WO1982000291A1 - Carba-2-penem compounds and process for preparing same - Google Patents

Abstract

Carba-2-penem compounds represented by the following general formula (I): (FORMULA) [wherein R<s1>s represents an alkyl group, an aryl group, an alkylthio group, an arylthio group, or an acylaminoalkylthio group, R<s2>s and R<s3>s each represents an alkoxycarbonyl group, a cyano group, or a group represented by -COR<s1>s (wherein R<s1>s is the same as defined above), or R<s3>s represents an alkyl group or an aryl group, and R<s4>s represents a hydrogen atom, an alkyl group, or an aryl group], the salts thereof, and a process for preparing them according to the following scheme: (FORMULA) [wherein -COOR represents a protected carboxy, and Z represents a phosphonio group or a phosphono group]. These compounds have excellent antibacteria action and //c-74lactamase-inhibiting action, and are utilized as medicines for humans and domestic animals.

Description

 Harm

 Cover 2 — penem compound and its production method

 Technical field

 TECHNICAL FIELD The present invention relates to a novel carbyl 2-penem compound, a salt or ester thereof, which has excellent antibacterial activity and lactamase inhibitory activity, and a method for producing the same.

 Background technology

 Conventionally, expression

In represented by having a basic skeleton "Power Luba - 2 ^ Nemu J The compound, Contact ¾ have the substituents' was also 1-position are many known (For instance JP ⁵ 3 -? 8 7 390), and very recently, a compound having one substituent at the 1-position has been reported (Japanese Patent Application Laid-Open No. 5569586/1988). The basic force "2-ぺ nemization ^" is still unknown

ここでは簡易化のためにべ- ^リン化学で繁用されているぺナム由来の 上述のごとき 「力 バー 2—ベネム」 と命名するものと 発 明 の 開 示 According to the systematic nomenclature, the basic skeleton of the cal. Par 2-penem compound is to be referred to as 7-oxo 11-azabi- sic mouth [3, 2, 0] heptane 1-2-ene. There is

Here, for the sake of simplicity, the term “force bar 2—venem” derived from Penum, which is frequently used in phosphorus chemistry, is used. Disclosure of the invention

The present invention relates to a novel compound having two substituents at the 1-position of the above-mentioned power bar

[In the formula, Rl represents an alk, aryl, acetyl, arylthio or aminoamino group, and R2 and R3 each represent an alkoxycarbonyl, cyano or the formula CORl (Rl is as defined above). a group, the more a key before Ariru group R3, R ⁴ is a hydrogen atom, a kill or cover 2 Bae Nemu compound represented by showing the Ari groups], a salt thereof or ester and their preparation Things.

 The inventors have calculated the formula

[Wherein, II ¹ , R ² R ³ and R ⁴ are as defined above, C00R is a protected carboxy group, and 2: is a phospho- or phosphono group.] And closing the formula

The cover 2 Bae Nemu compound [the symbols in the formula wherein as defined] represented by is obtained, cover ² obtained by as a write - base Nemu of ^

f OMPI The present inventors have found that (I) has excellent antibacterial activity and ^ -lactamase inhibitory activity, and have completed the present invention based on these. That is, the present invention provides an ω-force barene 2-penem compound (I), a salt or ester thereof,

 The present invention relates to a method for producing a cover 2-penem compound (I), which is characterized by closing a (≥) 化 ^ I>.

Examples of the above-mentioned alkyl, alkyl-alkyl and alkylaminoalkyl include, for example, methyl, ethyl, n-propyl, isobutyl, isobutyl, isobutyl, isobutyl, tert-butyl, and tert-butyl. A straight-chain or branched lower alkyl group having 1 to 6 carbon atoms, such as nityl and isopench, is used. As ary / u and aryti ary, for example, phenyl, naphthyl and the like are used. Examples of acylaminoalkyl include, for example, formyl, acetyl, propyl, and isobroviol: lower aliphatic radicals having 1 to 6 carbon atoms, such as butylidisobutyryl, for example, phenyl-acetyl, ³ -acetyl-phenyl. For example, an alkylcarbonyl group such as benzoyl or the like, or an aryl group such as an aryl group such as benzoyl is used. Examples of the alkoxy carboxy include, for example, methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and isopenki. Up to 6 linear or branched low-handed alkoxy groups are used. The above-mentioned alkyl group and aryl group may have a «group, for example, those having an alkoxy group as a substituent, such as methoxymethyl, 1- methoxethyl, 2-methoxyethyl, 2- methoxyl / ^, etc. Akoxyalkyl groups, o, m or p-methoxyphenic acid groups, o, m or p-ethoxyphene, etc., halogen groups such as fluorine, chlorine, bromine, etc.

OMPI Substituted mono-, di- or trichloromethy, mono-, di- or tri-symbol, 2-mono-, di- or trifluorochloro, 1-mono- or dichloro-methyl, o, a or ρ-chloro Alternatively, a halogeno group such as bromophene, 2,3-, 2,4- or 3,4-dichloro or dibromophene is used. The aryl group may be further substituted with the above-mentioned acryl group, and for example, a tri, xylyl, o, m or ρ-ethylfur- group is used. C00R represents a protected carboxy group, and examples of the protecting group R include aki, halogenoalk, akiki aki, aki-ki, aki-ki / carbo-oxyalkyl, arachi, penzhydrido, and phthalate. Azyl group and the like are used. In these groups, as aki, alkoxy, ash, and halogen, ^: for example, those described above are used. As aralkyl, for example, a substituent (for example, -toro group, , Halogen atom, aki group, alkoxy group, etc. as described above), benzene, phenethyl, benzene and the like are used.

In particular, when R1 is, for example, a low carbon atom having a carbon number of 4 to 4, phenyl, a lower alkyl having 1 to 4 carbon atoms, phenyl, acetylamino / 1 / methyl group, etc. In the case of a lower alkoxy force having 4 to 4 carbon atoms, such as bossiano or a low-alkoxy carbonyl group having 1 to 4 carbon atoms, R ³ is, for example, a low-alkyl carbine having 1 to 4 carbon atoms, fues, or carbon atoms In the case of a lower alkoxy group having 1 to 4 carbon atoms, a lower alkyl group having 1 to 4 carbon atoms, R4 is a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, etc. Is preferable.

 The culver 2- ぺ nemization ^ (I) of the target object is obtained by cyclizing the compound (1>!). Group in the starting material represented by the formula (Ϊ)

OMPI One of the familiar phospho- or phosphono groups in Wittig condensation reactions]), especially triaryls such as tri- or tri-treated alkyls such as tributyl phospho- or lower or lower alkyls A phosphono group diesterified with a divalent group (e.g., more strong when: is a phosphono group: a cation of a ^ group, particularly a suitable metal ion, e.g., including lithium, sodium or lithium ions In some cases, the group Z is preferably a tri-phosphonodi group, and in some cases, a diphenylphosphono group with a sodium metal ion such as a sodium ion.

 Ring closure can occur spontaneously, i.e., during the production of labor materials, or by, for example, heating to a temperature range of about 30 to about 200, preferably about 50 to about 150. You can.

The reaction is carried out in a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene, toluene, xylene or mesitylene, a halogenated hydrocarbon such as methylene chloride, ether, for example. Diethers, lower alcohols, lower alcohols, lower alcohols such as dimethoxyethane or diethyleneglycol dimethyl ether, or cyclic ethers, such as dioxane or tetrahydrofuran, power acid amides, such as dimethylformamide, lower alcohols In the presence of a sulfoxide, such as dimethyl sulfoxide, or a low handling alcohol, such as methanol / 1 /, ethanol / 1 /, or t-butanol, or a mixture thereof, if necessary under an inert gas atmosphere, such as an argon or nitrogen atmosphere Prefer to do under . The cover 2-penem compound (I) obtained by smearing can be separated and purified by known means, such as concentration, liquid conversion, phase transfer, solvent extraction, crystallization, recrystallization, chromatography, etc. But two You.

