (b) (4R)3(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-(2-hydroxyethyl )-Production of azetidin-2-one 390 mg of the disilyl compound obtained in Example 16(a) was
Dissolve in 90% methanol water and add 0.24 ml of concentrated hydrochloric acid under ice cooling.
was added dropwise, and the mixture was stirred for 2 hours under ice-cooling and then for 15 hours under water-cooling. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7, and the mixture was concentrated.The residue was dissolved in ethyl acetate, dried, and concentrated. The residue was subjected to silica gel column chromatography [solvent;
When purified with chloroform-methanol (7:1), 220 mg of the desired product was obtained as colorless crystals (yield 93.2%).
was gotten. IR value; ν ^KBr _nax cm ^-1 3400 (broad), 1750, 1710, 1610, 1540 PMR value; δ CDCl ₃ −CD ₃ OD (6:1) ppm 1.59-2.21 (2H, m), 2.05 (3H, s), 3.68 (2H, t, J=6Hz), 4.05 (2H,
s), 4.26 (1H, dd, J=9Hz, 4Hz), 4.63
(2H, s), 5.25 (2H, s), 7.52 (2H,
d, J = 9Hz), 8.20 (2H, d, J =
9Hz) (c) (4R)3(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-carboxymethyl-azetidine-2-
on manufacturing 220 mg of the alcohol obtained in Example 16(b) was dissolved in 3 ml of pyridine, and 490 mg of chromic anhydride was added thereto.
Add the solution dissolved in 6 ml of pyridine and stir at room temperature.
Stirred for 14.5 hours. 10 ml of water was added to the reaction solution, extracted with ethyl acetate, and the extract was dried and concentrated to obtain 276 mg of the crude target product as a brown oil. IR value; ν ^Film _nax cm ^-1 3240, 1750, 1600, 1520 (d) (4R)3(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-[3 -(p-nitrobenzyl)oxycarbonyl-2-oxopropyl]-azetidine-
Manufacture of 2-one 276 mg of the crude carboxylic acid obtained in Example 12(c) was dissolved in 4.8 ml of anhydrous tetrahydrofuran, 112 mg of N,N'-carbonyldiimidazole was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. Separately, 245 mg of malonic acid mono p-nitrobenzyl ester was dissolved in 3.8 ml of anhydrous tetrahydrofuran, and 88.3 mg of magnesium methoxide was dissolved in 3.8 ml of anhydrous tetrahydrofuran.
was added and stirred at room temperature for 1 hour. Concentrate this and
The above imidazolide solution was added to this residue, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, a mixture of ethyl acetate and 0.3N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and then dried to obtain a brown oil. This was subjected to silica gel column chromatography [solvent: chloroform-methanol (10:
1)], 175mg of the target product is obtained as colorless crystals.
(Yield: 51.5% compared to (c) above) was obtained. IR value; ν ^Film _nax cm ^-1 3360 (broad), 1740 PMR value; δ _CDCl3 ppm 2.10 (3H, s), 2.83 (1H, dd, J=
18Hz, 9Hz), 3.32 (1H, dd, J=
18Hz, 2Hz), 3.50 (2H, s), 4.40 (1H, m), 4.55 (1H, s), 4.63 (1H, s), 5.22 (4H, s), 6.50 (1H, s), 7.47 (4H ,d,J=
9Hz), 8.15 (4H, d, J = 9Hz) (e) (4R)3(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-4-[3-(p -Nitrobenzyl)oxycarbonyl-2-oxo-3-diazopropyl]-
Production of azetidin-2-one β-ketoester 175 obtained in Example 16(d)
mg was dissolved in 5.8 ml of acetonitrile, 0.058 ml of p-toluenesulfonyl azide and 0.130 ml of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 130 minutes. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography [solvent: ethyl acetate-n-hexane (1:1)] to obtain 176 mg (yield 96.0%) of the desired product as a yellow oil. IR value; ν ^Film _nax cm ^-1 3160 (broad), 2130, 1740, 1645, 1605, 1520 PMR value; δ _CDCl3 ppm 2.04 (3H, s), 3.02 (1H, dd, J=
18Hz, 9Hz), 3.58 (1H, dd, J=
18Hz, 3Hz), 4.48 (1H, m), 4.62
(2H, s), 5.22 (2H, s), 5.30 (2H, s), 6.68 (1H, broad s), 7.47 (4H, d,
J = 9Hz), 8.16 (4H, d, J = 9Hz) (f) (5R) p-nitrobenzyl 6(E)-[1-methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-1 -Production of azabicyclo[3.2.0]hepta-3,7-dione-2-carboxylate 176 mg of the diazo compound obtained in Example 16(e) was dissolved in 9.5 ml of degassed anhydrous benzene, and 0.3 mg of rhodium acetate was dissolved in 9.5 ml of degassed anhydrous benzene.
