KR810000607B1 - Process for preparing arylmalonamido-1-oxadethia cephalosporines - Google Patents

Abstract

Title compds.(I; Ar = thienyl, phenyl, p-hydroxyphenyl, protected p-hydroxyphenyl; COB1, COB2 = carboxy or portected carboxy; Het = 1-methyl tetrazol-5-yl, 1-carboxymethyltetrazol-5-yl, 1-thia-3,4-diazol-5-yl; Y = H, MeO) were prepd. by cyclization of azetidinones(II) in inactive solvent. Thus, 650mg II (Ar = phenyl; Het = 1-methyl tetrazol-5-yl; B1, B2= phenyl; R3 = phenyl) and 5ml dioxane were refluxed for 16 hr under N2 to give 423 mg I(Ar = phenyl; Het = 1-methyltetrazol 5-yl; B1,B2 = phenyl).

Description

Method for preparing arylmalon amido-1-oxadetia cephalosporin

The present invention relates to a method for preparing arylmalon amido-1-oxadetiacephalosporin of the general formula (I).

In the above formula,

또는 보호 P-히드록시페닐이고, COB¹및 COB²는 각각 카르복시 또는 보호된 카르복시기이며,Ar is

Or protective P-hydroxyphenyl, COB ¹ and COB ² are each a carboxy or protected carboxy group,

Het

(Where COB ³ is a carboxy or protected carboxy group) and Y is hydrogen or a methoxy group.

However, when Y is a methoxy group, Het

Cephalosporin flexible compounds having oxygen atoms at the positions of sulfur atoms in the nucleus are described in J.C. Heterocyclic Chemistry, Vol. 5, p. 779 (1968), German Patent Application (OLS) No. 2,219,601 (1972), Canadian Chemical Society, by Soul Wolf and his co-researchers. Vol. 52, p. 3996 (1974), and BG It is published by Christensen and his collaborators in the Journal of the American Chemical Society, Vol. 96, p.7582 (1974).

The present inventors have produced a large number of 1-oxadetia cephalosporins which are closely related to known (1--thia) -cephalosporins. B.C. proposing racemic 1-oxacephalosporins that exhibit about half the titers of (1-thia) cephalosporins. Contrary to the report of Christensen and its co-investigators, the optically active agents produced by the present invention were about four to eight times as potent as the corresponding (1-thia) cephalosporins in their antimicrobial activity. However, the β-lactam ring of 1-oxadeti acephalosporins was less stable as a clinical drug than the β-lactam ring of (1-thia) cephalosporins.

Compound (I) selected from the optically active agents prepared by the present inventors solves the above-mentioned drawbacks of 1-oxadetia cephalosporins.

Furthermore, compound (I) exhibited the following properties.

1) It has a great antibacterial activity against gram negative bacteria.

2) High stability of β-lactam ring.

3) The smallest difference in inhibitory concentration between β-lactamase producing and non-producing bacteria is small.

4) Less dependence on inoculum size.

5) Highly effective against other cephalosporins resistant bacteria (eg, enterobacteria, Serratia, indole-positive proteus).

6) High contribution to antimicrobial activity.

7) High blood levels.

Moreover, compound (I) whose Y is a methoxy group has the following excellence.

a) wide antibacterial range Example: Pseudomonas sp., 3.6γ / ml or more against Anaetobic bacteria (bacteroid pragillis).

b) High antibacterial activity against β-lactamase producing bacteria.

c) high blood stability.

d) low binding to serum proteins.

In general formula (I), Ar is preferably 3-thienyl, P-hydroxyphenyl and P-acyloxyphenyl, where acyl is 1-5C alkanoyl, carbamoyl, 2-6C N-alkyl Carbamoyl or ureido carbonyl.

In the definition of Ar, the Acyl group is an inorganic or organic acyl containing up to 8 carbon atoms, in particular 1-5C alkanoyl, 8-12C aralcanoyl, 7-9C aroyl, 2-5C alkoxycarbonyl, 8-20C Aralkyloxycarbonyl, carbamoyl, 2-6C N-alkylcarbamoyl and ureidocarbonyl.

