JPH01283288A - Novel penam derivative and salt thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is H, acyl, etc.; R<2> is (substituted) lower alkyl, cyano, etc.; R<3> is (protected) carboxyl or carboxylato; R<4> is H, lower alkoxy, etc.; n is 0 or 1] and its salt. EXAMPLE:6beta-Phenylacetamido-2-(trans-2-diphenylmethoxycarbonyl-vinyl )penam-3- carboxylic acid p-nitrobenzyl ester. USE:An antibacterial agent. It has broad antibacterial spectrum, stable to beta- lactamase and exhibits strong antibacterial activity even against resistant bacteria. PREPARATION:A compound of formula II [R<1a> is (phenyl)acetyl, etc.; R<3a> is (protected) carboxyl] is oxidized with an oxidizing agent such as chromium oxide, and the produced compound of formula III is made to react with a compound of formula IV [R<2a> is R<2>; R<6a>-R<6c> are (substituted) lower alkyl or aryl; X is halogen] preferably in the presence of a base such as pyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides novel penam derivatives and salts thereof; is an optionally substituted lower alkyl, aryl, or a heterocyclic group bonded to a ring carbon atom, a cyano group, an optionally protected carboxyl group, a nitro group, or the formula -COR (wherein R5 is an amine, mono-lower alkylamino, di-lower alkylamino, lower alkyl or aryl group); R3 is an optionally protected carboxyl or carboxylad group; R4 is a hydrogen atom, lower alkoxy, lower an alkylthio or formamide group; and n represents ○ or 1; ] The present invention relates to a novel penam derivative represented by and a salt thereof.

The aim of the present invention is to provide a broad spectrum of antimicrobial protection, namely:
Demonstrates excellent antibacterial activity against Durham-positive and Durham-negative bacteria, is particularly stable against β-lactamase, exhibits excellent antibacterial activity against resistant bacteria, and is useful as a medicine for humans and animals. The objective is to provide novel compounds that are

In general, another object of the present invention is to provide compounds useful as intermediates for penam derivatives.

[Prior Art] Conventionally known penam derivatives have a relatively broad antibacterial spectrum or have weak effects against resistant bacteria, and are not necessarily satisfactory.

[Problems to be solved by the invention] Under these circumstances, a penam derivative that has a broad antibacterial spectrum, is stable against β-lactamase, and exhibits strong antibacterial activity even against resistant bacteria. development was desired.

[Means for Solving the Problems] As a result of intensive research into compounds for solving the above problems, the present inventors discovered penam derivatives represented by -satsuhatsu [tech] and salts thereof, and completed the present invention. reached.

The present invention will be explained in detail below.

In this specification, unless otherwise specified, a lower alkyl group refers to a straight chain or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. Aryl group refers to, for example, phenyl, naphthyl, indanyl, etc. Halogen atom refers to, for example, fluorine atom, chlorine atom, bromine atom,
Iodine atoms, etc.; heterocyclic groups include, for example, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, 1,2.3-thiadiazol, 1°3.4
-thiadiazolyl, 1,3.4-oxadiazolyl, 1
,2.3-1~riazolyl, 1,2゜4-triazinyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl,
pyrimidinyl, pyrazinyl, pyridazinyl, 1,2.4
- triazinyl, -imidazo[1,2'-b]
[1,2,4] 1 to 4-membered, 5-membered, 6-membered or fused heterocyclic ring containing at least one Minoh atom selected from oxygen, nitrogen and sulfur atoms, such as 1 to riazinyl, pyrrolidinyl, morpholinyl, quinuclidinyl, etc. means the base;
Moreover, the heterocyclic group containing a nitrogen atom may be quaternized.

Examples of the amino protecting group in R1 include formyl, tert-butoxycarbonyl, tert-amyloxycarbonylyl, benzylidene, 2,2,2-triclo [1
Commonly known amine protecting groups such as oxycarbonyl, p-nitrobenzylidene, benzyloxycarbonyl, and lobenzyloxycarbonyl can be mentioned.

Examples of the acyl group in R1 include acyl groups commonly used in the field of penicillin and cephalosporin compounds, such as formyl, acetyl, 2,6-cymethoxyphenylcarponyl, 5-methyl- 3-phenylisoxazol-4-ylcarbonyl,
4-amine methylphenylacetyl, hydroxyacetyl, phenoxyacedel, 1-tetrazolylacetyl,
cyanmethyldioacetyl, carboxyethylthioacetyl, 2-thienyl acetyl, α-bromo-2-thienyl acedel, 5-methoxy-2-thienyl acetyl, phenylacetyl, α-aminophenyl acetyl, α-hydroxyphenylacetyl, α-Carboxyphenylacetyl, α-sulfophyl nylacetyl, 3-bromophenylacetyl, α-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide) phenylacetyl, α
-(/l-Ethyl-2,3-dioquine-1-piperazinecarboxamide')-p-hydroxyphenylacedyl, α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)-3,4 -dihydroxyphenylacetyl, α-(4-ethyl-2,3-dioxo-1-piperazinecarboxylic acid)-3,4-diacel-xyphenylacetyl, α-(4-ethyl-2,3- dioxo-1-piperazinecarboxamide)-α-(3,4-
diacetoxy-6-chlorophenyl)acetyl, α-(
4-ethyl-2,3-dioxo-1-piperazinecarboxamito)-α-(3,4-diaceryl-xy-6-fluorophenyl)acetyl, α-(4-ethyl-2,3-
Dioxo-1-piperazinecarboxamide)-(2-aminothiazol-4-yl)acetyl, α-(4-ethyl-2,3-dioxo-1-piperazinecarboxyrimido)-α-(6-chloro-3 , 4-dihydroxyphenyl)acetyl, α-(4-ethyl-2,3-dioxo-
1-piperazinecarboxamide>-α-(6-fluoro-3,4-dihydroxyphenyl)acetyl, α-(4
-cyclopropyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetyl, α-(2-oxo-1-imidazolidinecarboxamide)-α-phenylacetyl, α-13-(methylsulfonyl)-2-oxo- 1-imidazolidinecarboxamide]-α-phenylacetyl, α-14-hydroxy-1,5-naphthyridine-3-carboxamide)-α-phenylacetyl,
α-(4-phenyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetyl, α-[4-(○
, p-dichlorophenyl)-2,3-dioxo-1-piperazinecarboxamide]phenylacetyl, α-(4
-oxo-41-1-thiopyran-3-ylcarboxamide)-α-phenylacetyl, 2-thienyl-2-me]-ximinoacetyl, 2-(2-aminothiazol-4-yl)acetyl, 2 -(2-aminothiazole-
4-yl)-2-me-1-ximinoacetyl, α-difluoromethylthioacetyl, α-(CiS-2-cyanvinyl)thioacedel, α-[3”(4-phenylphenylcarbonyl)-3-methyl -1--Ureido]
-α-phenylacetyl, α-(4-chlorophenyl-
Imidazo-/C-4-yl) carboxamide phenylacetyl and the like.