 The thus-protected 3-hydroxy group at the 3-position of the compound (summer) can be converted into a free-oxygen group by a method known per se. For example, when the protecting group R is a halogeno-low-alkyl group (for example, a 2,2-dibromoethyl group, a 2,2,2-trichloroethyl group, etc.), the aralkyl group C " For example, in the case of a benzyl group, a p-nitrobenzyl group, etc. or a penzhydryl group, such as hydrogen-palladium carbon. In the case of, it is removed by pre-irradiation.

 The thus-obtained cover 2 — ぺ nemated ^ ί (I) may have an isomer based on the 1, 5, or 6 configuration. When the obtained compound (I) is a mixture of isomers, it can be removed by a method known per se, for example, by fractional crystallization of a mixture of isomers, adsorption mouth chromatography (column chromatography or thin layer chromatography) or It can be separated into individual isomers by other appropriate methods. The obtained racemate can be removed by a conventional method after introducing an appropriate forming group, for example, by forming a diastereomer salt mixture and converting the active salt to a free form, or by separating it from an optically active solvent. Depending on the crystallization, it can be divided into enantiomers of 偭 Α.

The power 2-penem compound (I) can be used as it is, but it can be used in a manner known per se 1) in the form of a pharmacologically acceptable salt. For example, lithium, sodium, potassium, calcium, magnesium, etc., aluminum or aluminum earth metal huang or ammonium, black ammonium, diisobutane, ammonium Gammon, etc. are used, such as ammonium, but preferably sodium and potassium.

The thus obtained cover 2-venem compound (I) or its そ の is a valuable antibiotic that is active against various Gram-positive and Duram-negative bacteria, and is used as a medicine for 1κ humans and livestock. It is safely used as an antibacterial agent for treating infections caused by positive or gram-negative bacteria such as Staphylococcus saii-reus, Escherichia coli, Klebzilla-Bunymo, etc. Agents may also be added to animal feeds as fungicides, for example, to preserve the feed, for example, to cover and inhibit the growth of harmful bacteria on medical and dental equipment and for industrial use, such as water. Harmful in white water of paint and paper mills based on ¾ As a bactericide to inhibit bacterial growth, 1 solution of the solution]? It can be used in an aqueous composition at a concentration in the range of 100 parts.- The target compound (I) of the present invention, ¾ or its ester, can be used alone in any of various ¾: pharmaceutical preparations. Or used in combination with other active ingredients, for example, _beta- butarate, which can be used as a capsule, tablet, powder or solution, suspension or elixir, orally, intravenously or It can be given intramuscularly.

 Tablets for oral administration may contain ordinary excipients such as binders such as sieves, gum arabic, gelatin, sorbitol, gum tragacanth or bolibi.

-Ruby mouth lidone, fillers such as ratatoose, sugars, corn starch, calcium phosphate, sorbitol or glycine, lubricants such as magnesium stearate, tac, polyethylene glycol, etc. Disintegrants such as potato cucumbers or sodium lauryl sulfate It may contain a wetting agent that can be used. Tablets may be coated by methods well known in the art. Oral liquid preparations can be aqueous or oily suspensions, solutions, emulsions, aqueous or elixirs, or dry products which are dissolved in water or other suitable solvent before use. Liquid preparations, suspensions such as sovito-sip, methicose, glucose / sugar-drop, gelatin, hydroxyshetticellose, carboxymethylcellulose, ammonium stearate or hydrogen Additional edible oils such as almond oil, fractionated oils, oily esters, propylene glycol or ethyl alcohol, preservatives such as methyl or buvir p-hydroxybenzoate or sorbic acid may also be included. Suppositories may use the usual suppository substrates such as cocoa 'butter or other glycerides.

 The injectable compositions may be presented in unit use form in a container with an ampoule or preservative. The composition may be in the form of a suspension, solution or emulsion in an oily or aqueous medium, such as a suspension, stabilizer and / or dispersant. A scavenger may be appropriately contained. The activity can also be shown in a powder form which is reconstituted with a suitable solvent, eg sterile pyrogen-free water, before use.

 It may also be formulated in a suitable form that is absorbed by the mucous membranes or bronchial tissue of the nose and throat, such as powder, liquid spray or inhalant, rosein, and throat. For pharmaceutical administration to the eye or ear, they may be used as forceps in liquid or semi-solid form or as drops. In addition, external preparations such as softeners, creams, lotions, paints, powders and the like may be used by using a soothing or hydrophilic agent.

懸濁剤、 站稠剤または風味剤 ¾どのよう 他の成分を含有し得る。 更に， 龃成物に他の活性成分を含有せしめてよ]?広いスぺクトルの抗菌活性を 与えることもできる。 Also, besides the carrier, a stabilizer , Antioxidant,

Suspensions, thickeners or flavors-any other ingredients may be included. In addition, the composition may contain other active ingredients.] It can also provide a broad spectrum antibacterial activity.

 For livestock, it may be formulated as an intramammary preparation in a long acting or rapidly releasing matrix.

 Dosage will be determined by the condition of the breather and the weight of the host being treated, the mode and frequency of administration, suitable for common infections, parenteral, and oral for enteral infections. In general, the daily oral dose is 1 dose]) 1 or more times! ¾ In the above application, the weight of the respirator is equivalent to kg)] The active ingredient is from about 15 to 60 Offflg. A suitable daily dose for adult humans is ??? 1 kg body weight))) The active ingredient is in the range of about 80 to 120 rag.

 The compositions of the present invention may be administered in a number of unit dosage forms, eg, as solid or liquid orally ingestible dosage forms. The compositions in liquid or solid form contain 0.5 to 99% of the active substance. A preferred range is about 10-60%. The compositions will generally contain from about 15 to 150 mg of active ingredient. However, it is generally preferred to use a dosage in the range of about 250 to 100 mg.

 The compound of the present invention, or its ester or ester, has a lactamase inhibitory activity in addition to the above-mentioned uses, and thus may be used in combination with a lactam antibiotic. Examples of such 91-ratatam antibiotics include, for example, penicillin, phenoxymethipenicillin, capecilisin, ambiline, amoxicillin, and sulpenicillin. Antibiotics can also be found, for example, in cephalolysin, cephalotin, cephazolin, cephalex 5 / n, cefoxitin, cephacetri, cephamand, cemetoxime, cefsulodin, cephrosin, and

OM? I —〗 0— Sim, cefavirin, ceftizoxime, cefradine, cephaloglysin ¾ Any cephalosbolin antibiotic can be mentioned.

The starting compound of formula (I) can be prepared, for example, according to the reaction scheme below. Stage

 Y

 Wherein w is an acyloxy, sulphonic, azide or halogen atom, X is a halogen atom or an organic suloxy group,

 The azetidinone of the formula (¾) is obtained by combining 41 W-azetidinone represented by the formula (H) with the formula

 0

 R2.

 R3

Wherein R1, R2, and R3 have the same meanings as defined above, and are reacted with an active methine compound represented by the formula ( ₁ ), and if desired, the resulting isomer mixture is separated into individual isomers. .

 The symbol w in the starting compound of the formula (W) is, for example, an oxy group, a sulfo-

OMP — 1

Group RO- S0 ₂ - from (including force Bonn optically active acid) (RO organic group), azido group or a C Gen atom a is _c Ashiru ingenuity ^ by us based on W § Le group organic force Bonn acid And a group R ⁵ -CO "(where R 5 is, for example, an optionally substituted lower alkyl group, ^ chloroalkyl group, ^ chloroalkyl-lower alkyl group, R0—S02—In the sulfo-group R0—S02—, R0 is, for example, an optionally substituted aliphatic or aromatic group having 12 or less carbon atoms. Aliphatic or aromatic hydrocarbon radicals], and especially methyl radicals substituted by lower alkyl radicals such as methyl, ethyl or optically active radicals, such as camphoryl radicals, or benzyl, phenolic or trityl radicals. A halogen group W is a bromine atom, an iodine atom or Is preferably a chlorine atom, W is preferably an acetyl group, and the reaction is preferably carried out in water, a water-miscible organic solvent or an organic solvent, and is preferably carried out under basic conditions. Examples of the group include alcohols of alkaline metal or alkaline earth metals (for example, sodium methylate, sodium methylate, potassium t-butoxide), and high hydrides (for example, sodium hydride, power). Hydride, potassium hydride>, hydroxide (eg, sodium hydroxide, sodium hydroxide), carbonate (eg, sodium carbonate, sodium carbonate) or n-butyllithium, phenyllithium, lithium Diisoproviramide, ί, 5-diazabic mouth [3,4,0] decane, etc. are used. Examples of the medium include lower alcohols (eg, methanol, ethanol A, ketone (eg, acetate), esters (eg, ethyl acetate), ethers (eg, ether, tetrahydrofuran, dioxane), and amides (eg, dimethylphos). The reaction is —80 to room temperature

O FI It can be done at a slightly higher temperature. The compound thus obtained

() Can be isolated and purified by known means as described above, but it can also be used as a raw material for the next reaction as a reaction mixture.

