JPS5936916B2 - Cephalosporin analogs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [I] [wherein X represents an amino group, an azido group, or a phthalylimino group, and R1 represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, Aralkyloxy group, acyloxy group, sulfonyloxy group, lower alkylthio group, arylthio group, aralkylthio group, lower alkylsulfinyl group, arylsulfinyl group,
Aralkylsulfinyl group, -5+R4R5 (however, R4
, R5 is the same or different lower alkyl group, aryl group, aralkyl group), lower alkylsulfonyl group, arylsulfonyl group,
Aralkylsulfonyl group, NfR6R7B8 (however, currently,
R7 and R8 represent the same or different lower alkyl group, aryl group, or aralkyl group.

) represents a quaternary ammonium group, arylseleno group, or arylzeleninyl group, R2 has the same meaning as R1 or a lower alkyl group, a lower alkyl group substituted with Nowagen, an azide group, a nitrile group, or NR9R, O( R9
, R, O are the same or different hydrogen atoms, lower alkyl groups, aryl groups, aralkyl groups); R3 is a hydrogen atom or an alkyl group,
Represents an aryl group, an aralkyl group, or a silyl group (which may be substituted or unsubstituted). ] and its salts. A cephalosporin analog represented by the general formula [1], that is, a carbacefem compound [the name of carbacefem is based on the Journal of the American Chemical Society No. 9]
6, p. 7584, 1974] will be explained in more detail. R1, R in general formula [I]
To explain 2 specifically, the halogen atom represents fluorine, chlorine, bromine, and iodine. Lower alkoxy groups include methoxy, ethoxy, linear or branched propoxy,
Aryloxy groups such as C1 to C5 alkoxo groups such as butoxy include phenoxy groups, phenoxy groups with substituents such as methyl, methoxy, and nitro groups at ortho, meta, and para positions, and benzyloxy groups as aralkyloxy groups.
C7 to ClO aralkyloxy groups such as phenethyloxy groups, substituted or unsubstituted C1 to C5 acyloxy groups such as acetoxy, propionyloxy, and trifluoroacetoxy, or benzoxy, ortho, meta, and para positions. Benzoxy, etc. with substituents such as methyl, methoxy, and nitro groups, and sulfonyloxy groups include C1 to C, alkylsulfonyloxy groups such as methyl, ethyl, propyl, butyl, and C6 such as benzenesulfonyloxy and toluenesulfonyloxy. -C8 arylsulfonyloxy groups and the like are exemplified. Examples of lower alkylthio groups include C, to C5 alkylthio groups such as methyl, ethyl, linear or branched propyl, butyl, etc., and arylthio groups include C6 to C, O such as phenylthio, methoxyphenylthio, and tolylthio. Examples of the aralkylthio group include C7 to ClO aralkylthio groups such as benzylthio, methoxybenzylthio, and phenethylthio; examples of the lower alkylsulfinyl group, arylsulfinyl group, and aralkylsulfinyl group include the aforementioned lower aralkylthio groups. Each sulfoxide type of an alkylthio group, arylthio group, aralkylthio group, etc. is a lower alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, and a sulfone type such as a lower aralkylthio group, an arylthio group, an aralkylthio group, etc., as described above. However, examples of the arylseleno group include arylseleno groups such as phenylseleno and orthonitrophenylseleno groups, and examples of the arylseleninyl group include the selenium oxide type of the arylselenyl group mentioned above.O As the lower alkyl group shown above, Examples of halogen-substituted lower alkyl groups include the above-mentioned lower alkyl groups substituted with fluorine, chlorine, bromine, and iodine, such as methyl, ethyl, linear or branched probyl, butyl, and other C1 to C5 alkyl groups. is exemplified.

In addition, the aryl groups shown above include phenyl, C6 to ClO aryl groups having substituents such as methyl, methoxy, and nito groups at the ortho, meta, and para positions, and the ralkyl groups include benzyl, phenethyl, and methoxy groups. Examples include C7-Cl5 aralkyl groups such as benzyl. -CO
Examples of the ester represented by OR3 include esters commonly used in penicillin and cephalosporin chemistry.

The ester is preferably one that can be converted into a carboxyl group without damaging substituents, functional groups, etc. in the molecule by selecting conditions. Preferred groups R3 include methyl, ethyl,
C1-C5 alkyl groups such as n-propyl, isopropyl, n-butyl, isobutyl, t-butyl groups, C1-C5 such as chloromethyl, 2,2,2-trichloroethyl, 2,2,2-triflorethyl, etc. C5 halogenated alkyl group, C7-C2O arylmethyl group such as benzyl, diphenylmethyl, triphenylmethyl, C7-C2O arylmethyl group having methoxy, nitro group, etc. on the phenyl nucleus, trimethylsilyl, triphenyl Examples include substituted silyl groups such as silyl. The compound represented by the general formula [1] includes all conceivable stereoisomers of the C, C4 (when Rl and R2 are not hydrogen), C6, and C positions.

Next, the compound [1] represented by the general formula [1] {hereinafter the compound represented by the general formula [1], [], ...... is referred to as the compound [1], the compound [...]...・The manufacturing method of } will be explained.

Compound [1] can be synthesized according to the following process I~ (1) Process I In the general formula [1], x is an azido group or a phthalylimino group, R1 is a hydrogen atom, and R2 is hydrogen The compound [1a] in which the atom or lower alkyl group, R3 is an alkyl group, an aryl group, or an aralkyl group (which may or may not be substituted) can be produced by the method shown in the reaction process diagram 1 below. I can do it.

{In the compound shown in the above process diagram, X1 represents an azide group or a phthalylimino group, R2l represents a hydrogen atom or a lower alkyl group, and R3l represents an alkyl group, an aryl group, or an aralkyl group (which may or may not be substituted) The active derivative of XlCH2COOH represents an acid halide, an acid anhydride, or a mixed acid anhydride} The starting material compound [ ] is a known compound.

Generally CH2=CHO-CH2・CH=CH-R2l
It is synthesized by Claisen rearrangement reaction of substituted allyl vinyl ether represented by the formula (wherein R2l represents the same meaning as above).

(Organic Reactions Vol. 22, p. 1 (19)
75) and Journal of the Chemical Society 1961, p. 4092). Compound [] is also a known compound and can be produced, for example, by the method described in German Patent Publication No. 236,546. Compounds such as R3l=TBu [] can also be produced by nitrosating diethylphosphonoacetate and then reducing the oxime group obtained as an oxime body by a conventional method. Each reaction shown in Reaction Process Diagram 1 can be carried out according to known reaction conditions that satisfy each reaction shown for each reaction.

(2) Process (indicating an alternative synthesis method for compound []) The compound [1a] can also be produced by the method shown in the following reaction process diagram H.

(However, in the compound shown in the above process diagram, X,, R2l and R3l represent the same meanings as above, and R'' represents methyl, ethyl or -CH (0R represents →?1).

Compound [] is also a known compound, and generally R2lCH-
It is synthesized by Claisen rearrangement reaction of substituted vinyl allyl ether represented by CH{)-CH2.CH=CH2. [Organic Reactions Vol. 22, p. 1 (1975)] Compound [ ] can be converted to compound [ ，゛You can do it in the evening.

Each reaction shown in the reaction process diagram can be carried out according to known reaction conditions that satisfy each reaction shown for each reaction. 3) Process - In the general formula [1], Compound [1b], which is a group (which may or may not be substituted), can be produced by the method shown in the reaction process diagram below.

(However, in the compound shown in the above process diagram, X,, R3l,
R'' has the same meaning as above, and Rll represents a lower alkylthio group, an arylthio group, an aralkylthio group or an arylseleno group).

Compound [X] is a known compound and can be synthesized, for example, by the method described in Izvestia Academy Nauk, USSR 1962, p. 2189. Each reaction shown in the above reaction process diagram can be carried out according to known reaction conditions that satisfy each reaction shown for each reaction. (4
) Process - In the general formula [1], X and R3 are as defined above, R1 is a hydrogen atom, and R2 is a halogen atom such as chlorine, bromine, or iodine [1C] is a compound of the general formula [1a]
] can be produced by the method shown in the reaction process diagram using the compound [1a''] represented by R2l=H as a raw material.

(However, in the compound shown in the above process diagram, Xl and R3 have the same meanings as above, and R22 is chlorine, bromine, chlorine,
:X: τ1゛I33,,7. . ．． The compound [1a] represented by the general formula [1a] obtained by 3I or [1a] is a compound represented by R2=H. The halogenation reaction shown in the process diagram generally uses a halogenating agent used for the halogenation reaction at the l-allyl position, such as N-halosuccinimide, N-haloacetamide bromine, and pyrrolidone hydrodriftamide, preferably dichloromethane,
The reaction is carried out using a halogenated hydrocarbon such as chloroform or carbon tetrachloride as a solvent, preferably at room temperature or the reflux temperature of the solvent.

Better results can be obtained by using a reaction initiator such as perbenzoic acid or azobisisobutyronitrile during the reaction. (5
) Process V - In the general formula [1], X and R3 represent the same meanings as above, R1 is a hydrogen atom, R2 is fluorine, an alkyl group, an acyloxy group, an alkoxy group, an aryloxy group, an aralkyloxy group, an alkylthio group , an arylthio group, an aralkylthio group, a primary, secondary, or tertiary amino group, an azide group, or a nitrile group.The compound [1d] represented by the general formula [Id] is a reaction process using the compound [Ic] as a raw material. It can be manufactured by the method shown in Figure V.

(However, in the compound shown in the above diagram, represents an arylthio group, an aralkylthio group, a primary, secondary, or tertiary amino group, an azide group, or a nitrile group.) In this reaction, a nucleophilic reactive group R23 anion is used to form a compound [
Compound [Id] is synthesized by replacing the halogen atom in [Ic] with another substituent R23.

(6) In process general formula [1], R3 represents the same meaning as above, and X
represents an azide group or a phthalylimino group, R2 is a hydrogen atom, and R1 is a compound represented by an alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinyl group, or an arylzeleninyl group, which also has the general formula [Ie] In, X1 has the same meaning as above, Rl2 is a lower alkyl group,
The compound [Ie] represents an aryl group or an aralkyl group, and Y is a sulfur atom or a selenium atom, and the compound [Ie] is represented by the general formula [1
], X1 has the same meaning as above R2=H, Rl=YRl2
(Y and Rl2 have the same meanings as above) In the same general formula [1b], X1 has the same meanings as above, R8l=R3, Rll=YR,2 (Y and Rl2 have the same meanings as above) It can be produced by the method shown in the reaction process diagram using the compound [Ib'] represented by [Ib'] as a raw material.

