JPS604814B2 - 2-azetidinone derivative and method for producing the same - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula [1] [wherein R is a hydrogen atom, an alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted acyloxy group, a substituted or unsubstituted sulfonyloxy group,
It represents a disubstituted amino group or an azido group, and R2 and R4 may be the same or different, and represent a hydrogen atom, an alkyl group, an aralkyl group, or a trialkylsilyl group (which may or may not be substituted). , R3
is an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an aralkenyl group, an alkynyl group, an aralkynyl group,
The present invention relates to a 2-azetidinone derivative represented by a heterocyclic group or an acyl group (which may or may not be substituted), a pharmaceutically acceptable salt thereof, and a method for producing the same. Practically, optically active 2-azetidinone derivatives represented by the general formula [B] (wherein R, , R2, R3 and R4 have the same meanings as above), their pharmacologically acceptable salts, and their Regarding the manufacturing method. Examples of R, to R4 are hydrogen atoms, alkoxy groups such as tetrahydropyranyloxy and t-butyloxy, aralkyloxy groups such as benzyloxy, carbobenzoxy, and acetyloxy groups. acyloxy groups such as p-toluenesulfonyloxy, sulfonyloxy groups such as methanesulfonyloxy groups, disubstituted amino groups such as dialkylamino, phthalyllimino, arylideneamino groups, or azido groups. These substituents include halogen atoms, lower alkyl,
Examples include lower alkoxy and nitro groups. R2 and R4
Examples are hydrogen atoms, lower alkyl groups such as methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, di(p-methoxyphenyl)methyl, trityl, These include aralkyl groups such as phthalidyl, and trialkylsilyl groups such as tritylsilyl and ten-butyldimethylsilyl. Examples of substituents include halogen atoms, lower alkyl, lower alkoxy, and nitro groups. Examples of R3 are lower alkyl groups such as methyl, ethyl, propyl, butyl, isobutyl, and bentyl, aryl groups such as phenyl and naphthyl, aralkyl groups such as benzyl, ethenyl, 1-probenyl, and 1-methyl-1. - lower alkenyl groups such as ethenyl, 1-methyl-1-probenyl, 2-obenyl, 3-butenyl,
Aralkenyl groups such as styryl and cinnamyl, lower aralkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-pronyl, 2-butynyl, aralkynyl groups such as 2-phenyl-1-ethynyl, 2-furyl, 3-furyl, 5- Methyl-2-furyl, 5-ethyl-3-furyl, 2-thienyl, 3-thienyl,
5-methyl-2-thienyl, 5-methyl-3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 8-methyl-2-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 3-pyrazolyl, 4-isoxazoyl, 2-indolyl, 3-
Enomoto cyclic groups such as indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, 2-benzo[b]furanyl, 3-benzo[b]furanyl, and acyl groups such as acetyl, propionyl, and butyryl. Examples of substituents for these groups are halogen atom, lower alkyl, lower alkoxy, lower acyloxy, hydroxy, amino, lower alkylamino, lower dialkylamino, thiol, lower alkylthio, arylthio, nitro group,
It is a disubstituted amino group. Examples of pharmaceutically acceptable salts of the compound of formula [1] according to the present invention include at least one of R2 and R4, an alkali metal such as sodium or potassium, or an alkali metal such as calcium or magnesium. or with organic bases such as triethylamine, dicyclohexylamine, morpholine, piveridine, pyridine. All of the compounds of the present invention are novel compounds that themselves have 8-lactamase inhibitory activity, and are expected to be used in the treatment of infectious diseases in combination with antibacterial agents such as penicillin and cephalosporin. It can also be used itself as an antibacterial agent. Also,
The compound of the present invention has the following general formula [A] {where R is a hydrogen atom, a hydroxyl group, an alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted acyloxy group, a substituted or unsubstituted sulfonyl Oxy group, amino group,
It represents a substituted amino group or an azide group, R2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or an aralkyl group, and Y is bonded to the 3 and 4 positions of the 1-azapicyclo[4,2,0]octene ring. is a substituted or unsubstituted aryl group or heterocyclic group}, and is also a useful compound as a raw material for 2-azetidinone derivatives and pharmacologically acceptable salts thereof. The compound of formula [A] is also a compound that has an ability to inhibit 8-lactamase, and is expected to be used in the treatment of infectious diseases in combination with antibacterial agents such as penicillin and cephalosporin. The compound of formula [A] is also useful as an antibacterial agent itself. Specific examples of compounds represented by the general formula [A] are {a} In the general formula [A], R and ' are hydrogen atoms,
Y is {wherein R6, R7, R8 and R9 may be the same or different and represent hydrogen, lower alkyl, lower alkoxy, acyloxy, hydroxy, amino, lower alkylamino, thiol, lower alkylthio, arylthi and halogen group } 2-azetidinone derivatives represented by the general formula [A-1] (R2, R6, R7, R8 and R9 have the same meanings as above), and general formula [A-2 which is an optically active substance thereof] ] (In the formula, R2, R6, R7, R8 and R9 represent the same meanings as above), an optically active 2-azetidinone derivative 'b} In the general formula [A], R and ' are hydrogen atoms, and Y is [in the formula, R6, R? represents the same meaning as above,
X is an oxygen atom, a sulfur atom, or N-Z (Z is a hydrogen atom,
(represents a lower alkyl group, aralkyl group or acyl group)] or general formula [A-5] (wherein RF, R?, x and R2 represent the same meanings as above) 2-azetidinone derivatives represented by the general formula [A-4] or general formula [A-6] (wherein R6, R7, X and R2 represent the same meanings as above) which are optically active substances thereof. It is an optically active 2-azetidinone derivative. Further, the compound represented by the general formula [1] is, for example, a ○-2-isocephem compound represented by the general formula [B] [T.W. Doyle et al. Can. J. C
hem. , 55, 484 (1977)] or its analogues, it can be an important intermediate for bicyclic 8-lactam antibiotics in which the 1-position is a carbon atom. In general, 8-lactam antibiotic backbone analogs are known to have a certain type of essential absolute coordination at the 4-position of 2-azetidinone in the molecule in order to exhibit antibacterial activity and 8-lactamase inhibitory activity. ing. That is, the general formula

The absolute structures at the 4-position of 2-azetidinone of compounds derived from L-aspartic acid related compounds shown in [0], [A-2], [A-4], and [A-6] are useful P
