JPH0321542B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel 1-
(3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1, a novel synthetic intermediate for sulfo-2-azetidinone derivatives
- sulfonic acid, or its salt or ester,
and their manufacturing methods. 1-Sulfo-2-azetidinone derivatives recently isolated from nature have attracted attention due to their unique structure and antibacterial activity [Nature]
Volume 289, page 590 (1981), Volume 291, page 489 (1981)].
Also, JP-A-55-164672 and JP-A-56-125362
discloses 1-sulfo-2-azetidinone derivatives in which the acylamino group at the 3-position of the β-lactam ring is variously changed, along with some substituents at the 4-position. The present inventors have discovered a novel and useful 1-sulfo-2
As a result of intensive research aimed at obtaining -azetidinone derivatives, (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-
Sulfonic acid (hereinafter referred to as "compound [A]"), its salt or ester and the formula [In the formula, R ¹ has the same meaning as above, R ⁴ represents a hydrogen atom or an amino group protecting group, and R ⁵ represents an ester residue] or a reactive derivative thereof is reacted, and then After removing the protecting group and optionally the ester residue, the formula A 1-sulfo-2-azetidinone derivative having a (3S,4S)-coordination represented by [the symbols in the formula have the same meanings as above], a salt or ester thereof, and the obtained compound [], The present invention was completed based on the discovery that the salt or ester exhibits a strong antibacterial effect against Gram-negative bacteria including Pseudomonas aeruginosa and is extremely stable against β-lactamases produced by microorganisms. That is, the present invention provides (1) compound [A], or a salt or ester thereof, (2) (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-
The present invention relates to a method for producing compound [A] or its sodium salt, which comprises reacting sodium 2-azetidinone-1-sulfonate with hydrogen in the presence of palladium on carbon for catalytic reduction. The alkyl of the lower alkyl group represented by R ¹ in the above formulas [] and [] preferably has 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isopropyl,
Isobutyl etc. are used. The ester residues represented by R ² in the formula [] and R ⁵ in the formula [] include, for example, biologically active ester residues that have the effect of increasing blood concentration and prolonging the effective time. , for example α-(C _1-4 )alkoxy (C _1-4 ) such as methoxymethyl, ethoxymethyl, isopropoxymethyl, α-methoxyethyl, α-ethoxyethyl, etc.
Alkyl groups, e.g. (C _1-4 ) alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; α such as pivaloyloxymethyl, α-acetoxyethyl, etc.
-(C _2-6 )acyloxy(C _1-4 )alkyl group, such as α-(C _1-4 ) such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, etc.
In addition to alkoxycarbonyloxy (C _1-4 ) alkyl groups, etc., ester residues usually used as protecting groups for carboxyl groups, such as t-
Butyl, benzhydryl, benzyl, p-nitrobenzyl, p-methoxybenzyl, p-nitrophenyl, β-trimethylsilylethyl, β,
β,β-trichloroethyl, trialkylsilyl (eg, t-butyldimethylsilyl, isopropyldimethylsilyl, etc.) and the like are used. Examples of ester residues as protective groups for carboxyl groups include t-butyl, benzhydryl, p-
-Nitrobenzyl and the like are preferred. As the protecting group for the amino group represented by R ⁴ in the formula [], those normally used for this purpose in the synthesis of β-lactam antibacterial compounds are conveniently employed. For example, formyl, acetyl,
Acyl groups such as monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, such as t-butoxycarbonyl, 2-cyanoethoxycarbonyl, β,β,β-trichloroethoxycarbonyl, β-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p
Esterified carboxyl groups such as -nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and diphenylmethyloxycarbonyl, as well as protecting groups for amino groups such as trityl and trialkylsilyl, are used. Among them, formyl, monochloroacetyl, trityl and the like are particularly preferred. Compound [] may be used with its sulfo group and carboxyl group free, but it can be treated with non-toxic cations such as sodium and potassium, basic amino acids such as arginine, ornithine, lysine and histidine, etc., by a conventional method. N
- Salts with polyhydroxyalkylamines such as methylglucamine, diethanolamine, triethanolamine, and trishydroxymethylaminomethane may be formed and used. The amino group at the 2-position of the thiazole ring may also be used in its free state, but it can be used in a conventional manner to form salts with organic acids such as acetic acid, tartaric acid, methanesulfonic acid, etc., such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. For example, salts with acidic amino acids such as aspartic acid and glutamic acid may be formed and used. Furthermore, the carboxyl group can also be used by forming an ester with a biologically active ester residue as described in the explanation of R ² and R ⁵ above. In addition, compound [] may be used as a racemate, but (3S,
