CS196418B2 - Method of producing 1-dethia-1-oxacephamderivatives - Google Patents

Abstract

PURPOSE:To prepare 1-oxadethiacephalosporin useful as an antibiotic or its intermediate, economically, by eliminating 3-position eliminable group of 3-eliminable group-substituted 1-oxadethiacepham compound which is an intermediate of cephalosporin.

Description

The present invention relates to a process for the preparation of 1-dethia-1-oxacepham derivatives of the general formula (I), in accordance with the following reaction scheme:

OCHk i ^J t ~ Ti

The formation and addition of aieth.a.aol

In the formulas in this scheme

A represents an amino or C 2 -C 5 -alkanoyl-protected amino group, a benzoyl group optionally substituted in the phenyl moiety with a nitro, a cyano, a halogen atom or a C 1 -C 3 alkyl, a C 2 -C 4 phenylalkanoyl moiety , or a (C 2 -C 4) phenoxyalkanoyl group in the alkanoyl moiety,

Y represents a divalent radical of the formula

—CHž —CHž —CHž —CHCZCHžX, 1 i —СНС — CH2, —CHC = CH2, Ί 1 \ Z 1 COB СОВ O COB

—CHž

II —CHCH2 or. I.

COB —CHz

- C = CCH 2

AND

COB where

COB. represents a carboxyl group or a carboxyl group protected in the form of an ester,

X is hydrogen, halogen, hydroxyl, optionally substituted C 2 -C 4 alkanoyloxy, C 1 -C 3 alkylthio, C 1 -C 3 alkylsulfonyloxy, toluenesulfonyloxy, phenylthio or 1-methylthetrazol-5-ylthio. Z represents a halogen atom, a hydroxyl group or an alkanoyloxy group. se 2 až 4.. carbon atoms.

Compounds of formula I are useful. as intermediates for the preparation of potent antibacterially active 1-oxadethiacephalosporins, or as antibacterial agents.

The starting materials for the process according to the invention, which may alternatively be described by the general formula IIa below, can be prepared from the corresponding oxazolinoazetidines of the general formula III by treatment. acid, in the sense of the following, reaction scheme:

R

Sobenim kydsj Oh

N-y tni)

(I / a)

In the formulas shown in this scheme, R is hydrogen, alkyl of 1 to 4. phenyl, optionally substituted by nitro, cyano, halogen or C 1 -C 3 alkyl, 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 is as defined above.

The protected carboxyl group in the meaning of the COB moiety can generally be any. a protecting group commonly used in chemistry, the lactam compounds stable under the reaction conditions. in the process according to the invention. The carboxyl group contained in the COB moiety may generally be protected in the form, for example. an ester [such as an alkyl ester (e.g. methyl, ethyl or tert-butyl ester), aralkyl ester (e.g. benzyl, diphenylmethyl or trityl ester), aryl ester (e.g. phenyl ester or indanyl ester) or ester containing an organometallic group (e.g. trimethylsilyl ester). Said protecting group may optionally be substituted with an electron-attracting or electron-providing substituent, such as a halogen, hydroxy, acyloxy, alkoxy, oxo, acylamino, nitro, alkyl, cyano, cyano or cyano groups. The aryl groups of the protecting groups include heteroaromatic cyclic groups, the protecting group is usually cleaved after the reaction and its structure can therefore be largely changed without any effect. The preferred protecting group is an ester moiety.

If the residues in the meaning of the symbols R,

COB, Y. or Z are subject. v. during the reaction according to. of the invention undesirable changes, can be in any. degree. of the process before the reaction is carried out and protected after the reaction. groups get rid of.

Carrying out the reaction

Compounds of formula (IIIa) may be prepared. from the corresponding. oxazolinoazetidines of the general formula. III by acid treatment. Like typical. examples of useful acids include mineral acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), sulfonic acids, and strong carboxylic acids. acids (e.g. methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid), Lewis acids (e.g. bontrifluoride, zinc chloride, tin tetrachloride, tin bromide, antimony trichloride or titanium tetrachloride). and similar acids. The reaction usually proceeds. 5 minutes to 10 hours in particular. 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 the compound of formula (IIa) in high yield. If desired, the reaction can be carried out with stirring or under an atmosphere of an inert gas (e.g. nitrogen, argon or carbon dioxide).

The reaction was. 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, carbon tetrachloride, or chlorobenzene). . ethers (e.g. 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. dimethylsulfoxide), nitriles. (for example, acetonitrile or benzonitrile) and similar solvents, as well as mixtures thereof. Solvents containing a hydroxyl group react with the starting material of formula II to form by-products, but these solvents can also be used under controlled reaction conditions. Typical examples of such hydroxyl-containing solvents are water, alcohols (e.g. methanol, ethanol, tert-butanol or benzyl alcohol), acids (e.g. formic acid, acetic acid or propionic acid) and mixtures thereof.

The terminal hydroxyl group is attached. The compounds of formula (III) may be protected from the reaction by a suitable hydroxyl protecting group readily cleavable under reaction conditions (e.g., a formyl group, tetrahydropyranyl group, and the like) from the reaction of Y in oxazolinoazetidine (III).

If necessary, the double bond may migrate during the reaction according to the invention _; introduction of nucleophiles, elimination or the like. Side reactions; however, such reactions may be used intentionally and are therefore within the scope of the invention.

A typical embodiment of the reaction according to the invention is as follows:

part of the oxazolinoazetidine of formula III 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 an ether type solvent (e.g. ether or dioxane) mixed with 0.005-5 moles of acid (e.g. boron trifluoride etherate, toluenesulfonic acid) , copper (II) sulfate, zinc chloride, or tin (II) chloride, and the solution is allowed to react for 0.5 to 10 hours at 10 to 60 ° C to give the corresponding compound of formula 11a in a yield of about 50 to 95%.

