CS196419B2 - Method of producing 1-dethia-1-oxacephamderivatives - Google Patents

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE INVENTION 196419 (11) (B2) (ί (22) Registered 14 02 78 (51) Int. Cl.3 C 07 D 498/04 fe) (21) (PV 6971-78) (32) (31) (33) Priority from 06 06 77 (67025) Japan OftAD FOR INVENTIONS (40) Published 29 OS 79 ( 45) Published 15 03 83 A DISCUSSIONS (72) YOSHIOKA MITSURU, UYEO SHOICHIRO, TOYONAKÁ,

Author of the invention HAMASHIMA YOSHIO, KYOTO, KIKKAWA IKUO, TAKARAZUKA, TSUJI TERUJI, TAKATSUKI and NAGATA WATAR, NISHINOMIYA (Japan) (73)

SHIONOGI & CO., LTD., OSAKA (Japan) "(54) Method for the production of 1-dethia-1-oxazamate

In the formulas given in this Scheme-1-Oxation of the Formula (III) Formula

(/IN)

In the formulas given in this Scheme A represents an amino or amino group protected with C 2 -C 5 alkanoyl, a benzoyl group optionally substituted in the phenyl part with an amino group, a cyano group with a halogen atom or an alkyl group having 1 to 3 carbon atoms, a phenylalkanoyl group having 2 to 4 carbon atoms carbon atoms in the alkanoyl moiety, or a phenoxyalkanoyl group having 2 to 4 carbon atoms in the alkanoyl moiety, E represents a hydrogen atom or a methoxy group, COB represents an ester-protected carboxyl or carboxyl group, 196413 according to the following reaction scheme

(III) X represents a hydrogen atom, a halo atom, a hydroxyl group or a halo-substituted alkanoyloxy group having 2 to 4 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, an alkylsulfonyloxy group. C 1 -C 3, toluenesulfonyloxy, phenylthio or 1-methylthrazol-5-ylthio; Z represents a halogen atom, a hydroxyl group or an alkanoyloxy group having 2 to 4 carbon atoms. .

The compounds of formula III are useful as intermediates for the preparation of effective antibacterially active 1-oxadethia-cephalosporins, or as antibacterial agents. The starting materials for the process of the invention, which may alternatively be described by the formula (I) below, may be prepared from the corresponding oxazolinoazetidine general formula (II) by treatment with an acid, in particular the following reaction scheme: ijA?

OH (II)

In the formulas given in this scheme, R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group optionally substituted with a n-tricyclic, a cyano group, a halogen atom or an alkyl group having 1 to 3 carbon atoms, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl moiety or phenoxyalkyl having 1 to 3 carbon atoms in the alkyl moiety, and Y represents a bivalent radical of formula -CH 2 -CH 2 -CH 2 i -CHCl 2 CH 2 -CHC-CH 2 -CH-C = CH2,

I -. I / I

GOB COB O COB —CH — CH2 II I '

—CH — CCH 2 X or — C — CCH 2 X

I I

COB - COB

In general, the protected carboxyl group of the COB moiety may be any protecting group conventionally used in chemically N-lactam compounds, stalases of the reaction conditions of the process of the invention. The carboxyl group contained in the COB moiety may generally be protected in the form of, for example, an ester [such as an alkyl ester (e.g., methyl ester, ethyl ester or tert-butyl ester), an aralkyl ester (e.g., benzyl ester, diphenylmethyl ester, or trityl ester), or an ester containing an organometallic moiety (e.g. trimethylsilyl ester, ethoxydimethylsilyl ester or trimethylstannyl ester, amide (e.g., N-methyl amide or diisopropyl ester hydrazide, anhydride, halide). the protecting group may optionally be substituted with electrons attracting or electron-providing a substituent such as halogen, hydroxy, acyloxy, alkoxy, oxo, acylamino, nitro, cyano or alkyl and the aryl moieties include heteroaromatic The cyclic group therefore, the action is cleaved and its structure can be varied remarkably without affecting the resulting product. A preferred protecting group is an ester group.

If the radicals R, COB, Y or Z undergo undesirable changes during the reaction according to the invention, they can be protected in any stage of the process before the reaction is carried out and deprotected.

Performing the reaction.

Compounds of formula (I) may be prepared from the corresponding oxazolinoazetidines of formula (II) by treatment with acid. Typical examples of useful acids include mineral acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), sulfonic acids, and strong carboxylic acids (e.g., methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid). ), Lewis acids (e.g. boron trifluoride, zinc chloride, tin tetrachloride, bromidium tetrachloride, antimony trichloride or titanium chloride) and the like acids.