 The compound r of the formula (¾) may be obtained as an optically inactive isomer mixture. The separation of the isomers is carried out by a usual method, particularly by chromatography and / or crystallization.

 The ffi emission represented by the formula (¾) is a publicized ^ J]) The method of Claussi et al. (Jussus Liebigs Ma "C Jus tus Li ebigs Annalen der Chemi ej 1997") 4-year 539 pages).

Step 2. The compound represented by the formula (Y) has the formula

 0

 OHC- — OR (K)

Wherein glyoxylic acid or a suitable derivative of the above [COOR is as defined above], for example, a hydrate, hemihydrate or semiacetal; And if desired], the mixture of isomers thus obtained is separated into the individual isomers. The addition reaction of the nitrogen source of the lactam ring with the glyoxy acid ester compound is carried out at room temperature or as desired.

]) For example, while heating to about 100 ° C. The use of a glyoxylic acid compound hydrate produces water, which may be removed by distillation, if desired by azeotropic distillation], or by a suitable dehydration method, such as molecular sieving. In the presence of toluene or dimethylformamide, or a mixture of these, under an inert gas atmosphere, e.g., nitrogen

ΟΜΡΙ —〗 3—

 It is better to do it in an atmosphere. The thus-obtained compound (Y) can be isolated and purified by known means as described above, but can also be used as a raw material for the next reaction as a reaction mixture.

 Step 3.

 The compound of the formula (F) (where ∑ is a halogen atom or a reactive ester residue, especially an organic sulfonic group) is used to convert a secondary hydroxyl group in the compound of the formula (Y) to a halogen atom such as a hydrogen atom or a bromine atom. Atoms or organic sulfo-oxy groups, such as low-sulfur / ^ sulfo-oxy groups (eg, methylsoxy group) or arylsulfo-oxy groups (eg, 4-methylenoxy) The desired mixture of isomers can be separated into the various isomers.

 The reaction with a halogenating agent such as thio-halide (eg, tallide), a phosphorous oxyhalide (eg, chloride) or a suitable esterifying agent, such as halophospho-dimhalide (eg, triphenylphosphine dibromide) Or a suitable organic sulphonic acid (eg, oxalic acid), preferably a base, especially an organic group, such as an aliphatic tertiary amide (eg, trietiamine, disopviretiamine or polystyrene). The reaction is carried out in the presence of a complex S-type base of the Hünig type or of the pyridine type (for example pyridine or collidine). The reaction is carried out in a suitable solvent such as dioxane or tetrahydrofuran or these. In the presence of a mixture of, if desired] while cooling and / or an inert gas Preparative performed under example under a nitrogen atmosphere 囲気 are preferred.

は反応性エステ 残基に変えるととができる。 例えば境素原子は相当す る氇素化合物を適当なヨウ化物塩例えばナトリウムョーダイドによって、 好ましくは適当 ¾溶媒例えばジメチ ホルムアミ ドの存在下で処理する ととによってヨウ素原子に変えるととができる。 かくして得られる化合 物（ F )は、 IW3の公知の手段によ]?単離精製するとともできるが、反 応混合液のまま次の反応の原料として用いるとともできる。 In the compound of the formula (If) thus obtained, a halogen atom or a reactive ester residue; X is converted to another halogen atom by a method known per se.

Can be changed to a reactive ester residue. For example, the boron atom can be converted to an iodine atom by treating the corresponding iodide compound with a suitable iodide salt, such as sodium iodide, preferably by treating the compound in the presence of a suitable solvent, such as dimethylformamide. . The compound (F) thus obtained can be isolated and purified by known means of IW3, but can also be used as a reaction mixture as a raw material for the next reaction.

 Both the optically inactive isomer of formula () and the mixture thereof can be used in the above reaction.

Step 4.

 The starting material of the formula (I) is a compound of the formula (F) (X is a halogen atom or a reactive ester residue) and a suitable phosphinated ^ / e.g. A tri-low alkyl; u phosphine (e.g. a tree n- Petite phosphine) or triphenyl phosphine (eg, triphenyl phosphine) or a suitable phosphite compound, eg, tri-lower aki phosphite (eg, triethyl phosphite) or metal dimethyl phosphite It is obtained by reacting it with an iron.

 The reaction is preferably carried out in a suitable inert solvent such as a hydrocarbon (eg, hexane, cyclohexane, benzene, toluene or xylene), or an ether (eg, dioxane, tetrahydrofuran or diethylene glycol dimethyl). Athe), amides (eg dimethyl A ^ formamide) or mixtures thereof. In reaction, the above operation may be performed at a reduced or elevated temperature, about 110 to 100, preferably about 20 to 80, and / or under an inert gas atmosphere, such as nitrogen. Perform in an atmosphere. In order to prevent the oxidation reaction, the catalytic amount of an antioxidant such as hydroquinone can be increased.

O PI If a phosphine compound is used, the reaction is usually carried out in the presence of a base, such as an organic base, such as an amine such as triethylamine, diisopropylamine, 2,6-glutidine, or a polystyrene-Hünig group. I do. The compound (I) thus obtained can be isolated and purified by the above-mentioned known means, but can also be used as a raw material for the present reaction as a reaction mixture.

 Both the optically inactive pure isomers of formula (I) and their mixtures or the corresponding optically activated ^ can be used for the next reaction.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Reference example /

Dissolve 5.7 g of 4-acetoxy S / —2 azetidinone 6.5 3 and 2,4-dimethoxyxan-3-methylpentane in 50 of tetrahydrofuran and stir to 15 with cooling. To this, 5N aqueous solution of 3N sodium hydroxide is added dropwise. After dropping, stir for ¹⁵ minutes with a -5 roll and extract with ethyl acetate. The organic layer was washed with saturated diet water, dried (N _a2 S0 ₄₎ was then, the solvent was distilled off. The obtained residue is purified by passing through a silica gel column. Elution with chloroform yields 3 · 2 δ g of 4- (1,1-diacetylethyl) -2-—azetidinone.

Melting point 7 2-74

Elemental analysis 值 C9H13NO3

 Calculated: C 59.00; H 7.15; N 7.65.

 Found = C 58.81; H 7.13; N 7.49.

Infrared absorption bitch door ^{(KBr): 1690cm "1,} Scm one ^{1, 1750cnT 1} nuclear magnetic resonance scan Bae-vector (60MHz, in CDC13): <5 1 · 3 7 (3 Η, Shin Gure' g), 2 * 20 (6 6, singlet), 2.4 6—3.3 4 (2Η

OMPI , Machibureto), 4.38 (1st, Double Tob Doublet), .00 (1m, Multipure)

Reference Example << 2

Suspension of 01 · 8 g of sodium hydride (oil-based 60%) is suspended in tetrahydrofuran 20 "and stirred under eternal cooling. To this is added 2.6 g of 2,4 dioxo- 3-ethylpentane and stirred for 10 minutes. After cooling to 110, add 2.6 g of 4-acetoxy 3--2-azetidinone to the mixture.After stirring for 5 minutes, pour the reaction mixture into saturated saline and extract with virulent acid. the organic layer was washed with saturated brine, drying (lia ₂ S0 _4). the solvent was concentrated under reduced pressure, the resulting residue was treated with isopropyl ether, the precipitated crystals were collected by filtration, dried, 4 one (1.1 diacetyl provir) to give 2-azetidinone 2.88 g.