mg was added thereto, and the mixture was stirred for 90 minutes at a bath temperature of 78°C under a nitrogen atmosphere. The reaction solution was filtered and concentrated to obtain 165 mg (yield 98.6%) of the desired product as a yellow oil. IR value; ν ^Film _nax cm ^-1 1750, 1605, 1520 PMR value; δ _CDCl3 ppm 2.08 (3H, s), 2.44 (1H, dd, J=
18Hz, 7Hz), 2.82 (1H, dd, J=
18Hz, 7Hz), 4.62 (1H, t, J=
7Hz), 4.70 (2H, s), 4.74 (1H, s),
5.24 (4H, s), 7.50 (4H, d, J=9Hz), 8.18 (4H,
d, J=9Hz) Example 17 (5R)p-nitrobenzyl 6(z and E)-[1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-(2-pyrrolimidinylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate Manufacturing of 74.0 mg of the bicycloketone obtained in Example 16 was mixed with 5.36 ml of acetonitrile and dimethylformamide.
Dissolve in 0.4 ml of the mixed solution, add 0.028 ml of diisopropylethylamine under ice cooling under a nitrogen atmosphere, then add a solution of 0.031 ml of diphenyl chloride phosphoric acid dissolved in 0.1 ml of acetonitrile after cooling to 0°C, and add under ice cooling. The mixture was stirred for 10 minutes. The reaction solution was cooled to -25°C, 0.102 ml of diisopropylethylamine and 16.9 mg of 2-mercaptopyrimidine were added, and the mixture was heated to 0°C.
After stirring for 30 minutes, the mixture was left in the refrigerator for 17 hours. Ethyl acetate was added to the reaction solution, washed with saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (30:1)], and then further separated by silica gel column chromatography [solvent: ethyl acetate-n-hexane (3:1)]. 38.9 mg (yield: 44.8%) of the desired E-isomer and 10.4 mg (yield: 14.2%) of the Z-isomer were obtained as a yellow oil. The physicochemical properties of all of these were consistent with the compound obtained in Example 13. Example 18 (5R)p-nitrobenzyl 6(E and z)-[1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-[2-(p-nitrobenzyloxycarbonyl)aminoethylthio]-1-azabicyclo[3.2.0]hept-2-ene-7 -Production of -one-2-carboxylate 138 mg of the bicycloketone obtained in Example 16 was mixed with 10 ml of acetonitrile and 0.5 dimethylformamide.
ml of the mixed solution, cooled to 0° C. and stirred under a nitrogen atmosphere. Diisopropylethylamine
After adding 38 mg and stirring for 1 minute, a solution of 75.65 mg of diphenyl chloride phosphate dissolved in 1.83 ml of acetonitrile was added after cooling to 0°C, and the mixture was stirred for 10 minutes.
The reaction solution was cooled to -25°C, 140mg of diisopropylethylamine was added, and immediately 72.09mg of N-p-nitrobenzyloxycarbonylcysteamine dissolved in 4.6ml of acetonitrile was added, and the mixture was heated at 0°C for 30 minutes.
After stirring for a minute, the mixture was left in the refrigerator for 15 hours.
Ethyl acetate was added to the reaction solution, which was then washed with water, dried, and concentrated to obtain 300 mg of a brown oil. This was applied to a silica gel column and chloroform-
Elution with methanol (20:1) followed by separation with n-hexane-ethyl acetate (2:1) yielded 58 mg of the desired (E) compound as a yellow oil (yield 29.2%).
and 27 mg (yield 13.6%) of the (Z) isomer were obtained. (E) Body Specific rotation: [α] ²² _D +20.0° (c2.9, THF) IR value: ν ^CHCl3 _nax cm ^-1 1755, 1715, 1520 UV value: λ ^THF _nax nm (ε) 249 ( 24100), 262 (34600) PMR value; δ _CDCl3 ppm 2.07 (3H, s), 2.8 to 3.6 (6H, complex m) 4.6 to 4.96 (3H, complex m) 5.0 to 5.65 (7H, complex m) 7.42 (2H, d, J = 8Hz), 7.51 (2H,
d, J = 8Hz), 7.63 (2H, d, J =
8Hz), 8.15 (2H, d, J = 8Hz), 8.17 (2H,
d, J = 8Hz), 8.20 (2H, d, J =
8Hz) (Z) body Specific rotation: [α] ²² _D −16.3° (c1.35, THF) IR value: ν ^CHCl3 _nax cm ^-1 1760, 1750 (shoulder) 1715, 1520 PMR value: δ _CDCl3 ppm 1.86 (3H, s), 2.70-3.60 (6H, complex m), 4.72 (1H, dd, J=8Hz,
10Hz), 5.04 (2H, broads), 5.08~
5.60 (6H, complex m), 7.25
(2H, d, J = 8Hz), 7.32 (2H, d, J
= 8Hz), 7.42 (2H, d, J = 8Hz),
8.04-8.35 (6H, complex m) Example 19 (5R) p-nitrobenzyl 6(E and z)-[1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-ethylthio-
1-azabicyclo[3.2.0]hept-2-ene-
Preparation of 7-one-2-carboxylate Example 18 was prepared using 152 mg of the bicycloketone obtained in Example 16 and 19.26 mg of ethyl mercaptan.