An optically active substance having 4S)-coordination exhibits essential antibacterial activity. The compound [ ] or its salts or esters are valuable antibiotics active primarily against gram-negative bacteria and are used in human and livestock medicine and as antibacterial agents to treat infections caused by various bacteria. Safely used as an agent. Furthermore,
The compounds [] or salts or esters are added to animal feed as fungicides, for example to preserve the feed. Also used as a disinfectant to destroy and inhibit the growth of harmful bacteria, e.g. on medical and dental equipment, and as an industrial disinfectant to inhibit the growth of harmful bacteria, e.g. in the white water of water-based paints and paper mills. As an agent, solution 1
It can be used in aqueous compositions at concentrations ranging from 0.1 to 100 parts per million parts of the compound or its salt or ester. The compound [ ], its salts or esters, can be used alone or in combination with other active ingredients in the formulation of any of a variety of pharmaceutical preparations, such as capsules, tablets, powders, solutions, suspensions or elixirs. It can be used as They can be administered orally, intravenously or intramuscularly. Tablets for oral administration may contain the usual excipients such as binders such as syrup, gum arabic, gelatin, sorbitol, gum tragacanth, polyvinylpyrrolidone and the like, fillers such as lactose,
sugars, corn starch, calcium phosphate, sorbitol, glycine, etc., lubricants such as magnesium stearate, talc, polyethylene glycol, silica, etc., disintegrants such as potato starch, or available moisturizing agents such as sodium lauryl sulfate. may contain agents.
Tablets can be coated by methods well known in the art. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be dry products that are dissolved in water or other suitable solvents before use. Good too. Such liquid preparations may contain suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel, hydrogenated edible oils such as almond oil, fractionated coconut oil, etc. , oily esters, etc., propylene glycol or ethyl alcohol, preservatives such as methyl or propyl p-hydroxybenzoate, sorbic acid, and the like. Suppositories can employ common suppository bases such as cocoa butter or other glycerides. Injectable compositions may be presented in unit dosage form in ampoules or in containers with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous solvents, optionally containing auxiliary agents such as suspending agents, stabilizing agents and/or dispersing agents. You may do so. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable solvent, eg, sterile pyrogen-free water, before use. They can also be formulated in suitable forms that are absorbed by the mucous membranes of the nose and throat or the bronchial tissues, such as powders, liquid sprays or inhalants, roseine, throat paints, and the like. For ocular or otic pharmaceutical administration, it may be used in liquid or semisolid form as capsules or as drops.
Furthermore, it may be used as an external preparation using a hydrophobic or hydrophilic base such as an ointment, cream, lotion, paint, or powder. In addition to carriers, for example, stabilizers, binders,
It may contain other ingredients such as antioxidants, preservatives, wetting agents, suspending agents, thickening agents or flavoring agents.
Additionally, other active ingredients may be included in the composition to provide a broader spectrum of antimicrobial activity. For livestock, it may be formulated as an intramammary formulation in a long-acting or fast-release matrix. The compound [ ], its salts or esters can be used as therapeutic agents for bacterial infections, such as respiratory infections in mammals, urinary tract infections, purulent diseases, biliary tract infections, intestinal infections, obstetric and gynecological infections, and surgical treatments. It can be used to treat infectious diseases, etc. The daily dosage depends on the condition of the patient being treated and the weight of the host, the method of administration (preferably parenteral for general infections and oral for intestinal infections) and frequency. It's coming. Generally, the daily oral dosage will consist of about 15 to 300 mg of active ingredient per kg of patient body weight in one or more applications per day. The recommended daily dosage for adult humans is about 10 to about 150 active ingredients per kilogram of body weight.