The above starting materials are prepared from 6-epipenicillin 1-oxides, for example according to the following reaction scheme, in which R, СОВ and X are as defined above:

'HN03U

198. 7

Structural modification of products

Was found; Accordingly, the products of the above cyclization can be subjected to various structural modifications common in the chemistry of [beta] -lactam derivatives to form. of the compounds of formula I - or II

О '* -' in which

A and Y are as defined above and

E represents a hydrogen atom - (II) or a methoxy group (I). .

It is to be understood that the amino function protecting groups in the meaning of the symbol A may vary widely as is common in penicillin and cephalosporin chemistry. In general, therefore, the symbol A may not only have the meanings mentioned above, but that the radical of the symbol may generally be an amino group, an acylamino group, for example:

alkanoylamino, aryloxyylkanoylamino, aroylamino, aralkanoylamino, aiminoarylacetamido, protected α-aminoarylacetamido, aureidoarylacetamido, aihydroxyarylacetamido, aiacyloxyylacetamido,.

aiheteroalOylammoarylacetamido, .alpha.-alkoxyiminoarylacetamido,.

gf α-carboxyaryl lacetamido, * protected aicarboxyarylacetamido, aisulfoarylacetamido, protected, α-sulfoarylacetamido, α-haloarylacetamido- or: benzyloxycarbonylamino, silylamino- (e.g., amino) amino (phenyl) amino) _An amino group substituted with a hydrocarbon radical (e.g., benzalamino, hydroxybenzalamino, 1-alkoxyalkylideneamino);

1-haloalkylidinamino or tritylamino),.

. diacylamino or the like - groups usually found in the side chains of penicillins - and cephalosporins. The aryl part of these exemplified radicals may be - a phenyl - or heterocyclic aryl radical which may be - optionally substituted by a hydroxyl group - halogen atoms, sulfonylamino, aminomethyl, hydroxymethyl and the like. Preferred aryl radicals include thienyl, thiazolyl and the like. the phenyl radical optionally substituted by halogen atoms, hydroxyl, acyloxy- or amino groups. Preferred " radical " optionally substituted " hetero-side " chains of natural penicillins, i.e. phenylacetamido and phenoxyacetamido, or side chains of natural cephalosporins, and their closely related degradation derivatives, i.e. optionally protected alpha-aminoadipoyl, gamma-oxoadipoyl and a uteryl residue. . '

The structural modification forming the subject-matter of the invention can, as mentioned above, be described by the following reaction scheme:

H

Ivorba. immu a.pá.k petition - ^!

Representative examples of other possible structural modifications include the following reactions:. .

r

elimination of HZ

<& 4 £. (Ереы chranici & oipiay amao Xgi / fctff / fCŠ.

c—— ^; --------- chrÁnéaí amine urnkce jín.® m Ufikaas ^- --4 '. '

In these schemes, the symbols have A, Y, X, Z,. COB and E defined above and Y ¹ has the same meaning given above .As pro- Y but differ od'symbolu Y in the starting material if it comes to · 'meaning. X, Z, and COB, or the double bond position.

Methoxylation according to the invention

The compounds of formula (II) may be oxidized on nitrogen in residue A to form the imino compound ([corresponding to formula (II)) wherein A and E together form a group. by the subsequent addition of methanol to the compounds. of formula (I) wherein E is - methoxy. .

When A is amino or amido, the compound of formula (II) is treated with a halogenating agent. The hydrogenation of the resulting intermediate is eliminated by treatment with a hydrogen halide to form the corresponding amino compound, which is then reacted with a methoxy group. The halogenation to nitrogen may be of the general formula I in which E represents a methoxy group. Allogeneation to nitrogen may be accompanied by halogenation of another part of the molecule from the product. however, these excessively introduced halogen atoms can be removed by reduction.

The above procedure 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 treated with methoxide. an alkali metal (e.g. lithium methoxide, sodium, potassium or potassium methoxide) or an alkaline earth metal methoxide (e.g. magnesium methoxide, calcium methoxide or barium methoxide) in methanol. .. '

2. The starting material is reacted with tert-butyl hypohalogenite a. Methanol in the presence of a base and. phenyllithium, optionally in the presence of an additional solvent (e.g. tetrahydrofuran). ·

3. The starting material is reacted with. tert-butyl hypohalogenite in the presence of sodium borate in methanol and the partially formed excess halogenated product is reduced with zinc, phosphite or the like.

4. The starting material is gradually treated with bromine, phosphorus pentachloride. in the presence of pyridine, bases, methanolic base and trialkylsilyl chloride or tetraalkylammonium chloride.

Alternatively, one may proceed. by treating compounds of formula II wherein E is hydrogen and A is amino with a suitable aldehyde (e.g., benzaldehyde, p-hydroxybenzaldehyde, or 3,5-di-tert-butyl-4-hydroxybenzaldehyde) to form a Schiff base, it is oxidized to an imine compound which is reacted with methanol and methanol. subsequent hydrolysis to give compounds of formula I wherein E is methoxy and A is amino.

9 '6 4 18

A typical example of a methoxylation reaction is as follows:

a portion of the amide of formula (II) is dissolved in 10 to 10. 50 parts of an inert solvent (e.g. dichloromethane, dioxane, ether, dipropyl ether or tetrahydrofuran), the solution is stirred for 2 to 10 minutes at a temperature of -70 ° C to -10 ° C with 1 to 5 mol equivalents of reagent halogenating nitrogen (for example molecular halogen in carbon tetrachloride or tert-butyl hypochlorite), then mixed with up to 4 equivalents of metal methoxide (for example, lithium methoxide, or magnesium methoxide) in methanol and 5 to 70 The reaction mixture can be neutralized with acetic acid or a mineral acid and the product taken up in an organic solvent. Of formula I in which E represents a methoxy group in a yield of up to 95%.

