JPH0578559B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides novel penam derivatives and salts thereof,
For more information, see the general formula

[In the formula, R ¹ represents a hydrogen atom, an amino-protecting group, or an acyl group; R ² represents a hydrogen atom; and Tz represents a 5-tetrazolyl group optionally protected with a tetrazolylphenam nitrogen-protecting group. ]

This invention relates to a penam derivative represented by and a salt thereof. [Prior Art] Conventionally known penam derivatives have a relatively wide antibacterial spectrum, but their effects against resistant bacteria are weak and are not necessarily satisfactory. [Problems to be solved by the invention] Under these circumstances, it is necessary to develop penam derivatives that have a broad antibacterial spectrum, are stable against β-lactamases, and exhibit strong antibacterial activity against resistant bacteria. It was wanted. [Means for Solving the Problems] As a result of intensive research to solve the above problems, the present inventors found that penam derivatives represented by the general formula [ ] and salts thereof have a broad antibacterial spectrum, and It exhibits excellent antibacterial activity against positive bacteria and Gram-negative bacteria, and is stable against β-lactamase, and at the same time has low toxicity and exhibits excellent therapeutic effects against diseases of humans and animals. It was discovered that it is useful as an intermediate leading to other penam derivatives, and the present invention was completed. The penam derivatives and salts thereof represented by the general formula [] of the present invention have a structural feature in that the tetrazolyl group is directly bonded to the 2-position of the penam ring. Hereinafter, the present invention will be explained in further detail. In the present invention, unless otherwise specified, "lower alkyl" refers to straight-chain or branched C _1-5 alkyl, such as methyl, ethyl, n-propyl,
It means isobutyl etc. Examples of the amino-protecting group in R ¹ include the amino-protecting groups described below, and examples of the acyl group include those commonly used in the penicillin and cephalosporin fields, such as formyl, α-amino-α-phenylacetyl, α -Phenylacetyl, α-phenoxyacetyl, α-(2-thienyl)acetyl, α-(3-bromophenyl)acetyl, α-carboxy-α-phenylacetyl, α-(1-tetrazolyl)acetyl, α -(5
-methoxy-2-thienyl)acetyl, α-cyanomethylthioacetyl, α-(2-carboxyethyl)thioacetyl, α-bromo-α-(2-thienyl)acetyl, α-sulfenyl-α-phenylacetyl, α- Hydroxy-α-phenylacetyl, α-hydroxyacetyl, α-(4-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-α-(4-hydroxyphenyl)acetyl, α-(4 -ethyl-2,3-dioxo-
1-piperazinocarbonylamino)-α-(3,4
-dihydroxyphenyl)acetyl, α-(4-
Ethyl-2,3-dioxo-1-piperazinocarbonylamino)-α-phenylacetyl, α-(4
-ethyl-2,3-dioxo-1-piperazinocarbonylamino)-α-(3,4-diacetoxyphenyl)acetyl, α-(4-oxo-4H-thiopyran-3-ylcarboxamide)-α -phenylacetyl and the like. When these acyl groups have an amino group, a hydroxyl group, or a carboxyl group, these groups may be protected with each of the protecting groups described below. Examples of protecting groups for amino groups include formyl, tert.-butoxycarbonyl, tert.-amyloxycarbonyl, trityl, trimethylsilyl, etc.; examples of protecting groups for hydroxyl groups include tetrahydropyranyl, benzyloxycarbonyl, trimethylsilyl, etc. , carboxyl group protecting groups include, for example, lower alkyl; benzyl, 4-methoxybenzyl, p-nitrobenzyl, phenethyl, benzhydryl, 3,4-dimethoxybenzyl, bis(methoxyphenyl)methyl, 3,5-di −
aralkyl such as tert.-butyl-4-hydroxybenzyl; phthalidyl; 2-iodoethyl;
Examples include halo-lower alkyl such as 2,2,2-trichloroethyl. Tz represents a 5-tetrazolyl group which may be protected with a tetrazolylpenam nitrogen protecting group, and the tetrazolylpenam nitrogen protecting group here is:
Those known in the field of penum compounds are listed.
For example, the one described in Japanese Patent Application Laid-Open No. 50-64295 can be mentioned. Preferred examples include alkoxycarbonylalkyl groups such as 2-(methoxycarbonyl)ethyl, and aralkyl groups such as 2,4-dimethoxybenzyl. Examples of the salt of the compound of the general formula [] include commonly known salts of basic groups such as amino groups or acidic groups such as 5-monosubstituted tetrazolyl groups, carboxyl groups, and hydroxyl groups. Examples of salts in basic groups include:
Salts with mineral acids such as hydrochloric acid and sulfuric acid; formic acid, citric acid,
Salts with organic carboxylic acids such as trichloroacetic acid and trifluoroacetic acid; salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and mesitylenesulfonic acid; salts with acidic groups include, for example, Salts with alkali metals such as sodium and potassium; calcium,
Salts with alkaline earth metals such as magnesium; ammonium salts; procaine, dibenzylamine,
N-benzyl-β-phenethylamine, 1-ephenamine, N,N-dibenzylethylenediamine, triethylamine, trimethylamine, tributylamine, pyridine N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, etc. Salts with nitrogen-containing organic bases can be mentioned. Among the compounds of the present invention represented by the general formula [], preferred are the general formula

[In the formula, R ¹ and R ² have the same meanings as above. ] and salts thereof. In general formula [a], the 5-tetrazolyl group has the following tautomers, and the present invention includes any of them.

[Chemical formula] In addition, in the compound of the general formula [] and its salt, when isomers (for example, optical isomers, geometric isomers, tautomers, etc.) exist, the present invention covers all such isomers. and all crystalline forms and hydrates. Next, a method for producing the compound of the present invention will be explained. The compound of the present invention can be produced, for example, according to the following production route.