The reaction is usually carried out for 5 minutes to 10 hours, especially for 15 minutes to 3 hours, at a temperature of from -30 ° C to + 50 ° C, in particular from 15 ° C to 30 ° C, to give a compound of the formula I in high yield. If desired, the reaction can be carried out by stirring or in an atmosphere of an inert gas (e.g., nitrogen, carbon, or carbon dioxide). The reaction is usually carried out in an inert solvent. Typical inert solvents include hydrocarbons (e.g., hexane, cyclohexane, benzene or toluene), halogenated hydrocarbons (e.g., dichloromethane, chloroform, dichloroethane, tetrachloromethane, or chlorobehzen), ethers (for example diethyl ether, isobutyl ether, dioxane or tetrahydrofuran), esters (e.g. ethyl acetate, butyl acetate or methyl benzoate), ketones (e.g. acetone, methyl ethyl ketone or cyclohexanone), sulfoxides (e.g. dimethyl sulfoxide), nitriles (e.g. acetonitrile) The solvent groups containing the hydroxyl group are reacted with the starting material of formula (II) to produce external products, but these solvents can be used under controlled reaction conditions. solvents containing hydroxyl groups are water, alcohols (eg d methanol, ethanol, tert-butanol or benzyl alcohol, acids (e.g. formic acid, acetic acid, propionic acid and mixtures thereof). The terminal hydroxyl group attached to the Y radical of the oxazolinoazetidine of formula (II) can be protected with a suitable hydroxyl function protecting group, readily cleavable under the reaction conditions (e.g., formyl, tetrahydropyranyl, and the like). According to the invention, the migration of the double bond, introduction of a nucleophile, elimination or similar side reactions can occur, but these reactions can be used intentionally and are therefore within the scope of the invention.

A typical embodiment of the invention is as follows: 1 part of the oxazolinoazetidine of formula (II) is dissolved in a mixture of 5 to 10 parts of a halogenated hydrocarbon (e.g. chloroform or dichloromethane) and 0 to 10 parts of a solvent ether type (e.g. ether or dioxane J, mixed with 0.005 to 5 mol equivalents of acid (e.g. boron trifluoride etherate, toluenesulphonic acid, sulphate-copper; zinc chloride, tin tetrachloride), and the solution is left for 0.5 to 10 hours at 10 DEG to 60 DEG C. to give the corresponding compound of the formula I in a yield of about 50 to 95 o / o.

The abovementioned starting materials of formula II are prepared from 1-oxides of 6-epipenitics, for example according to the following reaction scheme, wherein R, COB and X are as defined above: v 19 6 419

O

U ce. 19 6 419 • 7

Structural modification of products

It has been found that the products of the above-described cyclization can be subjected to various structural modifications customary in chemistry .beta.-lactam derivatives to give the compound of general formula A

wherein A, E and Y are as defined above.

It is to be understood that the protecting groups of the amino function within the meaning of the symbol A can vary widely, as is customary in the chemistry of penicillins and cephalosporins. In general, the symbol A may not only have the specific meanings given, but that radical may generally be an amino group, an acylamino group. (For example, alkanoylamino, aryloxyalkanoylaminoskupina, aroylamino, aralkanoylamino, and-aminoarylacetamidoskupiha, chráněná'a-aminoarylacetamidoskupina and ureidoarylacetamidoskupina-and-hydroxyarylacetamidoskupina and acyloxyarylacetamidoskupina-and-heteroaroylaminoarylacetamidoskupina and alkoxyiminoarylacetamidoskupina-and-karboxyarylacetamidoskupiha, protected a-karboxyarylacetamidoskupina and -sulfoarylacetamidoskupina, protected and sulfoarylacetamidoskupina-and-halogenarylacetamidoskupina neboběnzýloxykarbonylaminoskupinaj, siiylaminoskupina (e.g. trimeťhylsilyláminoskupinanebo dimethoxymethylsilyamirioskupina) sulfenylamiinoskupina (e.g. phenylsulfinyl enylamino) amino radical substituted with a hydrocarbon solvent (e.g. benzaíminoskupina, hydroxybenzalaminoskupina, 1-alkoxyalkylidenaminoskupina, 1-j halogenalkylidinaminoskupina nebotritylaminoskupina , a diacylamino group or the like group usually in the side The aryl moieties of these examples may be a phenyl radical or a heteroalkyl radical which may optionally be substituted by a hydroxyl group, a halogen atom, a sulfonylamino group, an aminomethyl group, a hydroxymethyl group, and the like. aryl radicals include thienyl, thiazolyl and phenyl radicals optionally substituted by halogen atoms, hydroxyl, acyloxy, amino or amino. Preferred residues within the meaning of the symbol A may be alternatively side chains of natural penicillins, i.e. phenylacetamido and enoxyacetamido groups, or side chains of naturalcephalosporins, and their closely related de-degradation derivatives, i.e., optionally protected α-aminoadipoyl, χ-oxoadipoyl and glutamic acid residues. .

The structural modification object of the invention can, as mentioned above, be described by the following reaction scheme:

As representative examples of other possible structural modifications, the following reactions are possible: 196419 10 1)

creation. (minu 4 ^ -0 apAkAdice N-γ njethaJaoiu 0 OCH,

3)

elimination of HZ »

cbrdctené dtmaove q '‘fu.r3.kce

COB <sd &amp; t &amp; p® and. cfil-A-nici group .j — aftat0 ° ^ ft * Q / g: e

4)

. ‘E

Jma - Q rt3.Of.lf (A.CG A, --—.— -r. -W-γ -r ° i .ii_V1 In these schemes, the symbols A, Y, X, Z, COB, and E have the above the meaning of aY1 has the same meaning as above for Y, but differs from the symbol Y in the starting point in terms of the meaning of the symbols X, Z and COB or as regards the position of the double bond.

Methoxylation

Compounds of formula A wherein E is hydrogen may be oxidized with nitrogen in residue A to form an imino compound (corresponding to formula A, wherein A and E together form a group - N =] and convert thereto to form methanol of formula A wherein E is methoxy.