- common to that of lactam antibiotic skeleton analogs,
This suggests further utility of these compounds. Next, a method for synthesizing the compound of the present invention will be explained. General formula [1] and

The compound represented by [0] is synthesized by the following methods. 'ee-general formula [1]' or general formula

[0]′ [in the formula,
R,, R2' and R3 have the same meanings as above, R4'
represents a substituted or unsubstituted alkyl group, aralkyl group or trialkylsilyl group] is a 2-azetidinone derivative represented by the general formula [m] or [W] [wherein,
R and R3 have the same meanings as above. However, when R3 is an acyl group and exists in the phenol form, it is protected with an henol ester such as henol acetate, an henol ether such as enol methyl ether, or the like. R2' represents a substituted or unsubstituted alkyl group, aralkyl group or trialkylsilyl group,
R5 represents an alkyl group, an alkenyl group, an aryl group, or an aralkyl group (which may or may not be substituted)] is treated with a halogenating agent to form an imidyl halide derivative. , and then treated with an alcohol or alkoxide to form an iminoether derivative, which is then hydrolyzed. [Ro General formula [1]'' or general formula m]
``[In the formula, at least one of R2'' and R4'' is a hydrogen atom, and the other is a hydrogen atom, an alkyl group, an aralkyl group (
These may or may not be substituted)
The 2-azetidinone derivative represented by the formula can be obtained by treating the compound of formula [1]' or the compound of formula [m' obtained in section {i} by a conventional method. That is, mono- or dicarboxylic acid type general formula [1]''
or

The 2-azetidinone derivative represented by [0]″ is
Gestel type general formula [1]' or

It is easily synthesized from the 2-azetidinone derivative represented by [0]'. In addition, the obtained general formula [1]′,

Groups R2', R2'', R4' of the compound represented by [0]', [1]'' and [ro]''
and R4'' can also be converted into another group R2', R2'', R4' or R4'' by a conventional method such as transesterification, esterification of carboxylic acid, etc. The formula [m] or The method for producing the compound of formula [W] is disclosed in Tokkotsu 1986-520 by the same applicant.
No. 68, No. 54-106457 and No. 54
It is described in No. 1130552. That is, the compound of formula [m] or formula [N] has the general formula [V] (wherein,
R,' is a hydrogen atom, a hydroxyl group, an alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted acyloxy group, a substituted or unsubstituted sulfonyloxy group,
represents an amino group, substituted amino group or azide group, R2
' represents the same meaning as above) and the aspartic acid converter represented by the general formula [W] R3CH○
[Town] (In the formula, R3 represents the same meaning as above)
It can be obtained by condensing an aldehyde represented by the formula and isonitrile represented by the general formula R5N3C (where R5 has the same meaning as above) in a suitable solvent. Specific methods for synthesizing raw material compounds are shown in Reference Examples 1 to 3. Although the synthesis method used in the method of the present invention, that is, the method of converting a secondary amide derivative into an ester via an iminoether compound, is known for other compounds,
This is the first time for a 2-azetidinone derivative such as the compound. Similar methods have been used to carry out amide hydrolysis in similar compounds such as 7-acylamidocephalosporin derivatives, but these methods are carried out not to obtain esters but to obtain amino compounds. Moreover, for 2-azetidinone, it is carried out to obtain the amino form at the 3-position [for example, Helv. Chim. To Acta 51
, p. 1108 (1968), J. big. Chem. ，
36, p. 1259 (1971), J. Antibio
tics, 25, p. 248 (1972), Japanese Patent Application Publication No. 1972
-2309, JP-A-52-31095, etc.].
Formula [1]' or

The ester group of the compound [0]' is selectively converted to a carboxylic acid to form a compound of the formula [1]'' or [b]''
Methods for obtaining the compound include methods that vary the strength of reagents such as acids and bases, and various reaction conditions such as reaction temperature and reaction time, hydrolyzing agents, reducing agents, hydrolyzing agents, dealkylating agents, etc. Any known method for converting an ester into a carboxylic acid can be selected depending on the groups R2' and R4'. To give an example of a practical method, in general formula [1]', R2
When ' = penzyl group and R4' = methyl group, the group CO is hydrogenated using palladium carbon as a catalyst.
OR2' is selectively hydrolyzed to form R2'=day, R4'
A compound (monocarboxylic acid) of formula [1]'' represented by = methyl group is obtained, R2' = rt-butyl group, R4'
In the case of a comethyl group, the group COOR4' is selectively hydrolyzed by hydrolysis using potassium carbonate as a catalyst, and the group COOR4' is selectively hydrolyzed, and the formula [1]'' is A compound (monocarboxylic acid) is obtained. Therefore, depending on the target compound, preferably the group R2
', R4' can be used as a raw material. In this case, the general formula [1]″
or in the compound represented by [b]'', R2'' or R4
In order to synthesize a compound in which one of `` is a day, it is preferable to use as a raw material a compound in which one of R2'' or R4'' has a group that is more easily converted to carboxylic acid than the other. In particular, as R2'', M is preferably a group that can be converted into carboxylic acid without causing any unfavorable changes in other parts of the compound.This is because the general formula [1] skin or

[0]'''In the formula, R.
, R3 and R4'' have the same meanings as above) is useful as a preferred raw material for the compound represented by the general formula [A].Next, regarding the method for producing the compound of the formula [1] The compound of formula [1] is prepared by reacting a halogenating agent with a compound of formula [m] to form a corresponding iminohalide, then reacting with an alcohol or alkoxide of an alkali metal to form an iminoether, and then converting the compound into an iminoether. A series of reactions are illustrated below using formulas. (In the formula, R,, R2', R3, R4' and R5 have the same meanings as above, and A represents a halogen atom.) The above series of reactions can be carried out successively in the same solvent, and usually each intermediate is not isolated. Examples of solvents used include chloroform, dichloromethane, dichloroethane, benzene, diethyl ether, tetrahydrofuran, and dioxane. In addition, there are various solvents that do not participate in this reaction.The reaction is carried out at a rate of 1mM/~2M/day, preferably 10mM/~2M/day of the starting material.