(However, in the compounds shown in the above process diagram, Xl, R3 and Rl2 have the same meanings as above).

Examples of the oxidizing agent include periodic acid or its salt, hydrogen peroxide, organic peracids such as methachlorobenzoic acid, and chloroauric acid. 7) Process - Compound represented by R3-H in general formula [1] [
10 can be produced by the method shown in the reaction process diagram using the compound [V] represented by R-R3l in the general formula [1] as a raw material.

(However, in the compounds shown in the above process diagram, X, Rl, R
2 and R3l have the same meanings as above). The above reaction is carried out using a method frequently used in the chemistry of penicillin and cephalosporin, and by selecting appropriate conditions and reagents, the compound [1''] can be produced without damaging substituents or functional groups in the molecule.
Compound [10] can be produced. In addition, when X is an azide group, when the group R3l is converted to H by a catalytic reduction method, the azide group may be reduced to an amino group, but compounds having a reduced amino group are also included in the object compound of the present invention. There is one.

3) Process - In the general formula [1], the compound [1h] represented by X=NlI2 is produced by the method shown in the reaction process diagram using the compound [Ig] represented by XN3 in the general formula [1] as a raw material. I can do it.

(However, in the formula, Rl, R2 and R3 have the same meanings as above.) The above reaction is carried out using a method frequently used in the chemistry of penicillin and cephalosporin, and under appropriate conditions,
By selecting reagents, compound [Ih] can be produced from compound [Ig] without damaging the substituents and functional groups in the molecule.

Preferred methods include a catalytic reduction method or a method in which sulfuric acid is reacted with arsenic in the presence of a base.

Preferred bases include triethylamine and pyridine. In addition, when using the catalytic reduction method, if a compound in which the group R3 is a substituted arylmethyl group such as benzyl, paramethoxybenzyl, paranitrobenzyl, benzhydryl, trityl, etc. is used as a raw material, the group COOR3 becomes CO
Compounds converted to OH may also be obtained. that's all(
The target compound of the present invention represented by the general formula [1] synthesized by the methods 1) to (8) is a compound [ The azide group and phthallimino group in 1] are converted to an amino group by a conventional method.

The compound represented by X=NH2 [10, that is, the general formula [
In 1], by introducing various acyl groups commonly used in the field of penicillin and cephalosporin chemistry into the amino group of a compound where X=NH2, a cephalosporin analog compound having strong antibacterial activity can be obtained. (See Reference Examples below) In the present invention, as a salt of a cephalosporin analog, in the general formula [1], X=N
Examples include inorganic acid salts and organic acid salts of the compound [1h] represented by H2, such as hydrochloride, sulfate, phosphate, formate, and malate. Also, in general formula [1], R
Compounds represented by 3=H [Examples include sodium salts, potassium salts, calcium salts, and organic amine salts of the carboxylic acid represented by 10. Next, examples of the present invention will be shown.

Example 1 (1) Cis, 2-t-butyloxycarbonyl J■■
t-2-ene-8-one {in general formula [1], X=
N3, R1=R2=H. R3=TBU, same general formula [
1a], X1=N3, R2l=H. ．． R3l=
Production of TBu in the cis form, that is, a compound represented by the formula.

This compound is produced through the following steps 1).
Note that cis or trans refers to the 3-position of the 2-azetidinone ring,
This refers to the stereoisomerism of hydrogen at the 4th position or the 6th and 7th positions of the 1-azabicyclo[4,2,0]octane ring, and the same applies below. 1) 2-[4-(3-butenyl)-3-
2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid-t-butyl ester {general formula []
Production of a compound represented by X1=N3, R2,=H, R3=TBU}.

t-Butyl-α-aminodiethylphosphonoacetate {
(Compound represented by R3,=TBU in the general formula [])} 447TI9 (1.78mm01e) was dissolved in anhydrous ether 25d and 4-benzene-1-al 164η
(1.96mm01e) and stirred at room temperature for 1 hour,
Molecular sieve (4A) (manufactured by Wako Pure Chemical Industries, Ltd., hereinafter used) 200Tf9 and anhydrous magnesium sulfate 150W were added and stirred for an additional hour.

The reaction solution was depressurized and the filtered solution was concentrated under reduced pressure to obtain a pale yellow oil.

Anhydrous benzene was added to this and the mixture was again concentrated under reduced pressure to obtain a pale yellow oil. (The formation of Schiff's base was confirmed by nuclear magnetic resonance spectroscopy.) 12.5d of cyclohexane and 12.5Tn1 of anhydrous benzene were added and dissolved, and triethylamine 0.369TrL1, (2.66
mm01e) and 200η of molecular sieve, and under stirring at room temperature, 31977V of azidoacetyl chloride (2.
A solution of 66 mm01e) dissolved in 12.5 d of cyclohexane was added dropwise over 1 hour and 30 minutes, and the mixture was further stirred for 30 minutes. The reaction solution was diluted by adding 10 d of benzene, washed successively with 5% dilute hydrochloric acid, saturated aqueous sodium bicarbonate, deionized water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a brown oil. In the general formula [], X1=N3, R2l=H,
It was identified as a crude product of the title compound represented by R31=t-butyl. This oily substance is mixed with silica gel [Wakogel 8C-
200 manufactured by Wako Pure Chemical Industries, Ltd., the same silica gel was used in the following examples and reference examples b] Charged to a column packed with 45 g, and the developing solvent [n-hexane: ethyl acetate = 1:2 (volume ratio The same applies hereinafter)] to obtain two types of isomers. These physical property values are shown below, and the cis isomer (345
η), and trans isomer (58m7).
The total yield was 54.2%. The physical property values are as follows. 2)C
+) cis, 2-t-butyloxycarbonyl-J-[azido-1-azabicyclo[4,2,0]oct-2-en-8-one {in general formula [1], X=N3, R1=R
Production of the cis form of the compound represented by 2=HSR3-TBU} Cis, 2-[4-(3-butenyl)-3-azido-2-oxoazetidin-1-yl] obtained in 1) above
-2-diethylphosphonoacetic acid-t-butyl ester 29
8my (0.716mm01e) was dissolved in 8.5ml of dioxane and 2.5ml of deionized water, 30η of osmium tetroxide was added, and the mixture was stirred for 30 minutes.

Powdered sodium periodate 496 (232) was added to the black reaction solution.
mm0Ie) was added over 20 minutes, and after stirring for one and a half hours, the reaction solution was extracted three times with 50 ml of ether, and the combined ether layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a blackish brown oil. Ta. This oil was charged to a column packed with silica gel 59, eluted using an elution solvent (benzene: ethyl acetate = 1:2), and fractions showing a positive 2,4-dinitrophenylhydrazine reaction were collected and concentrated. Then, an oily substance of 235η was obtained. (This is the general formula [
], X1=N3, R2,=H, R3,=t-B
It is the cis form of the aldehyde compound which is U. ) This oil was dissolved in 15 d of anhydrous acetonitrile and heated to 27.1'119 (0.563 mm) under a nitrogen stream while stirring at room temperature.
Add 50% sodium hydride from 01e). After stirring for 20 minutes, the reaction solution was poured into 2% aqueous acetic acid (20) ml, extracted 4 times with 50 wL of ether, and the ether layer was washed with saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain an oily product of 180 ml. Ta.

In the general formula [1], X=N3, R1=R2
= Target compound represented by HlR3-TBU (cis form)
It was identified as a crude product. This oil was charged to a column filled with silica gel 5F1 and eluted using an elution solvent [n-hexane:ethyl acetate = 3.5:1 (volume ratio)] to obtain 91% of white crystals of the target compound. Obtained. Yield 51%.
The physical properties of this product are as follows. Example 2 (1) Trans, 2-t-butyloxycarbonyl J
Me[azido-1-azabicyclo[4,2,0]oct-2-ene-8-one {in general formula [1], X=N3
, R, -R2-H. R3=TBU, same general formula [1a
], X1=N3, R2l=HlR3l=TBU
and trans isomer, i.e., trans,2-[4-(3-butenyl)-3- obtained in the same manner as in Formula Example 1-1).
Azido-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid-t-butyl ester 767 (1.
8mm01e) with 22wL1 of dioxane and 66L of deionized water.
．． 5d and 100η of osmium tetroxide was added thereto and stirred for 30 minutes.

1. Powdered sodium periodate was added to the obtained black reaction solution.
59 (7.04 mm01e) was added over 30 minutes, and after stirring for an additional hour, ether 15077! /3 times, and the ether layer was dried with Glauber's salt and concentrated under reduced pressure to obtain an oily substance. This oily substance is 20f of silica gel! The elution solvent (benzene: ethyl acetate = 1:
2), an oily substance of 561η was obtained from the 2,4-dinitrophenylhydrazine reaction positive fraction. (In the general formula [], X1=N3, R3l=TB
It is the trans isomer of the aldehyde compound that is U. ) Dissolve this in 6rn1 of anhydrous acetonitrile and add 50% sodium hydride (2.56mm01e) to 50%
The mixture was heated to .degree. C. and reacted for an additional 10 minutes, then poured into a 2% aqueous acetic acid solution, extracted with ether (4 times at 50 d), and the ether layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oil. This oily substance was charged to a column packed with silica gel 209 and eluted using an elution solvent (n-hexane:ethyl acetate = 3.5:1) to obtain 218T of white crystals of the target compound. l! I got it. In the general formula [1], X=N3, R1=
R2=H,. It was identified as the trans isomer of the target compound represented by R3=TBU. The physical properties of this product are as follows. Production of a compound represented by

(i) Cis, 2-t-butyloxycarbonyl-[azido-1-azabicyclo[4,2,
0] Octo-12-en-8-on 5577V (0.22
4mm01e) was dissolved in 2ml of trifluoroacetic acid, left at room temperature for 10 minutes, concentrated under reduced pressure, benzene was added again and concentrated under reduced pressure to obtain 51ml of yellow slurry.

The physical properties of this product were as shown below, and it was identified as the target carboxylic acid.

Yield 100%0r118j Example 4 (t)cis,2-t-butyloxycarbonyl-4-promoJ-[azido-1-azabicyclo[4,2,0]oct-2-ene-8-one {In general formula [1], X
=N3, R1=H, R2=BrlR3=TBUl In the general formula [Ic] also shown in Process V, X1=N
3, R22=Br. R3=TBU and cis form, i.e. Formula Example 3 ((trans)cis, 2-carboxyJ[azido-1-azabicyclo[4,2,0]oct-2-ene-8-one)
In general formula [1], X=N2, R1-R2=R3=H
, Similarly, in general formula [1a], X1=N3, R2,=
R3l=H and cis form, that is, a compound represented by the formula}
Manufacturing of.

