KR810000714B1 - Process for preparing 1-oxadethiacepham compounds - Google Patents

Abstract

Title compds.(I; A = NH2, substituted-NH2; E = H, MeO; COB = carboxy, protected carboxy; X = H) useful as intermediate for 1-oxadethia cephalosporine, were prepd. by elemination H-Z of II (Z = eliminative group). Thus, 1.50 g II(A = PhCONH; E = H; B = Ph2CHO; X = H) in 100 ml CH2Cl2 was stirred with 6.8 ml C6H5N while cooling and was filtered to give 2 kinds of I which the one was 2-cephem and the other was 3-cephem(yield 25.2% and 10.8%, resp.).

Description

Method for preparing 1-oxadethiacepam compound

The present invention relates to a process for the preparation of 1-oxadethiacepam compounds which are useful synthetic intermediates of 1-oxadethiacephalosporin useful as antibacterial agents.

1-oxadetiacephalosporin is an antisynthetic method based on total synthesis of azetidinone compatibility (Japanese Laid-Open Patent Publication No. 49-133594) and penicillin (Canadian, Journal of Chemistry) , Vol. 52, p. 3996 (1974), Japanese Patent Laid-Open No. 51-14925, which has not yet been industrialized. MEANS TO SOLVE THE PROBLEM This inventor reached | attained this invention after studying and studying the economic synthesis method of 1-oxadetia cephalosporin.

That is, according to the invention, the compound represented by the following general formula (I _d ), which is a useful synthetic intermediate of 1-oxadethiacephalosporin, which is a useful antimicrobial agent, is represented by the general formula HZ from the compound represented by the following general formula (II _d ) It is prepared by desorption of the compound represented.

Wherein A is an amino or protected amino group, E is a hydrogen or methoxy group, COB is a carboxy or protected carboxy, X is a hydrogen or nucleophilic group, and Z is a leaving group.

The protected carboxyl groups contained in COB are commonly used in the chemistry of B-lactams and are able to withstand these reaction conditions. Carboxylic acids generally contained in COB include esters [alkyl (methyl, ethyl, t-butyl, etc.); Aralkyl (benzyl, diphenylmethyl, trityl, etc.); Aryl (phenyl, indanyl, etc.); Or organometallic (trimethylsilyl, ethoxydimethylsilyl, trimethylstannyl) ester and the like], amide (N-methyl-amide, diisopropylhydrazide), anhydride, halide or salt. In such a part, especially, you may have arbitrary substituents, such as halogen, hydroxy, acyloxy, alkoxy, oxo, acylamino, nitro, cyano, or alkyl, and an aryl part also contains an aromatic bicyclic group. It shall be. These protecting groups are typically removed after the reaction, allowing a variety of structural changes without affecting the final product.

The nucleophilic group included in X is intended to include all the groups introduced in the substituted form of the acetoxy group in the 3-position in the chemistry of cephalosporin. Representative of such X is halogen (chlorine, cancellation, oxo, etc.), hydroxy, acyloxy (formyloxy, acetyloxy, trifluoroacetyloxy, benzoyloxy, nicotinoyloxy, toluenesulfonyloxy, car Barmoyloxy, methoxycarbonyloxy, nitrooxy), alkoxy (methoxy, ethoxy etc.), thiocarbamoylthio, arylsulfinyl and aromatic dicyclic arylthio (phenylthio, 1-methyltetrazol-5 -Ylthio, 1,3,4-thiadiazol-5-ylthio, 2-methyl-1,3,4-thiodiazol-5-ylthio, 1,2,3-triazol-4-yl Arylthio containing 1,3,4-triazin-2-ylthio, etc.) etc. are mentioned.

A leaving group represented by Z is a part showing a positive charge in a nucleophilic reagent, and is also a group that can be easily induced or substituted in these groups. Representatives of such leaving groups include halogen, hydroxy, acyloxy, arylthio, arylsulphenyl, arylserenyl, arylsulfinyl, alkylsulfinyl and the like.