Melting point 1 1 0-1 1 2

Elemental analysis value CioH 0 ₃

 Calculation 值: C 60.89; H 7.67; JK 7.10

 Obtained: C 61.02 J H 7.58; 1ί 7.12

Infrared absorption-spectrum ^{(KBr): 1685CHT 1, 1710CBT} 1, 1760CBT 1 nuclear magnetic resonance scan Bae click preparative (60 MHz, in CDC13): 0.90 (3 H, Application Benefits Puretsu preparative>, 2.05 (2 E, Kuwa Tetsuto) , 2.20 (3H, singlet), 2.21 (3E, singlelet), 2.54-3.37 (2H, multilett), 4.26 (1H, doublet doublet), 6.32 (1H) , Multiplied)

Reference example

 Diethyl acetyl acetyl malonate 2.0 δ s and 4-acetoxy 2-azetidinone 3.30 g dissolved in tetrahydrofuran 2: ^

ΟΜΡΙ Stir it. Add 1N aqueous sodium hydroxide solution 1 to the mixture and stir at room temperature for 1 δ hours. The reaction solution is extracted with severe acid, and the organic layer is washed with saturated saline and dried (Na ₂ SC). The solvent is distilled off under reduced pressure, and the obtained residue is purified by passing through a silica gel column. Elution was carried out with a black mouth tube to obtain 4- (1,1 * -jetoxycabon-2-oxoblovi) -12-azetidinone as an oil. 0 · 86 g.

 Nuclear magnetic field {j island spectrum (60MHz, in CDCI3): 1.32 (6H, triblet), 2.35 (3H, ^ nglett), 3.15 (2H, doublet doublet) 〉, 4.0-4.50 (1H, multi-blet), 4.34 (4E, quartet), 6.6 1 (1H, multi-blet)

)

 Reference example

Dissolve 2-32 g of 2-acetonate bioionate and 3.8 g of 4-acetoxy-2-azetidinone in 30 dew of tetrahydrofuran: Stir under cooling to 10 t! To this is added 3N aqueous solution of 1N sodium hydroxide and allowed to react for 2 hours. The reaction solution was extracted with acetic acid Echiru, the organic layer was washed with saturated diet water, dried (MgSO ₄₎ to. The residue obtained by evaporating the solvent under reduced pressure is purified by passing through a silica gel column. Elution is carried out with a black form to obtain 4- (1 "" acetyl-11-ethoxycarboxy-nA-thio) -12-azetidinone as an oil. δ .11 g.

Infrared absorption spectrum (liquid): 1705CBT ¹ , 1750cm- ¹

Nuclear magnetic resonance spectrum (60½2,00 (; ¾1)): 31.26 (3H, triblet), 1.36 (3H, S ^ glet), 2.17 (3H, singlet) door>, 2.6 0- 3.25 (2 H , Maruchiburetsu door), 4.1 7 (1 H _f Ma Chipuretsu door>, 4.28 (2 H, Kuwa Tetsu door), 6.96 (1 H ·

 OMPI

"ΡΟ ⁰ Machiblet>

Reference example

Dissolve 1-gano-hue-1-2-year-old kisopnon 0 · 796 g in 20 W of tetrahydrofuran, and add 1,8-diazabisik [5,4,0] -17- ゥ ndene 0 · 6 g of water: Stir for 5 minutes and cool to 10 Then add 0.65 g of 41-acetoxy-2-azetidinone: add 15 minutes and react at room temperature for another 30 minutes. Pour the reaction mixture into saturated saline and extract with ethyl succinate. The organic layer is washed with dilute hydrochloric acid and saturated saline, and the dried (Na ₂ SO ₄ ) solvent is distilled off under reduced pressure. The obtained residue is passed through a silica gel column and eluted with a chromatographic form to give 4- (11-cyano 1-phenyl-12-oxobrovir) -12-azetidinone as an oil. 0 · 473 g.

Nuclear magnetic field ¹ spec (601ίΗζ, in GDCI3): 2.30 (3Η, singlet), 2, 76—3.25 (2Η, multi bullet), 4.35 (1Η, multilett), 5.80 (“^ Η, Multiplied), 6.24 (, ma Λ ^ · pret)

, 7.36 (5Η. ^ Nglet)

 The oil obtained above is crystallized with a mixed solvent of ether-η hexane to obtain one of the isomers.

Melting point 1 1 5-1 2 1 i

Elemental analysis value Ci3Hi ₂ N _S 02

 Calculation 攛: C 68.40; H 5, 30 »Ή 12.28

 Measured value: C 68 -19ί Η 5.25; Ν 12.14

Infrared absorption spectrum Cr): 1710CHT ^1. '1725CBT ¹ , 1750cm " ¹ Nuclear magnetic resonance spectrum (601iHz, in CDCl3): S 2:30 (3H, S ^ G), 2.86 (2H, doublet) 4.38 (ίH, Riblet), 6.34 (1H, maslet), 7.50 (5mm, singlet h)

 Reference example

Dissolve 0 · 72 g of triacetimethane in tetrahydrofuran 1 and stir at room temperature. Add 1,8-diazavicik mouth [5,4,0] 7 0,76 g of 10-decene and stir for 10 minutes, then add 0.65 g of 4-acetox-2-azetidinone to the tore and leave at room temperature for 5 hours. mix. The reaction mixture is poured into saturated saline, adjusted to pH 5.0 with phosphoric acid, and extracted with ethyl acetate. The organic layer is washed with saturated saline and dried (Jia ₂ S0), and the solvent is distilled off under reduced pressure. The obtained residue is passed through a column of lizard and eluted with chloroform to obtain triacetylmethyl) 2-azetidinone as an oil. 5 fflg. When the tore is studied with isobrobiether, it crystallizes.

Melting point 82- 84

Elemental analysis value C10H13 O4

 Calculation 值: C 56.86; H 6.20; N 6.63

 Found: C 56.735 H 6.13; N 6.28

Infrared absorption spectrum (KBr) ··· 1695caT ¹ , 1725CST ¹ , 1763cm ” ¹ Nuclear magnetic tri-island vector (6011: 32; in 0» 0! 13): 8 2.29 (9H, singlet 〉, 2.a 4-1 3.31 (2U, multiple), 4.54 (1H, double to double), 6.63 (135, multiple)

Reference example

Suspend sodium hydride (oil-based, 60%) 0 * 4 g in tetrahydrofuran 15 and stir under water cooling. To this, add 1.95 g of methyl ² -pentylprobionate, stir for 10 minutes, and cool to 110.

O PI Reject. Then, add 1.3 g of 4-acetoki and 1-3 g of 2-azetidinone, and stir with 10-10 minutes for 30 minutes. Pour the reaction solution into saturated food water, extract with ethyl acetate, and saturate the organic layer! Washed with water, dried (Na ₂ S0 ₄₎ you. The residue obtained by distilling off the solvent under reduced pressure is passed through a silica gel column and dissolved in a sigma-form to obtain an oily substance. This is recrystallized from isobrovir ether to obtain crystals of 4- (1-benzyl-1-methoxycarboethyl) -12-azetidinone (1: 6 mixture of variants). 2.48 melting point 90-92

Elemental analysis ϋ C14H15NO4

 Calculation 值 = C 64.355 Η 5.79; Ν 5.36

 Measured value: C 64 · 40 ϊ Η 5.831 Ή 5.20

Infrared absorption spectrum (KBr): 1675CST ¹ , 1725cm " ¹ , ί 77 Ο Γ ¹ Nuclear magnetic resonance spectrum (60 MHz, in CDC13): 3 ί.56 (3, +, singlet), 3.60 (3 Η X, Singlet), 2.94 (2Η, multi

 ° ^ Nut), 3.68 (3Η χ ^ ·, ^ Glette), 3.70 (3H x +, singlet), 4.20 (1Η, multiplet), 6,70 (1Η, multiplet), 7.35—8.00 (5 Η, Maburetto)

 Example '

Dissolve 3.88 g of 4-acetiki ^ —2-azetidinone and 7,93 g of getylpenzomalonate in tetrahydrofuran 30 and stir under eternal cooling. To this is added 1 normal 7 aqueous sodium oxide solution 30, stirred for 30 minutes, and further reacted at room temperature. Pour the reaction mixture into saturated saline and extract with acid. The organic layer is washed with saturated saline, dried (Na ₂ SO ₄ ), and the solvent is distilled off under reduced pressure. The resulting residue is passed through a silica gel power ram.