The (t)-cis, 2-t-butyloxycarbonyl-[azido-1-azabicyclo[4,2] obtained in Example 1
, 0,] Octo 1 2-en 1 8-on 50 skill (0.20
Dissolve 3mm01e) in 2ml of anhydrous chloroform,
36.0mf! (0.202mm01e) of N-promosuccinimide and a catalytic amount of azobisulfuric acid, and the reaction solution was mixed with 5w
Dilute L1 with chloroform, 3 mI each! Water of,
After washing with saturated saline and drying the sodium sulfate and concentrating it under reduced pressure, it becomes 53 mfi.
! of oil was obtained.

This was charged to a column packed with silica gel 4.09, and the elution solvent (n-hexane: ethyl acetate = 3.5:1
) to give 23m7 of an oil. The physical properties of this product are as shown below.
It was identified as a compound with BU in the cis form. Yield 33%.
Example 5 C+. )1-trans,2-t-butyloxycarbonyl-4-promoJ[azido-1-azabicyclo[4,2
,0]-oct-2-en-8-one {in general formula [1], X=N3, R1=H, R2=Br. R3=TB
In the general formula [1c] also shown in Process V, X, -N3, R22=Br, . R3=TBU and trans isomer, ie, a compound represented by the formula}.

(1) 1-trans,2-t-butyloxycarbonyl-[azido-1-azabicyclo[4] obtained in Example 2
,2,0] Octo-12-en-8-on 100mf1(
0.407mm0Ie) was dissolved in 5wL1 of anhydrous carbon tetrachloride, 72.477V0)N-promosuccinimide was added, and the mixture was heated to reflux with stirring for 30 minutes.

Thereafter, 10 ml of methylene chloride was added, and the mixture was washed with 5 d of deionized water and 5 d of saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain an oily substance 10277V. Add this to silica gel 5f
! Charged to a column packed with
An oil of mfI was obtained. The physical properties of this product were as shown below, and it was identified as the target bromine compound {a compound in the general formula [Ic], where X=N3, R22=Br, R3=TBU, and is a trans form}. Yield 18.1%. Example
6 C+) cis, 2-t-butyloxycarbonyl-4-acetoxyJ me[azido-1-azabicyclo[4,2,0
] Octo-2-ene-8on {In general formula [1],
X=N3, R,=HsR2=0C0CH3, R3=TB
U, similarly in general formula [1d], X1=N3, R2
3=0C0CH3, R3=TBU and cis form, ie, a compound represented by the formula}.

Hy)cis,2-t-butyloxycarbonyl-4-promoJ[azido-1-azabicyclo[4,2,0]oct-2-ene-8-one { In general formula [1c], X1=N3, R22=Brl
R3=TBU and cis compound}75T19
(0.219 mm01e) was dissolved in 2 ml of acetic acid, 39.4 mm of silver acetate (0.241 mm01e) was added under light shielding, and the mixture was stirred for 2 hours and 20 minutes, then filtered and concentrated under reduced pressure.

The obtained crude acetoxy compound was charged to a column packed with 3.5 g of silica gel, and eluted using an eluent solution (n-hexane:ethyl acetate = 3.5:1) to obtain an oily substance of 517V. The physical properties of this product are as shown below, and the target acetoxy compound {general formula [1d], X,=
N3, R23=0C0CN8, R3=TBU and was identified as cis form}. Yield 72.1%. IRν0H04(
Dimensions: 2130, 1790, Max Example 7 ((trans)cis-2-t-butyloxycarbonyl-4-
Methyl-J me[azido-1-azabicyclo[4,2,0]
Octo-2-ene-8-one {X in general formula [1]
=N3, R, =HsR2=CH3, R3=TBU, similarly in general formula [1a], X1=N3, R2l=CH3
, R3l=TBU and cis form, that is, a compound represented by the formula}.

1) 2-[4-(2-methyl-3-butynyl)-3-azido-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid tert-butyl ester 25l {General formula []
In X1=N3, R2l=CH3, R3l=TBU
t-butyl-α-aminodiethylphosphonoacetic acid {in the general formula [], R3l=T
Compound x represented by BU}2.139 (8mm01
es) was dissolved in 80 ml of anhydrous ether, 3-methyl-4'-pentynal (9.2 mm 01 es) was added under stirring, and stirred at room temperature for 1 hour. Molecular sieve 4A, 900 η and magnesium sulfate 70071! F
135 was added and stirred for an additional 1 hour and 30 minutes.

The reaction solution was depressurized and the bottom liquid was concentrated to obtain a pale yellow oil. To this was added 30 d of anhydrous benzene and concentrated again to obtain 2.82 g of an oily substance. (The formation of Schiff's base was confirmed in this product by NMR.)
After adding 900 watts of molecular sieve (4A) and 1.67 w11 (12 mm0) of triethylamine to dry cyclohexane, 56a of anhydrous benzene, and stirring at room temperature, 1.439 (12 mm0) of azidoacetyl chloride was added.
1es) in dry cyclohexane was added dropwise over 1 hour and 30 minutes. After stirring for another 30 minutes, add 30rfL1 of benzene, transfer to a separation load, wash with 10% citric acid, saturated brine, saturated sodium bicarbonate solution, and saturated brine in this order with 30ml each, dry with Glauber's salt, and concentrate under reduced pressure. An oil of 2.89% is obtained. This product can be used on a thin layer chromatograph [silica gel plate, developing solvent n
-Hexane:ethyl acetate (1:1)] A mixture of isomers mainly consisting of two components was observed. This was charged to a column packed with silica gel 3009, and the developing solvent (n
- Elute using hexane:ethyl acetate = 1:1),
In the general formula [], X=N3, R2l=CH3, R3l=TB
The low polar isomer of the target compound represented by U is 380 tactile (
(yield: 11.0%), highly polar isomer: 570m (yield: 16%)
．． 7%) and a mixture of both 201 buttocks (yield 5.8%)
was gotten.

The physical properties of each isomer obtained are as shown below, and the high polar isomer was identified as the middle cis isomer of the target object! )(:+)cis-2-t-butyloxycarbonyl-
4-Methyl-J-[azido-1-azabicyclo[4,2,
0]-oct-2-en-8-one {in general formula [1], X=N3, R1=H, TR2=CH3, R3=B
u, similarly in general formula [1a], X1=N3, R2l
=CH3, R3l=TBU, cis form, ie, a compound represented by the formula}.

(±) cis-2-[4-(2-
methyl-3-butenyl)-3-azido-2-oxoazetidin-1-yl]-2-diethylsulfosphonoacetic acid,
Tertiary butyl ester 240m7 (0.56mm01e)
was dissolved in 6.6 ml of dioxane and 2 ml of deionized water, 20 ml of osmium tetroxide was added, and the mixture was stirred for 10 minutes.

Add 390 m7 (1.82 mm0Ie) of powdered sodium periodate to the black reaction solution in portions over 30 minutes. After stirring for 40 minutes, the reaction solution was extracted three times with 30 ml of ether and combined. The ether layer was washed with saturated brine, dried over sodium sulfate, and concentrated to obtain 230 m7 of an oil. This oil was charged to a column packed with silica gel 69, eluted using an elution solvent [benzene:ethyl acetate (1:2)], and fractions showing a positive 2,4-dinitrophenylhydrazine reaction were collected and concentrated. Then 185m of oily material! i is obtained. (In the general formula [], X1=N3lR
It is a cis form of an aldehyde compound represented by 2l=CH3 and R3l=TBU. ) Immediately dissolve this in 8 ml of anhydrous acetonitrile and add 21.6 ml (0.45 mm01e) of 50% sodium hydride under a nitrogen stream while stirring at room temperature. After stirring for 30 minutes, the reaction solution was poured into 15 ml of 2% aqueous acetic acid, extracted twice with 20 ml of ether, and the ether layer was washed with saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain an oil.

In the general formula [1], X=N3, R1=H
It was identified as a crude product of the target compound (cis form) represented by lR2=CH3 and R3=TBU.

This oily substance was charged to a column packed with silica gel 209, and the elution solvent [n-hexane: ethyl acetate = 3.5
:1 (volume ratio)] to obtain the target product as a colorless oil (70W9, yield 48.1%). This stuff crystallizes if left alone. The physical properties of this product are as follows. According to the above NMR data, the obtained crystal has 4α-
It was identified as an approximately 4:1 mixture of methyl form and β-methyl form.

(Example 8 (4) Cis, 2-t-butynoleoxy-5-phenylthio-J-[azido-1-azabishikuchi]
,2,0]oct-2-ene-8-one {general formula [1]
In, X=N3, R1=SC6H5, R2=H, R
3=TBU, also in general formula [1b], X1=N
3. Production of the cis isomer of the compound represented by Rll=SC6H5, R3,=TBU, that is, the compound represented by the formula}.

1) Compound [X]″{R″=CH in general formula [X]
3. Production of Schiff base represented by R3l=TBU}.

t-Butyl-α-aminodiethylphosphonoacetate {
A compound represented by R3l=TBU in the general formula []}1.089 (4mm01es) was added to anhydrous methylene chloride
4,4-dimethyl-trans-2-
A solution of butenal (general formula [represented by R1=methyl in X town]) in anhydrous methylene chloride (20d) of 580 watts (4.4 mm01es) is added and stirred at room temperature for 1 hour.

Add anhydrous magnesium sulfate 600TI1fi and add 1
Stir for an hour. The reaction solution was filtered under reduced pressure and methylene chloride was distilled off under reduced pressure to obtain an oily product having a concentration of 1.639. Yield 100%. The physical properties of this product are as shown below.
In general formula [X], R'=CH3, R3,=TBU
The compound represented by

2) Compound [XV]'' {In general formula [XV], X1=
Production of an acetal compound represented by N3, R′=CH3, R,,=TBU] and compound [X]″ {aldehyde compound represented by X1=N,, R, l=TBU in general formula [X]} 〇 Schiff base obtained in the above section 8-1) {compound [X!V)'} 1.69 (4.2 mm0
1e) with anhydrous benzene 30T! Ll and anhydrous triethylamine 0 dissolved in 30 mt of anhydrous cyclohexane.