Addition. .

Compounds of formula (I) or (II) containing an exomethylene group at the 3-position readily react with the addition agent XZ (e.g., molecular halogen, peracid, 'peroxide, hypohalogenity' in salt or ester form, peroxide heavy metal (e.g., osmium tetroxide or sulfenyl halide) in an inert solvent (e.g., hydrocarbon, halogenated hydrocarbon, ether, ester, etc.) to form compounds of formula I or wherein Y is a divalent group of formula —CH2.

—CH — CZ — CH 2 X

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

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

This modification proceeds by starting with the starting compound. of formula (I) or (II) cleaves the residue from together with the adjacent hydrogen atom, thereby obtaining A 2 - or Δ 5-cephem derivatives. ·. Isomers differing in the 'double bond' position form gray depending on the location of the hydrogen leaving, but the formation of the isomers may also be due to the migration of the already formed double bond under the reaction conditions or during processing.

. If the reactivity of the residue 'Z' is sufficiently high, the compound · HZ 'is free of po. use of any agent, for example by heating the starting material to an 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 (e.g. an aliphatic amine, an aromatic amine, an aromatic base, a weak salt) organic acids with strong base, alkali metal hydroxide, bicarbonate, carbonate, mercaptide or alkali metal oxide, oxide, hydroxide, bicarbonate or carbonate of alkaline earth, aluminum oxide or silica gel). .

When Z is a hydroxyl group, 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 or phosphonic acid, inorganic or organic base, alumina or Amidated silica gel], a halogenating agent (e.g. phosphorous halide, phosphorus trihalide, phosphorus oxyalloid, thionyl halide or sulfuryl halide), acylating agent (e.g. acid anhydride, acid halide or isocyanide) or a similar agent, optionally in the presence of an acid acceptor (e.g. the above acid acceptor).

The reaction can 'be · · effected at a temperature from -50 ⁹ C to 100 ° C · stirring under inert gas (e.g., nitrogen, argon or carbon dioxide) in a solvent (e.g. in the aforementioned hydrocarbon, and halogenated hydrocarbons, ethers, esters ketone, alcohol, sulfoxide, nitrile, a base such as pyridine or quinoline, an acid, an acid anhydride such as acetic anhydride or trifluoroacetic acid, or similar solvents or mixtures thereof).

Other modifications.

It has been found that compounds of general formula (I) or (II) may also be subjected to other structural modifications customary in β-lactam chemistry (such as, for example, 'double bond migration, protection and regeneration' of the carboxyl group) protecting and regenerating the amino group A, introducing or exchanging the X radical with a nucleophilic reagent, or converting the X and Z radicals as defined above, including acylation, hydrolysis, Oxidation or reduction, and similar modifications).

1984Д8

Utilization of side reactions

If the molecule contains - volatile - groups, these groups may occasionally be attacked by a reagent - or solvent during any of the above - reactions or during processing. Thus, for example, the halogen addition to the 3-oxomethylene group is accompanied by halogenation at the nitrogen of the 7-amido group; 'formation of the imine by the action of the base when introducing the 7-methoxy group' results in the elimination of the compound HZ when Z is a halogen atom or an alkanoyloxy group and a halogen substitution as defined. the symbol X with a 'basic nucleophilic' reagent leads to - elimination of the compound HZ when Z is a halogen atom. These reactions can be considered side reactions; in their deliberate use, however - in some cases - synthesis can be. more efficiently - than - through successive reactions.

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

Insulation and cleaning products. '

Compounds of formulas IIa and I or II, prepared by cyclization, methoxylation, addition, elimination or other modifications, can be isolated from the reaction mixture by removing the solvent, unreacted substances, by-products and other impurities by evaporation, extraction, washing, by drying or similar conventional methods, and purified by reprecipitation, - chromatography, crystallization, absorption or other similar purification operations. Stereoisomers differing in the configuration at the 3 or 7 position can be separated by careful chromatography, by traction, recrystallization or the like. If preferred, the stereoisomers may be subjected to further processing without separation.

Use of products.

The compounds of formulas IIa and Ia or II can be used as starting materials for the preparation of, for example, known antibacterially active 1-dethia-1-dioxacephalosporins (see Japanese Patent Laid-open Nos. 49-135594 and 51-149295) at high levels. yielding, by introducing or migrating the double bond to the 3-position, replacing the A residue with a side chain advantageous for antibiotic activity and / or regenerating the protected carboxyl group as a COB moiety, or after introducing the antibiotic activity of a suitable residue X to the methylene bond at the 3-position of the 1-dethia-1-oxacephem nucleus, as mentioned above. This double bond and the radicals A, COB and X can be replaced in terms of antibacterial efficacy by appropriate grouping before the formation of the desired cephem. system; '

The choice of the abovementioned residues A, - COB and X by default. - the material and in - intermediates may depend on ease, reaction, handling or use, - stability of the relevant - substances under reaction conditions or - during processing, waste products, costs or other practical factors .

Compounds of formula (I) or (II) containing a carboxyl group as defined above. COB groupings are antibacterially effective.

The advantages of this process over the prior art.

The known process for the preparation of 1-dethia-1-oxacephalosporins is based on penicillins (see Japanese Patent Application Laid-open No. 51-149295), whose thiazolidine-type is cleaved to form free azetidinonthiol and, by re-coupling The new five carbon carbon moieties are formed - bicyclic azetidine oxazine. Another totally synthetic procedure (see Japanese Published Application No. 49-133594) requires difficult to control intermolecular cyclization to form a dihydrooxazine ring. By working according to the invention, no carbon is removed from the starting penicillins, resulting in smoother intramolecular cyclization and the formation of fewer byproducts, resulting in a higher yield. '

Since the known processes are associated with the formation of a carbonate ion at the 4-position of the azetidinone starting material, they result in a 4: 1 and 4 '/ 3-ether mixture in a ratio of about 1: 1, thereby losing about half of the ether produced. . The process according to the invention, on the other hand, is stereoselective and there is practically no need to separate these stereoisomers.

