JPS5936915B2 - Cephalosporin analogs - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 7-acylamino-2-methyl-1-carb-3-cepheme-4-carboxylic acid (carbacememe is named J, Am, Chem,
Soc, 7584, 1974) and salts thereof.

General formula (I)

) Conventionally, carbacephem compounds such as yama-1-carbacephalotin represented by the formula □NCH2 □^xOAc are known to have antibacterial activity [J, Am.

Chem, Soc, 967584, (1974)]o
The present inventors conducted various studies with the aim of developing new analogs of cephalosporin. As a result, the present inventors previously found that the general formula (■) engineering□R' (1) [wherein X1 represents an amino group, an azide group, or a phthallylimino group,
R1 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, an aryloxy group, an aralkyloxy group, an acyloxy group, a sulfonyloxy group, a lower alkylthio group,
Arylthio group, aralkylthio group, lower alkylsulfinyl group, arylsulfinyl group, aralkylsulfinyl group, -S+R4R5 (wherein R4 and R5 represent the same or different lower alkyl group, aryl group, or aralkyl group) Sulfonium group, lower alkylsulfonyl group, arylsulfonyl group, aralkylsulfonyl group, N+R6R7R8 (however, R6, R7, R
8 is the same or different lower alkyl group, aryl group,
represents a quaternary ammonium group, an arylzeleno group, or an arylzeleninyl group represented by an aralkyl group), and R2 has the same meaning as R1 or a lower alkyl group, a halogen-substituted lower alkyl group, an azide group, a nitrile group, or an NR9R1o group (wherein R,,R1o are the same or different hydrogen atoms, lower alkyl groups, aryl groups, aralkyl groups), and R3 is a hydrogen atom or an alkyl group, an aryl group, an aralkyl group, or a silyl group (these are (may or may not be replaced)
have invented cephalosporin analogues and their salts represented by
JP-A-54-128591)).

After that, as a result of further research, the inventors found the general formula (
In), X1=NH2, R1=H, R2-CH3
, R3-R1, it was discovered that a new and useful compound could be obtained, and the present invention was completed.

The compound in the present invention is represented by the following general formula (1).

However, in the formula, X is an acyl group represented by X1CO,
The following four types are exemplified as X1.

(1) Group represented by X2CH2 [However, X2 is cyano, cyclohexadienyl, aゝ6Dy (however, a,
a' each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a C1-C4 alkyl, a C1-C4 alkoxy,
substituted or unsubstituted phenyl, hydroxyl group, halogen atom, C1
- represents a furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl or tetrazolyl group substituted with C4 alkyl, C1-C4 alkoxy, amino-octaaminomethyl, nitro group, etc.]. A group represented by H 2) 1 {However, X3 is the definition of X2 above excluding the cyano group, and Y is a hydroxyl group, a protected hydroxyl group, a carboxyl group, a sulfoxyl group, an amino group or NHCOY'[Y' is an amino group, substituted amino group, r-
81■be? -Et (Et=ethyl)) na? r? S
/\day-R0 (R0 = alkyl)], etc.}.

A-13): Group represented by (however, X3
The definition v〃 is the same as above, and Y is oxiimi8C1
- represents a hydroxyimino protected with a C4 substituted or unsubstituted alkyl or alkenyl group.

These are represented by -C-.

Here, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, branched butyl, allyl, propargyl, carboxymethyl, cyanomethyl, halogenomethyl, carbamoylmethyl, C1-C4 alkyloxycarbonylmethyl, etc. ). 1) X4
-X5-CH2 group (where X4 is cyano,
It represents the same group as trifluoromethyl, cyanomethyl and the above-mentioned X3, and X5 represents an oxygen atom or a sulfur atom).