It is carried out at a concentration of around 0.9 M/s. Examples of halogenating agents used in the iminohalide production reaction include phosphorus pentachloride, phosphorus oxyoxide, thionyl chloride, phosgene, oxalyl chloride, and a complex of dichlorophenylphosphine and chlorine. Preferably used. The halogenating agent used is
With respect to the starting compound IM of the formula [blood], IM to 10M is used, preferably IM to 2M is used. The reaction temperature and time vary depending on the type of raw material compound used and other conditions, but the reaction is carried out at a temperature of 178 o'clock to 15,000 o'clock, preferably -1000 o'clock to 50 o'clock o'clock, for a period of 10 minutes to 24 hours. A base can also be used as a catalyst during this reaction, and examples thereof include tertiary organic amines such as triethylamine, pyridine, quinoline, and dimethylaniline. The amount of base used varies depending on the reaction conditions and especially the amount of halogenating agent used, but it is used at a concentration of 5 mM from IM, preferably IM to 20 M, relative to the starting compound IM. As the alcohol or alkoxide used in the iminoether producing reaction product, lower alkyl alcohols such as methanol and isobutanol, lower haloalkyl alcohols, aralkyl alcohols, or their alkoxides with alkali metals are used. Generally, when alcohol is used, an excess of 20 to 100 mM is used relative to the raw material compound IM, and when an alkoxide is used, it is preferably 2M~50
Used between M. The reaction temperature and time vary depending on the halogenating agent, chlorine, type of alcohol or alkoxide used, etc., but are preferably -78°C to 150°C, preferably -40°C.
The test is carried out at a temperature between 00 and 50°C for a period of 10 minutes to 48 hours. The reaction for producing the ester of formula [1]' is carried out by reacting the obtained iminoether with an acidic solution, water, or aqueous alkaline solution. The properties of R5,
Although it varies depending on the reaction conditions up to this point, 0.1N to 1.0N hydrochloric acid water is generally used. In that case, the reaction temperature and time are preferably -10qo to 5
It is held between 0:00:00, 5:00 and 1:00 p.m. The 3-lactamase inhibitory activity of representative compounds according to the present invention is as follows. Concentration Rejection rateCompound of Example 1 50〃Tasso 22% Compound of Example 3 50〃Tasso 20%Example 4
Compound 50 of Antimicr with 34% activity using chromogenic cephalosporin as substrate
obiaI Ahokontand Chemo erapy
According to the method described in Volume 1, page 283 (1972),
Enterobacter sp. It was measured using B-lactamase produced by KY3073. Next, examples of the present invention will be explained. This example is merely provided for the purpose of limiting the scope of the invention. In the following, 2-azetidinone is replaced by 2-
It's called oxoazetidine. Example 1 (4S)-Methyl-Q(4-penzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(phenyl)acetate [R,=day in general formulas (1) and (0) , R4=-CQ] in an anhydrous chloroform solution containing 15.83 molar (76. hM) of phosphorus pentachloride under anhydrous conditions at 340° C.
Add (152.5 hM) of quinoline 18. To this, at 0°C, (4S)-phenyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(phenyl)acetamide consisting of an approximately 1:1 diastereomeric mixture is added. 21.0 evening (50.7
80 μM of anhydrous chloroform solution containing 80 mM) was added for 2 minutes, followed by incubation at 0-5° C. for 3 hours. Then at 0 °C, add 300 g of anhydrous methanol, then at room temperature
Perform Time Hawk Azusa. Next, at 0°C, add 400% of IN hydrochloric acid and 300% of methanol, and then incubate for 1 hour at room temperature. Next, about 60% of the reaction solution was distilled off under reduced pressure, and the remaining solution was extracted three times with 250% ethyl acetate each. The ethyl acetate layer was washed three times with saturated brine, and the organic layer was extracted. After drying with potato salt, the solvent is distilled off. The obtained oil was charged into a circular column with a diameter of approximately 8 cm filled with silica gel [Wako Gel C-200, Wako Pure Chemical Industries (hereinafter abbreviated as silica gel)] 650, and purified by column chromatography. Let's do it. After 1.4 hours of elution with a mixed solvent of hexane:ethyl acetate (volume ratio 5:2), elution is performed with a mixed solvent of hexane:ethyl acetate (volume ratio 3:2). The eluate was fractionated into 15 fractions,
Fractions numbered 63 to 104 were collected and the solvent was distilled off under reduced pressure to obtain an oily product with a yield of 7.9% (yield: 44.9%).
4%). The physical properties of the oily substances obtained from fractions Nos. 74 to 104 are shown below. Nuclear magnetic resonance spectrum 6CDC13 [Coupling constant: HZ in parentheses] 2.83 [d
do. 9th (2.5, 14.0)], 3.07 [d, I
H (4.0)], 3.12 [dd, o. 9 days (5.5,
14,0)], 3.60 (S, 1. Congee), 3.70 (S
,1. spots), 4.23 [t, 0. World 4.0)], 4.4
2 [dd, 0. beat (2.5, 5.5)], 4.70 (b
rs, IH), 5.20 (S, IH), 5.50 (S,
IH), 7-20 to 7-40km, 10H) Infrared absorption spectrum 〃S bag 13 (Ka-1) 1780 (sh),
1775,1750,1740 (sh) Mass spectrum (m/e) M+353,294,266,91 Thin layer chromatography Hexane:ethyl acetate (volume ratio 1:1, hereinafter referred to as solvent A) was used as the developing solvent, and a silica gel plate ( Rfo. It showed two points of 52 and 0.61. From the above data, the obtained oil is (4S)-methyl-Q-(4-penzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(phenyl)acetate (
It was identified as an approximately 1:1 diastereomeric mixture of two types. Example 2 (4S)-Methyl-Q-(4-penzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)acetate [R in general formula (1), (b) , = day, , R4 = CH8] In a chloroform-free solution containing 725 o (3.48 hM) of phosphorus pentachloride at 15.4', quinoline 0.825 {( 6.96mM). At 0°C, a diastereomeric mixture of (4S)-phenyl-Q-(4-penzyloxycarbonyl-2-oxoazetidin-1-yl) was added to this at 0°C.