When A is amino or amido, the compound of formula (A) is treated with a nitrogen-halogenating agent to remove hydrogen halide by treatment with a base to form the corresponding imino compound, which is then reacted with methanol to give the desired compound. of Formula A wherein E is methoxy. Halogenation on nitrogen may be accompanied by halogenation and other moieties, but from the product these excess halogen atoms may be removed by reduction.

The above process can be carried out by any of the following methods: 1. The starting amine or amide is reacted with a nitrogen-halogenating agent (for example, molecular halogen or tert-butyl hypochlorite) and the resulting product is treated with methoxide. an alkali metal (for example lithium methoxide, sodium methoxide or potassium methoxide) or an alkaline earth metal methoxide (for example, magnesium methoxide, calcium methoxide or barium methoxide) in methanol. 2. The starting material is reacted with tert-butyl hypohalide and methanol in the presence of a base and phenyllithium, optionally in the presence of a further solvent (e.g. tetrahydrofuran). 3. The starting material is reacted with a tert-butyl alcohol in the presence of borate in methanol and the partially formed excess halogenated product is reduced with zinc, phosphite or the like. 4. The starting material is sequentially treated with bromine, phosphorus pentachloride in the presence of pyridine, a base, a methanolic base with atrialkylsilyl chloride or tetraalkylammonium chloride. ,

Alternatively, compounds of formula A in which E is hydrogen and A is amino may be treated with a suitable aldehyde (e.g., benzaldehyde, p-hydroxybenzaldehyde or 3,5-di-tert-butyl). n-butyl-4-hydroxybenzaldehyde) to form a Schiff base, which is oxidized to an imino compound which is reacted with methanol and subsequent hydrolysis to give compounds of formula A wherein E is methoxy and A represents an amino group. 196419 11 12

A typical example of a piethoxylation reaction is as follows: 1 part of the amide of formula A is dissolved in 10 to 50 parts of an inert solvent (e.g. dichloromethane, dioxane; ether, dipropylether or tetrahydrofuran); stirring at -70 ° C for 2 to 10 minutes. C to -10 ° C with 1 to 5 molecviyalents of a nitrogen-halogenating agent (for example molecular halogen in carbon tetrachloride or tert-butyl hypochlorite), then mixing 1 to 4 equivalents of metal methoxide (for example lithium methoxide or methoxide magnesium in methanol) and stirring for 5 to 70 minutes at -50 DEG C. to 0 DEG C. The reaction mixture can be neutralized with acetic acid or a mineral acid and extracted with an organic solvent. wherein E represents a methoxy group, in a yield of up to 95%

The compound of formula (A) containing the exomethylene group at the 3-position (corresponding to formula IV) is readily reactable with the addition reagent XZ (e.g., with a molecular halide, peracid, peroxid, hypohalogenite salt) or an ester, a heavy metal peroxide, for example osmium tetroxide, or a sulfenyl logenide) in an inert solvent (for example, a hydrocarbon, halogenated hydrocarbon, ether, ester, and the like to form compounds of formula III wherein Y is a divalent group of formula -CH 2.

—CH — CZ — CH2X

COB wherein COB, X and Z are as defined above.

The addition can be carried out smoothly even at a low temperature ranging from -70 ° C to 0 ° V, for a period of from 5 minutes to 10 hours, in an inert solvent (especially in a halogenated hydrocarbon or in an ether-type solvent) to obtain the addition the product in up to 90% yield due to the high reactivity of the 3-exomethylene double bond to the particular agent. When the reagent is a molecular halogen, the halogenation can be accelerated by irradiation with light or addition of a catalyst (e.g., copper, sulphide, copper (I) chloride or triphenylphosphine oxide), with the addition of high yield.

Elimination

This modification is carried out by removing from the starting compound of formula (A) the residue Z together with the adjacent hydrogen atom, thereby obtaining kají2- or -3-cefem-derivatives. Isomers differing in the position of the double bond are formed depending on the location of the cleaving hydrogen, but the formation of these isomers can also result from the migration of the already formed double bond under the reaction conditions or during processing.

If the reactivity of residue Z is sufficiently high, the compound HZ is eliminated without using any reagent, for example by heating the starting material to elevated temperature.

When Z is a halogen atom (e.g. chlorine, bromine or iodine) or an alkanoyloxy group as defined above, the elimination is accelerated by the addition of an acid acceptor (for example an aliphatic amine, an aromatic amine, an aromatic base, a strong base of a weak organic acid, an alkali metal hydroxide, alkali metal oxide, hydroxide, bicarbonate or carbonate of an alkaline metal, bicarbonate, carbonate, mercaptide or alkoxide of an alkali metal, alumina or silica gel metal oxide.

When Z is a hydroxyl group, the elimination is accelerated by the addition of a dehydrating agent (e.g. thionyl halide, phosphorus pentoxide, mineral acid, Lewis acid, strong carboxylic acid, aliphatic or aromatic sulfonic acid, inorganic or organic base, alumina or amidated silica gel), a halogenating agent (e.g., phosphorus halide, phosphorous halide, phosphorous oxyhalide, thionyl halide or sulfuryl halide), an acylating agent (e.g., acid anhydride, acid halide or acid isocyanide or the like) an agent, optionally in the presence of an acid acceptor (for example the acid acceptor mentioned above).

The reaction may be carried out at a temperature of from about -50 ° C to about 100 ° C with stirring under an inert gas (e.g., under nitrogen, argon carbon dioxide) in a solvent (e.g., the aforementioned hydrocarbon, halogenated hydrocarbon, ether, ester, ketone, alcohol, sulfoxide) , a nitrile, a base such as pyridine or quinoline, an acid, an anhydride, such as acetic or trifluoroacetic anhydride, or similar solvents or mixtures thereof).