Furthermore, the carboxylic acid protecting group represented by R1 in the formula is an ester protecting group commonly used in the synthesis of penicillins and cephalosporins, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. , C1-C5 alkyl groups such as t-butyl, chloromethyl, 2,2,2-trichloroethyl, 2,2,2
- C1-C5 halogenated alkyl groups such as trifluoroethyl, C7-C2O arylmethyl groups such as benzyl, diphenylmethyl, triphenylmethyl, or C7-C2 having a methoxy, nitro group, etc. on the phenyl nucleus thereof
Arylmethyl group of O, . ``Substituted silyl groups such as trimethylsilyl and triphenylsilyl, and groups that are eliminated enzymatically and non-enzymatically to υn in vivo, e.g.
(R2 is a hydrogen atom or a C1-C5 lower alkyl group, R3 is a C1-C5 lower alkyl group, a C1-C5 lower alkyl group,
5 (lower alkoxy group, phenyl group), etc.

When R1 is hydrogen, or when the acyl group X contains a free carboxyl group or amino group, the compound represented by the general formula (1) can be combined with a pharmacologically acceptable inorganic or organic base or acid. May form salts. Specific examples include hydrochloride, sulfate, phosphate, formate, malate, sodium salt, potassium salt, calcium salt, and organic amine salt. The compound represented by the general formula () is C6,
It includes all stereoisomers and mixtures thereof at the C7 and C2 positions (corresponding to the C4 position when the carbacefem nucleus is designated as 1-azabicyclo[4,2,0]-octane), but at the C6 and C7 positions. Those whose hydrogen is cis isomer have stronger antibacterial activity than the corresponding trans isomer, and have high utility value as antibiotics. In addition, regarding the conformation of the methyl group at the C2 position (C4 position when the carbacefem nucleus is named 1-azabicyclo[4,2,0]-otatane), there is an isomerism that is located on the same side as the hydrogen at the C6 and C7 positions. The body generally exhibits stronger antibacterial activity and is more useful than other isomers. The -NOR group in the acyl side chain has the following S
It contains two geometric isomers, yn and Anti.
The isomer has better antibacterial action than the anti-isomer and is more useful as an antibiotic.

'S,. Furthermore, it is known that the thiazolyl to 1N group represented by H2N- In the following, both isomers are expressed as a thiazolyl group, but both isomers due to this tautomerism are included.

The compound represented by the general formula (1) is the corresponding 7-amino compound ([in the general formula (), X1=NH2,R, -
H, R2-CH3, R3-R'] according to the reaction process diagram (1).

Reaction process diagram (1) (R' and X are the same as above) The acylation reaction may be carried out by an acylation method commonly used in the chemistry of penicillin and cephalosporin.

That is, in general, the corresponding carboxylic acid of the acyl group X or a reactive derivative thereof, such as an acid halide, an acid anhydride (
(including mixed acid anhydrides). When using a carboxylic acid corresponding to X, carbodiimides such as synchhexylcarbodiimide are preferred.
If the acylating agent used contains amino groups, hydroxyl groups, or carboxyl groups that may be acylated, these groups are appropriately protected by conventional methods. These protecting groups are R'(
In the case of atoms other than hydrogen atoms), the desorption can be carried out simultaneously with or independently of the desorption by a conventional method. If necessary, the raw material (V) is silylated with a silylating agent (trimethylchlorosilane monobase, hexamethyldisilazane, N,O-bistrimethylsilylacetamide, etc.) to make it soluble in organic solvents and to activate the amino groups. It is also a preferred method to accelerate the reaction. The raw material compound represented by the general formula () can be produced by the method disclosed in Japanese Patent Application No. 53-34696.

As an example, it can be produced according to the reference reaction process diagram (V). Reaction process diagram (V) ＼ (However, R' represents a carboxylic acid protecting group.

Note that Compound 3 is separated into cis and trans forms at the 3 and 4 positions as necessary. Compound 5 can also be used as C4
Separation between epimers is performed. ) In the above process diagram, compounds 6 and 7 are examples of compounds represented by the general formula (1) used as raw material compounds.Specific production methods for these are shown in the reference examples. Compound (V) in which R'=H in formula (1) can also be produced by an elimination reaction of the carboxyl protecting group according to the reaction process diagram ().

Reaction process diagram () (However, R' is a carboxylic acid protecting group, and X has the same meaning as above).

This deesterification reaction can also be carried out by following the method frequently used in the chemistry of ordinary penicillins and cephalosporins.Depending on the reagent, it may involve removal of the protecting group in X, but this also serves the purpose. That's true.