silica gel chromatography using n-hexane-ethyl acetate (1:1), followed by chloroform-methanol (50:1).
separated by silica gel chromatography using
After purification, the desired (E) form 48 mg (yield 29.2%)
and 7 mg (yield 4.3%) of the (Z) isomer were each obtained as a yellow oil. (E) Body IR value: ν ^CHCl3 _nax cm ^-1 1765, 1730 (shoulder), 1525 PMR value: δ _CDCl3 ppm 1.18 (3H, t, J=6Hz), 2.07 (3H,
s), 3.05-3.90 (4H, complex m), 4.50-4.90 (3H, complex m), 5.19 (1H, d, J = 14Hz), 5.20 (2H,
s), 5.41 (1H, d, J = 14Hz), 7.45
(2H, d, J = 8Hz), 7.54 (2H, d, J
= 14Hz), 8.12 (2H, d, J = 8Hz), 8.14 (2H, d, J = 8Hz) (Z) body PMR value: δ _CDCl3 ppm 1.19 (3H, t, J = 6Hz), 1.85 (3H,
s), 3.0-3.8 (4H, complex m), 4.5-4.9 (1H, m), 5.04 (2H, broad s), 5.20 (1H, d, J=14Hz), 5.24 (2H,
s), 5.50 (1H, d, J = 14Hz), 7.52
(2H, d, J = 8Hz), 7.63 (2H, d, J
= 8Hz), 8.17 (2H, d, J = 8Hz), 8.20 (2H, d, J = 8Hz) Example 20 (5R) p-Nitrobenzyl 6 (E and z) - [1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-(2-pyridylthio)-1-azabicyclo[3.2.0]hept-2-
Production of en-7-one-2-carboxylate Example 18 using 142 mg of the bicycloketone obtained in Example 16 and 32.2 mg of 2-mercaptopyridine.
After reaction treatment in the same manner as above and separation and purification using silica gel column chromatography [solvent: n-hexane-ethyl acetate (2:5)], the desired (E) form was obtained.
73.6 mg (yield 44.2%) and 5.1 mg (yield
3.1%) were obtained in each case as a yellow oil. (E) Body Specific rotation: [α] ^22.5 _D −30° (c1, THF) IR value: ν ^CHCl3 _nax cm ^-1 2940, 1760, 1710, 1610, 1560 UV value: λ ^THF _nax nm (ε) 285 (15600), 262 (23900) PMR value: δ _CDCl3 ppm 2.08 (3H, s), 3.03 (1H, dd, J=
18Hz, 8Hz), 3.33 (1H, dd, J=
18Hz, 10Hz), 4.68 (2H, broad s), 4.84 (1H, m), 5.19 (2H, s), 5.28
(1H, d, J = 14Hz), 5.56 (1H, d,
J=14Hz), 7.20 (1H, m), 7.36-7.64
(4H, complex m), 7.69 (2H,
d, J = 8Hz), 8.24 (4H, d, J =
8Hz), 8.49 (1H, dd, J=5Hz, 2Hz) (Z) body IR value: ν ^CHCl3 _nax cm ^-1 2910, 1750, 1605, 1570, 1560 PMR value: δ _CDCl3 ppm (main peak) 1.79 (3H , s), 5.06 (2H, s), 5.25
(1H, d, J=14Hz), 5.28 (2H, s), 5.43 (1H, d, J=14Hz), 7.0~7.3
(1H, m), 7.4-7.8 (6H, complex m), 8.24 (4H, d, J = 8Hz), 8.48
(1H, m) Example 21 (5R) p-nitrobenzyl 6(E and z)-[1
-Methyl-2-(p-nitrobenzyl)oxycarbonyloxyethylidene]-3-(4,6-dimethyl-2-pyrimidinylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one- 2-
Production of carboxylates 119 mg of bicycloketone and 4,6-dimethyl-2-mercaptopyrimidine obtained in Example 16
Using 34 mg, reaction treatment was carried out in the same manner as in Example 18, and n-
Separation and purification by silica gel chromatography using hexane-ethyl acetate (1:2) and then chloroform-methanol (20:1) as solvents yielded 60 mg (yield 41.2%) of the desired (E) form and 10 mg of the (Z) form. (yield 6.9%) were obtained as pale yellow powders. (E) Body IR value: ν ^CHCl3 _nax cm ^-1 1760, 1715 (shoulder), 1560, 1525 PMR value: δ _CDCl3 ppm 2.10 (3H, s), 2.35 (6H, s), 3.20