Other modifications

It has been found that compounds of general formula (A) can be subjected to other structural modifications customary in the chemilipid chemistry (such as, for example, the migration of a double bond, the protection and regeneration of a carboxyl group in the sense of a COB group, the protection and regeneration of the amino group in the the symbol A, introducing or exchanging the residue X by the action of a nucleophilic agent, or converting the residue in the meaning of X and Z within the above definition, including acylation, hydrolysis, oxidation or reduction, and the like ).

Use of side reactions

If the molecule contains unstable groups, these groups may occasionally be coated with a reagent or solvent during some of the above reactions or during processing. Thus, for example, halogen addition to the 3-exomethylene moiety is accomplished by halogenation at the 7-amido nitrogen; base formation in the case of the introduction of a 7-methoxy group causes elimination of the compound HZ when Z represents a halogen atom or an alkanoylpyridine, and the substitution of halogen for the symbol X with a basic nucleophilic agent leads to the elimination of the compound HZ when Z is a halogen atom. These reactions may be considered more responsive, but in some applications, the synthesis may in some cases be more effective than successive reactions.

Typical suggestions for using these side reactions are set forth in the Examples. Said use of side reactions is also within the scope of the invention.

Product isolation and cleaning

Compounds of the formulas I, A and III prepared by cyclization, methoxylation, addition, elimination or other modifications can be isolated from the reaction mixture by removal of the solvent, unreacted substances, by-products and other impurities by evaporation, extraction, washing , drying or similar methods, and purifying by precipitation, chromatography, crystallization, absorption, or other similar cleaning operations. Stereoisomers differing in the 3-position or 7-position configuration may be separated by bombardment chromatography, fractional recrystallization or the like in conventional manner. If preferred, the stereoisomers may be subjected to further processing without separation.

Use of products

The compounds of formulas I, A and III can be used as starting materials for the preparation of, for example, high yields of known antibacterial 1-dethia-1-oxacephalosporins (Japanese Patent Application Serial No. 49-133594 and 51-149295) by by migration of the double bond to the 3-position, replacing the A-residue with a side chain of the preferred antibiotic activity and / or the re-generation of the protected carboxyl group in the meaning of the COB moiety, optionally with respect to the antibiotic X-residue in the 3-position methylene bond 1-oxafemic core, as mentioned above. This double bond and the A, COB, and X residues may be replaced by suitable groupings, as appropriate, prior to the formation of the desired chemical system for antibacterial activity. '

The choice of the abovementioned A, COB and X residues in the starting material and in the intermediates may depend on the ease of carrying out the reaction, the handling or use, the stability of the substances under reaction conditions or the processing, the waste products, the cost factors or other practical factors.

The compounds of formulas A 'and III containing a carboxyl group in the meaning of COB are antibacterially effective. Advantages of this process over the prior art.

The known method for the preparation of 1-dethia-1-oxation-phospho sporins is based on penicillins (Japanese Patent Application No. 51-149295), the thiazolidine ring of which cleaves to form free azetidinonthiol and bicyclic azetidinooxazine is formed by re-bonding the new five-carbon alcohol residues. Another totally synthetic procedure (see Japanese Patent Application Publication No. 49-133594) requires difficult to control intermolecular cleavage resulting in the dihydrooxazine ring formation. In the process according to the invention, no carbon is removed from the starting penicillins, resulting in smoother intramolecular cyclization and the formation of a minor amount of by-products, resulting in a higher yield.

Since the known processes are associated with the formation of the carbonium ion in the 4-position of the azetidine starting material, a mixture of 4α and 4-ether is formed in the proportion of about 1: 1, losing about half of the ether produced. . The process of the invention, on the other hand, is stereoselective and practically does not require the separation of these stereoisomers. As a result of these stereospecific, high yield yields, the products are easily crystallized after simple and commercially feasible cleaning.

The invention is illustrated by the following non-limiting Examples.

The compounds exemplified contain the following numbered and named nuclei:

196419 15 16 1/3, 5, / SH- or (1R, 5S) -7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene 6

1-dethia-1-oxacepham.

The stereochemistry around carbon # 1 of the bicyclo-hept-2-ene system is the same as the stereochemistry at position 6 of the 6-epipenicillin and the stereochemistry around carbon # 5 of the bicyclohept-2-ene system is reversed than that of the cefa-losporin in position 6.

Stereochemistry around carbon # 6 in the 1-de-thia-1-oxacepha-ring ring system is identical to the stereochemistry at position 6 of cefalo-sporins.

The stereochemistry of the COB grouping in the individual samples is usually the same as that of the penicillins, i. however, it is not limited to this configuration.

The experimental errors in the IR spectra are in the range of + 10 cm -1, and in the NMR spectra in the range + 0.2 ppm.

Melting points are not corrected. Sodium sulphate anhydrous is used to dry the solutions.

