JPS60197689A - Vinylthio derivative of oxacephalosporin - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [u, v and w are H or substituent group; x is H, alkyl, aryl, heterocylic group, cyano, hydroxymethyl, or (protected) carboxy; y is H, light metal, or carboxyprotecting group; z is halogen, acyloxy or heterocyclic-thio]. EXAMPLE:7beta-( 2-Bisdiphenylmethoxycarbonylmethylenedithiolane-4-carbonamido )- 7alpha - methoxy-3- ( 1-methyl-5-tetrazolyl ) thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid diphenylmethyl ester. USE:An antibacterial agent having low side effect and high stability and effective even to resistant bacteria. PREPARATION:For example, 1mol of the amine of formula II is made to react with preferably 1-2mol of the carboxylic acid of formula III in the presence of a condensation agent (e.g. N,N-dicyclohexylcarbodiimide), preferably in an inert solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a 7β-vinylthioacetamide-7α-methoxy-3-substituted methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid derivative represented by formula (I), and a method for producing the same. , methods of use, and drugs containing this compound as an active ingredient.

(In the formula, uVW is a hydrogen atom or a substituent; Carboxy protecting group; 2 represents an acyloxy group or a heterocyclic thio group, respectively.) The substituent represented by V is an alkylthio group, an aryl group, etc. The substituent represented by W is an alkyl group, an aryl group,
A heterocyclic group, a cyano group, a carboxy group, a protected carboxy group, a halogen atom, etc. are shown respectively. In addition, U and V combine to form a -6- group or a -CH2S- group;
V and W may be combined to represent a -(CH2)3C〇- group or the like.

The acyloxy group represented by 2 is an alkanoyloxy group, a carbamoyloxy group, a substituted carbamoyloxy group, or the like. A heterocyclic thio group is a 5- or 6-membered monocyclic or bicyclic unsaturated group having 1 oxygen atom, 1 sulfur atom and/or 1 to 4 nitrogen atoms as heteroatoms. .

Derivatives at the carboxyl group mainly include esters,
There are amides, salts, and the like, each of which is useful as a carboxy protecting group or a pharmaceutical derivative.

In the chemical field of penicillin and cephalosporin, the carboxy protecting group in the protective carboxy group represented by Protecting groups known as esters, such as aralkyl esters (esters such as benzyl, methylbenzyl, dimethylbenzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, aminobenzyl, diphenylmethyl, phthalidyl, phenacyl, etc.), substituted alkyl esters (esters such as trichloro esters of ethyl, t-butyl, allylnato), aryl esters (esters of pentachlorophenyl, indanyl, etc.), esters of N-hydroxyamino compounds (acetone oxime, acetophenone oxime, acetaldoxime, N-hydroxysuccinimide, N- esters with hydroxyphthalimide etc.)
There are protecting groups that form acid anhydrides with carbonic acid or carboxylic acid. Amides with high reactivity such as substituted amides and substituted hydrazides are also included as equivalent carboxy protecting groups. This protective group moiety may have various replacement bones as described above.

These will be desorbed in the final destination, so
As long as the purpose of protection is achieved, the structure is often not necessarily important, and a wide range of equivalent groups can be exchanged.

Particularly useful carboxy derivatives are those well known to those skilled in the art as suitable for pharmaceutical use, principally light metal salts and pharmacologically active esters.

Pharmacologically active esters mainly include esters that exhibit strong antibacterial properties when administered orally or parenterally, especially substituted alkyl esters (alkanoyloxyalkyl esters,
Alkoxyformyloxyalkyl ester, methoxymethyl ester, tetrahydropyranyl ester, 2-
oxo-1,3-dioxolenyl methyl ester, etc.)
, substituted aralkyl esters (phenacyl esters, phthalidyl esters, etc.), and substituted aryl esters (phenyl esters, xylyl esters, indanyl esters, etc.) are well known and can also be used in compound (I).

The light metal salt is preferably a salt of a light metal atom belonging to Groups 1 to 1 of the Periodic Table, Periods 2 to 4, which can form physiologically acceptable ions, especially lithium, sodium,
Examples include salts of potassium, magnesium, calcium, aluminum and the like.

In the definitions of each group above, the alkyl moiety is a straight chain, branched or cyclic alkyl group. The acyl moiety is a straight chain, branched or cyclic alkanoyl, alkenoyl, carbalkoxy, carbamoyl, sulfo, alkylsulfonyl, sulfamoyl, heterocyclic ring in which the aryl moiety has a heteroatom such as nitrogen, oxygen, or sulfur. and monocyclic or bicyclic acyl groups such as aroyl, aralkayl, arylalkenoyl, carboaralkoxy, and arylsulfonyl.

The aryl moiety is a monocyclic or bicyclic 5- or 6-membered aryl group, and may be a heterocyclic ring having a heteroatom such as nitrogen, oxygen, or sulfur in the skeleton.

Here, representative examples of the heterocyclic group include pyrrolyl, furyl, chenyl, pyrazolyl, imidazolyl, oxasilyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridyl, pyronyl, thiopyronyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,
indolyl, benzofuryl, benzothenyl, tetracylopyridazinyl, purinyl, quinolyl, inquinolyl,
Examples include pyridopyridyl and benzopyrronyl.

Each of the above groups may further have an unsaturated bond, a heteroatom, etc. in the skeleton.

Moreover, each group can have various substituents. Here, the substituents include carbon groups (alkyl, alkenyl, alkylidene, alkynyl, aralkyl, aryl, carboxy, protected carboxy, carbamoyl, alkanoyl, alkenoyl, aralkayl, aroyl, aminoalkyl, cyano, etc.), nitrogen groups (amino, hydrazinyl, acid,
Diazo, alkylamino, arylamino, acylated amino, alkylidene, ami/, imi/, nitroso, nitro), oxygen groups (hydroxy, alkoxy, aralkoxy, aryloxy, acyloxy, oxo, etc.),
Examples include sulfur groups (mercapto, alkylthio, arylthio, acylthio, thioxy, sulfinyl, sulfonyl, sulfo, protected sulfo, etc.), phosphorus groups (phosphorus, etc.), halogen atoms (fluorine, chlorine, bromine, iodo), and other substituents. . These may further have the same or different substituents. Furthermore, two or more types of substituents may be combined to form a cyclic group. Among these substituents, those which are unstable in production or use shall also be protected by methods known to those skilled in the art.

In addition, as protective groups, suitable hydrocarbon groups, acyl, alkylated silyl, alkoxysilyl, alkylphosphinyl, etc. can be used for hydroxy, amine, mercapto, and other groups that may cause undesirable changes during the reaction. , carboxy, sulfo, etc. are esters, acid anhydrides, amides, etc.
Protecting groups utilized in the art are used, such as groups forming hydrazides and the like. In particular, a group having a partial structure that is known to be able to be attached to and detached from other parts of the molecule without adverse effects is preferred.

Particularly useful substituents include alkyl, alkenyl, cyano,
Carboxy, protected carboxy, carboxyalkyl, hydroxyami7carbonylalkyl, carbamoylalkyl, cyanoalkyl, ami/alkyl, ureidoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, haloalkyl, sulfamoylalkyl , alkoxysulfonylalkyl, alkylsulfonylalkylnitro, ami/, hydroxy, alkyloxy, acyloxy, aryloxy, oxo, halogen, and the like. These may further have commonly used substituents and protecting groups.

Compound (1) exhibits antibacterial activity against aerobic or anaerobic Durham-positive bacteria (such as Staphylococcus) and Gram-negative bacteria (such as Escherichia coli), and is useful for the prevention and treatment of bacterial infections due to its sterilization of susceptible bacteria and bacteriostasis. It can be used as a medicine for animals, as a veterinary drug, and as a disinfectant, antiseptic, and preservative.

Compound (1) is stable, has few side effects, and has excellent pharmacological properties such as antibacterial activity, absorption, distribution, metabolism, and excretion, which is effective against bacteria resistant to other drugs.

When used as a medicine, it is formulated by adding commonly used additives if necessary, and the compound (I) is used for external use at a dosage of 10
A daily dose of μg to 1 mg, 0.2 to 5 g for intravenous injection, and 1 to 2 g for oral administration can be used to prevent or treat susceptible bacterial infections if administered externally, topically, orally, or by injection. .

Such preparations include ampoules, vials, powders, pallets, granules, capsules, tablets, dry syrups, suspensions, solutions, emulsions, ointments, injections, oral preparations, and inhalants. Examples include poultices, eye drops, nasal drops, ear drops, oral preparations, suppositories, sprays, etc.
Each can be used for internal use, external use, or local administration.

Among compound (I), carboxylic acids and light metal salts can be used in ampoules, vials, etc., along with stabilizers and solubilizers if necessary, for intravenous injection, infusion, intramuscular injection, subcutaneous injection, etc. Available as an injection. Pharmacologically active esters can be used internally as powders, pallets, granules, capsules, dry syrups, liquids, tablets, suspensions, etc., and externally as liquids, emulsions, ointments, suppositories, sprays, etc. It can also be used for local administration.

Compound (I) can also be used as a raw material for the synthesis of other antibacterial compounds within and outside the definition, a material for bacterial susceptibility testing, and the like.