One O PI _ Elute with chloroform to obtain an oil. The tore is crystallized from ether-isobrobyl ether to obtain 4- (11-pentozy-1,1-diethoxycarbo-; umethyl) -12-azetidinone. 2 56 g ₀

 Melting point 8 0-8 1

Elemental analysis value Ci ₇ Hi ₉ N0 ₆

 Calculation 值 ··· C 61.25; H 5.72 J N 4.20

 Found: C 61.12; H δ.69ί N 4.32

Infrared absorption spectrum ^{(Or):. 1690cm- 1,} 1720cnT 1 1750ciri "¾ nuclear magnetic resonance spectra (60MHJ5, in CDCl3): ^ 1.12 (3H, tributyl toilet), 1.22 (3 H, Toriburetsuto), 3.2 § (2H, multiple),

4.27 (2H, quad / ^), 4.37 (2H, quad), 4.66 (1H)

, Doublet doublet), 6.46 (1H, multiplet), 7.4 δ

-8.10 (5Η, multiple bullets)

Reference example

0.4 g of sodium hydride (oil-based, 60%) is suspended in tetrahydrofuran 5 and stirred. Under ice-cooling, 1.76 g of methyl 2-ethylthiocarbonyl brobionet was added thereto, and the mixture was stirred for 10 minutes. The reaction solution was cooled to 110, and then 4-acetidine 1-2-azetidinone 1.2 was added. Obtain 9 g. After stirring for 40 minutes, pour the reaction mixture into saturated saline and extract with acetic acid. The organic layer AraiKiyoshi with saturated diet榼水, dried (MgSO ₄₎ was then, the solvent was distilled off under reduced pressure. The obtained residue is passed through a column of norica gel, and eluted with a black form to obtain 41- (diethylthiocarbo-1--1-methoxycarboxy-l-butyl) -12-azetidinone as an oil. t. 3 1 go

Infrared absorption-spectrum ^{(liquid): ΙΖεθαη ". 1 1720cm *} " 1 Nuclear and magnetic spectra (60 MHz, CDC: L3): 1.25 (3H, triplet), 1.50 (3Η, singlet), 2.74-3.11 (4H, multibret), 3 · δ ( 3 E, Ng Nut), 4.30 (1 Η, τ multi-plate), 7.04 (1 マ, // ^ ")

Reference example /. .

Suspend 0 · 08 g of sodium hydride (oil-based, 60%) in tetrahydrofuran 1 and stir under eternal cooling. Add 2,4 dioxo-3-ethylpentane 26 Offlg to the mixture, stir for 10 minutes, cool to 10 and add 26 mg of 4-phenylsulfo-2-azetidinone to the extract. Stir at the same temperature for 5 minutes, then stir at room temperature for 10 minutes, then pour the reaction mixture into saturated saline and extract with ethyl acetate. The organic layer was washed with saturated brine, dried (lia2S0 ₄₎ the solvent was removed under reduced pressure to give After. The obtained residue is passed through a column of a force gel and eluted with a gel form to obtain an oil. The residue is crystallized from izobiproviete to give 4 (ί, 1diacetinorepvinole) —2-azetidinone. 1 28fflg.

This product was identified by comparing the infrared absorption spectra and nuclear magnetic resonance spectra obtained in Example 2 with _β

Reference example //:

4-Acetoki-2-azetidinone 1.3 g and 2,4-dioxo-3 1-methylbentan 1 · 5 g are dissolved in acetone 2, and this is potassium carbonate! Add 40 g and stir at room temperature for 6 days. The insolubles of the reaction solution were removed by filtration, and the filtrate obtained was concentrated under reduced pressure. The resulting residue is passed through a silica gel and eluted with chloroform to give 4- (,, 1-diacetylethyl) -1-2-azetidinone? ^ _Β 1 .2 1 go

 This product is the same as that obtained in Example 1 and the infrared absorption spectrum and nuclear magnetic resonance spectrum

Ο ΡΙ Torr was compared and identified.

 Example/:

(1) 4- (1,1 dipsetetic / 1) -12-azetidinone 0.86 g and p-tropendyl glyoxylate. Monohydrate 1.55.5 g of tetrahydro 7-lane 20 » And add 11 g of Molecular ^ Bus (3A) to the mixture and leave at room temperature for 8 days. The molecular sieves are removed by filtration, and the obtained filtrate is concentrated under reduced pressure. The resulting residue is passed through a silica gel power column, and eluted with a mixed solution of severe acid and hexane ^ (2: 1), resulting in 4-(1, 1-diacetylethyl) — 1 — <1-1 p — Tongue Pencil Age Carbo-Lu 1-Hydroxymethyl) 1-2 to obtain azetidinone. Oil, 0.96 g _e

 (2) According to the method of (1)]? Obtained 4- (1, 1 diacetylethyl)-1-1 (1-ρ-nitto-pentyl penzilla) Dissolve 5.986 g of 2-azetidinone in 100 of tetrahydrofuran, and stir the mixture under cooling with a nitrogen stream. To this is added 3,6 g of 2,6 / 1/1 thiidine, and then 3,64 g of thi-norrechloride is added dropwise. After dropping, react for 温度 0 min 'at the same temperature ^:

Add W a The precipitated insoluble matter is removed by filtration, and the obtained filtrate is concentrated to dryness under reduced pressure to give 4- (1,1,1-diacetylethyl) -111- (1-p-nitropentoxycarbonyl). (1) Chloromethyi> (1) A crude product of azetidinone is obtained, which is dissolved in dried dioxane (380) without purification, and 2,6-monoretidine (3,27S) and triphosphosbuin (8 g) are added thereto. The mixture was stirred for 23 hours under a nitrogen stream at 50. The insoluble material was removed by filtration, and the obtained filtrate was concentrated under reduced pressure.The obtained residue was passed through a silica gel column, and ethyl acetate and n-hexane were passed through. Eluted with a mixed solvent (1: 1>) of 4 "(1 , 1-Diazetchi)-1 ~ (11-p--Pentyl pentoxy). Bo = 1-Triphenylphosphora: = Redenmethi)-2-azetidinone is obtained in powder form. This is dissolved in toluene ²⁰⁰ ^, hydroquinone 2 Offlg is added thereto, and the mixture is reacted under a nitrogen stream at 90 for 4 hours. Destroy solvent

Distilled, and the obtained 留 -Ruo is passed through a silica gel column and dissolved in a mixed solvent (1: 1) of black and ethyl ester to obtain an oil. When this was recrystallized from a mixed solvent of black formal ether, it was found that the crystal of p-to-pentopene β 1 -acetyl; ΐ / · ~ 1 · 2-dimethylcarba 2- ぺ nem-13-carboxylate Is obtained. ί10 g ₀

Melting point 1 44— 1 4 δ t!