The physical product constants are summarized in Table III. I. Preparation of Starting Materials by Cyclization (Reference Examples Examples I-1 to 32

The oxazolinoazetidine of formula (II) is dissolved in a solvent and under the conditions of Table I below to give the desired 1-dethia-1-oxa-oxidation of the formula (I) by treatment with the acid. -

The details of the cyclization reaction are described below in reaction example # 13 of Table I:

Pb

N ^ O \ t

JJJCHO-CH3COOCHPbzPbCONH- by 11 *

CHOHOH

CHC ~ GHS i ·

I OH COOCHP,

CH $ COOCHPb ^ (1) A solution of 12.0 g diphenylmethyl-2 - ((1, R, 5S) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl) -2-isopropenylacetate, 1.0 g of osmium tetroxide and 12.0 g of potassium chloride in a mixture of 400 ml of tetrahydrofuran and 200 ml of water are stirred at 58 for 3.5 hours. ° C. After cooling, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine, 10% aqueous sodium thiosulphate and finally with aqueous sodium bicarbonate solution, dried and evaporated. 12.88 g of diphenylmethyl-2 - ((1R, 5S) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6 are obtained. -yl) -3,4-dihydroxy-3-methylbutyrate.

• · ·. I = 3500 (broad band), 1770 (broad band), 1742, 1636 curt (2) To a solution of 10.88 g of the product prepared in (1) above in 300 ml of ether, add 0.075 ml of boron trifluoride etherate, mixture 3, It is stirred for 5 hours at room temperature in a nitrogen atmosphere, then poured into cold aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine and evaporated. Wash the residue with a mixture of dichloromethane and ether to give 15 g of a mixture of isomers of diphenylmethyl-7α-benzamido-3-methyl-3 H -hydroxy-1-dehium-1-oxacepham-4α-carboxylate. guration in position 3. av ». max = 3560.3445, 1774, 1739, 1670 cm @ -1.

This mixture was chromatographed on a silica gel column deactivated with 10% water. For 19841917, the product eluted with benzene / ethyl acetate (4: 1) was recrystallized from acetone / ether and then from acetone / dichloromethane to give two separate stereoisomers. Example 1 - 33

Ph Λ O OCHO1— | CH 2 '' COOCH / h.

PhCONH

COOCMfk (a) To a solution of 54 mg benzyl 2 - ((1R, 5S) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene -6-yl) -3-phenyloxymethyl-2-butenoate in 2 ml of methanol was added 19 µl of boron trifluoride ether with cooling to -20 ° C, and the mixture was stirred at -20 ° C for 40 minutes. at 0 DEG C., then at 0 DEG C. for 2 hours and finally at room temperature for 1 hour, then stirred with 5% aqueous sodium bicarbonate solution and extracted with dichloromethane. Wash the extract with water and evaporate after drying. Crystallization of the residue from methanol yields 10 mg of benzyl-7'-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate (20% yield). mp 208-212 ° C. (b) In a similar manner as above, except that 5 μΐ of trifluoromethanesulfonic acid is used instead of boririfluoride and the mixture is stirred for 130 minutes with ice cooling, or 0.5 ml of 0.38 N hydrochloric acid. methanol and the mixture was stirred for 3 hours, the same product having a melting point of 208-212 ° C can be prepared in a yield of 14 mg (27.5%), respectively. 5 mg (7%). II Addition of the Invention Examples II-1 to 1¾-3,3-Methylene-1-dethia-1-oxacefamido derivative of formula I are dissolved in the solvent and mixed with the addition reagent XZ to give the conditions given in Table II below to give the desired adduct. product. In order to illustrate the experimental embodiment, the reactions of Nos. 3, 4 and 15 of Table II are described in detail.

Reaction # 3 To a solution of 519 mg of diphenylmethyl-7α-benzamido-3-exomethylene-1-dethia-1-oxa-1-amine-4α (carboxylate in 5 mL of dichloromethane adds 1.6 mL of 0.76 N chlorine solution in The mixture was stirred at -20 DEG C. to -30 DEG C. for 40 minutes under tungsten lamp irradiation, then 0.14 ml of cyclopentane was mixed and stirred for a further 5 minutes.

The reaction mixture was stirred with 0.14 ml of 1,5-diazabicyclo [3.4.0] non-5-ene for 10 minutes at -20 ° C, then washed with dilute acid, hydrochloric acid and water, dried will evaporate. Recrystallization of the crystalline residue from methanol gave 484 mg of diphenylmethyl-7α-benzamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate (86% yield), m.p. to 128 ° C, Reaction # 4 To a solution of 103 mg diphenylmethyl-7α-benzo-196419 19 amido-3-methylene-1-dethia-1-oxacefam-4α-carboxylate in 1 ml methylene chloride, add 0.3 ml 0, 75 N chlorine solution in tetrachloromethane, the mixture is left behind the irradiated tungsten lamp. For 30 minutes at -20 ° C to -30 ° C, and then evaporated under reduced pressure. 120 mg of diphenylmethyl-7α-behamido-3β-chloro-3β-chloromethyl-1-dethia-1-oxacepham-4α-carboxylate are obtained.

Reaction # 15

In an analogous manner as above, by reaction of 705 mg of diphenylmethyl-7α-phenylacetamido-20 -3-methylene-1-dethia-1-oxacepham-4α-carboxylate with 1.77 equivalents of chlorine in 7 ml of methylene chloride at a temperature of —25 ° C. diphenylmethyl-7 (z-phenylacetamido-3 H -chloro-3-chloromethyl-1-dethia-1-oxacefam-4α-carboxylate.