Specific examples of acyls include formyl, acetyl, propionyl, butyryl, isobutyryl, enanthyl, phenylacetyl, phenylpropionyl, benzoyl, toluyl, carmethoxycarbonyl, benzyloxcarbonyl, carba Moyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isobutylcarbamoyl, N, N-dimethylcarbamoyl, carbamoylcarbamoyl, Na-methyl Ureidocarbonyl and the like acyl.

COB ¹ , COB ² and COB ³ may be carboxy or protected carboxy groups known in penicillin and cephalosporin combinations which normally contain up to 15 carbon atoms. These protecting groups may be the same or different for each carboxyl group in the molecule. Typically, protecting groups are removed in any synthetic step of compound (I) to give free carboxy or salt. Therefore, the structure of the carboxy protecting group can be varied widely without changing the gist of the present invention. In other words, their structures have no specific meaning other than protection, deprotection and salt formation (if included).

Specific examples of the protecting groups include esters (optionally substituted alkyl esters such as t-butyl, mono-hydroxy-tbutyl, 2, 2, 2-trichloroethyl and acyloxymethyl esters; aralkyl esters such as Benzyl, P-tolylmethyl, P-nitrobenzyl, P-methoxybenzyl, phenalidyl, diphenylmethyl, trityl and phenacyl esters; metal esters such as trimethylsilyl, dimethylyl methoxysilyl, trimethylste Nile esters, and other readily removable aliphatic esters; also aromatic esters such as phenyl, toryl, 3,4-dimethylphenyl and 5-indenyl esters, and pharmacologically acceptable salts (alkali metal salts) Such as magnesium, calcium and acyloxy calcium salts, and salts with organic bases such as procaine, triethylamine and dicyclohexylamine. Each carboxy in the molecule may be free or protected by the same or different groups.

Preferably COB ¹ , COB ² and COB ³ may be free carboxy or pharmacologically acceptable salts thereof.

Another preferred COB ¹ is 5-indenyloxycarbonyl, phenoxycarbonyl or dimethylphenoxycarbonyl.

However, some carboxy protecting groups are useful for altering the character of the product as a medicament. In such cases, they may be certain known groups for medicaments known in the art. These groups include the following pharmacologically acceptable groups: phthalidyl, acyloxymethyl, indenyl, phenyl, ponyl, dimethylphenyl and carmethoxymethylesters.

Preferred Y is methoxy, but it is always important that Y is hydrogen.

Typically, compound (I) is used as a salt for administration to humans or livestock. Most preferred salts are sodium or potassium salts, or salts with organic bases. These are selected according to stability, solubility, safety, and the like.

Important examples of compound (I) include the following.

7β- [α- (2-thienyl) -α-carboxacetamido] -3- (1-methyl-tetrazol-5-yl) thiomethyl-1-oxadetia-3-cepem-4-car Acid,

7β- [α- (2-thienyl) -α-carboxacetamido] -3- (1-carboxymethyl-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cefe-4 Carboxylic acids,

7β- [α- (2-thienyl) -α-carboxacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia -3-cefe-4-carboxylic acid,

7β- [α- (3-thienyl) -α-carboxacetamido] -3- (1-methyl-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4- Carboxylic Acid,

7β- [α- (3-thienyl) -α-carboxacetamido] -3- (1-carboxymethyl-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cefe-4 Carboxylic acids,

7β- [α- (3-thienyl) -α-carboxacetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia -3-cefe-4-carboxylic acid,

7β- (α-phenyl-α-carboxacetamido) -3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4-carboxylic acid,

7β- (α-phenyl-α-carboxacetamido) -3- (1-carboxy-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4-carboxylic acid,

7β- (α-phenyl-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia-3-cepem- 4-carboxylic acid,

7β- (α-P-hydroxyphenyl-α-carboxacetamido) -3- (1-methyl-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4-car Acid,

7β- (α-P-hydroxyphenyl-α-carboxacetamido) -3- (1-carboxy-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cefe-4-car Acid,

7β- (α-P-hydroxyphenyl-α-carboxacetamido) -3- (1-carboxy-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cefe-4- Carboxylic Acid,

7β- (α-P-hydroxyphenyl-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia- 3-cefe-4-carboxylic acid,

7β- (α-P-acetoxyphenyl-α-carboxacetamido) -3- (1-methyl-tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4-car Acid,