If any of the above-described COB or Z group changes unsuitably in the reaction described below, this part can be protected in advance and then deprotected at any stage after the reaction.

The starting material is capable of various structural modifications according to conventional methods in B-lactam chemistry to obtain a compound of the following formula.

(Wherein A is amino or substituted amino, E is hydrogen or methoxy, and Y is a divalent group represented by the following structural formula:

Wherein COB is carboxy or protected carboxy, X is hydrogen or nucleophilic group and Z is leaving group

Wherein A group is amino, acylamino (e.g., alkanoylamino, aryloxyalkanoylamino, aroylamino, arkananoylamino, α-aminoarylacetamido, α-protected aminoarylacetamido, α- Ureidoarylamido, α-hydroxyarylacetamido, α-acyloxyarylacetamido, α-tetroaroylaminoarylacetamido, α-alkoxyiminoarylacetamido, α-carboxyaryl Acetamido, α-protected carboxyarylacetamido, α-sulfoaralacetamido, α-protected sulfoarylacetamido, α-haloarylacetamido, carbobenzooxyamino and the like, silylamino (e.g. , Trimethylsilylamino, dimethoxymethylsilylamino, etc.), sulfphenylamino (e.g., phenylsulphenylamino), hydrocarbylamino (e.g. benzalamino, hydroxybenzalamino, 1-alkoxyalkylideneamino, 1- Halo-alkylideneamino, tritamiami O), diacylamino, or other known penicillins and cephalosporins. The aryl moiety as exemplified above may be phenyl or heterocyclic aryl optionally substituted with hydroxy, halogen, sulfonylamino aminomethyl, hydroxymethyl, etc., with preferred aryl optionally substituted with thienyl, thiazolyl and halogen Phenylhydroxy, acyloxy, or amino. In addition, preferred alternatives to group A for synthesis include natural penicillin side chains, ie phenylacetamido or natural cephalosporin side chains, and sensitive groups closely related thereto, ie, optionally protected α-aminoadipo. Neyl, (gamma)-oxo adiponyl, glutaryl, etc. are mentioned.

The above structural modification is represented by the following scheme.

(Wherein A, Y, X, Z, COB and E are as defined above and Y ¹ is the same as that of Y but differs from Y with respect to X, Z, COB or double bond positions).

Desorption of the Z group in the starting compound (A) is carried out by adjacent hydrogen to obtain a Δ ² -or Δ ³ -cefe compound. The double bond isomers are formed depending on the position of the leaving hydrogen, but the isomers result from the transition of the formed double bonds in the reaction conditions or the preparation period.

When the reaction activity of Z is sufficiently high, HZ may be detached without maintaining a specific reagent by only maintaining the elevated temperature.

When the Z is halogen (e.g. chlorine, cancellation, oxo or the like or acyloxy (e.g. photoacid acyloxy, optionally substituted alkanoyloxy, carbamoyloxy, sulfonyloxy, phosphoryloxy, etc.), the acid acceptor (e.g., Aliphatic amines, aromatic amines, aromatic bases; salts of organic weak acids with strong bases, hydroxides of alkali metals, bicarbonates, carbonates, vercaptides, or alcohols; alkaline earth metal oxides, hydroxides, hydrogencarbonates or carbonates; alumina, Silica gel) otherwise promote the reaction.

When Z is hydroxy, a dehydrating agent (e.g., thionyl halide, phosphorus pentoxide, mineral acid, Lewis acid, strong carboxylic acid, aliphatic or aromatic sulfonic acid or phosphoric acid, inorganic or organic base, alumina, silica gelamide), halogenating agent ( For example, if reagents such as phosphorus halide, phosphorus trifluoride, phosphorus oxyhalogenation, thionyl halide, sulfuryl halide, and acylation reagents (e.g., anhydrous acid, acid halide, isocyanic acid) are required, By using in the presence of the acid acceptor described above, the desorption reaction can be promoted.