mg, divided into 2 to 4 times daily, approximately 2.5 to approximately
It is appropriate to administer parenterally in an amount of 75 mg/Kg. Compositions containing the compound [], its salts or esters may be administered in several unit dosage forms, such as solid or liquid orally ingestible. The liquid or solid unit use compositions contain from 0.5 to 99% of active substance. The preferred range is approximately
It is 10-60%. The composition generally contains active ingredients of about
Contains 15-1500mg. However, it is generally preferred to use dosages in the range of about 250-1000 mg. Compound [] can be produced by reacting compound [A], its salt or ester with carboxylic acid [] or a reactive derivative thereof, and then removing the protecting group and, if necessary, the ester residue. Compound [A] may be used in its free form, but it may also be used as a salt or ester as described for compound []. Carboxylic acid [ ] is used as a reactive derivative of the carboxyl group in addition to using the carboxyl group as it is. Examples of reactive derivatives of carboxylic acid [] include acid halides, acid anhydrides, active amides, active esters, and active thioesters. Specific examples of such reactive derivatives are as follows. 1. Acid halide: As the acid halide, for example, acid chloride, acid bromide, etc. are used. 2. Acid anhydride: Examples of the acid anhydride include monoalkyl carbonic acid mixed acid anhydride, aliphatic carboxylic acid (e.g., acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.) mixed acid anhydride, Mixed acid anhydrides of aromatic carboxylic acids (eg, benzoic acid, etc.), symmetrical acid anhydrides, and the like are used. 3. Active amide: As the active amide, for example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc. are used. 4 Active ester: Examples of the active ester include methyl ester, ethyl ester, methoxymethyl ester, propargyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, and pentachlorophenyl ester. In addition to esters such as , mesyl phenyl ester, esters with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. are used. 5 Active thioester: Here, as the active thioester, for example, 2
-Thioesters with heterocyclic thiols such as -pyridylthiol and 2-benzthiazolylthiol are used. The various reactive derivatives described above are appropriately selected depending on the types of R ¹ , R ⁴ and R ⁵ in the carboxylic acid []. In this method, first, carboxylic acid []
Alternatively, the reaction is carried out by reacting 1 mol or more, preferably 1 to 4 mol, of a reactive derivative thereof. This reaction is usually carried out in a solvent. As the solvent, water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, or other general organic solvents that do not participate in the reaction are used. Of these, hydrophilic solvents can also be used in combination with water. When carboxylic acid [] is used in its free state, it is preferable to carry out the reaction in the presence of a condensing agent, such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N' -morpholinoethylcarbodiimide, N-
Cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-
N'-(3-dimethylaminopropyl)carbodiimide and the like are used. Also, for example, alkali metal carbonates, trimethylamine, triethylamine,
Tributylamine, N-methylmorpholine, N-
Trialkylamines such as methylpiperidine, N,
N-dialkylaniline, N,N-dialkylbenzylamine, pyridine, picoline, lutidine,
1,5-diazabicyclo[4,3,0]non-5
-ene, 1,4-diazabicyclo[2,2,2]
Octane, 1,8-diazabicyclo[5,4,
4] This reaction can be carried out in the presence of a base such as undecene-7, and a liquid base or the above-mentioned condensing agent can also be used as a solvent. Although the reaction temperature is not particularly limited, it is usually carried out under cooling or at room temperature. Few minutes~
The reaction is completed in several tens of hours. The product obtained in this reaction can be isolated and purified by means known per se, such as concentration, liquid conversion, dissolution, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography, etc. The reaction mixture may be used as a raw material for the next step without separating it. The product obtained by the above acylation reaction is then used as a raw material for the step of removing the protecting group and, if necessary, the ester residue. Here, the ester residue to be removed if necessary is generally used as a protecting group for the carboxyl group and can be easily removed after the acylation reaction, and is simultaneously removed from the protecting group for the amino group represented by ^R4 . Alternatively, the amino group may be removed before or after the protecting group of the amino group is removed. Furthermore, depending on the type of amino group-protecting group and carboxyl group-protecting group, there are cases where they are eliminated under the above acylation reaction conditions, and in this case, it is not necessary to perform a new elimination step. do not have. As a method for removing the protecting group for the amino group and the protecting group for the carboxyl group, depending on the type of the protecting group, for example, a method using an acid, a method using a base, a method using a reduction, etc. can be selected as appropriate. . In the case of a method using an acid, examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, and benzenesulfonic acid, although it depends on the type of protecting group and other conditions. acid, p