[In the above formula, R ^1a is the same acyl group as explained for R ¹ , R _1b is the amino protecting group, R ³ is the same tetrazolylphenam nitrogen protecting group as explained for Tz, and R ² has the same meaning as described above. ]

As the amino protecting group for R ^1b , those known in the art (for example, those described in JP-A-51-54581), specifically, 2, 2, 2
-trihaloethoxycarbonyl group, optionally substituted trityl group, etc., and trityl group is particularly preferred. (1) Cyclization A compound represented by the general formula [d] or [e] can be obtained by reacting the compound represented by the general formula [] or [] with an azide ion generator. Examples of the azide ion generator used here include tri-lower alkylsilyl azides such as trimethylsilyl azide and triethylsilyl azide; potassium azide, sodium azide, tributylammonium azide, N,N-dimethylanilium azide, and N-methylmorphol. Examples include azide salts such as nium azide, pyridinium azide, and tetramethylguanidinium azide, with trimethylsilyl azide being particularly preferred. When this reaction is carried out in a solvent, it is not particularly limited as long as it is inert to the reaction, but specific examples include halogenated carbons such as methylene chloride, chloroform, and 1,2-dichloroethane; Examples include dipolar neutral solvents. The amount of the azide ion generator used is about 1.0 to 1.1 times the mole of the compound represented by the general formula [] or []. This reaction may be carried out at 10 to 35°C for 30 minutes to 24 hours. (2) Elimination of the amino protecting group and tetrazolylpenam nitrogen protecting group From the compound represented by the general formula [d] or [e] to the compound represented by the general formula [g] or [f], respectively Removal of amino protecting group and general formula [d] or [c]
From the compounds represented by the general formula [
The removal of the tetrazolylpenam nitrogen protecting group leading to the compound represented by [e] or [b] is carried out, for example, under the conditions described in JP-A-50-64295 or conditions similar thereto. (3) Acylation If a compound of general formula [f] or [g] or a salt thereof or a reactive derivative thereof at the amino group is reacted with a carboxylic acid of general formula [] or a reactive derivative thereof, each It can be derived into a compound of general formula [b] or [c] or a salt thereof. In addition, as the reactive derivative at the amino group of the compound of general formula [f] or [g] or a salt thereof, for example, isocyanate, the compound of general formula [f] or [g] or a salt thereof, an aldehyde, a ketone, etc. Schiff's base (imino type or its enamine type isomer) produced by the reaction with a carbonyl compound such as, a compound of general formula [f] or [g] or a salt thereof and bis(trimethylsilyl)acetamide, trimethylsilylacetamide, Silyl compounds such as trimethylsilyl chloride, phosphorus trichloride,

【formula】

【formula】

_[ Formula _{] Silyl derivatives , phosphorus derivatives , or} All compounds frequently used in acylation reactions, such as tin derivatives, are included. Specifically, the reactive derivatives of the compound of general formula [] include acid halides, acid anhydrides,
Examples thereof include mixed acid anhydrides, active acid amides, active esters, and reactive derivatives of the compound of the general formula [] with the Vilsmeier reagent. The mixed acid anhydride includes, for example, a mixed acid anhydride with a carbonic acid monoalkyl ester such as carbonic acid monoethyl ester and carbonic acid monoisobutyl ester, and a lower alkanoic acid which may be substituted with a halogen such as pivalic acid and trichloroacetic acid. Mixed acid anhydrides with and the like are used. Examples of active acid amides include N-acylsactucalin,
N-acylimidazole, N-acylbenzoylamide, N,N'-dicyclohexyl-N-
Acyl urea, N-acysulfonamide, etc. are used. Next, as the active ester, for example, cyanomethyl ester, substituted phenyl ester, substituted benzyl ester, substituted thienyl ester, etc. are used. In addition, examples of derivatives reactive with the Vilsmeier reagent include N,N-dimethylformamide,
Acid amides such as N,N-dimethylacetamide are reacted with halogenating agents such as phosgene, thionyl chloride, phosphorus trichloride, phosphorus tribromide, axyphosphorus chloride, phosphorus pentachloride, trichloromethyl chloroformate, and oxalyl chloride. Examples include derivatives reactive with Vilsmeier's reagent obtained by When the compound of general formula [] is used in the form of a free acid or salt, a suitable condensing agent is used.
Such condensing agents include, for example, N,
N,N'-disubstituted carbodiimides, such as N'-dicyclohexylcarbodiimide, N,N'-
Dehydrating agents such as azolide compounds such as thionyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline, phosphorus oxychloride, and alkoxyacetylene, 2
-Halogenopyridinium salts (eg, 2-chloropyridinium methyl iodide, 2-fluoropyridinium methyl iodide), etc. are preferred. This acylation reaction is generally carried out in a suitable solvent.
It is carried out in the presence or absence of a base. Examples of the solvent include chloroform, halogenated hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran and dioxane, N,
N-dimethylformamide, N,N-dimethylacetamide, acetone, water or a mixture thereof can be used. The bases used here include alkali hydroxide, alkali hydrogen carbonate,
Inorganic bases such as alkali carbonate or alkali acetate, tertiary amines such as trimethylamine, triethylamine, tributylamine, pyridine, N-methylpiperidine, N-methylmorpholine, lutidine, collidine, or secondary amines such as dicyclohexylamine, diethylamine, etc. Can be mentioned. The amount of the compound of general formula [] to be used is usually about 1.0 to 1.5 times the molar amount of the compound of general formula [If] or [Ig]. This reaction may be carried out usually at -50 to 40°C for 10 minutes to 48 hours. The compound of the general formula [] or a salt thereof of the present invention obtained as described above can be isolated by a conventional method. The compound represented by the general formula [] or [], which is a raw material in the present invention, can be produced, for example, according to the following production route.

[In the above formula, R ⁴ has a hydrogen atom, a lower alkyl group, or an aralkyl group such as p-nitrobenzyl group, and R ^1b , R ² and R ³ have the same meanings as described above. ]