The reaction can be carried out under an inert gas (e.g. nitrogen, argon or dicyclic carbon, etc.) under a solvent (e.g. hydrocarbon, halogen hydrocarbon, ether, ester, ketone, alcohol, sulfoxide, nitrile, pyridine or quinoline, base, acid, acetic acid). Or anhydrous acids such as trifluoroacetic anhydride, or a solvent composed of these mixtures) and at -50 to 100 ° C.

(Other variations)

Compound (A) is a conventional modification of β-lactam chemistry (e.g., transfer of double bonds, protection and deprotection of carboxybox groups to COB, protection and deprotection of amino groups to A, introduction of group X). And substitution with a nucleophilic reagent or conversion by acylation, hydrolysis, oxidation or reduction of X or Z).

(Use of side reactions)

When the molecule contains an unstable group, it can be affected by a reagent or a solvent during the reaction. For example, the addition of halogens to 3-exomethylene groups involves the N-halogenation of 7-amides. That is, the imino formation using base for 7-methoxy introduction results in the desorption of HZ when Z is halogen or acyloxy, and the replacement of X being halogen with a basic nucleophilic reagent causes HZ to desorb when Z is halogen. do. These are regarded as side reactions. By using such side reactions deliberately, one can achieve more effective synthesis than one reaction.

Representative examples of these are given in the following Examples, but the unit variations in the molecules indicated therein are each within the scope of the present invention.

(Glass and tablets of the product)

As described above, the compounds (Id) and (A) prepared by the desorption reaction or other modification are removed after concentration, extraction, washing, drying, etc. It is obtained by purification by conventional methods such as precipitation, chromatography, recrystallization, and absorption. In addition, three- or seven-position stereoisomers can be separated by performing precise chromatography and fractional recrystallization. However, these stereoisomers may be passed on to subsequent processing without separation if necessary.

(Use of product)

Replacement of group A by an antimicrobially preferred side chain prior to the double bond at the 3 position using the above compounds (I _d ) and (A) as starting materials, and / or 1-deria-1 as necessary Known 1-dethia-1-oxacephalosporin antibiotics by a method such as deprotection of a protective carboxyl group against COB after the transfer of an antimicrobially suitable X to the methylene bond at the 3-position of the oxase fem nucleus (Japanese Patent Publications Nos. 49-133594 and 51-149295). The double bonds of A and COB and X described above may, of course, be replaced with other antimicrobially suitable ones before forming the desired cefe system. The choice as groups A, COB and X in the starting materials and intermediates depends on the ease of reaction, handling or use, stability under reaction conditions, waste, cost and other practical requirements.

Here, compound (A) having carboxy as COB is a useful antimicrobial agent.

Advantages of the Invention Method Over the Prior Art

A known method for preparing 1-dethia-1-oxacephalosporin (Japanese Patent Laid-Open Publication No. 51-149295) is to separate the thiazolidine ring from penicillin to make an azetidinone thiol isolate and to form a new 5-carbon alcohol. The units are recombined to form azetidinooxazine double rings. Another fully synthetic method (Japanese Patent Laid-Open No. 49-133594) requires an intermediate molecular cyclization reaction to form a dihydrooxazine ring. In the method according to the present invention, there is no loss of carbon from the starting penicillin, and the cyclization reaction between the molecules is smooth, and there are few by-products and therefore a high yield can be obtained.

Due to the interposition of the carbonium ions at the 4-position of the azetidinone starting material, a mixture of 4α and 4β ethers is formed at a ratio of about 1: 1, resulting in the loss of half of the ether produced. In contrast, the method according to the present invention is stereoselective, and such stereoisomers are not actually separated out.

In addition, as a result of the high yield of stereoscopic reaction, the product can be easily crystallized after industrial stagnation.

Such embodiments of the present invention will be described below, but the scope of the present invention is not limited thereto.

The co-nucleus of the compound of the present invention is as follows.

The stereochemistry around carbon No. 1 of the bicyclo-hept-2-ene system is the same as that of 6-epipenicillin at the 6-position, and cephalosporin around carbon No. 5 of the bicyclohept-2-ene system It is the opposite of that of the six-position of.