Examples of substituents for the optionally substituted lower alkyl, aryl, or heterocyclic group bonded to a ring carbon atom in R2 include a halogen atom, a hydroxyl group,
Acyloxy groups such as acetyloxy and benzoyloxy; amino groups; lower alkoxy groups such as methoxy and ethoxy; aryloxy groups such as phenyloxy; sulfonyl groups; mono-lower alkylamino groups such as methylamine and ethylamino; Di-lower alkylamino group, nitro group, carboxyl group, IM m-cyclic thio group, pyridinium, imidazolium, quinolium,
Groups such as cyclic ammonio groups such as 1-methylpyrrolidinium are mentioned, and the lower alkyl, aryl or heterocyclic group in R2 is substituted with one or more substituents selected from the above substituents. may have been done. In addition, examples of the heterocyclic group of the heterocyclic thio group include the same groups as the above-mentioned heterocyclic group.

Examples of the optionally protected carboxyl group of R3 include those conventionally known in the field of penicillin and cephalosporin compounds, such as:
Ester-forming groups that are eliminated by treatment with catalytic reduction, chemical reduction, or other mild conditions, or that are easily eliminated in vivo, or that are easily eliminated by treatment with water or alcohol. Nisdel-forming groups such as an organosilyl group, an organophosphorus group, or an organotin group that release are mentioned. Among these protecting groups, suitable protecting groups include, for example, methyl,
Lower alkyl groups such as propyl and tert-butyl; Aryl group: Allyl group; Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 3,4-dimethoxybenzyl,
4-hydroxy 1 mouth - C 3,5-di(te+'t-butyl) aralkyl group such as benzyl, phenethyl, diphenylmethyl, trityl, bis(methoxyphenyl)methyl; phthalidyl group; 2-iodoethyl, 2.2 .Halo-lower alkyl groups such as 2-trichloroethyl; acetoxymethyl, p[1-pionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, 1-acetoxyethyl , 1-pivaloyloxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxy-n-propyl, and other acyloxy-lower alkyl groups; (5-methyl-2-oxo-1°3-dioxo-4- (5-lower alkyl-2-oxo-1,3-dioxo-4-yl) lower alkyl groups such as methyl (5-lower alkyl-2-oxo-1,3-dioxo-4-yl): alkoxy-lower alkyl groups such as methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, etc.: methoxy carbonyloxymethyl,
The lower alkoxy group of alkoxycarbonyloxy-R4, such as 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, etc., is the same lower alkoxy group as explained for the substituent of R2. Examples of the lower alkylthio group include lower alkylthio groups such as a methylthio group and an ethylthio group.

When each of these R1 to R4 groups and their substituents have a group such as an amine group, a mono-lower alkylamino group, a hydroxyl group, or a carboxyl group, these groups may be protected by commonly known protective groups. may be protected. Protecting groups for amine groups and mono-lower alkylamino groups include, for example, the same amino protecting groups as those mentioned above (for R1), and examples of protecting groups for hydroxyl groups include small lumyl, acetyl, benzyl, tetrahydropyrani, etc. , benzyloxycarbonyl, trimethylsilyl, p
-nitrobenzyloxycar small nyl group and the like. In addition, as protecting groups for carboxyl groups, for example,
The same carboxy protecting groups as mentioned for R3 can be mentioned.

Examples of the salt of the compound of the general formula [E] include commonly known salts with a basic group such as an amine group or an acidic group such as a hydroxyl group or a carboxyl group. Salts of basic groups include, for example, salts with mineral acids such as hydrochloric acid and sulfuric acid; salts with carboxylic acids such as chloroacetic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid; methanesulfonic acid, benzenesulfonic acid, p - Salts with sulfonic acids such as toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid, and salts with acidic groups such as salts with alkali metals such as sodium and potassium; salts with alkali metals such as calcium and magnesium; Salts with earth metals; ammonium salts; trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,
N-methylmorpholine, diethylamine, dicyclohexylamine, propylene, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N,
Examples include salts with nitrogen-containing organic bases such as N-dibenzylethylenediamine.

Furthermore, when isomers (e.g., optical isomers, geometric isomers, tautomers, etc.) exist in the compound of -Fukudai [I] and its salt, the present invention includes all such isomers. However, it also includes all crystalline forms and hydrates.

Next, a method for producing the compound of the present invention will be explained.

The compound of general formula [I] and its salt can be produced, for example, according to the following production route.