. The result of these - stereospecific reactions taking place - in high yield - is the formation of products which, after simple and even industrial scale purification, can be easily crystallized. ..

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention in any way.

The compounds of the Examples - contain numbered and named nuclei as follows:

AND

1S

S 6418

1 H, 5 H- or (1R, 5S) -7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene

1-dethia-1-ox.acpham

The stereochemistry about the carbon # 1 of the bicyclohept-2-ene system is the same as the stereochemistry at the 6-position of the 6-epipenicicins and the stereochemistry about the carbon # 5 bicyclohept-2-ene system is reversed than the cephalosporins at the 6-position.

The stereochemistry about carbon # 6 in the 1-dethial-1-oxacepham ring system is identical to the stereochemistry at the 6-position of the cephalosporins. . . The stereochemistry of the COB grouping in the individual samples is usually the same as that of penicillins, i.e.. however, it is not limited to this configuration.

Experimental errors of IR spectra are in the range of + 10 cm ^-1 . NMR spectra were in the range + 0.2 ppm.

Melting points are not corrected.

Anhydrous sodium sulfate is used to dry the solutions.

The physical constants of the products are summarized in Table III.

I. Preparation of cyclic starting materials (Reference Examples) in K1 and D 1 to 32

The oxazolinoazetidine of formula III is dissolved in a solvent. and under the conditions set forth in Table I below, the acid affords the desired 1-dethia-1-oxacepham derivative. of the general formula · Ha. · ;.

Individual cyclization details. reactions are described. See also reaction # 13 of Table I below:

Ph

(1) »

W <№ .J »—N C-HC-CH 3,

COOCHPh ^

PhCONH (1)

her . . . . ch _z oh - * J - b <C / ^H < ^{CH 2} and ^CH i OH COOCHPI 1 _z

СН ₃

COOCHPh _from (1). A solution of 12.0 g of diphenylmethyl-2 - [(1R, 5S-O-phenyl-4-oxo-4-oxa-4-diazabicyclo [3.2.0] hept-2-en-6-yl) - 2 - isopropenylacetate, 1.0 g of osmium tetroxide ¹ and 12.0 g of potassium chlorate in a mixture of 400 ml of tetrahydrofuran and 200 ml of water are stirred for 3.5 hours at a temperature of 58 DEG. After cooling, the reaction mixture was poured. into ice water and extracted with ethyl acetate. The extract was washed with sodium chloride solution, 10% aqueous sodium thiosulfate and finally with aqueous sodium hydrogen carbonate 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-] were obtained. yl] -3,4-dihydroxy-3-methylbutyrate.

_Т Л. CHC1S

IC. V max - 3500 (wide belt), 1770 (wide belt), 1742, 1636 cm -1.

(2) To a solution of 10.88 g of the product prepared in (1) above in. 300 ml of ether was added with 0.075 ml of boron trifluoride etherate, stirred for 3.5 hours at room temperature under nitrogen, then poured into cold aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with brine and evaporated. The residue was eluted with a mixture of dichloromethane and ether to give 15 g of a mixture of isomers of diphenylmethyl-2-benzenesamido-3 H -methyl-3 H -hydroxy-1-dethla-1-oxacepham-4α-carboxylate, differing in the 3-position configuration.

ID No .: v

CHC1J max = 3560,3445,1774, 1739, 1670 ^cm-first

This mixture was chromatographed on a silica gel column deactivated with 10% water; 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

Pii qcho ₃ > ₃

COOCH _of Ph

PhCONh f

Ph (a) - To a solution of 54 mg benzyl-2 - [(1R, 5SJ-3-phenyl-7-oxo-4-oxa-2,6-diabicyclo [3.2.0] hept-2-eh-6) 3-formyl-oxomethyl-2-b-utenoate 19 µl of boron trifluoride etherate are added in 2 ml of methanol under cooling to -20 ° C, the mixture is first stirred at -20 ° C to 0 ° C for 40 minutes. then for 2 hours at 0 ° C and finally 1 hour at room temperature and then stirred with 5 ^lo / o aqueous sodium bicarbonate and extracted with dlchlormethanem.

The extract was washed with water and evaporated to dryness. Crystallization of the residue from methanol gave 10 mg of benzyl-7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate (20% yield), m.p. 208-212 ° C.

(b) By the same procedure as above, except that 5 μl of trifluoromethanesulfonic acid was used instead of bortrifluorld and the mixture was stirred for 130 minutes under ice cooling, or 0.5 ml of 0.38 N hydrogen chloride in methanol and the mixture was stirred for 3 minutes. hours, the same product can be obtained, m.p. 208 DEG-212 DEG C. in a yield of 14 mg (27.5%), respectively. 5 mg (7%).

II. Methoxylation according to the invention

Examples II to 24

The 7 (3-unsubstituted 7α-amido-1-dethla-1-oxacepham-derivative of formula (II) is dissolved in a solvent and mixed under the conditions given in Table II below with a nitrogen-halogenating agent and a base in methanol to give the corresponding 7α-methoxy. -7 / 3-amino compound.

In order to illustrate an experimental embodiment of methoxylation, the embodiments of reactions 5 and 9 of Table II are described in detail below.