Anhydrous chloroform solution 6 containing 1.03 hM (2.32 hM) of 1-Q-(3-methoxyphenyl)acetamide was added at 1 minute, and then incubated at 0-5°C for 3 hours and 30 minutes. Next, 14' of anhydrous methanol was added at 0°C, followed by incubation for 3 hours at room temperature. Then, at 0°C, IN hydrochloric acid 1
Add 8 ml and 18 ml of methanol, then heat for 1 hour at room temperature. Next, about 60% of the reaction solution was distilled off under reduced pressure, and the remaining solution was extracted three times with 30% ethyl acetate.The organic layer was washed three times with saturated brine and dried over moss salt. After that, the solvent is distilled off. The obtained oil was charged into a circular column with a diameter of about 4 mm filled with 120 ml of silica gel, and purified by column chromatography. Elution is performed with a mixed solvent consisting of hexane and ethyl acetate (volume ratio 3:2). The eluate was separated into 6 fractions each, fractions numbered 56 to 82 were collected, and the solvent was distilled off under reduced pressure to obtain 473 of 9 as an oil (yield 53.2%). The physical properties of the oil obtained from fractions Nos. 66 to 82 are shown below. Nuclear magnetic resonance spectrum 6CoC13 [Coupling constant: HZ in parentheses] 2.85 [d
d, 2-3 days (2.5, 15.0)], 3.07 [d,
2/3rd (4.0)], 3.27[dd, 2/3rd (5.0)
．． 5, 15.0)], 3.63 (S, IH), 3.40
(S, spot), 4.23 [t, 1/3 day (4.0)], 4
．． 45 [dd, 2/3 days, (2.5, 5.5)], 4.
72, 4, 74 (ABdo riblet, 4'3H), 5.
20 (S, 2/3H), 5.48 (b Dai, IH), 6.
70 to 7.40 (m, field) Infrared absorption spectrum 〃Jyogata 13 (Ka-1) 1780 (sh), 1770, 175
0,1740 (sh), 1600, 1590 Mass spectrum (m・e) M+383, M11:384,324,296 91 Thin layer chromatography Rfo. 47 and 0.51 (the quantitative ratio was estimated to be about 2:1). From the above data, the obtained oil is ($)-methyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)acetate (approximately 2:1 It was identified as a diastereomeric mixture of two types. Similarly, the oil obtained from fractions No. 56 to 82 was identified as a mixture of two diastereomeric compounds in a ratio of about 1:1. Example 3 (4S)-Methyl-Q-(4-penzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(5-methylfuran-2-yl)acetate [general formula (1), (
B) Preparation of a compound with RI=day, R4=-C ratio] A solution of 0.46% of quinoline at 000% under anhydrous conditions was added to 8.6% of an anhydrous chloroform solution containing phosphorus pentachloride 403 (1.94mM). [(3.87mM) is added. To this, (4S)-phenyl-Q-1(4-benzyloxycarbonyl-2-oxoazetidin-1-yl) consisting of a diastereomeric mixture of about 1:1 at 0°C.
-Q-(5-methylfuran-2-yl)acetamide 54
Anhydrous chloroform solution containing 0.9 (1.29 hM) 6
Add saw for 10 minutes, then 3 hours and 30 at 0-500
Perform a worship service. Next, add 000 to 7.6' of anhydrous methanol, followed by rinsing for 3 hours at room temperature. then 0
Add IN hydrochloric acid low' and 10 liters of methanol at 0.degree. C., and then evaporate for 1 hour at room temperature. Next, about 60% of the reaction solution was distilled off under reduced pressure, and the remaining solution was extracted three times with 30 portions of ethyl acetate each, and the organic layer was washed three times with saturated brine and then dried with ramie. After that, the solvent is distilled off. The obtained oil was charged into a circular column with a diameter of about 3 mm filled with 60 mm of silica gel, and purified by column chromatography. Elution is performed with a mixed solvent consisting of hexane:ethyl acetate (volume ratio 3:2). The eluate was fractionated into three fractions each, fractions numbered 55 to 72 were collected, and the solvent was distilled off under reduced pressure to obtain 191 female oil (yield 41.4%). The physical properties of the oil obtained from fractions No. 60 to 65 are shown below. Nuclear magnetic resonance spectrum 6 CDC13 [Coupling constant: Hz in parentheses] 2.17 (S
,1. ), 2.23 (S, 1.ga), 2.87 [dd
, 0, Group (2, 5, 14.5)], 3.10 [d, 0,
Thin (4.0)], 3.30 [dd, 0. Group (5.0,1
4.5)], 3.65 (S, 1. group), 3.73 (S,
1. ), 4.18 [t, 0.4 days (4.0)], 4.
