JPS6225152B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to a method for producing oxazolinoazetidinone derivatives () useful as synthetic intermediates for antibiotics. The compound () represented by the formula () is produced by subjecting the penicillin 1-oxide compound () represented by the formula () to a ring-opening and closing reaction.

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[Formula] (wherein R ¹ is an alkyl, aralkyl or aryl group optionally substituted with aryloxy,
R ² is hydrogen or carboxy protecting group, R ³ is hydrogen,
Halogen or hydroxy group, R ⁴ is hydrogen or alkoxy group. However, in formula (), the S→O bond and the C-CH ₃ bond are assumed to be in cis coordination. ) It is already known that a thiazolinoazetidinone derivative can be obtained by heating and dehydrating a penicillin 1-oxide compound in the presence of a desulfurizing trivalent phosphorus compound. For example, as shown in the reaction formula below, the formula (-
When the compound represented by a) is heated to reflux in toluene in the presence of trimethylphosphite, the formula ()
A thiazolinoazetidinone derivative represented by [RDGCooper etal., J.Amer.Chem.Soc.,
92 5006 (1970)], and by heating and refluxing the compound of formula (-b) in benzene in the presence of triphenylphosphine, the compound of formula () can be obtained (Japanese Patent Laid-Open No. 48-4459) ). On the other hand, as shown in the formula below, penicillin 1-oxide (-
It is also known that by heating c) in the presence of a trivalent phosphorus compound as mentioned above, an oxazolinoazetidinone derivative () in which the oxazoline ring is in α coordination can be obtained (Japanese Patent Laid-Open No. 53-87388). . (In the formula, R ¹ ' is an organic group or hydrogen, and R ² and R ³ have the same meanings as above.) The present inventors have developed the formula (-a) and (-
As in the compound shown in b), penicillin 1-oxide in which the amide side chain at position 6 is β-coordinated,
When a desulfurizing trivalent phosphorus compound is applied in the presence of a small amount of acid catalyst, thiazolinoazetidinone derivatives as shown in the above formulas () and () are not produced at all, and the oxazoline ring is in β coordination. It was discovered that oxazolinoazetidinone derivatives () can be obtained, and the present invention was completed. In the above formulas () and (), the organic group represented by R ¹ is an alkyl group that may be substituted with aryloxy (methyl, ethyl,
pentyl, phenoxymethyl, phenoxypropyl, etc.), aralkyl (benzyl, phenethyl, etc.), aryl (phenyl, o-, m- or p
-tolyl, xylyl, naphthyl, etc.). These R ¹ groups may be substituted with halogen, alkyl, alkoxy, acyloxy, oxo, acylamino, nitro, etc.
The aryl group may be a 5- or 6-membered aromatic ring having a different atom in the nucleus. Of particular interest are compounds in which R ¹ CO is an acyl group that constitutes a side chain in natural or synthetic penicillins and cephalosporins. R ² is a protecting group for a carboxy group commonly used in hydrogen or β-lactam chemistry, the latter being able to withstand the reaction conditions of the production process of the present invention. Such protecting groups include, for example, alkyl (methyl, ethyl, t-butyl, etc.), aralkyl (benzyl, diphenylmethyl, trityl, etc.), aryl (phenyl, indanyl, etc.), organometallic (trimethylsilyl, ethoxydimethylsilyl, trimethylstannyl, etc.) etc.), metal atoms, etc. These protecting groups may have substituents such as halogen, hydroxy, acyloxy, alkoxy, oxo, acylamino, nitro and alkyl, and the aryl moiety is intended to also include an aromatic heterocycle. These protecting groups are usually removed after the reaction, so
Structural changes are often of no significance to the invention. R ³ is hydrogen or a nucleophilic group such as a halogen or hydroxy group. In the method of the present invention,
R ³ may be other nucleophilic groups, such as 3 in the chemistry of cephalosporins.
All groups introduced to replace the acetoxy group at position are included. Such nucleophilic groups include, for example, acyloxy (formyloxy,
Acetyloxy, benzoyloxy, nicotinoyloxy, carbamoyloxy, methoxycarbonyloxy, etc.), alkyloxy (methoxy,
ethoxy, etc.), thiocarbamoylthio, arylthio, aromatic heterocyclic group thio (1-methyltetrazol-5-ylthio, 1,3,4-thiadiazol-5-ylthio, 2-methyl-1,3,4-
thiadiazol-5-ylthio, 1,2,3-triazol-4-ylthio, 1,3,4-triazin-2-ylthio, etc.). R ⁴ is hydrogen or alkoxy (methoxy, ethoxy, etc.). As mentioned above, compound () can be produced by subjecting compound () to ring opening and closing reaction in the presence of a desulfurizing trivalent phosphorus compound and an acid catalyst.