7β- (α-P-acetoxyphenyl-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia- 3-cefe-4-carboxylic acid,

7β- (α-P-propionyloxyphenyl-α-carboxacetamido) -3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4-car Acid,

7β- (α-P-pentanoyloxyphenyl-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) -thiomethyl-1-oxadetia -3-cefe-4-carboxylic acid,

7 β- (α-P-carbamoyloxyphenyl-α-carboxacetamido) -3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem-4 Carboxylic acids,

7β- (α-PN-methylcarbamoyl oxyphenol-α-carboxacetamido) -3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem- 4-carboxylic acid,

7 β- (α-PN-pentylcarbamoyloxyphenol-α-carboxacetamido) -3- (2-methyl-1,3,4-thiadizol-5-yl) -thiomethyl-1- Oxadetia-3-cefe-4-carboxylic acid,

7β- (α-P-ureidocarbonyloxyphenol-α-carboxacetamido) -3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem- 4-carboxylic acid,

7 β- [α- (2-thienyl) -α-carboxacetamido] -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3 -Cefem-4-carboxylic acid,

7 β- [α- (3-thienyl) -α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3 -Cefem-4-carboxylic acid,

7 β- (α-phenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyl) -tetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem- 4-carboxylic acid,

7 β- (α-P-hydroxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3- Cefem-4-carboxylic acid,

7 β- (α-P-acetoxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3- Cefem-4-carboxylic acid,

7β- (α-P-propionaloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3- Cefem-4-carboxylic acid,

7β- (α-P-benzoyloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3-cepem -4-carboxylic acid,

7β- (α-P-carbamoyloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia-3 -Cefem-4-carboxylic acid,

7 β- (α-PN-methylcarbamoyloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia -3-cefe-4-carboxylic acid,

7β- (α-PN-propylcarbamoyloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia- 3-cefe-4-carboxylic acid,

7β- (α-P-ureidocarbonyloxyphenyl-α-carboxacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxadetia- 3-cefe-4-carboxylic acid,

7β- (α-P-Nα-methylureidocarbonyloxaphenyl-α-carboxyacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-oxa Dethia-3-cepem-4 -carboxylic acids, and salts thereof (salts with inorganic or organic bases such as sodium, potassium, magnesium, calcium and other alkali or alkaline earth metal salts, triethylamine, dicyclohexyl Amine, morpholine or N-methylmorpholine salts), esters (e.g. t-butyl, t-amine-, 2,2,2-trichloroethyl, acyloxymethyl, phthalidyl, diphenylmethyl, trityl) Pharmacologically acceptable groups in the form of (benzyl, P-nitrobenzyl, P-methoxybenzyl, phenacyl, phenyl or indenyl ester) or derivatives whose carboxyl is protected by known groups and groups of the same kind.

Compound (I) having (1-methyltetrazol-5-yl) thiomethyl in the third position has the advantage of having the highest antibacterial activity against Gram-negative bacteria and a small decrease in the antibacterial activity at high bacteria content.

Compound (I) having (1-carboxymethyltetrazol-5-yl) thiomethyl in the third position has a high blood plasma concentration, and thus has a stronger anti-infective effect in vivo than antibacterial activity in vitro.

Compound (I) having phenylmanonamido, (2-thienyl) malonamido, or (3-thienyl) malonamido at position 7 exhibits particularly strong antimicrobial activity against Gram-negative bacteria.

P-hydroxy phenylmalon amido, P-acetoxyphenyl malon amido, P-carbamoyloxyphenyl malon amido, PN-methylcarbamoyloxyphenyl malon amido, or P-ureido at position 7 Compound (Ⅰ) having carbonyloxyphenyl malon amido has a low antimicrobial activity which is less active compared to the corresponding unsubstituted allyl malon amido compound in animal organisms because of its low level of serum monovalent binding and low blood concentration. Have They also show very potent activity against Pseudomonas strains, including carbenicillin resistant bacteria.

Compound (I) in which Y is a methoxy group at position 7α has a more stable and broader effect on β-lactamase (e.g., improved activity against Pseudomonas and other Gram-negative bacteria), and is more active than a compound whose Y is hydrogen. high.

All compounds (I) are novel substances exhibiting strong antimicrobial activity and are useful as medicines, animal medicines and bactericides.