Among the compounds of the present invention represented by the general formula (1), those in which R'=H exhibit excellent antibacterial activity against Gram-positive bacteria or Gram-negative bacteria, as shown in an example below. It can be used for the prevention or treatment of infectious diseases caused by bacteria, or as a bactericidal agent.

In addition, compounds in which R5 is other than H can be used as raw materials for the production of compounds in which R' is H, and some compounds, when administered as such, are converted to R' = H in vivo and exhibit antibacterial activity. . In the following Examples, specific examples of methods for producing the compounds of the present invention are shown.

Example 1...cis-7β-[(8)-2-phenyl-2-t-butyloxycarbonylaminoacetamide]-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct Method for producing 121ene-18-one (cis refers to the stereochemistry at the C6 and C7 positions, the same applies hereinafter).

Moreover, BOc represents a butyloxycarbonyl group. )(
W-N-t-Butyloxycarbonylphenylglycine 132W9 (0.53 mm01e) was dissolved in 5 ml of dry tetrahydrofuran at 0 °C IN-N-methylmorpholine 0.53 ml (0.53 mm01e), IN
-isobutyl chloroformate 0.53mi (0.53mm0
After adding 1e) and stirring for 15 minutes, triethylamine 0.
07ml (0.5mm01e) and the cis-7β-amino-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0
]-Octo-2-ene-8-one hydrochloride 144W! F
7 (0.5 mm01e) and stirred at 0°C for 1 hour and then at 5-10°C overnight.

The crude acyl compound obtained by diluting with 10 ml of ethyl acetate, washing with 10% citric acid, saturated sodium bicarbonate solution, and saturated saline in that order, drying with sodium sulfate, and concentrating the resulting crude acyl compound was subjected to silica gel chromatography [Wakogel C-200 (hereinafter referred to as silica gel)]. is the same product), 30
9, solvent, n-hexane-ethyl acetate volume ratio of 3:1 or less] to obtain the target product in powder form from 150 to (6
1.7%) was obtained.

1r (KBr) ν question Ax329O, l78O, l72O
, l685, l665, nmr(CDCl3)δ(PF
I) 7.34 (5H, s), 6.60, 6.49 (IH
) D, J = 7Hz), 6.11, 6.04 (IH) respectively
D, J = 2Hz) 5.66, 5.60 (IH) D, J = 7Hz), 5.18 (2H, m) 3.86
(IH, m), 2.46 (IH, m), 1.75 (2
H, br), 1.51 (9H, s), 1.42 (9H,
s), 1.15, 0.98 (3H) respectively D, J= 7.
5Hz) Example 2 Ex-7β-[(110-2-phenyl-2-aminoacetamide]-4β=methyl-2-carboxy-1-azabicyclo[4,2,0]-oct-2-ene-8- On, a method for producing trifluoroacetate.

The output cis-7β-[(B)-2=
phenyl-2-t-butyloxycarbonylaminoacetamide]=4β-methyl-2-t-
Butyloxycarbonyl-1=azabicyclo[4,2,
0]-Octo-1 2-En-18-On 100W9(
Dissolve 0.21 mm01e) in 1 ml of anhydrous methylene chloride and add 1 ml of trifluoroacetic acid while cooling in an ice water bath.
Leave at ℃ for 3.5 hours. Shake occasionally during this time. Concentrate under reduced pressure, add anhydrous ether to the residue, tritulate well, and remove the ether layer by decantation. Perform this operation 3
The cake was repeatedly dried under reduced pressure to obtain 70 mf7 (75%) of the target product in powder form. Ir(KBr)νselfX3
45O(Sh), 3230(Sh), 3,060,29
60~2800,1769,1695 (Sh), 1
681 (Sh), 1673I dishr (DMSO-D6)
δ (PF) 9.29 (IH, t, J = 8Hz), 7.
49 (5H, s), 6.11, 6.04 (IH) each D
, J=2Hz), 5.30 (IH, m), 4.97 (I
H, d, J = 4Hz), 3.82 (IH, br), 2
．． 44 (Br, partially overlaps with DMSO-D6 signal), 1.82 (2H, br), 1.14, 0.91
(3H) D, J = 7.5Hz each) Example 3-cis-7β-[(B)-2-phenyl-2-t
-butyloxycarbonylacetamide]-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-ene-8-
On manufacturing method.