The compounds of this invention can also be produced using the methods described below.

l) Production of salt Compounds in which the 4-position substituent of the cephem ring is carboxy (1
) is reacted with a base or with a light metal salt of another type of carboxylic acid by the exchange decomposition method, a light metal salt compound (
I) can be produced. As the operating method, methods used in this field can be applied. For example, a method of neutralizing a free acid with a light metal hydrogen carbonate salt, or a method of reacting an alkali metal salt of a lower carboxylic acid in a polar organic solvent such as alcohol, ketone, or ester, and then adding a sparingly soluble solvent to form the desired salt. A method of precipitation is preferred.

The reaction is usually completed in 1 to 10 minutes when carried out at a temperature below 50°C, but it can be allowed to stand for a longer period of time if no side reactions occur.

The salt produced in this way is separated as a solid such as crystals or powder, and after adding additives if necessary, it is formulated into a formulation by a conventional method, but it can also be made into an antibacterial formulation by a freeze-drying method or the like.

2) Removal of carboxy-protecting group The compound (1) having a carboxy-protecting group is subjected to a deprotection reaction commonly used in the art to form a free carboxy compound (1).
It can be done. For this deprotection reaction, procedures commonly used in this field, such as those described below, can be applied.

a) Carboxy protecting groups in the form of highly reactive esters, amides, anhydrides, etc. can be deprotected by contacting with acids, bases, buffers, ion exchange resins, etc. in an aqueous solution. Even when the reactivity is low, it may be possible to easily deprotect by increasing the reactivity using a known method. Typical examples include trichloroethyl ester, metal and acid, P
-Nitrohensyl ester V Hanawa fake city: g! I; Mensunko↓・7 Kinte There are activation methods such as light irradiation for phenacyl ester.

b) Aralkyl esters can be deprotected by catalytic reduction in the presence of a catalyst such as platinum, palladium or nickel using hydrogen in the presence of a catalyst such as platinum, palladium or nickel.

C) Aralkyl ester, cyclopropyl methyl ester, sulfonyl ethyl ester Nato can be deprotected by solvolysis reaction or the like. This reaction uses mineral acids, Lewis acids (aluminum chloride, tin chloride, titanium tetrachloride, etc.)
, sulfonic acid (methanesulfonic acid, sodium trifluoromethanesulfonic acid), strongly acidic carboxylic acid (trifluoroacetic acid, etc.), if necessary, in the presence of a cation scavenger.

d) Phenacyl esters, alkenyl esters, hydroxyaralkyl esters, etc. can be deprotected by the action of bases, nucleating agents, etc., and photochemically active phenacyl esters can be deprotected by light irradiation.

e) 2-alkenyl ester with alkali alkanoic acid [
Protect h? Alkali metal salts can be produced by reacting 7--L II M E...1'' in the tube.

f) Other equivalent carboxy protecting group removal methods can be used.

3) Introduction of a substituent at the 3-position If a heterocyclic thiol, an aromatic base, or a reactive derivative thereof corresponding to the starting compound in which the 3-position of compound (I) is a leaving group-substituted methyl group is reacted with, the objective can be achieved. The compound (I
) can be manufactured. Here, the leaving group is preferably an active leaving group such as halogen, sulfonyl t-+, alkanoyloxy, dihaloacetoxy, or trihaloacetoxy. As the reactive derivative of thiol, alkali metal salts, ammonium salts, carboxylic acid esters, etc. are preferable. The reaction takes place at θ℃ in both anhydrous and aqueous solvents.
It progresses well at ~60°C. This reaction is promoted by a dehydrating agent, a phosphoryl chloride compound, a rhodan compound, or the like.

Compound (I) having an alkanoyloxymethyl group or carbamoyloxymethyl group at the 3-position has N-
Protective power A method is used in which a reactive derivative of rubamic acid is applied and then deprotection is performed at a point where a carbamoyloxymethyl group can remain in the final product.

4) By reacting carboxylic acid (H) or its reactive derivative with the amidated amine (II) shown below or its reactive derivative, the desired compound (I) or its derivative can be produced. 0Oy (I) As a reactive derivative of amine (n), the amine 7 group at position 7 is a silyl group (trimethylsilyl, methoxydimethylsilyl, t-butyldimethylsilyl, etc.), stannyl group (trimethylstannyl, etc.), alkylene group (aldehyde,
acetone, acetylacetone, acetate ester, acetoacetonitrile, acetoacetanilide, cyclopentanedione, acetylbutyrolactone, etc.), alkylidene group (
1-haloalkyritene, 1-haloararal + IJden,
1-alkoxyalkylidene, 1-alkoxyaralkylidene, 1-alkoxy-1-phenoxyalkylidene, alkylidene, aralkylidene, etc.) - acids (in the form of salts with mineral acids, carboxylic acids, sulfonic acids, etc.), easily removed acyl groups Examples include those activated with other groups (such as alkanoyl), and those activated with other functional groups in the molecule as described above.

Reactive derivatives of carboxylic acid (III) are commonly used acylating derivatives such as acid anhydrides, acid halides, active esters, active amides, and azides.

Acylating agents that can be used for this acylation and their usage modes are listed below.

a) Free acid (II) 1M mixture [carposiimyl'(N,
N'diethylcarposiimide, N,N'-dicyclohexylcarposiimide, etc.), carbonyl compounds (carbonyldiimidazole, etc.), inxacillinium salts, acylamino compounds (2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline, etc.), amidating enzymes, etc.] - preferably an active hydrogen-free solvent (
Preferably, the amine (II) is reacted with 1 to 2 moles of the carboxylic acid (■) and 1 to 2 moles of the condensing agent in a halogenated hydrocarbon, nitrile, ether, amide solvent, etc., and mixtures thereof.

b) Acid anhydrides These include symmetrical anhydrides of carboxylic acids (I ), intramolecular anhydrides (ketene, incyanate, etc.), acid halides (mixed anhydrides with hydrogen halides), etc.

Preferably, 1 to 2 mol of acid anhydride and 1 to 0 mol of acid scavenger [inorganic base (oxides, hydroxides, carbonates, bicarbonates, etc. of alkali metals, alkaline earth metals, etc.), organic base] (tertiary amines, aromatic bases, etc.), oxiranes (alkylene oxides, aralkylene oxides, etc.), pyridinium salts (tripyridinium triazine trichloride, etc.),
adsorbents (such as Celite, etc.), preferably active hydrogen-free solvents (halogenated hydrocarbons, nitric acid, etc.).
1z, ether, amide solvent, etc. or mixtures thereof) or in an aqueous solvent under Schotten-Baumann reaction conditions with amine (II) or a reactive derivative thereof.

Acid, r) A/10 saponified product This is a mixed acid anhydride of a carboxylic acid (N) with a hydrohalic acid, and it is mixed with a solvent (especially, hydrogen halides, nitrites, ethers, esters, ketones, dialkylamides, aqueous solvents, etc., or mixtures thereof) or in an aqueous solvent under Schotten-Baumann reaction conditions, per mole of amine (II) or its reactive derivative. d) Active esters of carboxylic acid (III), such as enol esters (vinyl esters, impropenyl esters), aryl esters (phenyl esters,
(halophenyl ester-nitrophenyl ester, etc.)
, heterocyclic esters (pyridyl esters, benzotriazolyl esters, etc.), esters with N-hydroxy compounds, esters with diacylhydroxylamines (esters with N-hydroxyphthalimide, N-hydroxyphthalimide, etc.), thiol esters (aralkyl thiol ester, tetrazolyl thiol ester, etc.) and other known acylating agents based on activated ester groups. These active esters are reacted, for example, by the method described below. Furthermore, enzymatically active esters such as lower alkyl esters (4) are reacted in the presence of an amidating enzyme in an aqueous solvent by a conventional method.

e) Active amides These include aromatic amides of carboxylic acids (m) (imidazole, triazole, 2-ethoxy-1
, amide with 2-dihydroquinoline, etc.), diacylaniline, etc. This reaction is also carried out under the conditions described below, for example.

f) Formimino compound For example, N,N-dimethylformimino ester halide of carboxylic acid (■).

In the reactions d) to f) described above, the amine (II) or its Reactive derivative 1
Reactive derivatives of carboxylic acid (I[) 1-2 per mole
5) Add an N-halogenating agent, a dehydrohalogenating agent, and methanol to a compound that does not have a methoxy group at the 7-position of the methoxylated compound (1). The corresponding compound (I) can be produced by reacting them sequentially. In this case, 7β-amide-
7a-methoxy form is produced. Examples of operating methods include the following.

a) Alkyl hypochloride (such as t-butyl hypochloride) and alkali wire mesh methoxide (lithium methylate,
sodium methylate, etc.) in methanol.

b) A halogen molecule and a base (metal alkoxide such as lithium methoxide, sodium methoxide, magnesium methoxide, DBLlll; ethylamine, picoline, etc.) are reacted in methanol.

C) Hypohalite, hypohalite ester, N-
After an N-halogenating agent such as haloamide or N-haloimide and a dehydrohalogenating agent such as an alkali metal alkoxide or aryl alkali metal are allowed to act, methanol is made to act.

d) Other methods used in the art.