For example, these compounds are administered orally or parenterally to humans or animals, eg, at a dose of 0.05 to 50 mg per day, per kg of body weight. In addition, these effective amounts may be administered by known methods in the form of various pharmaceuticals, such as homemade, injectable, ointment, liquid, tablet, powder and capsule, together with pharmacologically acceptable excipients, adjuvants, diluents or stabilizers. Salts, including alkali metal salts, are mainly administered parenterally. Acyloxymethyl, indenyl, phenyl, phthalidyl esters and the like are also suitable for oral administration. It is also useful as other synthetic intermediates outside the range or range of the compound of formula (I) having a carboxy protecting group.

The compound (I) can be prepared from the corresponding ringed azetidinones by, for example, a ring closure reaction by a wittig reaction. For example, azetidinone of the following general chamber (II) is heated in an inert solvent such as ether, aromatic hydrocarbon, halohydrocarbon, amide, sulfoxide and anhydrous solvent to prepare compound (I) in high yield.

Wherein Ar, COB ¹ , COB ² , Het and Y are as defined above, each of which is an alkyl or aryl group optionally substituted as the same or different.

When Ar is P-hydroxyphenyl, the compound can first protect its hydroxy group with a protecting group which is easy to remove and then deprotect to produce the desired hydroxyphenyl compound. Representative protecting groups include esters [C ₁ -C ₆ α-haloalkanoyl (eg trifluoroacetyl, trichloroacetyl), C ₁ -C ₆ alkanoyl (eg acetyl, formyl), C ₄ -C ₈ β-keto carboxyacyl (e.g. acetoacetyl), C ₂ -C ₁₂ alkoxycarbonyl (e.g. t-butoxycarbonyl, cyclopropylmethoxycarbonyl, norbornyloxycarbonyl, 2, 2, 2 -Trichloroethoxycarbonyl), C ₈ -C ₁₅ aralkyloxycarbonyl (e.g. benzyloxycarbonyl, P-methoxybenzyloxycarbonyl, P-nitro- or P-methylbenzyloxycarbonyl, di Phenylmethoxycarbonyl) and homogeneous acyl] and ethers [C ₁ -C ₆ alkyl (eg methyl, t-butyl, cyclopropylmethyl, isobornyl, tetrahydropyranyl, methoxymethyl) C _{7 -} C ₁₅ aralkyl group may be one of (benzyl, P- methoxy, methyl or P- P- nitrobenzyl, diphenylmethyl, trityl) and the same kind comprising a group of - those forming the. This protecting group is preferably introduced at the stage of its reactive derivative.

Deprotection is, for example,

1) Acylate with acid (mining, Lewis, strongly acidic carboxylic acid, sulfonic acid) or base (sodium carbonate or potassium, sodium hydroxide or potassium, organic base) at room temperature or high temperature in the presence of a cationic scavenger, if necessary Or disintegrate the ted,

2) It can be carried out by hydrotreating P-nitrobenzyloxycarbonyl or benzyloxycarbonyl with hydrogen and platinum or palladium according to a known method.

When the carboxy in the side chain or Het at the 4th or 7th position is protected, the protecting group can be deprotected according to known methods for removing the protecting group to give the desired compound (I). for example,

1) highly reactive esters, amides and anhydrides are readily hydrolyzed by acids or bases,

2) 2-haloethyl, benzyl, methylbenzyl, nitrobenzyl and diarylmethyl esters are used for mild reduction (divalent chromium salts in the presence of tin, zinc or acid; sodium itionate; platinum, palladium, nickel, etc. Decomposed by contact hydrogenation with hydrogen),

3) Benzyl, methoxybenzyl, methylbenzyl, dimethoxybenzyl, t-alkyl, trityl, diarylmethyl and cyclopropylmethyl esters may be reacted with an acid or (if necessary, in the presence of a cationic acceptor such as Decomposed by solvation decomposition) by a mineral acid, a lauric acid such as aluminum chloride, a sulfonic acid such as toluene-P-sulfonic acid, and a strongly acidic carboxylic acid such as trifluoroacetic acid, and the like.