(a) Deacylation A compound represented by the general formula [] or a salt thereof or a compound represented by the general formula [XI] is deacylated to form a compound represented by the general formula [] or a salt thereof or the general formula [XII], respectively.
To obtain a compound represented by
Laquiyue de Travo Chimique de Payba (Recl.Trav.Chim.Pays−Bas) Volume 89, No.
This can be carried out by the method described in p. 1081 (1970) or Japanese Patent Publication No. 55-38954, or by a method analogous thereto. (a) Protection of amino group The amino group at position 6 of the compound represented by the general formula [] or its salt or the compound represented by the general formula [XII] is protected to form the respective general formula []
To obtain the compound represented by or a salt thereof or the compound represented by the general formula・The Journal of American Chemical Society
Chemical Society) Volume 84, Page 2983 (1962
It can be carried out by the method described in 2010) or by a method similar thereto. (c) Amidation A compound represented by the general formula [] or a salt thereof, or a reactive derivative thereof in the carboxyl group, and a compound represented by the general formula [] or a salt thereof are reacted to form a compound represented by the general formula [] or its salt can be obtained under the same conditions as the amidation used in the art, for example, by the method described in JP-A No. 50-64295 or a method analogous thereto. (d) Iminochlorination A compound represented by the general formula [] can be obtained by reacting the compound represented by the general formula [] with a halogenating agent in the presence of a base. Examples of the halogenating agent used here include phosgene, trichloromethyl chloroformate, thionyl chloride, and phosphorus pentachloride, with phosgene or trichloromethyl chloroformate being particularly preferred. Examples of bases used include trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, N
-Methylmorpholine, pyridine, etc., and pyridine is particularly preferred. When this reaction is carried out in a solvent, there are no particular limitations as long as it is inert to the reaction, but specific examples include methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, etc., with methylene chloride being particularly preferred. . The amount of the halogenating agent used is about 1 to 3 times the mole of the compound represented by the general formula [], and the amount of the base used is about 1.0 to 1.2 times the mole of the halogenating agent. This reaction may be carried out at -20 to 30°C, preferably at 25°C for 2 to 5 hours. The compound represented by the general formula [] thus obtained can be subjected to the next reaction without being isolated. (e) Carbamylation and dehydration A compound represented by the general formula [] or a salt thereof is carbamylated to obtain a compound represented by the general formula [], which is then subjected to a dehydration reaction to obtain a compound represented by the general formula [XI]. To obtain the compound,
Conventional carbamylation and dehydration reactions can be used, e.g.
American Chemical Society
Journal of American Chemical Society) No.
Volume 75, page 3637 (1953) or Japanese Patent Application Publication No. 1973-
It can be carried out under the conditions described in No. 54581, etc., or by a method similar thereto. If isomers or the like exist in the compounds or salts thereof obtained in each of the steps described above, they can be isolated and purified by conventional methods. In addition, in the acylation reaction, if a group active in the reaction exists in the R ^1a group, it can be optionally protected with a normal protecting group during the reaction, and the protecting group can be removed by a conventional method after the reaction. can also be removed. The compound represented by the general formula [] or its salt, which is the raw material for the compound represented by the general formula [] and [], is available from Reason Advances in the Chemistry of Beta-Lactam Antibiotics (The Chemical Society, Burlington House) [Recent
Advances in the Chemisty of β−lastam
Antibiotics (The Chemical Society,
Burlington House), pages 214-230 (1977), or a method similar thereto. [Effects of the Invention] Next, the results of the pharmacological effects of representative compounds of the present invention will be shown. (1) Antibacterial activity test method Japanese Society of Chemotherapy Standard Method [CHEMOTHERAPY Volume 29, No. 1, No. 76
79 (1981)] at 37°C for 20
Heart Infusion agar contains a bacterial solution that has been cultured for a long time and contains a drug.
After inoculating the medium (manufactured by Eiken Kagaku Co., Ltd.) and culturing at 37°C for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was determined by MIC (μg/
ml). However, the amount of inoculated bacteria was 10 ⁴ cells/plate (10 ⁶ cells/ml). Table 1 shows the results.
Shown below. test compound

[ka]