144T instead of the raw material compound in Example 1! Cis-7β-amino-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]- of 19
Oct-2-ene-8-one (obtained according to Reference Example 2).

) was carried out in the same manner as in Example 1 except that 140Tf9 was used.
(57.6%) of the target product was obtained. Ir (KBr) ν Meng X333O, l792 (Sh), 1782, 1730,
1692,1675nmr(CDCl3)δ(PfEl
) 7.34 ( 5H, s), 6.73, 6.60) (
IH) respectively D, J = 7Hz), 6.28 (IH, t, J
= 6Hz), 5.60 (IH, m) 5.43-5.1
8 (2H, m), 3.82 (IH, m), 2.5.5 (
IH, m), 1.69 (2H, m), 1.51 (9
H, s), 1.41 (9H, s), 1.09, 1.0
3 (3H, each D, J = 7Hz) Example 4 outputs 7
Production of β=[(10-2-phenyl-2-aminoacetamide]-4α-methyl-2-carboxy-1-azabicyclo[4,2,0]-oct-12-en-8-one trifluoroacetate) Law.

Cis-7β = [(10-2-phenyl-
Example except that 80 my of 2-t-butyloxycarbonylaminoacetamide]-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one was used. 2
Target product 73Tnf7 (100%) was obtained in the same manner as above. Ir(KBr)νMengX343O, 32OO, 3O6O
, 296O~ 2650, 1780 (Sh), 1770
, 1695 (Sh), 1680 nmr (DMSD-D6
) δ (Ppm) 9.36 (IH, d, J = 8Hz),
7.47 (5H, s), 6.28 (IH, d, J=6
Hz), 5.40 (IH, m), 4.98 (IH, m)
, 3.70 (IH, br), 2.45 (Br, DMSO
- partially overlaps with D6 signal), 1.80 (2H,
m), 1.06, 0.95 (3H) respectively D, J = 7
．． 5Hz) Example 5 Cis-7β-[2-(2-tritylamino-4
-thiazolyl)-2-methoxyiminoacetamide]-
Process for producing 4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one (method A) (1) Cis-7β-amino-4α-methyl -2-t-butyloxycarbonyl-
1-Azabi 1cyclo[4,2,0]-octo-2-ene-8on 88η (0.35mm0Ie) in 1.5m1
2-(2-tritylamino-4-thiazolyl)-2-Antimethoxyiminoacetic acid (0.35 mm) was dissolved in anhydrous methylene chloride, and 1.5 ml of anhydrous dioxane was added to make a homogeneous solution. .

Add to this synchhexylcarbodiimide 80Tf1fi
! (0.39 mmOle) was dissolved in 1 ml of dioxane and stirred overnight at 5-10°C. After removing the white precipitate that had formed, 10 ml of ethyl acetate and 5 ml of ethyl acetate were added, and the mixture was washed three times with 5 ml of 1% cold phosphoric acid water, saturated sodium bicarbonate water, and dried over Glauber's salt.