6) Structural transformation of side chain acyl group A compound having 7 acylamide groups with an appropriate functional group at the 7β position and having the same structure as compound (I) in other parts is subjected to various structural transformation reactions such as those shown below. If carried out, the compounds of this invention can be produced.

a) Reductive elimination reaction A compound in which the acylamide 7 group is substituted with an ethylthio group having a leaving group at the 1st and 2nd positions is a metal, an acid,
Hydrogenation can produce vinylthioacetamide compound (1) through the action of a reducing agent such as a fluorine complex compound. Examples of leaving groups include halogen, alkylthio, sulfinyl, hydroxy, and acyloxy. The reaction is carried out in an inert solvent.

b) Elimination reaction This is an acetamide in which the 7β-position acylamide group is substituted with an ethylthio group having hydrogen and a leaving group at the 1st and 2nd positions, and the other parts of the molecule change to a compound with the same structure as compound (I). , vinylthio compound (I) can be deoxidized by the action of a base.
can be manufactured.

As the leaving group, those described in a) above can be used. The bases are DBjJ, DBN-
A wide range of reagents can be used, including tertiary bases and aromatic bases.

In addition to commonly used dehydrohalogenating agents such as the joint action of lithium halide and dimethylformamide, and dehydrating agents such as thionyl chloride and a base when the leaving group is hydroxy, thermal decomposition can also be applied. If necessary, a heavy metal catalyst can be added to promote the reaction.

fc) Addition reaction A halobinylthio compound (I) can be produced by reacting a compound whose side chain at the 7β-position is halotioacetamide and whose other part of the molecule has the same structure as compound (I) with the corresponding ethynyl compound. Similarly, by reacting a haloethynyl compound with a compound (1) whose 7β-position substituent is a mercaptoacetamide group, the corresponding halobinylthio compound (1-) can be produced. Furthermore, when the 7β-position substituent is an ethynylthioacetamide group, the corresponding compound (I) can be obtained by adding an alkylmercaptan or hydrogen halide by a conventional method.
can be synthesized.

d) Substitution reaction/condensation reaction When an enol substitution reaction is performed on a compound in which the 7β side chain of compound (I) is replaced with a formylmethylthioacedoate 2do group with phosphorus pentahalide-phosphorus oxyhalide, alkyl mercaptan, etc., the reaction occurs. Vinylthioacetamide compound (I) can be produced. In addition, 7β of compound (1)
Halobinylthioacetamide compound (I) can be produced by reacting vinylene civalide in the presence of an aromatic base such as picoline with a compound in which the amide group is replaced with a mercaptoacetamide group. Halobinylthioacetamide compound (1) can be produced by reacting halothioacetaldehyde with a compound in which the 7β-position amide group of compound (I) is replaced with a haloacetamide group in the presence of a base. Similarly, the corresponding vinylthioacetamide compound (I) is obtained by the action of trifluoromethylthioacetaldehyde or alkylthioacetaldehyde. A halogenating agent is applied to a compound in which the amide group at the 7β-position of compound (I) is replaced with a protected carboxymethylene diethane carboxamide group or a trialkylsilyl-substituted protected carboxymethylene dichetane carboxamide group to obtain the corresponding protected carboxyhalomethylene diene. A chetane carboxamide compound (1) can be produced.

e) Starting materials The raw materials used in the reactions a) to d) above can be produced by reacting a reactive derivative of a carboxylic acid having an acyl group with the amine CD) or its reactive derivative in a conventional manner. .

7) Protection of carboxy groups and other reactive functional groups In each of the above production methods, when compound (i) is subjected to a chemical reaction to convert it into another compound (I), etc., the target group is protected. It may be necessary to protect other reactive functional groups. In this case, protection can be achieved by applying methods commonly used in this field depending on the type of reactive functional group. Such methods are detailed in various texts.

Regarding protective groups for protecting reactive groups in each of the above sections, and methods for introducing and removing them, see, for example, J.

F.W. McOmie Ed,” Protecti
ve Groupsin Organic Chemi
sty'' P, 183 (1973) PLEUM Pr
ess, N, Y, :ya S, Patai, Edi
T.

”The Chemistry of Function
nal Groups”.

P, 505 (1'969), Interscience
ePubl,.

John Wiley & 5ons Ltd, Lon
Don: Flynn Ed, “Cephalospori
ns and Pencillins”Academ
It is also possible to use methods described in detail in books such as ic Press, N, Y, (l 972) or various patent documents.

For example, acylation, etherification, etc. for hydroxy groups, acylation, enamination, silylation, etc. for ami7 groups, etc.
The carboxy group can be subjected to esterification, amidation, acid anhydride, etc. using conventional methods. In addition, the reaction in this section also includes the use of pharmacologically active esters in order to modify the pharmacological properties and impart desired properties. In this case, the desired compound (1) can also be synthesized by reacting carboxylic acid (1) with a base to form a salt and reacting with a halide of a desired ester group.

8) Synthesis of side chain acyl group moiety The acyl group constituting the 7β-position side chain can be synthesized from known compounds by combining known methods.

Generally, an acyl moiety is synthesized by an elimination reaction or an addition reaction, and if necessary, it is made into a free carboxylic acid or a reactive derivative, which can then be used in the amide reaction described in item 4). Furthermore, a carboxylic acid having a desired acyl group can be obtained by appropriately modifying the reactive moiety in the molecule.

a) Elimination reaction 1. A 2-disubstituted ethylthioacetic acid derivative can be subjected to an elimination reaction to form the corresponding vinylthioacetic acid derivative.

Examples of substituents here include halogen, alkylthio, acyloxy, hydroxy, and phosphonium, and usually a reducing agent such as a metal and an acid, a hydrofluoric acid compound and an acid, etc. are reacted in an inert solvent.

An ethylthioacetic acid derivative having a leaving group and a hydrogen atom at the 1st and 2nd positions of the ethyl group can be converted into the corresponding vinylthioacetic acid derivative by the action of a base or the like. In this case, examples of leaving groups include halogen, acyloxy, alkoxy, and hydroxy. As a base, DBU,
A wide variety of reagents can be used, ranging from strong bases such as DBN and tertiary bases to weak bases such as pyridine and picoline. In some cases, ordinary dehydrochlorination agents such as the action of lithium chloride and N,N-dimethylformamide, dehydrating agents such as thionyl chloride and a base, or thermal decomposition may be applied.

b) Addition reaction of ethynylthioacetic acid or a derivative thereof with an alkyl mercaptan, preferably in the presence of a weak base such as an aromatic base,
The reaction can produce alkylthiovinylthioacetic acid or its derivatives. Furthermore, vinylthioacetic acid or a derivative thereof can also be produced by reacting an ethynyl compound with thioglycolic acid or a reactive derivative thereof.

C) Substitution Reaction A vinyl thioacetic acid derivative can be produced by reacting a thioglycolic acid derivative with a vinyl compound having a leaving group-substituted vinyl group. In this case, upon closer inspection, it is often found that an addition reaction similar to b) above and an elimination reaction belonging to a) occur together, resulting in an apparent substitution reaction.

d) Other transformations When the thioglycolic acid derivative produced as described above has a functional group, it can be converted into a desired structure by applying known methods. Further, the above-described structural transformation can be performed by newly introducing a functional group and performing a known general reaction.

9) Reaction conditions Synthesis method 1)-8) is usually carried out at a temperature of -30°C to 100°C, particularly -20°C to 50°C, for 10 minutes to 10 hours. These are carried out in a solvent, optionally under anhydrous conditions. Any other conventional law may be applied.

Hydrocarbons (pentane, hexane,
octane, benzene, toluene, xylene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, chlorobenzene, etc.), ethers (diethyl ether, methylisobutylethyl, dioxane, tetrahydrofuran, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), esters (ethyl acetate, isobutyl acetate, methyl benzoate, etc.), nitrohydrocarbons, tromethane, nitrobenzene, etc.), nitriles (acetonitrile, benzonitrile, etc.), amides (formamide, acetamide, etc.) , dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide, etc.),
Sulfoxides (dimethyl sulfoxide, etc.), carboxylic acids (formic acid, acetic acid, propionic acid, etc.), organic bases (diethylamine, triethylamine-pyridine, picoline,
collidine, quinoline, etc.), alcohol (methanol,
Examples include ethanol, propanohexanol, octatool benzyl alcohol, etc.), water, industrial solvents belonging to other series, or mixtures thereof.

10) The target products for post-treatment are unreacted raw materials, by-products,
After removing impurities such as solvents by conventional methods such as extraction, evaporation, astringency, concentration, precipitation, filtration, and drying, adsorption, elution,
It can be isolated by a combination of conventional post-treatment methods such as distillation, precipitation, precipitation, and chromatography.

11) Production Examples and Examples The present invention will be explained in detail below by showing production examples and Examples of raw materials for synthesis of the 7-position side chain.

In the examples, the part representing the amount is the weight ratio to 1 part by weight of the raw material β-lactam, and the molar equivalent number is the weight ratio to 1 part by weight of the raw material β-lactam.
Shows the number of moles per mole.

For post-treatment in the examples, usually water, an acid, a solvent such as dichloromethane is added to the reaction solution as necessary, and after branching, the organic layer is washed with water, dried, and concentrated under reduced pressure to remove the resulting residue. If necessary, use a combination of methods such as purification using silica gel or chromatography, followed by collection by crystallization, precipitation, or filtration. The measured physical constants of the product agree with those of the separately synthesized product.