【table】

〔Example〕

Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto. Reference example 1 (1) (3S,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamide-4-thia-1-azabicyclo[3.2.0]heptane 14.10g to 282ml of methylene chloride
suspended in N,N-dimethylaniline 12.16
ml and cooled to -60°C. Add 9.99 g of phosphorus pentachloride to this mixture and react at -40 to -30°C for 1 hour. Next, the reaction solution was cooled to -50°C, 90ml of anhydrous methanol was added, and the temperature was raised to 0°C.
After reacting for a minute, add 100ml of water and leave at the same temperature.
Stir for 30 minutes. The precipitated crystals are collected, washed sequentially with 42 ml of methylene chloride and 28 ml of water, and dried, showing a melting point of 99-100°C (decomposed) (3S,
5R,6R)-6-Amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane hydrochloride 10.10 g (yield 87.8%) is obtained . (2) 9.90 g of (3S,5R,6R)-6-amino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane hydrochloride in acetic acid. Suspend in 100 ml of ethyl and 75 ml of water and PH with sodium bicarbonate.
Adjust to 7.0. Separate the organic layer and add saturated saline solution
After washing with 30 ml, dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 100 ml of methylene chloride and cooled to 0°C. In this, 5.46ml of triethylamine
After adding 11.40g of trityl chloride,
React at 0°C for 3 hours. Then, add water to the reaction solution.
After adding 50ml and separating the organic layer, add saturated saline solution.
Wash with 40 ml and dry with anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Merck Silica Gel 60, No. 7734, elution solvent; benzene:ethyl acetate = 100:1 to 50:1 (volume ratio). ]
If purified, amorphous (3S, 5R,
6R)-6-tritylamino-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4
-thia-1-azabicyclo[3.2.0]heptane
Obtain 10.40 g (yield 67.5%). IR (KBr) cm ^-1 : ν _c=p 1780, 1740 NMR (CDCl ₃ ) δ value: 2.97 to 3.37 (2H, m),
3.92~4.72 (4H, m), 5.13 (2H, s), 7.04~
7.62 (17H, m), 8.14 (2H, d, J = 9Hz) (3) (3S, 5R, 6R)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-
8.50 g of 6-tritylamino-1-azabicyclo[3.2.0]heptane in tetrahydrofuran
Dissolve in 170 ml, cool to 0°C, add a solution of 2.90 g of sodium sulfide nonahydrate dissolved in 52 ml of water, and react at 0°C for 30 minutes. Then, the reaction solution was adjusted to pH 7.0 with 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. Add 170 ml of water and 43 ml of diethyl ether to the resulting residue,
After separating the aqueous layer, add 170ml of ethyl acetate.
Adjust the pH to 2.0 with 1N hydrochloric acid. Separate the organic layer,
After sequentially washing with 50 ml of water and 40 ml of saturated saline, drying with anhydrous magnesium sulfate. Then, by distilling off the solvent under reduced pressure, the melting point is 159-165.
(3S, 5R, 6R)-3-carboxy-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane showing °C (decomposition)
Obtain 4.00 g (61.8% yield). IR (KBr) cm ^-1 : ν _c=p 1780, 1730 NMR ( _d6 -DMSO) δ value: 2.75-3.50 (2H,
m), 3.75-4.65 (4H, m), 7.00-7.60 (15H,
m) (4) Dissolve 4.0 g of (3S,5R,6R)-3-carboxy-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane in 40 ml of methylene chloride, and -Methylmorpholine
Add 1.08 ml and cool to -30 to -20°C. Add 0.93 ml of ethyl chlorocarbonate to this solution and react at the same temperature for 1 hour. Next, 1.10 ml of β-alanine methyl ester was added and the temperature was raised to 0°C.
After reacting for 1 hour, add 20 ml of water and separate the organic layer. Further, the organic layer is washed successively with 15 ml of water and 10 ml of saturated saline, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Merck Silica Gel 60, No. 7734, elution solvent: benzene:ethyl acetate = 20:1 to 10:1].
(volume ratio)], (3S, 5R, 6R)-3
4.0 g of -[N-(2-methoxycarbonylethyl)carbamoyl]-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane (yield 83.5%) is obtained. Melting point: 165-166°C (Recrystallization solvent: methanol) IR (KBr) cm ^-1 : _NH 3300ν _c=p 1780, 1740, 1660 NMR (CDCl ₃ ) δ value: 2.47 (2H, t, J=6
Hz), 2.90-4.70 (8H, m), 3.68 (3H, s),
6.84 (1H, t, J=6Hz), 7.10~7.70 (15H,
m) The following compound is obtained in the same manner. Γ(3S,5R,6R)-3-[N-(2,4-dimethoxybenzyl)carbamoyl]-7-oxo-
4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane (amorphous) IR (KBr) cm ^-1 : ν _c=0 1770, 1650 NMR (CDCl ₃ ) δ value: 3.00 to 4.70 (8H , m),
3.76 (3H, s), 3.79 (3H, s), 6.30~7.65
(19H, m) Reference Example 2 (1) (3R,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamide-4-thia-1-azabicyclo[ 3.2.0] Dissolve 8.66 g of heptane in 200 ml of methylene chloride and cool to -65°C. To this, N, N-
9.94 ml of dimethylaniline and 5.31 ml of phosphorus pentachloride
After reacting at -60 to -50°C for 1 hour, 48 ml of anhydrous methanol was added and the temperature was raised to room temperature over 1.5 hours. Next, 100 ml of water was added to the reaction solution under ice cooling, and after stirring for 10 minutes,
Adjust the pH to 7.0 with sodium bicarbonate. After separating the organic layer and washing with 100 ml of saturated saline,
Dry with anhydrous magnesium sulfate. To this solution was added 1.59 ml of pyridine under ice-cooling, then 5.47 g of trityl chloride was added in portions over 10 minutes, and the mixture was stirred at the same temperature for 20 minutes. Add the reaction solution to 80% water
ml and 60 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako Silica Gel C-200, elution solvent: benzene:ethyl acetate = 50:1 to 30:1]
(volume ratio)], amorphous (3R,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-6
-tritylamino-1-azabicyclo [3.2.0]
7.85 g of heptane (yield 70.7%) is obtained. IR (KBr) cm ^-1 : ν _c=0 1780, 1735 NMR (CDCl ₃ ) δ value: 2.86 (1H, dd, J=6.5
Hz, J=13Hz), 3.33-4.70 (5H, m), 5.20