The semi-solid crude target product 290 obtained by concentration under reduced pressure was charged to a column packed with silica gel 279, and eluted using a developing solvent (n-hexane-ethyl acetate-2:1 volume ratio, the same hereinafter). The eluate was concentrated under reduced pressure to 170 m9 (
72%) of the target compound is obtained. (Method B) 243.9η (0.55mm01e) of 2-(2-tritylamino-4-thiazolyl)-2-Anti-methoxyiminoacetic acid
After adding 0.55 ml (0.55 mm01e) of 1N-N-methylmorpholine dissolved in 1 ml of anhydrous tetrahydrofuran, 0.55 ml (0.55 mm01e) of 1N-isobutyl chloroformate was added dropwise while cooling to 0°C and stirring.
Stir for an additional 15 minutes. Triethylamine 0.11ml
After adding (0.5 mm01e) (t)cis-7β-amino-4α-methyl-2-t-butyloxycarbonyl-1 azabicyclo[4,2,0]oct-2-ene8-
Add 144 watts (0.5 mm 01e) of on hydrochloride, and
Stir overnight at ~10°C. After concentration under reduced pressure, ethyl acetate 10
Add m1, wash with 5% hydrochloric acid, saturated brine, saturated sodium bicarbonate solution, and saturated brine in that order, and dry with sodium sulfate. The crude product obtained by concentration under reduced pressure was charged to a column packed with silica gel 259, eluted using a developing solvent (n-hexane-ethyl acetate-5:3), and the eluate was concentrated under reduced pressure to 250 (74 ．．
0%) of the target product. The physical properties of this product matched well with those obtained by (Method A). Example 6 (e)cis-7β-[2-(2-amino-4-thiazolyl)-2-Anti-methoxyiminoacetamide]-
4α-methyl-2-carboxy-1-azabicyclo[4
,2,0]-Production method of oct-2-ene-18one The cis-7β-[2-(2-tritylamino-4-thiazolyl)-2-Anti-methoxyiminoacetamide]- obtained in Example 5 4α-Methyl 2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-octo-2
-En-8- 5 on 70mg (0.103mm01e
) anhydrous methylene chloride 0.5ml11 anisole 0.1d
Dissolve and cool to 0°C, add 0.5a of trichloroacetic acid, and leave on an ice water bath for 3.5 hours.

Concentrate under reduced pressure, add 5d of anhydrous ether, and tritify well.

The white powder obtained by filtration is dissolved in 2d of 50% acetic acid, left at room temperature for 2.5 hours, and then left at 5-10°C overnight. 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 drying of P1 yields 20-(51%) of the desired product. Example 7 (1) 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 (1) Cis-7β-
Target product 251η (53?) is obtained from amino-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]-oct-2-en-8-one 202~(0.7mm01e). Obtained.

Example 8 (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-8-one (mino-4-thiazolyl)-2-methoxyiminoacetamide]-4β-
Methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]oct-2-en-8-one 70
The same procedure as in Example 6 was carried out except that the target object was 22
η (56%) was obtained.

The following table shows the antibacterial activity of the compounds obtained in Examples 2, 4, 6, and 8 above.

Measurement is done with HeartInfusiOnAgarDilut
This was carried out by the iOn method (PH7.2). Cefazolin was used as a control. Example 9 (1) Cis-7β-[2-(2-chloroacetylamino-4-thiazolino(ha)-2-Syn-methoxyiminoacetamide]-4α-methyl-2-carboxy-1-
Process for producing azabicyclo[4,2,0]-otato-2-ene-8-one (2-chloroacetylamino-4-thiazolyl)-2-Syn-methoxyiminoacetic acid 172 mI! (
0.62mm01e) to 3.6ml of anhydrous dichloromethane
Suspend in triethylamine 68,9η (0.68 m
m01e) to make a homogeneous solution.

Cooled in an ice salt bath and stirred, 129η (0.62mm0
Add phosphorus pentachloride (1e) and stir 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.
m1 to obtain a solution of acid chloride.
1 On the other hand, the output 7 obtained in Reference Example 4
β-Amino-4α-methyl-2-carboxy-1-azabicyclo[4,2,0]-oct-2-en-18-one trifluoroacetate (160η (0.52 mm01e)) was dissolved in 50% tetrahydrofuran and water. Add Triethylamine 209 (2.06 mrn01e). The above acid chloride solution is added to this while stirring under ice cooling. After stirring for an additional 1.5 hours at the same temperature, 1N monohydrochloric acid was added to adjust the pH to 4-5, and the mixture was extracted three times with 10 ml of ethyl acetate. The ethyl acetate solution was washed with brine, dried over Glauber's salt, and concentrated under reduced pressure to obtain the desired product 147-(52.1%). Example 10 (1) Cis-7β-[2-(2-amino-4-thiazolinori-2-Syn-methoxyimino-acetamide]-
4α-Methyl-1-azabicyclo[4,2,0]-oct-2-en-8-one chloroacetyl compound 1472-(0.321mm01e
) is dissolved in 0.5 ml of dimethyl sulfoxide and 2.5 ml of dimethylformamide, and while stirring at room temperature, thiourea 47~ (0.64 mm01e) is added and stirred for 14 hours.

