CA1260004A - Method for production of 1,3,2-dioxaphospholes - Google Patents

Abstract

Abstract of the disclosure The invention relates to a method of producing a 1,3,2-dioxaphosphole of the formula [I]B
[I] B

wherein represents a benzene ring which may be substituted and R repre-sents an aryl, alkoxy or aralkyloxy group which may be substituted, which comprises reacting a catechol compound of the formula [II]B

[II]B

wherein is as defined above, with a compound of the formula [III]B

[III]B

wherein X is a halogen atom and R is as defined above, at a temperature not higher than about 30°C in the presence of a base. The compounds of formula [I]B
are useful, for example, as neutral catalysts in deriving cephalosporin anti-biotics, which have important value in the treatment of bacterial diseases.

Description

1 2~205-~91~

This invention relates to the preparation of 1,3,2-dioxaphospholes of the formula [I]B

~ O ~ \ R

wherein ~ and R are as defined hereinbelow.
The invention of this application is divided out of copending parent application serial no. 411,185 filed on September lO, 1982. The invention of the parent application relates to a novel method of producing a cephalosporin compound of the formula RlNH S
CH2R [I]

COOR
~herein Rl is a hydrogen atom or an acyl group; R is a hydrogen atom or an ester residue; the dotted line means a double boncl in 2- or 3-position of the cephem ring; and R is a nucleophilic compound residue, or a salt thereof, directly in one step from a compound of the formula R NH ~ S ~
o,~ ~L_ CH2011 LII]
2a C~OR
wherein R1J R and the dotted line have the same meanings as defined above, or a salt thereof, being useful in an industrial production.

The present i.nvention concerns the preparation of lJ3J2-dioxaphos-pholes of the formula ~8~

~ Q ~ ~ [I]B

wherein ~ represents a benzene ring which may optionally be substituted and R represents an aryl, alkoxy or aralkyloxy group which may optionally be substituted.
According to the present invention there is provided a method of producing a 1,3,2-dioxaphosphole of the formula [I]B

~ O R [I]B
wherein ~ represents a benzene ring which may be substituted and R
represents an aryl, alkoxy or aralk~loxy group which may be substituted, which comprises reacting a catechol compound of the formula [II]B
OH

~ OH [II]B

wherein ~ is as defined above, with a compound of the formula [III]B
X ~ ~0 [III]B
X ~ ~ R
wherein X is a halogen atom and R is as defined above, at a temperature not higher than about 30C in the presence of a base.
The compounds of .formula [I]B are useful, for example as netural catalysts in deriving cephalosporin antibiotics, which have important value in the treatment of bacterial diseases, or intermediates therefor rom peni-cillin compounds by ring expansion (3apanese Published Unexamined Patent Appli-cation ~091/1975) and are also useful in the production of cephalosporin compounds having at position 3 a methyl group substituted with a nuclcophilic group, whi.ch compounds are :important as antibiotics or intermediates therefor ~6~
_ 2a -by reaction of deactylcephalosporin C ~DCPC) obtainable by fermentative culture or a derivative thereof or of cephalosporin C also obtainable by fermentatiorl, which derivative has a -CH20H group at position 3, with a nucleophilic reagent as mentioned hereinbcfore.
A number of investigations have so far been made for the production of such 1,3,2-dioxaphospholes of formula [I]B, and [1] the route involving , ~ [L. Anschutz, Annalen, 454, 109-120 (1927)], [2] the route ~ -> Q ~ ~ ~ ~ [T. A. Khwaja et al., J. Chem. Soc. (C), 1970, 2092-2100], and L3] the route ~ -> ~ ~ ~ [H. Gross et al., Chem. Ber., 96, 13~7-1394 (1963) and East German Patent 50606 (laid open - 3 ~

May 5, 1971)], for instance, are known~ as illus-trated i.n the followlng:

~ PC~5 ~ ~>Pel3 -~3~-~ ~ >P~oc~ ¦

PCl ~ C12 / (C~3CO)20 ~

~ ~ P-Cl ~ ~ Cl ~ O>P`CRl.

wherein R is an alcohol residue. However, ~ethod ~1) is disadvantageous in that the raw ~aterial PC15 is su~ a~le, hence can be handled with difficulty, that the yield is low and that ~ethylchloride, which has an offensive odor and is hazardous, is produced, method [2~ is also dis-advantageous in that the nu~er of steps involved is large 3 that the yield is low and that distillation of intermediates ~ and ~ gives large a~ounts of residue having a tendency toward solidification, hence difficult to handle, and even ~ethod [3] is pro~le~atic in that the yield is low. Moreover, for all of methods ~ - ~ , inter~ediates ~ , ~ and are hygroscopic and easily deco~pose upon a~sorption of ~oisture, so that they are di~ficult to handle. ~or these and other reasons, these ~ethods are all disadvantageous for large scale co~ercial production of [I~B. A ~ore adv-antageous ~ethod f`or the prod-lction of [I]B has been lorlged for to ~e developed.
The present inventors conducted various investigations ;6~
4 24205-~9lD

on the production of compounds [I]B and ha~e now unexpectedly found that compounds [1]~ can be obtained in one step in an industrially very advantageous manner in good ylelds in a short period of time by reacting a compound of the formula OH
[IL]B
OH

wherein ~ is as defined above, with a compound of the formula X \ ~0 ~III]B
X / ~ R

wherein X is a halogen atom and R is as defined above, at a temperature not higher than about 30C in the presence of a base.

Thus, the method of the preparation producing 1,3,2-dioxaphospholes [I]B, comprises reacting compound [II]B with compound [III]B at a -temperature not higher than about 30C in the presence of a base.
In the above ~ormulas, ~ is a benzene ring which may optionally be substituted and the benzene ring may have one to four substituents, which are inert to the reaction, each selected from among a straight or branched Cl-C6 lower alkyl group (e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl, pentyl), a straight or branched Cl-C6 lower alkoxy group (e.g. methoxy, ethoxy, isopropyloxy)l a straight or branched Cl-C6 lower alkylthio group (e.g. methylthio, ethylthio, n-propylthio, isopropythio), a C2-C6 lower acyl group (e.g~ acetyl, propionyl), a C2-C6 lower acyloxy ~L~6~

group (e.g. acetoxy, propionyloxy), a C2-C6 lower acylamino group (e.g. acetylamino), a di-lower (Cl-C6) alkylamino-lower (Cl-C6) alkyl group (e.g. dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl), a Cl-C6 lower alkoxycarbonyl or C6-C10 aryloxycarbonyl group (e.g.
methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl), nitro, halogen (Br, Cl, I, F), cyano, carboxy, hydroxy or a like monovalent group. Furthermore, the benzene ring may have such a divalent substituent as methylenedioxy, ethylenedioxy, ~ or ~
which substituent may further be substituted, for example with halogen, cyano, nitro, oxo and/or carboxyl Specific examples of the compound of formula [II]B are pyrocatechol, homocatechol, pyrogallol, methyl 3,4-dihydroxybenzoate, 2-hydroxy-4-propionylphenol, 3,4-dihydroxychlorobenzene, 3,4-dihydroxy-methoxybenzene and 1,2-dihydroxynaphthalene. In particular, pyrocatechol, for instance, is preferred.
In the above formula [III]Bt X is a halogen atom such as F, Cl or Br. In particular, when X is Cl, good resu~ts are obtainable. R is an aryl, alkoxy or aralkyloxy group which may optionally be substituted. The aryl group includes, among others, phenyl, tolyl, xylyl, biphenylyl and naphthyl. The alkoxy group is, for example, a straight or branched Cl-C6 lower alkoxy group such as mentioned above Eor ~ . The aralkyloxy group includes benzyloxy, phenethyloxy, phenylpropyloxy, naphthylmethoxy, etc.
These aryl, alkoxy and aralkyloxy groups may optionally be substituted and the optional substituents include such halogen, nitro, cyano, l~a3~t~

oxo, C1-~6 lower alkoxy, C1-C6 lower alkylthio and alkoxy-car~onyl groups as ~entioned abo~e for ~ and ~urther a C1-C6 lower alkylsulfonyl group (e.g.
~ethylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropyl-sulfonyl, n-~utylsulfonyl~, allylsulfonyl, etc. SpeciEic and preferred exa~ples of R are ~ethoxy, ethoxy, propyloxy, isopropyloxy, ~utyloxy~ n hexyloxy, benzyloxy, phenethyloxy,

2-cyanoethoxy, 2-~ethylsulfonyle-thoxy, 2-~ethoxycar~onylethoxy and 2-~ethoxyethoxy. In particular, when R is, for exa~ple, a lower alkoxy such as ~ethoxy or ethoxy, good results are o~tained.
The ~ethod of the preparation is carried out by reacting co~pound ~I~ Bwith co~pound ~ Bat a te~perature not higher than a~out 30C in the presence of a ~ase.
Co~pound ~ Bis su~itted to the reaction either in the ~ree or in the for~ of a salt with a ~ase such as ~entioned here-in~elow. ~he ~ase to ~e used in practicing the method includes, a~ong others, tertiary a~ines such as tri~ethyla~ine, triethyla~ine, tri-n-~utylanine, N-~ethylpiperidine, cyclo-hexyldi~ethyla~ine and ~-~ethyl~orpholine, dialkyla~ines such as di-n-~utyla~ine, diiso~utyla~ine and dicyclohexyla~ine, aro~atic a~ines such as pyridine, lutidine and y-collidine, other organic amines, alkali metals such as lithium, sodiu~ and potassiu~, alkaline earth ~etals such as calciu~ and ~agnesiu~, quaternary a~oniu~ such as tetraethyla~oniu~ and tetra~utyla~oniu~, and other inorganic bas~s. Said ~ase ~ay ~e used in the Eor~ o~ a salt with the phenolic hydroxyl group oE co~pound CII~BOr ~ay ~e added in carrying out the - 7 - ~6~

reaction or ~ay ~e used in ad~ixture with co~pound CII~B.
Prefera~le ~ases are tri-lower (C1_C6j alkyla~ines such as tri~ethyla~ine, triethyla~ine and tri-n-~utyla~ine and aromatic amines having a six-membered ring such as pyridine and lutidine. In particular, -triethyla~ine, tr.i-n-~utyla~ine, pyridine and the like are preferred.
~ he reaction is pre~era~ly carried out ~y ~ixing co~pound CII~Bwith co~pound LIII~ Band then ~ixing the ~ixture with a base at ~elow about 30C, ~y ~ixing co~pound ~ B with a ~ase and -then ~ixing the ~ixture with co~pound ~ B at ~elow a~out 30C, or ~y ~ixing a salt o~ co~pound rII~B and a ~ase such as ~entioned a~ove with co~pound [III~B at below a~out 3~C. ~he reaction te~perature is prefera~ly 0C or below, ~ore prefera~ly -5C to -40C. ~he reacti.on can ~e carried out in a ~ore advantageous ~anner ~y using a solvent.
As the solvent, an org~nic which is inert to the reaction is used. Since the starting compound [III]B and the product [~ Bare easily hydrolyza~le upon contact wlth water, the use of an anhydrous aprotic solvent is practical. Exa~ples of such solvent incapa~le oY reacting with co~pound ~ B are halogenated hydrocar~ons such as ~ethylene chloride, chloro~or~, car~on tetrachloride, 1,2-dichloroethane and 1,1,2-trichloroethane, ethers such as di~ethyl ether, ~ethyl ethyl ether, diethyl ether, tetrahydro~uran and dioxane, organic nitriles such as acetoni-trile and propionitrile, nitroalkanes such as ni-trol~ethane and nitroethane, esters such as ~eth~l aceta-te, e-thyl acetate and ~ethyl propionate, ke-tones such 8 24205-~9lD

as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, chlorobenzene and bromobenzene, aliphatic hydroca~bons such as petroleum ether, hexane and cyclohexane, sulfones such as sulfolane, and mixtures of these. Among such usable solvents, preferred are halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether and tetrahydrofuran and organic nitriles such as ace-tonitrile and propionitrile. Especially preferred are dietyl ether, methylene chloride and acetonitrile, among others. When such an organic solvent is used, the reac-tion is generally carried out by miY~ing compound [II]B with compound [III]B in the organic solvent and mixing the mixture with a base at below about 30C, by mixing compound [II]B with a base in the organic solvent and mixing the mixture with compound [III]B at below about 30C/ or by mixing a salt of compound [II]B and a base such as mentioned above with compound [III]s in the organic solvent at below about 30C.
Compound [III]B is used generally in an amount of 0.8 to 1.2 moles, preferably 0.95 to 1.05 moles, per mole of compound [II]B.
Stoichiometrically, 2 moles of the base is required per mole of compound [II]B, since the reaction yields 2 moles of a hydrogen halide per mole of compound [II]B and the hydrogen halide Eorms a salt with the base. However, the base is used, unless the reaction is adversely affected, in an amount of 1.6 to 2.4 moles, preEerably 1.8 to 2.2 moles, per mole of compound [II]B. When an organic solvent is used, it is used in an amount of 0.1 to 20 liters, preferably 0.5 to lO litres, per mole oE compound [II]B.
The reaction - 9 - l te~perature is desired -to ~e low and is generally about 30C
or ~elow since higher tenperatures tend to cause easy for~a-tion of ~yproducts. Considering the yields of byproducts and the extent of cooling realizable in the commercial practice, it lies generaliy within the range o~ 30C to -100C. When the purity ànd yield of the desired product and the efficiency of cooling are taken into consideratian, it is advantageous fro~ the industrial viewpoint to carry out the reaction at a te~perature within the range of 10C to -50C, ~ore prefera~ly -10C to -30C. The reaction is exothermic and vigorous in the step of ~ixing co~pound CII]Bwith co~pound [II~ Bin the presence oX a ~ase and therefore it is advisa~le to perfor~ the ~ixing portionwise under cooling. ~he reaction ti~e is several ~inutes to several hours depending on the efficiency of cooling and other factors. Furthernore, since the starting co~pound ~ Band the product [I~B can easily react with wa-ter, it is prefera~le that the starting ~aterials and solvent to ~e used contain only a minimal arnount of water and it is also prefera~le to conduct the reaction under protection ~ro~ noisture.
The product tI~B produced ~y the reaction ~ay ~e used in the for~ oX a reaction ~ixture. As necessary, the reaction nixture containing ~B is stored at a low te~perature, na~ely at ~elow a~out 30C~ prefera~ly a-t 10C to -50C, under protection fro~ ~oisture, since, in -the presence of a ~a~e or hydrochloride thereof, t~3iS unsta~le at higher te~peratures and further~ore can easily reac-t with water.