(2H, s), 7.00-7.70 (17H, m), 8.09 (2H,
d, J=9Hz) (2) (3R,5R,6R)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-4-thia-
Dissolve 6.00 g of 6-tritylamino-1-azabicyclo[3.2.0]heptane in 70 ml of tetrahydrofuran and add 24 ml of water. A solution of 2.42 g of sodium sulfide nonahydrate dissolved in 15 ml of water is added to this, and the mixture is reacted at 0 to 5°C for 1 hour. The reaction solution was adjusted to pH 7.0 with 6N hydrochloric acid, and the solvent was distilled off under reduced pressure. After washing the residue with 50 ml of diethyl ether, 100 ml of ethyl acetate was added.
Adjust the pH to 2.0 with 6N hydrochloric acid. Separate the organic layer,
After sequentially washing with 40 ml of water and 30 ml of saturated saline, drying with anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 3.20 g of amorphous (3R,5R,6R)-3-carboxy-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane ( Yield 90.2%)
get. IR (KBr) cm ^-1 : ν _c=p 1780, 1735 NMR (CDCl ₃ ) δ value: 2.86 (1H, dd, J=6.5
Hz, J=13Hz), 3.83-4.83 (5H, m), 7.00
~7.70 (15H, m) (3) (3R,5R,6R)-3-Carboxy-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane 4.09g to 50ml chloride Dissolve in methylene and cool to -20°C. N
- Add 1.15 ml of methylmorpholine and 1.09 ml of ethyl chlorocarbonate and stir at -15 to -10°C for 1.5 hours, then add 1.23 ml of β-alanine methyl ester and react at the same temperature for 30 minutes. The reaction solution was washed successively with 30 ml of water and 20 ml of saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako silica gel C-200, elution solvent: benzene:ethyl acetate = 5:1 (volume ratio)] to obtain (3R, 5R, 6R)-3-[N
-(2-methoxycarbonylethyl)carbamoyl]-7-oxo-4-thia-6-tolylamino-1-azabicyclo[3.2.0]heptane 3.48
g (yield 71.0%) is obtained as crystals. Melting point: 196-197℃ (decomposition) (recrystallization solvent: methanol) IR (KBr) cm ^-1 : ν _NH 3330, ν _c=p 1770, 1730,
1660 NMR (CDCl ₃ ) δ value: 2.55 (2H, t, J = 6
Hz), 2.91 (1H, dd, J=6.5Hz, J=13Hz),
3.20~4.70 (7H, m), 7.00~7.70 (16H, m),
3.69 (3H, s) In the same manner, the following compound is obtained. Γ(3R,5R,6R)-3-[N-(2,4-dimethoxybenzyl)carbamoyl]-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane Melting point: 169 ~170℃ (Re-solidification solvent: chloroform) IR (KBr) cm ^-1 : ν _c=p 1770, 1660 NMR (CDCl ₃ ) δ value: 2.83 (1H, dd, J=6.5
Hz, J=13Hz), 3.30-4.67 (7H, m),
3.70 (3H, s), 3.74 (3H, s), 6.25-7.70
(19H, m) Reference example 3 (1) (3R,5R,6R)-3-carboxy-7-oxo-6-phenylacetamide-4-thia-1
- Suspend 4.3 g of azabicyclo[3.2.0]heptane in 60 ml of methylene chloride, add and dissolve 1.62 ml of N-methylmorpholine. Next, this solution was cooled to -30℃, 1.40ml of ethyl chlorocarbonate was added, and after reacting at -10 to -15℃ for 1.5 hours, 4.37N
Add 4.80 ml of an ethanolic ammonia solution dropwise over 10 minutes. After dropping, keep at -10 to -5℃ for 1 hour.
React at 5-0°C for 30 minutes and at 0-20°C for 30 minutes. Then, after adding 15 ml of water to the reaction solution,
Adjust the pH to 2.0 with 2N hydrochloric acid. Separate the organic layer,
After washing with 10 ml of saturated saline, dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Add 20ml of ethyl acetate to the resulting residue, stir for 30 minutes, remove the crystals, and the melting point is 159-160.
(3R, 5R, 6R)-3-carbamoyl-7-oxo-6-(phenylacetamide-4-thia-1-azabicyclo[3.2.0]
2.5 g of heptane (yield 58.3%) is obtained. IR (KBr) cm ^-1 : ν _c=p 1770, 1670, 1640 NMR (d ₆ −DMSO) δ value: 3.10 (1H, dd, J=
7Hz, J=13Hz), 3.54 (2H, s), 3.92~
4.40 (2H, m), 5.20~5.60 (2H, m), 6.93~
7.41 (6H, m), 7.71 (1H, bs), 8.39 (1H,
d, J=8Hz) (2) (3R,5R,6R)-3-carbamoyl-7-
Oxo-6-phenylacetamide-4-thia-
Suspend 2.85 g of 1-azabicyclo[3.2.0]heptane in 30 ml of methylene chloride, add 3.10 ml of pyridine, and add 2.70 g of trifluoroacetic anhydride under ice cooling.
ml dropwise over 15 minutes. After dropping, the reaction solution was heated to room temperature and 15 ml of water was added. Then, the organic layer is separated, washed with 10 ml of saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-200, elution solvent; benzene:ethyl acetate = 10:1 (volume ratio)]
If purified by
2.20 g (yield 82.0%) of cyano-7-oxo-6-phenylacetamide-4-thia-1-azabicyclo[3.2.0]heptane is obtained. IR (neat) cm ^-1 : ν _c ≡ _p 2230, ν _c=p 1780, 1665 NMR (CDCl ₃ ) δ value: 3.00 (1H, dd, J=6
Hz, J=13Hz), 3.58 (2H, s), 4.11 (1H,
d, J = 6Hz), 4.43 (1H, d, J = 13Hz),
5.29 (1H, d, J = 4Hz), 5.54 (1H, dd, J
=4Hz, J=8Hz), 6.81(1H, d, J=8
Hz), 7.27 (5H, s) (3) (3R,5R,6R)-3-cyano-7-oxo-6-phenylacetamide-4-thia-1-azabicyclo[3.2.0]heptane 4.10 g was suspended in 82 ml of methylene chloride, 5.43 ml of N,N-dimethylaniline was added, and the mixture was cooled to -60°C. Furthermore, 4.46 g of phosphorus pentachloride is added, and the mixture is allowed to react at -60 to -50°C for 1 hour. Next, add 25 ml of anhydrous methanol to -50
The mixture is added at 0.degree. C., heated to 0.degree. C., and reacted for 1 hour. Add 20ml of water and pH with sodium bicarbonate.
Adjust to 1.0 and separate the aqueous layer. Furthermore, add 5.0 ml of water to the organic layer, separate the aqueous layer, combine it with the previous aqueous layer, add 20 ml of methylene chloride,
Adjust the pH to 7.5 with sodium bicarbonate. Separate the organic layer and add 10ml of methylene chloride to the aqueous layer.
Repeat the extraction operation 10 times. The extract and the organic layer were combined, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. When diethyl ether is added to the resulting residue and crystallized, it shows a melting point of 117-121°C (decomposition) (3R,
5R,6R)-6-amino-3-cyano-7-oxo-4-thia-1-azabicyclo[3.2.0]