53 [dd, 0. Song (2.5, 5.0)], 4.90,
4.93 (AB doublet, 1.), 5.20 (
S, 0. Thin), 5.57 (S, IH), 5.87 (m,
IH), 6.17 [d, 0. Group (3.0)], 6.23
[d, 0.4 days (3.0)], 7.30 (S, ga)],
7.37 (S, fine) infrared absorption spectrum Wild pitch 13
(c-,) 1780 (sh), 1770, 1775,
1740 (sh) Mass spectrum (m/e) M135
7,329,298,270,91 Thin layer chromatography TL using plate A with solvent A as the developing solvent
Rfo. It showed 1 point of 49. From the above data, the obtained oil is (4S)-methyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-o-(5-methylfuran-2-yl)acetate (approximately 2:3 It was identified as a diastereomeric mixture of species. Similarly, the oil obtained from fractions No. 55 to 72 was identified as an approximately 2:3 diastereomeric mixture of two species. Example 4 (4S)-Methyl-o-(4-carboxyl-2-oxoazetidin-1-yl)-Q-(phenyl)acetate [general formulas (1) and (0), and R. Preparation of (100 million)-methyl-Q-(4-benzyloxycarbonyl-2-oxoazethi) consisting of the approximately 1:1 diastereomeric mixture obtained in Example 1. Jin-1-yl)-o
4.0 mmol (11.3 mM) of mono(phenyl)acetate was dissolved in 250 ml of dioxane, and 10%
1.0 tm of palladium-carbon catalyst was added thereto, and hydrogen gas was bubbled through at room temperature under atmospheric pressure for 17 hours. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain a 2.89 ml oil. The physical properties of this oil are shown below. Nuclear magnetic resonance spectrum 8C0CI3 [Coupling constant: HZ in parentheses] 2.70 to 3
．． 50 (m, 2H), 3.70, 3.73 (each S, coarse), 4.07-4.50 (m, IH), 5.47, 5.
53 (S, IH, respectively), 7.30, 7.33 (S, IH, respectively),
Group) Infrared absorption svector Rejokura 13 (skin-,) 17
80 (sh), 1775, 1755, 1740 (sh
), 1730 (sh), 1710 (sh) Thin layer chromatography Benzene: Ethyl acetate: Acetic acid (volume ratio 6:2
:1) (hereinafter referred to as solvent B) as a developing solvent, Rfo. It showed 1 point of 32. From the above data, the obtained oil is composed of (4S)-methyl-Q-(4-lupoxy-2-oxoazetidin-1-yl)-Q-(phenyl)acetate (two diastereoisomers in a ratio of approximately 1:1). The product was identified as a mixture of mercury and mercury (yield 97.0%). Example 5 ($)-Methyl-Q-(4-carboxyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)acetate [R,=day, R2 in general formulas (1) and (0) Preparation of (4S)-methyl-Q-(4-benzyloxycarponyl-2-oxoazetidine) consisting of the approximately 1:1 diastereomeric mixture obtained in Example 2. -1-yl)-Q-(3-methoxyphenyl)acetate 470-9(
1.23 hM) was dissolved in 25 w' of dioxane, 10% palladium-carbon catalyst was added to the solution, and hydrogen gas was bubbled through for 1 hour at room temperature and atmospheric pressure under a box frame. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain 354-9 oil. The physical properties of this oil are shown below. Nuclear magnetic resonance spectrum 6CoC13 [Coupling constant: HZ in parentheses] 2.73 to 3
．． 50 (m, wide), 3,70-3,80 (m, bait), 4
．． 13-4.50 (m, IH), 5.47 (S, 0. spot), 5.53 (S, 0, spot), 6,73-7,47 (m
, Misaki) Infrared absorption spectrum Remi bag 13 (伽-,) 1
780 (sh), 1770, 1750, 1740 (sh
), 1730 (sh), 1710 (sh), 1600,
Rfo. It showed 1 point of 26. According to the above data, the obtained oil is (4S)-methyl-Q-(4-ruboxyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)acetate (two diastereoisomers in a ratio of approximately 1:1). Merrick mixture) (yield 98.0%). Example 6 (4S)-Methyl-Q-(4-carboxyl-2-oxoazetidin-1-yl)-Q-(5-methylfuran-
2-yl) acetate [compound of general formula (1), (b) with R, = day, R2 = day, R4 = -C ratio] Approximately 2:3 diastereoisomer obtained in Example 3 (4S)-Methyl-Q-(4-Besozyloxycarbonyl-2-oxoazetidin-1-yl)-
Q-(5-methylfuran-2-yl)acetate 180
Dissolve 9 (0.5 hM) in 12.5 m dioxane, add 10% palladium-carbon catalyst 50 m, and heat hydrogen gas for 1 hour at room temperature and atmospheric pressure. Ventilate. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain 130x9 oil. The physical properties of this material are shown below. Nuclear magnetic resonance spectrum 6 CDC13 [Coupling constant: HZ in parentheses] 2,22 (S
,1. Group), 2.27 (S, 1.2H), 2.77-3
, 57 (m, ga), 3.77 (S, ga), 4,07~4
, 63 (m, IH), 5.60 (brs, IH), 5.
93 (m, IH), 6-25 [d, 0-Mother's Day (3-0)
], 6-32 [d, 0-4 days (3.0)] Infrared absorption spectrum 〃Ryoukura 13 (hada-,) 1780 (sh), 1
770, 1755, 1740 (sh), 1730 (sh
), 1710 (sh) thin layer chromatography Rfo. It showed 1 point of 27. From the above data, the obtained oil is (4S)-methyl-Q-(4-lupoxyl-2-oxoazetidine-1
-yl)1o-(5-methylfuran-2-yl)acetate (approximately 2:3 diastereomeric mixture of two species)
It was identified as (yield 97.0%). Reference Example 1 Production of (4S)-phenyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(phenyl)acetamide (raw material compound used in Example 1) L-aspartic acid- Q-Benzylester 4
Suspended 1.3 methanol (179.2 hM) in methanol, and added 19 mn (179.2 hM) of benzaldehyde to this suspension.
M) and phenylisonitrile 19.4 m (188.2 m)
Add M) and perform roping for 6 hours at room temperature in a nitrogen stream. The solvent was distilled off under reduced pressure, and the resulting oil was diluted with 50% saturated brine.
Extraction was performed by adding 500 g of ethyl acetate and 500 g of ethyl acetate, and the ethyl acetate layer was washed three times with saturated brine. After drying the ethyl acetate layer with trinitric nitrate, the solvent was distilled off under reduced pressure. The oil was charged into a circular column with a diameter of about 8 arcs filled with 600 ml of silica gel, and purified by column chromatography. n-hexane:ethyl acetate (volume ratio 1:1)
Elution is performed with a solvent consisting of: The eluate was divided into 18 fractions each, fractions numbered 79 to 129 were collected, and the solvent was distilled off under reduced pressure to obtain a glassy solidified product of 22.02 mm. The physical properties of this product are as follows.