- 10 - ~26~

If desired, LI~B can easily be isolated ~rom the reaction ~ixture, for exa~ple ~y re~oving the hydrohallde salt of the ~ase (precipitate) ~y filtration or other ~eans with or without adding to the reaction ~ixture a hydrogen halide or a solvent in which the salt of the ~ase and hydrogen halide as yielded by the reaction is sparingly soluble but ~I~B is readily solublej adequately selected from among ether, benzene, ~ethylene chloride, acetonitrile, ethyl acetate, etc., and then concentrating the filtrate or the like. The thus-o~tained ~I)B may further be purif~ed by distillation, crystallization or other purification procedures.
~ he starting co~pound ~III)B to be used in the method of the preparation can easily be prepared, for example by reacting a co~pound of the for~ula R- H (R ~eing as defined a~ove) with a phosphorus oxyhalide or a diphosphoryl tetrahalide ~Mizu~a et al., Yakugaku Zasshi, 81, 51-52 (1961) and H. Grunze, Che~O
~er., 92, 850-854 (1959)~ or ~y using a ~odification of such reaction.

Thus, in accordance with the method o-f the preparation, the desired product ~I~B can be produced in high purity and ~ood yield in one step under mild conditions in a short period of time from raw materials which can be handled with ease in indu~trial operations and are inexpensive. Therefore, the method of the preparatiOn is an industrially very advan-tageous method for the production of ~I~B.

The cephalosporin compound [I] is not only a valuable antimicrobial compound but also is an important ;ntermed;ate compound ~Eor -the production o~
such cephalosporin compounds. There are known a variety of processes for the production o~ the compounds [I~ but yet not known a satisfactory process for preparing the compounds [I] directly from the compounds [II~ as the starting material.
Among the kno~Yn processes for the production of the compounds [I], are (i) the processes wherein a cephem compound having an acyloxymethyl group in 3-position of the cephen ring and a thiol compound are (1) reacted in ~ater or a mixture of water with an organic solvent under~acid;c to weakly alkaline conditions ~Japanese Published Examined Patent Applica~ion Nos. 17936/1964, filed by Glaxo Laboratores, Ltd. and published on August 26, 1964~ and 13023/
1971, filed by Fujisawa P~larmaceutical Co., Ltd. and published on April 3, 19717 United States Patent No. 3,6~1,021, filed by Eli Lilly and Co. and patented on February 8, 1972, British Patent Nos. 1,283J811, filed by Eli L;lly and Co.
and complete specification published on August 2, 1972, and 1,321~412, filed by Merck and Co., Inc. and complete specification published on June 27, 1973, and O~S No. 2,262,477, filed by Eli Lilly and Co. and published on June 2S, 1973, etc.~, ~2) heated in an organ;c solvent (Japanese Published Unexamined Patent Application No. 43043/1980, filed by Sankyo Co., Ltd. and published on March 26, 1980, etc.), ~3) reacted in the presence of an acid or an acid complex in our organic solvent (OLS No. 2,804,896, Toyan~a Chemical Co., Ltd. and published on August 17, 1978, United States Patent No. 4,317,907 and No.
4,312~986 filed by Toyama Chemical Co., Ltd. and patented on March 2, 1982 and January 26, 1982, respect;vely, Br;tish Patent No. 2,048,257, filed by Yamanouchi Pharmacc-~utical Co., Ltd. and published on December lO, 1980, Jap?nese Published Une~camined Patent Applicat;on Nos. 20724/1980, filed by Toyama Chemical Co., Ltd. and publ;shecl on ~ebruary 1~, 1980, ~l9383/1980 .

filed by Yamanouchi Phnrmaceutical Co., Ltd. and publishe~ on November 29, 1980,etc.), (ii) the process in which the acetoxy group in the 3-acetoxy-methyl group oE the cephem nucleus is substituted ~ith a nucleophilic reagent [A.B. Taylor: Journal of the Chemical _13 - ~ ~6~

Society, p. 7020 (1965)], (iii) the process in which the hydroxy group in the 3-hydroxymethyl group of the cephem ring is converted into a halogen and the latter is then substituted with a nucleophilic compound [A. B. Bywood et al, Recent Advances in the Chemistry of ~-Lac-tam Antibiotics, 139, 1977], (iv) the process in which the

3-hydro~ymethyl group of the cephem nucleus is acylated to an acyloxymethyl group followed by substitution with a nucleophilic reagent [Tsushima et al: Chemical and Pharmaceutical Bulletin 27; 696 (1979)] and so forth.
However, in the processes (i)(l) and (2), the quality and yield of the product compound are low due to hydrolysis of the ~-lactam ring under the reaction conditions,for instance. In the process (i) (3), side reactions such as lactonization and fission of the ~-lactam ring are liable to take place. Moreover, when a Lewis acid or a complex thereof is.used as said acid, the reaction equipment is subject to limitations and post-treatments are com-plicated. Furthermore, after the reaction, the acid must be separated by neutralization with an alkali which is liable to cause decomposition and coloration of the produc-t.
The yield of the product compGund [I] is also very poor depending on the types of starting material and acid~
If lactonization, decomposi-tion of the ~-lactam ring or color-ation takes place, the corresponding impurities derived therefrom tend to Eind their way into the product [I] and removal of such impurities would be troublesome and cause a decrease of yield. Moreover, in the process (i) ~3), the startlng material must be low in moisture content in order to avoid infiltration of moisture but this requires a drying step and the dry powder tends to be scattered to affect the working environment. For example, since 7-amino-cephalosporanic acid has the property to cause contact dermatitis in humans [Kirk-Othmer, Encyclopedia of Chemical Technology, The Third Edition, 1978, Volume 2, p. 907-908], the process is disadvantageous from industrial points of view. In the process (ii) which involves severe reaction conditions, the starting material and product compound are liable to be decomposed. In the process (iii), in order ihat lactonization may be avoided, the 4-carbox~ group must be esterified or otherwise protected, and the esterified or protected compounds are easily subject to isomeri~ation of the double bond in the cephem ring. In the process (iv), the reactionconditions may be somewhat mild as compared with the process (ii) bu-t are not sufficiently mild. Further, excepting the case in which a special acylating agent is employed, it is generally necessary to carry out an acylation reaction and a substitution reaction in distinct phases, thus detracting from the yield and quality of the final compound. Thus, the process is -time-consuming, requires additional equipment and is, there~ore, .15 . ~6r~

not .satisfactory for industrial purposes.
After a thorough exploration of possible processes for the production of cephalosporin compounds II~, using as the starting material compounds of the formula ~II]
including deacetyl-cephalosporin C (DCPC) and a compound which is obtainable by chemical or enzymatic treatment of DCPC or cephalosporin C, the present inventors found surprisingly that it is possible to react in an organic solvent a compound ~ or a salt thereof, a nucleophilic compound or a salt thereof and (1) a trivalent or pentavalent cyclic phosphorus compound having a partial structure of formula .[III]

W
~ >P cm ) w wherein W is an oxygen atom, a sulfur atom or NR ; Wl is an oxygen atorn, a sulfur atom or NR ; R and R3 are the same or different and each is a hydrogen atom or a hydrocarbon group, or a salt thereof, or (2) a reaction product of a compound having a partial structure of formula ~ V~

WH
)~ W'H

wherein W and W have the same meanings as defined above, or a salt thereof, with a phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalider that the reaction proceeds under very mild conditions (i.e., in a short time, ~Z~0~

at low temperature, atmospheric pressure, etc.) to give the cephalosporin compound [I] in good yield, that the subject compound [I] obtained from the anhydrous reaction system can be used without complex drying steps required, when the compound [I] is subjected to an acylation or deacylation reaction under anhydrous conditions in the subsequent step, and that therefor the reaction is useful in a method for preparing the compound [I] directly in one step from the compound [II] in an industrial production, enabling the production of compounds [I3 at a lower cost.

-:17 - .

In the above formulas, Rl is a hydrogen atom or an aeyl group. The acyl group represented by R includes, among others, those aeyl groups whieh are the substituents on the amino group at the 6-position in so far known penieillin derivatives or at the 7-position in eephalosporin derivatives. Sueh aeyl groups may be represented, for example, by the formula R - CO - [V]
wherein R5 is a hydrogen atom or an alkyl, phenyl* or hetero eyelie*
group, or by the formula R - NH - CH - CO -R7 [VI]

wherein R6 is a hydrogen atom, an amino acid residue, an amino-proteeting group or a group of the formula R - (CH2)n - CO - ~in which R8 is a heterocyclic* group and nl is an integer of 0-2) and R7 is an alkyl, phenyl* or heterocyclic* group, or by the formula R - R - CO - ~VII]
wherein R9 is a group of the formula Rll _ C -Il O - R
in which Rll is an alkyl*, heterocyclic* or phenyl* group and Rl2 is a hydrogen atom alkyl group or a group of the formula -Rl3-Rl4 (R]-3 being an alkylene or alkenylene* group and Rl being a phenyl*, earboxyl, esterified earboxyl or mono- or dialkylamino), and RlO is a bond or a group of the formula - CO ~ NH - CH(R ) - (Rl5 being an alkyl, phenyl* or ~6 thiazolyl* group, or by the fo:rmula ~ 7 ~ C H - C 0 - [VIII~
Rl'; J
wherein R16 is ~ hydroxy, hydroxysulfonyloxy, carboxy, ureido*, sulfamoyl*, sulfo, phenoxy*carbonyl or formyloxy and R17 is hydrogen, alkyl, alkoxy, halogen, ni~ro or hydroxy, or by the formula ~ 9-CH2-CO - ~IX~
wherein R18 is a cyano, phenyl*, phenoxy*, alkyl*, acyloxy, alkenyl* or heterocyclic* group and RI9 is a bond or --S--.

o~a~

When the above-mentioned groups represented by symbols R5 to Rl9 are "groups which may optionally be substituted", the names of such groups herein shall be designated by a super-script as-teris~. Thus, for example, "an alkyl which may optionally be substituted" shall be denoted as "alkyl*". In such case, the number of substituents is not limited to one but the relevant substituted group may have two to several substituents which may be the same or different. The alkyl is preferably a straight or branched lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl. The alkenyl is preferably a straight or branched lower alkenyl containing 2-6 carbon atoms, such as vinyl, allyl, isopropenyl, 2-methallyl, 2--butenyl or 3-butenyl.
The heterocyclic group includes, among others, groups derived from 5- to 8 membered rings con-taining one to several hetero atoms such as nitrogen (which may be in the form of N-oxide), oxygen and/or sulfur atom or atoms or fused rin~ correspond-ing thereto, such as 2- or 3- pyrrolyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-pyridyl, N-oxido-2-, 3- or 4-pyridyl, 2-, 3- or 4-piperidinyl, 2-, 3-or 4-pyranyl, 2-, 3- or 4 thiopyranyl, pyrazinyl, 2-, 4-or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxido-3- or 4-pyridazinyl, 2-, 4- or 5 pyrimidinyl, N-oxido-2-, 4- or 5-pyrimidinyl, _ 20 _ piperazinyl, ~- or 5-(1,2,3-thiadia~olyl), 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, ~-or 5-(1,2,3-oxadiazo~yl), 3- or 5-(1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3- or 1,2,4-triazolyl, lH or 2H-tetrazolyl, pyrido[2,3-d]pyrimidyl, benzopyranyl, 1,~-, 1,5-, 1,6-, 1,7-, 2,7- or 2,6-naphthyridyl, quinolyl and thieno[2,3-b]pyridyl, which are frequently used. The alkoxy is preferably a straight or branched lower alkoxy containing 1-5 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobu-toxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy or isohexyl-oxy. The halogen includes fluorine, chlorine, bromine and iodine. The amino acid residue includes glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteyl, cystyl, methionyl, ~- or ~-aspartyl, ~- or ~-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl, prolyl and so on. The alkylene is preferably a lower alkylene containing 1-6 carbon atoms, such as methylene, ethylene, propylene or isopropylene. The alkenylene is preferably a straight or branched lower alkenylene containing 2-4 carbon atoms, such as vinylene or propenylene. The ester-forming group for the carboxyl group is, for example, a lower alkyl group containing 1-6 carbon atoms such as methyl, ethyl, propyl, n-bu-tyl, isobutyl or tert-butyl. The amino-protec-ting group may be any of the conventional ones used for the same purpose in the fields of beta-lactam chemistry and peptlde syntheses and thus includes aromatic acy:L yroups, such as phthaloyl, 3'4~

toluoyl, naphtlloyl, benzoyl, chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert_butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl an~ phenylacetyl, aliphatic acyl groups, such as formyl, acetyl, propionyl, valeryl, caprylyl, n-decanoyl, acryloyl, pivaloyl, monochloroacetyl, dichloroacetyl, trichloro-acetyl, methanesulfonyl, ethanesulfonyl, camphorsulfonyl, trifluoroacetyl, maleyl and succinyl, esterified carboxy groups, such as methoxycarbonyl, ethoxy-carbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, ~ -trichloroethoxycarbonyl, ~trimethylsilylethoxycarbonyl, ~-methylsul-fonylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxyben-zyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetyl-methyloxycarbonyl, isobornyloxycarbonyl and phenyloxycarbonyl, substituted carbamoyl groups, such as methylcarbamoyl~ phenylcarbamoyl and naphthylcarbamoyl, further trityl, 2-nitrophenylthio, benzylidene, ~-nitrobenzylidene, trialkyl-silyl, benzyl, p-nitrobenzyl, phosphoryl groups, such as diethylphosphoryl, dimethylphosphoryl, diphenylphosphoryl, diisopropylphosphoryl, diisobutylphos-phoryl, dibutylphosphoryl, o-hydroxyphenylphosphoryl and methyl(o-hydroxyphenyl)-phosphoryl, phosphinyl groups, such as dimethylphosphinyl and diphenylphosphinyl, phosphonyl groups, such as phenylphosphonyl and butylphosphonyl, and like amino-protecting groups other than acyl groups. The selection of the amino-protecting group is not critical. The acyl moiety of the acyloxy group ls as ment.ioned below in R to R 2 ~nong these, the alkyl and alkenyl may be substituted by one to three substituents, for example, cycloalkyl*, _ 22 _ cycloalkenyl*, aryl*, heterocyclic group*, alkoxycarbonyl, acyl, oxo, haloyen, cyano, trifluoromethyl, hydroxy, alkoxy, aryl*oxy, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkyl-sulfonyloxy, aryl*sulfonyloxy, nitro, amino, carboxy, amino-carbonyl, alkylthiocarbonyl, mercapto, alkylthio, aminoalkyl-thio, acylaminoalkylthio, aral~yl*thio, aryl*thio, hetero-cycle*thio and/or quaternary ammonium*. The substituted alkyl group may be the one represented, for example, by the formula - C - (CH2) - R [X]
R21 n2 wherein n2 is an lnteger of O to 3, R20 and R21 are the same or different and each is hydrogen atom, alkyl, cyclo-alkyl*, aralkyl*, aryl*, he-terocyclic* group, alkoxycarbonyl or acyl, or R and R combinedly represent oxo, and R2~
is hydrogen a-tom, alkyl, cycloalky:L*, aryl*, heterocyclic*
group, halogen, cyano, hydroxy, alkoxy, aryl*oxy, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, aryl*-sulfonyloxy, nitro, amino, carboxy, alkoxycarbonyl, amino-carbonyl, alkylthiocarbonyl, acyl, mercapto, alkylthio, amino-alkylthio, acylaminoalkylthio, aralkyl*thio, aryl*thio, heterocycle*thio or quaternary ammonium*. Referring to R , R
and R , the cycloalkyl preferably contains 3-8 carbon atoms and is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl. The aryl is, for example, phenyl, ~-naphthyl, ~-naphthyl, biphenyl or anthryl;
in particular, phenyl, naphthyl and the like are frequently used. The aralkyl includes benzyl, phenethyl, phenylpropyl ~.26~

and naphthylmethyl. The acyl ~roup includes formyl, alkyl-carbonyl, aryl*carbonyl, aralkyl*carbonyl, heterocycle*carbonyl, heterocycle*acetyl, etc. Preferred among others are acetyl, propionyl, n-buty~yl, isobutyryl, n-pentanoyl, n-hexanoyl, benzoyl, 4-hydroxybenzoyl, 4-methoxybenzoyl, phenylacetyl,