1.30 g of heptane (54% yield) is obtained. IR (KBr) cm ^-1 : ν _C ≡ _N 2240, ν _c=p 1755 (4) (3R, 5R, 6R)-6-amino-3-cyano-7-oxo-4-thia-1-azabicyclo[ 3.2.0] Suspend 1.30 g of heptane in 26 ml of methylene chloride and cool to 0°C. triethylamine
Add 1.18 ml and 2.34 g of trityl chloride one after another, and react at room temperature for 30 minutes. Add the reaction solution to 13 ml of water.
ml and 13 ml of saturated saline, and then the organic layer is dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 10 ml of benzene is added to the resulting residue to crystallize it, resulting in a melting point of 198-200.
2.88 g of (3R, 5R, 6R)-3-cyano-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane
(yield 91%). IR (KBr) cm ^-1 : ν _c ≡ _N 2220, ν _c=O 1770 Example 1 (3S, 5R, 6R)-3-[N-(2-methoxycarbonylethyl)carbamoyl]-7-oxo-
Dissolve 5.20 g of 4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane in 52 ml of methylene chloride, cool to -5°C, add 2.45 ml of pyridine and 1.21 ml of trichloromethyl chloroformate, and cool to room temperature. and react for 4 hours. Then, after distilling off the solvent under reduced pressure, the resulting residue was dissolved in 52 ml of methylene chloride, and 1.43 ml of trimethylsilyl azide was added under ice cooling, followed by reaction at room temperature for 1 hour. Then, add 26ml of water and PH with 1N hydrochloric acid.
2.5, separate the organic layer, wash the organic layer sequentially with 20 ml of water and 10 ml of saturated saline, and then dry over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Merck silica gel].
60, No. 7734, Elution solvent; Benzene: Ethyl acetate =
If purified at a ratio of 20:1 to 15:1 (volume ratio), (3S,
5R,6R)-3-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]-7-oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane (4.98 g) rate of 93.4%). Melting point: 190°C (reconsolidation solvent: methanol) IR (KBr) cm ^-1 : ν _c=p 1775, 1730 NMR (CDCl ₃ ) δ value: 2.84 to 3.80 (4H, m), 3.64
(3H, s), 4.20-4.75 (5H, m), 4.95 (1H,
t, J=8Hz), 7.05-7.63 (15H, m) The following compound is obtained in the same manner. Γ(3S,5R,6R)-3-[1-(2,4-dimethoxybenzyl)tetrazol-5-yl]-7
-oxo-4-thia-6-tritylamino-1
-Azabicyclo[3.2.0]heptane Melting point: 178-179℃ (reconsolidation solvent: ethyl acetate) IR (KBr) cm ^-1 : ν _c=p 1770 NMR (CDCl ₃ ) δ value: 3.00-4.90 (6H, m ),
3.68 (3H, s), 3.77 (3H, s), 5.32 (2H,
s), 6.30-7.70 (18H, m) Example 2 (3S,5R,6R)-3-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]-4
-oxo-4-thia-6-tritylamino-1-
Dissolve 6.50 g of azabicyclo[3.2.0]heptane in 65 ml of methylene chloride, add 1.84 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, and react overnight at room temperature. Then, the solvent is distilled off from the reaction solution under reduced pressure, and 200 ml of water and 100 ml of ethyl acetate are added to the resulting residue, the pH is adjusted to 8.0 with 1N hydrochloric acid, and the aqueous layer is separated. Furthermore, ethyl acetate is added to the aqueous layer.
Add 150ml, adjust the pH to 2.0 with 1N hydrochloric acid, and separate the organic layer. Combine the organic layer with 70 ml of water and 50 ml of saturated saline.
ml and then dried over anhydrous magnesium sulfate. Then, if the solvent is distilled off under reduced pressure,
(3S, 5R, 6R) -3- with a melting point of 130℃ (decomposition)
(5-tetrazolyl)-7-oxo-4-thia-6
-Tritylamino-1-asabi dichloro [3.2.0]
4.33 g of heptane (yield 77.5%) is obtained. IR (KBr) cm ^-1 : ν _c=p 1780 NMR (d ₆ −DMSO) δ value: 2.95 to 3.70 (2H, m),
4.18-4.80 (3H, m), 5.16 (H, t, J=8
Hz), 7.00 to 7.65 (15H, m) Example 3 (3S,5R,6R)-3-(5-tetrazolyl)-
7-oxo-4-thia-6-tritylamino-1
- Dissolve 4.00 g of Asabicyclo[3.2.0]heptane in 20 ml of ethyl acetate, and dissolve p-toluenesulfonic acid.
After adding an ethyl acetate solution of monohydrate (prepared by dissolving 1.67 g of p-toluenesulfonic acid monohydrate in 8.0 ml of ethyl acetate) and stirring at room temperature for 15 minutes,
Add 28 ml of diethyl ether and further boil at the same temperature for 30 ml.
Stir for a minute. After collecting the precipitated crystals and washing them with 15 ml of diethyl ether, the crystals were dissolved in 10 ml of water and 5 ml of ethyl acetate, and the pH was adjusted with sodium hydrogen carbonate.
Adjust to 4.0 and stir on ice for 30 minutes. If you take the precipitated crystals, wash them with 2 ml of water and 5 ml of acetone, and then dry them, the melting point is 170-175°C (decomposition).
(3S, 5R, 6R)-6-amino-3-(5-
1.05 g (56.1%) of tetrazolyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane are obtained. IR (KBr) cm ^-1 : ν _c=p 1785 NMR (D ₂ O−DMSO−NaHCO ₃ ) δ value: 3.16
(1H, dd, J=8Hz, J=13Hz), 4.19 (1H,
dd, J=6Hz, J=13Hz), 4.47(1H, d, J
=4Hz, 5.01 (1H, dd, J=6Hz, J=8Hz),
5.31 (1H, d, J = 4Hz) Example 4 (3S, 5R, 6R)-6-amino-3-(5-tetrazolyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane Suspend 40 mg in 1.5 ml of N,N-dimethylformamide, add 0.026 ml of triethylamine, and cool to -10°C. On the other hand, D-α-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide) phenyl acetic acid 60
mg was suspended in 2.0 ml of methylene chloride, and N-
Add 0.023 ml of methylmorpholine and 0.018 ml of ethyl chlorocarbonate, and react at -30 to -20°C for 1 hour. This reaction solution was heated to −10 to −5°C with the previously prepared N,
Drop into N-dimethylformamide solution. After dropping, react at the same temperature for 1 hour, add 1.0 ml of methanol, raise the temperature to room temperature, and react at the same temperature.
Stir for 30 minutes. Then, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 5.0 ml of water and 5.0 ml of ethyl acetate.
, adjust the pH to 2.0 with 1N hydrochloric acid, and separate the organic layer. Furthermore, the aqueous layer was extracted three times with 3 ml of ethyl acetate, the extract was combined with the organic layer, and this was added with 5.0 ml of water.