The abbreviations used are as follows.

DMSO dimethyl sulfoxide TSOHD-1-luenesulfonic acid DBU 1,5-diazabicyclo[5,4,O) -!
5-Undecene DHP Dihydropyran NET3 Triethylamine PMB Paramethoxybenzyl TMS Trimethylsilane NBS N-Promosuccinimide Production Example I I3 r [IJ[23 [3] [4] NyuC1-1=c[-1scH2COOC2H5-→[
6] ) N CH=CH8CH2COOH [7] 1) r-acetylpyridine (1,12,429 to 99
% ethanol 25m7! 2.2-ml of concentrated hydrochloric acid was added dropwise, and the mixture was concentrated under reduced pressure. The residue is dissolved in 25d dichloromethane and 1.025-bromine is added dropwise with stirring at room temperature. If the precipitate is collected and washed with ether, r-bromoacetylpyridine hydropromide [2J 5.312
get g.

Yield: 94%.

NMR (CD30D) δppm' 3.35 (s
, 2H).

7.85 (d, J=5.5Hz, 2H),
8.55 (d, I=5.5Hz.

2H).

2) Sodium 871"? was dissolved in anhydrous ethanol 60-, and while stirring under water cooling, thioglycolic acid ethyl ester 4.14- was added dropwise. After stirring for 30 minutes, r-promoacetylpyridine hydropromide [2
Add J5.312 f little by little and leave at room temperature for 1.5 hours.
Stir for 15 minutes at 50°C.

Filter the reaction solution, take the r solution, and concentrate. The residue was purified by chromatography to obtain 3.1 g of r-pyridylcarbonylmethylthioacetic acid ethyl ester [3,].

Yield: 68%, NMR (CDCl3) δ: 1
．． 31 (t, J=7Hz, 3H), 3.34(P
m', 2H), 4.03(s, 2H), 4.22((
+, J=7Ht, 2H), 7.74(Q, J=4.5
Hz: 0.5) (Z.

2H) 8.83 (Q, J=4.5H2: 0.5f-
1t, 2H).

3) (2-r-pyridyl-2-oxoethyl)thioacetic acid ethyl ester (3) 3.5 R39 water-cooled water 1
In addition to 5rnl, 6.011nl of 20% sodium hydroxide solution was added dropwise while stirring to form a solution. At the same temperature, sodium borohydride 285 ~ was added little by little and stirred at the same temperature for 1 hour and at room temperature for 30 minutes, cooled with water, added glacial acetic acid 2-, left overnight, and adjusted to pH 2 with 10% hydrochloric acid. Afterwards, it is extracted with methyl ethyl ketone. Ethanol was added to the extract, the solvent was distilled off, and the residue was diluted with ethanol 30% again.
rnl, acidified with hydrochloric acid, and heated under reflux for 1.5 hours. The solvent is distilled off, ethyl acetate and water are added, the mixture is made alkaline with aqueous sodium bicarbonate, and extracted with ethyl acetate.

After washing the extract with water and drying, the solvent was distilled off (2-r
-pyridyl-2-hydroxyethyl)thioacetic acid ethyl ester (4J3.l) is obtained.

Yield: 86%.

NMR (CDCl + CD OD ) δ ・1.27 (
t.

3　3　PPm.

J=7Hz, 3H), 2.93(q, J=5.5H
1: 7. OHE, 2H), 3.27 (S, 2H)
, 4.15 (Q, J=7Hz, 2H), 4.84 (
9, J=5.5Hz: 7. □Ht, IH), 7.3
5 (d, J-5,5Hz, 2H), 8.44 (d,
J = 5.5Hz, 2H).

4) (2-γ-pyridyl-2-hydroxyethyl)thioacetic acid ethyl ester (4J) Dissolved in 510-99.5% ethanol 13-, added dropwise 275 μl of concentrated hydrochloric acid while stirring under water cooling, and after stirring for 15 minutes, Benzene 15-
Add and concentrate. Dissolve the remaining hydrochloride in dichloromethane 1
5- Suspend the mixture in water, add 200 μj of thionyl chloride while stirring under water cooling, stir at the same temperature for 1 hour, then at room temperature for 1 hour, and then concentrate. The residue is dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to give (2-r-pyridyl-2-chloroethyl)thioacetic acid ethyl ester (5J).

NMR (CD(:l3)δPPm: 1.27(
L, J=7.3H), 3.17 (S, 2l-1
), 3.30 (d, J=7Hz.

2H), 4.19 ((1, J=7H6,2H), 5.
07 (t pJ=7Hz, l IH) 17.3-7.
7 (m, 2H).

8.65 (brs, 2H).

5) (2-r-pyridyl-2-chloroethyl) obtained above
Thioacetic acid ethyl ester [5] in dichloromethane 13m
/DBL1338μ while stirring under water cooling.
After stirring at room temperature for 1 hour and under reflux for 5 hours, the mixture was passed through a column of silica gel 459 and eluted with ethyl acetate. Concentration of the effluent yields (2-r-pyridylvinyl)thioacetic acid ethyl ester [6'', 173η.

NMR (CDCI!) δ °1.27 (L, J=
7.584.

3 PPm' 3H), 3.57 (8,2H), 4.24
(q, J=7.5HE, 2H), 6.44(d,
J=15.5Hz, IH).

7.0-7.6 (m, 3H), 8.53 (br, d
, 2H) Summer R (CHC/3) υ, -1: 1729
,1593°1283.1129,1021.991.
9316) This product (6J734!) was dissolved in 6.5 ml of water, and 1.45 ml of 20% sodium hydroxide solution was added under water cooling.
After stirring at the same temperature for 15 minutes and at room temperature for 3 hours,
Add 10% hydrochloric acid to adjust pH to 3. The precipitate was collected in a furnace, washed with water, dried, and dried with phosphoric anhydride to obtain (2-r-pyridylvinyl)thioacetic acid [7J 435η.

Yield near 0%, mp, 238-239°C (decomposed).

Production Example 2 (8) (9) [10] 1) 2-Methyl-5-vinylpyridine [8J23.7g
was dissolved in 100 rnl of ethylene glycol, bromine 32j9 was added dropwise under water cooling, and the mixture was stirred for 15 minutes.
The solution is added dropwise at the same temperature and heated to 100° C. for 3 hours. Add 200rnl of water to the reaction solution, concentrate under reduced pressure, and take off the precipitated crystals to obtain 2-methyl-5-cotinylpyridine [9
) 9.6 g is obtained. Yield: 41%. NMR (DMSO)
δ・2.42 (S, 3H).

ppm' 4.22 (8, IH), 7.17 (d, IH,
J=8.0).

7.67 (dd, J=8.0: 2.0,
IH), 8.46 (5 ml of tetrahydrofuran solution and 2.25 ml of thioglycolic acid dissolved in 3.8 ml of 20% sodium hydroxide solution are mixed under water cooling, and heated at room temperature for 1 hour and at 50°C for 3 hours. .The reaction solution was cooled on ice and diluted to 60%.
After adding 3.45% of perchloric acid and stirring for 15 minutes,
Extract with methyl ethyl ketone. Wash the extract with water, dry it,
Concentrate. The residue is made alkaline with 5% hydrogen carbonate water, washed with ether to remove raw materials, brought to pl-11 to 2 with 10% hydrochloric acid, and extracted with ethyl acetate.

The extract is washed with water, dried, and then concentrated. If the remaining white solid is filtered off, 2-methyl-5-pyridylvinylthioacetic acid [10] 2.719 is obtained. Yield: 65%. NMR
(d13-DMSO) δ'2.59(S.

ppm' 3H), 3.64 (B, 2H), 6.52 (d,
J=10°5Hz, IH), 6.88(d, J=
10.58Z, 10), 7.85(d, J=8.IH
), 8.43 (d, J-BHz, IH), 8.56
(')'', lH). (external reference TMS).

Production Example 3 H3 [13] H3 [14J 1) A solution of 0.77-diisopropylamine in 30i of tetrahydrofuran (5.46mM) was cooled to -30°C, and to this was added 3.4ml of a 1.62M n-butyllithium hexane solution ( 5,46mM) and stirred for 30 minutes. Cool the reaction mixture to -78°C, and add 4-methyl-1,4-
Thiazin-3-one [11J358”? (2,73m
Add 2rnl of tetrahydrofuran solution of
Stir for a minute. Then 0.49 ml of carbon disulfide (8,
19mM) and stir for 1 hour. -50 for this
Cool to 9°C and add 0°24rnl (2,73ml) of methyl acetate.
(mM) and stir for 1 hour.

After adding 1.5-mL of acetic acid to the reaction mixture, the mixture was poured into ice-diluted hydrochloric acid, extracted with ethyl acetate, washed with water, dried, and concentrated. The residue was purified by silica gel chromatography and eluted with a dichloromethane-ethyl acetate (2:1) mixture to give (methyl 4-methyl-3-oxo-1,4-thiazine-2-thiocarbonylthioacetate (12) 441η get.

Yield: 57.8%.

NMR (CDCI!) δ' 2.42-3.97
(m.