After adding 84d (7mm01es), a solution of azidoacetyl chloride 580W (4.8mm01es) in cyclohexane (40d) was gradually added dropwise at room temperature.

After the dropwise addition took about 1.5 hours, the mixture was further stirred at room temperature for 1 hour. Benzene was added to the reaction mixture, which was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.889 of a crude product. This was packed into a column packed with silica gel 909 and eluted with an elution solvent (n-hexane: ethyl acetate = 1:2), resulting in compound [Xv)'55
0 mV (28.2%) and compound [delivery] ″220η (
11.3%) is obtained. The physical properties of the obtained acetal and aldehyde compounds are as shown below.

x Note that the above aldehyde compound can also be produced by the following method using an acetal compound as a raw material.

Acetal compound obtained in 8-2) above {general formula [X
V], X1=N3, R'=CH3, R3l=T
Acetal compound represented by BU}520η(1.1
3mm01e) was dissolved in 10d of acetone, 50mfi of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 1 hour and 45 minutes.

Add 20 d of ethyl acetate to the reaction solution, then add 5% aqueous sodium bicarbonate,
The reaction solution was washed with saturated saline, dried over Glauber's salt, and concentrated under reduced pressure to give the aldehyde (compound [X]''430η (91
．． 8%) is obtained. Compound [X] 5 {General formula [X
VI], X,=N3, Rll=SC6H5, R3
Production of a thiophenyl compound represented by l=TBU}.
Add 50% sodium hydride 120T19 (2.5 mm01 es) to a mixture of 970 η (8.8 mm0 Ie) of thiophenol and 6.5111 l of absolute ethanol.

After the sodium hydride has completely reacted, dry ice-
Cool the reaction solution to -78°C in a methanol bath. Aldehyde compound [X] 5920η (2
．． A solution of 2 mm01 es) in ethanol (6.5.d) is added dropwise over about 15 minutes. Stir for 2 hours at a bath temperature of -78 to -20°C. Add acetic acid and water, raise the temperature to room temperature, extract with ether, wash the ether layer with saturated saline,
After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure to obtain an oily product.
Get 129. This was charged to a column packed with silica gel 609 and eluted with an elution solvent (n-hexane: ethyl acetate = 2:1) to obtain a thiophenyl compound {general formula [X
VW], X1=N,,R,,=SC6H5,R3
thiophenyl compound represented by l=TBU}4701
(40.4%). The physical properties of this product are as shown below. 4) (1) Cis, 2-t-butyloxycarbonyl-5-phenylthio J-[azido-1-azibicyclo[4,2,0]oct-2-en-8-one {X1 in general formula [Ib] 2N3, R1l 2SC6H5
, R3l=TBU and the cis form, that is, the compound represented by the formula}
Manufacturing of.

The thiophenyl compound (compound [
X]″) 470 mV (0.89 mm01e) is dissolved in anhydrous dimethoxyethane 14W1I3 and 50% sodium hydride 47η (0.98 mm01e) is added.

The mixture was stirred at room temperature for 3.5 hours, added with ether, washed with saturated ammonium chloride water and saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain an oily product of 340 mv. (This is a mixture of stereoisomers at the 5-position of the target compound.) This oil was charged to a column packed with silica gel 159, and the eluent solution [n-hexane:ethyl acetate = 4: ethyl acetate (volume ratio )〕
When eluted with , two types of isomers are obtained.

Each of these has the following physical property values, and the target compound {
In general formula [1b], X1=N3, Rl,=SC6H
5, R3, = TBU, cis form} low polar isomer (SC6
The configuration of H5 is the same as the configuration of hydrogen at the 6th and 7th positions),
It was identified as a more polar isomer (the configuration of SC6H5 is opposite to the configuration of hydrogen at the 6th and 7th positions). Low polar isomer Yield: 807!19 {yield 9.7%, calculated from compound [X] 5} The above low polar isomer can also be produced by the following method.

Add 50% sodium hydride 5677V (1.16 mm01e) to a mixed solution of thiophenol 440TI9 (4 mm01es) and absolute ethanol 3rn1.

After the sodium hydride has completely reacted, it is cooled to -75°C in a dry ice-methanol bath. Aldehyde compound [X]''440η (1.
06mm01e) in ethanol (3wL1) was added dropwise and stirred at -75°C for 50 minutes. Acetic acid and water were added, the temperature was raised to room temperature, extracted with ether, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain crude product 59577.
Get V. This was dissolved in anhydrous dimethoxyethane 15d and 50% hydrogenated Naloum 53T1! fl(1.1mm0
Add 1e). After stirring at room temperature for 1 hour and 45 minutes, ether was added, and the mixture was washed with saturated ammonium chloride solution and saturated brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain an oily substance of 410 η. This was charged to a column packed with 16 g of silica gel, and the elution solvent {n-hexane: ethyl acetate = 4:1 (
volume ratio)} to elute the desired low polar isomer with 100 TI
IV (25.4%). The physical properties of this product were consistent with those of the above-mentioned low polar isomer. In this case no highly polar isomer was obtained. Spoon Example 9 (Yoshisu, 2-t-butyloxycarbonyl-5-phenylthio J me[azido-1-azabicyclo[4,2,0
] Oct-2-ene-8-one, s-oxide {In general formula [1], X=N3, υR,=↑, R2=H
, R3=TBU, also 0'] i▼General formula [Ie
], X,=N3, Rl2=C6H5, Y=SSR
3=cis form of the compound represented by TBU, that is, the formula
.

Production of a compound represented by

The (t)cis, 2-t-butyloxycarbonyl-5-phenylthio-azide obtained in Example 8
Azabicyclo[4.2,0]oct-2-en-8-one (low polar isomer) 11077Z7 (0.296mm0
1e) was dissolved in 8d of methanol and 0.8a of benzene, and 140% of sodium periodate (0.655mm01
Add the aqueous solution of e) and stir at room temperature for 60 hours.

Water is added to the reaction solution, and then 15 mj of methylene chloride is added for extraction. The methylene chloride solution is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an oily substance with a size of 105 η. The physical properties of this material are as shown below, and the objective (1)
cis, 2-t-butylo 3xycarbonyl-5-phenylthio J me[azido 1-azabicyclo[4,2,0
] oct-2-ene-8-one, S-oxide (I:l mixture of two possible stereoisomers at the sulfur atom). Example 10 Cis, 2-carboxyJ[amino-1-azabicyclo[4,2,0]oct-2-en-8-one {in general formula [1], X=NH2, R1=R2= R32H
, Similarly, in the general formula [Ih], R12R2=R3=
Production of an amino compound represented by H}.

(t)cis,2-carboxyJ[azido-1-azabicyclo[4,2,0]otato-12-en-8-one {general formula [X in 10] obtained in the same manner as in Example 3
=N3, R2=HxRl=H} 91 mv was dissolved in 6.5 ml of ethanol, 10% 26T19 baradium-carbon was added, hydrogen gas was passed through the mixture at normal pressure and room temperature for 2 hours with stirring, the catalyst was removed, and the mixture was concentrated under reduced pressure. Methanol IOa again
After stirring, 10% palladium on carbon was immediately added, followed by catalytic reduction at room temperature and normal pressure for 3 hours and 50 minutes, passed through a fuchi filter aid (Hyflo Super Cell), and concentrated under reduced pressure to give 88T.
A semi-solid of T9 (100%) is obtained.

The physical properties of this product were as shown below, and it was identified as the target amino compound. VD Example 11 Preparation of cis,7-amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-otato-12-en-8-one.

(i) cis,7-azido-21t- obtained in Example 1
Butyloxycarbonyl-1-azabicyclo[4,2,
0]-octo-12-en-8-one 178my(0.6
7mm01e) in 10ml of ethanol,
25% palladium on carbon (catalyst) was added, and the mixture was stirred at room temperature under a hydrogen stream for 50 minutes.

Then, the catalyst is removed and the mixture is concentrated under reduced pressure to obtain the desired compound as a pale yellow oil. Example 12...Preparation of a compound represented by the formula cis,2-t-butyloxycarbonyl-4-methyl-J[azido-1-azabicyclo[4,2,0]oct-12-ene-8-one.

This compound is produced through the following steps 1) and 2).

1) 2-[4-(2-methyl-3-butenino(c)-3-azido-2-oxoazetidin-1-yl]-2-
Production of tert-butyl ester diethylphosphonoacetic acid t-butyl-α-aminodiethylphosphonoacetic acid 2.13
9 (8mm01es) was dissolved in 80ml of anhydrous ether, and the 3-methyl-
After adding 4-pentynal and stirring at room temperature for 1 hour, 1900 ml of molecular sieve 4A and 700 ml of magnesium sulfate were added and further stirred for 1 hour and 30 minutes.

The reaction solution was filtered under reduced pressure and the bottom liquid was concentrated to obtain a pale yellow oil. Add 30ml of anhydrous benzene to this and concentrate again.
2.829 of an oil was obtained. (Formation of Schiff's base was confirmed with Rlrnr.) 56 ml of this oil was
of dry cyclohexane, dissolved in 56 ml of anhydrous benzene and molecular sieve (4A) 90071! After adding 1.67 ml (12 mm 01 es) of Fll triethylamine, 1.439 ml (1 ml) of azidoacetyl chloride was added under stirring at room temperature.
A solution of 2mm01es) dissolved in 56ml of dry cyclohexane was added dropwise over 1 hour and 30 minutes. After stirring for another 30 minutes, 30ml of benzene was added and transferred to a separation load.
Wash with 30 ml each of 10% citric acid, saturated saline, saturated sodium bicarbonate, and saturated saline in this order, dry with sodium sulfate, and concentrate under reduced pressure to obtain 2.8 fl of an oil. This product was observed on a thin-layer talomatograph (silica gel, plate, developing solvent n-hexane:ethyl acetate (1:1)) to be a mixture of isomers mainly consisting of two components. This was charged to a column packed with silica gel 300f1 and eluted using a developing solvent (n-hexane:ethyl acetate = 1:1), and 380mf1 of the low polar isomer of the target compound was found (yield 11.0%). , highly polar isomer 570% (yield 16.7
%) and a mixture of the two (201η) (yield 5.8%) were obtained. The substance values of each isomer obtained are as shown below, and the highly polar isomer was identified as the middle cis isomer of the target product.

2) (1) Production of cis-J-[azido-1-2-t-butyloxycarbonyl-4-methyl-J-m[azido-1-azabicyclo[4,2,0]-oct-2-en-8-one) (t)cis-2-[4-
(2-Methyl-3-butenyl)-3-azido-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid, tert-butyl ester 240TnfI (0.56 mm
1e) was dissolved in 6.6 ml of dioxane and 2 ml of deionized water, 21 w of ossium tetroxide was added, and the mixture was stirred for 10 minutes.