ml and adjust the pH to 7.5 with sodium bicarbonate. Separate the aqueous layer, add 10 ml of ethyl acetate, and add 1N
Adjust the pH to 2.0 with hydrochloric acid and separate the organic layer. Further, the aqueous layer is extracted twice with 5.0 ml of ethyl acetate, the extract is combined with the organic layer, washed with 5 ml of saturated brine, and then dried over anhydrous magnesium sulfate.
Then, the solvent is distilled off under reduced pressure, diethyl ether is added to the resulting residue, and the crystals are collected.
(3S,5R,6R)-6-[D-α-(4-ethyl-
2,3-dioxo-1-piperazinecarboxamide)phenylacetamide)-7-oxo-7-thia-3-(5-tetrazolyl)-1-azabicyclo[3.2.0]heptane 50 mg (yield 49.9%) get. IR (KBr) cm ^-1 : ν _c=p 1780, 1720, 1675 Example 5 (3R, 5R, 6R)-3-[N-(2-methoxycarbonylethyl)carbomoyl]-7-oxo-
Dissolve 3.60 g of 4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane in 50 ml of methylene chloride, add 2.08 ml of pyridine, and cool to -10°C. 0.84 ml of trichloromethyl chloroformate 5
The mixture was diluted with ml of methylene chloride, added dropwise at -5°C or below, heated to room temperature, and stirred for 4 hours.
The solvent was distilled off under reduced pressure, the resulting residue was dissolved in 50 ml of methylene chloride, and 2.31 ml of trimethylsilyl azide was added under ice cooling, followed by reaction at room temperature for 1 hour. Add 20ml of water to the reaction solution and adjust the pH to 2.5 with 3N hydrochloric acid.
Adjust to. The organic layer is separated, washed successively with 20 ml of water and 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-200, elution solvent; benzene:ethyl acetate = 9:1 to 7:1 to 5:1 (volume ratio)] (3R,5R,6R)-3-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]
-7-oxo-4-thia-6-tritylamino-
3.41 g of 1-azabicyclo[3.2.0]heptane (yield
92.6%) is obtained as crystals. Melting point: 192℃ (decomposition) (reconsolidation solvent: methanol) IR (KBr) cm ^-1 : ν _c=p 1770, 1730 NMR (CDCl ₃ ) δ value: 2.80 to 3.40 (3H, m), 3.59
(3H, s), 4.00~5.00 (7H, m), 7.00~7.80
(15H, m) The following compound is obtained in the same manner. Γ(3R,5R,6R)-3-[1-(2,4-dimethoxybenzyl)tetrazol-5-yl]-7
-oxo-4-thia-6-tritylamino-1
-Azabicyclo[3.2.0]heptane IR (KBr) cm ^-1 : ν _c=p 1780 NMR (CDCl ₃ ) δ value: 2.94 (1H, dd, J=6.5
Hz, J=13Hz), 3.70 (3H, s), 3.74 (3H,
s), 3.50-4.69 (5H, m), 5.29 (2H, s),
6.25-7.68 (18H, m) Example 6 (3R,5R,6R)-3-[1-(2-methoxycarbonylethyl)tetrazol-5-yl]-7
-oxo-4-thia-6-tritylamino-1-
2.50 g of azabicyclo[3.2.0]heptane is dissolved in 30 ml of methylene chloride, 0.71 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene is added under ice cooling, and the mixture is allowed to react overnight at room temperature. Add 20 ml of water to the reaction solution, adjust the pH to 2.0 with 3N hydrochloric acid, and separate the organic layer. The aqueous layer is extracted twice with 20 ml of methylene chloride, the organic layers are combined, washed successively with 50 ml of water and 30 ml of saturated brine, and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, (3R, 5R, 6R)-7-
Oxo-3-(5-tetrazolyl)-4-thia-6
-tritylamino-1-azabicyclo [3.2.0]
2.00 g (yield 93.0%) of heptane is obtained as crystals. Melting point: 130°C (decomposition) (reconsolidation solvent: methylene chloride) IR (KBr) cm ^-1 : ν _c=p 1770 Example 7 (3R, 5R, 6R)-7-oxo-3-(5-tetrazolyl) -4-thia-6-tritylamino-1
-Dissolve 2.15 g of azabicyclo[3.2.0]heptane in 10 ml of ethyl acetate, and dissolve p-toluenesulfonic acid.
Ethyl acetate solution of monohydrate (prepared by dissolving 850 mg of p-toluenesulfonic acid in 5 ml of ethyl acetate)
Add and react at room temperature for 15 minutes. Add 15 ml of diethyl ether to the reaction solution, stir for another 30 minutes at the same temperature, collect the precipitated crystals, and add 10 ml of diethyl ether.
Wash with Dissolve these crystals in 10 ml of water, add 10 ml of ethyl acetate, and adjust the pH to 4.1 with a saturated aqueous sodium bicarbonate solution under ice cooling. Take the precipitated crystals,
When further washed with 5 ml of water, 3 ml of methanol and 5 ml of diethyl ether, (3R, 5R, 6R)-6-amino-7-oxo-3-(5-tetrazolyl)-4-thia exhibits a melting point of 180-183°C. -1-Azabicyclo[3.2.0]heptane 420mg (yield 41.8%)
get. IR (KBr) cm ^-1 : ν _c=p 1780 NMR (D ₂ O−DMSO−NaHCO ₃ ) δ value: 3.31
(1H, dd, J=6Hz, J=13Hz), 3.87~4.02
(2H, m), 4.99 (1H, m), 5.24 (1H, d, J
=4Hz) Example 8 (3R,5R,6R)-6-amino-7-oxo-
After sequentially adding and dissolving 2 ml of N,N-dimethylformamide, 1.5 ml of methanol and 98μ of triethylamine to 100 mg of 3-(5-tetrazolyl)-4-thia-1-azabicyclo[3.2.0]heptane,
Cool to −15°C. On the other hand, 150 mg of D-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide) phenyl acetic acid was suspended in 2 ml of methylene chloride, and 54μ of N-methylmorpholine was added at -20°C.
and 47μ of ethyl chlorocarbonate, −20 to −
Stir at 15°C for 1 hour. After dropping this reaction solution into the previous solution at -15 to -10°C, the reaction solution is heated to room temperature over 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was mixed with 20 ml of ethyl acetate and 10 ml of water.
ml, adjust the pH to 2.5 with 1N hydrochloric acid, and separate the organic layer. Add 10 ml of water to this organic layer, adjust the pH to 6.5 with a saturated aqueous sodium bicarbonate solution, and separate the aqueous layer. This was freeze-dried and (3R, 5R, 6R) −
6-[D-α-(4-ethyl-2,3-dioxo-
1-Piperazinecarboxamide)phenylacetamide]-7-oxo-3-(5-tetrazolyl)-
170 mg (yield 70.0%) of the sodium salt of 4-thia-1-azabicyclo[3.2.0]heptane is obtained. IR (KBr) cm ^-1 : ν _c=p 1780, 1720, 1675 NMR (d ₆ -DMSO) δ value: 1.08 (3H, t, J=7
Hz), 2.80-4.10 (8H, m), 5.00 (1H, m),
5.32-5.70 (3H, m), 7.10-7.70 (5H, m) Compounds shown in Table 2 are obtained in the same manner.