The latter product is reacted with 0.16 ml of piperidine at 15 ° C for 40 minutes to yield 586 mg (yield: 78.4%) of diphenylmethyl-7α-phenylacetamido-3-chloromethyl-1-dethia-1-oxa -3-cephem-4-carboxylate melting at 179-182 ° C with decomposition. Example 11-17

To a solution of 1.405 g (3.0 mmol) of diphenylmethyl-7α-benzamido-3-methylene-1-detium-1-oxacepham-4-carboxylate in 28 ml of dry dichloromethane cooled to -26 ° C, 14 mg of copper powder were added under stirring under nitrogen, 6.3 ml (2.5 equivalents) of a 1.2 M solution of chlorine in chloroform were added dropwise over 10 minutes and the resulting mixture was stirred at -22 DEG for 3 hours. The reaction mixture was stirred with an aqueous solution of 2.98 g (4 equivalents.) Of sodium thiosulfate pentahydrate, extracted twice with dichloromethane, the extract was washed with aqueous sodium bicarbonate solution, then twice. Sodium chloride solution, dried over magnesium sulfate and evaporated The residue is chromatographed on 190 g of silica gel, eluting with a 3: 1 mixture of benzene and ethyl acetate, to give 1.541 g of colorless foamed phenylmethyl-7a-benzamido. -3α-chloro-3/3-chloromethyl-1-dethia-1-oxacefam-4α-carboxylate (95.2% yield). double / bond grace (reference examples) Example A-1 To a solution of 100 mg of 7β-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylic acid in 10 ml of acetone are added to 0.1 ml of triethylamine and the mixture is left to stand for 6 days. The blends which the reaction mixture is thin-layer chromatographed are 7-benzamido-7a-methoxy-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid and the starting material. material. Example A-2 To a solution of 5.0 g of diphenylmethyl-7a-benzamido-3,3: methylene-1-dethia-1-oxacepham-4a-carboxylate x in 25 ml of dichloromethane was added 0.5 ml of triethylamine, The mixture was stirred at room temperature for 80 minutes. After the addition of a small amount of benzene, it was concentrated and the residue was diluted with ether. 4.5 g (90% yield) of crystalline diphenylmethyl-7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate are obtained.

Fifteen-hour equilibration of this mixture at room temperature yielded 50.8% of the A2-isomer, 4.1% of the A2- and AMsomer, and 38.3AMsomer. (after chromatographic separation) Example A-3 To a solution of 100 mg of 7α-benzamido-3-methylene-1-dethia-1-oxaacetamide-4-carboxylic acid in 10 mL of acetone was added 0.1 mL of triethylamine and is left for 5 days. Thin layer blemishes corresponding to the reaction mixture correspond to 7ar-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylic acid, 7a-benzamido-3-methyl-1-dethium. 1-oxa-3-cephem-4-carboxylic acid and starting material. B. Cleavage of the carboxyl protecting group (reference examples) Example B-1 To a solution of 960 mg diphenylmethyl-7'-benzamido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethium-1 trifluoroacetic acid (10 ml) was added at 0 ° C in anisole (4 ml), the mixture was stirred for 15 minutes and then evaporated under reduced pressure. Using ether 21 196419 and n-hexane, the residue is taken up in a solid to give 470 mg (70% yield) of 7β-benzamido-7α-methoxy-3α-methyl-, 3β-acetoxy-1- dethia-1-oxacepham-4α-carboxylic acid in the form of a colorless powder, decomposing at 203-208 ° C. Celsius.

In a similar manner, the following free carboxylic acids are prepared from the corresponding diphenylmethyl ester: 7β-benzamido-7α-methoxy-3α-hydroxy-η 5 -methyl-1-dethia-1-oxacepham-α-carboxylic acid melting point with decomposition at 100 DEG-105 DEG C. 7'-7-Benzamido-7α-methoxy-3'-trifluoro-acetoxy-3'-methyl-1-dethia-1-oxacepham-4-carboxylic acid, m.p. 7,1-Benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylic acid, m.p. 195 DEG-198 DEG C., .delta. V max 3250, 1766, 1742, 1642 cm -1 of α, 7α-benzamido-3β-chloro-3β-chloromethyl-1-dethia-1-oxaacetam-4α-carboxylic acid melting at 118-122 ° C with decomposition. Celsius. Example B-2 To a solution of 1.125 g of diphenylmethyl-7α-benzamido-3-exomethylene-1-dethia-1-oxa-cefam-4α-carboxylate in a mixture of 15 ml of dichloromethane and 3.5 ml of anisole is added dropwise stirring at at -20 ° C, a solution of aluminum chloride (625 mg) in 20 ml of nitromethane, and the mixture was stirred at -10 ° C to -20 ° C under nitrogen for 30 minutes. The extract was washed with saturated aqueous sodium bicarbonate solution, the washings were acidified with concentrated hydrochloric acid and extracted again with ethyl acetate, and the organic layer was washed with water. After drying, the mixture was evaporated to give 623 mg of 7α-benzamido-3-oxomethylene-1-dethia-1-oxacein-4α-carboxylic acid.