Ether is added and the supernatant is decanted, dissolved in a small amount of dimethyl sulfoxide and adsorbed onto a column of Diaion HPlOlOml. After washing with 240a of water, collect the flowing fraction with methanol:water (1:10) to (1:2), remove methanol under reduced pressure, adsorb it again on a column of Diaion HP-1010ml, and add 500ml of water. After washing methanol:water (1:1
) When the fractions flowing out are combined and concentrated under reduced pressure, 50
．． 2η (41.1%) of the target product is obtained. The antibacterial activity of the compound obtained in Example 10 was evaluated using HeartInfuslOn
It was measured by the AgarDilutiOn method (PFl7.2).

The results are shown in the table below. Cefazolin was used as a control.
Reference Example 1 (1) Production of a compound represented by the formula cis-2-t-butyloxycarbonyl-4methyl-J[azido-1-azabicyclo[4,2,0]oct-2-ene-8-one.

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

1) 2-[4-(2-methyl-3-butenino(c)3-
Production of t-butyl-2-oxoazetidin-1-yl]-2-diethylphosphonoacetic acid tert-butyl ester (-゛? mutual employment? U゜) t-butyl-α-aminodiethylphosphonoacetic acid 2.139 (8mm01es) was dissolved in 80 ml of anhydrous ether and mixed with 902 η (9.2 mm 0 es
) and stirred at room temperature for 1 hour, then added Molecular Sheep 4A1900 and 700 mg of magnesium sulfate, and stirred for an additional 1 hour and 30 minutes.

The reaction solution was filtered under reduced pressure and the slurry 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 Rlnlr.) This oil was mixed with 5611
Dry cyclohexane of 1, dissolved in 56 ml of anhydrous benzene, 900 molecular sieves (4A) and 1.67 ml (12 mr) of triethylamine were added, and then 1.439 (12 mr) of azidoacetyl chloride was added under stirring at room temperature.
A solution of 567n1 of mm01es) dissolved in dry cyclohexane was added dropwise over 1 hour and 30 minutes. After stirring for another 30 minutes, add 30ml of benzene and transfer to a separation load.
The mixture was washed with 30 ml each of 10% citric acid, saturated brine, saturated sodium bicarbonate solution, and saturated brine in this order, dried over sodium sulfate, and concentrated under reduced pressure to obtain 2.8 g of an oily substance. This product was observed on thin layer chromatography (silica gel, plate, developing solvent n-hexane:ethyl acetate (1:1)) as a mixture of isomers mainly consisting of two components. This was charged to a column packed with silica gel 3009 and eluted using a developing solvent (n-hexane: ethyl acetate = 1:1), and the low polar isomer of the target compound was immediately detected at 380 nm (yield: 11.0).
%), the highly polar isomer 570 (yield 16.7%) and a mixture of both 201Tnf7 (yield 5.8%) were obtained. The substance values of each isomer obtained were as shown below, and the highly polar isomer was identified as the middle cis isomer of the target product.

Low polar isomer High polar isomer (cis form) Production of 1-2-ene-8-one cis-2[4-(2-methyl-3-butenyl)-3-azido-2-oxoazetidin-1-yl]- obtained in Reference Example 1-1) 2 diethylphosphonoacetic acid, tertiary butyl ester 240~(0.56mm01e) 6.611
To 1 part of dioxane and 2 ml of deionized water were added 20 to 20 parts of osmium tetroxide, and the mixture was stirred for 10 minutes.

3907n9 (1.82mm01e) in the black reaction solution
Add powdered sodium periodate little by little 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 is washed with saturated brine, dried over sodium sulfate, and concentrated to obtain an oily substance with a compound size of 230~. 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 an oily substance (aldehyde) 18
5η is obtained.

Immediately dissolve this in 8 ml of anhydrous acetonitrile,
21.6T119 (0.
Add 45 mm 01e) of 50% sodium hydride.
After stirring for 30 minutes, the reaction solution was poured into 15 ml of 2% acetic acid water and extracted twice with 20Tn1 of ether. The ether layer was washed with saturated brine, dried over Glauber's salt, 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)] to obtain the target product as a colorless oil (70η, yield 48.1%).