The stereochemistry around carbon No. 6 of the 1-dethia-1-oxampem ring system is the same as that of the 6-position of cephalosporin.

The stereochemistry of COB in the general formula is usually the same as that of penicillin. That is, when the presence of an isomer is possible, it has R coordination, but is not limited thereto.

The experimental error of the IR spectrum is in the range of ± 10 cm ^-1 and the error in the NMR spectrum is in the range of ± 6.2 ppm.

Melting point was not corrected.

Anhydrous sodium sulfate was used for solution drying.

Physical constants of the products are shown in Table III.

[Examples I-1 to 20]

A solution of the 1-dethia-1-oxacepam compound dissolved in a solvent is mixed with a desorption agent under the conditions shown in Table-4 to obtain 1-dethia-1-oxacefem compound (I).

An experimental procedure of the detachment reaction is exemplified as Reaction No. 12 as follows.

1.50 g of 7α-benzamido-3ε-hydroxy-3ε-methyl-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl is suspended in 100 ml of dichloromethane, where 6.8 ml and thionyl chloride are added thereto. 3 ml are added with stirring under ice-cooling, and then the mixture is stirred at the same temperature for 4.25 hours followed by 2.25 hours at room temperature and then poured into ice water. The organic layer is separated, washed with water and evaporated to dryness. The obtained residue was chromatographed on 350 g of 10% functional inert silica gel, and eluted with a mixture of benzene and ethyl acetate (9: 1) to obtain 7α-benzamide-3-methyl-1-dethia-1-oxa-3-cepem- 2.65 g of 4-carboxylic acid diphenylmethyl (yield 25.2%, melting point 144-146 degreeC) and 7 (alpha)-benzamido-3-methyl- 1-dethia- 1-dethia- 1 -oxa-2- cefe-4 (alpha) 1.05 g of diphenylmethyl carboxylic acid (yield 10.8%);

3440, 1745, 1676, 1663sh ㎝^-1)IR:

3440, 1745, 1676, 1663sh cm ^-1 )

Get

II. Continuous reaction

EXAMPLE 2-1-8

Dissolve 7α-amide-7β-unsubstituted-3-exomethylene-1-dethia-1-oxacepam in dichloromethane and mix with halogenated reagent and base in methanol to mix under the conditions shown in Table-5 under 3-halogen Obtain 3-halomethyl-7α-methoxy-7β-amido-1-dethia-1-oxacepam. In some cases, the 3-halogen atom is desorbed with adjacent hydrogen to obtain the corresponding 3-cefem compound.

Examples 5-6 will be described in detail to exemplify experimental procedures of the addition reaction, the methoxylation reaction and the continuous reaction of elimination.

246 mg of 7α-p-cyanobenzamido-3-exomethylene-1-dethia-1-oxapepam-4α-carboxylic acid diphenylmethyl was dissolved in 8 ml of cold dichloromethane at -50 ° C, followed by 1.2M of chlorine carbon tetrachloride. A solution is added and the mixed solution is stirred for 7 minutes under irradiation with 300 W tungsten or the like. Lithium in methanol in this reaction mixture containing 7α- (N-chloro-p-cyanobenzamido) -3-exomethylene-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl 1.57 ml of a 2M solution of methoxide is added and stirred at -50 to -60 ° C for 10 minutes, then 0.2 ml of acetic acid is added to ice-water and extracted with dichloromethane. The resulting extract was diluted with an aqueous sodium hydrogen carbonate solution and water, dried and concentrated to 7α-cyanobenzamido-7α-methoxy-3-chloromethyl-1-dethia-1-oxa-3-cepem-4-carboxyl A residue containing acid diphenylmethyl is obtained, which is dissolved in 6 ml of dichloromethane and stirred for 1 hour at room temperature in 3 ml of water with 100 mg of sodium 1-methyltetrazol-5-metcaptide and 20 mg of tetrabutylammonium bromide. The reaction mixture was poured into ice water, extracted with dichloromethane, washed with water, dried, concentrated and purified by silica gel chromatography to obtain 7β-p-cyanobenzamido-7α-methoxy-3- (1-methyltetrazole-5 251 mg of -ylthio) methyl-1-dethia-1-oxy-3-cepem-4-carboxylic acid are obtained.