In an analogous manner, 1.8 g of diphenylmethyl-7'-benzamido-3-methyl-1-dethium-1-oxa-2-cephem-4α-carboxylate in 25 ml of dichloromethane is solvolysed at room temperature for 30 minutes. -10 ° C 5.8 ml of anisole, 1.026 g of aluminum chloride and 36 ml of nitromethane to give 935 mg (72.6% yield) of 7α-benzamido-3-methyl-1-dethia-1-oxa -2-cephem-4-carboxylic acid. C. Protection of the amino group and removal of the protecting group (reference examples) Example C - 1 To a solution of 25 mg diphenylmethyl-2'-amino-3-methylene-1-dithiarl-oxacepham-4-carboxylate at 0, 5 ml of dichloromethane are added in a nitrogen atmosphere at -20 ° C with 7 µl of pyridine and 10 µl of benzoyl chloride, the mixture is stirred for 1 hour, then poured into ice, stirred for 5 minutes and then extracted with dichloromethane. ' The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and again with water, dried and evaporated to give 28 mg (86% yield) of diphenylmethyl-7α-benzamido-3-methylene-1-dethionyl. 1-oxation-fam-4a-carboxylate, identified by thin layer chromatography and NMR spectroscopy: Example C-2 To a solution of 94 mg of diphenylmethyl-7'-benzamido-3-methylene-1-dethium- of 1-oxacepham-4a-carboxylate in 4 ml of dichloromethane under N 2 at -40 ° C, add 32 µl of pyridine and 1.08 ml of a 0.37 M solution of phosphorus pentachloride in dichloromethane, warm to room temperature, After stirring for 1 hour, the mixture is again cooled to -40 DEG C., mixed with 8 ml of methanol, warmed to 0 DEG C., mixed with 0.8 ml of water and evaporated under reduced pressure. in ethyl acetate (20 ml), the solution was washed with water and extracted with aqueous sodium bicarbonate solution.

The combined extracts and washings were overlayed with ethyl acetate, pH was adjusted to 7.0 and extracted with ethyl acetate. The organic layer was separated, washed with water and evaporated to give 29 mg (40% yield) of difluoromethyl-7α-amino-3-methylene-1-dethia-1-oxacefam-4α-carboxylate. au *, v max 3000, 1770 (arm), '1760, 1740 cm1.

D. Replacing and Transforming X and Z Symbols (Reference Examples) Example D - 1 23

196419

In this scheme, the pH and —Strat symbols are as defined below. (1) To a solution of 108 mg of diphenylmethyl-7'-benzamido-3'-hydroxy-3'-bromomethyl-1-dethia * 1-oxacefam-4-carboxylate in 5 ml of acetone containing 10% of water add 50 mg of potassium carbonate mixture The mixture was stirred at room temperature for 1.5 hours, then diluted with brine and extracted with dichloromethane. The extract was dried over magnesium sulfate and evaporated. The residue (90 mg) after purification by thin layer chromatography on silica gel in a benzene-ethyl acetate (2: 1) solvent system gave 40 mg of diphenylmethyl-7α-benzamido-3,3-epoxymethanol-1-dethia-1-oxation-fam-4a -carboxylate (isomer A).

Stereoisomer B, differing in position. 3 from the above product, 140 mg of stereoisomeric material can be obtained in 56 mg yield with the starting material described above in configuration 3. (2) To a solution of 20 mg of 1-methyltetrazol-5-lythiol in 2 ml of tetrahydrofuran was added with 0.05 ml of n-butyl lithium solution. in hexane (1.5M), the mixture was stirred for 30 minutes, then treated with a solution of 56 mg diphenylmethyl-7'-benzamido-3,3-epoxymethano-1-dethia-1-oxa-cefam-4'-carboxylate ( epimer B) in 1 ml of tetrahydrofuran, stirred for 1 hour, treated with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed on a 1 g silica gel inactivated 10% water. Elution with benzene / ethyl acetate (9: 1) gave 43 mg of diphenylmethyl-7'-benzamido-3- (1-methyltetrazol-5-yl) thiomethyl-3-hydroxy-1-dethia-1-oxacepham-4a- carboxylate (epimer B). Example D-2 (1) 6 mg of monohydrate is added to a solution of 100 mg of diphenylmethyl 1-7α-benzamido-3 H -hydroxy-3--methyl-1-detyl-1-oxacepham-4-carboxylate in 5 mL of iso-propenylacetate. p-toluenesulfonic acid and heated to 60 ° C for 75 min. After cooling, the reaction mixture is poured into a mixture of water with ice of dilute aqueous bicarbonate solution. sodium chloride, and extracted with dichloromethane. The organic layer was separated, washed with water, dried and evaporated. The yield of 30.5% yields diphenylmethyl-7α-benzamido-3α-acetoxy-3β-methyl-1-dethia-1-oxacepham-4-carboxylate. (2) The same starting material as in (1) can be treated with a mixture of 1.1 equivalents of lithium diisopropylamide, 1.2 equivalents of acetyl chloride and 20 volumes of tetrahydrofuran for 45 minutes at -40 ° C for 15 minutes at -20 ° C and then for 20 minutes at 0 ° C, or 1 equivalent of pyridine and 1.2 equivalents of acetyl chloride in dichloromethane. (3) To a solution of 52 mg of diphenylmethyl 1-7 / 3-benzamido-7α-methoxy-3α-hydroxy-3, 2-methyl-1-dethia-1-oxacepham-4α-carboxylate in 1 ml trifluoroacetic anhydride (0.1 ml) was added to the nitrogen atmosphere under ice-cooling, the mixture was allowed to react for 2 hours at room temperature, mixed with 0.3 ml of water, stirred for 30 minutes, diluted with water and ice. extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 64 mg of oily diphenylmethyl-7β-benzamido-7α-methoxy-3-iodo-trifluoroacetoxy-3 l-methyl-1-dethion-1-ol. oxacefam-4a-carboxylate. (5) A solution of 112 mg of diphenylmethyl-7'-benzamido-3'-hydroxy-3'-hydroxyme '196419 28 25 thyl-1-dethia-1-oxacepham-4'-carboxylate in a mixture of 0.5 ml of pyridine and 0, Acetate (3 ml) was allowed to stand at 0 ° C overnight, then the reaction mixture was concentrated in vacuo, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dilute hydrochloric acid, aqueous sodium bicarbonate solution and water, dried and concentrated. There were obtained 54 mg of diphenylmethyl-7'-benzamido-3'-hydroxy-3'-benzyl. cethoxymethyl-1-dethia-1-oxacefamurecarboxylate in the form of crystals melting at 118 to 120 ° C. (6) 0.078 ml of pyridine and 0.075 ml of methanesulfonyl chloride are added to a solution of 350 mg of diphenylmethyl-7-benzamido-3H-hydroxy-3H-hydroxymethyl-1-dethia-1-oxacepham-4a-carboxylate in 3 ml of dichloromethane. The mixture was stirred for 1 hour at 0 DEG C. and then for 3 hours at room temperature, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, aqueous sodium bicarbonate solution and re-dried. The residue is chromatographed on silica gel to give 145 mg of diphenylmethyl-7β-benzamido-1-hydroxy-3 H -methanesulfonyloxymethyl-1-dethia-1-oxacepham-4-carboxylate. the examples describe the preparation of compounds.