Production route [In the formula, Rla is a phenylacetyl group, phenoxyacetyl group, acetyl group, or an amine protecting group similar to R1; R28 is an optionally substituted aryl similar to R2 or a hetero bonded to a carbon atom of the ring A cyclic group, a cyano group, an optionally protected carboxyl group, a nitro group, or a group represented by the formula -COR (wherein, R5 has the same meaning as above); R3a is the same protected group as R3. 6a 6b R, R and R6° are the same or slightly substituted and optionally substituted lower alkyl or aryl group; X is a halogen atom: R1, R3, R4 and n has the same meaning as above. ] General formula Ia], [from], [Ic
], [■] or [1] include the same salts as mentioned for the salts of the compounds of -Fukudai [technique].

(1) - Method for producing the compound of Clothing Costume [III]- Clothing Costume [II]
The compound or salt thereof can be produced by subjecting it to an oxidation reaction in the presence or absence of a solvent.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction, for example, water; tetrahydrofuran, dioxane,
, 2-dimethoxyethane, diethyl ether, and other ethers; benzene, toluene, and other aromatic hydrocarbons;
Amides such as N,N-dimethylformamide; halogenated hydrocarbons such as methylene chloride and 10 vol;
Examples include ketones such as acetone and methyl edyl ketone; dimethyl sulfoxide; and sulfolane; two or more of these solvents may be used in combination.

The oxidizing agents used in this reaction include dimethylsulfoxide-N,N-dicyclohexylcarbodiimide,
Examples include dimethyl sulfoxide-acetic anhydride, chromium oxide, and mankane dioxide.

The amount of the oxidizing agent to be used is usually at least equimolar to the compound or salt thereof of -Fukudai [II].

This reaction may be carried out generally at -50 to 180°C, preferably 0 to 30°C, for 5 minutes to 30 hours.

(2) - Process for producing the compound of Fukudai [Ia] - The compound of Fukudai [In] or its salt, - Fukudai [IV]
] or [V] in the presence of a solvent, the compound or salt thereof can be produced.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, water: ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diethyl ether; benzene. , aromatic hydrocarbons such as toluene; amides such as N,N-dimethylformamide; alcohols such as methanol and ethanol; halogenated hydrocarbons such as methylene chloride and chloroborum; and sulfolane. , these solvents are 2
You may use a mixture of more than one type.

In this reaction, when using the compound of -Fukudai [IV], it is preferable to react in the presence of a base, and examples of the base used include pyridine, dimethylaminopyridine,
Triethylamine, dimethylaniline, diethylaniline, 1,8-diazabicyclo[5,4,0]undec-
Organic bases such as alkali acetates such as 7-ene (DBU) and sodium acetate; inorganic bases such as alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate, and alkali hydroxides such as sodium hydroxide. ; n-butyllithium, potassium tert
- Organometallic bases such as butoxide and lithium methoxide; metal hydrides such as sodium hydride and lithium hydride; and the like.

- The amount of the compound of formula [1v] or ir] is -4
1 The amount is usually equal to or more than the same mole relative to the compound of formula [1] or a salt thereof.

In addition, the amount of the base used if desired is determined by the formula [
The amount is equal to or more than the equivalent molar amount to the compound of [I] or its salt.

This reaction is usually carried out at -20 to 180°C, preferably at
It may be carried out for 5 minutes at 0 to 30°C for 30 hours.

(3) - Process for producing a compound of the formula [from] - By removing the acyl group or amine protecting group of the compound of the formula [Ia] or a salt thereof, - - Formula [Ib]
It is possible to produce a compound or a salt thereof.

Specifically, - the compound of formula [Ia] or a salt thereof is reacted with a halogenating agent such as one pentachloride to form an iminohalide, then reacted with alcohol to form an iminoether, and further hydrolyzed. can be derived from the formula [from] or a salt thereof.

Furthermore, specifically, Journal of the Chemical Society (J, Chem, Soc,) Volume 83, Page 320 (1903), Canadian Patent No. 770125, British Patent No. 1041985, Japanese Patent Publication No. 49-4047
The compound of formula [Ib] or a salt thereof can be produced by the method described in No. 9 and Japanese Patent Publication No. 45-40899@, or a method analogous thereto.

(4) - Process for producing a compound of formula [C] - A reaction of a compound of formula [VI], a salt thereof or a reactive derivative thereof in the presence of a solvent; By reacting the chemical derivatives, a compound of the formula [C] or a salt thereof can be produced.

- Reactive derivatives of the compound of formula [VI] include acid halides, acid anhydrides, and mixed acid anhydrides described in JP-A-56-127375, JP-A-59-93085 @ and JP-A-62-135477, etc. Active acid amides, active esters, active dioloesters, acid azides and general formula [VI
] and reactive derivatives of the Vilsmeier reagent.

In addition, examples of the reactive derivatives of the compound of the formula [I, Organic silyl groups such as methoxysilanyl, dimethoxysilanediyl, or dimethoxyphosphinyl,
1.3.2-dioxophos i1 cran-2-yl,4-
Methyl-1,3゜2-dioxophosphoran-2-yl,
Examples include compounds in which an organic phosphorus group such as 1,3.2-sioxophosphan-2-yl is bonded to an amine group serving as a reaction site.

The solvent used in this reaction is not particularly limited as long as it is inert to the reaction. For example, water; ethers such as tetrahydrofuran, diethyl ether, and dioxane; halogenated solvents such as methylene chloride, chloroform, etc. Hydrocarbons; Nitriles such as acetonitrile; Alcohols such as methanol, ethanol, isopropanol; N,N-dimethylformamide, N
.