Reaction # 5

To a solution of 486 mg of diphenylmethyl-7α-benzamido-3α-hydroxy-3β-methyl-1-dethia-1-oxacepham-4α-carboxylate in 20 mL of anhydrous dichloromethane at -50 ° C was added 0.15 mL of tert. butylhypochlorite and 1.1 ml of a 2 N solution of lithium methoxide in methanol, stirred for 15 minutes, treated with 1.2 ml of acetic acid, stirred for 5 minutes, then diluted with an ice-cold aqueous solution of sodium bicarbonate and extracted with dichloromethane. The extract was washed with aqueous sodium bicarbonate solution and water, dried and evaporated. The colorless foam residue gave 250 mg (48% yield) of diphenylmethyl-7β-benzamido-7α-methoxy-3'-hydroxy-3H-methyl-1-dethia-1-oxacepham-4α-carboxylate after silica gel chromatography .

Reaction # 9

To a solution of 187 mg of diphenylmethyl-7α-benzamido-3β-bromo-3β-bromoethyl-1-dethia-1-oxacepham-4α-carboxylate in 1 mL of anhydrous dichloromethane was added at room temperature. -30 ° C add 46 μΐ of tert-butylhypochlorite and 0.17 ml of a 2M solution of lithium methoxide in methanol, stirred at the above temperature for 1 hour, then admixed with a solution of 100 milliliters of sodium-1-methyltetrazol-5-ylmercaptide in 1 ml of acetone and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and brine, dried and evaporated. The residue weighing 180 mg was chro. It is chromatographed on a silica gel column. Elution with a mixture of equal parts of benzene and ethyl acetate yielded 108 mg of diphenylmethyl-7,3-benzamido-7α-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-1-dethia-1-oxa-3-cephem- 4-carboxylate.

III. Additions (Reference Examples)

Example 1 a d у III to 16

The 3,3-methylene-1-dethia-1-oxacephamine derivative of formula (IIa) is dissolved in a solvent and combined with the addition agent XZ under suitable reaction conditions to provide the desired addition product.

To illustrate the experimental embodiments of the addition, the following three reactions are described in detail below:

Reaction 1

To a solution of 519 mg of diphenylmethyl-7α-benzamido-3-exomethylene-1-dethla-1-oxacepham-4α-carboxylate in 5 ml of dichloromethane is added 1.6 ml of a 0.76 N solution of chlorine in carbon tetrachloride, the mixture is irradiated with a tungsten lamp. The mixture was stirred at -20 ° C to -30 ° C for 40 minutes, then treated with 0.14 ml of cyclopentene 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 at -20 ° C for 10 minutes, then washed with dilute hydrochloric acid and water, dried and evaporated. Recrystallization of the crystalline from methanol yielded 484 mg of diphenylmethyl-7α-benzamido-3-chloromethyl-1-dethia-1-oxa-cephem-4-carboxylate (86% yield), m.p. 120-128 ° C. .

Reaction 2

To a solution of 103. mg of diphenylmethyl-7α-benzamido-3-methylene-1-dethia-1-oxaceph-4-carboxylate in 1 ml of methylene chloride was added 0.3 ml of 0.75 N chlorine in carbon tetrachloride, reacting under irradiation from a tungsten lamp 30 minutes reaction at -20 ^{| O} C to -30 ° C and then evaporated under reduced pressure. 120 mg of diphenylmethyl-7α-benzamido-3'-chloro-3'-chloromethyl-1-dethia-1-bxacepham-4'-carboxylate are obtained.

Reaction 3

In analogy to the above procedure, a reaction of 705 mg of diphenylmethyl-7α-phenylacetamido-3-methylene-1-dethia-1'-oxacepham-4-carboxylate with 1.77 equivalents of chlorine in 7 ml of methylene chloride at a temperature below -25 ° C yields diphenylmethyl -7α-phenylacetamido-3β-chloro-3β-chloromethyl-1-dethia-1-oxacepham-4α-carboxylate.

The latter was reacted with 0.16 ml of piperidine at 15 ° C for 40 minutes to give 586 mg (yield).

78.4%) diphenylmethyl-7α-phenylacetamido-3-chloromethyl-1-dethia-1-oxa-3-cephem-4-carboxylate melting with decomposition at 179-182 ° C.

Example III - 17

Ph £ ONH '

RkCONH

COOCHPhž

and

Ct-Cu.

CH _Z ^CH Z ^CI COOCHPh

To a solution of 1.405 g (3.0 mmol) of diphenylmethyl-7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate in 28 mL of dry dichloromethane cooled to -26 ° C was stirred under nitrogen 141 mg of copper powder was added to the atmosphere, 6.3 ml (2.5 equivalents) was added dropwise over 10 minutes.

Of a 1.2 M solution of chlorine in chloroform, and the resulting mixture was stirred at -22 ° C to -30 ° C for 3 hours. The reaction mixture was stirred with an aqueous solution of 2.98 g (4 equivalents) of sodium thosulfate pentahydrate, extracted twice with dichloromethane, washed with brine, dried over magnesium sulfate and evaporated. Chromatography of the residue on 190 g of silica gel, eluting with a 3: 1 mixture of benzene and ethyl acetate, yielded 1.541 g of colorless foamed diphenylmethyl-7α-benzamido-3α-chloro-3, p-chloromethyl-1-dethia-1-oxacepham- 4α-carboxylate (95.2% yield).

A. Double bond migration (reference examples)

Example A-1

To a solution of 100 mg of 7/3-benzamido-7α-methoxy-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylic acid in 10 ml of acetone was added 0.1 ml of triethylamine and the mixture was stirred for 6 hours. days stand. The spots given by the reaction mixture in thin layer chromatography correspond to 7β-benzamido-7'-methoxy-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid and the starting material.

Example A - 2

To a solution of 5.0 g of diphenylmethyl-7α-benzamido-3,3-methylene-1-dethia-1-oxacepham-4α-carboxylate in 25 ml of dichloromethane is added 0.5 µl of triethylamine, the mixture is stirred at room temperature for 80 minutes, after addition of a small amount of benzene, it is concentrated and the residue is diluted with ether. 4.5 g (yield 90%) of crystalline diphenylmethyl-7α-benzamido-3-methyl-1-dethia-1-oxa-3-cephem-4-carboxylate are obtained.