- In addition to organic acids such as toluenesulfonic acid, acidic ion exchange resins and the like are used. In the case of a method using a base, the base may be a hydroxide or carbonate of an alkali metal such as sodium or potassium, or an alkaline earth metal such as calcium or magnesium, although it depends on the type of protecting group and other conditions. In addition to inorganic bases such as metal alkoxides, organic amines, and organic bases such as quaternary ammonium salts, basic ion exchange resins and the like are used. When a solvent is used in the above acid or base method, a hydrophilic organic solvent, water or a mixed solvent is often used. In the case of the reduction method, it depends on the type of protecting group and other conditions, but for example, metals such as tin or zinc or metal compounds such as chromium dichloride or chromium acetate are combined with organic compounds such as acetic acid, propionic acid, hydrochloric acid, etc. A method using an acid such as an inorganic acid, a method of reduction in the presence of a metal catalyst for catalytic reduction, etc. are used. Examples of catalysts used in the catalytic reduction method include platinum wire, platinum sponge, platinum black,
Platinum catalysts such as platinum oxide, colloidal platinum, such as palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium barium carbonate, palladium carbon, palladium silica gel, colloidal palladium, etc., such as reduced nickel, nickel oxide, Raney nickel, Examples include nickel catalysts such as Urushibara Nickel. In the case of a reduction method using a metal and an acid, a metal compound such as iron or chromium and an inorganic acid such as hydrochloric acid or an organic acid such as formic acid, acetic acid or propionic acid are used. The reduction method is usually carried out in a solvent, and for example, in the catalytic reduction method, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, ethyl acetate, etc. are often used. Furthermore, in the method using a metal and an acid, water, acetone, etc. are often used, but when the acid is liquid, the acid itself can also be used as a solvent. The reaction temperature in the acid method, the base method, and the reduction method is usually carried out under cooling or heating. Further, in order to remove a protecting group containing a silyl group, a compound containing a fluorine ion such as tetrabutylammonium fluoride or potassium fluoride can also be used. Furthermore, when the protecting group for the amino group is a monochloroacetyl group,
For example, it can be easily removed by using thiourea or sodium N-methyldithiocarbamate. Further, the compound [] is, for example, the compound [A]
[For example, the expression ], its salt or ester and the formula The formula obtained by reacting a compound represented by [wherein R ⁴ has the same meaning as above] or a reactive derivative thereof A compound represented by the formula [wherein R ⁴ has the same meaning as above], a salt or ester thereof, and a compound represented by the formula H ₂ N−OCH ₂ COOR ² [] [wherein R ² has the same meaning as above] or It can also be produced by subjecting the salt to dehydration condensation, followed by removing the protecting group and, if necessary, the ester residue. The thus obtained compound [ ] from which the protecting group and, if necessary, the ester residue have been removed, is isolated and purified by means known per se as described above. In addition,
Since the compound [ ] has an amino group in addition to a sulfo group and a carboxyl group, it can generally react with a base or an acid to form a salt. Therefore, the compound [] may be collected as a salt, and the obtained salt may be made into a free form, or may be used as other salts. Furthermore, the compound [ ] obtained in free form may be used as a salt. As a method for converting the compound [ ] obtained as a salt with a base into a free form, for example, a method using an acid is used. The acid used varies depending on the type of protecting group and other conditions, but examples include hydrochloric acid, sulfuric acid,
Inorganic acids such as phosphoric acid and organic acids such as formic acid, acetic acid and p-toluenesulfonic acid are frequently used. In addition, acidic ion exchange resins and the like are used. Further, as the solvent, for example, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane, water, or a mixed solvent is often used. This method is usually carried out at room temperature, but it may also be carried out under cooling or heating. The reaction time varies depending on the type of acid and solvent and the temperature, but it is generally preferable to complete the reaction in a short time. The resulting free form of the compound [] can be isolated by known means as described above. Furthermore, the compound [ ] obtained in free form or as a salt can also be converted into an ester according to conventional methods. Note that the raw material compound [A] used in the above method can be produced, for example, by the method shown below or a method analogous thereto. Cis-3-amino-4-methoxycarbonyl-1-(2,4-
dimethoxybenzyl)-2-azetidinone []
For example, the Journal of the American Chemical Society
It is a known compound described in vol. 99, p. 2352 (1977) of American Chemical Society, and can be easily obtained. Raw material compound [A] thus obtained
may be used as a raw material for the next step after being separated and purified by the above-mentioned known methods or as a reaction mixture. The present invention will be further explained in detail with the following experimental examples, working examples, and reference examples, but these examples are merely illustrative and do not limit the present invention, and without departing from the scope of the present invention. It may be changed. Unless otherwise specified, elution in column chromatography for Examples and Reference Examples was performed using TLC (Thin
This was done under observation using layer chromatography (thin layer chromatography). For TLC observation, Merck is used as a TLC plate.