Amides such as N-dimethylacetamide; benzene,
Examples include aromatic hydrocarbons such as toluene; esters such as methyl acetate and ethyl acetate; ketones such as acetone; dimethyl sulfoxide; and pyridine; two or more of these solvents may be used in combination. .

Moreover, this reaction can be performed in the presence of a base. Examples of the base that may be used as desired include the same bases listed in (2).

- When the compound of formula [VI] is used in the form of a free acid or a salt with a nitrogen-containing siliceous salt, a suitable condensing agent is used. Condensing agents used include, for example, N,N-disubstituted carbodiimides such as N,N-dicyclohexylcarpodiimide.

The amount of the compound of the general formula [VI], its salt, or its reactive derivative to be used is preferably 0.9 times or more, preferably 0.9 times or more, respectively, per the compound, its salt, or their reactive derivative of the formula [I]. is 0.9 to 1.5 times the mole.

This reaction is usually carried out at -50 to 80°C for 5 minutes to 30 minutes.
All you have to do is time it.

General formula % formula % used in each step explained above] [1 [1] When the compound or its salt exists as an isomer, each can be isolated and purified by a usual method.

In addition, in the groups of R, R and R3a, active 1a for the reaction is added.
When a 2a group is present, it may be protected with a conventional protective group during the reaction, or the protective group can be removed by a conventional method after the reaction.

Further, the compound of the general formula [I] or a salt thereof, in which R- is an optionally substituted lower alkyl group, is a compound of the formula [Eng.
], [Ibl or [C] compounds or their salts, for example, hydrolysis, substitution, acylation, oxidation, reduction, halogenation, algylation, amination, thiolation,
It can be induced by commonly known methods such as quaternization and by appropriately combining these methods. More specifically, for example, a compound of the general formula [I] in which R2 is an optionally substituted methyl group is a compound of the formula [I
a], the protecting group of the compound in which R2a is a protected carboxyl group is removed, and then reduced to form R2
is a hydroxymethyl group, and this is halogenated to derive a compound of the general formula % [I] where R2 is a halogenomethyl group. When subjected to a substitution reaction, other compounds of the present invention in which R2 is an optionally substituted methyl group can be derived.

Further, the compound of the general formula [I] or a salt thereof, in which R4 is a lower alkoxy group, can be converted into the compound of the general formula [I], or a salt thereof, in which R4 is a hydrogen atom, according to a conventional method. General formula where R4 is a lower alkylthio group [
The compound of the formula [Ibl] or the salt thereof can be prepared by protecting the amino group of the compound of the formula [Ibl or its salt with, for example, the above-mentioned amine protecting group, and then introducing a lower alkylthio group, or further deprotecting if desired. Alternatively, after deprotection, it can be obtained by subjecting it to the above-mentioned acylation reaction (4). A compound of the general formula [I] in which R4 is a formamide group or a salt thereof can be obtained by formamidating a compound of the general formula [I] or a salt thereof in which R4 is a lower alkylthio group. Specific methods for introducing a lower alkylthio group and formamidation include, for example, the method described in JP-A-58-38288 or a method analogous thereto.

Furthermore, for example, esterification, hydrolysis, addition, acylation, oxidation, reduction, cyclization, halogenation, alkylation, amination, thiolation, quaternization, aryloxylation, sulfonylation, alkylamination or Witzteich The compound of the present invention can also be derived into other compounds of the present invention by commonly known methods such as reaction, and by appropriately combining these methods.

Next, the compound of general formula [IV] or [V], which is a raw material for producing the compound of the present invention, is obtained from, for example, Organic Reactions (organrcReaCti).
OnS) Volume 14, pp. 270-490 (1965)
It can be produced by suitably combining methods described in et al. or methods known per se. Examples of production routes include the routes shown below.

(Hereinafter, blank spaces) [In the formula, R2'', R6a, R6b, R''01 and X have the same meanings as described above. ] Furthermore, the compound of general formula [II] or its salt, which is a raw material for producing the compound of the present invention, may be used, for example, as described in the Journal of the American Chemical Society (J
, Am, Chem, Soc,) Volume 71, Page 122 (
(1949) or by appropriately combining methods known per se.

Tablets, capsules, powders, syrups, granules, suppositories, ointments,
Prepare into injections, etc. In addition, the administration method, administration M, and number of administrations can be appropriately selected depending on the patient's symptoms, and usually for adults, oral or parenteral (for example,
The drug may be administered by injection, infusion, rectal administration, etc., in 0.1 to 100 m37 divided into 9 doses per day to several doses.

[Effects of the Invention] Next, the antibacterial effects of representative compounds of the present invention will be shown.

1. Antibacterial activity test method: Japanese Society of Chemotherapy standard method and chemotherapy (chemotherapy)
therapy) Volume 29, No. 1, pp. 76-79 (
1981)], peptone broth (Pep
tone broth) (manufactured by Eiken Chemical Co., Ltd.) at 37°
One platinum loopful of the bacterial suspension prepared by culturing with Cl2O for 10 hours was inoculated into Heart Infusion Agar medium (manufactured by Eiken Kagaku Co., Ltd.) containing a drug, and incubated at 37°C. After culturing for 20 hours, the presence or absence of bacterial growth was observed, and the minimum concentration at which bacterial growth was inhibited was defined as the MIC (trd!).

The results are shown in Table-1. Moreover, the symbol nido in Table 1 means a β-lactamase producing strain.

Note that 2t used in the test compound means an ethyl group, and R2 means a substituent of the compound represented by the following formula.

(The following is a blank space) Test compounds are shown in Table 1. Antibacterial activity (MIC: 埒/d) [Example] Next, the present invention will be explained with reference to reference examples and examples. Note that the symbols used in Reference Examples and Examples have the following meanings.