4) Penacyl, ethynyl and P-hydroxy-3,5-di-t-butylbenzyl esters were prepared by the action of the base (alkali metal thiophenoxide, inorganic base, basic salt) and the same method. Decompose

Compound (I) having one or more free carboxy is known by the known method (for esters, by the action of the corresponding alcohol and the condensing agent, diazide, haloformate, etc., and for salts, alkali metals By the action of a hydroxide, carbonate or alkanoate salt or by the action of an organic base, an ion exchange resin), a protective group or substituent can be converted to the corresponding derivative by carboxylization.

The following examples are presented to illustrate the invention in detail. Elemental analysis and physical constants of the product in each example are inconsistent with a predetermined structural formula. In each of the examples below, the product generally contains nearly equivalent amounts of isomers to the α-asymmetric carbon atom in its amide side chain. These isomers are included within the scope of the present invention and, if necessary, can be separated by chromatography or other known methods. The nomenclature in each Example was based on what was described in the Japan patent application (exc. No. 49-133594) filed by US Merck Incorporated.

Production Example 1 (Preparation of 7α-amino Compound)

(1) 7β-phenylacetamido-3- (1-methyltrezol-5-yl) thiomethyl-1-oxadethia-3-cepam-4-carboxylic acid diphenylmethyl (955 mg); To the solution with methylene chloride (24 ml), phosphorus pentachloride (666 mg) and pyridine (0.258 ml) are added at -20 ° C in the presence of nitrogen gas. After stirring for 30 minutes at -20 ° C and 30 minutes at room temperature, the mixture is mixed with methanol (12 ml) at -20 ° C and stirred for 30 minutes at room temperature. The reaction mixture is diluted with water (6 ml), stirred for 30 minutes and concentrated under reduced pressure. The residue was dissolved in 5% aqueous sodium hydrogen carbonate solution under ice cooling and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The separated crystals were collected by filtration and washed with ether to prepare 7β-amino-3- (1-methylterazol-5-yl) thiomethyl-1-oxaderia-3-cepem-4-carboxylic acid diphenylmethyl (661). Mg). Melting point: 151 ~ 154 ℃ Yield: 86.5%.

3430, 3345, 1790, 1718, 1630㎝^-1 IR:

3430, 3345, 1790, 1718, 1630 cm ^-1

NMR: δ CDCl ₃ 1.75 brs ₂ H, 3.81 s ₃ H, 4.28 brs 2 H, 1.50 d (4 Hz) 1 H, 4.64 brs 2 H, 4.98 d (4 Hz) 1 H, 6.90 s 1 H, 7.20-7.7 mlOH.

286nm (ε=8695).UV:

286 nm (ε = 8695).

-232.8±7.6(c=0.360, (CH₃)₂SO).

-232.8 ± 7.6 (c = 0.360, (CH ₃ ) ₂ SO).

(2) 7β-phenylacetamed-3- (2-methyl-1,3,4, -thiadiazol-5-yl) -thiomethyl-1 in the same manner as described in the above (1). -A solution of oxaderia-3-cepem-4-carboxylic acid diphenylmethyl (381.5 mg) and methylene chloride (8 ml) was treated with phosphorus pentachloride (259 mg) and pyridine (0.1 ml) at -20 ° C. , 7-amino-3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-1-oxadetia-3 by treating with methanol, methanol (8 ml) and water (4 ml) in this order. Generate cefem-4-carboxylic acid diphenylmethyl (273.3 mg). Yield 88.8%.

3420, 3350, 1794, 1723㎝^-1 IR:

3420, 3350, 1794, 1723 cm ^-1

NMR: δ CDCl ₃ 1.88 s ₂ H, 2.67 s ₃ H, 4.25 + 4.55 ABq (14 Hz) 2 H, 4.52 d (4 Hz) 1 H, 4.68 s 2 H, 5.00 d (4 Hz). 1 H, 7.07 s 1 H.