60 ₂₅₄ manufactured by Co., Ltd. was used as the developing solvent and the solvent used as the elution solvent in column chromatography, and a UV detector was used as the detection method. Also, spray 48% hydrobromic acid onto the spot on the TLC plate.
After being heated and hydrolyzed, ninhydrin reagent was sprayed and heated again, and the color changed from red to reddish purple. This was also used as a detection method to confirm the elution fraction containing the target substance and collect it. When two or more types of developing solvents are used, unless otherwise specified, the first solvent used is used to elute the by-product, and the second solvent used is used to elute the target product. In column chromatography purification using "Amberlite", unless otherwise specified in the examples and reference examples, water was first used as the developing solvent, and then ethanol aqueous solution was used while gradually increasing the concentration. . When drying the solution containing the target product, anhydrous sodium sulfate was used as a desiccant unless otherwise specified. “Amberlite” is manufactured by Rohm & Hass Co.in USA, and “Dowex” is manufactured by Dow Chemical Company (Dow Chemical Company).
Chemical Co.). The NMR spectrum is
Measurements were made with an EM390 (90 MHz) or T60 (60 MHz) type spectrometer using tetramethylsilane as an internal or external standard, and all δ values were expressed in ppm. The symbols in Examples and Reference Examples have the following meanings. s: singlet d: doublet q: quartet ABq: AB type
quartet) dd: double doublet m: multiplet br.: broad J: coupling constant Hz: Hertz mg: milligram g: gram ml: milliliter Ph: phenyl MeOH: methanol CHCl ₃ : chloroform DMSO: dimethylsulfoxide Experimental example For the target product obtained in Example 1 (2), the MIC
(mcg/ml) was measured by the following method and summarized in the table below. Measurement method The MIC of the test compound was determined using the agar dilution method (agar dilution method).
dilution method). That is, 1.0 ml of a sequentially diluted aqueous solution of the test compound is poured into a Petri dish, and then 9.0 ml of Trypticase soy agar is poured and mixed. A suspension of test bacteria (approximately 10 ⁶ CFU/ml) is smeared onto the mixed agar plate. 37℃
After overnight incubation, the lowest concentration of the test compound that completely inhibits the growth of the test bacteria is called the minimum inhibitory concentration (MIC).
concentration). Test bacteria (1) Enterobacter cloacae IFO 12937 (2) Klebsiella pneumoniae
pneumoniae) TN 1711 (3) Pseudomonas aeruginosa (Pseudomonas aeruginosa) GN 3407 Results

[Table] Reference example 1 Cis-3-amino-4-methoxycarbonyl-
23.54 g of 1-(2,4-dimethoxybenzyl)-2-azetidinone and 16.17 g of di-(p-toluoyl)-D-tartaric acid monohydrate were dissolved in acetonitrile.
Add to 600ml, heat to melt, filter, and let cool. The precipitated crystals are collected by filtration and washed with cooled acetonitrile to obtain 20.3 g of salt. This was recrystallized from 300 ml of acetonitrile to obtain 16.3 g of salt. Melting point: 165-168°C [α] ²² _D +71.9° (c = 0.985, MeOH) Dissolve this salt in a mixture of 100 ml of water and 200 ml of tetrahydrofuran, and add 6.1 g of sodium hydrogen carbonate. Next, add 4.2 ml of carbobenzoxy chloride while stirring under ice-cooling. After stirring for 1 hour under ice-cooling and 1 hour at room temperature, tetrahydrofuran was distilled off under reduced pressure at a bath temperature of 30°C or less. Add 400 ml of ethyl acetate and 200 ml of water to the residue and shake. The aqueous layer is re-extracted with 200 ml of ethyl acetate, and the extracts are combined and washed twice with 2% aqueous sodium bicarbonate. Then saline solution, 1N
Wash sequentially with hydrochloric acid and brine, and after drying, the solvent is distilled off under reduced pressure, and 30 ml of ether is added to the residue. The crystals formed are collected by filtration, dissolved in 50 ml of ethyl acetate by heating, and 50 ml of hexane is added to the filtrated solution, which is then allowed to cool. When the precipitated colorless crystals are collected by filtration (3S, 4S)
-cis-3-benzyloxycarboxamide-4
-methoxycarbonyl-1-(2,4-dimethoxybenzyl)-2-azetidinone (6.45g (37.5
%)can get. Melting point 120-121℃ [α] ²² _D +24.4゜ (c = 1.08, CHCl ₃ ) IRν Nudiol maxcm ^-1 : 3300, 1770, 1745, 1695 Elemental analysis value C ₂₂ H ₂₄ N ₂ O ₇ as C (% ) H (%) N (%) Calculated value 61.67 5.65 6.54 Actual value 61.50 5.59 6.37 Reference example 2 (3S,4S)-cis-3-benzyloxycarboxamide-4-methoxycarbonyl-1-(2,
4-dimethoxybenzyl)-2-azetidinone
Dissolve 12.8g in 300ml of tetrahydrofuran and add 28% of sodium borohydride while stirring under ice cooling.