Me: methyl, [t: ethyl, AC niacetyl, PN
B:I)-nitrobenzyl, DPM:diphenylmethyl The mixing ratios of mixed solvents are all volume ratios, and the carrier in column chromatography is silica gel [Kieselgel 60] manufactured by Merck & Co., unless otherwise specified.
, art, 7734 (Kiese1ge160, drunkenness
, 7.734)] was used.

Reference Example 1 (3R14R)-4-(diphenylmethoxycarbonylmethylthio)-3-phenylacetamido-2-azetidinone 50.09, glyoxyl Mp-nitrobenzyl ester monohydrate 24.7 g and methylene chloride 40
1,8-diazabicyclo[5
,4,0] After adding 0.79 d of undec-7-nin,
Stir at room temperature for 2 hours.

The reaction solution was poured into 200 d of water, and the pH was adjusted to 3.0 with 2N hydrochloric acid.
After adjusting the amount, separate the organic layer. After drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure to obtain (3R1
4R)-4-(diphenylmethoxycarbonylmethylthio)-1-[hydroxy-(p-nitrobenzyloxycarbonyl)methyl]-3-phenylacetamide-2
-Azetidinone 74, Og (yield 97.6%) is obtained.

IR (KBr) cm″1 1770.1750O Reference Example 2 (3R14R)-4-(diphenylmethoxycarbonylmethylthio)-1-[hydroxy-(p-nitrobenzyloxycarbonyl)methyl]-3-phenylacetamide-2- To a solution of 25.09 mQ of azetidinone and 200 mQ of tetrahydrofuran was added 6.527 mQ of 2,6-lutidine under water cooling, and then 3.7 mQ of thionyl chloride was added.
5 drops over a period of 5 minutes. After stirring at the same temperature for 30 minutes, the precipitated crystals were removed and the solvent was distilled off under reduced pressure.

30 ml of toluene is added to the obtained residue, and the solvent is distilled off again under reduced pressure.

The resulting residue was dissolved in 200 d of methylene chloride,
Under water cooling, 7.169 g of m-chloroperbenzoic acid was added in portions over 10 minutes, and after stirring at the same temperature for 30 minutes, the reaction solution was poured into 200 d of ice water and adjusted to pH 7 with a saturated aqueous sodium hydrogen carbonate solution. Adjust to. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, amorphous (3
R14R) -"l-[chloro-(p-nitrobenzyloxycarbonyl)methyl]=4-(diphenylmethoxycarbonylmethylsulfenyl)-3-phenylacetamido-2-azetidinone is obtained. This is dissolved in 500 parts of anhydrous tetrahydrofuran. After adding 10.15 m of N,O-bistrimethylsilylacetamide under water cooling, the mixture was stirred at room temperature for 15 minutes.
Cool to 8°C and add 50% hexamethylphosphoryltriamide.
After adding d, a solution of the lithium salt of hexamethyldisilazane [prepared from 9,46d of hexamethyldisilazane, 50 ml of tetrahydrofuran and 29.9 ml of a 15%-lobetyllithium hexane solution] was prepared at the same temperature for 15 minutes. The mixture was added dropwise and stirred for an additional 15 minutes at the same temperature. The reaction solution was mixed with 400 ml of water, 200 ml of ethyl acetate, and 6 ml of ethyl acetate.
Pour into a mixture of 7.5 ml of N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, 100% of toluene is added to the resulting residue, and the precipitate is removed, showing a melting point of 184-185°C (decomposition) (S)
-6β-phenylacetamido-2-diphenylmethoxycarbonylpenam-3-carboxylic acid-1-oxide p
-nitrobenzyl ester 4.59 (yield 18.1%)
).

”'JA-IR(KBr) cm-1; v 1780.175
0.1730.1650CO Roughly, the furnace solution was subjected to column chromatography [elution solvent;
If purified with toluene:ethyl acetate=3:1], the melting point is 2.
(R)-6β showing 00.5-200.6°C (decomposition)
-Phenylacetamido-2-diphenylmethoxycarbonylpenam-3-carboxylic acid-1-oxide p-nitrobenzyl ester 4,5J (yield 18.1%) is obtained.

IR (KBr) cm”; v 1800.17
40.1655O Reference Example 3 6β-phenylacetamido-2-diphenylmethoxycarbonylpenam-3-carboxylic acid-1-oxide p-
Nitrobenzyl ester 5,03, methylene chloride 25mf and N,N-dimethylformamide 25mf! To the mixed solution was added 3.52+1 phosphorus tribromide at -30'C, and the mixture was stirred at the same temperature for 30 minutes. Pour the reaction solution into 150 m of water! !
and 100 parts of ethyl acetate while adjusting the pH to 117 with a saturated aqueous sodium carbonate solution. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, diethyl ether 5 (7) and ethyl acetate were added to the resulting residue, and the precipitate was collected. −
Phenylacetamido-2-diphenylmethoxycarbonylpenam-3-carboxylic acid p-nitrobenzylnisder 4.29 (yield 86.1%) is obtained.

IR (KBr) cm-1: u 1775.173
5.1685O Reference Example 4 4.0 g of 6β-phenylacetamido-2-diphenylmethoxycarbonylpenam-3-carboxylic acid p-nitrobenzylnisder, mixed solution of fx methylene 2(7) and anisole 207!, - A solution of 2.5913 aluminum chloride and 10 mf! of anisole was added at 30°C.
It takes a few minutes to drip. After stirring at the same temperature for 20 minutes,
Pour the reaction solution into 150ml of water! and 100 parts of ethyl acetate. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography [elution solvent: chloroform:methanol-100:1 to 10:1]. Water 50m
1! and ethyl acetate 5 (dissolved in a mixture of 7, 2N
After adjusting the pH to 2.0 with sulfuric acid, the organic layer is separated. After sequentially washing with water and saturated saline, drying with anhydrous sodium sulfate.