This stuff crystallizes if left alone. 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 (e)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. Reference example 2 (e) Cis-7β-amino-4α-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]
-Manufacture of oct-2-ene-18-one Low polar isomer synthesized by Reference Example 1-2) (1) cis-7β-azido-4α-methyl-2-t-butyloxycarbonyl-1-
Azabicyclo[4,2,0]-octo-12-en-18-
Dissolve 255m9 of On in 10TfL1 of ethanol.
00 immediate 10? Add palladium on carbon and hydrogenate for 1.5 hours.

The catalyst is removed, washed well with methanol, and the bottom liquid and washing liquid are combined and concentrated under reduced pressure to obtain a pale yellow oil. Dissolve in 8 ml of ethyl acetate, extract 5 times with 3 ml of 10% citric acid, and neutralize the aqueous layer with potassium carbonate to pH 6-7, which turns cloudy.

The mixture was extracted twice with 5 ml of ethyl acetate, washed with saturated brine, and dried with sodium sulfate to obtain the target product in the form of an oil, 177Tf19 (76.6%). Ir(CHCl3)νMax34OO, l77
O,l72O,l63Onmr(CDCl3)δ(PP
[0) 6.23 (1H, d, J-5.0Hz), 4.5
3 (1H, d, J-5.8Hz), 3.93-3.47
(1H, m), 2.56 (1H, m), 1.92 (2H
, br), 1.80 to 1.60 (2H, m), 1.50
(9H, s), 1.31 (3H, d, J-7.0Hz)
Reference example 3 (1) Cis-7β-amino-4β-methyl-2-t-butyloxycarbonyl-1-azabicyclo[4,2,0]
- Preparation of oct-2-en-18-one Highly polar isomer cis-7β-azide-4β obtained by Reference example 1-2)
-Methyl- 2-t-butyloxycarbonyl-
1-Azabicyclo[4,2,0]-oct-2-ene-8-one 655Tny (2.35mm01e) for 6m
Dissolve 3N-HCIO in ethanol. 79ml (
2.37 mmOle) and hydrogenated for 70 minutes with 200 m9 of 10% palladium on carbon.

Add methanol to thoroughly dissolve the precipitated salt, remove the catalyst by filtration, and concentrate to obtain a crude product. Thoroughly tritify with ether, remove and dry to obtain the desired hydrochloride salt 512~(75. 4%). Melting point 216
~221°C (decomposition) Ir (KBr) ν MengX343O, 259O, 178O,
l762, l7l2, l63O Reference example 4 Reference example for the production of cis-7β-amino-4α-methyl-2-carboxy-1-azabicyclo[4,2,0]-oct-12-en-18-one trifluoroacetate Cis-7β-amino-4α-methyl-2-t obtained in 2
-butyloxycarbonyl-1-azabicyclo[4,
2,0] - Octo 1 2 - En 1 8 - On 196? Nf
7 (0.78mm01) to anhydrous dichloromethane 4.2
1.8 ml 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 to tritulate and filtered to obtain the powdered target product 167-(69.3
%).

Ir(KBr)νMengX(CTrL'l): 3460,2
980-2500, 1780, 1685, 1630Pm
r (D2O, internal standard DSS) δ: 6.77 (IH, d
, J = 5.8Hz), 5.00 (IH, d, J = 5.
6Hz), 4.10 (IH, m), 2.83 (IH, m
), 1.86 ( 2H, m), 1.15 ( 3H, d, =
8.0Hz)

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is a phenylglycyl group, an N-alkoxycarbonylphenylglycyl group, 2-(2-amino-4-thiazolyl) -2-alkoxyimino-acetyl group, 2-
(2-tritylamino-4-thiazolyl)-2-alkoxyimino-acetyl group or 2-(2-haloalkanoylamino-4-thiazolyl)-2-alkoxyimino-acetyl group, R^1 is a hydrogen atom or Indicates an alkyl group. ] Cephalosporin analogues and their salts.