Elemental analysis value C fake day 22N204 (molecular weight 414.44
) Calculated value (%) C: 72.45, H: 5.35
, N: 6.76 Actual value (%) C: 72.57, H: 5
．． 50, N: 6.57 Infrared absorption spectrum〃S bag 1
3(佽-,)1780(sh)、1770、1750(
sh), 1695, 1602 nuclear magnetic resonance spectrum 8C
0CI3 [Coupling constant: HZ in parentheses] 2.67 to 3.5
0 (m, 2H), 3.87, 4.53 [t, (4.
0), dd, (2.5, 5.5), IH], 4.83,
5.15, 5, 20 (S, respectively), 5.50, 5.5
7 (S, IH each), 6.87-7.80 (m, 1 group)
,873,9.80 (brs, IH respectively) Mass spectrum (m/e) M1414, M+1:415,294,266,204
, 91 Thin Layer Chromatography TLC using plate A using n-hexane:ethyl acetate (volume ratio 1:1) as a developing solvent showed a single spot with Rf=0.54. From the above data, the obtained glassy solidified product is (4S)
1-phenyl-2(4-benzyloxycarbonyl-2)
-oxoazetidin-1-yl)-Q-(phenyl)-acetamide (about 1:1 diastereomeric mixture of two types) (yield 29.7%). Reference Example 2 Synthesis of (4S)-phenyl-Q-(4-penzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)acetamide (raw material compound used in Example 2) L-aspartic acid. - Suspend 2.239 g of pendyl ester ((1 dish M) in 80 g of methanol, add 1.36 g of m-anisaldehyde (and 1 M) and 1.0 g of phenylisonitrile.
Add 800mg (10.5mM) and incubate at room temperature for 45 minutes in a nitrogen stream.
Perform time management. The solvent is distilled off under reduced pressure, and the resulting oil is charged into a circular column with a diameter of 5 mm filled with silica gel 2502, and purified by column chromatography. n-hexane:ethyl acetate (volume ratio 3:2
). The extract was divided into 15 portions each, fractions numbered 61 to 93 were collected, and the solvent was distilled off under reduced pressure to obtain an oily product with a yield of 1.05 mm. The physical properties of this product are as follows. Elemental analysis value Calculated value (%) as C Shiji 24N205 (molecular weight 444.47) C: 70.25, H: 5.44, N:
6.30 Actual value (%) C: 70.33, H: 5.75
, N: 6.19 Infrared absorption spectrum 〃S Shibu 13 (Skin-
, ) 1780 (sh), 1770, 1750 (sh),
1695,1602 nuclear magnetic resonance spectrum 6CDC13
[Coupling constants in parentheses: HZ] 2.73 to 3.60 (m,
), 3.67, 3.70 (respectively S, general), 3.90,
4.57 [t, (4.0), dd, (2.5, 5.
5), IH], 4.87, 5.17, 5.20 (S
, 2H), 5.47, 5.53 (S, IH)), 6
．． 67-7.83 (m, 14H), 8.70, 9.80
(brs, IH, respectively) Mass spectrum (m/e) M+
444,324,296,234,91 Thin layer chromatography Rf = 0 by TLC using plate A using n-hexane:ethyl acetate (volume ratio 1:1) as the developing solvent.
．． 54 single spots were shown. From the above data, the obtained oil is ($)-phenyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)-acetamide (approximately 1:1 (yield 23.6%). Reference Example 3 (4S)-phenyl-o-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-. Preparation of -(5-methylfuran-2-yl)acetamide (raw material compound used in Example 3) 22.23 g of L-aspartic acid-Q-pendyl ester (1 M) was suspended in 80 g of methanol, This has 5-methyl-
Add 2-furfural (1.1% IQhM) and phenylisonitrile (10.5% IQhM), and carry out oxidation at room temperature in a nitrogen stream for 6 days. The solvent was distilled off under reduced pressure, and the resulting oil was purified using silica gel 3.
The product was charged into a circular column with a diameter of about 6 mm and packed with 50 ml of silica, and purified by column chromatography. n-
Elution is carried out with a solvent consisting of hexane:ethyl acetate (3:2 by volume). The port liquid was separated into 10 pieces each.
Fractions numbered 80 to 129 were collected and the solvent was distilled off under reduced pressure to obtain 558-9 oil. The physical properties of this product are as follows. Elemental analysis value C thy day 2
Calculated value (%) as 2N205 (molecular weight 418.43)
C: 68.89 H: 5.30, N: 6.70 Actual value (%) C: 69.22, H: 5.41, N: 6.55
Infrared absorption spectrum 〃Wild Pitch 13 (Suppression-,) 1780
(sh), 1770, 1740, 1700, 1603 nuclear magnetic resonance spectrum 6 CoC13 [Coupling constants in parentheses:
HZ] 2.10, 2.16 (each S, thin)), 2.77
~3.53 (m, group), 3.97, 4.59 (respectively m,
IH), 4.97, 5.23 (brs, 2H, respectively), 5
．． 53, 5.57 (S, IH, respectively), 5.83 (m, I
H) 6.26 (m, IH), 6.80-7.80 (m,
10H)), 8.63, 9.37 (brs, IH respectively)
)Mass spectrum (m/e)M+418,298,2
70,208,91 Thin layer chromatography Rf=0.58 and Rf=0.