Add 390 wa (1.82 mm 01e) of powdered sodium periodate to the black reaction solution in portions over 30 minutes. After stirring for 40 minutes, the reaction solution was extracted three times with ether 30a and combined. The ether layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give an oil of 230η. This oil was charged to a column packed with silica gel 69 and the elution solvent [
Elute with benzene:ethyl acetate (1:2)],
, 4-dinitrophenylhydrazine reaction positive are collected and concentrated to obtain 185η of an oil (aldehyde).

Immediately dissolve this in 8d of anhydrous acetonitrile and add 21.6η (0.45mm) under a nitrogen stream while stirring at room temperature.
Add 50% sodium hydride from 01e). After stirring for 30 minutes, the reaction solution was poured into 15 ml of 2% aqueous acetic acid, extracted twice with 20 ml of ether, and the ether layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain an oil.

This oily substance was charged to a column packed with silica gel 209, and the elution solvent [n-hexane: ethyl acetate = 3.5
:1 (volume ratio)], and the desired product was obtained as a colorless oil (70 w, yield 48.1%). This product crystallizes when left standing.

The physical properties of this product are as follows. The obtained crystals were identified to be a mixture of 4α-methyl form and 4β-methyl form at a ratio of about 4:1 based on the above Nmr data.

This mixture was again chromatographed on silica gel (n-
It can be separated by hexane-ethyl acetate (3:1).

The highly polar isomer (4β form) is (t)cis-7β-azido-4β-methyl-2-t-butyloxycarbonyl-1
-Azabicyclo[4,2,0]-Octo-12-En-18
-on, and the low polar isomer is its 4α isomer, and the separated two have the following physical properties. Highly polar isomer (1) cis-7β-azido-4β obtained by Example 12-2)
-Methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one (655 m7 (2.35 mm01e)) was dissolved in 6d of ethanol and dissolved in 3N-HCtO. 79ml (2,37mm01
Add e) and hydrogenate for 70 minutes with 200η of 10% palladium on carbon.

Add methanol to thoroughly dissolve the precipitated salt, remove the catalyst, and concentrate to obtain crude Example 13 (4) Cis-7β
-amino-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-
Preparation of en-8-one Low polar isomer (4) synthesized according to Example 12-2) cis-7β-azido-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2, 0]-octo12-en18-on25
Dissolve 5mI (1) in 10mI! of ethanol, add 100η of 10% palladium on carbon, and hydrogenate for 1.5 hours.

The catalyst is filtered out and thoroughly washed with methanol, and the combined solution and washings are concentrated under reduced pressure to obtain a pale yellow oil. Dissolve in 8 ml of ethyl acetate and extract 5 times with 3 ml of 10% citric acid. The aqueous layer is neutralized to pH 6-7 with potassium carbonate and becomes cloudy.

Extract twice with ethyl acetate 5a, wash with saturated saline, and dry with sodium sulfate to obtain the desired product as an oil with a concentration of 177 mV (7.66%). Example 14 Cis-7β-amino-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]
-Production of oct-2-en-18-one Oct-12-en-18-one trifluoroacetic acid (1) Cis,7β-azido-4α-acetoxy-1-azabicyclo[4] obtained in the same manner as in Example 6 ,2,0
]-Production of oct-2-ene-8-o salt (:1:)cis-7β-amino-4α-methyl- obtained in Example 13
2-t-butyloxycarbonyl-1-azabicyclo [
4,2,0]-Octo12-En18-On196 Takumi (
0.78mm01e) in anhydrous dichloromethane 4.2wL
1.8 mj of trifluoroacetic acid is added under stirring at room temperature.

After 1.5 hours, it was concentrated under reduced pressure, anhydrous benzene was added and azeotropically distilled off, and ether was added to the obtained oil, tritiated, and filtered to give 167 m7 (6.9 m) of the desired product in powder form.
3%).

Example 16 (4) Production of cis,7β-azido-4α-acetoxy-1-azabicyclo[4,2,0]-oct-2-en-8-one-2-carboxylic acid (a) (+:)cis-7β −
Azido-4α-acetoxy-1-azabicyclo[4,2
,0]-Oct-2-en-18-one-2-carboxylic acid 7β-azide obtained in the same manner as in Example 6
4α-acetoxy-2-t-butyroxycarbonyl-1
-azabicyclo[4,2,0]-o 3q ct-2-en-8-one 179mv with 3wL1 methylene chloride and 3
After dissolving rn1 in trifluoroacetic acid and allowing it to stand at room temperature for 2 hours, the reaction solution was concentrated to obtain the desired product 145m7 as a yellow powder.

(Yield 100%). (b) (4) cis, 7β-amino-
4α-acetoxy-1-azabicyclo[4,2,0]-
Method for producing oct-2-ene-8-one-2-carboxylic acid After that, the reaction solution is filtered and then concentrated.
β-amino-4α-acetoxy-1-azabicyclo[4
,2,0]-oct-2-ene-8-one-2-carboxylic acid is obtained. Example 17 7β-azido-2-t-butoxycarbonyl-4α-hydroxy-1-azabisic[4,2,0]oct-2-en-8-one {X in general formula [I] =
N3, R1=H, R2=0H, . Preparation of R3-TBU in the cis form, i.e., the compound represented by the formula} Cis, 2-t-butoxycarbonyl-7-azido-1-azabicyclo[4,2] obtained in the same manner as in Example 1 ,0
] 200 ~ oct-2-en-8-one was dissolved in 8.8 ml of carbon tetrachloride, and 134.9 ml of N-promosuccinimide and a catalytic amount of α,α'e-azobisisobutyro Add nitrile and heat under reflux for 30 minutes.

After cooling the reaction solution, it was diluted with 5 ml of chloroform, washed with 3 portions of water and saturated brine, dried over sodium sulfate, filtered, and concentrated to obtain the same oily 4-bromine compound as in Example 4. Immediately dissolve this in 10ml of acetone and add 50W of silver carbonate! 9
Add 50 μt of water, stir at room temperature for 10 minutes, filter and concentrate to obtain the crude target product. This crude product was mixed with silica gel 2
09 was charged to a column filled with light, eluted with n-hexane-ethyl acetate (2:l), and after concentration, 86.4 mv of the target product was obtained as pale yellow crystals (yield: 40.7%). The physical properties of this product are as follows. MplOO. O~101
．． 0riCI R(CHCmu) ν:-1x2130, 1790, 163
5, 1630 NMR (CDC) δPpm6.3O (I
H, d, J = 5Hz), 5.03 (IH, .d, .J =
5.2), 4.47 (1H1m), 3.93 (IH,
m), 3.20 (1H.br), 2.1 to 1.8 (
2H. m), 1.55 (9H, s) Example 18 (Preparation of old cis, 7-amino-2-carboxy-l-azabicyclo[4,2,0]oct-2-en-8-one (alternative method) 7-Amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2-en-8-one 30 obtained in the same manner as in Example 11
Dissolve 0m of wax in 3.0ml of methylene chloride,
Add trifluoroacetic acid from step 1 and leave at room temperature for 1 hour and 20 minutes.

Then, the mixture was concentrated, benzene was added to the residue, and the mixture was concentrated again to obtain 250 mv of the target trifluoroacetate as a yellow powder. The physical properties of this product are as follows. IR (KBr)
ν=Axl78O, 1680, 1630 The above trichloroacetate was dissolved in 2 cups of water, and the pH was adjusted to 7 with a saturated aqueous sodium bicarbonate solution.
．． When adjusted to 0, crystals will precipitate.

The crystals are collected by filtration to obtain the desired target, 7-amino 2
129 m of -carboxy-1-azabicyclo[4,2,0]oct-2-en-8-one was obtained. The physical properties of this product were consistent with those obtained in Example 10 above. Example 19 Production of 7β-azido-2-carboxy-4α-methyl-1-azabicyclo[4,2,0]oct-2-en-8-one , 7β-azido-2-t-butyloxycarbonyl-4α-methyl-1-azabicyclo[4,2,0]oct-2-en-8-one 238m9 (0.703mm
01e) 4m1! of trifluoroacetic acid and stirred at room temperature for 1
Leave for 0 minutes.

Concentrate under reduced pressure at 25°C, add 5 g of dry benzene, and repeat the reconcentration twice.

The resulting 255 rwi oil was dissolved in 5" of ethyl acetate, extracted twice with 10% potassium carbonate, 2 Ri, and the aqueous layer was brought to a pH of about 3 with 0.5 N-Hct. The aqueous layer was then extracted with 5" of ethyl acetate to a pH of about 3. Extract twice and dry with anhydrous sodium sulfate.
Distill the solvent under reduced pressure to obtain the oily target product of 166 (
Yield 83.8%). This oil crystallizes on standing. The physical properties of this product are as follows. M. p. l2l.
5-123.0℃ IRV: -1x (CHC): 2110, 1769, 1
750, 1716, 1630 NMR (CD3OD) δ:
6.47 (IH.d.J=5.6Hz), 5.22 (I
H. d. J=5.0), 4.2-3.7 (IH.m)
, 2.3-2.9 (1 Br.), 1.11 (3H
．． d. J = 7.2) Example 20 Production of 7β-amino-2-carboxy-4α-methyl-1-azabicyclo[4,2,0]oct-2-en-8-one trifluoroacetate ( Alternative method) Example 19
7β-azido-2-t- obtained in the same manner as
Butyloxycarbonyl-4α-methyl-1-azabicyclo[4,2,0]oct-2-ene-8-one2
Dissolve 00rf9 in 2 parts of water and 2 parts of ethanol.

75η of 10% Pd-carbon is added, and hydrogen gas is bubbled through the mixture under stirring at normal pressure.

After 20 hours, the mixture is filtered under reduced pressure, and two portions of trifluoroacetic acid are added to the cake to dissolve it, and the catalyst is filtered off.

The solution was concentrated under reduced pressure, 10 g of dry ether was added, and the precipitated crystals were collected in a furnace to obtain 120 mf1 of the target product (yield: 4
3%). The physical properties of this product were consistent with those obtained in Example 15.

Reference examples below demonstrate that compounds derived from compound [I] obtained by the present invention are useful compounds having excellent antibacterial activity.