4-hydroxyphenylacetyl, 4-methoxyphenylacetyl, 2-thienylcarbonyl, 2-furylcarbonyl, 2-, 4- or 5-thiazolylacetyl, 2- or 3-thienyl-acetyl, 2- or 3-furylacetyl, 2-amino-4~ or 5-thiazolylacetyl, etc. The quaternary ammonium group is, for example, pyridinium or quinolinium. The cycloalkenyl group includes, for example, those having 3 to 8 carbon atoms such as l-cyclopropenyl, 1-cyclohexenyl, l-cycloheptenyl, etc.
The substituents on the cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic and quaternary ammonium groups include alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, trihaloalkyl, hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, acyl-amino, hydroxyalkyl, carboxyalkyl, haloalkyl, mono- or di-alkylaminoalkyl, etc., wherein said alkyl, alkoxy, alkenyl, aryl, aralkyl and acyl are as above mentioned.
The phenoxy* may have the same substituents as mentioned above for the aryl*. Furthermore, the thiazolyl* may be substituted by an acylamino group containing 2-4 carbon atoms which in turn is substituted by alkyl, alkoxy, halogen, hydroxy, amino, etc. The he-terocyclic* group may be substituted by a phenyl group substituted by alkyl, alkoxy~ halogen, nitro, amino etc. The subs-tituen-t on the ureido* is, for example, sul~o in the form of an adequclte sal-t wi-th sodium, potassium, etc., carbamc)yl, sulfamoyl, amindino, Cl 3 alkyl, 2~ _ etc. The substituent on the sulfamoyl* is, for example, Cl 3 lower alkyl or amidino. The substituent on the alkenylene* is, for example, carboxy or cyano.

The formula ,RI' --C--N

in R represents the syn isomer having the formula R~l-C -N
O--Rl2 as well as the anti isomer having the formula Rll -C -R12_o/or a mixture of these.
Referring to the above acyl group, a typical one of the acyl group represented by the formula [V] is a group of the formula R5a _ CO - [v]a wherein R a is a hydrogen atom, Cl 6 alkyl, phenyl which may be substituted with nitro or 5- or 6-membered heterocyclic group containing 0, S and/or N as a hetero atom or atoms which may be substituted with a Cl 6 alkyl, oxo, phenyl or halogenophenyl group; a typical one of the acyl group re-presented by the formula [VI] is a group of the formula R6a _ NH-CH - CO ~ ~vI]a R7 a wherein R a is a hydrogen atom or a group of the formula R8a _ (CH2~nl - CO - (whe.rein R8a is a 5- or 6-membered heterocyclic group containing 0, S and/or N as a hetero atom or atoms or :Eused ring corresponding thereto which may be substituted with a Cl 6 alkyl, oxo, hydroxyl, carboxyl, formyl, halogen or Cl 6 alkylsulfonyl and nl is as defined abo~e) and R7a is phenyl which may be substituted with hydroxyl, alkoxyl or benzyloxy, or thienyl group;
a typical one of the acyl group represented by the formula ~VII~ is a group of the formula R~a _ RlOa _ CO - ~IIJ
wherein R9a is a group of the formula Rlla C
N

O _ R12a wherein Rl1a lS a 5-membered heterocyclic group containing 0, S and/or N as a hetero atom or atoms which may be sub-stituted with amino group, or phenyl, and R12a is a hydrogen atom ox a group of the formula - R13a - R14a (wherein R13a is CH3 - CH2 - or - C - and R14a is carboxyl), and RlOa is a bond; a typical one of the acyl group re-presented by the formula [VIII] is a group of the formula R17a - CH - CO - [VIII]a _ 26 _ wherein R16a is hydroxyl, carboxyl or sulfo, and R17a .is hyclrogen or hydroxyl; a typical one of the acyl group represented by the formula .~IXJ is a group of the formula R18a _ R19a _ CH2 - C0 - ~IX]

wherein R18a is cyano, phenoxyr cyano-Cl_6alkyl or 5-membered heterocyclic group containing 0, S and/or N as a hetero atom or atoms which may be substituted with amino, and Rl9 is a bond.
Further, frequently used one of the above acyl group is a group of the formula Ra Rb CO IA]
wherein Ra is an aryl, 5-membered heterocyclic group ~.
containing nitrogen and/or sulfur atom which may be sub-stituted with amino group or a group of the formula CH ~ Rd wherein Rc is amino wh:ich may be protected and Rd is carboxyl which may be protected and Rb is a Cl 6 alkylene group or a group of the :Eormula - C -gRe wherein R is a Cl 6 alkyl group which may be substitutedwith carboxyl group; and more frequently used one thereof is a ~roup of the formula R - Rg - C0 - ~B]
wherein Rf is phenyl, thienyl, thia201yl substituted with amino, or a group o~ the Eormula CH <R

t~

wherei.n Rc and R have -the same meaninys as defined above, and Rg is a Cl_6 alkylene group or a group of the formula - C - wherein Rh is a Cl_6 alkyl group.
N

OR
A preferable one of the acyl group represented by is a group of the formula:
R - CH(CH2)3CO -COOH
wherein Ra is an amino group protected, for example, with an aromatic acyl or esterified carboxyl group.
Referring to the above acyl group, examples of the -acyl group represented by the formula R -CO- are formyl, acetyl, hexanoyl, benzoyl, p-nitrobenzoyl, 3-(2,6-dichloro-phenyl)-5-methylisoxazol-4-yl-carbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl and 4-ethyl-2,3-dioxo-1-piperazino-carbonyl.
Examples of the acyl gxoup represented by the formula R - NH - CH - CO -are D-alanyl, benzyl N -carbobenzoxy-y-D-glutamyl-D-alanyl, D-phenylglycyl-D-alanyl, N-carbobenzoxy-D-alanyl, N-carbo-benzoxy-D-phenylglycyl, D-alanyl-D-phenylglycyl, y-D-glutamyl-!O i~

D-alanyl, 2-(~-e-thyl-2,3-dioxo-1-piperazinocarboxamido)-2-phenylacetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-sulfoxyphenyl)acetyl, N-(4-ethyl.-2,3-dioxo-1-piperazino-carbonyl)-D-alanyl, N-(4-ethyl-2,3-dithioxo-1-piperazino-carbonyl)-D-phenylylycyl, 2,2-bis-(4~e-thyl-2,3-dioxo-1-piperazinocarboxamido)acetyl, 2-(2-amino-4-~,hiazolyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)acetyl, 2-(4-hydroxy-6-methylnicotinamido)-2-phenvlacetyl, 2-(4-hydroxy-6-methylnicotinamido)-2-(4-hydroxyphenyl)acetyl, 2-[5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyrido[2,3-d]-pyrimidine-6-carboxamido]-2-phenylacetyl, 2-(3,5-dioxo-1,2,4-triazine-6-carboxamido)-2-(4-hydroxyphenyl)acetyl, 2-(3-furfurylideneamino~2-oxoimidazolidine-1-carboxamido)-2-phenylacetyl, 2-(coumarin-3-carboxamido)-2-phenylacetyl, 2-(4-hydroxy-7-methyl-1,3-naphthyridine-3-carboxamido)-2-phenylacetyl, 2-(4-hydroxy-7-trifluoromethylquinoline-3-carboxamido)-2-phenylacetyl, N-[2-(2-amino-4-thiazolyl)-acetyl]-D-phenylglycyl, 2-(6-bromo-1-ethyl-1,4-dihydro-4-oxothieno[2,3-b]pyridine-3-carboxamido)-2-phenylacetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienyl-acetyl, 2-(4-n-pentyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 2-(4-n-octyl-2,3-dioxo-1-piperazino-carboxamido)-2-thienylacetyl, 2-(4-cyclohexyl-2,3-dioxo-l-piperazinocarboxamido)-2-thienylacetyl, 2-[4-(2-phenyl-ethyl)-2,3-dioxo-1-piperazinocarboxamido]-2-thienylacetyl, 2-(3-methylsulfonyl-2-oxoimidazolidine-1-carboxamido)-2-pheny:lacetyl, 2-(3-furfurylideneamino-2-oxoimidazolidine-l-carboxamido) 2-l4-hydroxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo-l-piperazinocarboxamido)-2-(4~benzyloxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-methoxy-phenyl)acetyl, and 2-(3-hydroxy-1,5-naphthyridine-7-carboxamido).-2-phenylacetyl.
Examples of the acyl group represented by the formula R9-R -CO- are N-[2-(2-amino-4-thiazolyl)--2-methoxyimino-acetyl]-D-alanyl, N-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetyl]-D-phenylglycyl, 2-(2-amino-4-thiazolyl)-2-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]acetyl, 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazoIyl)-2-ethoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-butoxyimino-acetyl, 2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetyl, 2-(2~amino-4-thiazolyl)-2-allyloxyiminoacetyl, 2-(2-amino-

5-chloro-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-5-bromo-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl~-2-oxyiminoacetyl, 2~(2-amino-4-thiazolyl)-2-[(1-methyl-l-carboxyethyl~oxyimino]acetyl, 2-(2-amino-4-thiazolyl)-2-carboxymethyloxyiminoacetyl, 2-thienyl-2-methoxyimino-acetyl, 2-furyl-2-methoxyiminoacetyl, 2-(1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl, 2-(1,2,4-thiazol-5-yl)-2-methoxy-iminoacetyl, 2-(1,3,4-thiadiazolyl)-2-methoxyiminoacetyl, 2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetylj 2-phenyl-2-oxyiminoacetyl, 2-[4-(Y-D-~lutamyloxy)phenyl]-2-oxyiminoacetyl, and 2-[4-(3-amino-3-carboxypropoxy)phenyl]-2-oxyiminoacetyl.

Examples of the acyl group represented by the Eormula Rl?
~CH-CO-¦

are ~-sulfophenylacetyl, c~-carboxyphenylacetyl, ~-hydroxy-phenylacetyl, c~-ureidophenylacetyl, c~-sulfoureidophenylacetyl, ~-sulfamoylphenylacetyl, c~-phenoxycarbonylphenylacetyl, c~-(p-tolyloxycarbonyl)phenylacetyl, and ~-formyloxyphenyl-acetyl.
Examples of the acyl group represented by the formula R -R -CH2-CO- are cyanoacetyl, acetoacetyl, phenylaeetyl, phenoxyacetyl, 5-amino-5-carboxyvaleryl, 5-oxo-5-carboxy-valeryl, 4-carboxybutyryl, trifluoromethylthioacetyl, cyanomethylthioacetyl, lH-tetrazolyl-l-acetyl, -thienyl-acetyl, 2-(2-amino-4-thiazolyl)acetyl, 4-pyridylthioacetyl, 2-thienylthioacetyl, 3,5-dichloro-1,4-dihydro-4-oxopyridine-l-acetyl, 3-carboxyvinylthioacetyl, and 2-(2-aminomethyl-phenyl)acetyl.
The arnino and/or carboxyl and/or hydroxyl group in the above acyl yroup may have a protective group.
The protective group for said amino group may be the same as the protective group for the above-mentioned amino group. The protective group for the carboxyl group may be any of known carboxyl-protecting groups generally usable in the field of beta-lactam and organic chemistry, for example, ester residues, silyl groups and so on, such as Cl_6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, tert-butyl, ter-t-amyl, e-tc.)~ aralkyl*(e.g. benzyl, - 31 ~

3,5-di-tert-butyl~l-hydroxybenzyl, p-nltrobenzyl, p methoxybenzyl, ctc.), l-indanyl, aryl*(e.g. phenyl, p-nitrophenyl, etc.), alkyl*(e.g. methoxymethyl, benzhydryl~ ethoxymethyl, phenacyl, benzyloxymethyl, acetoxymethyl, pivaloyloxy-methyl, ~-methylsulfonylethyl, ~-trimethylsilylethyl, methylthiomethyl, trityl, ~ trichloroethyl, ~-iodoethyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesyl-benzoylmethyl, phthalimidomethyl, propionyloxymethyl, l,l-dimethylpropyl, succinimidomethyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, di-methylaminoethyl, pyridine-l-oxido-2-methyl, methylsulfinylmethyl, bis(p-meth-oxyphenyl)methyl and 2-cyano-1, l-dimethylethyl, etc.), alkenyl*(e.g. 3-methyl-3-butenyl, etc.), silyl (e.g. trimethylsilyl, dimethylsilyl, etc.). The pro-tective group for the hydroxyl group may be any of hydroxyl-protecting groups generally usable in the field of beta-lactam and organic chemistry, for example, ester residues such as acetyl and chloroacetyl, esterified carboxyl groups such as ~ trichloroethoxycarbonyl and ~-trimethylsilylethoxycarbonyl, ether residues such as tert-butyl, benzyl, p~nitrobenzyl, trityl, methylthiomethyl and ~-methoxyethoxymethyl, silyl ether residues such as trimethylsilyl and tert-butyldimethylsilyl, and acetal residues such as 2-tetrahydropyranyl and 4-methoxy-4-tetrahydropyranyl. The selection of the above protective groups is not critical as in the case of the amino- and carboxyl-protecting groups.
The symbol R in formulas [I] and [II] represents a hydrogen atom or an ester residue. The ester residue represented ~6~

by R includes, among o-thers, Cl 6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-amyl, etc.), aralkyl*
(e.g. benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, bis(p-methoxyphenyl)methyl, etc.) and -the like.
The symbol R in formula ~I] represents a residue of a nucleophilic compound. The nucleophilic compound includes a wide variety of nucleophilic substances so far described in the literature in the field of cephalosporin chemistry and characterized by their havingr ~or instance, a nucleophilic nitrogen, carbon or sulfur atom. Such nucleophilic compound is, for example, a nucleophilic sulfur containing compound, a nucleophilic nitrogen containing compound or a nucleophilic carbon containing compound. The nucleophilic sulfur containing compound (R4a-S~) includes, among others, alkyl*thiol, aryl*thiol, aralkyl*thiol or nitrogen-containing hetero-cyclethiols which contain 1-5 nitrogen atoms and may contain an oxygen, sulfur and/or other hetero atom or atoms than nitrogen (alkyl*, aryl* and aralkyl* have the same meaning as defined above in Rl). The heterocyclethiols may be sub-stituted on their nucleus. Examples of such nitrogen-containing heterocyclic groups are 6-membered nitrogen-containing heterocyclic groups such as pyridyl, N-oxidopyridyl, pyrimidyl, pyridazinyl, N-oxidopyridazinyl and triazinyl, 5-membered nigrogen-containing heterocyclic groups such as imidazolyl, -thiazolyl, thiadiazolyl, oxadiazolyl, triaæolyl and tetrazolyl, and fused rings corresponding thereto.