Equilibrating the mixture at room temperature for 15 hours afforded 50.8% of the ^{2 2} -isomer, 4.1% of the a ³ -isomer, and 38.3% of the ^{3 3} -isomer (chromatographic separation).

Example A - 3

To a solution of 100 mg of 7α-benzzido-3-methylene-1-dethia-1-oxacepham-4α-carboixylic acid in 10 mL of acetone was added 0.1 mL of triethylamine and the mixture was allowed to stand for 5 days. The spots given by the reaction mixture in thin layer chromatography correspond to 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4-carboxylic acid, 7α-benzamido-3-methyl-1-dethia- 1-oxa-3-cephem-4-carboxylic acid and starting material.

B. Cleavage of the carboxyl function protecting group (Reference Examples).

Example 1 a d В - 1

To a solution of 960 mg of diphenylmethyl-7α-benzo-amido-7α-methoxy-3α-methyl-3β-acetoxy-1-dethia-1-oxacepham-4α-carboxylate in 4 ml of anisole was added at a temperature of 10 ml of trifluoroacetic acid are added at 0 ° C, the resulting mixture is stirred for 15 minutes and then evaporated under reduced pressure. Using ether / n-hexane, the residue was solidified to give 470 mg (70% yield) of 7 (3-benzamido-7α-methoxy-3α-methyl-3 H -acetoxy-1-dethia-1). oxacepham-.alpha.-carboxylic acid in the form of a colorless powder, melting with decomposition at 203 DEG-208 DEG.

The following free carboxylic acids are prepared analogously from the corresponding diphenylmethyl esters:

7. (3-Benzamido-7α-methoxy-3α-hydroxy-3S-methyl-1-dethia-1-oxacepham-4α-carboxyloic acid melting at 100-105 ° C with decomposition;

7α-benzamido-7α-methoxy-3α-trifluoroacetoxy-3 H -methyl-1-dethia-1-oxacepham-4α-carboxylic acid, m.p. 108-113 ° C;

70-benzamido-7α-methoxy-3-methyl-1-dethia-1-oixa-2-cephem-4-carboxylic acid, m.p. 195-198 ° C;

_T «. ^KBr

JLU. U max

3250, 1766, 1742, 1642 cm ^-1 , and

7α-Benzamido-3β-chloro-3β-chloromethyl-1-dethia-1-oxacepham-4α-carboxylic acid melting at 118-122 ° C with decomposition.

Example V - 2

To a solution of 1.125 g of diphenylmethyl-7α-benzamido-3-exomethylene-1-dethia-1-oxacepham-4α-carboxylate in a mixture of 15 mL of dichloromethane and 3.5 mL of anisole was added dropwise an aluminum chloride solution at -20 ° C with stirring. 625 mg) in 20 ml of nitromethane and the mixture was stirred at -10 ° C to -20 ° C for 30 minutes under nitrogen. The reaction mixture was poured into ice water containing hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, the washings were acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. The organic layer was washed with water and evaporated to dryness. 623 mg of 7α-benzamido-3-exomethylene-1-dethia-1-oxacepham-4α-carboxylic acid are obtained.

In an analogous manner, 1.8 g of diphenylmethyl-7'-benzarnido-3-methyl-1-dethia-1-oxa-2-cephem-4a-carboxylate in 25 ml of dichloromethane is solvolyzed for 30 minutes at -10 ° C with 5.8 ml of anisole. , 1.026 g of aluminum chloride and 36 ml of nitromethane gave 935 mg (72.6% yield) of 7α-benzamido-3-methyl-1-dethia-1-oxa-2-cephem-4α-carboxylic acid.

C. Protection of the amino group and deprotection (Reference Examples)

Example C - 1 ·

7 μΐ of pyridine and 10 μ1 are added to a solution of 25 mg of diphenylmethyl-7α'-amino-3-methylene-1-dethia-1-oxacepham-4α-carboxylate in 0.5 ml of dichloromethane at -20 ° C under nitrogen. The mixture was stirred for 1 hour, poured into ice water, stirred for 5 minutes, then extracted with dichloromethane. The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and again with water, dried and evaporated. 28 mg (86% yield) of diphenylmethyl-7α-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate are identified, identified by thin layer chromatography and NMR spectroscopy.

Example - 2

To a solution of 94 mg of diphenylmethyl-7, .alpha.-benzamido-3-methylene-1-dethia-1-oxacepham-4α-carboxylate in 4 ml of dichloromethane was added 32 .mu.l of pyridine and 1.08. ml of a 0,37 M solution of phosphorus pentachloride in dichloromethane,. The mixture was warmed to room temperature, stirred for 1 hour, then recooled to -40 ° C, treated with 8 mL of methanol, warmed to 0 ° C, treated with 0.8 mL of water and evaporated under reduced pressure. pressure. The residue was dissolved in 20 ml of ethyl acetate, washed with water, then extracted with aqueous sodium bicarbonate solution and water. Combined extracts and washing liquids. The mixture was then overlaid with ethyl acetate, adjusted to pH 7.0 and extracted with ethyl acetate. The organic layer was separated, washed with water and evaporated to dryness. 29 mg (yield 40%) of diphenylmethyl-7α-amino-3-methylene-1-dethia-1- oxacepham-4α-carboxylate are obtained.

• 3000, 1770 (arm),

1760, 1740 ^cm-first

Ď. Exchange and transformation of symbols X and Z (reference examples).