3 PPm' 4) 1), 3.03 (If, 3H), 3.70 (
S, 3H), 4°07 (S, 211), 4.67
(S, IH).

2) (Dissolve 12J of the compound in 8d of dichloromethane and prepare
1,58mM) was added under water cooling, then DBLIo, 7
Add 1m/(4,74mM). After stirring for 1 hour, the reaction solution was washed with dilute hydrochloric acid and water, dried, and concentrated. The residue was purified by silica gel chromatography and eluted with dichloromethane-ethyl acetate to give 2-(4
-Methyl-3-oxo-1,4-thiazin-2-ylidene]-dichetane-4-carboxylate (13J22
7 Yield of obtaining 6■: 51°6%.

NMR (CDC13) δ: 2.83-3.03 (m, 2
H).

2.99 (S, 3H), 3.7-3.86 (m, 2H
), 3.83 (@, 3H), 4.91 (s, IH)
.

I R(CHCz 3')υ. -1: 1740,16
10゜3) Dissolve 266 rng of this product [13] in acetone 1-, and add 1 rn IN-sodium hydroxide under ice cooling.
Add l and stir for 30 minutes. The reaction solution is concentrated to remove acetone, and the aqueous portion is washed with ethyl acetate. The aqueous layer is acidified with dilute hydrochloric acid and extracted with ethyl acetate.

The extract is washed with water, dried, and then concentrated to obtain the corresponding carboxylic acid (1432391n9. Yield: 94°5%)
.

NMR (CDC/ +CD30D (4:1)) δpp
m'2.85-3.06 (m, 2H), 2.
99(8,3H).

3.73-3.87 (m, 2H), 4.95 (B,
IH).

IR (Nujol) υ -1: 1700.1590゜0m Production Example 4 [15] (16) 1 [18] [19] [20] 1) Compound 2.4729 of formula [15] was dissolved in 100 ml of dry dichloromethane, Bromine 8 while stirring at room temperature.
Add 67 μE dropwise and heat under reflux for 3 days.

From now on, if we calculate the number of precipitates, the compound of formula [16] will be 2.62
get g. Yield near 1%.

IR (nujol) υ(,-1:3099,1713゜1682.1654,1603,1296,1235゜1173.1002.953.856゜2) Sodium 2 s s my is dissolved in 99.5% ethanol 150 ηJ and cooled with water. 1.42 ml of thioglycolic acid ethyl ester was added dropwise to the bottom while stirring, and after stirring for 15 minutes, 2.74'l of the compound of formula [16] was added little by little. After stirring at the same temperature for 2 hours and then at 50°C for 1 hour, the precipitate was removed. Concentrate the mother liquor, treat it with ether to make a powder, take it off and wash it with ether to obtain the formula [1
7] compound 1.406p is obtained. Yield: 45%.

48 (s, 2l-1), 3.37 (s, 2
H), 4.14((+.

J = 7.0.28), 8.42 (S, IH).

3) Add 1.124 g of the compound of formula [17] to water 18-, and add 20% sodium hydroxide while stirring in an ice-cold oven.
66- was added dropwise and stirred for 30 minutes, then 77.5 mW of boron hydride was added little by little at the same temperature, stirred at room temperature for 2 hours, cooled with water again, 10 drops of acetic acid was added dropwise, and then Stir for 15 minutes.

Adjust the pH to 1-2 with hydrochloric acid, extract with methyl ethyl ketone and ethyl acetate, dry with sodium sulfate, add 35 mZ of ethanol, and evaporate under reduced pressure to obtain formula [18]
Compound 855■ is obtained. Yield near 6%. This product is used as it is in the next step.

4) Dissolve 855 mg of the compound of formula [18] in 7rnl of dry dichloromethane and 7n4 of dry methyl ethyl ketone, add 180mW of TSOH and molecular sieves, and heat under reflux on an oil bath for 5 hours. From now on, ethanol 1
Add 5- and 1 drop of concentrated hydrochloric acid and concentrate under reduced pressure. After repeating this operation twice, the residue was placed in a column of silica gel 509 and developed with a mixed solvent of dichloromethane and ethanol in a ratio of 9:1 to obtain compound 542■ of formula [19].

Yield: 68%.

mp=194-197°C.

NMR (CDC/ +CD OD) δ ・1.26 (3
3ppm't, J = 7.5, 3H), 3.50 (S,
2H), 4.20 (q.

J = 7.5, 2H), 6.25 (d, J
=15.5, LH), 7.18 (d, J
= 15.5, IH), 7.31 (S.

IH) IR (nujol) υmaKcrn-1:316811
736.1665, 1300, 1223, 1176゜1
025.940.856°5) 101 m9 of the compound of formula [19] is suspended in 1.54 m of water, and while stirring while cooling with water, 1.60 m of 20% sodium hydroxide is added dropwise, and the mixture is stirred for 5 minutes.

After further stirring at room temperature for 1.5 hours, the pH was adjusted to ~2 with 10% hydrochloric acid, extracted with methyl ethyl ketone, the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 85 m9 of the compound of formula [20]. get. Yield: 95
%.

Production Example 5 (21) (22) [23J H3 [24] [25] Synthesized in the same manner as in Production Example 4 using the compound of formula [21J] as a starting material. The physical properties of the product at each stage are shown below.

[22] Yield: 83%. mP = 245-248℃0
1R (nujol) υ -1+ 3082.2998゜rllaKCm 1740.1663.1592.997.889.76
2゜[23] Yield: 81%.

NMR (DMSO) δ: 1.07 (t, J=7.
0.3H).

Pm 3.20 (S, 2H), 3.28 (S, 3H),
3.84(S, 2J, 4.01(q, J=7.0,2
H), 8.36CB.

IH) (External reference TMS) IR (Nujol) υmalc, CM-1: 309
8, 3030°1737.1718,1682,16
48.1591゜1190.1013.896.879
．． 762° [24] Yield: 65%.

Use as is for the next step.

[25] Yield: 41%.

NMR (CDC/) δ: 1.33 (t, J=7.
0゜3 PPm 3H), 3.45 (5, 3H), 3.54 (S, 2H)
, 4.27((1, J=7.0.2H), 6.23(d
, J=15.5, IH), 7.24(S, IH),
7.33 (d, J = 15.5.1) 1) [26] Yield: 93% Production Example 6 [27] These products were prepared by the method described in the literature (G.

Nanni et al: J, Antibio
tics 34 (41412 (1981)). However, the compound in the literature is [-butyl ester.

(27J NMR(CDC/)δ': 3.60
(S.

3 PPm 2H), 6.05 (d, J = 10.LH), 6.96 (
S.

IH), 7.30 (m, 11H).

(28,1NMR(CDCl3)δppm: 3
．． 41 (S.

2H), 5.97 (d, J = 15.5, IH
), 6.93 (S, IH), 7.30 (m, l0H)
, 7.75 (d, J-15,5, IH).

Production Example 7 [29] [30] 1) Propionaldehyde diethyl acecool (29)
A catalytic amount of TSOH was added to a mixture of 25 mA, 10-ethyl thioglycolate and 25 rnl of toluene, and 120
React for 3 hours in an oil bath at °C. If distilled under reduced pressure, cis-
2.5 g of 2-methylvinylthioacetic acid [30] is obtained. Yield 17%, bP = 75'C/4rttnH
90I R(CHCl3) υ, -1: 173
ON MR(CDCl3)δppm: 1.2
7 (t, l=7,3H), 1.62-1.87
(m, 3H), 3.33 (S, 2H),
4.17 (q, J=7.2H), 5.40-6.20
(m.

2H).

2) Dissolve (30J 2.5I/) in 20Tnl of methanol and add IN-sodium hydroxide 16- under water cooling.

After stirring at room temperature for 1 hour, pour into water and extract with ethyl acetate to remove neutral substances. The aqueous layer is acidified with hydrochloric acid,
Extract with ethyl acetate. When the solvent is distilled off, the free acid (30) (31) 1.709 is obtained as an oily substance. Yield: 8
2%.

NMR (CDC/3) δPPm: 1.63-1.8
3 (m, 3H), 3.35 (S, 2H), 5
．． 40-6.17 (m, 2H).

Production Example 8 [32] C333 [34J [35] [36] + -n + 1) Methyltriphenylphosphonium bromide (32)
22.49 is dissolved in 300 rnl diethyl ether and cooled to -70°C. Add 44ml of a hexane solution of 1.4N-butyllithium, and raise the temperature to 0°C over 30 minutes. Cool again to −60° C. and add 7.1 rnl of ethyl trifluoroacetate. After raising the temperature to 15°C over a period of about 20 minutes, pour into 2% hydrochloric acid (450°C), scrape off the precipitated crystals, separate the organic layer of iPl'&, wash with water, and distill off the solvent. do. When the residue and the crystals taken off the coast are combined, trifluoroacetylmethylene-triphenylphosphorane [
33) Get 8.5p. Yield 43%.

IR (CHC/3)'can-1' 158oONMR
(CDC/ )δ −4,23(d, J=40°3 P
Pm' IH), 7.20-7.88 (m, 15H).