Reference example 1 (2-carboxy, 2-(thiophene-2-yl)acetylamino)-1-azabicyclo[4,2,0]oct-2-ene-8-one [represented by the formula Preparation of the amino compound obtained in Example 10 {compound represented by X=NH2, R1=R2=R3=H in general formula [I]}88Wi (0.489 mm01e) was mixed with 2 mi of deionized water. Dissolve in 1ml of acetone, add 84~84ml of aqueous sodium bicarbonate, and dissolve 78ml of 2-thienyl acetyl chloride in 0.5ml of acetone and drop the solution under ice cooling.

After the dropwise addition, the mixture was stirred for 30 minutes and the reaction solution was washed with ethyl acetate. Next, the aqueous layer was adjusted to pH 2. with concentrated hydrochloric acid. The cloudy solution was extracted three times with ethyl acetate (5g), and the ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain a yellow oil. This was charged to a column packed with silica gel 4.01 and eluted with chloroform. The obtained syrup was crystallized from chloroform-ethanol to obtain 30 mW crystals. The physical properties of this product were as shown below, and it was identified as the target compound. (Yield 20.1%)
Melting point: 181-183 C IRvKBr (Cfn-ri: 1775, 1690, 1
650, maX1615N MRδ (CD3OD) PFI: 7.16-6.88
(3H, m), 6.18 (IH, t), 5.16 (I
H, d. J=5Hz), 3.80(IH)m), 3.3
7 (2H.m), 2.5-1.30 (4H.m) Reference Example 2 Obtained in Reference Example 1 (former cis, 2-carboxy 7[2-(thiophene-2-yl)acetylamino]
The antibacterial activity of -1-azabicyclo[4,2,0]oct-2-en-8-one was determined by the agar dilution method at 1rV) PH
7. The results measured with O are as shown below.

Reference example 3 (branch) Cisu Jyo k2 -(2-tritylamino-
4-thiazolyl)-2-Anti-methoxyiminoacetamide]-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2-ene-8
Method for producing ion (method a) Tansisu J■■-Azabicyclo[4,2,0]-oct-2-en-8 obtained by the method of Example 11
-On 7 3fnfI (0.307mm01e) and 2
-(2-tritylamino-4-thiazolyl)-2-
Anti-methoxyiminoacetic acid 135.9 mg (0.
307mm01e) was dissolved in 2rn9 of anhydrous methylene chloride, and synchrohexylcarbodiimide 69 was added under ice-cooling and stirring.
．． Add 6 m9 (0.307 mm01e) of 1 ml of anhydrous methylene chloride solution, stir for 3 hours, and then react at 10°C overnight.

The reaction solution was washed with a 1% aqueous phosphoric acid solution, then washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product 257W19. This was purified by silica gel chromatography [Wako Gel C-100 (hereinafter silica gel refers to the same product), 129, solvent n-hexane-ethyl acetate 1:l] and a pale yellow glassy state was obtained as 73Tn9 (
35.9%) of the desired product was obtained. IR(KBr)νMax
(Cm-1): 1780, 1725, (b method) 2-(2
-Tritylamino-4-thiazolyl)-2-Anti-
Methoxyiminoacetic acid 524.9mv (1.18mm01
e) in 10 d of dry tetrahydrofuran, -3
While cooling to 0°C, 1.18ml of 1N-N-methylmorpholine-tetrahydrofuran solution (1.18mm01e) and 1.18d of 1N-isobutyl chloroformate-tetrahydrofuran solution (1.18mm01e) were added, and after stirring for 40 minutes, ) cis-J me[amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2
1-en-8-on 235Tf9 (0.987mm01e
) was dissolved in 5 ml of anhydrous methylene chloride and added dropwise to 30
After stirring for 2 hours at O℃, ethyl acetate (10
Add d) and wash in the order of water, saturated sodium bicarbonate solution, and saturated saline solution,
After drying the Glauber's salt and concentrating under reduced pressure, 865 mf of a crude product is obtained.

According to (method a), silica gel chromatography (silica gel 40f
! ), and 580 wa (87.5%) of the target product was obtained.
The Ir and Nmr spectra of this product matched those obtained by (method a). Reference example 4 (t) Cis-Jyorok2-(2-amino-4-thiazolyl)2-Anti-methoxyimino-acetamide]-1
-Azabicyclo[4,2,0]-Octo-12-En-18
-Production method of -one-2-carboxylic acid.

2-(2-Tritylamino-4-thiazolyl)-2-Anti-methoxyimino-acetamide]-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0] obtained in Reference Example 3 ]-Octo-12-en-8-on 500η (0.754mm01e) for 5m
1 part trifluoroacetic acid, 2.5 ml anhydrous methylene chloride,
Dissolve in 2.5wL1 of anisole mixture, leave for 3 hours and 40 minutes at O℃, concentrate under reduced pressure, add 5ml of 50% acetic acid water, stir at room temperature for 3 hours, concentrate under reduced pressure, tritulate thoroughly with ether, wash, and filter out the solid. The crude product 244T11f
get.

Column chromatography using PH-10 (HP-1010a,
Purified with solvent methanol/water 2:5) to give pale yellow powder 90%
TnfI (32.7%) was obtained. --4 Reference Example 5 (t) Cis-Jyorok (10-2-phenyl-2-t-butyloxycarbonylaminoacetamide)-2-t-
Butyloxycarbonyl-azabicyclo[4,2,0
]-Production method of oct-2-ene-8-one.

(Method a) ((transformation) cis-J me[amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2
-en-8-on 81m7 (0.34mm01e) and (
R) -N-t-Butyloxycarbonylphenylglycine 94.0 mV (0.34 mm01e) was dissolved in 2 ml of anhydrous methylene chloride and cooled with ice and salt. (0.3
Add 4 mm01e) of didichlorohexylcarbodiimide dissolved in 1 TIL1 of anhydrous methylene chloride.

After reacting for 2 hours under ice cooling, 2 drops of acetic acid were added, stirred for an additional 20 minutes, and filtered under reduced pressure. The cake was washed with 20 ml of ethyl acetate, 20 ml of ether was added to the filtered liquid and the washing liquid, washed with 1% aqueous phosphoric acid, saturated aqueous sodium bicarbonate, and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to obtain 187 mv of crude product. can get. This was purified by silica gel chromatography (silica gel 99, solvent n hexane: ethyl acetate 1:1) to obtain the target product 104rI1f1I (64.9%) in the form of a colorless glass.
Method b) (B) -Nt-butyloxycarbonylphenylglycine 297.3η (1.18mm01e)
1 in anhydrous tetrahydrofuran at -30°C.
N-methylmorpholine-tetrahydrofuran 1.18ml
(1.18mm01e), N-isobutyl chloroformate 1
．． Add 18ml (1.18mm01e) and stir for 30 minutes.

Dissolve 23477V (0.983 mm01e) of cis-J amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one in 5 ml of anhydrous methylene chloride. Add 4 at -30℃
The mixture was reacted for 5 minutes and further reacted for 4 hours and 15 minutes at 0°C. Diluted with methylene chloride (15 ml), washed with water, 1N-HCI water, and saturated saline in that order, dried over Glauber's salt, and concentrated to obtain the crude acyl compound 5.
88 was obtained and purified with silica gel chromatography (silica gel 289) according to method a) to obtain the target product in the form of a colorless glass.
Obtained 22 rumors (69.4%). The Ir, nmr spectrum of this product matched that obtained by method a). Reference example 6-res-Jyo-k(8)-2-phenyl-2-aminoacetamide]-1-azabicyclo[4,2,0]
- A method for producing oct-2-ene-8-one-2-carboxylic acid trifluoroacetate.

(t)cis-Jyorok(auto)-2-phenyl-2-t-butyloxycarbonylaminoacetamide-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0 ]-octo12-en18-on2
801!9 (0.59 mm01e) was dissolved in 25 d of anhydrous methylene chloride and 25 d of anisole, and heated under ice cooling for 50 d.
of trichloroacetic acid was added and left to stand under ice cooling for 4 hours and 50 minutes, concentrated, 10 d of ether was added to the residue, stirred at room temperature for 1 hour, the resulting precipitate was collected, and the desired product as a pale yellow powder was dissolved in 202Tf1V (
70.9%) was obtained.

(1) Diastereolysis of cis-2-phenyl-2-aminoacetamide-1-azabicyclo[4,2,0]-oct-2-en-8-one-2-carboxylic acid Isometric separation.

50 m(i) of the compound obtained above was dissolved in 150 µt of water and poured into high performance liquid chromatography 8 times using Bondapak C-18 (manufactured by Waters) as a carrier and a solvent of 7%-methanol-0.2N dipotassium phosphate. do.

Two fractions are collected by absorption analysis at 254 nm, and each fraction is lyophilized after removing methanol under reduced pressure.

It was dissolved in water again and adsorbed on a Diaion HP-10 (manufactured by Mitsubishi Chemical Corporation) 20d column, and 20077! / After washing with water, elution was carried out with 20% ethanol water, and the ninhydrin-colored fraction was collected and lyophilized to obtain 14.0 r1 of each A isomer! F. A white powder containing 24.6 w of B isomer was obtained. The antibacterial activity of the A isomer and B isomer obtained here is determined by HeartInfurlOnAgarDilutiOn.
(pH 7.2).

The results are shown in the table below. Cefazolin was used as a control.
Reference example 7 (7 [(B)-2-phenyl-2-(
4-Ethyl-2,3-dioxo-1-piperazinylcarbonylamino)-acetamide]-2-t
-Butyloxycarbonyl-1-azabicyclo[4
,2,0]-oct-2-en-8-one.

Method a) (branch) Cis-J me[amino-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-octo-2
-en-8-on 68η (0.286mm01e)
and (F3)-2-phenyl-2-(4-ethyl2,3-dioxo-1-piperazinylcarbonylamino)acetic acid 100.4 mV (0.286 mm01e)
Dissolved in 2ml of anhydrous methylene chloride and cooled on ice.70q (ice.315mm01e)
Synchronohexylcarbodiimide was added thereto, stirred for 6 hours, further stirred overnight at 10°C, filtered, and the cake was washed with methylene chloride. The filtrate and washing liquid were combined and washed in the order of 1% phosphoric acid, saturated aqueous sodium bicarbonate, and saturated brine. After drying with Glauber's salt and concentrating, 189 m of a crude acyl compound was obtained.