A solution of g dissolved in 150 ml of cold water was added dropwise over 10 minutes. After the addition is complete, stir under ice cooling for 1 hour and at room temperature for 3 hours. Tetrahydrofuran is distilled off under reduced pressure at a bath temperature of 30°C or lower, water is added to the residue, and the mixture is filtered.
Washing with water and ethyl acetate yields 44 g of crude crystals. Combine the mother liquor and washing solution, shake and separate the ethyl acetate layer. The aqueous layer is re-extracted with ethyl acetate, and the ethyl acetate layers are combined and washed with 1N hydrochloric acid and brine. After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the crude crystals obtained above were combined with the residue and recrystallized from ethyl acetate to give (3S,4S)-cis-3-benzyloxycarboxamide-1-
(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-azetidinone as colorless crystals at 9.1
g (76%) obtained. Melting point 137-138℃ [α] ²⁵ _D +32.7゜ (c=1, CHCl ₃ ) IRν Nudiol maxcm ^-1 : 3480, 3345, 1740,
1715, 1695 NMR ( _CDCl3 ) δ: 3.5-3.9 (3H, _C4 -H, _C4
−CH ₂ ), 3.78 (3H, s, OCH ₃ ), 3.79 (3H,
s, OCH ₃ ), 4.35 (2H, s, N ₁ −CH ₂ ), 4.9
~5.2 (1H, m, C ₃ −H), 5.07 (2H, s,

[Formula]), 6.06 (1H, d, J = 10 Hz, C ₃ -NH), 6.3-6.6 (2H, m, aromatic proton), 7.1-7.3 (1H, m, aromatic proton), 7.32 ( 5H,s,

[Formula]) Elemental analysis value C ₂₁ H ₂₄ N ₂ O ₆ C (%) H (%) N (%) Calculated value 62.99 6.04 7.00 Actual value 62.92 5.90 7.03 Reference example 3 (3S, 4S)-cis-3 -benzyloxycarboxamide-1-(2,4-dimethoxybenzyl)-
4-hydroxymethyl-2-azetidinone 2.0g
Dissolve in 40 ml of methylene chloride, and add 0.52 ml of chlorosulfonyl isocyanate while stirring under ice cooling. After stirring for 30 minutes under ice cooling, add 0.35 ml of chlorosulfonyl isocyanate and stir for another 10 minutes. Add 1.26g of sodium sulfite to the reaction solution and water.
Add the solution dissolved in 30 ml under ice cooling and stir at room temperature for 1 hour. Methylene chloride was distilled off under reduced pressure and the residue was extracted with chloroform. The extract is washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ether was added to the residue, and the residue was filtered to obtain 2.46 g of crude crystals. By recrystallizing this product from ethyl acetate-hexane,
(3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-1-
1.72 g (77.7%) of (2,4-dimethoxybenzyl)-2-azetidinone is obtained as colorless crystals. Melting point 179-180℃ [α] ^24.5 _D +34.5゜ (c=0.8, DMSO) IRν ^KBr _nax cm ^-1 : 3410, 3300, 1760, 1710 NMR (d ₆ -DMSO) δ: 3.74 (3H, s,
OCH ₃ ), 3.76 (3H, s, OCH ₃ ), 3.7-4.3
(3H, m, _C4 -H, _C4 - _CH2 ), 4.20(2H,
ABq, J = 15Hz, N ₁ - CH ₂ ), 4.92 (1H, d.