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% 27 196419 28 (1) To a solution of 4.6 g of diphenylmethyl-2- (3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-ene) 6-yl] -3-methyl-3-butenoate in 70 ml of ethyl acetate was added 3.8 ml of 2.74 M hydrochloric acid in ethyl acetate and 12 ml of 1.47 M solution of chlorine in carbon tetrachloride, and the mixture was stirred for 15 hours. 80 ml of a 5% aqueous solution of sodium thiosulfate, 3.4 g of sodium bicarbonate and 240 ml of acetone were added, and the reaction mixture was allowed to stand at room temperature for 2.5 hours. extraction with ethyl acetate, drying of the extract with sodium sulfate and evaporation to obtain 3.33 g of diphenylmethyl 2- (3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo [3.2.1 &lt; 2,7 &gt; O] hept-2-en-6-yl) -3-chloromethyl-3-butenoate of 82 DEG-83 DEG C. (2) The product prepared above is dissolved in 25 ml of acetone, mixed with 3.3 g of sodium iodide and the mixture are allowed to react at room temperature for 2 hours The acetone was evaporated and the residue was extracted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and water, dried over sodium sulfate and evaporated to give 3.0 g of the corresponding iodide. (3) To a solution of 1.59 g of residue (2) in a mixture of 13 ml of dimethylsulfoxide and 3 ml of water was added 0.77 g of copper oxide and the mixture was stirred at 39 ° C for 1 hour. The reaction mixture was filtered to remove solids. and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated. 0.35 g of diphenylmethyl 2- (3-benzyl-7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-en-6-yl) is obtained. 3-hydroxymethyl-3-butenoate, mp 40-55 ° C. The following are table summarizing the reaction conditions, starting and endpoints, product yields of the individual reaction types described above, as well as the physical constants of the individual compounds. In these tables, the individual abbreviations and symbols have the following meanings: -Ph-Phenyl-STetr = 1-methyl-1,2,3,4-tetrazol-5-yl-C6H4CH3-p = p-nitrophenyl-C6H4CH3 -P = p-tolyl-C6H4Cn-p-p-cyanophenyl-beta-p-t-p-chlorophenyl-Bu-t-tert-butyl-acet-acetoxy. the double line between X and Z (, =) = CH 2 X and Z together represent a methylene group —O— between X and Z = X and Z represent an epoxy group. A = amino group or substituted amino group = CH 2 = 3-exomethyleneate starting weight

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Claims (2)

19B419 29 39 OBJECT CLAIMS 1. A process for the preparation of 1-dethia-1-oxacefamido derivatives of Formula III wherein A represents an amino or amino group protected with an alkanoyl group having from 2 to 5 carbon atoms, a benzoyl group optionally substituted in the phenyl group by an amino group, a cyano group, a halogen atom or an alkyl group having from 1 to 3 carbon atoms, a phenylalkanoyl group having from 2 to 4 carbon atoms in alkanoyl, or a phenoxyalkanoyl group having 2 to 4 carbon atoms in the alkanoyl moiety. E represents a hydrogen atom or a methoxy group, COS represents a carboxyl group or a carboxyl group protected in the form of an ester, X represents a hydrogen atom, a halogen atom, a hydroxyl group or a halo-substituted alkanoyloxy group having 2 to 4 carbon atoms, (C 1 -C 3) alkylthio, (C 1 -C 3 -C 3) alkylsulfonyloxy, toluenesulfonyloxy; phenylthio or 1-methyltetrazol-5-ylthio and Z is a halogen atom, a hydroxyl group or an alkanoyloxy group having from 2 to 4 carbon atoms, characterized in that the compound of formula IV is In which A, E and CQB are as defined above, they act as a diluent. wherein X and Z are as defined above, in an organic solvent, at a temperature of from -70 to 0 ° C, for a period of from 5 minutes to 10 hours. ' 2. A process according to claim 1 wherein the organic solvent is selected from the group consisting of hydrocarbons, halogenated hydrocarbons, ethers and esters. Isvsrogrsfta, a., Plant 7, Most