[)04~ 242o5-491D

These nitrogen-containing heterocyclic groups may have such substituents as hydroxyl, amino, carboxyl, trifluoromethyL, carbamoyl, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl), lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), halogen (e.g. chloro, bromo) and various substituents having a valence through a polyvalent group such as lower alkylene, -S- or -N-. When the polyvalent group is a lower alkylene group, the substituents may be mono- or di-lower 10 alkylaminor morpholio, carboxyl, sul~o, carbamoyl, alkoxy-carbonyl, lower alkylcarbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, morpholinocarbonyl, etc. (the acyl group is as defined above in R ). When the polyvaîent group is -S- or -N-, the substituents may be lower alkyl, lower alkylene having such a substituents as mentioned above, etc. Furthermore, when the polyvalent group is -N-, an alkoxycarbonyl, acyl, carbamoyl, lower alkylcarbamoyl or like group may directly be bonded thereto. A
20 typical one of R4a is a Cl 6 alkyl, phenyl which may be substituted with carboxyl or an unsubstituted or substituted 5- or

6- memberad nitrogen containing heterocyclic group or its group fused with benxene, the substituent being a Cl 6 alkyl, mono- or di-Cl 6alkylamino-C1 6alkyl, carboxy-Cl 6alkyl, oxo, hydroxyl, carboxyl, or Cl 6alkoxycarbonyl-C1 6alkylthio.
Specific examples of the heterocyclethiol are pyridinethiol, pyrimidinethiol, methylpyridazinethiol, 4,5-dihydro-6-hydroxy~-methyl-1,2,4-triazin-3-thiol, 2-methyl-5,6-dioxo-1,2,5,6~tetrahydro-1,2,4-triazin-3-thiol, 2,5-dihydro-2-30 methyl-5-oxo-1,2,4-triazin-3-thiol, imidazol-thiol, 1,3,4-~2~
33a 24205-491D

thiadiazolethiol, 1,2,3-thiadiazol -5-thiol, 2-methyl-1,3,4-thiadiazolethiol, thiazolethiol, 5-methyl-1,3,4-oxadiazolethiol, 1,2,3-triazol-5-,~r~

3~

thiol, l-methyltetrazolethiol, l-(2-dimethylaminoethyl)-tetrazole-thiol, 1-(2-sulEoethyl)-tetrazolethiol, l-sulfomethyltetrazolethiol and l-carboxymethyltetrazolethiol. There rnay also be used aliphatic or aromatic thiols such as methanethiol, ethanethiol and thiophenol, thiourea, thiourea derivatives such as N-methylthiourea t thioamide derivatives such as thioacetamide and thiobenzamide, and so on.
These nucleophilic sulfur-containing compounds may be submitted to the reaction in the free form or in the form of salt formed between their acidic group and a base or between their basic group and an acid. The nucleophilic nitrogen-containing compound in-cludes, among others, secondary or tertiary aliphatic, aromatic, aromatic-aliphatic and cyclic amines, for example, dialkylamine (e.g. dimethylamine, diethylamine), trialkylamines (e.g. triethyl-amine), pyridine bases (e.g. pyridine, alkylpyridines) and hetero-cyclic amines containing more than one hetero atoms at least one of which is a nitrogen atom, such as pyrimidines, morpholines, purines, pyridazines, pyrazines, pyrazoles, imidazoles, triazoles and thiazoles. Preferred nucleophilic nitrogen-containing com-pounds are compounds of the formula ~ ~ ~ (R )n3 [XI]

wherein n3 is an integer of 0 or 1-5 and R 3 t which, when n3 is 2-5, may be the same or different, is an aliphatic group such as lower alkyl (e.g. me-thyl, ethyl, n-propyl, isopropyl), an aryl group such as phenyl, an aromatic-aliphatic group such as phen~l-lower alkyl (e.g. benzyl, phenylethyl), alkoxymethyl such as methoxymethyl, ethoxymethyl, n-propoxymethyl or isopro-poxymethyl, acyloxymethyl such as alkanoyloxymethyl (e.g. acetoxy-methyl), ~ormyl, carbamoyl, acyloxy such as alkanoyloxy (e.g.
acetoxy), esterified carboxy, alkoxy such as methoxy, ethoxy, n-propoxy or isopropoxy, aryloxy such as phenoxy, aralkoxy such as bezyloxy, alkylthio such as methylthio or ethylthio, arylthio, aralkylthio, cyano, hydroxy, N-mono-lower alkylcarbamoyl such as N-methylcarbamoyl or N-ethylcarbamoyl, N,N-di-lower alkylcarbamoyl such as N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl, N-(hydroxy-lower alkyl)carbamoyl such as N-(hydroxymethyl)carbamoyl or N-(hydroxyethyl)carbamoyl, carbamoyl-lower alkyl such as carbamoyl~
methyl or carbamoylethyl, or the like group. A frequently used one of a nucleophilic nitrogen-con-taining compound is a compound of the ~ormula R23a N ~ R23b \R23c wherein R23a, R23b and R23C may be the same or di~erent and each is hydrogen or a Cl 6 alkyl which may be substituted with a cyano group or a 5-membered nitrogen-containing heterocyclic group; or 20 R23a, R23b and R 3 comblnedly with the nitrogen atom adjacent to them represent an unsubstituted or substituted 5- or 6- membered nitrogen-containing heterocyclic group, the substituent being carbamoyl, cyano, Cl 6 alkoxycarbonyl or Cl 6 alkyl group.

C~
~ 36 -~

Specific exa~ples are such nitrogen-con-taining heterocyclic co~pounds as pyridlne, picoline, nicotinic acid, nicotina~ide, isonicotina~ide, pyridinesul~onic acid, pyrazine, 2-car~a~oylpyrazine, pyridazine, pyri~idine, i~idazole and 1-methyl-imidazole. The nucleophilic carbon-containing compound includes inorganic cyanides~ pyrrole and subs-tituted pyrroles (e~g.
indoles) and co~pounds capa~le of yielding sta~ilized car~anions, such as acetylenes~ ~-diketone compounds, e.g. acetoacetic acid esters and ~alonic acid esters as well as cyclohexane~
diones, ena~ines, ina~ines and enols. For instance, co~-pounds capa~le of introducing a group represented ~y the for~ula R21 - CH2.C. COn R25, I - ~XII]
R~

wherein R24 and R25 ~ay ~e the sa~e or different and each is hydrogen, cyano, lower alkyl (e.g. ~ethyl, ethyl), phenyl, su~stituted phenyl (e.g. halo-, lower alkyl-, lower alkoxy-, nitro-, a~ino- or lower alkyla~ino-phenyl), lower alkoxycar~onyl, ~ono- or diaryl-lower alkoxycar~onyl, lower alkylcar~onyl9 aryl-lower alkyl or C5 or C6 cycloalkyl, and R2 is hydrogen, lower alkyl (e.g. ~ethyl, ethyl)~ pheny~, su~stituted phenyl (e.g.
halo-, lower alkyl- 5 lower alkoxy-, nitro-, a~ino- or lower alkyla~ino-phenyl), aryl-lower alkyl or C5 or C6 cycloalkyl, into the su~stituent at the 3-posi-tion of the cephalosporin nucleus are used.

A preEerable one of the nuc].eophilic compound is a group of the formula R4b SH [C~

wherein R4b is a Cl 6 alkyl, phenyl which may be substituted ~ith carboxyl or substituted or unsubstituted tetrazolyl, thiadiazolyl, benzothiazolyl, benzoxazolyl, benzoimidazolyl, pyrimidinyl, N-oxido-pyridyl or trlazinyl, the substituent being a Cl_6 alkyl, di-Cl 6 alkylamino-Cl 6 alkyl, carboxy Cl_6 alkyl, Cl_6 alkoxy-carbonyl-Cl 6 alky].thio, oxo, hydroxyl or carboxyl; or a group of the formula N ~ R [D]
\R4e whereln R4C, R4d and R4 may be the same or different and each is hydrogen, a Cl 6 alkyl, cyano-Cl 6 alkyl or tetrazolyl-Cl 6 alkyl, or R4C, R4d and R4e combinedly with the nitrogen atom adjacent to them represent a substituted or unsubstitu-ted pyridine or pyrrole, the substituent being carbamoyl, cyano, Cl 6 alkoxy-carbonyl or Cl 6 alkyl.

-3~ _ In for~ula ~I~ and ~ , the dotted line ~S ~
~ .
either ~OR
denotes the dou~le ~ond at position 2 of the cephe~ ring structure ~ S
~N ~

~OOR

or the dou~le ~ond at pcsition 3 CC)OR
The cyclic co~pound of trivalen-t or pentavalent phosphorus to be used in the practice of the invention has the partial structure represented ~y for~ula ~ as the ~ain part, or at least as part, of its che~ical structure. Accordingly, P in for~ula ~ represents a tri~alent or pentavalen-t phosphorus ato~. In for~ula ~ , W is an oxygen or sulfur ato~ or NR2, and W1 is an oxygen or sulfur ato~ or NR3. W and w1 ~ay ~e the sa~e or differen-t. Generally, it is ad~antageous that W and W1 are the sa~e. R2 and R3 are the sa~e or different and each is a hydrogen ato~ or a hydrocar~yl group. '~he hydro-car~yl group represented ~y R2 and/or R3 includes, a~ong others, alkyl*, cycloalkyl*, alkenyl*, cycloalkenyl*, alkynyl*, aryl*
and aralkyl*. As the alkyl*, cycloalkyl*, alkenyl*, cyclo-alkenyl*, aryl* and aralkyl* grou~s, those ~entioned for the sy~ols R5 Rl~ are preferredly used. '~he alkynyl group is 3~
~9 prefera~ly a straigh-t or ~ranched lower alkynyl containing 2-6 car~on ato~s, such as ethynyl, 1-propynyl or 2-propynyl.

The alkynyl ~ay ~e su~stituted ~y such a su~stituent as ~entioned as the su~sti-tuent for the alkyl* and alkenyl* groups represented ~y R5_R1 9 .
Such cyclic trivalent or pentavalent phosphorus co~pound ~ay ~e represented, for exa~ple, ~y the for~ula Q~ W X
~ > ~ ~ Y ~XIII~
Q2~WI z or ~y the for~ula . Q2 ~ > ~XIV ~

wherein Q1 and Q2 are the sa~e or different and each is a hydrocar~yl group or a heterocyclic* group or Q1 and Q2 co~inedly together with ~ represent a cyclic hydrocar~yl group or a heterocyclic* group, X, Y and Z are the sa~e or different and each is a group represented ~y the for~ula _ w2_ Q3 in which w2 is an oxygen or sulfur ato~, NR28 (R28 ~eing a hydrogen ato~ or a hydrocar~yl group) or a ~ond and Q3 is a halogen ato~ or a hydrocar~yl or heterocyclic* group and in which, when Q3 is a halogen ato~, w2 is a ~ond.
or two of X, Y and Z co~inedly represent an oxo group or a group represented ~y the f`or~ula - W3_ Q4 ~4 in which ~4 is a hydrocar~on or heterocyc].ic* group and W3 and 3~
- '10 -W4 are the same or different and each is an oxygen or sulfur ato~, NR29 (R29 ~eing a hydrogen atorc or a hydrocar~yl group) or a bond valence), X further represents a group of the for~ula _ ~5 - P~ ~ Q2 1 or - Ws- P <Wl ~ Q2 in which W5 is an oxygen or sulfur ato~ or NR30 (R30 ~eing a hydrogen ato~ or a hydrocar~yl group) and other sy~ols are as defined previously, and the re~aining sy~bols W and W1 are as defined a~ove. In for~ulas ~XIII~ and ~XIV~, Q1 and Q2 are the sa~e or different and each is a hydrocar~yl or hetero-cyclic* group. The hydrocar~yl group represented ~y Q1 and/or Q2 includes those examples mentioned above for R2 and R3~ for instance, and the heterocyclic* group includes those ~entioned a~ove for R5-R19, a~ong others. Further~ore, Ql and Q2 ~ay~ co~lnedly together with the adjacent hydrocaron group ( ~ ), represent a cyclic hydrocar~yl or heterocyclic* group. Said cyclic hydrocar~yl group is, for exa~ple, a cycloalkenyl* or aryl*
group. The cycloalkenyl* and aryl groups each includes those exa~ples given a~ove for R and R3, a~ong others. Generally, it is advantageous that Q1 and Q2 are the sa~e or that they co~inedly represent a cyclic hydrocar~yl group. X, Y and Z

are the sa~e or different and each is a group of the forn!ula _ w2 _ Q3 wherein w2 is an oxygen or sulfur ato~, NR28 (R28 ~eing a hydrogen aton! or a hydrocar~yl group) or a ~ond valence and Q3 is a halogen ato~ or a hydrocar~yl ~r heterocyclic* group and wherein, when Q3 is a halogen ato~, W is a ~ond valence.
R28 in NR28 represented ~y w2 is a hydrogen ato~ or a hydro-car~yl group. lhe hydrocarbyl group represented by R28 andthe hydrocar~yl and heterocyclic* groups represented ~y Q3 respectively include the exarnples l~entioned a~ove for Q1 and Q2, ~or instance. w2 ~ay ~e the sar~e as or different fro~ the above-~entioned W and/or W1. ~he halogen ato~
represented ~y Q3 includes those exa~ples given above for R5-R19. lwo of X, Y and Z, for exarnple X and Y, or Y and Z, ~ay cornbinedly represent a group of the forrnula -W3-Q4-W4-.
Q4 is a hydrocarbon or heterocyclic* group, and such hydrocarbon and heterocyclic groups include t~o~e examples rnentioned a~ove for Q1 and Q2, for instance. W3 and W4 ~ay be the sar~e or different and each is an oxygen or sulfur atorn, NR29 or a ~ond valence. R29 is a hydrogen atom or a hydro-car~yl group. The hydrocar~yl group represented ~y R29 includes those exarrples rnentioned above for R2 and R3, a~ong others. W3 and W4 each rnay be the sarre or different frorn the above-~entioned W and/or W1. Furtherrnore, X nay ~e a group represented ~y the for~ula - W5 - P~WI~Q2 or -W -P <~yl~ Q2 wherein W, W1, Q1 and Q2 are as defined above. W5 is an oxygen or sulfur ato~ or NR30 in which R3 is a hydrogen atorr or a hydrocar~yl group. ~he hydrocar~yl group represented ~y R30 includes those exarnples r~en-tioned a~ove for R2 and R3, for instance. Preferred arnong such cyclic trivalent or pentavalent phosphorus co~pounds are cyclic phosphorus corrpounds represented, ~or exar~ple, ~y the forrnula - 42 ~