Two points showing diastereomeric mixtures of 61 were shown. From the above data, the obtained oil is composed of (4S)-phenyl-Q-(4-benzyloxycarbonyl-2-oxoazetidin-1-yl)-Q-(5-methylfuran-2-yl)-acetamide (approximately 1:1 (yield 13.8%). Reference example 4 ($)-methyl-5,8-dioxo-penzo[C]-1
-Azabicyclo[4,2.0]octane-2-ylcarboxylate [compound with general formulas (A-1) and (A-2) where R6=R7=R8=R9=day and R2=C ratio]
(4S)-Methyl-Q-(4-carboxy-2-oxoazetidin-1-yl)-Q-(
phenyl) acetate at 1.16 m (4.39 hM),
Add 36 cm of anhydrous ether and to this add 10.2 mm of thionyl chloride (14 hM) at room temperature. Thereafter, the mixture was heated under reflux for 5 hours, and then ether and excess thionyl chloride were distilled off under reduced pressure. The obtained oil was dissolved in 100% of anhydrous methylene chloride, and this was
Anhydrous aluminum chloride powdered under Takaazusa at room temperature 3.1
The mixture was added dropwise over 15 minutes to 200 mL of anhydrous methylene chloride containing 300 mg (23.8 hM). After that, 1 hour 30
After gently heating to reflux, the reaction solution was cooled, 20 parts of ice and 100 parts of IN hydrochloric acid were added, and the mixture was heated for 20 minutes. The methylene chloride layer was separated from the aqueous layer, and the aqueous layer was heated once more for 100°C.
of methylene chloride. Combine the methylene chloride solutions, wash twice with saturated saline, and dry with trinitrate. The oily substance obtained by distilling off the solvent is charged into a circular column with a diameter of approximately 6 mm filled with 200 μm of silica gel, and purified by column chromatography. Elution is performed with a mixed solution of hexane:ethyl acetate (volume ratio 1:1). The eluate was fractionated in 10 fractions each, fraction numbers 61 to 1.
10 fractions were collected and the solvent was distilled off under reduced pressure.
Obtain 689 Hadayu Crystal. The physical properties of this material are shown below. Nuclear magnetic resonance spectrum 6C. CI3 [Coupling constant in parentheses: day 2] 3.14 [dd, I
H (2.5, 15.0)], 3.63 [dd, IH (6
．． 0, 15.0)], 3.77 (S, thin), 4.58 [
dd, IH (2.5, 6.0)], 5.63 (S, IH
), 7.27-8.30 (m, cape) infrared absorption spectrum Pubukuro 13 (skin-,) 1780 (sh), 1775,
17551700,1600 mass spectrum (m/e
) M1245 217,180 1 Spot melting point 140-141°C (further recrystallized from ethyl acetate/petroleum ether) Thin layer chromatography Rfo. It showed 1 point of 42. From the above data, the obtained crystal is ($)-methyl-5
,8-dioxobenzo[C]-1-azabicyclo[4
, 2.0] octane-2-yl carboxylate. Note that this product is only one of the two possible diastereoisomers (yield: 6
4.0%). Reference Example 5 ($)-Methyl-5,8-dioxo(5-methoxybenzo)[C]-1-azabicyclo[4,2.0]octan-2-ylcarboxylate [General formula (A-1)]
, (A-2) in which R6, R8:R9 = day, R7, OCH3, R2, CH3] (4S)- To 320 μg of methyl-Q-(4-carboxy-2-oxoazetidin-1-yl)-Q-(3-methoxyphenyl)-acetate (0.87 mM) was added 7.7 μl of anhydrous ether; , add 2.2' (3 MM) of thionyl chloride to the bottom of the tube at room temperature. Thereafter, the mixture was heated under reflux for 4 hours, and then ether and excess thionyl chloride were distilled off under reduced pressure. 80% of anhydrous chloroform was added to the resulting oil, and 60% of powdered anhydrous aluminum chloride was added to the resulting solution under swarm at room temperature.
70:9 (5.0 hM) was added all at once, and the mixture was allowed to float at room temperature for 1 hour, and then the reaction was further carried out at 40°C for 1 hour. After cooling to 0° C., 50 minutes of ice and 30 minutes of IN hydrochloric acid were added, and the mixture was lit for 10 minutes to separate the chloroform layer from the aqueous layer. The aqueous layer is further extracted twice with 30' chloroform.
The obtained chloroform layer was washed twice with saturated saline solution and dried with ramie salt, and the obtained oil was charged into a circular column with a diameter of 3 cm packed with 60 mm of silica gel, and purified by column chromatography. Let's do it. Extraction is performed with a mixed solvent consisting of hexane:ethyl acetate (volume ratio 3:2). The eluate was fractionated at 5M each, fractions numbered 60 to 88 were collected, and the solvent was distilled off under reduced pressure to obtain 9.
Obtain 0 to 9 crystals. The physical properties of this material are shown below.
Nuclear magnetic resonance spectrum 6 CDC13 [Coupling constant: HZ in parentheses] 3.13 [dd, IH (3.0, 16.0)]
, 3.62 [dd, IH (6.0, 16.0)], 3.
80 (S, Thin), 3.90 (S, So), 4.53 [dd
, IH (3.0, 6, 0)], 5.60 (S, IH),
6.95 (d, IH (2.5)], 6.97 [dd, I
H (2.5, 10.0)], 8.10 [d, IH (10
．． 0)] Infrared absorption spectrum S bag 13 (skin-,) 1
780 (sh), 1775, 1755, 1695, 16
00 mass spectrum (m/e) M+275,247,
216,188 melting point 138-140.55oo (further recrystallized from chloroform-petroleum ether) thin layer chromatography Rfo. It showed 1 point of 38. From the above data, the obtained crystal is (muscle)-methyl-5
,8-dioxo(5-methoxybenzo)[C]-1
-Azabicyclo[4,2.0]octane-2-ylcarboxylate. This product is one of two possible diastereoisomers (yield: 30.