This was subjected to silica gel chromatography (silica gel 99, solvent n-
Purified with hexane:ethyl acetate 1:2) to form highly polar isomer 431? Vl, 20mW of a low polar isomer, and 11.1rI of a mixture of both were obtained (total 54.1%). Highly polar isomer: Ir(CHC4) νMax(CTn-1): 17
80,1720,1695 (Sh), engineering 685nmr (
CDCmu) δ: 7.73 (D, lHjJ = 7.0),
7.37 (S, 5H), 6.2.5 (M.IH), 5.
7-5.0 (M, 2H), 4.3-3.0 (M,
7H), 2.6-0.7(M, 4.H), 1.50(
S, 9H), 1.20 (T, 3H) Low polar isomer Ir (CHC) νMax (I: 1780, 16
95, 1685, 1620 nmrδ (CDC): 7.
77 (D, lHjJ=8.0), 7.30 (M, 5H)
, 6.21 (M.IH), 5.67-5.33 (M.
2H), 4.5-3.2 (M, 7H), 3.5-1
．． 0 (M, 4H), 1.50 (Sl9H), 1.20 (
T,3H)b method) (auto)-2-phenyl-2-(
4-Ethyl-2,3-dioxo-1-biperazinylcarbonylamino)acetic acid 428.5Wi (1.13m
m01e) in 10d of dry tetrahydrofuran -
At 30°C, 1.25 ml (1.25 mm) of 1N-N-methylmorpholine-tetrahydrofuran, 1.25 ml (1.25 ml) of 1N-isobutyl formate-tetrahydrofuran (
After stirring for 30 minutes, 2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-ene-8- On 235r!1f (1,13mm01e) was dissolved in anhydrous methylene chloride 5d and added, reacted for 1 hour, and further stirred overnight at 10°C.

Add ethyl acetate (20d) and dilute with water, 0.1N.
-HCt, washed with saturated sodium bicarbonate solution and water, dried with Glauber's salt and concentrated to obtain crude acyl compound R57OWIV, purified and fractionated with silica gel chromatography (silica gel 279) according to method a) to obtain high polar isomer 73q, low polar isomer 1 ft of isomer 61TI (total 65.4%) was obtained. The Irsnmr spectrum of each isomer was consistent with that of each isomer obtained by method a). Reference example 8 (1) cis-2-phenyl-2-(4-ethyl2,3-dioxo-1-biperazinylcarbonylamino)acetamide]-1-azabicyclo[4,2 ,0]-octo12-en18-on-2
-(t)cissu obtained in Reference Example 7 of the production method of carboxylic acid
J Yorok8-2-phenyl-2-(4-ethyl-2,3-
dioxo-21-biperazinylcarbonylamino)acetamide]-2-t-butyloxycarbonyl-1-
Azabicyclo[4,2,0]-octo-12-en-18-
On 103η (0.248mm0Ie) 5JF! / of trifluoroacetic acid, 5w11 methylene chloride, 2 drops of acetic acid
The mixture was dissolved in a mixture of 5-nisole, reacted at 0°C for 2 hours, and then concentrated under reduced pressure.

Add dry benzene and concentrate again. Ether is added to the obtained oil and stirred at room temperature to precipitate a yellow powder. The crude product 104W1V is obtained by filtration. Dissolve saturated sodium bicarbonate in ethyl acetate (Extract with water three times (5d each), wash with ethyl acetate, and add 0.5N-Hct to pH 2.0 while cooling on ice.
The extract was extracted with ethyl acetate three times (5 wL1 each), washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain pale yellow powder 41q (46.0%). Next, the antibacterial activity of the compounds obtained in Reference Examples 4, 6, and 8 above will be shown.

Measurement is done with HeartInfusiOnAgarDilut
This was done by the ial method. Reference example 9 using cefazoline as a control
-butyloxycarbonylaminoacetamide]-4β
-Production method of methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one (cis refers to the stereochemistry at the C6 and C7 positions) ,same as below.

Moreover, BOc represents a butyloxycarbonyl group. )(
R) -Nt-Butyloxycarbonylphenylglycine 132g (0.53mm01e) was dissolved in 5d dry tetrahydrofuran and heated to 0°C, 1N-N-methylmorpholine 0.53ml (0.53mm0Ie), 1N-isobutyl chloroformate. After adding 0.53 (0.53 mm01e) and stirring for 15 minutes, 0.07 m1 (0.53 mm0) of triethylamine was added and stirred for 15 minutes.
．． 5mm01e) and the cis-7β-amino-4β-methyl-2-butyloxycarbonyl-1-azabicyclo[4,2,0]-octo-2- obtained in Example 14
En-18-one hydrochloride 144mf! (0.5mm01
Add e) and stir at 0°C for 1 hour, then stir at 5-10°C overnight.

The crude acyl compound obtained by diluting with 10 WLI of ethyl acetate, washing with 10% citric acid, saturated aqueous sodium bicarbonate, and saturated saline in that order, drying with sodium sulfate, and concentrating the resulting crude acyl compound was subjected to silica gel chromatography.
Wako Gel C-200 (hereinafter referred to as silica gel), 3
0f! , solvent, n-hexane-ethyl acetate volume ratio 3:1
The same applies hereafter] and refine the target product in powder form to 150η
(61.7%). Ir(KBr)ν;x:3290
, 1780, 1720, 1685, 1665 nmr (C
DCmu) δ (PF) 7.34 (5H.s), 6.60,
6.49 (IH, each D, J = 7Hz), 6.11, 6
．． 04 (IH, each D, J = 2Hz), 5.66, 5.
60 (IH, each D.J=7Hz), 5.18 (2H
．． m), 3.86 (IH.m), 2.46 (IH.m)
, 1.75 (2H.br), 1.51 (9H.s),
1.42 (9H.s), ☆1.15, 0.98 (3
H, each D. J=7.5Hz) Reference example 10) Cis-7β-[(Company)-2-phenyl-2-aminoacetamide]-4β-methyl-2-carboxy-1-azabicyclo[4,2,0]-octo-1 2-ene-8-one,
(B)cis-7β-[(B)-2-phenyl-2-t-butyloxycarbonylaminoacetamide]-4β-methyl-2-t-butyloxycarbonyl obtained in Reference Example 9 of the production method of trifluoroacetate -1-Azabicyclo[4,2,0]-octo-12-ene-8-one10
IT is 0mv (0.21mm01e)! Ll! of trifluoroacetic acid dissolved in anhydrous methylene chloride and cooled in an ice-water bath.
Add the ingredients and leave at 0-5℃ for 3.5 hours.

Shake occasionally during this time. Concentrate under reduced pressure and add anhydrous ether to the residue.
Add m1, tritulate well, and remove the ether layer by decantation. This operation is repeated three times and the cake is dried under reduced pressure to obtain the desired product in powder form 70Wi (75%). Ir(KBr)ν'77! -13450 (Sh), 3
230max (Sh), 3060, 2960-2800
, 1769, 1695 (Sh), 1681 (Sh), n
mr (DMSO-D6) δG) 49.29 (IH, t.
J = 8Hz), 7.49 (5H.s), 6.11,
6.04 (IH, each J = 2Hz), 5.30 (1H
．． m), 4.97 (IH, d.J=・4Hz), 3.
82 (IH.br), 2.44 (Br.DMSO-D6
(partially overlaps with the signal of ), 1.82 (2 Br), 1
．． 14, 0.91 (3H. each d) J = 7.5Hz) Reference example 11 (branch) cis-7β-[IB)-2-phenyl-2-t-butyloxycarbonylacetamide]-
4α-methyl-2-t-butyloxycarbonyl-1-
Azabicyclo[4,2,0]-Octo-12-En-1 8
-Production method of on.

In place of the raw material compound in Reference Example 9, 144 compounds of 7β-amino-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-ene were used. 8-one (obtained according to Example 13).

) was carried out in the same manner as in Reference Example 9 except that 140 m11
(57.6%) of the target product was obtained. Ir(KBr)ν:
"Alx333O, 1792 (Sh), 1782, 17
30, 1692, 1675nmr (CDC) δ (MB
) 7.34 (5H, s), (1) cis-7β-[(R)-2-phenyl-2-t-butyloxycarbonylaminoacetamide] synthesized according to Reference Example 11 in place of the starting compound in Reference Example 10 -4α-methyl-2-
t-Butyloxycarbonyl-1-azabicyclo[4,
2,0] - Octo 1 2 - En 1 8 - On 80? The target object 73m7 (10
0%) was obtained.

Reference Example 12 (1) Cis-7β-[(auto)-2-phenyl-2-phenyl-2-aminoacetamide]-4α-methyl-2-
A method for producing carboxy-1-azabicyclo[4,2,0]-oct-2-en-8-one trifluoroacetate.

Reference example 13 (t)cis-7β-[2-(2-tritylamino-4-
thiazolyl)-2-methoxyiminoacetamide]-4
A method for producing α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one.

(Trt represents a trityl group; the same applies hereinafter) (Method A) C+. ) cis-7β-amino-4α-methyl-2-t-
Butyloxycarbonyl-1-azabicyclo[4,2,
0]-octo12-en18-on88m7 (0.35
mm01e) in 1.5 ml of anhydrous methylene chloride to give 2-(2-tritylamino-4-thiazolyl)-2-A.
nti-methoxyiminoacetic acid 155q (0.35mm0
1e) was added, and 1.5d of anhydrous dioxane was added to make the solution homogeneous.

Add to this 80W of synchhexylcarbodiimide (0.3
9mm01e) was dissolved in 1 ml of dioxane and stirred overnight at 5-10°C. After removing the resulting white precipitate, 10 ml of ethyl acetate and 5 ml of ether were added to 5 ml of I% cold phosphoric acid solution.
Wash with Tn1 three times, saturated sodium bicarbonate solution, and dry with Glauber's salt. Charge 290 mv of the semi-solid crude target product obtained by concentration under reduced pressure to a column packed with silica gel 279 and elute using a developing solvent (n-hexane-ethyl acetate = 2:1 volume ratio, the same hereinafter). The liquid was concentrated under reduced pressure to 170η (7
2%) of the target compound is obtained. 2-(2-Tritylamino-4-thiazolyl)-2-Anti-methoxysominoacetic acid 243.9η (0.05 mm01e) was dissolved in 5d of anhydrous tetrahydrofuran and 1N-N-methylmorpholine 0.55! ! After adding Lt (0.55mm01e) 0
While cooling to ℃ and stirring, add 1N-isobutyl chloroformate 0.
．． Drop 55ml (0.55mmn1e) and add 1
Stir for 5 minutes.