Example D - 1

P1CO1Wi '·'; - _Q ¹

Νϊ £ ° 3. Y ^ CHBr ⁽¹⁾ /

% Of% (2)

PhCONH

₂

ČOOČHPh. _of

C18 H16 H16 N @ + Ttn

ČXOCCHPl _Z

In this scheme, -Ph and -rSTttr have the meanings given below. '(1) K. solution · 108 mg · diphenylmethyl-7α-benzamido-3s-hydroxy-3β-bromomethyl-1-dethia-1-oixacepham-4 (x-carboxylate) in 5 'ml of acetone containing 10 · ° / o water milligrams of potassium carbonate;

The mixture was stirred at room temperature for 1.5 hours, then diluted with sodium chloride solution and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated. 90 mg yields after purification by thin layer chromatography. Silica gel in benzene-ethyl acetate (2: 1) solvent system 40 mg of diphenylmethyl-7α-benzamido-3,3-poly-methano-1-oxacepham-4α-carboxylate (isomer A).

Stereoisomer B, having a different configuration at position 3 from the above product, is. a yield of 56 mg can be obtained from 140 mg of the sterexisomeric starting material with the starting material described above in the 3-position configuration.

(2) To a solution of 20 mg of 1-methyltetrazol-4-ylthiol in 2 ml of tetrahydrofuran, add 0.05 ml. solution of n-butyllithla · in hexane (1.5 · M), stirred for 30 minutes, then · mixed with a solution of 56 mg of diphenylmethyl-7α-benzamidx-3,3-poxymethane-1-iethia-1 -oxacepham-4α-carboxylate (epimer B) in 1 ml of tetrahydrofuran, stirred for 1 hour, mixed with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO 4) and evaporated. The residue is chromatographed on a column of 1 g of inactivated 10% water. Elution with a mixture of benzene and ethyl acetate (9: 1) gave 43 mg of diphtoylmethyl-7α-beozamido-3- (1-methyltetrazol-5-yl) thiomethyl-3-hydroxy-1-dpthia-1-oxacephamine. 4α-carboxylate (ppimtr · (B)).

EXAMPLE 1 D-2 (1) To a solution of 100 mg of diphenylmethyl-7α.

-benzamide x-3, .alpha.-aydroxy-3H-lethylll-dethla-1-X ' xacpham-4-carboxylate in 5 ml of isopropenyl acetate. 6 mg of p-toluenesulfonic acid monohydrate and mixture are added. The mixture was heated at 60 ° C for 75 minutes. After cooling, the reaction mixture was poured into a mixture of water and ice and a dilute aqueous solution of sodium hydrogen carbonate, and extracted with standard salt. The organic layer was separated. washed with water, dried and evaporated. Yield

30.5% yield of diphenylmethyl-7α-benzamide x-2α-acetoxxy-3 H -methyl-dethia-1-xacampham-4α-carboxylate. .

(2) The same starting material as in (1) may be treated with a mixture of 1.1 equivalents of litalum diisopropylamide 1.2. of acetyl chloride and 20 parts by volume of tetrahydrofuran at -40 ° C for 45 minutes, at -20 ° C for 15 minutes, and then at 0 ° C for 20 minutes, or with 1 equivalent of pyridine and 1.2% by weight. equivalent of acttyl chloride in dichloromethane.

(3) To a solution of '52 mg of diphenylmethyl-7β-benzamido-7α-methoxy-3α-hydroxy-3-methyl-1-di-thia-1-oxacepham-4α-carboxylate in ml of dioxane st under a nitrogen atmosphere · Add 0.1 ml · trifluoroacetic anhydride under ice-cooling, allow to react for 2 hours · at room temperature, then mixed with 0.3 ml of water, stirred for 30 minutes, diluted with water and ice and extracted with ethyl acetate. · The extract was wash with water, dried and evaporated to give 64 mg of oily-diphenylmethyl-71-Zα-benzaelido metaxxy-3α - гii: luorac: _ptxxy-3-one No mettlall-L-L-iθtttla oxacpfam-4a- carboxylate.

(5) · A solution of 112 mg of diphenylmethyl-7α-beosamide x-3β-hydroxy-3β-hydroxymethyl-1-dethia-1-xxacepham-4α-carboxylate in a mixture of 0.5 ml. of pyridine and 0.3 ml of acetic anhydride are allowed to stand over temperature at room temperature. 0 ° C, then reaction. the mixture is concentrated in vacuo, poured into ice-water, and extracted with ethyl acetate. The extract is washed with dilute water, - hydrochloric acid, aqueous sodium bicarbonate solution, and water, and dried. thicken. 54 mg of diphenylmethyl-7α-benzamido-3β-hydroxy-3β-acetoxymethyl-11-dethia-1-oxacepham-4α-carboxylate are obtained in the form of crystals melting at 118 to 120 ° C. .

(6) To a solution of 350 mg of diphenylmethyl-7α-benzamido-3β-hydroxy-3 H -hydroxymethyl-1-dethia-1-oxacepham-4-carboxylate in 3 ml of dichloromethane is added 0.078 ml of pyridine

Ph.

(COOCHPhz fa) and 0.075 ml of methanesulfonyl chloride, - the mixture - is stirred first for 1 hour at - 0 ° C and then for 3 hours at room temperature. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract was washed with water, an aqueous solution of bicarbonate. sodium and again with water, dried - and evaporated. 370 mg of a residue are obtained which, after chromatography on silica gel, yields - 145 mg of diphenylmethyl-7α-benzamido-3 H -hydroxy-3 _! f-methanesulfonyloxymethyl-1-dethial-1-oxacepham-4α-carboxylate.

The following examples describe the preparation of starting materials.

Preparation 1

Ph.