(1H, dd, J = 18Hz, 10Hz), 3.86
(1H, dd, J = 18Hz, 10Hz), 4.70
(2H, broad s), 4.87 (1H, dd, J
= 10Hz, 8Hz), 5.22 (2H, s), 5.26 (1H, d, J = 14Hz), 5.50 (1H,
d, J=14Hz), 6.73 (1H, s), 7.45
(2H, d, J = 8Hz), 7.64 (2H, d, J
= 8Hz), 8.14 (2H, d, J = 8Hz),
8.18 (2H, d, J = 8Hz) (Z) body IR value: ν ^CHCl3 _nax cm ^-1 1765, 1715 (shoulder), 1590, 1530 PMR value: δ _CDCl3 ppm 1.85 (3H, s), 2.41 (6H, s), 3.15
(1H, dd, J = 18Hz, 8Hz), 3.92 (1H,
dd, J=18Hz, 10Hz), 4.82 (1H, dd, J=10Hz, 8Hz), 5.06
(2H, s), 5.24 (1H, d, J = 14Hz), 5.26 (2H, s), 5.52 (1H, d, J =
14Hz), 6.80 (1H, s), 7.53 (2H, d, J=
8Hz), 7.65 (2H, d, J = 8Hz), 8.20 (4H, broad d, J = 8Hz) Example 22 (5R)6(E)-(1-methyl-2-hydroxyethylidene)-3-( Production of 2-pyridylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid 57 mg of p-nitrobenzyl ester [(E) form] obtained in Example 20 was mixed with 2.4 ml of dioxane and pH 7.0.
The mixture was dissolved in a mixture of 1.4 ml of phosphate buffer, 57 mg of 5% palladium on carbon was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere (1 atm). When this was treated and purified in the same manner as in Example 7, 5.7 mg of the target product was obtained as a pale yellow powder (yield:
19.9%) was obtained. Specific optical rotation: [α] ²⁵ _D −115° (c0.3, water) IR value: ν ^KBr _nax cm ^-1 1760, 1730, 1600, 1575 UV value: λ ^PBS _nax (PH7.0) nm (ε) 290.5 (6620), 238 (14100) PMR value: δ _D2O ppm (with heavy water as 4.80) 2.11 (3H, s), 2.98 (2H, d, J=
10Hz), 4.28 (2H, s), 5.10 (1H, m), 7.56
(1H, dd, J = 6Hz, 4Hz), 7.76 (1H,
d, J = 8Hz), 7.89 (1H, m), 8.62 (1H, broad s, J = 4Hz) Example 23 (5R)6(E)-(1-methyl-2-hydroxyethylidene)-3-( Production of 4,6-dimethyl-2-pyrimidylthio)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylic acid 60 mg of p-nitrobenzyl ester [(E) form] obtained in Example 21 was mixed with 2.54 ml of dioxane and pH 7.0.
The mixture was dissolved in a mixture of 1.6 ml of phosphate buffer, 60 mg of 5% palladium on carbon was added, and the mixture was stirred for 2 hours under a hydrogen atmosphere (1 atm). This was treated and purified in the same manner as in Example 7 to obtain 24.7 mg (yield 78.5%) of the target product as a pale yellow powder. Specific optical rotation: [α] ²⁹ _D −145.2° (c0.785, water) IR value: ν ^KBr _nax cm ^-1 1745, 1620 (shoulder), 1590 UV value: λ ^PBS _nax (PH7.0) nm (ε ) 282 (6850), 239 (13470) PMR value: δ _D2O ppm (with heavy water as 4.80) 2.08 (3H, s), 2.51 (6H, s), 2.98
(1H, dd, J = 17Hz, 9Hz), 3.48 (1H,
dd, J = 17Hz, 10Hz), 4.30 (2H,
s), 5.06 (1H, dd, J=10Hz, 9Hz),
7.16 (1H, s).

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₂ are the same or different and represent a methyl group or a hydroxymethyl group, R ₃ is a pyridyl group or a pyrimidinyl group optionally substituted with a lower alkyl group, and R ₄ is a hydrogen atom or a substituted A compound represented by (representing a benzyl group which may have a benzyl group) and a salt thereof.