[Table]
Example 9 (3R,5R,6R)-3-[1-(2,4-dimethoxybenzyl)tetrazol-5-yl]-7-
Dissolve 1.00 g of oxo-4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane in 5 ml of ethyl acetate, and add 1.57 g of p-trienesulfonic acid monohydrate under ice cooling. 1 more at room temperature
After stirring for an hour, 5 ml of diethyl ether are added. After thoroughly loosening the precipitated crystals, filter and wash twice with 2 ml of diethyl ether, the melting point will be 160-165℃.
(decomposition) (3R, 5R, 6R)-3-[1-(2,
4-dimethoxybenzyl)tetrazol-5-yl]-7-oxo-4-thia-6-amino-1-
840 mg (yield 95.0%) of p-tolueneproate of azabicyclo[3.2.0]heptane is obtained. IR (KBr) cm ^-1 : 1765 NMR (d ₆ -DMSO) δ value: 2.30 (3H, s), 3.34
(1H, dd, J=6Hz, J=13Hz), 3.78 (6H,
s), 3.60-4.30 (2H, m), 4.88 (1H, d, J
=4Hz), 5.33~5.60 (3H, m), 6.43~7.70
(7H, m) Example 10 (1) (3R,5R,6R)-3-[1-(2,4-dimethoxybenzyl)tetrazol-5-yl]-
700 mg of p-toluenesulfonate of 7-oxo-4-thia-6-amino-1-azabicyclo[3.2.0]heptane was added to 15 ml of methylene chloride and water.
Suspend in 10 ml of mixed solvent, adjust the pH to 7.0 with saturated aqueous sodium hydrogen carbonate solution, and separate the organic layer. The organic layer was further washed with 5 ml of saturated brine and then dried over anhydrous magnesium sulfate. (2) Meanwhile, 440 mg of D-α-(4-ethyl-2,3-dioxo-1-pepyrazinecarboxamide)phenylacetic acid was suspended in 4.5 ml of methylene chloride,
Add 0.17 ml of N-methylmorpholine and 0.14 ml of ethyl chlorocarbonate at -20°C, and stir at -20 to -15°C for 1 hour. This reaction solution was heated at -15 to -10℃.
After dropping into the solution of (1), the mixture is heated to room temperature over 30 minutes. Next, add 10ml of water and adjust the pH to 7.0 with a saturated aqueous sodium bicarbonate solution.
and separate the organic layer. water in this organic layer
Add 10ml, adjust the pH to 2.5 with 1N hydrochloric acid, and separate the organic layer. After sequentially washing with 10 ml of water and 10 ml of saturated saline, drying over anhydrous magnesium sulfate, and evaporating the solvent under reduced pressure. The obtained residue was subjected to column chromatography [Wako silica gel C-200, elution solvent: benzene: ethyl acetate =
1.2 (volume ratio)], (3R, 5R, 6R)
-6-[D-α-(4-ethyl-2,3-dioxo-1-pepyrazinecarboxamide)phenylacetamide]-3-[1-(2,4-dimethoxybenzyl)tetrazol-5-yl ]-7-oxo-4-thia-1-azabicyclo[3.2.0]
Obtain 650 mg of heptane (yield 74.8%). Melting point: 172 to 175°C (decomposition) (recrystallization solvent: methylene chloride) IR (KBr) cm ^-1 : 1785, 1720, 1685 NMR (CDCl ₃ ) δ value: 1.15 (3H, t, J = 7
Hz), 2.90-4.10 (8H, m), 3.78 (3H, s),
3.80 (3H, s), 4.85 (1H, m), 5.25~5.80
(5H, m), 6.30-7.60 (8H, m), 8.77 (1H,
d, J=9Hz), 9.95 (1H, d, J=6Hz) Example 11 (3R,5R,6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-pepyrazine carboxamide) phenyl acetamide]-3-[1-(2,4
-dimethoxybenzyl)tetrazol-5-yl]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane (500 mg) was mixed with 1 ml of a buffer solution previously adjusted to pH 3.0 with 1N hydrochloric acid and 1M sodium acetate. Dissolve in a mixed solvent of 9 ml of acetonitrile. Add 1.24 g of cerium (IV) ammonium nitrate at room temperature and adjust the pH with an aqueous sodium bicarbonate solution.
Adjust to 0.7-1.0 and react for 10 minutes. Then,
Add 30 ml of ethyl acetate and 15 ml of water sequentially, adjust the pH to 2.0 with 1N hydrochloric acid, and separate the organic layer. Further, extract the aqueous layer twice with 5 ml of ethyl acetate, combine the extract with the organic layer, add 10 ml of water, and adjust the pH to 7.5 with sodium hydrogen carbonate. Separate the aqueous layer,
Add 10 ml of ethyl acetate, adjust the pH to 2.0 with 1N hydrochloric acid, and separate the organic layer. Furthermore, the aqueous layer is extracted twice with 5 ml of ethyl acetate, the extract is combined with the organic layer, washed with 10 ml of saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and 2 ml of ethyl acetate was added to the resulting residue.
is added, crystallized, and then removed, (3R,
5R, 6R)-6-[D-α-(4-ethyl-2,3
-dioxo-1-pepyrazinecarboxamide)phenylacetamide]-7-oxo-3-(5-tetrazolyl)-4-thia-1-azabicyclo[3.2.0]heptane 97 mg (yield 25%) . If this compound is dissolved in water containing an equal amount of sodium bicarbonate and lyophilized, (3R, 5R,
6R)-6-[D-α-(4-ethyl-2,3-dioxo-1-pepyrazinecarboxamide)phenylacetamide]-7-oxo-3-(5-tetrazolyl)-4-thia- The sodium salt of 1-azabicyclo[3.2.0]heptane is obtained. The physical properties (IR value) of this compound were consistent with those obtained in Example 8. Example 12 (3R,5R,6R)-3-cyano-7-oxo-
Dissolve 1.0 g of 4-thia-6-tritylamino-1-azabicyclo[3.2.0]heptane in 20 ml of chloroform, and dissolve 0.65 g of N-methylpiperidine hydrochloride.
0.90 ml of N-methylpiperidine and 0.31 g of sodium azide are sequentially added, and the mixture is heated under reflux for 30 minutes.
Then, after cooling to room temperature, add 10 ml of water to the solution, adjust the pH to 1.0 with 1N hydrochloric acid, and separate the organic layer. Furthermore, add 10 ml of water and 5 ml of saturated saline solution to the organic layer.
ml and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, (3R,
1.0 g (yield: 91%) of heptane is obtained as crystals. The physical properties (melting point, IR) of this compound matched those of the compound obtained in Example 6.

Claims (1)

[Claims] 1 General formula [Formula] “In the formula, R ¹ is a hydrogen atom, an amino protecting group or an acyl group; R ² is a hydrogen atom; and Tz is
Tetrazolylpenam Each represents a 5-tetrazolyl group optionally protected with a nitrogen protecting group. ” Penam derivatives and their salts.