2) Bis(ethoxycarbonylmethyl)disurbide 1.
Dissolve 2y in tetrahydrofuran 15- and cool to -20°C - 4.0 ml of 1.25N-chlorine in carbon tetrachloride solution
Add and stir at -20℃ to 0℃ for 10 minutes. then 0
Add 3.70 g of the above phosphorane [33,] at ℃ and add 1
Stir for 0 minutes. Hydrogen carbonate) Pour into IJum water,
Extract with methylene chloride. The extract is washed with water, the solvent is distilled off, and the residue is recrystallized from a methylene chloride-ether mixture to obtain 1-(trifluoromethyl)-1-(ethoxycarbonylmethylthio)methylene triphenylphosphorane [
34J 4.0011 is obtained. Yield 89%.

lR(CHC/3)υcrn-1: 1720,
1555°NMR (CDC/3) δppm: 1.
20 (t, J=7, 3H2,70(b,s,2H
), 4.00 (q, J=7,2H), 7.37-7.9
3 (m, 15H).

3) Dissolve in thiomethylene phosphorane (3413,0091￥ acid 30-, add sodium cyanoporohydride (N a B Ha CN ) 3.Of at room temperature over 30 minutes, and stir further at room temperature for 4 hours. Remove the solvent under reduced pressure. left,
The residue was poured into 30 ornl of 1% aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water, the solvent was distilled off, and the residue was separated by silica gel column chromatography to obtain ethyl ester 960~ (yield 66%) represented by formula [35] and its cis form [35') 370■ ( yield of 25%).

Physical properties of compound [35J: l R(CHCl!3)υcIl, -1: 173
0.1615°NMR(CDC/3)δppm
: 1.30 (t, J=7,3H), 3.50 (8
, 2H), 4.23 (q, J = 7, 2H), 5.67 (
d-, Q, J=7.16. IH), 7.07 (d.

Q, J=1.16. IH).

Physical property values of compound [3ri',]: IR(CHC13)υ. -1: 1725, 1615° NMR (CDCl 3 ) δppm 71.28 (t
, J=7.

3H), 3.40(S, 2H), 4.22((1,J=
7゜2H2), 5.63 (d, q, J = 9.10,
IH), 6.82 (d, J=10, IH).

4) Ethyl ester [35) 730■ methanol 5
-, add IN-sodium hydroxide 3.8-,
Separate the aqueous layer. The aqueous layer is acidified with hydrochloric acid, extracted with ethyl acetate, the extract is washed with brine, and the solvent is distilled off.
36] of trans-2-trifluoromethylvinylthioacetic acid is obtained as an oily substance. Yield: 9
4%O NMR (CDCI!) δ: 3.5'5 (8,2
H), PPm 5.68 (d, d, J=16.6.IH), 7.07
(d.

d, J=16.1. IH).

Production Example 9 [37] p [38] [39] C/ [40] [41] [42] -n-1''- [41'] [42'] 1) Monothioglycol 3o8y to potassium carbonate 544
．． Dissolve in 8g of water, 1200ml of solution, and add 800ml of ethyl acetate.
- and tetra-n-butylammonium bromide 6.6g
Add. Next, add 380ml of methyl chloroacetate to 10~
Add dropwise over 30 minutes at 18°C. Further stir at 18-20°C for 2 hours and 20 minutes. Separate the organic layer, extract the aqueous layer twice with ethyl acetate, combine all the organic layers, wash with brine, remove the solvent, and distill the residue under reduced pressure to obtain methyl hydroxyethylthioacetate (37). Obtain 514g.

Yield 87%, b, 1+, I, , = 120-127°C 0I
R(CHCl!3)υcrn-1: 3450.1
720°NMR (CDC/3) δppm: 2.8
2 (t, J=6.28), 2.82 (S, IH),
3.28 (S, 2H), 3°73 (g, 3H), 3.
77 (L, J=6.2H).

2) To 249.8rnl of thionyl chloride (37,14
76 g was added dropwise over 50 minutes at 30±2°C. 3 more
After stirring at the same temperature for 0 minutes, distillation under reduced pressure yields methyl chloroethylthioacetate (38 J 429.1 (l). Yield 80%, bp 7 mm = 104-105°C.

IR(CHCI!3)υ, -1:1725°NMR(C
DC1,'+)δ: 2.97 (t, J=7.2 HP
m), 3.27 (s, 2H), 3.67 (t, J=7
．． 20).

3.72 (s, 3H).

3) Dissolve chloroethyl thioester (383429,19 in 820 m/m of benzene, add DBU419-, and heat under reflux for 1.5 hours. Dilute with ethyl acetate, wash sequentially with dilute hydrochloric acid and brine, and remove the solvent. Distilled,
Distillation of the residue under reduced pressure yields methyl vinylthioacetate (39)
Obtain 247g.

Yield 73%, bp 4-5M++ = 59-65.5°C
IR(CHC/3)υ. -1: 1725°NMR (C
DCl5) δppm: 3.45 (S, 2H)
, 3.75 (s, 311), 5.17 (d, J=1
7. IH), 5.27 (d.

J=10.17. IH).

4) Vinylthio-ester (39) 11.65 f is dissolved in 220 Tnl of methylene chloride and cooled to m-20°C. After adding a small amount of a 1.25N solution of chlorine in carbon tetrachloride, it was cooled to -60°C and a solution of 75N of chlorine in carbon tetrachloride was added.
After stirring for 15 minutes, the mixture was washed successively with an acidic sodium sulfite aqueous solution and brine, and the solvent was distilled off to leave methyl 1,2-dichloroethylthioacetate [40]. This residue [40] was dissolved in dimethylamide 50
- or [7. Add lithium chloride 109 and 70℃
Stir in a water bath for 30 minutes. The extract was poured into water and extracted with ethyl acetate, the extract was washed with salt, the solvent was distilled off, and the residue was distilled under reduced pressure.
A ratio of 4 gives 11.1'. Yield 80%, bP2rIr
In-75-85°C.

Physical properties of trans form [41J: NMR (CDCl) δ: 3.38 (S, 2H).

3 PPm 3.75 (S , 3H), 6.10 (d,, l=1..
3, IH).

6.47 (d, J=13.1H).

Physical property values of cis form [41'): NMR (CHCl3) δppm: 3.43 (S
, 2H), 3.75 (S, 3H), 6.19 (d
, J=17. IH), 6.48 (d, J=7.LH).

5) 2-chlorovinylthio-ester [41) (41
' 6.709 of a mixture of 3 and 13.4rnl of methanol
Dissolve, cool to -10°C, add 4rnl of 3N sodium hydroxide, 13°, and stir at 0°C for 15 minutes.

Pour into water and extract with ethyl acetate, remove neutral substances, acidify the aqueous layer with hydrochloric acid, and extract with ethyl acetate. The solvent was distilled off, and the residue was recrystallized from a mixed solvent of benzene:hexane-1:3 to obtain the cis form of 2-chlorovinylthioacetic acid (42'
We get 34.29. Yield 68%. The recrystallized mother liquor was concentrated and trans-2-chlorovinylthioacetic acid [42J920
■ Get. Yield 15%.

Physical property values of compound [42]: J R (CHCl3) 'cm 1' ” 7”
O.

NMR (CDC/) δ: 3.40 (S, 2H), 6
゜ PPm 17 (d, J = 15, IH), 6.48
(d, J=15.

IH), 11.33 (S, IH).

Production Example 10 [43) (44) [45'' 1) 4°63N in a mixture of 4.47- and propargyl alcohol 4.47- and propargyl alcohol
-Add 0.2- of sodium methylate/methanol solution and stir at 100°C for 6 hours and then at room temperature for 2 days.

Pour into water and extract with ethyl monoacetate, wash the extract with an aqueous potassium carbonate solution and an aqueous sodium chloride solution, distill off the solvent, and purify the resulting residue by silica gel column chromatography to obtain compound 1. of formula [43]. Obtain 25g.

I R(CHCl!3)υmax, c, , -1 : 1
725.

NMR (CDC/3) δppm=3.67 (S, 2H)
, 3°73 (S, 3H), 4.10-4.40 (m,
3H), 5°6.3-5.98 (m, IH),
6.13 (d, J=10, IH) 2) Methyl ester compound represented by formula [43] 0゜4
59 was dissolved in dichloromethane 3.5-DHPo.

Add 3 ml, add a catalytic amount of T s OH-020, and stir for 10 minutes under water cooling, and then for 10 minutes at room temperature.

The mixture is poured into an aqueous sodium bicarbonate solution, the organic layer is separated, and the solvent is distilled off to obtain ester 670 of formula [44].

3) Dissolve 0.67 g of ester represented by formula (44) in 5 rnl of acetone, and add 2.5-mL of IN-sodium hydroxide.
Add and stir at room temperature for 20 minutes. Pour into water and extract with ethyl acetate to remove neutral parts. The aqueous layer is made acidic with phosphoric acid and extracted with ethyl acetate. The Q-extract is washed with aqueous sodium chloride, and the solvent is distilled off. obtain.

Production Example 11 [46] [47] [48] [49] 1) Formula (46J O) h Rupho:/acid compound 2.20
115mM) in dimethylformamide 9- and cooled on ice with NET32.8m/(2QmM) and P-methoxybenzyl chloride 40I! (20mM) was added sequentially,
Stir for 2 hours. After quenching with ice water, extraction with ethyl acetate, distilling off the solvent, and recrystallizing the residue from cyclohexane yields PMB ester 2.7 of formula [47].
Get 49. Yield: 68.7% omp=R9-60°C.