(A)nc ~ > P~Z ~XV~

whereln A is a su~stituent on the ~enzene ring, na is an integer of O to 4 and Xl is halogen, alkyl~, aralkyl~, allcyl~oxy, aryl*oxy, aralkyl~oxy, alkyl*amino, aryl~amino, aralkyl~amino or aryl* or by the formula - (A)na ~ O > P - Xl ~ ~XVI~

wherein A, na and Xl are as defined above, or by the formula ~A)na ~ > p ~ ~ ~XVII~

wherein A and na are as defined above and XO, YO and ZO are the same or different and each has the sa~e ~eaning as X1. A in forr~ulas XV , XVI and XVII is a su~stituent on the ~enzene ring and ~ay ~e any one inert to the reaction, for instance, alkyl*, alkyl*oxy, alkyl*thio, halogen ato~9 nitro, cyano, hydroxyl, carboxyl, alkyl~oxycarbonyl, alkyl~sulfonyl, carbamoyl, alkyl*carbamoyl, aliphatic acyl (e.g~ acetyl, propionyl) or aromatic acyl (e.g. benzoyl, p-chlorobenzoyl). ~urthermore, A may be methylenedioxy, a group of the forrnula ~ ~ .
~ i or ~

or a like group, which ~ay ~e su~stituted ~y halogen (e.g., chlorine, b.romine, etc.), nitro, cyano and/or the lil;e. Referring to A, X1, XO, YO and ~, the halogen ato~, and all;yl~, aryl* and aralkyl* groups each includes the corresponding exa~ples such ~2~
- - ~13 -as mentioned :Eor ~ -Rl9. Preferred examples oE Xl, XO, YO
and ZO axe halogen atoms such as chlorine, bromine and fluorine, Cl_5 lower alkyloxy groups, which may be substituted, such as methoxy, ethoxy, 2,2,2-trichloroethoxy, 2-cyanoethoxy and 2-methylsulfonylethoxy, aryloxy groups, which may be substituted, such as phenoxy, 4-chlorophenoxy and 4-nitro-phenoxy, aralkyloxy groups, which may be substituted, such as benzyloxy, aryloxy, p-nitrobenzyloxy and l,l-dimethylaryloxy, alkyl groups which may be substituted, such as methyl, ethyl, propyl, 2-chloroethyl and 2-methoxyethyl, and aryl groups which may be substituted, such as phenyl, tolyl and chlorophenyl. Two of XO, YO and ZO, for instance XO and YO, or YO and ZO, may combinedly represent o-phenylenedioxy, ethylenedioxy or the like. In formulas IXV] and [XVI], Xl may also represent a linking group -O-, so that the cyclic phosphorus compound may be in the form of dimer.
A frequently used one of the trivalent or pentavalent cyclic phosphorus compound is a compound of the formula Q ~ > a [E]
Q2a~` 0 or Q;a xa ~ ]

wherein Qla and Q2a are a Cl 6 alkyl or Qla and Q2a combinedly together with 3 represent benzene which may be substituted with a Cl 6 alky:L, hyclroxyl or Cl 6 alkoxycarbonyl, and xa, 3~
_ 4~ -ya and za are the same or differen-t and each is a halogen atom, a Cl_6 alkylamino, C6_10 aryl or a group of the formula _0~ Q3a wherein Q3a is an unsubstituted or substituted Cl_6 alkyl~ C2_6 alkenyl, C3_8 cycloalkyl or C6 10 aryl, the substituent being a halogen atom or nitro group, or two of xa, ya and za combinedly represent an oxo group or a group of the formula -' ~ (Aa) a wherein Aa is a halogen atom and na is an integer of O to 4.
A preferable one of the pentavalent cyclic phosphorus compound is a compound of the formula (A')nb ~ ' ~ P''O

wherein A' is hydroxyl, C1 6 alkyl or Cl 6 alkoxycarbonyl, nb is zero or 1 and Xb is a Cl 6 alkoxy, phenyl or phenoxy.

- ~5 _ Examples of the cyclic phosphorus compound are o-phenylene phosphorochlor.idate, o-phenylene phosphorofluoridate, methyl o-phenylene phosphate, ethyl o-phenylene phosphate, n-propyl o-phenylene phosphate, isopropyl o-phenylene phos-phate, n-butyl o-phenylene phosphate, isobutyl o-phenylene phosphate, sec-butyl o-phenylene phosphate, cyclohexyl o-phenyelen phosphate, phenyl o-phenylene phosphate, p-chlorophenyl o-phenylene phosphate, p-acetylphenyl o-phenylene phosphate, 2-chloroethyl o-phenylene phosphate, 2,2,2-tri-chloroethyl o-phenylene phosphate, ethoxycarbonylmethyl o-phenylene phosphate, carbamoylmethyl o-phenylene phosphate, 2-cyanoethyl o-phenylene phosphate, 2-methylsulfonylethyl o-phenylene phosphate, benzyl o-phenylene phosphate, 1,1-dimethyl-2-propenyl o-phenylene phosphate, 2-propenyl o-phenylene phosphate, 3-methyl-2-butenyl o-phenylene phos-phate, 2-thienylmethyl o-phenylene phosphate, 2-fur~uryl-methyl o-phenylene phosphate, bis-o-phenylene pyrophosphate, 2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2-(p-chloro-phenyl)-1,3,2-benzodioxaphosphole-2-oxide, 2-(n-butyl)-1,3,2-benzodioxaphosphole-2-oxide, 2-anilino-1,3,2-benzo-dioxaphosphole-2-oxide, 2-phenylthio-1,3,2-benzodioxaphos-phole-2--oxide, 2-methoxy-5-methyl-1,3,2-benzodioxaphosphole-2-oxide, 2-chloro-5-ethoxycarbonyl-1,3,2-benzodioxaphosphole-2-oxide, 2-methoxy-5-e-thoxycarbonyl-1,3,2-benzodioxaphosphole-2-oxide, 5-ethoxycarbonyl-2-phenyl-1,3,2-benzodioxaphosphole-2-oxide, 2,5-dichloro-1,3,2-benzodioxaphosphole-2-oxide, ~-chloro-2-metiloxy-1,3,2-benzodioxaphosphole-2-oxide, - ~6 ~

2-methoxy-~-me-thyl 1,3,2-benzodioxaphosphole-2-oxide, 2,3-naphthylene methyl phosphate,5,6-dimethyl-2-methoxy-1,3,2-benzodioxaphosphole-2-oxide,-2,2-dihydro-4,5,6,7-tetrachloro-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-4,5,6,7-tetrach].oro-2,2,2-triphenoxy-1,3,2-benzodioxa-phosphole, 2,2-dihydro-2,2-ethylenedioxy-2-methoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2-benzyl-2,2-dimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-4,5-benzo-2,2,2-trimethoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,2,2-triphenoxy-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,2-(o-phenylenedioxy)-2-phenoxy-1,3,2-benzodioxaphosphole, 2-chloro-2,2-dihydro-2,2-(o-phenylenedioxy)-1,3,2-benzo-dioxaphosphole, 2,2-dihydro-2-methoxy-2,2-(o-phenylene-dioxy)-1,3,2-benzodioxaphosphole, 2,2-dihydro-2,2,2-trichloro-1,3,2-benzodioxaphosphole, 9,10-phenanthrenedioxy-trimethoxyphosphorus, o-phenylene phosphorochloridite, o-phenylene phosphorobromidite, o-phenylene phosphorofluoridite, methyl o-phenylene phosphite, n-butyl o-phenylene phosphite, methoxycarbonylmethyl o-phenylene phosphite, phenyl o-phenylene phosphite, p-chloro(or p-nitro)phenyl o-phenylene phosphite, 2-phenyl-1,3,2-benzodioxaphosphole, bis-o-phenylene pyrophosphite, 2-methoxy-5-methyl-1,3,2-benzodioxaphosphole, 5-acetyl-2-phenoxy-1,3,2-benzodi-oxaphosphole, 9,10-phenanthrene phosphorochloridite, 2-chloro ~-methyl-1,3,2-benzoclioxaphosphole, 5-ethoxy-carbonyl-2-phenyl-1,3,2-benzodioxaphosphole, 2-chloro-2-thioxo-1,3,2-benzodioxaphosphole, 2-phenoxy-2-oxo-1,3,2-~6~
_ ~7 -benzodiazaphosphole, 2-phenoxy-l/3,2-benzoxazaphosphole, 2,2-dihydro-2-oxo-2-methoxy-4,5-dimethyl-l,3,2-dioxa-phosphole, 2,2-dihydro-2-oxo-2-chloro-4,5-dimethyl-l,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-(l-imidazolyl)-4,5-dimethyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2-ethylene-dioxy-2~methoxy-4,5-dimethyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2-dime-thoxy-2-phenoxy-4,5-dimethyl-l,3,2-dioxa-phosphole, 2,2-dihydro-2,2,2-trimethoxy-~,5-dimethyl-l,3,2 dioxaphosphole, 2,2-dihydro-2,2,2-triphenoxy-4,5-dimethyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-triethoxy-4,5-diphenyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4,5-diphenyl-l,3,2-dioxaphosphole, 2,2-dihydro-2-oxo-2-methoxy-4,5-diphenyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-phenyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-methyl-l,3,2-dioxaphosphole, 2,2-dihydro-2,2,2-trimethoxy-4-methyl-5-phenylcarbamoyl-l,3,2-dioxaphosphole, 2,2,4,5,6,7-hexahydro-2,2,2-trimethoxy-l,3,2-benzodioxaphosphole, 2,2l-oxybis(4~5-dimethyl-2~2-dihydro-l~3~2-dioxaphosphole)r and 2,2'-oxybis(4,5-dimethyl-2,2-dihydro-l,3,2-dioxaphosphole-2-oxide). These cyclic phosphorus co~pounds are ei-ther availa~le co~ercially or per se known co~pounds ~R~ S.
Ed~undson et al., Che~istry and Industry, 1962, 1770-1778;
K. Darell Berlin et al., Tetrahedron, 1904, 20, 2709-271~;
~. Ra~irez et al., Te-trahedron, l968, 24, 5041-5051; ~.
AnschUtæ e-t al., Annalen, 1927, 454, 109-120; T. Koizu~i et al., Tetrahedron I.etters, 197~, 4703-476~; P. C. Crofts et al., ~6~

- ~8 -J. Chem. Soc., 1958, ~250.~25~; Mariamle M. C. F. Castelijins et al., J. Org.
Chem., 1981, ~6, ~7-53] or can be produced by the known methods. 'I'hey may be used either in a purified form or as yielded by the reaction.
A product resulting from the reaction of a compound having the partial structure [IV] with a phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide may be used iTl place of the cyclic trivalent or pentavalent phos-phorus compound mentioned above. The compound having the partial structure [IV] is, for example~ a compound of the formula Ql ~ WH [XVIII]
Q WlH
wherein the symbols are as defined above. A preferred example ls a compound of the formula WH
(A) a ~ XIX]
~TlH

~o~
_ ~9 _ wherein the symbols are as defined above. And, a frequently used one is a compound of the formula Qlb 3 WH [G]
Q2b W'H

wherein Q b and Q b combinedly represent an aryl group which may be substituted with a Cl_6 alko,cycarbonyl group. Specific examples are catechol, ethyl 3,4-dihydroxybenzoate, 2,3-dihydroxy-naphthalene, 3,4-dihydroxytoluene, 2,3-dihydroxytoluene, 3,4-dihydroxychlorobenzene and o-aminophenol. The halogen in said rhosphorus oxyhalide, phosphorus trihalide and phosphorus pentahalide is, for example, chlorine or bromine. Thus, specifically, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide and phosphorus oxybromide, for instance, are used. The reaction prodùct from a compound having the partial structure ~IV~ and a phosphorus a3~
_ 50 -oxyhalide, phosphorus trihalide or phosphorus pentahalide is, for example, the reaction mixture as obtained from the reaction therebetween. Generally, an about equimolar amount of a phos-phorus oxyhalide or phosphorus trihalide or about 1/3 to 1.0 mole equivalent of a phosphorus pentahalide is used per mole of the compound having the partial structure [IV]. The reaction is preferably carried out in a solvent, such as methylene chloride, 1,2-dichloroethane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, ether, benzene or bromobenzene.
Among others preferred are methylene chloride, acetonitrile and tetrahydrofuran. In some cases, favorable results are obtained by carrying out the reaction in the presence of a base. Usable bases are, for example, triethylamine, di-cyclohexylamine, diisobutylamine and di-n-butylamine, and preferred amines are, for example, triethylamine, tri-n-butylamine and di-n-butylamine. The reaction is carried out generally at -50C to ~100C, preferably at -20C to ~50C, for 5-120 minutes, preferably 10-60 minutes. However, the reaction temperature and period are not limited to the above provided that the desired reaction product is obtained.
Generally, the reaction mixture is used as it i.s as a raw material for the reaction proper without isolation. However, if necessary, the unreacted starting material, namely the compound having the partial structure [IV], the phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide and/or the hydrogen halide resultinq ~rom -the reac-tion or the salt thereof with the base may be separated prior to the reaction proper, Some of the compounds having the partial structure [IV] are com-mercially available and others can be produced by known methods or modifications thereo:E.
The desired products [I] can be produced by reacting a compound [II]
with a nucleophilic compound and (1) a cyclic trivalent or pentavalent phos-phorus compound having the partial structure [III] or ~2) a reaction product ~rom a compound having the partial struc-ture [IV] and a phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide ~such reaction product llerein-after also referred to simply as "reaction product"), in an organic solvent.
The compound [II] may be used either in the free form with regard to the acidic group such as carboxyl or sulfo or in the form of salt with a nontoxic cation such as sodium or potassium or an organic amine such as tri-ethylamine, tri-n-butylamine, di-n-butylamine, dicyclohexylamine, pyridine, collidine or 2,6-lutidine. ~hen a basic group is contained in R and/or Rl, said group may be in the form of salt with an organic acid such as acetic acid, tartaric acid or methanesulfonic acid or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid or the like. The nucleophilic compound may take the ~orm oE basic salt or acidic salt depending on the kind thereof, and such basic salt and acidic salt may also be used as a raw material. The basic salt and acidic salts are, for example, of the same kind as tllose mentioned above for compound [II].