CH _Z

Ъ ^X CW, OM I, COOCHPPx * (b) *

To a solution of 512 mg of compound (a) in a mixture of 10 ml of benzenes and 1 ml of methanol was added - 0.4 g of triphenylphosphine, and the mixture was stirred at 65 ° C for 1.5 hours. -. The residue is chromatographed on a 30 g silica gel column containing 10% water. Elution with benzene containing 20-30% acetic acid afforded 202 mg of (b).

t «. I want;

1b. V max

3370, 1782, 1755, 1635 cm -1.

NMR: δ CDCl 3

2.50-3.35- m 1 H, 4.18- 2 H, 5.08 s 1 H, 5.22 s 1 H,

5.28 d (3Hh) 1H, 5.5O s 1H, 6.08-d (3 Hz) 1H, 6.93 s 1H, 7.20-8.00 m 15H.

Preparation 2

CHJh. л r 7 L - ^VV _M f_N'cMC = CHZ ⁰ СаХСНРР ^

3) H _Z O * n 'у

VIC ^H of ^CH, X-NCHCO-CH

AND

COOCHPhz (1) - To a solution of 4.6 g of diphenylmethyl-2- (3-benzyl-7-oxo-2,6-palza-4-oxabicyclo [3.2.0] oct-2-en-6-yl) Of 3-methyl-3-butenoate - in 70 ml of ethyl acetate - 3.8 ml of a 2.74 M solution of hydrochloric acid in ethyl acetate and 12 ml of a 1.47 M solution of chlorine in carbon tetrachloride are added, and the mixture is stirred for 15 minutes at room temperature, 80 ml of a 5% aqueous sodium thiosulphate solution are added,

3.4 g of sodium bicarbonate and 240 ml of acetone and the reaction mixture were allowed to stand at room temperature for 2.5 hours. room temperature. The product is isolated by extraction - ethyl acetate, drying - the extract with sodium sulfate and evaporation. 3.33 g of diphenylmethyl-5-N-benzyl-4-oxo-2,6-aza-4-oxabicyclo [3,2,0-bept-2-en-O-yl) -3-chloromethyl is obtained. M.p. 82-83 ° C. (2) Prepared as above. the product is dissolved in 25 ml of acetone, the solution is treated with 3.3 g of sodium iodide and the mixture is left to react at room temperature for 2 hours. OF . The reaction mixture was evaporated with acetone and the residue was extracted with ethyl acetate.

The extract was 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 the residue obtained in (2) in a mixture of 13 ml of dimethylsulfoxide and 3 ml of water, 0.77 g of copper oxide is added and the mixture is 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) -3-hydroxymethyl- is obtained. 3-butenoate, m.p. 40-55 ° C.

The following tables summarize the reaction conditions, the starting and resulting materials, the yields of the products of the various types of reactions described above, and the physical constants of each compound.

In these tables, the abbreviations and symbols have the following meanings:

—Ph-phenyl '—STetr = 1-methyl-1,2,3,4-tetrazol-5-yl — C6H4NO2-P - p-nitrophenyl — C6N4СН3-Р = p-tolyl — C6H4CN-P = p-cyanophenyl - C6H4Cl-P = p-chlorophenyl-Bu-t = tert-butyl-EtOAc == acetoxy double line between X and Z (=) = OH 2 and

Z together represent a methylene group -O- m at X and Z = X and Z represent an epoxy group

A = the amino or substituted amino group is present at the RiCONH moiety = CHa = mass of the starting 3-exomethylenderivative

Hm = weight of starting material EtOAc - ethyl acetate THF => tetrahydrofuran

DMF = Ν, Ν-dimethylformamide

C-H2SO4 = concentrated sulfuric acid Et2O - diethyl ether t-BuOCl = tert-butyl hypochlorite eq - equivalent

DBN = 1,5-diazabicyclo [3,4,0] non-5-ene (CH 2) 5 NH - piperidine temp = reaction temperature tm = room temperature reflux = reflux reflux h = hour time = reaction time hv - mild radiation

A ² or Δ ³ for Z = instead of splitting. With the group at the 3-position, a double bond is present at the 2 (3) or 3 (4) position. . ,

For the NMR spectra in Table III, the symbols have the following meanings.

s = singlet d = doublet t = triplet q = quartet w = broad signal, m = multiplet

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В 418

Claims (1)

Method of production of 1-dethia-1-oxacephamderivatives of general I vistortee in which A represents an amino group or an amino group protected with 2 to 5 carbon alkanoyl, a benzoyl group optionally substituted in phenyl. parts with nitro, cyano, halogen or C 1 -C 3 alkyl, phenylalkanoyl. a (C 2 -C 4) alkanoyl moiety, or a (C 2 -C 4) phenoxyalkanoyl moiety. Y represents a divalent radical of formula —CH2 —CH2 — CH2 —CHC2CH2X, - CHC = CH2, —CHC — CH2, I I \ / I CQB СОВ OCOB —CH II —СНССНгХ I сов or —CH2 I —С = ССНгХ I сов where СОВ means 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, optionally a C 2 -C 4 alkanoyloxy group, a C 1 -C 3 alkylthio group, a C 1 -C 3 alkylsulfonyloxy group, a toluenesulfonyloxy group, a phenylthio group or a 1-methyltetrazole group and 1-methyltetrazole. Z represents a halogen atom, a hydroxyl group or an alkanoyloxy group having from 2 to 4 carbon atoms. characterized in that the compound of formula (II): wherein: A and Y are as hereinbefore defined, subject to imine formation and methanol addition by treatment with molecular halogen or non-tert-butyl hypochlorite as a nitrogen-halogenating agent and a metal methoxide selected from the group consisting of lithium, sodium, potassium, magnesium, calcium or barium using a hydrocarbon or ethereal solvents, wherein the N-halogenation is conducted at a temperature from -70 to -10 ° C for 2-10 minutes and the addition of methanol at a temperature of from -50 to 0 ^e C for 5-70 minutes.