Compound () is known. The preferred desulfurizing trivalent phosphorus compound used in this reaction is triarylphosphine or trialkylphosphine, but trialkylphosphites, aralkylphosphites, arylphosphites, etc. can also be used. These desulfurizing trivalent phosphorus compounds are preferably used in an amount of 1 mol or more based on compound (). Typical acid catalysts include pivalic acid, pyridinecarboxylic acids, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfinic acid, and squaric acid. It is most preferable to use As the acid catalyst, in addition to those mentioned above, protic acids used in producing desacetoxycephalosporanic acid from penicillin sulfoxide can also be used, but those with strong nucleophilicity are not preferred. The amount used may be a catalytic amount, for example 0.05 molar equivalent of compound () or less. Preferably, this reaction is carried out in a solvent. Suitable solvents include hydrocarbons (benzene, toluene, hexane, etc.), halohydrocarbons (methylene chloride, 1,2-dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (dioxane, tetrahydrofuran, etc.), amides (N.N.
-dimethylformamide, N/N-dimethylacetamide, hexamethylphosphorotriamide, etc.), esters (ethyl acetate, amyl acetate, etc.),
Mention may be made of alcohols (ethanol, butanol, t-butanol, etc.) and mixtures thereof, particularly preferred are benzene, 1,2-dichloroethane, toluene and mixtures of 1,2-dichloroethane and toluene. The reaction temperature ranges from 0° to 180°C, but below 70°C the reaction is slow (especially in the case of β-sulfoxide), and above 130°C the decomposition products tend to increase. Therefore, the preferred temperature range is 70°
to 130℃. The reaction time is 10 minutes to 15 hours.
It usually takes 2 to 5 hours to complete. During the reaction, water derived from oxide is generated, but
It can be removed by adding molecular sieves to the reaction solution, by drying the reflux solution, or by azeotropic dehydration. Although such a dehydration operation is not essential for this reaction, it has the effect of accelerating the reaction. The manufacturing method according to the present invention is preferably carried out as follows. That is, compound (), which is a raw material, is dissolved in a mixture of 7 to 15 times by weight of a hydrocarbon solvent (preferably benzene, toluene) and 7 to 15 times by weight of a halohydrocarbon solvent (preferably dichloroethane). 1.1 to 1.3 molar equivalents of a desulfurizing trivalent phosphorus compound (preferably triphenylphosphine) and about
0.01 to 0.10 molar equivalents of an acid catalyst (preferably squaric acid and about 3 to 5% of the amount of solvent N·N-
(combined with dimethylacetamide) and heated under reflux for 10 minutes to 15 hours, usually 2 to 5 hours, while drying the reflux solution. The reaction mixture is washed with water, dried, concentrated and, if necessary, purified using a silica gel column. The production method according to the present invention described above is an extremely suitable method for producing an oxazolinoazetidinone derivative having an isopropenyl group in its side chain. Note that when R ³ at the allylic position in compound () is hydrogen, it can be converted to a halogen, and when R ³ is a halogen, it can be converted to another halogen or hydroxy. For example R ³
If chlorine acts on a compound () in which is hydrogen,
A compound () in which R ³ is chlorine is obtained, and when this is treated with sodium iodide, a compound () in which R ³ is iodine is obtained. If treated with cuprous oxide or the like, a compound () in which R ³ is hydroxy can be obtained. Furthermore, even if a compound () in which R ³ is iodine is treated with silver trifluoroacetate to form a compound () in which R ³ is trifluoroacetoxy and this is brought into contact with hydrous silica gel, a compound () in which R ³ is a hydroxyl group can be obtained. ) is obtained. A method for producing the compound () by converting these R ³ to other R ³ is also included in the present invention. Compound () can be used as an intermediate for the synthesis of β-lactam compounds such as 1-oxacephem compounds useful as antibacterial agents. For example R ³
When a compound () in which is hydroxy is treated with an acid, preferably a Lewis acid, the ring is closed to form 1-oxa-
A 3-exomethylenecephalic skeleton is produced. This can be further converted to other 1-oxadethiacephalosporins. Examples and manufacturing methods of the present invention will be described below with reference to Examples. Example 1 Production of oxazolinoazetidinone compound () from penicillin 1-oxide () Table 1 shows the reaction conditions for the ring opening and closing reaction, and Table 2 shows the physical constants of the product. To show details of operation, Table 1 No. 3 and No. 18
The reaction and post-treatment operations are described below. (No. 3) 10.0 g (19.9 mmol) of 6β-benzamidopenicillanic acid diphenylmethyl ester/1β-oxide and 6.78 g of triphenylphosphine
(25.9 mmol) was dissolved in 100 ml of toluene, and 113 mg (0.995 mmol) of squaric acid and 5 ml of N.N-dimethylacetamide were added to this solution.