Elemental analysis 值 Οι ₈ Ηι ₈ 1Γ2θ6

 Calculation 值: C 60.33; Η 5.06; Ν 7.82

 Actual measurement = C 60.34; Η 5.13; Ν 7.83

Infrared absorption spectrum ^{(KBr): 1700CIT 1, 1720ΟΠ} ". 1 1780cm" 1 NMR-spectrum (90 MHz, in CDCl3): 1.30 (3E, Thing

 Let), 2.03 (3H, singlet), 2.23 (3H, singlet),

 3.20 (2Η, doublet AB quartet), 4.26 (ίH, doublet doublet), 5.35 (2）, doublet), 7.64 (2Ε, doublet), 8.21 (2Ε, doublet)

Example2

 ρ- ■ = Tropendil 1-acetyl-1,2, -dimethicar-2-enem-31-carboxylate 0-36 g is dissolved in severe acid 3 and sodium hydrogencarbonate 0-126 g is added thereto. 15 W containing water and 0.36 g of 10% paradigm carbon are added, and hydrogen is passed through at room temperature for catalytic reduction. After anti-iS for 45 minutes, the catalyst is removed by filtration, and the obtained filtrate is separated. Ann water layer ^

, Ni hi ^ Pass through a column of One Light XAD-2, elute with water and lyophilize. A colorless powder of sodium acetyl-1,2-dimethylcarb-2-ene-3 sodium carbonate is obtained. 0 · 10 g.

Elemental analysis CnHi ₂ N0 Na- 1.5H ₂₀

 Total value: C 48.53 i H 5.55; N 5.15

 Observed: C 48.10; H 5.51 5 N 5.07

Infrared absorption spectrum (KBr): 177δ η ", 1740 η one ^1, 1703CHT ¹ nuclear magnetic resonance spectrum (90MHz, in DgO): δ 1,39 (3Η · Shingure Tsu door), 1.98 (3Η, ^ Nguretto ), 2 «44 (3Η · ^ great), 3.35 (2Η, doublet AB quartet), 4.53 (1H, doublet doublet)-Examples

 (1) 4 1 (1,1 diacetyrpvir) 1 2 —azetidinone 3.8 g and p nitopen pen ^ xylate xylate monohydrate 5.3 g dissolved in benzene 100 * This is heated and refluxed for 7 hours using a Deans Stark apparatus. The solvent was distilled off under reduced pressure, and the obtained residue was passed through a silica gel column, eluted with a mixed solvent of dichloromethane and acetic acid (4: 1) to obtain a powdered 1.1-diacetyl. (Buguchi Building) (1 t> 1-Trondyl 1-Hydroxymethyl) 1-2-azetidinone 7. 70 go

 (2) 4 -— (1,1-Diacetylpropyl) 1-1p-Tropene-zil-xylcarboxy-l- (1-hydroxymethyl) -1-2-azetidinone 7.70 S dissolved in tetrahydrofuran 100 I ^ Under a nitrogen stream—5! Stir the mixture to ~ 10. To this, add 6.72 g of 2.6-glutidine and 6.78 g of thio-chloride, and react for 10 minutes. Reaction liquid

/ c I, Pentose 100W was added to the mixture, and the insoluble material precipitated was removed by filtration, and the obtained filtrate was reduced under reduced pressure to obtain 4- (1, 1 diacetylrubil) -1-1 (1-—; A crude product of 1-chloromethyl-1-2-azetidinone can be obtained in powder form.

When Les purifying and dissolved into the Jiokisan 1 00 * ¾, then ² 6- lutidine 4 · 07 g and preparative riff enyl phosphine 1 0 g to take ¾1 e -. - nitrogen stream Te, 1 50 ¾ 8 Let react for hours. The insoluble material is removed by filtration, and the obtained filtrate is reduced by JET reduction. The residue is passed through a silica gel and eluted with chloroform, and the residue is dissolved in 4- (1-, 1-diacetylbrovir) -1-1- (1-1-ρ-dito-pentyloxycabo-1-tri-le-phosphora- (Ridenemethyl) -12-azetidinone is obtained in powder form.

To a solution of the residue in toluene 15 was added 2 mg of hydroquinone, and the mixture was reacted at 90 ° C for 18 hours under a nitrogen stream. The reaction solution is compressed under reduced pressure, and the obtained residue is passed through a gel of silica gel and eluted with a mixed solvent of chloroform and severe acid (7: 1). The obtained oil was crystallized with ether to obtain 1-to-benzyl 1-acetyl-1-ethyl-1: 2-methylcarber 2-benenemu 3 carboxylate. 43 5fflge melting point 1 48-1 5 O i Elemental analysis 值 'Ci _& H £ oN ₂ 06

 Calculated: C 61.28; H 5.41 J Έ 7.52 Observed: C 60.94; H 5.36 7. N 7.45

Extraordinary absorption spectrum (KBr): 1690ΟΓ ¹ , 1722CBT ¹ , 1780cnT ¹ Nuclear magnetic resonance spectrum (90MHz, in CDCI3): 3 0.86 (3H, triblet), 1,50—2.15 (2H, ), 2 ^ 03 (3S, Shingure Tsu door), 2,22 (3Ε, ^ Nguretsuto), 3,30 (2Ε, doublet Obu _"λ,

OMPI_ "IPO AB） 4.4), 4.42 (1H, doublet doublet),

5.3 5 (2 ,, Α quartet), 7, 6 4 (2 ,, doublet), 8.22 (Η, doublet)

 Example

 ^ (1-acetyl-1-ethoxycarbo η-leethyl)-1-2-azetidinone 4.26 g and ρ-12-opening pendant gliochelate · monohydrate 4.9.9 g are dissolved in pentane 1 δ 0 W, The residue is heated under reflux for 20 hours using a Dean'Stark apparatus. The solvent is distilled off under reduced pressure, and the oily substance obtained is purified by passing it through a column of gel. Elution with a mixed solvent of dichloromethane and ethyl acetate (4: 1) yields 4 1 (1 acetyl- 1 ethoxy carbyl) 1 1 1 (1 ρ 1-to-pentopenoxycarbonyl) — 1-Hydroxy ^ methyl> -8.2-111 g is obtained as a 2-azetidinonka oil, which is dissolved in tetrahydrofuran 100 **, and 2,6-thidine 6.7β is added thereto. In addition, stir the mixture to cool to 10. Then add 28.2 W of thio-chloride dropwise and let it spread for 10 minutes.Pour the reaction solution into water and extract with ethyl acetate. The water, dry

<MgSO _4), and the solvent is distilled off under婊圧, 4 i (1 - Asechiru 1 one Etokishika Bo ^: Ruechiru) Single 1 i (1 one p- preparative port Penjiru ingenuity mosquito Ruboniru 1 chloromethyl) Single 2 Azechijinoン · 48 g obtained as an oil. This was dissolved in W, N-dimethylformamide 70, and then triphenylphosphine, 90 g, sodium iodide 2,55 g and 2,6-lutidine 2.2 W were added thereto. Stir for 8 hours at room temperature under air current. The reaction solution was extracted with Kokusan Wechiru poured into water, the organic layer is washed with water, dried (MgSO _4), evaporated reduced ffiT the solvent. The residue obtained is passed through a silica gel column for purification. When eluted with black-mouthed form,

OMPI T Seti 1 1—Ethoxycarboyl phenyl) 1 1 1 (1—1 1 p—-Pentoxylka)

9.0 g of 2-azetidinone is obtained in powder form. Dissolve 5.00 g of this product in toluene 350 and react under nitrogen stream for 90 hours. The residue obtained by shrinking the solvent under S is passed through a silica gel column and eluted with _β- chloroform, which is then purified. P-Tropopendyl 1-etoxy-propanol-1,2-dimethylcarba-2-enem One 3-carboxylate is obtained as an oil. 2 · 14 g (1: ί mixture of isomers). Nuclear magnetic resonance spectrum (90MHz, in CDC13): 3 1.26 (3HX, triplet), 1.27 (3Hx, triplet), 1.36 (3HX "!, singlet), 1.49 (including 3HX, singlet), 2.06 (3, angle), 2.30 (3HX, singlet), 3.10 (2H <■ ¾ ·, doublet AB quartet), 3.17. (2E E, doublet A quartet), 3.86 (1H, doublet doublet), 4.20 (2Hx-, AB quad), 4.22 (2Hx, quartet)

, 4.47 (1H x-¾-, doublet doublet), 5.37 (2H, AB double A), 7.66 (2H, doublet), 8,25 (2Η, doublet) : 1 isomer mixture) is recrystallized from ether to yield one of the isomers as colorless crystals.