By distilling off the solvent under reduced pressure, amorphous 6β-phenylacetamido-2-carboxypenam-3-carvone Ip
-21 helobenzyl ester 2.4 g (yield 80.0
%).

Reference Example 5 Oxalyl chloride 1.29 was added to a solution of 0.577 N,N-dimethylformamide and 10 d of methylene chloride under water cooling.
After stirring at room temperature for 15 minutes, the solvent was distilled off under reduced pressure. This was added to a solution of 1.8 g of 6β-phenylacetamido-2-carboxypenam-3-carbonyl-nitrobenzyl ester and 20 parts of tetrahydrofuran at -30°C, and the mixture was heated in a colander at -20 to -15°C for 1 hour.
Stir for an hour. Then, the reaction solution was cooled to -78°C,
A solution of 0.289% sodium borohydride and 5% N,N-dimethylformamide was added dropwise over 2 minutes,
Stir for an additional 15 minutes at -70°C. Add 30% of the reaction solution to water
The mixture was poured into a mixed solution of 307 g of ethyl acetate and ethyl acetate, and the pH was adjusted to 6.5 with a saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2.29 g of amorphous 6β-phenylaredamide-2-hydroxymethylpenam-3-carvone lp-nitrobenzyl ester (yield 70%) is obtained.

IR(KBr) cm-'; v 178
0.1750.1740.1670O Example 1 6β-phenylacetamido-2-hydroxymethylpenam-3-carvone % p-nitrobenzyl ester4.
19, benzene 157 and dimethyl sulfoxide 15
To a mixed solution of tn(!, 4.589 g of N,N-1 dicyclohexylcarbodiimide and 10 g of dichloroacetic acid was added under water cooling.
．． Add 37 parts in sequence. After stirring at the same temperature for 30 minutes, the reaction solution was poured into a mixture of 50 ml of water and 50 d of ethyl acetate, and saturated sodium hydrogen carbonate aqueous solution was added to
Adjust to 7. After removing the insoluble matter, separate the organic layer,
Wash with water and saturated saline, and dry over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 6β-phenylacetamido-2-formylpenam-3-carbonyl-lovenzyl ester (compound A) is obtained.

On the other hand, diphenylmethoxycarbonylmethyltriphenylphosphonium bromide 7.69 and N.

To a solution of N-dimethylformamide 3 (7) was added 1.27 g of potassium tert-butoxide under water cooling and stirred at room temperature for 1 hour. Again under water cooling, a solution of compound A and tetrahydrofuran 206 was added over 5 minutes. After dripping,
Stir at the same temperature for 30 minutes and then at room temperature for 1 hour. The reaction solution was poured into a mixture of 100 ml of water and 507 ml of ethyl acetate, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [elution solvent: toluene:ethyl acetate-10:1] to obtain 6β-phenylacetamide-2 with a melting point of 115-118°C. -(trans-2-diphenylmethoxycarbonylvinyl)penam-3-carboxylic acid p-
Nitrobenzyl ester 3.25y (yield 55.2%
).

IR (KBr) cm-': Q 1780.1
740.1705.1645O NMR (CDCl2>δ value: 3.52 (2H, S), 4.74 (IH, m).

5, 23 (2H, s), 5.32 (IH, d, J=5
H2).

5, 63 (IH, dd, J=5Hz, J=8Hz)
, 6.06 (IH, m).

6, 18 [IH, d, J=8Hz), 6.40 (I
H, m16, 68 (IH, d, J=8Hz), 6
．． 90 (IH, s), 7.15 (5H, s).

7.28 (10H, S), 7.40 (2H, d, J Kamo H
2).

8, 12 (2H, d, J=9H2) In the same manner, the compounds shown in Table 2 were obtained.

(Margin below) Table 2 ■ Example 2 6β-phenylacetamide-2-(trans-2-
Diphenylmethoxycarbonyl vinyl) penam-3-carboxylic acid nitrobenzyl ester 3.258, methylene chloride 30m and anisole 30d mixed solution, -
At 40° C., a solution of 1.929 ml of aluminum chloride and 20 ml of anisole is added dropwise over a period of 5 minutes. -30~-
After stirring for 30 minutes at 20'C, it is poured into a mixture of 50 ml of water and 70 ml of ethyl acetate. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is purified by column chromatography [elution solvent: chloroform:methanol=100:1 to 10:1]. This was dissolved in 30 d of ethyl acetate and 30 d of water, and the pH was adjusted to 2.0 with 2N sulfuric acid. The organic layer is separated, washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. If the solvent is distilled off under reduced pressure, 6
β-Phenylacetamido-2-(trans-2-carboxyvinyl)penam-3-carboxylic acid p-nitrobenzyl ester 1.899. (yield 77.1%).

IR (KBr) cm-1; v 1780.174
0,1710.1645O Example 3 0.8 oxalyl chloride was added to a solution of 0.37 d of N,N-dimethylformamide and 20 d of methylene chloride under water cooling.
After adding 4d, stir at room temperature for 15 minutes. Then, the solvent is distilled off under reduced pressure to dryness. The obtained crystal is 6β
-Phenylacetamide-2-(tranS-2-Carboxyvinylrubonic acid p-nitrobenzyl ester 1.899% and tetrahydrofuran 307% solution is added at -30°C, and then stirred at -20 to -10°C for 1 hour. Then -7
After cooling to 0°C, a solution of 420 mg of sodium borohydride and 15 parts of N,N-dimethylformamide was added dropwise over 5 minutes, followed by stirring at the same temperature for 15 minutes. The reaction solution was poured into a mixed solution of 50 d of water and 30 ml of ethyl acetate. The organic layer is separated, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography using elution solvent: toluene:ethyl acetate=5:1] to obtain 6β-phenylacetamide-2-(tra
ns-3-hydroxy-1-propenyl)penam-3-
Carvone lp-nitrobenzyl ester 1.079 (
A yield of 58.2%) is obtained.