NMREM-39Q(CDC/)δ'3.79(3
PPm'S, 3H), 5.17 (S, 2H), 6.
90, 7.33 (ABq, J-9Ht, 4
H), 7.23-7.61 (m.

5H).

2) ethyl thioglycolate 0.55ml (5mM),
PMB Ethyl[47] 1.339 (5mM) in dimethylformamide 5-solution at 27°C was added with DB.
Add LI7Qμl (react exothermically to a maximum of 40°C).
). After quenching with ice water and extracting with ethyl acetate, the resulting oily substance is treated with silica gel column chromatography (benzene/ethyl acetate = 19/1) using a Lober column to obtain the ethyl ester compound of formula [48]. Obtain 1.31 g. Yield: 67.9%.

gt=o, 29 (benzene/acetic acid-19/1).

NMREM-390 (CDC/)δ: 1.233
PPm (t, J=7) 1z, 3H), 3.45 (S, '2H)
, 3.77 (S , 311) , 4.17 ((1, J=
7Hz, 2H), 4.90(s, 211),
5.96 (S, IH), 6.80, 7.09
(ABM, J=8Hz, 4H), 7,3.3(S, 5H
).

3) Ethyl ester represented by formula [48] 386 mf
1 (1mM) in 2rnl of acetone, add 1.2ml of IN-hydroxide under ice cooling, and stir for 30 minutes. After distilling off the solvent, the aqueous solution is acidified with 10% hydrochloric acid and extracted with ethyl acetate to obtain 380m9 of the compound represented by formula [49] as an oily substance.

NMREM-390 (CDC/3) δppm:
3.46 (S, 2H), 3.77 (S, 3H)
, 4.90 (S.

2H), 5.99 (S, tH), 6.80.7.0
7 (ABq.

J=9Hz, 4H), 7.33 (S, 5H), 9.3
7 (S, IH).

Production Example 12 [50] [51] [52] 1) Bis(ethoxycarbonylmethyl) disulfide 4
Add 2mM of chlorine in carbon tetrachloride solution to 00μl (2mM) of ethyl acetate 4-solution at room temperature and stir for 25 minutes. After the solvent was distilled off, it was dissolved in 3-ethyl acetate and added with 440 μl of ethynylbenzene (50) at room temperature. (
4mM) and stir for 2 hours. After distilling off the solvent, the residual liquid is treated with silica gel column chromatography (benzene/ethyl acetate - 19/1) to obtain a complete set [51
] Compound 850''W is obtained. Yield: 82.7%.

NMREM-390(CDCl!3)δppm:
1.22 (t, J=8I-11,3-H), 3.10(
S, 2H), 4°12 (9pJ-8Ht, 2H)
, 6.66 (S-IH).

7.15-7.60 (m, 5H).

2) Ethyl ester 850m9 (
3.31mM) was suspended in 4ml of acetone, and 4.31mM of IN-sodium hydroxide was suspended under water cooling. , add l/(15~
Clear solution after 20 minutes). After 40 minutes, acetone was distilled off, and an ethyl acetate-water mixture was added to branch. If the aqueous solution is made acidic and extracted with ethyl acetate, the formula 2 [52
] is obtained quantitatively.

NMREM-39Q(CDCl)δ-3,13(S
.

3PPm' 2H), 6.69 (S, IH), 7.30~
7.60 (m, 5H), 9.38 (bs, IH).

[51] 1) Compound 447 of formula [51] was dissolved in dry ethyl acetate 2
- 1.6N hydrochloric acid/ethyl acetate 10% under ice cooling
- and stir at room temperature for 17 hours. The mixture was quenched with 5% sodium hydrogen carbonate under water cooling, and the organic layer was dried and distilled off to obtain 428 ml of residual liquid. This one is NMR
According to the method, it is a [51M[53] mixture of approximately 1/1 ratio.

Physical property values of compound [53]: NMREM-39Q (CDCl) δ ・1.18
(3PPm't, J = 8Hz, 3H), 3.20 (S
, 2H)', 4.06(q, J=8Ht, 2H
), 6.35 (S, IH) 7.3-7.6 (m, 5H
).

2) 1=1 mixture 42 of compounds of formulas [51] and [53]
8.8 (1.67 mM) was dissolved in acetone 2-, and while cooling with water, 2 rnl of IN-sodium hydroxide was added for hydrolysis (45 minutes). Ethyl acetate-water was added, the aqueous solution was made acidic with 10% hydrochloric acid, and extracted with ethyl acetate. By drying the solvent and distilling it off, 378 rng of an oily substance is quantitatively obtained. This substance was determined by NMR to have the formula (s2J/(s4J
= 1/1 mixture.

Physical property values of compound [54]: NMREM-390 (CDC13) δPPm: 3.23
CB, 2H), 6.35 (S, IH), 7.3-7
．． 6 (m.

58), 9.43 (bs, IH).

Example 1 (Sodium salt, formulation, usage) (A) COO (g) a, K) (B) 1 g of carboxylic acid (A) was dissolved in 0.5% sodium bicarbonate water, and the pH was adjusted to 7 with hydrochloric acid. After washing with ethyl acetate and desalting, the mixture is placed in a 10-vial and freeze-dried by a conventional method to obtain a powder of the corresponding sodium salt (B).

1 g of the above sodium salt prepared under aseptic conditions was dissolved in 4 g of distilled water for injection, and 5 taphylococci
C. cus aureus infection can be treated by intravenous injection twice daily.

If this sodium salt (B) is taken and the minimum inhibitory concentration is measured according to the method prescribed by the Japanese Society of Chemotherapy, it is found that Streptococcus pyogenes
Less than 1 part g/m7 for C-203, Escherichia coli Esche
1 ttg for richia coli JC-2
/mt or less.

Example 2 (Deesterification) COOy (A) (B) y=-CH2C6H40CJ(3-P, -CHph
21) P-methoxybenzyl ester or diphenylmethyl ester (A) 1 part cyclomethane 0.3-3
parts, 0.3 to 3 parts of trifluoroacetic acid and 0 parts of anisole.
．． Dissolve in 5 to 5 parts and stir at -10 to 40°C for 10 minutes to 3 hours. The reaction solution is concentrated under reduced pressure to remove the solvent and reagents, and the residue is washed with benzene to obtain the corresponding free acid (B).
can be produced with a yield of 70-90%.

2) Dissolve 1 part of the starting material (A) in a mixture of 5 to 9 parts of dichloromethane and 2 to 8 parts of anisole, and heat to -10 to 10°C.
After adding 2 to 4 molar equivalents of aluminum chloride or titanium tetrachloride, the mixture is stirred for 1 to 3 hours. If the reaction solution is washed with dilute hydrochloric acid and water, dried, and then concentrated, the corresponding free acid (B) can be produced in a yield of 80 to 95%.

Example 3 (Introduction of 3-position - heterocyclic thio group) (A) Cα row (B) Z - heterocyclic thio group 1) 1 part of 3-chloromethyl compound (A), heterocyclic thiol sodium salt 1.2 equivalents and a catalytic amount of tetrabutylammonium bromide are dissolved in 10 to 2 parts of dichloromethane,
Stir at room temperature for 30 minutes to 3 hours.

The organic layer is washed with water, dried, and then concentrated under reduced pressure to obtain the corresponding heterocyclic thio compound (B). Yield, 80-90%.

2) 1 part of 3-chloromethyl compound (A) and 1.2 equivalents of heterocyclic thiol sodium salt are dissolved in 3 to 5 parts of N,N-dimethylformamide and stirred for 30 minutes to 3 hours.

The reaction solution was poured into water and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure to obtain the corresponding heterocyclic thio compound (B).

Yield: 80-90%.

Example 4 (Amidation) Cα addition (B) By the acylation reaction of the above formula, 1 mole of the corresponding 7β-amino compound (B) was added with the carboxylic acid (C ) or its reactive derivative can be reacted to synthesize amide (A).

1) 100 volumes of dichloromethane, 1.1 mol of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyphosphorus, 1.1 mol of N,N-dicyclohexylcarposiimide, 1.5 mol of pyridine and carboxylic acid (C ) Stir in a 1.1 mol mixture at θ°C to room temperature for 1 to 6 hours.

2) In a mixture of 1.1 mol of di-2-pyridyl disulfide, 1.1 mol of triphenylphosphine, and 1.1 mol of carboxylic acid (C) in 10 volumes of ethyl acetate, 10 to 50°C
Stir for 2 to 6 hours.

3) 3 times the volume of dichloromethane, carboxylic acid (C) 1°1
mol, 1,3.5-tripyridinium triazine trichloride in a mixture of 4 mol at -10 to 10°C for 1 to 5 hours.

4) Carbon tetrachloride 30 times volume weight N-methylmorpholine 1.5
-20 to io in a mixture of 1.1 mol of tris-diethylaminophosphine and 1.1 mol of carboxylic acid (C).
Leave at ℃ for 1-5 hours.

5) A mixture of 10 volumes of chloroform, 10 volumes of dimexyethane, 1.5 moles of pyridine, and a mixed anhydride of carboxylic acid (C) and isobutoxyformic acid was mixed at 5 to 10°C.
Stir for 0 minutes to 6 hours.