Melting point 1 2 0-1 22 Π

Elemental analysis 值 Οι ₉ Η2θϊί2θ7

 Calculated value: C 58.761 Ε 5.195 Κ 7.21

 Measured value: C 58,90i Η 5.10! Ν 7.20

Infrared absorption spectrum ^{(KBr): 1780cm "1,} 1720cm 1

Nuclear magnetic resonance spectrum (90MHz, in CDCls): 1 · 26 (3Η, trip ), 1.49 (3H, singlet), 2.06 (3 3, ^ gret),

3.10 (2 Η, doublet AB quartet), 3.86 (1H, doublet doublet), 4.20 (2E, AB quartet),

 5.3 7 (2H, AB Quartet), 7.66 (2H, doublet), 8.25 (2H, doublet)

 Kosuke

 (1) Dissolve 5.7 ag of 4-hydrazine pentahydrate with 5.5 g of 2-azetidinone and 5.7 g of ρ-tropenzyl glyoxylate monohydrate in benzene 8 This was heated to reflux for 8 hours using a Dean-Stark apparatus. The solvent was distilled off under reduced pressure, and the obtained residue was passed through a silica gel column and eluted with a mixed solvent of dichloromethane and ethyl acetate (3: 1) to give a solution of 4- (1-benzoyl-1-methoxycarboethyl). ) 1-1-(1-p-: Benziroki carboninole 1-1-dimethyl) 1-2 azetidinone: ^ 800 g obtained as an oily substance.

Dissolve the residue in tetrahydrofuran 8 Ο ι ^, and stir it in a nitrogen stream at 15 to 110 ° C. After adding 2,6-lutidine 4.33 W thereto, thiochloride 2.47 is added dropwise. After the dropwise addition, the mixture is allowed to react at the same temperature for 20 minutes. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with a 5% aqueous solution of sodium hydrogen carbonate and saturated saline, and dried (Na ₂ SO ₄ ). The solvent was distilled off under reduced pressure, 4 one (1 one ^: Nzoi one ¹ - main Tokishika Ruboniruechi) Single 1 i (1 one p- nits port Penjiru old Kishikarubo two Lou

7,3-S is obtained as 1-chloromethyi) -1-azetidinone as an oil. 4.89 g of this oily substance was dissolved in N.N-dimethylformamide 40 *, and 2,6-thidine 1 · 15 », triphenylphosphine was added thereto.

ΟΙ.ίΡΙ 5.25 g and 1.5 g of sodium iodide are added all at once, and the mixture is stirred at room temperature under a nitrogen stream for about 7 hours. The reaction solution is poured into water and extracted with fermented acid. The organic layer was washed with water and saturated diet border water, dried (lia ₂ S0 ₄ "to. The solvent to a distilled off under reduced pressure and the resulting residue was passed through a column of silica gel, the black hole Holm and severe acid Echiru Elution with a mixed solvent (1: 1) yields 4— (ί-benzo-1-methoxyvoluethyl) -1 "J— (1—ρ——13pentyl; ^ xycarbo——1—to Dissolving the residue in toluene 150 «, adding hydroquinone 2 Omg and reacting at 90 ¾ under a nitrogen stream for 20 hours. Is distilled off under reduced pressure, and the residue obtained is passed through a silica gel column and eluted with a mixed solvent of octaform and ethyl acetate (6: 1) to give an oil. Crystallized in a mixed solvent of P-nitrobenzyl 1-methyl-1- 1-methoxy Sicarbo--2-phenylcarber 2-Penemu 3-kabokiretoka S 2.30 g (mixture of 7: 3 isomers) o

Nuclear magnetic resonance spectrum (60MHz, in CDC13): 1.38 (3Η, singlet), 1.46 (3Ε, singlet), 2,65—3.50 (2Η, multiblet), 3.65 (3ΗX, ^ nglet) · 3.83 (3ΕX, singlet), 4 * 13 (lHx, doublet doublet), 4.74 (1ΗΧ ^ ¾, doublet doublet), 5.14 (2B:, AB quartet), 6.90—7,35 ( 7H, multiple), 8.01 (2H, doublet)

 When this product is further recrystallized with a ether, three different hangers are obtained as colorless crystals.

Melting point 1 1 5-12 1 Likelihood analysis 值 Οζ3ΕζθΝζ η

 Calculated value = C 63.30; H 4.62J 2Τ 6.42

 Actual value ··· C 63.395 Η 4.47; Ν 6.29

Infrared absorption spectrum (KBr) ··· 1720caT ¹ , \ 735aa ~ ^] , 1790cm ” ¹ nuclear magnetic IJ spectrum (90MHz, in CDCI3): 3? .42 (3H, singlet), 3.26 (2H , Doublet AB Quartet), 3.61 (3H, Singlet), 4.7 Ϊ (1H, Doublet Doublet), 5.14 (2H, AB Quartet), 00-7.35 (AH, Multi: 7 * dot), 8.07 (2H, doublet)

 Example

 Nitropentinole 1-Methyl 1-Methoxycarbo 1- 2-Felpalper 21-Nem-3 3 ^ Carboke ^ Rate (mixture of 7 and 3 isomers) 43a fflg to ethyl acetate 30 * The mixture is added with 15-15 of water containing 0.10 g of sodium hydrogen carbonate and 44 Offlg of 0% palladium on carbon, and subjected to normal pressure catalytic reduction at room temperature (1 hour 45 minutes). The aqueous layer separated into two layers of the filtrate obtained by filtering off the catalyst is taken. Lyophilize the aqueous layer, dissolve the residue in water, pass through a column of Sephadex LH-20 (manufactured by Rohm and Haas) and elute with water. The fraction containing the target substance is freeze-dried, and the 1-methyl-1-carbonate 2-carbene-2-enem-3 sodium ribonate as a colorless powder containing 275 fflg (7 : Isomer mixture of 3 · ¾) obtained.

Infrared absorption spectrum (KBr): 1725cuT ¹ , 1760cnr ^!

Nuclear magnetic resonance spectra (901 ^ 2, <16-1> 1! 30): δ 1.24 (3Ε X

. シングレツト） ， 3.9 0 ( 1 H X ,ダブレツト ォブ ダブ ト） ， 4.44 ( 1 H

-^ Q. ^ Gringet>, 1.30 (3EX5¾ ", singlet), 3.14 (2H,

Singlet), 3.90 (1HX, double-dubbed), 4.44 (1HX)

 Angle)

Example

 4-(I-Benzoyl 1, 1-jetoki carbo-methyl)-2-Azetidinone 1.3 g and ρ-= pendant glyoxylate · monohydrate 1 · 09 g are dissolved in benzene 50 Is heated to reflux for 8 hours using a Dean-Stark apparatus. The solvent was distilled off under reduced pressure, and the residue obtained was passed through a column of force gel and eluted with a mixed solvent of dichloromethane and ethyl acetate (6: 1) to give 4- (1-pentylol 1,1-— 0.869 g of diethoxycarbomethyl) -111 (111-p- = pentyl-l-xylcarboxyl-l-hydroxymethoxy) -2-azetidinone is obtained as an oil.