0%). Reference example 6 ($)-Methyl-5,8-dioxo (5-methyl-furo) [2,31C]-1-azabicyclo [4,2.0]
Octane-2-yl-carboxylate [general formula (A-
3), (A-4), then R6 this day, R7 = one CH8
, yl)-Q-(5-methylfuran-
To 2-yl) acetate 123 (0.36 hM) was added 3.4 μl of anhydrous ether, and to this was added 0.95 μl of thionyl chloride (13.1 mM) at room temperature. Thereafter, the mixture was heated under reflux for 4 hours, and then ether and excess thionyl chloride were distilled off under reduced pressure. 40% of anhydrous chloroform was added to the obtained oil, and to this obtained solution, 9 (2.4 mM) of powdered anhydrous aluminum chloride 319 was added at once under stirring at room temperature, and 1% of anhydrous aluminum chloride was added at once at room temperature. After performing the time hawk worship, the reaction was further performed at 4000 for 1 hour. After cooling to 0°C, 5 parts of ice and 15 parts of IN hydrochloric acid were added, and the solution was stirred for 1 minute to separate the chloroform solution layer from the aqueous layer. The aqueous layer was extracted twice with 15' chloroform. The obtained chloroform layer was washed twice with saturated saline, dried over young salt, and then the solvent was distilled off. The obtained oil was charged into a circular ram with a diameter of approximately 2 mm filled with 350 kg of silica gel, and purified by column chromatography. Elution is performed with a mixed solvent consisting of hexane:ethyl acetate (volume ratio 3:2). The eluate was fractionated in 4 fractions each, fractions numbered 32 to 48 were collected, and the solvent was distilled off under reduced pressure to obtain an oily product numbered 9 of 39. The physical properties of this material are shown below. Nuclear magnetic resonance spectrum 6CoC13 [Coupling constant: HZ in parentheses] 2.37 (S
, 9H), 3.07 [dd, IH (3.0, 16.0)
], 3.55 [dd, IH (6.0, 16.0)], 3
-84 (S, Chihito), 4.38 [dd, IH (3.0,
6.0)], 5.63 (S, IH), 6.35 (brs
, IH) Infrared absorption spectrum 〃S skin 13 (arc-.)
1780, 1760, 1745 (sh), 1695 mass spectrum (m/e) M1249 M+1:250,
190,162 thin layer chromatography Rfo. It showed 1 point of 47. From the above data, the obtained oil is ($)-methyl-5,8-dioxo (5-methyl-5-dioxo) [2,3,C
]-1-Azabicyclo[4,2.0]octane-2-ylcarpoxylate. Note that this product is only one of two possible diastereoisomers (yield: 43.3%). Reference example 7 ($)-methyl-5,8-dioxobenzo[C]-1
-Azapicyclo[4,2.0]octane-2-carpoxylic acid [general formula (A-1), (A-2)
In R6=R7=R8=R9, R2=day compound]
($)-Methyl-5,8-dioxobenzo[C]-1-azabicyclo[4,2.0] obtained in Production Reference Example 4
] Octane-2-ylcarboxylate 81-9(0
．． Dissolve 33hM) in a mixed solvent consisting of 9 parts of tetrahydrofuran and 7 parts of water, add 274 parts of anhydrous potassium carbonate (2.05 hM) to this mixture at room temperature, and continue to incubate for 1 hour and 30 minutes. . After distilling off tetrahydrofuran under reduced pressure, the aqueous layer was washed twice with chloroform and then adjusted to pH 1.0 with IN hydrochloric acid.
After adjusting the concentration to 5.5, the extract was extracted three times with 5 parts of ethyl acetate, washed twice with saturated brine, dried over moss salt, and then the solvent was distilled off. The obtained crude crystals are recrystallized from a mixed solvent of ethyl acetate and petroleum ether to obtain 83 double 9 crystals. The physical properties of this material are shown below. Nuclear magnetic resonance spectrum 6ooゞD [Coupling constant: Hz in parentheses] 3.10 [dd, IH (3.0, 15.0)], 3.6
3 [dd, IH (6.0, 15.0)], 4.60 [d
d, IH (3.0, 6.0)], 5.67 (S, IH)
, 7.30-8,23 (m, cape) Infrared absorption spectrum 13 (inhibition,) 1770, 1755 (sh),
1740 (sh), 1700, 1600 melting point 129-1
30qo (recrystallized from ethyl acetate-petroleum ether) Thin layer chromatography Rfo. It showed 1 point of 34. From the above data, the obtained crystal is ($)-5,8-dioxobenzo[C]-1-azapicyclo[4,2.0
] It was identified as octane-2-ylcarpoxylic acid. In addition, this product is a combination of two possible diastereomers.
Only one of the isomers is present (yield: 87.2%). Reference example 8 Next, among the compounds shown in the reference example, 8 of the following representative compounds
- Shows lactamase inhibitory activity. Concentration Inhibition rate Compound synthesized in Reference Example 6 21 is 8% Compound synthesized in Reference Example 7 10 10% Activity is Antim using chromogenic cephalosporin as a substrate
iorobia I A bag ntand Chemo era
Enterobacter sp. 3 produced by KY3073
- Measured using lactamase.

Claims (1)

[Claims] 1 General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. , represents a substituted or unsubstituted sulfonyloxy group, disubstituted amino group, or azido group, and R_2 and R_4 may be the same or different, and represent a hydrogen atom, an alkyl group, an aralkyl group, or a trialkylsilyl group (these are substituted or unsubstituted sulfonyloxy groups, disubstituted amino groups, or azido groups). (may or may not be present), and R
_3 represents an alkyl group, an aryl group, an aralkyl group, an alkenyl group, an aralkenyl group, an alkynyl group, an aralkynyl group, a heterocyclic group, or an acyl group (which may or may not be substituted) -Azetidinone derivatives and pharmacologically acceptable salts thereof. 2 General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1, R_2, R_3 and R_4 represent the same meanings as above.) Optically active claim 1 described in claim 1 compound. 3 General formula [III] ▲ Numerical formulas, chemical formulas, tables, etc. Represents a sulfonyloxy group, a disubstituted amino group or an azido group, R'_2
represents an alkyl group, an aralkyl group, or a trialkylsilyl group (which may or may not be substituted), and R_3 represents an alkyl group, an aryl group, an aralkyl group,
represents an arakenyl group, an aralkenyl group, an alkynyl group, an aralkynyl group, a heterocyclic group, or an acyl group (which may or may not be substituted), and R_5 is an alkyl group, an alkenyl group, an aryl group, or an aralkyl group (
These may or may not be substituted)
A general formula characterized in that a 2-azetidinone derivative represented by is reacted with a halogenating agent to form an imidoyl halide derivative, then reacted with an alcohol or alkoxide to form an iminoether derivative, and then hydrolyzed. [I]'▲ Numerical formulas, chemical formulas, tables, etc. (which may or may not be present).