The compound [II], the nucleophilic compound and (1) the cyclic trivalent or pentavalent phosphorus compound haviny the partial structure [III] or (2) the reaction product from the compound having the partial structure [IV] and phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide as well as the organic solvent may be charged in an optional order. When the compound [II], nucleophilic compound, cyclic phosphorus compound and organic solvent are used, the reaction is generally carried by mixing the compound [II] with the nucleophilic compound in the organic solvent followed by addition of the cyclic phosphorus compound or a solution thereof in an organic solvent, or by mi~ing the cyclic phosphorus compound with the nucleophilic compound in the organic solvent followed by addition of the compound [II] or an organic solvent solution thereof. Also when the reaction product from the compound--:~
having the partial structure [IV] and phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide is used, the reaction is carried out in the same manner as in the case where the cyclic phosphorus compound is used. As ror the mixing ratio, it is preferable -to use the nucleophilic compound in an amount of not less than 1.0 mole, more preferably 1.0-10.0 moles, per mole of the compound [II] and the cyclic phosphorus com-pound in an amount of not less than 1.0 mole, more preferably 1.0-6.0 moles, on the same basis. When the reaction product from the compound having the partial structure ~IV] and phos-phorus oxyhalide, phosphorus trihalide or phosphorus pentahalide is used, it is preeerab:Le -to use not less than 1.0 mole, more preferably 1.0-10.0 moles, of the nucleophilic compound, 1.0-6.0 moles of the compound having the par-tial structure [IV] and Yl2~

1.0-6.0 moles of the phosphorus oxyhalide or phosphorus tri-halide or 1/3-2.0 moles of the phosphorus pentahalide per mole of the compound [II].
Any organic solvent inert- to the reaction may be used as the solvent in the reaction. Thus, usable are, for instance, amides such as formamide, dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as chloroethane, isobutyl chloride, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, l,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, fluorobenzene and dichlorobenzene, ethers such as dimethyl ether, diethyl ether, tetrahydrofuran and dioxane, carboxylic acids such as glacial acetic acid and propionic acid, esters such as methyl acetate, ethyl acetate, isobutyl acetate, methyl propionate and ethylene carbonate, nitriles such as acetonitrile, propionitrile and benzonitrile, nitro compounds such as nitromethane and nitroethane, ke-tones such as acetone and methyl ethyl ketone, and hydrocarbons such as benzene, toluene and mesitylene, and mixtures of these. In particular, favorable results can be obtained when the reaction is carried out in such an organic solvent as methylene chloride, acetonitrile, formamide, formamide-ace-tonitrile mixture, methylene chloride-tetrahydrofuran mixture or methylene chloride-acetonitrile mixture. When the reaction product from the compound having the partial structure [IV] and phosphorus oxyhalide, phosphorus trihalide or phosphorus pentahalide is used, said reaction mixture itself may serve as the organic solvent. Depending on the kind of each starting material and/or organic solvent,the addition of a base may ad-vantageously influence the reaction. The addition of such base can be made in an adequate manner at the time of mixing of the starting - 5~
materials and organic solvent. Generally, said base is mixed with the organic solvent together wi-th the compound [II] or nucleophilic compound. The base is preferably used generally in an amount of 0-5 moles per mole of the compound [II].
Any base capable of accelerating the reaction or neutralizing the acid resulting from the reaction or solubilizing any of the starting materials but inert to the reaction may be used as the base. For instance, Cl 6 alkylamine such as triethyl-amine, tri-n-butylamine, di-n-butylamine and diiso-butylamine, C3 8 cycloalkylamine such as dicyclo-hexylamine, cyclic amine such as pyridine and lutidine are preferably used. The reaction temperature and period may be varied depending on the kind and amount of compound [II], cyclic phosphorus compound or reaction product, nucleophilic compound, organic solvent and/or base. In some cases, the reaction is complete in a moment at a temperature as low as -60C. Generally, however, the reaction is carried Ollt under mild conditions at -80C to 50C and is complete in several seconds to ten and odd hours. In particular, the reaction is preferably carried out at -40C to 40C for 5-120 minutes. ~though it is a general rule that a higher reaction temperature results in a shorter reaction time, the reaction is preferably carried out at relatively low temperature for prevention of side or secondary reactions, among others. The thus-obtained cephalosporln compound [I] can be isolated and purified by per se known methods, such as solvent extraction, pH adjustment, phase transfer, salting out, crystallization, recrystallization and chromatography. When the acyl group represented by Rl is of a specific kind, it is also possible to convert [I], withou-t isolation thereoE, into the corresponding

7-aminocephem compound (compound of formula [I] wherein Rl is a hydrogen atom), which is useful as an intermedia-te for the production of antibacterial substances, by a known method of cleaving acyl groups at position 7 which comprises adding to the reaction mixture dimethylaniline, trimethylsilyl chloride, phosphorus pentachloride, methanol and water in that order.
When the product [I] is in the free form, it may be converted into a salt in a conventional manner. The desired product of formula [I] also includes such a salt form. The salt forming component of such salt of product [I] may be of the same kind as that mentioned for the starting material [II]. Thus, the salt includes salts of the acidic group of [II] with alkali metals such as lithium, sodium and potassium, alklaine earth metals such as magnesium and calcium and amines such as di-n-butylamine, dicyclohexylamine, diisobutylamine, di-tert~butyl-amine, triethylamine, pyridine, ~,6-lutidine and tributylamine, and salts of the basic group of [II] with inorganic acids such as hydrochloric acid and sulfuric acid, organic acids such as oxalic acid, formic acid, trichloroacetic acid and trifluoro-acetic acid, sul.fonic acids such as methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphor-sulfonic acid, phosphoric acids such as methylphosphoric acid, dimethylphosphoric acid and diphenylphosphoric acid, and phosphonic acids such as phenylphosphonic acid. Some of the thus-ob-tained products [I] are per se useful as antibacterial agents and others are useful as raw ma-terials for the production ~ 55a ~

of more potent antibacterial agents. For instance, the cephalosporin compound ~IJ which has a 5-phthalimido-5-carboxyvaleryl group as Rl can be converted to the 7-~2-(2-aminothiazol-4-yl)acetamido] or 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamidoJ compound by cleavage of the acyl group at position 7 of [I] by a conventional method,,followed by reaction with (2-aminothiazol-4-yl)acetic or 2-(2-aminothiazol-4-yl)~2-methoxyiminoacetic acid or a reactive derivative thereof. Anantibiotic substance, 7-~2-(2-aminothiazol-4-yl).acetamido]-3-[1-(2-dimethylaminoethyl)-lH-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid, 7-L2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, for instance, can further be produced therefrom.

~ 2 ~b~

The following examples and reference examples illustrate the methods according to this invention and that of the copending parent application.
Prep_ration of some of tlle starting compounds [XV], i.e. 1,3,2-dioxaphosplloles Reference Example 1 Pyrocatechol (1.691 g, 15.36 mM~ was dissolved in 60 ml of ether.
Triethylamine (3.109 g, 30.72 mM) was added dropwise. The dropping funnel was washed with 10 ml of ether. The mixture, together with the washings, was stirred, and 2.287 g ~15.36 mM) of methyl dichlorophosphate was added dropwise with cooling at -40C to -35C. The dropping funnel was washed with 10 ml of ether and the mixture, together with the washings, was stirred at the same temperature for 10 minutes. The cooling bath was then removed and, after the temperature returned to roo~ temperature ~20-25C), the reaction mixture was placed in a glass filter and filtere~ under a nitrogen pressure. The residue on the filter was washed with two 15-ml portions of ether. The filtrate and washings were concentrated under re~uced pressure on a water bath at 20C. There was obtained 1.847 g ~96 0% yield) of methyl o-phenylene phosphate as a colorless viscous oil. Upon standing in a refrigerator, it crystallized, 2Q NMR (CDC13) : 3,82 and 4.03 (3H, each s, P-OCH3), 7.09 ~4H, s, ~ ).
Signals -for trace amounts of ether and triethylamine lYere also observed.
Rf in TLC:0.31 (Kieselgel*) 60F-254, acetonitrile: water: 99%
formic acid = 220 : 20 : 1) *Trade mark Reference Exam~le 2 Pyrocatechol (1.249 g, 11.35 mM) was dissolved i.n 42 ml of ether and, using 2.297 g (22.70 mM) o~ triethylamine and 1.849 g (11.35 mM) of ethyl dichlorophosphate, the reaction was carried ou-t at -40C to -35C and the reaction mixture treated in the same manner as in ReEerence Example 1. There was obtained 2.159 g (95.0% yield) of ethyl o-phenylene phosphate as a colorless viscous oil.
NMR~CDC13)~ : 1.42 (3H, t, J = 7Hz, C-CH3), 4.23 and 4.40 (2H, each q, J = 7Hz, P-O-CH2), 7.08 (4H, s, ~ ).
Signals for trace amounts o ether and triethylamine were also observed. Rf in TLC: 0.36 tunder the same conditions as in Reference Example 1) Reference Exam~le 3 Pyrocatechol (0.993 g, 9.02 mM) was dissolved in 50 ml o ether and, using 1.825 g (18.04 mM) o~ triethylamine and 1.723 (9.02 mM) of n-butyl dichlorophosphate, the reaction was carried out at -5~C to O~C and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 1.914 g (93.0% yield) of n-butyl o-phenylene phosphate as a colorless viscous oil.

0~

NMR(CDC13)~ : 0.7~2.0 (7H, m, C-CH2CH2CH3), 4~13 and 4.28 (2H, each t, J - 6.5Hz, P-O-CH2), 7.10 (4H, s, ~ ).
Signals for trace amounts of ether and triethylamine were also observed. Rf in TLC: 0.45 (under the same conditions as in Reference Example 1) Reference Rxample 4 Pyrocatechol (0.856 g, 7.77 mM) was dissolved in 32 ml of ether and, using 1.573 g (15.54 mM) of triethylamine and 1.484 g (7.77 mM) of n-propyl dichlorophosphate, the reaction was carried out at -30C to -25C and the reaction mixture treated in the same manner as in Reference Example 1. There was obtained 1.695 g (95.6~ yield) of n-propyl o-phenylene phosphate as a viscous oil (slightly turbid).
NMR(CDC13) S: 0.97 (3H, t, J = 7Hz, C-CH3), 1.77 (2H, q, J = 7 x 7.5Hz, O-C-CH2), 4.15 and 4.29 (2H, each q, J = 7.5Hz, P-O-CH2), 7.08 (4H, s, ~ ).
Signals for trace amounts oE ether and triethylamine were also observed. Rf in TLC: 0.41 (under the same conditions as in Reference Example 1).

~z~
59 24205-49]~

~e-fere_ e_~m~lQ~
Triethylamine (2.211 g, 21.86 mM) was added to a solution of 1.989 g (10.93 mM) of ethyl 3,4-dihydroxybenzoate in 30 ml of ether. The mixture was cooled to -30C to -20C and a solution of 1.627 g (13.93 mM) of rnethyl dichlorophosphate in 10 ml of ether was added thereto dropwise with stirring over 10 minutes. The reaction mixture was stirred at the same temperature for 5 minutes, the bath was then removed and the temperature was allowed to rise to 20C~ Filtration and washing were carried out by the procedure of Reference Example 1, and the filtrate and washings were concentrated at room temperature (20 ~25C) under reduced pressure. There was obtained 2.387 g (84.6~ yield) of 5-ethoxycarbonyl-2 methoxy-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.
NMR(CH2C12) ~ : 1.26 (3H, t, J - 7Hz, C CH3), 3~84 and 4.05 (3H, each s, P-O-CH3), 4.34 (2H, q, J = 7Hz, C-CH2), 7.0 ~8.0 (3H, m, ~ ).
Signals for CH2C12 and a trace amount of ether were also observed.
Rf in TLC: 0.38 (under the same conditions as in Reerence Example 1).

\
~L;26t~

Reference Example 6 3,4-Dihydroxytoluene (1.686 g, 13.58 mM) was dissolved in 40 ml of ether and, using 2.748 of triethylamine and 2.022 g of methyl dichlorophosphate/ the reaction mixture was treated in the same manner as in Reference Example 5. There was ohtained 2.400 g (88.4% yield) of 2-methoxy-5-methyl-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.
NMR(CH2C12)~ : 2.32 (3H, s, C-CH3) 3.78 and 3.99 (3H, each s, P-O-CH3), 6.8 ~7.1(3H, m, ~ ).
Signals for CH2C12 and a trace of ether were also observed. Rf in TLC: 0.31 (under the same conditions as in Reference Example 1) ReEerence Example 7 2,3-Dihydroxynaphthalene (1.747 g, 10.91 mM) was dissolved in 40 ml of ether and, using 2.208 g of triethylamine and 1.625 g of methyl dichlorophosphate, the procedure o~
Reference Example 5 was followed to give 2.20 g (85.4~ yield) of 2-methoxy-2-oxo-naphtho~2,3-d]-1,3,2-dioxaphosphole as a white powder.
NMR(CH2C12)~ : 3.82 and 4.03 (3H, each s, P-OCH3), 7.1 ~ 7.9 (6H, m, ~ o / '\ O_ 61 ~L~ 24205~491D

Rf in TLC: 0.30 (under the same conditions as in Reference Example 1) Reference Exam~le 8 To 1~180 g (10.72 mM) of pyrocatechol were added 11 ml of methylene chloride and 1.596 g of methyl dichlorophosphate, the mixture was stirred at room temperature (20~25C) for 20 minutes and then cooled to -30C. Thereto was added 2.169 g of triethylamine dropwise with stirring at -30DC to -20C over 7 minutesO The droping funnel was washed with 1 ml of methylene chloride and the washings were added to the mixture. The reaction mixture was stirred at the same temperature for 15 minutes and, after it returned to 10C, filtered to remo~e the triethylamine hydrochloride precipitate, which was washed with methylene chloride. The filtrate and washings were analyzed by NMR
spectrometry, by which it was revealed that the yield of methyl o-phenylene phosphate as found in the filtrate and washings was 89~.
NMRtCH2C12)~ : 3.81 and 4.02 (3H, each s, P-OCH3), 7.16 (AH, s, ~0\ ~0 Signals due to the presence of CH2C12 and triethylamine hydrochloride as well as a weak signal (multiplet) at 6.2 7.6 ppm due to ~ . The yield of the desired product was calculated based on the ratio (89~) between the signal (7.16 ppm) of ~
of the desired product and the signal in the 6.2 7.6 ppm region.

62 ~260~0~ 24205-~91D

Reference Example 9 To 0.710 g (6.45 mM) of pyrocatechol was added 7 ml of methylene chloride. Then, 0.960 g of methyl dichlorophosphate and 1 ml of methylene chloride were added. The mixture was cooled to -15C to -10C with stirrin~ and 2.390 g of tri-n-butylamine was added dropwise thereto over 8 minutes. The dropping funnel was washed with 3 ml of methylene chloride and the washings were added to the reaction mixture. The mixture was stirred at the same temperature for 5 minutes and then allowed to return to 10C.
Analysis of the liquid reaction mixture by NMR spectrometry indicated that the yield of methyl o-phenylene phosphate was 89~.
NMR(CH2C12) ~: 3.81 and 4.02 (3HI each s, P-OCH3), 7.14 (4H, s, ~ /P~ ).