IR (KBr) cm-1; v 1780,174
5.1670O NMR (CDCl2>δ value: 3, 80 (2H, s), 3.98 (1H, d,
J=11Hz).

4,02(1N,d,J=11Hz14,50~4.
71 (2H, m).

5, 23-5. 33 (3H, m), 5. 5
5 ~5. 73 (2N, m).

6, 26(it(, d, J=81-1z), 7.13(
1) 1, ml'7.27 (5) 1, s).

7, 42 (21-1, d, J=91-IZ), 8.
16(21-1,d, J=9)12)=45 Example 4 6β-phenylacetamide-2-(trans-3
-Hydroxy-1-propenyl) penam-3-powerbonne Mp nitrobenzyl ester 50m! Dissolve j in methylene chloride 2d, add pyridine 0.1m and acetic anhydride 0.
．． After adding 1 m in sequence, leave it at room temperature overnight. The reaction solution was poured into 5 ml of water, and the pH was adjusted to 2 with 2N hydrochloric acid.

The organic layer was separated, washed with saturated brine, and dried over anhydrous sulfuric acid magne. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [elution solvent; toluene: ethyl acetate]. -10: If purified with a moon, 38 mg (yield 70.4%) of 6β-phenylaceto7mitoh2-(trans-3-acetoxy-1-propenyl)penam-3-carphonic acid p-nitrobenzyl ester will be obtained. .

IR (KBr) cm-1 Niji 1785.1740.
1675CO Example 5 6β-phenylacetamide-2-(trans-3-
Hydroxy-1-propenyl)penam-3-penylboni
100 mg of p-nitrobenzyl ester in N.

Dissolved in 2 m of N-dimethylformamide, cooled with water, 8 omg of triphenylphosphine and 100 g of carbon tetrabromide.
After sequentially adding my, the mixture was stirred at the same temperature for 30 minutes. After adding ethyl acetate 1 (7) to the reaction solution, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [elution solvent; toluene:ethyl acetate - 20:11] to obtain 6β- Phenylacetamide-2-(trans-
3-bromo-1-propenyl)penam-3-carboxylic acid p-nitrobenzyl ester 80mp (yield 70.8
%).

-47= IR (KBr) cm-1 Niji 1'780.1745
．． 1665O Example 6 6β-phenylacetamide-2-(trans-3-
Bromo-1-propenyl) penam-3-carvone lp-
70 m3 of nitrobenzyl ester was dissolved in 2 tnl of N,N-dimethylformamide, and under water cooling, 30 m3 of sodium salt of 5-mercapto-1,2;3-thiadiazole was dissolved.
Add mFl and stir at the same temperature for 1 hour.

The reaction solution was poured into a mixture of 10 parts of ice water and 10 parts of ethyl acetate. The organic layer is separated, washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [elution solvent: toluene:ethyl acetate-20:1] to convert 6β-phenyla 4B-set to 7 mido 2- [trans -3-(1, 2, 3
-thiadiazol-5-yl)thio-1-propenyl]
Penamu 3-carvone lp-nitrobenzyl ester 5
5m5 (yield 73.3%) is obtained.

IR (KBr) cm-1: v 1780.174
5.1670O 6β-phenylacetamide-2-(trans-3-
Bromo-1-propenyl)penam-3-carciboxylic acid p
- A mixed solution of 80 mg of nitrobenzyl ester, 22 m3 of sodium iodide and 2 parts of pyridine is stirred at room temperature for 3 hours. Then, the solvent was distilled off under reduced pressure, 10 parts of diethyl ether was added to the resulting residue, and the precipitate was removed to give 6β-phenylacetamide-2-(trans
-3-pyridium-1-propenyl)penam-3-carboxylic acid p-nitrobenzyl ester iodide 901
11jj (yield 91.8%) is obtained.

IR (KBr) cm-': 17B0,1740
．． 1660O The following compound was obtained in the same manner.

IR (KBr) cm”: 1780.1745.
1650O t 6β-phenylace1-amide-2-[trans-2
-(1,2,3-thiadiazol-5-yl)vinyl]
Penamu 3-carboxylic acid nitrobenzyl ester 15
To a mixed solution of 0.1 ld of N,N-dimethyl 7 . Then, the mixture was cooled to -40°C, 0.33 parts of methanol was added, and the mixture was stirred at -20 to -15°C for 2 hours. The reaction solution was poured into 30% water, stirred for 2 minutes, and then adjusted to pH 7 with saturated aqueous sodium bicarbonate solution. The generated 6-amino-2-[trans-2-('1,2.
3-thiadiazol-5-yl)vinyl] penamoo 3-
The organic layer containing carboxylic acid nitrobenzyl ester is separated, washed with saturated saline, and then dried over anhydrous magnesium sulfate.

The solution was cooled to -20°C and D-α-(4-ethyl-2,3-dioquine-1-piperazine-lupoxamide)
After adding 150 my of phenylacetyl chloride, -1
Stir at 0°C for 1 hour. Pour the reaction solution into 5 d of water,
Adjust the pH to 7 with saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed with saturated brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [elution solvent: chloroform:acetone-5:1] to obtain D-6β-[α
-(4-ethyl-2,3-dioniso-1-piperazinecarboxamide)phenylacetamide]-2-[tr
130 mg (yield: 65%) of ans-2-(1,2,3-thiadiazol-5-yl)vinyl]penamo 3-carboxylic p-nitrobenzyl ester is obtained.