The distillate is refluxed for 90 minutes while being dehydrated using a Dean-Stark dehydrator packed with molecular sieves. After cooling, benzene was added to the reaction mixture, washed with water, and dried over anhydrous magnesium sulfate. The solvent is distilled off, acetonitrile is added to the residue, triphenylphosphine sulfide (Ph ₃ P=S) is precipitated and removed in the cold, and the residue is crystallized from isopropyl alcohol to obtain the desired oxazolinoazetyl. 7.60g (m.
p.133.5-135℃) is obtained. (No. 18) 5.7 mg of squaric acid and 0.23 ml of N·N-dimethylacetamide are stirred at room temperature for about 30 minutes to form a solution, and 2.25 ml of benzene and 138 mg of triphenylphosphine are sequentially added thereto. 284 mg of the starting material was added to the resulting solution, and the distillate was dehydrated using a Dean-Stark dehydrator packed with molecular sieves.
Reflux for 10 minutes. After cooling, the reaction mixture is poured into an ice-cooled 5% aqueous sodium bicarbonate solution, the mixture is extracted with ethyl acetate, the extract is washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was chromatographed on Prepack Column A (manufactured by Merck & Co.) with a benzene-ethyl acetate mixture to obtain 70 mg (26%) of an oxazolinoazetidinone compound. Example 2 Chemical modification of allylic position (Part 1: R ³ = H to R ³
= Conversion to Cl) Table 3 shows the reaction conditions. The physical constants of the products are the same as shown in Table 2. Table 3 No. 1 and No. 2 to show details of operation.
The reaction and post-treatment operations are described below. (No. 1) Oxazolinoazetidinone compound (R ¹ = phenyl, R ² = diphenylmethyl, R ³ = R ⁴ = H)
Dissolve 4.00 g in 250 ml of ethyl acetate, and add chlorine to a carbon tetrachloride solution (0.98
mol/1.7 equivalents) was added dropwise over 75 minutes.
After 30 minutes, the above reaction solution is poured into 60 ml of water containing 3.00 g of sodium bicarbonate and 1.68 g of sodium sulfite, and stirred vigorously for 2 hours. The organic layer of the reaction solution is separated, and the aqueous layer is extracted with ethyl acetate. The organic layer and extract were combined, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue is chromatographed on silica gel to obtain the allyl chloride in which R ³ is chlorine. Recrystallized from ethyl ether, 3.02g (mp. 138-140℃) as the first crystal,
Obtain 0.40 g as second crystal. Yield 3.42g (80
%). This reaction applies to compounds where R ¹ is other than benzyl. (No. 2) Oxazolinoazetidinone compound (R ¹ = benzyl, R ² = diphenylmethyl, R ³ = R ⁴ = H)
Dissolve 5.00 g (10.74 mmol) in 300 ml of methyl acetate, and slowly add a cold solution of hydrogen chloride in methyl acetate (1.0 equivalent). Then, in a nitrogen stream, a cold solution of chlorine in carbon tetrachloride (0.98 mol/, 1.7 equivalents) was added.
Drop in about 60 minutes. After 30 minutes, water containing 4.51 g of sodium bicarbonate and 2.70 g of sodium sulfite
Pour the above reaction solution into 100 ml and stir vigorously for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate, and then the solvent is distilled off. The residue is chromatographed on silica gel to obtain 1.70 g of allyl chloride in which R ³ is chlorine. This reaction applies to compounds where R ¹ is benzyl. Example 3 Chemical modification of allylic position (part 2: conversion from R ³ = halogen to R ³ = other halogen or hydroxy) Oxazolinoazetidinone compound (R ¹ = phenyl, R ² = diphenylmethyl, R ³ = Cl , R ⁴ =
H) Add 18 g (0.123 mol) of cold sodium iodide to a solution of 3.0 g (6.16 mmol) in 30 ml of acetone and react at room temperature for 6 hours. The reaction solution is poured into a mixture of benzene and water, and extracted with benzene.
The extract is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain a crude product of allyl iodine compound in which R ³ is iodine. For purification, chromatograph on silica gel. Dissolve the crude allyl iodine in 50 ml of ethyl acetate,
A solution of 2.59 g of sodium hydrogen carbonate in 25 ml of water is added to this solution to form two layers. Add 5.31 g of m-chloroperbenzoic acid (purity 80%) to this mixture and stir vigorously for 2 hours. After the reaction is complete, the ethyl acetate layer is separated, washed with a 5% aqueous Na ₂ S ₂ O ₃ solution, water, then saturated brine, and dried over anhydrous magnesium sulfate. When the solvent is distilled off, crude crystals of the alcohol in which R ³ is hydroxy are obtained. This is recrystallized from ethyl ether. Yield 1.88g (65%). Other reaction examples are shown in Table 4. The physical constants of the products are the same as those shown in Table 2.

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Claims (1)

[Claims] 1. A method for producing a compound represented by formula (), which comprises reacting a compound represented by formula () with a trivalent phosphorus compound in the presence of carboxylic acid or squaric acid: [Formula ] [Formula] (wherein R ¹ is an alkyl, aralkyl or aryl group optionally substituted with aryloxy,
R ² is hydrogen or carboxy protecting group, R ³ is hydrogen,
Halogen or hydroxy group, R ⁴ is hydrogen or alkoxy group. However, in formula (), the S→O bond and the C-CH ₃ bond are assumed to be in cis coordination. ).