A. Transfer of Double Bonds

Example A-1

100 mg of 7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cepem-4-carboxylic acid was dissolved in 10 ml of acetone, and 0.1 ml of triethylamine was added thereto. The mixture is left for 6 days. Peptide chromatography of this reaction mixture shows spots of 7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-3-cepem-4-carboxylic acid and starting material.

Example A-2

5.0 g of 7α-benzamido-3,3-methylene-1-dethia-1-oxacefem-4α-carboxylic acid diphenylmethyl was dissolved in 25 ml of dichloromethane, and 0.5 ml of triethylamine was added thereto to prepare the mixed solution. After stirring for 80 minutes at room temperature, a small amount of benzene was added, followed by concentration and dilution with ether to give 7α-benzamido-3-methyl-1-dethia-1-oxa-3-cefe-4-carboxylic acid diphenylmethyl. 4.5 g (90% yield) is obtained as crystals.

After equilibration to 15 hours at room temperature the mixture separated by chromatography △ ² - isomer 50.8%, and △ ² △ ³ - isomer 4.1% and △ ³ - isomer shows a 38.3%.

Example A-3

100 mg of 7α-benzamido-3-methylene-1-dethia-1-oxacepam-4α-carboxylic acid is dissolved in 10 ml of acetone, 0.1 ml of triethylamine is added thereto, and the mixture is left to stand for 5 days. Caterpillar chromatography of this reaction mixture was carried out with 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cepem-4-carboxylic acid, 7α-benzamido-3-methyl-1-de Thia-1-oxa-3-cepem-4-carboxylic acid, and the spot of the starting material.

B. Removal of Carboxy Protectors

Example B-1

960 mg of 7β-benzamido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl was dissolved in 4 ml of anisole, 10 ml of fluoroacetic acid is added, stirred for 15 minutes and concentrated under reduced pressure. The residue was solidified in ether and n-hexane mixture to give 470 mg of 7β-benzamido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacepam-4α-carboxylic acid colorless. Obtained as a powder. Yield 70%, Melting Point 208-203 캜 (Decomposition)

In the same manner, the following free carboxylic acid can be produced from the corresponding diphenylmethyl ester.

7β-benzamido-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacepam-4α-carboxylic acid, melting point 100 to 105 ° C (decomposition)

7α-benzamido-7α-methoxy-3α-trifluoroacetoxy-3β-methyl-1-deria-1-oxacepam-4α-carboxylic acid, melting point 108 to 113 ° C.

7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cepam-4-carboxylic acid, melting point 195-198 ° C.

3250, 1766, 1742, 1642㎝^-1 IR:

3250, 1766, 1742, 1642 cm ^-1

7α-benzamido-3ε-chloro-3ε-chloromethyl-1-dethia-1-oxacepam-4α-carboxylic acid, melting point 118 to 122 ° C. (decomposition).

Example B-2

1.125 g of 7α-benzamido-3-oxomethylene-1-dethia-1-oxacepam 4α-carboxylic acid diphenylmethyl is dissolved in a mixture of 15 ml of dichloromethane and 3.5 ml of anisol, followed by 625 mg of aluminum trichloride and nitro A solution of 20 ml of methane is added dropwise at -20 占 폚 and stirred at -10 to -20 占 폚 under nitrogen stream for 30 minutes. The reaction mixture is poured into ice-water containing hydrochloric acid and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution, acidified with concentrated hydrochloric acid and reextracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain 623 mg of 7α-benzamido-3-exomethylene-1-dethia-oxacepam-4α-carboxylic acid diphenylmethyl.