-부톡시카르보닐메틸테트라졸-5-일) 티오메틸-1-옥사데리아-3-세펨-4-카르복실산 디페닐메틸(189mg)을 얻었다. 수율 : 76%.(3) 7β-phenylacetamed-3- (1-t-butoxycarbonylmethyldetrazol-5-yl) thiomethyl-1-oxade in the same manner as described in the above (1). A solution of thia-3-cepem-4-carboxylic acid dephenylmethyl (300 mg) with methylene chloride (10 ml) was treated with phosphorus pentachloride (180 mg) and pyridine (0.07 ml) at -20 ° C, followed by menol and (4 ml). ) And water (4 ml) to obtain 7β-amino-3- (1-

-Butoxycarbonylmethyltetrazol-5-yl) thiomethyl-1-oxaderia-3-cepem-4-carboxylic acid diphenylmethyl (189 mg) was obtained. Yield 76%.

1795,1753,1722cm^-1.IR:

1795,1753,1722 cm ^-1 .

NMR: δ CDVI ₃ 1.45s9H, 1.60-2.00m2H, 4.30s2H, 4.40-2.60m1H, 4.65brs2H, 4.86s2H, 5.00d (4Hz) 1H, 6.95s1H.

-메톡시의 도입)]Production Example 2 (7

Introduction of methoxy)]

-메톡시-3-(1-메틸테트다졸-5-일)티오메틸-1-옥사데티아-3-세펨-4-카르복실산디페닐메틸(906mg)을 특히 순황색 포상체(泡狀體) 상태로 얻었다. 수율 : 99.7%(1) 7β-amino-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadetia-3-cepem-4-carboxylic acid diphenylmethyl (600 mg) and 3,5-di- A solution of t-butyl-4-hydroxybenzaldehyde (353 mg) dissolved in a mixture of benzene (15 ml) and methylene chloride (5 ml) is refluxed for 1 hour while removing water with a sneaky sieve in a Dean stark water branch. The resulting 7β- (3,5-di-t-butyl-4-hydroxybenzal) amino-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadetia-3-cepem The 4-carboxylic diphenyl solution was cooled to -10 ° C to 15 ° C, mixed with anhydrous magnesium sulfate (1 g), followed by mixing with nickel peroxide (0.69 g) with stirring and 30 at -10 ° C to -15 ° C. The mixture is stirred for 15 minutes at room temperature. The reaction mixture is filtered to wash the replacement components with benzene. The resulting 7β- (3,5-di-t-butyl-4-oxo-2,5-cyclohexadienylidenemethyl) -amino-3- (1-methyltetrazol-5-yl) thio Methinol (10 ml) is added to a methyl-1-oxadethia-3-cepem-4-carboxylic acid diphenylmethyl solution, and the solution is allowed to stand at room temperature for 1 hour and evaporated to tightness under fitting. The residue was chromatographed on silica gel containing 10% moisture and eluted with a mixture of benzene and ethyl acetate (4: 1) to give 7β- (3,5-di-t-butyl-4-hydroxybenzal) amino. -7

-Methoxy-3- (1-methyltetazol-5-yl) thiomethyl-1-oxadetia-3-cepem-4-carboxylic acid diphenylmethyl (906 mg) in particular pure yellow foam I got in a state. Yield: 99.7%

-메톡시-3-(1-메틸테트라졸-5-일) 티오메틸-1-옥사데리아-3-세펨-4-카르복실산디페닐 메틸(469 mg)을 얻는다. 본 실시예를 통한 총수율 : 73.6% 융점 : 160~162℃(분해)(2) Girad T reagent (315 mg) was added to a solution of this product with a mixture of methol (10 ml) and tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 1 hour and diluted with water. Export to methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated to solidity under reduced pressure. The residue was purified by chromatography on silica gel (30 g) containing 10% of moisture and eluted with a mixture of ethyl acetate: benzene: methylene chloride (1: 1: 1) to give 7β-amino-7

-Methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxaderia-3-cepem-4-carboxylic acid diphenyl methyl (469 mg) is obtained. Total yield through this example: 73.6% Melting point: 160 ~ 162 ℃ (decomposition)

3425,3350,1792,1724cm^-1.IR:

3425,3350,1792,1724 cm ^-1 .

NMR: δ CDCl ₃ 2.00brs2H, 3.38s3H, 3.875s3H, 4.32s2H, 4.73s2H, 4.92s1H, 7.00s1H.

As is apparent from the above preparation, it was found that nickel peroxide was one of the optimal oxidants of the phenolic intermediate for introducing methoxy at the seventh position of the 1-oxa and 1-thiacefem rings.