IR (KBr) cm-'; ν 1'785.174
5.1715.1680O NMR (CDCl2>δ value: 1.20 (3H, t, J=7H2L3.43-4.45
(6H, m).

4.91 (2H, m), 5.40 (2H, S), 5.5
0~6.20 (41Lm) 6,78 (IH, d, J=
11Hz), 6.86 (IH, d, J=9Hz).

7, 35-7.70 (7H, m), 8.40 (2H,
d, J=10Hz).

8, 79 (1H, sl 10.04 (IN, d, J
=7Hz) In the same manner, the compounds shown in Table 3 were obtained.

(Margins below) Table 3 53-Example 9 Neck 6β-phenylacetamide-2-(trans-3-
Hydroxy-1-propenyl)penam-3-penylboni
To a mixed solution of 300 ml of p-nitrobenzyl ester and 5 d of methylene chloride, under water cooling, 0.084 ml of 1 to 3-dimethylsilicate and 0.08 ml of triethylamine were added.
Add 4 m in sequence and stir for 30 minutes at 10-15°C.

After cooling to -30°C and adding 0.23% of dimethylaniline, 160#lj/ of phosphorus pentachloride was added, and the mixture was heated to -30 to -
Stir at 20°C for 1.5 hours. Then, it was cooled to -40'C, and 0.73 methanol was added to -30 to -20'C.
Stir at C for 2 hours. The reaction solution was poured into 3 ml of water, and then adjusted to pl-17 with a saturated aqueous sodium bicarbonate solution.

Produced 6-amino-2-(trans-3-hydroxy-1-propenyl)penam-3-carboxylic acid A
- Separate the organic layer containing the nitrobenzyl ester, wash with saturated saline, and dry over anhydrous magnesium sulfate.

The solution was cooled to -20'C, 250m=j of D-α-(4-ethyl-2,3-diogyso-1-piperazinecarboxynamido)phenylacetyl chloride was added, and -1
Stir at 0°C for 1 hour. The reaction solution was poured into 5 d of water and adjusted to p[17] with a saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed with saturated brine, and then dried over anhydrous magnesium sulfate. D-6β-
[α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamide)phenylacetamide] -2-(
trans-3-hydroxy-1-propenyl)penam-3-carboxylic acid p-nitrobenzyl ester 2501
n3 (61% yield) is obtained.

Portion D-6β-[α-(4-ethyl-2,3-dioxo-1
-piperazine carboxamide) phenylacetamide]
-2-[trans-2-(1,2,3-thiadiazol-5-yl)vinyl]penamu 3-carvone Ip-
5% palladium on carbon 10 in a mixed solution of 120 mg of nitrobenzyl ester, 3 Inl of water and 3 Inl of ethyl acetate.
Add 0my and hydrogenate for 1.5 hours. After adding 13 m5 of sodium hydrogen carbonate and stirring for 10 minutes, the catalyst was removed and the aqueous layer was separated. After concentrating this aqueous solution to about half-solid, column chromatography [LC-3ORB 4
0-60. D-6β-[α-(4-ethyl-2,3-dioxo-1) with a melting point of 180-183°C]
-piperazinecarboxamide)phenylacetamitoco-2-[trans-2-(1,2,3-thiadiazol-5-yl)vinyl]penamu 3-carboxylic acid sodium salt 50my (yield 50%) is obtained.

IR (KBr) cm-1; 1765, 1710, 16
70,1600NHR (d6-D, MSO) δ value: 1, 10 (3H, t, J=7H7), 3.20 ~
4.03 (6H, m).

4.24 (IH, d, J=2.5H2).

5, 10 (IH, dd, J=2.5Hz, J=11
Hz).

5.20 (IH, d, J=4H2).

5.43 (IH, dd, J=4Hz, J=8Hz).

5.73 (IH, d, J=8Hz), 6.07 (
IH, m).

6, 70 (IH, d, J=11Hz), 7.25
(5H, m).

9.02 (11-1, d, J = 8 Hz), 9.24 (I
H,s).

9.75 (廿, d, J=8Hz) In the same manner, the compounds shown in Tables 4 and 5 were obtained.

(Left below) Table 4 -59 Example 11 e 6β-phenylacetamide-2-[trans-2-
6β-phenylacetamide-2-(pyridin-3-yl)vinyl]penamum 3-carboxylic acid sodium was dissolved in water, an equimolar amount of hydrochloric acid was added, and the mixture was dried under reduced pressure.
[trans-2-(pyridin-3-yl)vinyl]
25 m3 of Penamoo 3-carboxylic acid and 1 m of N,N-dimethylformamide! ! Methyl iodide 0 in a solution of
．． Add 02mff and stir at room temperature for 4 hours. Then,
The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [LC-3ORB 40-60. 6β-phenylacetamido-2-[trans-2-(1-methyl-3
-pyridinio)vinyl]penamum 3-carboxylic acid inner salt (10 mg (yield 38.5%)).

IR (KBr) cm-1 Niji 1760.1640.
1600O The following compound was obtained in the same manner.

Melting point: 210-215°C

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, an amino protecting group, or an acyl group; R^2 is an optionally substituted lower alkyl, aryl, or ring A heterocyclic group, a cyano group, an optionally protected carboxyl group, a nitro group, or a group of the formula -COR^5 (wherein R^5 is amino, mono-lower alkylamino, di-lower alkylamino , lower alkyl or aryl group); R^3 is an optionally protected carboxyl or carboxylate group; R^4 is a hydrogen atom, lower alkoxy, lower alkylthio or formamide group; and n represents 0 or 1. ] Penam derivatives and salts thereof.