Signals due to the presence of CH2C12 and tributylamine hydrochloride as well a weak signal (multiplet) at 6.2-7.6 ppm due to ~ . The yield of the desired product was determined in the same manner as in Reference Example 8.
Reference Example 10 The procedure of Reference Example 9 was followed using di-n-butylamine or pyridine in place of tri-n-butyl-amine, the yield of methyl o-phenylene phosphate in the liquid reaction mixture as determined in the same manner as ln ReEerence Example 9 being 71~ or 91~, respectively.

63 ~ 24205-491D

ReEerence Example 11 To 1.~18 g of pyrocatechol were added 1~917 g of methyl dichlorophosphate and 11 ml of acetonitrile. The mixture was cooled to -25C and 2.605 g of triethylamine was added dropwise at -25C to -20C with stirring. The dropping funnel was washed with 1 ml of acetonitrile and the washings were added to the mixture.
After stirring at the same temperature for 10 minutes, the reaction mixture was allowed to return to 10C and then filtered.
The filtration residue was washed with a 5-ml and 3-ml portion of acetoni-trile. The filtrate and washings were concentrated under reduced pressure on water bath at 15C to 20C to give 3.102 g of methyl o-phenylene phosphate as a slightly turbid oil.
NMR(CH2C12)~ : 3.81 and 4.01 (3H, each s, P-OCH3), 7.12 (4H, s, ~cO~ ~0 Signals for contaminants, CH2C12 and triethylamine hydrochloride (about 0.25 mole per mole of the desired product), were also observed.
Reference Example 12 To 0.963 g of pyrocatechol were added 7 ml of methylene chloride and 1.30 g of methyl dichlorophosphate. The mixture was stirred at room temperature (20-25C) for 10 minutes and then, wi-th cooling to -20C to -15C, 1.86 g of triethylamine was added dropwise. The dropping funnel was washed with 1 ml of methylene chloride and the washings were added to the mixture.

64 ~ 24205-491D

The resulting mlxture was stirred at the same temperature for 5 minutes to give a reaction mixture containing methyl o-phenylene phosphate and triethylamine hydrochloride.

To a solution of 3.11 g of phenylphosphonic acid dichloride in 10 ml of ether were added 1.76 g of pyrocatechol and 20 ml of ether. The resulting solution was cooled to -25C to -28C and a solution of 3.23 g of triethylamine in 10 ml of ether was added dropwise thereto with stirring over 8 minutes.
Thereafter, the reaction mixture was allowed to return to room temperature (20-25C), and the precipitate was Eiltered off under nitrogen atmosphere and washed with 30 ml of ether. The filtrate and washings were combined and the ether was distilled oEf under reduced pressure to give 3.46 g (94.4% yield) of 2-phenyl-2-oxo-1,3,2-benzodioxaphosphole as a colorless oil. Upon standing in a refrigerator overnight, it crystallized.
NMR(CDC13)~ : 7.11 (4H, s, ~ ), 7.2 ~8.1 (SH, m, ~ ).
Signals for a trace amount oE ether were also observed. Rf in TLC: 0.35 (under the same conditions as in Reference Example 1) Reference Example 14 -A solutlon oE 1.75 g of 7B-(D-5-carboxy-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid di-tri-n-butylamine salt and 0.35 g of 5 mercapto-l-methyl-lH-tetra~ole in 20 ml of methylene chloride was cooled to -25C, 0.74 g of methyl o-phenylene phosphate was added thereto, and the mixture was stirred at -25C to -20C for 2 hours. To the reaction mixture, there were added 15 ml of tetrahydrofuran and 15 ml of water, followed by stirring and phase separation. The aqueous layer was extracted with the mixture of 5 ml of tetrah~drofuran and 10 ml of methylene chloride. The organic layer and the extracts were combined, washed with 20 ml o~ water, and dried over anhydrous magnesium sulfate. The solvents were distilled off under reduced pressure, and the residue was dissolved in a small amount of acetone and the solution was added to 100 ml of ether. The resulting precipitate was collected by filtration, washed with ether and dried in vacuo to give 1.14 g (94.7~ yield) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid.
I R (KBr)cm : 3340, 2950, 1775, 1715, 1534, 1394 NMR(DMSO-d6)~: 1.40 2. 40(6H, m,-(CH2)3-), 3.62(2H, broad, 2-CH2), 3.94(3H~s~N-cH3)~ 4.30 (2H,ABq,J=15Hz,3-CH2), 4.73( ~t~ 9 ~ 5. 0l (~ a ~ d.
5. ~ 2 ~ &
2 ,7~ 7. 9 1 ( 4 ~ 7 ~ ~ ,d ,J ~8a~, - co~

Reference Example l_ A solution of 3.52 g of 7~-(D-5-carboxy-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4~carboxylic acid di-triethylamine salt and 1.00 g of 5-mercapto~l-methyl-lH-tetrazole in 25 ml of methylene chloride was cooled to -20C, and 0.25 g of triethylamine was added thereto with stirring.
To this solution was added the whole reaction mixture prepared in Reference Example 12 dropwise with stirring at-20C to -15C. me dropping funnel was washed with 6 ml of methylene chloride and the washings were added to the reaction mixture. The mixture was stirred at the same temperature for 20 minutes and then at -5C to 0C for 60 minutes. Following addition of 10 ml of water to the reaction mixture, the solvent was distilled off under reduced pressure, and a new 30-ml portion of methylene chloride and 15 ml of tetrahydrofuran were added to the residue. After phase separation, the organic layer was washed with 1 N hydrochloric acid and then with saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The,solvents were distilled off under reduced pres-sure, the residue was dissolved in a small amount of acetone, the solution was poured into ether, and the resulting precip-itate was collected by filtration, washed with ether and dried in vacuo to give 2.82 g(93.8~ yield) of the same pro-duct as obtained in Reference Example 1~. The IR and NMR

spectra for this product confirmed the identity thereof with the substance obtained in Reference Example 1~.

17~6~

In the Reference xamples and Examples~ the elution in column chromatography was carried out with observation of TLC (Thin Layer Chromato-graphy). In the TLC, were employed Merck pre-coated TLC plate 60F254 and UV
lamp for detection.
For silica gel chromatography, "silica gel 60 for column chromato-graphy" manufactured by E. Merck in ~ermany was used. The resin named "Amberlite* XAD-2" is a product manufcctured by Rohm ~7 Haas Co. in U.S.A. All the temperatures are uncorrected and tlle expression "room temperature" means 20-25C. The percentages are all on weight basis, except the cases of solvents.
In those cases, the percentages are all on volume basis. The NMR spectra given therein were measured using a Varian Model EM 390 (90 MHz~ or Hitachi Perkin-Elmer R-20 (60 Mllz) spectrometer with tetramethylsilane or sodium 2,2-dimethyl-2-silapentane~5-sulfonate as the internal or external reference and all ~ values are in ppm. The symbol s stcmds for a singlet, d a doublet, q a qua~ter, ABq a AB type quartet, t a triplet, dd a double doublet, m a multiplet, br broad and J a coupling constant. Infrared (IR) spectra were recorded on a llitachi EPI-S2 spectrometer. And, symbols in Examples and Reference Examples have the following meanings, respectively;

*Trade mark mg : milligram g : gram ml : milliliter ~ : percent mM : millimole Hz : Herz C : centigrade degree NMR : Nuclear Magnetic Resonance IR : Infra-Red absorption DMSO : dimethylsulfoxide D20 : heavy water v/v : volume per volume THF : tetrahydrofuran TLC : Thin layer chromatography - 69 - ~ 4 Example 1 To 0.70 g of 5-mercapto-1-methyl~lH-tetrazole were added 30 ml of methylene chloride and 0.61 g of triethyl-amine and 1.14 g of o-phenylene phosphorochloridate was added at room temperature (20-25C).The solution w~ c~ole~ to -60C
and a solution of 2.~2 g of 7~-(D 5-carboxy-5-phthalimido-valeramido)-3 hydroxymethyl-3-cephem 4-carboxylic acid ditriethylamine salt in 10 ml of methylene chloride was added all at once. The ~ixture was once warmed to 15C and, then, cooled, and 20 ml o~ tetrahydrofuran (THF) and 20 ml of water were added. After phase separation, the aqueous layer was extracted with 5 ml of THF and 10 ml of methylene chloride. The organic layer and the extract were combined, dried with anhydrous magnesium sulfate, concentrated to about 10 ml under reduced pressure, and added to 100 ml of ether. The precipitate was collected by filtration, washed with ether and dried in vacuo to give 1.33 g (yield 73.7%) o~ 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl~3-cephem-4-carboxylic acid;
IR (KBr) cm 1; 3340, 2950, 1775, 1715, 1534, 1394 N M R (DM S O -d6 ); ~ 1.4 0 ~ 2.~0 ( 6 H ,m ,- (CH2)3 --), 3.62(2~I,br,2--CH2) 3.9~1 ( 3I-I, s,~ ClI3), ~1.3 0 ( 2 H ,~ Bcl,J =1 5 Hz ,3 -C~I2),4 7 3 (1 H, t IJ =8 Hz , ~CH-) ,5.01 (1~ ,J = 5~l~., 6-H ), 5 6 2 ( 1 H, q , J= 5~8I-Iz ,7 -H ) ,7.9 1 ( ~
o H , s,l ~ - ) , 8.77 (l H ,~i ,J= 8H z,- C ON
) Example 2 To 1.04 g of 1-(2-dime-thylaminoe-thyl)-5-mercap-to-lH-tetrazole were added 60 ml o~ methylene chloride and 0.61 g of -triethylamine,and :L.14 g o~ o-phenylene phosphorochloridate was added at room temperature. The mixture was cooled to -60C and a solution of 2.12 g of 7~-(D-5-carboxy-5-phthal-imidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt in 10 ml of methylene chloride was added all at once. The mixture was warmed to 15C and the precipitate was collected by filtration and washed with methylene chloride. The solid substance was suspended in 30 ml of methylene chloride and 0.71 g of triethylarnine was added under ice-cooling. The suspension was stirred for 30 minutes and the insoluble matter was filtered off. Then, at 0C or below, 10 ml of 1 N ethanolic hydrochloric acid and 20 ml of ether were added dropwise to the filtrate. The precipitate was collected by filtration, washed with methylene chloride and dried in vacuo to give 1.51 g (yield 72~4%) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-[1-(2-dimethyl-aminoethyl~-lH-tetrazol-5-yl]-thiomethyl-3-cephem-4-carboxylic acid hydrochloride.
IR (KBr) cm~l; 1775, 1715, 1640 N M R (D M S O -d 6 ); ~ 1.30 -2.4 0 ( 6 H ,m , -( C H2 )3 - ), 2.8 3 ( 6 H ,s ,N ~C H3 )~ 3.5~ 3-8 (4 H , m , 2 - C H2 ~ - C H2N''), 4.3 0 ( 2 H , br, ;
3 - C H2), 4 5 ~ 4 9 ( 3 H , m ,-C H< ~ =
C H2 ) , 5 03( 1 H , d , J = 5 H z .C6 - H ) , 5.60 ( 1 H ,q ,J = 5.nd 8l-Iz ,C7- H ) ,7.90 ( 4~I, s , N- ), 8.7 7 (1 H ~ 8 Hz~ - CO N H - ) xample_3 To ~ mixture of 2.12 g of 7B-(D-5-carboxy-5-phthal-imidovaleramido)-3-hydroxymethyl-3-cephem-~carbo~Yylic acid ditricthylamine salt and O . 52 g of 5-mercapto-1-methyl-lEi-- 71 - ~2Ei~3~

tetrazole were acldecl 30 ml of methylene chlori.de and 0.61 g of trie-thylamine,and the resultant solution was cooled to -15C
To this solution wa~added 1.67 g of methyl o-phenylene phosphate and the reactionwas allowed to proceed at -15C
to -10C for 30 minutes. To the reaction mixturewere added 20 ml of THF and 20 ml of water and the whole mixture was adjusted to pH 2 with 6N-hydrochloric acid. After phase separa-tion, the aqueous layer wasextracted with 5 ml of THF and 10 ml of methylene chloride. The organic layer and the extractwerecombined and dried over anhydrous magnesium sulfate.
The above productwas further treated as in Example 1 to give 1.64 g (yield 90.9%) of the desired product. The IR and NMR spectra of this productwere identical with those of the compound obtained in Example 1.
Example 4 To a solution of 1.71 g of o-phenylene phosphoro-chloridate in 15 ml of methylene chloridewa~ added 0.91 g of triethylamine. Then, at room temperature, 0.23 y of methanolwas added and the reaction was allowed to proceed at room temperature for 10 minutes. Using the thus-obtained methyl o-phenylene phosphate solution in place of 1.67 g of methyl o-phenylene phosphate, the reaction and after-treatmentwere carried out in the same manner as Example 3 to give 1.62 g (yield 89.8%) o~ the desired product. The IR spe_-trum of this product was identical with that of the compound ob-tained in Example 1.
Example 5 A solution of 1.75 g of 7~-(D-5-carboxy-5-phthalimid valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine sal-t and 0.35 g of 5-mercapto-1-methyl-l~-tetrazole in 20 ml of methylene chloride was cooled to -20"C. To this solutionwas added 0.7~1 g of methyl o-phenylene phosphate and the reac-tion was allowed -to proceed at -25 -to -20C for 2 hours. To the reaction mixture were added 15 ml of T~IF and 15 ml of water and the whole mixture was thoroughly stirred and allowed -to stand for phase separa-tion. The aqueous layer was extracted with 5 ml of THF and 10 ml of CH2C12. The organic layer and the extract were comblned~ washed with 20 ml of water and dried over anhydrous magnesium sulfate~ The solvent was then distilled off under reduced pressure and the residue was dissolved in a small amount of acetone and added to 100 ml of ether. The pre-cipitate was collected by filtration, washed with ether and dried in varuo to give 1.14 g (yield 94.7%) of the desired product. The IR spectrum of this product was identical with that of the compound obtained in Example 1.
Example 6 To 0.52 g of 1-(2-dimethylaminoethyl)-5-mercapto-lH-tetrazole were added 40 ml of methylene chloride and 0.40 g of triethylamine, followed by addition of 1.41 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4~carboxylic acid ditriethylamine salt. To the mixture was added 1.12 g of methyl o-phenylene phosphate and the reaction was allowed to proceed at 20-25C for 10 minutes. The reaction mixture was cooled, and 5 ml of 1 N ethereal hydrochloric acid was added dropwise at 0C
or below. The precipitate was collected by filtration and washed with methylene chloride. The solid matter was sus-pended in 20 ml of methylene chloride and 0.47 g of tri-ethylamine was added under ice-cooling. The mixture was stirred for 30 minutes and the insoluble matter was filtered off. Then, at 0C or below, 6.7 ml of 1 N alcoholic hydro-chloric acid and 10 ml of ether were added dropwise to the filtrate. The precipitate was collected by filtration, washed with methylene chloride and dried in vacuo to give 1.00 g (yield 71.96) of the desired product. The IR and MMR spectra of this compound were identical with those of the compound obtained in Example 2.
_xample 7 In 10 ml of methylene chloride was dissolved 0.76 g of o-phenylene phosphorochlorida-te, followed by addition of 0.~0 g ~26~

triethylamine. Then, at room temperature, 0.56 g oE p-nitro-phenol was added portionwise, and the reaction was allowed to proceed at room temperature for 10 minu-tes. The reaction mixture was added to a solution cooled to -20C of 1.41 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt, 0.35 g of 5-mercapto-1-methyl-lH-tetrazole and 0.20 g of triethylmaine in 20 ml of methylene chloride, and the reaction was allowed to proceed at -20~2C for 20 minutes. The reaction mixture was further treated in the same manner as Example 3 to give O.9ll g (yleld 75.7%) of the desired product. The IR
spectrum of this product was identical with that of the com-pound obtained in Example 1.
Example 8 In 10 ml of methylene chloride was dissolved 0.74 g of 2,2,2-trichloro-1,3,2-benzodioxaphosphole, followed by ad-dition of 0.30 g of triethylamine. Then, at room temperature, 0.10 g of methanol was added and the reaction was allowed to proceed at room temperature for 10 minutes. The reaction mixture was ice-cooled, and 0.20 g of triethylamine, 0.17 g of 5-mercapto-1-methyl-lH-tetrazole and 0.71 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt were added in that order. The reaction was allowed to proceed under ice~cooling for 30 minutes. The reaction mixture was treated in -the same manner as described in Example 3 to give 0.404 g of (yield 6608~) of the desired product. The IR spectrum of this product was identical with that of -the compound ob-tained in Example l.
Example 9 In 10 ml of methylene chloride was dissolved 0.74 g of 2,2,2--trichloro-1,3,2-benzodioxaphosphole, followed by addition of 0.4 g of triethylamine. Then, at room tempera-ture, 0.51 g of p-chlorophenol was added portionwise, and 0.2 g o triethylamine, 0 17 g of 5-mercapto-1-methyl-lH-tetrazole and 0.71 g of 7~-(D-5-carboxy-5-phthalimidovaleramido) 7 D, ~ ~ 6 ~