Example 1

α- [4β- (1-methyltetrazol-5-yl) thioacetonyloxy-3β- (α-phenyl-α-diphenylmethoxycarbonylacetamido) -2-oxazetidin-1-yl The solution of) -α-triphenylphosphoranilidene acetate diphenylmethyl (650 mg) and dioxane (5 ml) was refluxed in a nitrogen atmosphere for 16 hours. The reaction mixture is concentrated under reduced pressure. The residue was purified by chromatography on silica gel (20 g) with a water content of 10%, and eluted with a mixture of benzene and ethyl acetate (4: 1) to obtain 7β- (α-phenyl-α-diphenylmethoxycarbonylacetamido. ) -3- (1-methylterazol-5-yl) thiomethyl-1-oxyderia-3-cepem-4-caroacid diphenylmethyl (432 mg) is obtained. Melting point: 107-109 ° C., yield: 80%.

3610, 1793, 1719, 1694, 1630, 1600㎝^-1 IR:

3610, 1793, 1719, 1694, 1630, 1600 cm ^-1

Example 2

In a manner similar to Example 1, α- [4β- (1-methyltetrazol-5-yl) thioacetonyloxy-3β- (α-phenyl-α-diphenylmethoxycarbonylacetamido) -3α -Methoxy-2-oxoazetimin-1-yl] -α-triphenyl phosphoanilidene acetate diphenylmethyl was refluxed in nitrogen for 15 hours, purified by chromatography on silica gel (15 g) to obtain 7β- ( α-diphenylmethoxycarbonyl-α-phenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) thiomethyl-1-oxadetia-3-cepem-4- Obtained carboxylic acid diphenylmethyl (540 mg). Yield 67%.

Example 3

In a manner similar to Example 2, α-3β- (α-P-benzyloxyphenyl-α-diphenylmethoxycarbonylacetamido) -3α-methoxy-4β- [3- (1-methyltetrazole -4-yl) thiomethyl-2-oxopropoxy] -2-oxoazetidin-1-yl-α-triphenylphosphate anilinene acetate diphenylmethyl in reflux in dioxane under nitrogen stream for 10 hours Purification by chromatography on gels 7β- (α-diphenolmethoxycarbonyl-α-P-benzyloxyphenylacetamido) -7α-methoxy-3- (1-methyltetrazol-5-yl) Thiomethyl-1-oxadetia-3-cefe-4-carboxylic acid diphenylmethyl is obtained.

The starting material of this process is a series of 1) peracids, 2) t-butyl chlorite, 3) lithium methoxide, 4) lithium 1-methyltetrazol-5-yl mercaptide, and 5) chromium trioxide. Reaction was prepared from α- (3β-benzamido-4β-allyloxy-2-oxo mazetidin-1-yl) -α-isopropylidene acetate diphenylmethyl to produce α- [3β-benzamido- 3α-methoxy-4β-3- (1-methyltetrazol-5-yl) thiomethyl-2-oxopropoxy-2-oxoazetidin-1-yl] -α-isopropylidene acetate diphenylmethyl Which is treated with 6) phosphorus pentachloride, 7) methanol and 8) triethylamine, and treated with α {3β-amino-3-methoxy-4β- [3- (1-methyltetrazol-5-yl) thiomethyl -2-oxopropoxy] -2-oxoazetidin-1-yl} -α-isopropylidene acetate diphenylmethyl, which is 9) chloride α-P-benzyloxylphenyl-α-benzyloxycarb Carbonylacetyl and triethylamine, 10) ozone, 11) zinc and acetic acid, 12) thionyl chloride and pyridine, and 13) it is treated with triphenylphosphine.

Claims (1)

A method for producing arylmalon amido-1-oxadetia cephalosporin and its derivatives according to formula (I), wherein the azetidinones of formula (II) are heated and closed in an inert solvent.

Wherein each Ar is thienyl, phenyl, P-hydroxyphenyl, protected P-hydroxyphenyl, COB ¹ and COB ² are each a carboxy or protected carboxy group, Het

or

Wherein COB ³ is a carboxy or protected carboxy group, Y is hydrogen or a methoxy group. However, when Y is a methoxy group, Het

. Each of the three R's is the same or different, optionally substituted alkyl or aryl groups.