This was dissolved in a tetrahydrofuran 12 fog, and the solution was dissolved in a nitrogen stream 10. Stir and cool to ~ 5! To this, 2,6-thidine 0.45 W is added, and then thiochloride 0.232 is added dropwise. After reacting for 10 minutes after the dropwise addition, pour the reaction solution into water and extract with ethyl acetate. The organic layer is washed with water, 5% aqueous sodium bicarbonate solution, saturated food, and dried (Na ₂ SO ₄ ). When the solvent is distilled off under reduced pressure, 4- (1-pentylyl-1,1-diethoxycarbonylmethyl) 1-1-1 (1-ρ-nitto-pentyloxy ^ carbo-l-1-1-1-chloromethyl) 1-2-azetidinone is obtained as an oil. Is obtained as

This was dissolved in W, Ν-dimethylformamide (12 W), to which was added sequentially 2,6-glutidine (0.22 W), triphenylphosphine (0.84 g) and sodium iodide (0.24 g). Stir at room temperature for 21 hours in a stream of air. The reaction solution was poured into water and extracted with ethyl succinate, and the organic layer was washed with water and saturated saline. CLEANING, dried (Ifa ₂ S0 _4). The residue obtained by distilling off the solvent under reduced pressure is passed through a column of Rica gel, and eluted with a mixed solvent of mouth form and ethyl acetate (6: 1). Jetoxycarbol-methyl) 1,1- (11-ρ--tol-pentyloxycarboxy-l-1-triphenylphosphora-redenemethy) -12-azetidinone is obtained in powder form. The residue is dissolved in toluene δ 0, and hydroquinone 20 is added thereto, and the mixture is reacted under a nitrogen stream at 90 for about 5.5 hours. The solvent is distilled off under reduced pressure, and the obtained residue is passed through a column of silica gel and eluted with a mixed solvent of chloroform and acetic acid (9: 1) to obtain an oil. Crystallization with ら れ る -Nitrobenzyl 1, 1-Jetoki 5 carbonyl ^ "2-Fe-capa-2-enem ~~ 3-carboxylate 1 1 9fflg ₀

Melting point .1 08 1 1 1

Elemental analysis value σ ₂₆ Η2 ίΓ2θ9

 值 Min 值 · 'C 61.41 i H 4,76i N 5.51

 Actual value ··· C 61.45; E 4.64J M ”5.59

Infrared absorption spectrum (KBr) 1725cnT ¹ , 1795cnT ¹

Nuclear magnetic resonance spectrum (90MHz, in CDCI3): δ 0.83 (3Η, triplet), 1.30 (3Ε, triplet), 2.90 (Ί ダ, da: 7 * top doublet), 3.55 (1Η, Doublet doublet), 3.94 (2 Η, multiple), 4.34 (2 ,, ヮ ^), 5.17 (3ΑΒ ΑΒ quartet and doug nud ダ up doublet), 7.05—7.35 (7Η, multi) ), 8.08 (2Η, doublet)

Example

 4-(1 -ethylthiocarbonyl-t-methoxy ^ carbo: = rutile)

_ ΟΜΡΙ -2-45 g of azetidinone and p-= pendant glyoxylate · monohydrate 2 · 72 g are dissolved in benzene 8, and the mixture is heated under reflux for 9 hours using a Dean-Stark apparatus. The solvent was distilled off under reduced pressure, and the obtained residue was passed through a column of silica gel, eluted with a mixed solvent of dichloromethane and ethyl ethyl ester (8: 2), and purified. 3.95 g of mexica-voluethyl)-(-l-ρ- = benzyl-l-l-l-hydroxyl-x-methyl) -l-azetidinone as oil is obtained. Dissolve the residue in 60 W of tetrahydrofuran and stir it in a nitrogen stream-10 cooling. This ^2, 6-1 cytidine ² · 0 4, is added dropwise Chionirukurori de ί · 1 6 W Tsu. After reacting for 10 minutes after the dropwise addition, pour the reaction mixture into water and extract with Shirojuntil. The organic layer is washed with water, a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and dried (MgS0). The solvent was distilled off blinking pressure ⁴ - (1 - E Chi Chioka ball - - 1 - main Tokishikarubo - Ruechiru) - I - (1 one p two preparative port base Njiruokishikaru ball - Lou 1 one Kuroromechi) Single 2- Azechijinon is Obtained as an oil. This was dissolved in ,, Ν-dimethylformamide 50, and the mixture was dissolved in 2,6-—idine 0.92 5 »ί, triffee-lufosbuin 4.1 19 2 gi? And sodium iodide 1.2 g. And stir at room temperature under a nitrogen stream for 37 hours. The reaction solution was extracted with酴酸chill poured into water, the organic layer with water and saturated diet water ^ Kiyoshi, dried (M _g S0 ₄₎ to. The residue obtained by distilling off the solvent under reduced pressure was passed through a silica gel column and eluted with a mixed solvent of n-hexane and enzymatic acid (1: 1). 1 over main preparative Kishikarubo ^ Ruechiru) 1 i (1 one ρ- eth port pen Jill O propoxycarbonyl sulfonyl 1 Ichito re phenyl phosphoramidite two Ridenmechiru) - 2 Azechidzunon obtain 1 1 6 ² g powdered.. Dissolve this in xylene 10

t OMH Hydroquinone (20 fflg) is added to the mixture, and the mixture is stirred under a nitrogen stream at 140 ° C for 22 hours. The residue obtained by distilling off the reaction solution under reduced pressure is passed through a silica gel and eluted with a mixed solvent ( ⁴ : 1) of octaform and ethyl acetate to obtain an oil. Crystallization of the residue with ether yields p--tropendyl 1-methyl-1-methoxy-2-carboyl-2-ethylthiocarper 2--penem 3-force boxylate ί90 fflg.

 Melting point 1 3 1 1 3 2

 Elemental analysis value C19H20N2O7S

 Calculated: C 54.28; H 4.79; N 6.66 Found: C 54.33; H 4.63; N 6.67

Infrared absorption spectrum (KBr): 1730cffl— ', 1790CBT ¹

Nuclear magnetic resonance spectrum (90MHz, in CDCl3): ^ 1.20 (3H, triplet), 1.46 (3H, angle), 2,8a (2Η, AB quartet), 3.23 (2Η, doublet quartet) , 3.a (3Η, singlet), 4.3a (1Η, double doublet), 5, 37 ”(2Η, double quartet), 7.64 (2Ε, doublet), 8.24 (2Η, doublet)

Example

 ■ ρ-Nitrobenzyl 1-methyl-1- 1-Methoxycarbonyl 2- ヱ Tilthiocover 2-Venem-3-carboxylate 0.21 g is dissolved in severe oxygen 1 δ », and sodium hydrogen carbonate is added to this. 5 Add 8 ml of water containing 1 fflg and 0.25 g of 10% palladium-carbon, and make contact with hydrogen by passing hydrogen at room temperature. After reacting for 1 hour, the catalyst is removed by filtration, and the obtained filtrate is separated.

The aqueous layer is passed through a Sephadex LH-20 column. After elution with water and lyophilization of the fraction containing the objective ¾, "I-Met — 1—

TA OLiPI Calcium 2-2-ethylthiocarba 2-penem-3-carbonic acid sodium salt is obtained in powdered form at 4 nig.

Infrared absorption spectrum ^{(KBr) = 1 730cnT 1,} 1 760cffl one ¹

 Industrially available PHP

 Capene 2-penem compound (I) has excellent antibacterial activity and lactamase activity in rats, and has the ability to harm rats and mammals, including dogs, cats, cows, horses, mice, guinea pigs, etc. -For the treatment of infectious diseases caused by positive or negative bacteria, as a preservative for animal feed, industrial water or as a disinfectant for sanitary appliances, and in combination with 3-lactam antibiotics] It is used as a decomposition inhibitor for the antibiotic.

Claims

The scope of the claims 1 set

[In the formula, Rl represents an alkyl, aryl, alkylthio, arylthio or acylaminoalkylthio group, and R ² and R ³ represent an alkoxycarbol, cyano or a formula CORl (R1 has the same meaning as described above). R ³ further represents an alkyl or aryl group; R ⁴ represents a hydrogen atom, an alkyl or aryl group], a salt or ester thereof. 2. Expression  R3 R2  R4,, . .  C00R Wherein R ¹ is an alkyl, aryl, alkylthio, arylthio or acylaminoalkylthio group; R ² and R ³ are alkoxycarbol, cyano or a formula C 0 R 1 (R 1 is as defined above) R ³ further represents an alkyl or aryl group, R ⁴ represents a hydrogen atom, an alkyl or aryl group, C 00R represents a protected carboxyl group, and Z represents a phosphono group or a phosphono group.) Which is characterized by ring closure of the compound

Culver ² [symbols in the formula the same meanings as defined] represented by - preparation ₀ velvet 'Nemu compound  OMPI IPO