After adding 0.11 ml (0.5 rrm1e) of triethylamine (1) cis-7β-amino-4α-methyl-2
-t-butyloxycarbonyl-1-azabicyclo[4
,2,0] Octo-2-ene-8one hydrochloride 144η
(0.5 mm01e) and stirred at 5-10°C overnight. After concentrating under reduced pressure, 10 d of ethyl acetate was added, washed in the order of 5% hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate, and saturated brine, and dried with sodium sulfate. The crude product obtained by concentration under reduced pressure was transferred to silica gel 2.
59, elute using a developing solvent (n-hexane-ethyl acetate = 5:3), and concentrate the eluate under reduced pressure to obtain the desired product of 250η (74.0%). The physical properties of this product matched well with those obtained by (Method A). Reference Example 14 (1) Cis-7β-[2-(2-amino-4-thiazolyl)-2-Anti-methoxyiminoacetamide]-
4α-methyl-2-carboxy-1-azabicyclo[4
,2,0]-Oct-2-en-18-one Production Method Obtained in Reference Example 13...cis-7β-[2-(2-tritylamino-4-thiazolyl)-2-Anti-methoxyiminoacetamide ]-4α-Methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one 70 mfi (0.103 mm
01e) was dissolved in 0.5w11 of anhydrous methylene chloride and 0.1ml of anisole, cooled to 0°C, and diluted with 0% trichloroacetic acid.
．． Add 5R1 and leave on an ice water bath for 3.5 hours.

Concentrate under reduced pressure and anhydrous ether 5R! 1I! Add and tritulate well.

The white powder obtained by filtration is dissolved in 50% acetic acid of 2a, left for 2.5 hours at room temperature, and then left overnight at 5-10°C. After further standing at room temperature (25°C) for 6 hours, the mixture was concentrated under reduced pressure to obtain a glassy compound. Thorough trituration with ether and filtration drying yields 2019 (51%) of the desired product. ? Example 15 (t)cis-7β-[2-(2-tritylamino-4-
thiazolyl)-2-methoxyiminoacetamide]-4
Production of β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-18-one (preparation according to Method B of Reference Example 13) cis-7β-
The target product 251η (53%) was obtained from 202m7 (0.7mm01e) of amino-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one. Ta.

Winter example 16 (1) Cis-7β-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-4β-methyl-2-carboxy-1-azabicyclo[4,2,0]
-Production method of oct-2-en-18-one (sub)cis-7β-[2-(2-tritylamino-4-thiazolyl)-2 obtained in Reference Example 15 in place of the starting material in Reference Example 14 -Methoxyiminoacetamide]-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one 70TI
The same procedure as in Reference Example 14 was carried out except that IV was used, and 22 m7 (56%) of the target product was obtained.

Reference example 17 (Tasis7β-[2-(2-chloroacetylamino-
A method for producing 4-thiazolyl)-2-Syn-methoxyiminoacetamide]-4α-methyl-2-carboxy-1-azabicyclo[4,2,0]-oct-2-en-8-one.

The following table shows the antibacterial activity of the compounds obtained in Reference Examples 10, 12, 14, and 16 above.

Measurement is done with HeartInfuslOnAgarDilut
This was carried out by the iOn method (PH7.2). Cefazolin was used as a control. (2-chloroacetylamino-4
-Thiazolinori-2-Syn-methoxyiminoacetic acid 17
2 m7 (0.62 mm01e) of anhydrous dichloromethane 3
．． Suspend in 6ml of triethylamine 68.9rNi1
(0.68 mm01e) to make a homogeneous solution. 129m7 (0.62mm01e) while cooling and stirring in an ice salt bath
) of phosphorus pentachloride is added and stirred for an additional 1.5 hours. Add 13.8 ml of n-hexane to this, remove the supernatant by decantation, and remove 1.3 ml of anhydrous tetrahydrofuran.
to obtain a solution of acid chloride. On the other hand, (1) cis-7β-amino-4α-methyl-2- obtained in Example 15
Carboxy-1-azabicitalo[4,2,0]-oct-2-en-8-one trifluoroacetate 160 m7 (
Dissolve 0.52 mm01e) in 50% tetrahydrofuran and water, and dissolve triethylamine 209r117 (2.06
mm01e). This is added to the above acid chloride solution under ice-cooling and stirring. After further stirring at the same temperature for 1.5 hours, 1N monohydrochloric acid was added to adjust the pH to 4 to 5, and the mixture was extracted three times with 10 mj of ethyl acetate. After washing the ethyl acetate solution with brine, drying the mirabilite solution and concentrating it under reduced pressure, the desired product was obtained at 147mv.
(52.1%). Reference Example 18 (1) Cis-7β-[2-(2-amino-4-thiazolyl)-2-Syn-methoxyiminochoacetamide]-
A method for producing 4-α-methyl-1-azabicyclo[4,2,0]-oct-2-en-8-one-2-carboxylic acid.

Chloroacetyl compound 147m9 obtained by Reference Example 17
(0.321mm01e) with dimethyl sulfoxide 0
．． Thiourea 47rI9 (0.64 mm01
Add e) and stir for 14 hours.

Ether is added and the supernatant is removed by decantation, dissolved in a small amount of dimethyl sulfoxide, and adsorbed onto a Diaion HP-10, 10 column. After washing with 240 g of water, methanol:water (1:10) to (1:2)
) to collect the fractions flowing out, remove methanol under reduced pressure, and re-incubate the Diaion HP-10, 10mi,
After washing with 500 g of water, the fractions flowing out are combined with methanol:water (1:1) and concentrated under reduced pressure to obtain 50.2η* (41.1%) of the target product. Ir(KBr)νI: 1760, 1680, 165
5maXpmr(DMSO-D6)δ:9.2(IH,
d, J=9.0Hz), 7.15 (2H.br), 6.
75 (1H.s), 6.31 (IH.d.J=4.2
Hz), 5.58 (IH.br), 3.85 (3H.s
), 2.60 (IH.m), 1.67 (2H, br)
, 1.08 (3H, d.J = 8Hz) Reference example 19 h) Cis-7-[2-(2-chloroacetylamino-4-thiazolyl)-2-Syn-methoxyiminoacetamide]-1-azabicyclo[ 4, 2,
0]-Production method of oct-2-en-8-one-2-carboxylic acid.

2-chloroacetylamino-4-thiazolyl-2-
Methoxyiminoacetic acid (Syn type) 54.2m9 (0.
195mm01e) was suspended in 0.98g of anhydrous methylene chloride, and triethylamine 23.48~(0.195mm
Add 01e) and dissolve.

Phosphorus pentachloride 40.8Tn9 (0.195mm01) under ice cooling
After adding e), stir for 20 minutes, and add 3 n-hexane to this.
．． Add 92 Go and decant and remove Dosumi, 1.96 T
n1! of tetrahydrofuran and dissolve. On the other hand, the azabicyclo[4,2,0]-oct-2-
45.9 m9 of trifluoroacetate of en-8-one (
0.155mm01e) was dissolved in 50% aqueous tetrahydrofuran, and triethylamine 47.4η(0.4
69mm01e).

The acid chloride solution prepared above was added to this solution under ice cooling, and the mixture was further stirred for 2 hours. PH2. with 10% hydrochloric acid. Adjust to O, extract 3 times with ethyl acetate, wash with saturated saline,
Dry and concentrate over anhydrous sodium sulfate to obtain 80 m9 of the desired product as a pale yellow powder.

Ir(KBr)νc! n: 1760, 1710, 16
60maXpmr (DMSO-D6) δ: 16.64 (
IH. br), 9.39 (IH.d.J=8.8Hz)
, 7.47 (IH,s), 6.31 (IH.t), 5.
51 (IH, d- D, J = 5.5, 8.8z), 4
．． 38 (2H.s), 3.89 (3H.s), 2.
54- 0.8 (4H.m) Reference example 20 Tansisu J Yorok2 -(2-amino-4-naazolyl)-2-Syn-methoxyiminoacetamide-1-azabicyclo[4,2,0]-oct Preparation of 12-ene-18-one-2-carboxylic acid 80η of the compound prepared according to Reference Example 19 was dissolved in 0.96Tn1 of dimethylacetamide.

Add 27.5r19 of thiourea under stirring at room temperature, stir for 14 hours, add ether and decant the supernatant.
The red oily residue was purified with Diaion HP-10 and 1
A target product of 9.2 mfI was obtained. The antibacterial activity of the compounds obtained in Reference Examples 18 and 20 was evaluated using HeartInfusiO.
Measured by nAgarDiIutiOn method (PH7.2).

The results are shown in the table below. Cefazolin was used as a control.
Reference Example 21 (1) Cis, 7β-(2-thienylacetylamide)-4α-acetoxy-1-azabicyclo[4,2,0]-
Process for producing oct-2-ene-18-one-2-monocarboxylic acid (branch)cis,7β-amino-4α obtained in Example 16
-acetoxy-1-azabicyclo[4,2,0]-oct-2-ene-8-one-2-carboxylic acid 126m
Fi was directly dissolved in 3.0 g of dioxane and 4.0 g of water, cooled in an ice-salt bath, 105 η of sodium bicarbonate was added, and 84 mfi of thienyl acetyl chloride dissolved in 1 g of dioxane was added for 1 hour. Stir.

Then, the reaction solution was adjusted to pH 2.0 with IN hydrochloric acid. The mixture was extracted with ethyl acetate three times, and the combined ethyl acetate layers were washed with saturated brine and dried over sodium sulfate. Then, it is filtered, concentrated, and eluted with chloroform-ethanol (20:1, volume ratio) using a column chromatograph packed with Wako Gel C-200. The fraction containing the target product was concentrated to dryness to obtain the target product 89.
．． Imf1 is obtained as a pale yellow powder. (Yield 47%) The physical properties of this product are as follows: Ir, spectrum (KBr
) νm-11780, MaX l745, 1660 NMR spectrum (CDC.mu+CD3OD) δ: 7
．． 27-6.93 (M, 3H), 6.39 (D.J=5
．． 4Hz,. 1H), 5.43 (D.J= 4.9z
, IH), 5.40 (M, IH), 3.79 (S, 2H
), 2.10-1.26 (M, 2H), 2.06 (S,
3H) The antibacterial activity of this product was measured in the same manner as in the above reference example.

The results (MIC) are shown below. Staphylococcus aureus 209-P3. l2 Staphylococcus epidermidis 12.5 Staphylococcus aureus Smith 25 Escherichia coli NIHJC-21
00〃 JUhtIOO

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, cephalosporin analogs and salts thereof, represented by atoms, halogen atoms, alkyl groups, hydroxyl groups, or alkanoyloxy groups.