d, J = 5, 10Hz, C ₃ −H), 5.05 (2H, s,
CH ₂ Ph), 7.35 (5H, s, ph), 7.87 (1H,
d, J = 10Hz, C ₃ -NH) Elemental analysis value C ₂₂ H ₂₅ N ₃ O ₇ C (%) H (%) N (%) Calculated value 59.59 5.68 9.48 Actual value 59.30 5.70 9.57 Reference example 4 (3S ,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-1-
Suspend 1.60 g of (2,4-dimethoxybenzyl)-2-azetidinone, 1.41 g of potassium persulfate, and 0.85 g of dipotassium phosphate in a mixture of 36 ml of acetonitrile and 18 ml of water, and stir for 80 minutes at a bath temperature of 95°C under an argon atmosphere. . Acetonitrile was distilled off under reduced pressure, and 10 ml of brine was added to the residue, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran. 5% extract
After washing with a sodium bicarbonate solution and a saline solution, drying with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the solidified residue was recrystallized from ethyl acetate to give (3S,
426 mg (40.3%) of 4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azetidinone is obtained as pale yellow crystals. The mother liquor was concentrated and purified by silica gel column chromatography (70 g, developing solution: CHCl ₃ -MeOH-ethyl acetate, 85:10:5) to obtain an additional 353 mg of crystals (colorless). Total yield 779mg (73.6%) Melting point 191-192℃ [α] ²⁵ _D +60.6゜ (c=1, MeOH) IRν ^KBr _nax cm ^-1 : 3400, 3300, 1755, (sh), 1745,
1695 NMR ( _d6 -DMSO) δ: 3.70-4.25 (3H, _C4-
H, _C4 - _CH2 ), 4.95 (1H, d, d, J=5,
10Hz, C ₃ −H), 5.05 (2H, s, CH ₂ Ph),
6.47 (2H, br.s, CONH ₂ ), 7.33 (5H, s,
Ph), 7.92 (1H, d, J = 10Hz, C ₃ −NH),
8.30 (1H, br.s, N ₁ -H) Elemental analysis value C ₁₃ H ₁₅ N ₃ O ₅ C (%) H (%) N (%) Calculated value 53.23 5.15 14.32 Actual value 52.83 5.02 14.26 Reference example 5 (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-
Dissolve 293 mg of azetidinone in 10 ml of dioxane,
Add 477 mg of anhydrous sulfuric acid-pyridine complex and stir at room temperature for 14 hours. Dioxane is distilled off under reduced pressure, 20 ml of water and 20 ml of Dowex 50W (Na) are added to the residue, and the mixture is stirred at room temperature for 1 hour. The resin is filtered off and the filtrate is concentrated under reduced pressure. amber light residue
Subjected to XAD-2 column chromatography, water,
Elute sequentially with 5% ethanol and 10% ethanol. Fractions containing the target compound are combined, concentrated under reduced pressure, and lyophilized to yield sodium (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2-azetidinone-1-sulfonate as a colorless powder. 270 mg (64%). [α] ²⁵ _D +29.4° (c=0.715, water) IRν ^KBr _nax cm ^-1 :3500, 3370, 3320, 1795, 1760,
1730, 1690 NMR ( _d6 -DMSO) δ: 3.85-4.40 (3H, _C4-
H, _C4 - _CH2 ), 4.92 (1H, dd, J=5.10Hz,
_C3 -H), 6.10-6.65 (1H, _CONH2 ), 7.35
(5H, s, Ph), 7.98 (1H, d, J=10Hz,
C ₃ −NH) Elemental analysis value C ₁₃ H ₁₄ N ₃ NaO ₈ S・11/2H ₂ O C (%) H (%) N (%) Calculated value 36.97 4.06 9.95 Actual value 37.24 4.13 10.02 Example 1 ( 1) (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-
Sodium 2-azetidinone-1-sulfonate
Dissolve 422 mg in a mixture of 10 ml of water and 10 ml of tetrahydrofuran, add 422 mg of 10% palladium on carbon, and stir for 1 hour at room temperature under a hydrogen atmosphere. The catalyst is filtered off and washed with 30 ml of a mixture of water and tetrahydrofuran (1:1). Combine the filtrate and washing liquid and add 202 mg of baking soda while stirring under ice cooling.