In the same manner, 1.8 g of 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cepam-4α-carboxylic acid diphenylmethyl is dissolved in 25 ml of dichloromethane, and this is 5.8 ml of anisole trichloride. Solubilization of solubilization at -10 ° C. for 30 minutes using 1.026 g of aluminum and 36 ml of nitromethane to give 935 mg of 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cepam-4α-carboxylic acid. Obtained (yield 72.6%)

C. Protection and Deprotection of Amino Groups

Example C-1

25 mg of 7α-amino-3-methylene-1-dethia-1oxacepam-4α-carboxylic acid diphenylmethyl is dissolved in 0.5 ml of dichloromethane, and 7 μl of pyridine and 10 μl of benzoyl chloride are added at -20 ° C under a nitrogen stream. . The mixture is stirred for 1 hour, poured into ice water, stirred for 5 minutes, and then extracted with dichloromethane. The organic layer was separated, washed with water, an aqueous sodium bicarbonate solution and then water, dried and evaporated to obtain 28 g of 7α-benzamido-3-methylene-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl. Yield 86%) was obtained, the product was identified by TLC and NMR.

Example C-2

Dissolve 94 g of 7α-benzamido-3-methylene-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl in 4 ml of dichloroethane, 32 μl of pyridine and 1.08 ml of 0.37 M phosphorus / dichloromethane solution. Is added at -40 ° C under a stream of nitrogen. The mixture is warmed to room temperature and stirred for 1 hour, cooled to -40 ° C, then mixed with 8 ml of methanol, warmed to 0 ° C, and 0.8 ml of water is mixed and evaporated under reduced pressure. The residue obtained is dissolved in 20 ml of ethyl acetate and washed with water. This solution is extracted using sodium bicarbonate and water. Combine the aqueous extract with the tax solution, cover with ethyl acetate, adjust to pH 7.0 and extract with ethyl acetate. The organic layer was separated, washed with water, dried, and evaporated to obtain 29 mg (yield 40%) of 7α-amino-3-methylene-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl.

3000, 1770sh, 1760, 1740㎝^-1.IR:

3000, 1770 sh, 1760, 1740 cm ^-1 .

D. Substitution and Deformation of X and Z

Example D-1

(1) 108 mg of 7α-benzamido-3ε-hydroxy-3ε-bromomethyl-1-methia-1-oxacepam-4α-carboxylic acid diphenylmethyl is dissolved in 5 ml of 10% functional acetone, and potassium carbonate 50 mg is added, stirred at room temperature for 1.5 hours, diluted with brine and extracted with dichloromethane. The extract is evaporated to dryness over magnesium sulfate. 90 mg of the obtained residue was purified by thin layer chromatography on a silica gel plate [solvent type: benzene + ethyl acetate (2: 1)] to obtain 7α-benzamido-3,3-epoxymethano-1-dethia-1- 40 mg of oxacepam-4α-carboxylic acid diphenylmethyl is obtained. Stereoisomer B (56 mg) in 3-position of this product was obtained in 3-position at 140 mg of the starting material stereoisomer.

(2) 20 mg of 1-methyltetrazol-5-yl-thiol was dissolved in 2 ml of tetrahydrofuran, and then 0.05 ml of n-butyl / lithium 1.5 ml hexane solution was added and stirred for 30 minutes, followed by 7α-benzamido- 56 mg of 3,3-epoxymethano-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl (epimer B) was mixed with a solution dissolved in 1 ml of tetrahydrofuran, stirred for 1 hour, and aqueous sodium hydrogen carbonate solution. It is added and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate. The obtained residue was chromatographed on a 10% water-inactivated silica gel (1 g) column, eluted with a mixture of benzene and ethyl acetate (9: 1) to 7α-benzamido-3- (1-methyltetrazol-5-yl 43 mg of thiomethyl-3-hydroxy-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl (Epimer B) is obtained.