6) Ethyl acetate (0 chloro, 1,2-dichloroethane 10
double volume, N-methylmorpholine 1.5 mol, carboxylic acid (
Heat under reflux in a mixture of 1.1 mol of the symmetrical anhydride of C) for 10 minutes to 2 hours.

7) 100 volumes of dichloromethane, 1.5 mole% of pyridine @
Stir in a 1.1 mol mixture for 1 to 3 hours while raising the temperature to 0°C.

8) 10 times the volume of ethyl acetate, 1.5 mol of mixed acid anhydride of diethyl phosphate and carboxylic acid (C), and Pirig 2
Stir in a 1.5 molar mixture at 0-10°C for 1-5' hours.

9) Stir in a mixture of 7 volumes of ethyl acetate, 100 volumes of dichloromethane, 1 mole of pyridine and 1.1 moles of a mixed acid anhydride of carboxylic acid (C) and phosphoric acid dichloride at 0°C to room temperature for 1 to 3 hours.

10) Lutidine 1.5 mol, dichloromethane 10 m/,
'Phosphoric acid dimethylamide monochloride and carbo
Stir in a mixture of 1.1 to 2 moles of mixed anhydride with phosphoric acid (C) at 0 to 30°C for 1 to 4 hours.

11) Diku 0 mouth Tatafu 5 times volume, trifluoroacetic anhydride 1.5 mol, pyridine 3 mol and carboxylic acid (C)
Stir in a 1.5 mol mixture at 0°C to room temperature for 1 to 5 hours.

12) Stir in a mixture of 100 volumes of dichloromethane, 12 moles of bromide of diethyl phosphate, 2.5 moles of N-methylmorpholine and 1.2 moles of carboxylic acid (C) at 0°C to room temperature for 1 to 3 hours.

13) When the substituent at the 4-position of the cephem ring of compound (B) is a carboxy group, it is dissolved in 10 times water containing 2.5 mol of sodium bicarbonate, and the carboxylic acid (C) qS compound 1
．． Add 1 mol dropwise and react at -5°C to room temperature for 30 minutes to 2 hours.

14) When the substituent at the 4-position of the cephem ring of compound (B) is carboxy, O-silylation is performed by reacting 1.2 moles each of trimethylsilyl chloride and triethylamine,
4 molar equivalents of pyridine and 1.1 chloride of carboxylic acid (C)
After adding moles at -30°C and reacting for 30 minutes to 2 hours, the silyl ester is hydrolyzed with acid.

15) 4 moles of picoline and chloride of carboxylic acid (C) 1.
In a solution of 2 moles dissolved in 20 volumes of methane, 0
Stir at ℃~-30℃ for 30 minutes~2 hours.

16) A mixture of 1.1 mol of triethylamine and 1.1 mol of chloride of carboxylic acid (C) in a solution of 2 volumes of dimethylformamide and 10 volumes of ethyl acetate was heated from 0°C to -20°C.
Stir for 30 minutes to 3 hours.

17) Stir at -30 to 10°C for 30 minutes to 2 hours in a mixture of 30 volumes of methane, 1.1 mole of cyanuric chloride, 4 moles of pyridine, and 1.1 moles of carboxylic acid (C).

18) Stir at -10 to 10°C for 20 minutes to 2 hours in a mixture of 3 volumes of methane, 1.1 moles of phosphorous oxychloride, 1.5 moles of pyridine, and 1.1 moles of carboxylic acid (C).

19) By allowing trimethylsilyl chloride to act with an acid scavenger,
An N-trimethylsilyl compound is prepared, and 1.5 moles of phosphorus oxychloride, 1.2 moles of carboxylic acid (C), and 4 moles of pyridine are reacted with 1 mole of this in 5 times the weight of dichloromethane at 0°C to room temperature for 30 minutes to 2 hours. .

20) Stir at −30 to θ° C. for 1 to 5 hours in a mixture of 8 times the volume of the jig, 1.5 mol of thionyl chloride, 2.5 mol of pyridine, and 1.1 mol of carboxylic acid (C).

21) Stir at -50 to 10°C for 10 minutes to 2 hours in a mixture of 3 volumes of chloroform, 1 volume of toluene, 1.1 mol of carboxylic acid (C), 2 mol of picoline, and 1 mol of oxalyl chloride.

22) In a mixture of 20 volumes of dichloromethane, 3 moles of pyridine, 3 moles of 1-oxybenzotriazole ester of carboxylic acid (C), and 3 moles of N,N-dicyclohexylcarposiimide, at 10 to 50°C Stir for ~30 hours - 23) In a mixture of 20 volumes of methane, 2.1 moles of 1-hydroxybenzotriazole, 2.5 moles of N,N-dicyclohexylcarposiimide and 2 moles of carboxylic acid (C), Stir at room temperature for 1-15 hours.

24) Stir at 10 to 50°C for 2 to 8 hours in a mixture of 10 volumes of dioxane, 2 moles of phthalimide of carboxylic acid (C), and 2 moles of N,N-dicyclohexylcarposiimide - 25) 10 volumes of methyl isobutyl ketone content, carboxylic acid (
C) in a mixed solution of 1.5 mol of saguccinimide and 1.5 mol of N,N-dicyclohexylcarposiimide, 0 to 40
Stir at ℃ for 2-9 hours.

26) Stir in a mixture of 1.1 mol of carbonyldiimidazole, 10 mol of tetrahydrofuran, 5 chloro of dimethylacetamide, and 1.1 mol of carboxylic acid (C) at θ°C to room temperature for 1 to 5 hours.

27) Carboxylic acid (C
) and dimethylformamide Vilsmeier reagent 1.1
mol and dimethylaniline in a mixture of 1.3 mol at room temperature for 1 to 5 hours.

28) 10 volumes of methane, 5 volumes of dimethylformamide, 1 volume of N,N-dicyclohexylcarposiimide.
1 mol, picoline 1.2 mol, carboxylic acid (C) 1.
Heat in 1 molar mixture for 2 to 24 hours.

In the above description, the volume indicates the ratio of the number d to the number of grams of the raw material amine (B).

Example 5 (Methoxylation) 1 part of 7α-amido-3-substituted methyl-1-dethia 1-oxer 3-cephem-4-carboxylic acid derivative was dissolved in 10 parts of dichloromethane, and 1 part of tertiary butyl hypochloride was dissolved.
．． Add 1 molar equivalent and leave at -20°C for 3 hours. To this was added 1.2 molar equivalents of lithium methoxide dissolved in methanol, and the mixture was allowed to react for 30 minutes. The reaction solution is acidified with acetic acid and diluted with dichloromethane. If this is washed with water, dried, and concentrated under reduced pressure, the corresponding 7β-amide-7α-methoxy-3-substituted methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid derivative can be obtained with a yield of 40-85%. Can be manufactured.

Example 6 (Pharmacologically active ester) (A) 1) 1 mmol of carboxylic acid potassium salt (A) was mixed with N,N-
Dissolve in 2 to 5 parts by weight of dimethylformamide and add 1 to 2 equivalents of pivalic acid iodomethyl ester while cooling with water.
Stir for 5 minutes to 2 hours. The reaction solution was diluted with ethyl acetate, washed with ice water and sodium bicarbonate water, and dried.
Concentrate under reduced pressure.

The residue is recrystallized from ethyl acetate to obtain pivaloyloxymethyl carboxylic acid (B).

2) The same product can be produced by using a sodium salt in place of the potassium salt (A) in 1) above and reacting under the same conditions.

3) Pivaloyloxymethyl ester (B) of 1) above
25 (150 μg of I+Fung starch and 5 mW of magnesium stearate are mixed and granulated using a conventional method, and the mixture is filled into gelatin capsules.

One to three capsules can be administered orally three times a day to patients with susceptible staphylococcal infections to treat this disease.

Example 7 (Side chain conversion) COOCHPh2 7β-(2-bisdiphenylmethoxycarbonylmethylenedithiolane-4-carbonamide)-7α-methoxy-3-(l-methyl-5-tetrazolyl)thiomethyl-
670 ~ of 1-dethia 1-oxer 3-cephem-4-carboxylic acid diphenylmethyl ester and 0.3- of trifluoroacetic acid are reacted at 0°C for 30 minutes in a mixture of 0.3 rnl of anisole and 2- of dichloromethane. The reaction solution was concentrated to dryness, and the residue was washed with petroleum ether and ether to obtain 270 mg of the corresponding tricarboxylic acid.

Compounds produced according to the methods described in Examples 1 to 7 above are listed. In the table, IR is crn-1
The value and NMR were expressed as δ value. The J value represents the coupling constant (Hz value).

Claims (1)

[Scope of Claims] Ill 7β-vinylthioacetamide-7α-methoxy-3-substituted methyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid derivative represented by formula (1). (In the formula, u, v, w are hydrogen atoms or substituents; hydrogen atom, alkyl group, aryl group, heterocyclic group, cyano group, hydroxymethyl group, carboxy group or protected carboxy group; γ is hydrogen atom, a light metal atom or a carboxy-protecting group; 2 represents a halogen atom, an acyloxy group, or a heterocyclic thio group; A method for sterilizing a susceptible bacterium by bringing the compound according to claim 1 into contact with the compound. (4) The compound according to claim 1 is subjected to amidation, heterocyclic thiolation, methoxylation, nuclear synthesis, A method of producing by deprotection, salt formation or esterification.