Next, 614 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-(p-nitrobenzyloxycarbonylmethoxyimino)acetyl chloride hydrochloride is added. After stirring for 30 minutes under ice cooling, adjust the pH to 5 with 1N hydrochloric acid and concentrate to 30 ml under reduced pressure. Add 10 ml of tetrahydrofuran to the residual liquid, then add 129 mg of sodium N-methyldithiocarbamate, and stir at room temperature. After 40 minutes and 80 minutes, 129 mg of sodium N-methyldithiocarbamate was added,
Stir for a total of 2 hours. Tetrahydrofuran is distilled off under reduced pressure, and the remaining aqueous solution is washed with ether and concentrated again under reduced pressure. The residue was subjected to column chromatography using Amberlite XAD-2 (200ml), water, 5% ethanol, 10%
Elution was performed sequentially with ethanol, 15% ethanol, and 20% ethanol, and the fractions containing the target product were collected, concentrated under reduced pressure, and lyophilized.
4S)-cis-3-[2-(2-amino-4-thiazolyl)-2-(Z)-(p-nitrobenzyloxycarbonylmethoxyimino)acetamide]-
500 mg (76%) of sodium 4-carbamoyloxymethyl-2-azetidinone-1-sulfonate are obtained as a pale yellow powder. [α] ²⁶ _D +10.1° (c=1, water) IRν ^KBr _nax cm ^-1 : 1760, 1720 (br.sh), 1670 NMR (d ₆ -DMSO) δ: 3.9 to 4.4 (3H, C ₄ −
H, _C4 - _CH2 ), 4.78(2H,s, _OCH2-
COOCH ₂ ), 5.28 (1H, dd, J=4.5, 10Hz,
C ₃ −H), 5.35 (2H, s, OCH ₂ −COO
CH ₂ ), 6.45 (2H, br.s, CONH ₂ ), 6.76 (1H,
s, thiazole ring 5-position proton), 7.18 (2H,
br.s, thiazole ring 2-position amino group), 7.68
(2H, d, J=8Hz, aromatic proton),
8.19 (2H, d, J = 8Hz, aromatic proton),
9.18 (1H, d, J = 10Hz, C ₃ −NH) Elemental analysis value C ₁₉ H ₁₈ N ₇ NaO ₁₂ S ₂・2H ₂ O as C (%) H (%) N (%) Calculated value 34.60 3.36 14.87 Actual value 34.44 3.10 14.82 (2) (3S,4S)-cis-3-[2-(2-amino-
4-thiazolyl)-2-(Z)-(p-nitrobenzyloxycarbonylmethoxyimino)acetamide]-4-carbamoyloxymethyl-2-
Sodium azetidinone-1-sulfonate 350
Dissolve mg in 20ml of water, 10% palladium carbon 350
mg and stirred at room temperature under hydrogen atmosphere for 1 hour. Filter off the catalyst and wash with water. Combine the filtrate and washing liquid, add 40 ml of Dowex 50W (H), and stir under ice cooling for 1 hour. The resin is filtered off and washed with water and a mixture of water and acetone. The filtrate and washings were combined and concentrated under reduced pressure, and the residue was subjected to column chromatography using Amberlite XAD-2 (150 ml), eluting with water and then 5% ethanol. When the fraction containing the target product is concentrated under reduced pressure and lyophilized, (3S,4S)-cis-3-
[2-(2-amino-4-thiazolyl)-2-
(Z)-(carboxymethoxyimino)acetamide]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid as a colorless powder
164 mg (61%) obtained. [α] ²⁶ _D −45° (c=1, DMSO) IRν ^KBr _nax cm ⁻¹ : 1760, 1715, 1670, 1640 NMR (d ₆ −DMSO) δ: 3.9 to 4.4 (3H, C ₄ −
H, _C4 - _CH2 ), 4.66 (2H, s, NO- _CH2 ),
5.28 (1H, dd, J=4.5, 10Hz, _C3 -H),
6.92 (1H, s, thiazole ring 5-position proton),
9.33 (1H, d, J = 10Hz, C ₃ −NH)

Claims (1)

[Claims] 1 (3S,4S)-cis-3-amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, or a salt or ester thereof. 2 (3S,4S)-cis-3-benzyloxycarboxamide-4-carbamoyloxymethyl-2
(3S,4S)-cis-3-, characterized by catalytic reduction of sodium azetidinone-1-sulfonate with hydrogen in the presence of palladium on carbon.
A method for producing amino-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid or its sodium salt.