Example D-2

(1) 100 mg of 7α-benzamido-3α-hydroxy-3β-methyl-1-dethia-1-oxacepam-4-carboxylic acid diphenylmethyl was dissolved in 5 ml of isopropenyl acetate and p-toluenesulfonic acid- 6 mg of monohydrate is added and heated to 60 ° C. for 75 minutes. After cooling, the reaction mixture is poured into a mixture of ice water and a rare aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, washed with water, dried, and evaporated to obtain 7α-benzamido-3α-acetoxy-3β-methyl-1-dethia-1-oxapam-4α-carboxylic acid diphenylmethyl in a yield of 30.5%.

(2) A starting material as described in (1) was used with 1.1 equivalents of lithium diisopropylamide, 1.2 equivalents of acetyl chloride and 20 parts of tetrahydrofuran for 45 minutes at -40 ° C, 15 minutes at -20 ° C, and then 0 Treatment for 20 minutes at < RTI ID = 0.0 > C < / RTI > or treatment with one equivalent of pyridine and 1.2 equivalents of acetyl chloride dissolved in dichloromethane.

(3) 52 mg of 7β-benzamido-7α-methoxy-3α-hydroxy-3β-methyl-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl was dissolved in 1 ml of dioxane, 0.1 ml of fluoroacetic anhydride is added under an ice-cold nitrogen stream, the mixture is kept at room temperature for 2 hours, 0.3 ml of water is added thereto, stirred for 30 minutes, diluted with iced water, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 64 mg of 7β-benzamido-7α-methoxy-3α-trifluoroacetoxy-3β-methyl-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl. Get as an oil.

(5) A mixture of 112 mg of 7α-benzamido-3ε-hydroxy-3ε-hydroxymethyl-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl containing 0.5 ml of pyridine and 0.3 ml of acetic anhydride Dissolve in and leave at 0 ° C. overnight. The mixture is concentrated in vacuo and then poured into ice water and extracted with ethyl acetate. The extract was washed with water, diluted hydrochloric acid, aqueous sodium hydrogen carbonate solution, and then water, dried, and concentrated to obtain 7α-benzamido-3ε-hydroxy-3ε-acetoxymethyl-1-dethia-1-oxacepam-4α- 54 mg of diphenylmethyl carboxylic acid are obtained as crystals having a melting point of 11 (to 120 ° C).

(6) 350 mg of 7α-benzamido-3ε-hydroxy-3ε-hydroxymethyl-1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl was dissolved in 3 ml of dichloromethane, and 0.078 ml of pyridine and 0.075 ml of methanesulfonyl chloride is added, and the mixture is stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract was washed with water, an aqueous sodium hydrogen carbonate solution, and then water, dried, and evaporated, and then purified by silica gel chromatography at 370 mg of residue, followed by silica gel chromatography, 7α-benzamido-3ε-hydroxy-3ε-methanesulfonyloxy-methyl. 145 mg of 1-dethia-1-oxacepam-4α-carboxylic acid diphenylmethyl are obtained.

Symbol description in subsequent tables

-Ph = phenyl-C ₆ H ₄ CN-p = cyanophenyl

-STetr = 1-methyl-1,2,3,4-tetrazol-5-yl -C ₆ H ₄ Cl-p = p-chlorophenyl

-C ₆ H ₄ NO ₂ -p = p-nitrophenyl-Bu-t = quaternary butyl

-C ₆ H ₄ CH ₃ -p = p-tolyl -OAc = acetoxy

= Between X and Z indicates that CH ₂ X and Z are both methylene groups.

-O- between X and Z indicates that X and A are ethoxy.

A double bond at the Δ ² or Δ ³ = 2 (3) or 3 (4) position with respect to Z represents the substitution of the leaving group at the 3-position.

TABLE 1

TABLE 2

TABLE 3

Claims (1)

A method for producing a compound represented by the following general formula (Id), characterized by desorbing a compound represented by the general formula H-Z from a compound represented by the following formula (IId).

Wherein A is amino or substituted amino, E is hydrogen or methoxy, COB is carboxy or protected carboxy, X is hydrogen or nucleophilic group, and Z is leaving group.