3-hydroxymethyl-3-cephem-4-carboxylic acid di-triethylamine salt were added in that order. The reac-tion was allowed to proceed at room tempera-ture for 40 minutes. The reaction mixture was further treated in the same manner as described in Example 3 to give 0.436 g (yield 72.0~) of the desired product. The IR spectrum of this product was identical with that of the compound obtained in Example 1.
Example 10 In 1~ ml of methylene chloride was dissolved 1.13 g of bis(o-phenylenedioxo)chlorophosphorus and, under ice-cooling, 0.2 g of triethylamine, 0.17 g of 5-mercapto-1-methyl-1~-tetrazole and 0.71 g of 7~-(D-5-carboxy-5-phthalimidovaler-amido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-ethyalmine salt were added in that order. The reaction was allowed to proceed under ice-cooling for 30 minutes. The reaction mixture was further treated in the same manner as described in Example 3 to give 0.43 g of the desired pro-duct. The IR spectrum of this product was identical with that of the compound obtained in Example 1.
Example 11 In 5 ml of methylene chloride were dissolved 0.71 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 0.17 g of 5-mercapto-1-methyl-lH-tetrazole. To this solution were added 0.2 g of triethyalmine and 0.51 g of methyl o-phenylene phosphite and the reac-tion was allowed to proceed at room temperature for 22 hours. The reaction mixture was further treated in the same manner as described in Example 3 to give 0~41 g (yield 67.7~) of the desired product. The IR and NMR spectra of this product were identical with those of the compound obtained in Example 1.
Example 12 A solution of 874 mg of 7~-(D-5-carboxy-5-phthalimido-valeramido)-3 hydroxymethyl-3-cephern-4-carboxylic acid di-tri-n-butylamine salt and 251 mg of 2-mercaptobenzothiazole in 10 ml of me-thylene chloride was cooled to -10C, and ~L2~
~ 75 -400 mg of ethyl o-phenylene phoslhate was added. The mixture was sti~red at-10C to -5C for 2 hours. To the reac-tion .
mixture wereadded 8 ml of THF and 8 ml of water and the whole mixture was stirred and allowed to stand for phase separa-tion. The aqueous layer was extracted wi-th 5 ml of methylene chloride, and the organic layer and the extract were combined, followed by addition of 10 ml of water. After phase separa~
tion, the organic layer was dried overanhydrous ma~esium sulfate. The solvent was then distilled off under reduced pressure and the residue was dissolved in a small amount of a mixture of acetonitrile, water and formic acid (20:2:0.1) and subjected to silica gel column chromatography. The fractions (Rf: about 0.43) containing the desired product were collected and concentrated under reduced pressure. To the oily residuewas added ether and the resultant powder wascollected by filtration,washed with ether and dried to give 555 mg (yield 85.0%) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-[(benzothiazol-2-yl)thiome-thyl]-3 cephem-4-carboxylic acid.

I R ( K Br ) cm~l :3 3 2 0, 1 7 7 5, 1 7 1 5 NMR ( DM S O--(16) ~ 1. 3 () ~ 2. 4 0 ( 6 H, m, --CH2CH2CH2--), 3.6 2 ( 2 H, ABq, J=1 8Hz, 2--CH~), 4.3 8 ( 2 H , ABq, J= 1 4 Hz,3~CH2), 4. 7 3 ( 1 H, t, J = 7 Hz, ,C H--) 9 5. 0 4 ( 1 H, d, J = 5 Hz, C6--H ), 5. 6 3 ( 1 H, ~1 ~ J=
5 ~ 8 H z, C 7--H ) 7. 8 6 ( 4 H 9 S ~ , 8.80 ( 1 H, (l, J = 8 H%, --C ONll--) Example 13 A solution of 874 mg of 7~-(D-5-carboxy-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid di-tri-n-butylamine salt and 198 mcJ of 5-mercapto-2-methyl-~ ~t)~

1,3,4-thiadiazole in 10 ml of methylene chlori~e was cooled to -20C to -15C. To this solution was added 375 mg of methyl o-phenylene phosphate and the mixture was stirred under ice-cooling for 1.5 hours. The reactlon mixture was further treated in the same manner as Example 12 to give 502 mg (yield 81.3%) of 7~-(D-5-carboxy-5-phthalimidovaler-amido)-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem 4-carboxylic acid.

I R ( K B r ) ~cm~~: 3 30 0 ,1 77 5 ,1 71 5 N M R ( D ~ S O - d 6 ) ~ 1. 3 0 ~ 2. 4 0 ( 6 H, m, - CHzCH2CH2 - ) 9 2.71 ( 3 H , s, - CH~ ), 8.62 (2 H ,A Bq , J= 1 9 Hz, 2 - CH2 ), 4.3 7 (2 H ,ABq, J= 1 3Hz, 3--CH2), 4.7 6 ( lH, ~, J= 7~Iz,~CH~
5.0 6 ( 1 H, d, J= S Hz , C6 - H ), 5.6 5 ( 1 H, q ,J
=5&8Hz ,C7 - H), 7.92 (4H, s, ~ ), 8.81 d, J=8Hz, ColYIl) Example 14 A solution of 477 mg of o-phenylene phosphorochloridate in 5 ml of methylene chloridewascooled to -20C to -10C.
To the solution were added 463 mg of tri-n-butylamine and 235 mg of phenol and the mixturewas stirred at the same temperature for 5 minutes to make a phenyl o-phenylene phos-phate solution. On the other hand, with stirring and ice-cooling, 278 mg of tri-n-butylamine was added to a solution of 874 mg of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine sal-t and 312 mg of 2-carboxymethylthio-5-mercapto-1,3,4-thiadiazole in 5 ml of methylene chloride. The mixture was cooled to -10C to -5C and the above~mentioned phenyl o-phenylene phosphate solutionwas added. The whole mixture was stirred atroom temperature or 2 hours. The reaction ~L2~a-~o~

mixture was treated further in the same manner as Example 12 to give 501 mg (yield 72.2%) of 7~-(D-5-carboxy-5-phthalimidc-valeramido)-3-[(2-carboxy~ethylthio-1,3,4-thiadiazole-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
I R ( K B r ) cm~~: 3 30 0 , 17 7 5 , 171 3 N M R ( D M S O - d 6 ) ~ 1.3 0~ 2.~ 0 (6 H ,In, --C H2 C H2 C H2--) , 3.5 9 ( 2 H 9 b r , 2 --C H2 ) .4.1 3 (2H , s, - S C H2 C O O - ) , 4.3 3 (2 H , A B(l ,J =
1 3Hz ,3 -C H2) ,4 7 2( l H ,t ,J= 6 Hz, ,C H ), 5.0 4 (l H ~ ,J = 5 H~ , C6 - H ) ~5.40 ~ 58 0 ( l~I.
~r , C7 - H ) ,7.9 0 ( 4H, s, ~ .), 8.7 8 ( 1 ~I, ,J - 8 Hz , -C O N H - ) Example 15 To a mixture of 874 mg of 7~-(D-5-carboxy-5-phthal-imidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt and 312 mg of 1-carboxymethyl-5-mercapto-lH-tetrazolewas added 10 ml of methylene chloride and 2~8 mg of tri-n-butylamine was added under ice-cooling.
The mixture was stirred for 10 minutes, after which 372 m~ of methyl o-phenylene phosphate was added at -25 to -20C an~
the whole mixture was stirred at the same -temperature for 2 hours. The reaction mixture was further treated in the same manner as Example 12 to give 476 mg (yield 73.7%) of 7~D-5-carboxy-5~phthalimidovaleramido)-3-[(1-carboxymethyl-lH-tetra~ol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.
I ~ ( K Br ) Cll~ 3 3 0 0, 1 7 7 3, 1 7 1 3 N M R ( D M S O - (I 6 ) ~ 0 ~ 2.~10 ( 6H ,n-~ -C:112CiI2CII2~ 3 6 2( 2~-I, I)r, 2--CH2), 4~3 3 ( 2H , AB q, J= 1 4Hz, 3--CH2), 4.7 1 ~ l H, t, J = 6Hz , CE~ ) , 4.9 9 ( l H, d , J= 5Hz , C6--H), 5.2 8 ( 2H, s, ~NCH2 CO--), 5.6 2 ( 1 H 9 9, J=5 &~8H~ ,C7--H), 7.89 (4H, s. ~ ), 8.77 ( lH, d, J=8Hz,--CONH--) Example 16 Using 354 mg of 2-ethoxycarbonylmethylthio-5-mercapto-1,3,4-thiadiazole in place of 2-mercaptobenzothiazole, the procedure of Example 12 was repeated to give 600 mg (yield 83.2%) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-[(2-ethoxycarbonylmethylthio-1,3~4-thiadiazol-5-yl)thiomethyl~-3-cephem-4-carboxylic acid.

I R ( K B r ) cm~l: 3 3 2 0, 1 7 1 5, 1 'l 1 S
Nl~R ( DM S O--d6): o 1.0 0~2.~ 0 ( 9 H, m, --C H3-~-C H2C H2C H2 -) , 2.9 ~ 4.5 ( 811,m , 2 -C H2 , 3-CH2, -S-CH2CO-, CO2CH2), 4.75 (lH, t, J=6, ~CH-), 5.06 (lH, d, J=5Hz, C6-H), 5,4 0~ 5.9 0 ( l H, ~lr, C7 - H ) ,~.90 ( 4 H . s~

8.60~ 9,1 0 (l H , br 9 - C ON~

Example 17 In 10 ml of me-thylene chloride was dissolved 874 mg of 7~-~D 5-carboxy-5-(benzamido)valexamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid di-tri-n-bu-tyl.amine salt and, under cooling at -50C to -40C, 198 mg of pyridine and _ 79 _ ~ ~6~

a solution of 372 mg of methyl o-phenylene phosphate in 3 ml of methylene chloride were added in that order.
Then, at -10C to 0C, the mixture was stirred for 2 hours.
To the reaction mixture was added 15 ml of water and the mixture was adjusted to pH 7.0 and allowed to stand for phase separation. The aqueous layer was washed -twice with 5 ml portions of methylene chloride, adjusted again to pH
6.0 and concentrated under reduced pressure. The residue was subjected to Amberlite XAD-2 column chromatography (XAD-2 of 100-200 mesh: 100 ml, column height: 32 cm), elution being carried out with water and water-methanol (10 : 2~. The fractions were checked by TLC (developing solvent: acetonitrile 15: water 5: 99~ formic acid 0.25) and the fractions (Rf:
about 0.24) containing the desired product were pooled and concentrated to give 410 mg ~yield 73.1~) o N-~7~-ID-5-(benzamido)adipinamido]-3-cephem-3-ylmethyl]pyridinium-4-carboxylic acid monosodium salt.
I R ( K B ~ ) cm~': 3 3 6 0 ,3 2 5 0 ,1 7 6 5 , 1 6 45 ,1 ~ 30 ,1 ôO 5 N M R ( D2O ) ~ 1.5 0~ 2G 0 (S H ,m , -(CH2)~-), 3.1 4( 2H ,AB q , J= 1 9 Hz,2 - CH2 ), 436(lH, , ~CH-),505(1H,~,J=5H~,C 6 - H ) ,5 32 ( 2 H ,A Bq ,J= 1 5 Hz ,3 -C H2 ), 5.60 (1 H ,~ ,J
= 5 H~, C7 - H ) , 7.0~ 9.0 (1 O H , m, Example 18 To a solu-tion of 286 mg of o-phenylene phosphoro-chloridate in 3 ml of methylene chloride was added 174 mg of 5-mercapto-1-me-thyl-lH-tetrazole and the mixture was cooled to -20C to -10C. A solution of 152 mg oE triethyl-amine in 1 ml of methylene chloride was added under stirring and then the mixture was allowed to stand at 20C to 25C.
The mixture was poured into a solu-tion of 710 mg of 7~-[D-5-carboxy-5-(benzyloxycarbonylamino)valeramido]-3-~ ~c~c~'~,~*~k hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt in 7 ml of methylene chloride under cooling at -30C to -20C and stirring. The whole mixture was stirred at the same temperature for 5 minutes and 15 ml of 2 N HC1 and 10 ml of tetrahydrofuran were added. The organic layer was taken, washed twice with 5 ml portions of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, concentrated under reduced pressure and added -to ether. The powdery precipitate was collected by filtration, dissolved in acetonitrile-water and subjected to silica gel column chromatography tsilica gel: 20 g, column height:
24 cm), elution being carried out with acetonitrile-water-formic acid (20:2:0.1). The fractions were checked by TLC (developing solvent: the same as the above eluent) and the fractions (Rf:
about 0.24) containing the desired product were collected and concentrated and ether was added. The resultant powder was collected by filtration and dried to give 370 mg (yield 61.1%) of 7 ~ -[D-5-carboxy-5-(benzyloxy-carbonylamino)valeramido~-3-[(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 : 3300, 1775, 1715 NMR
(D~SO-d6) : ~ 1.30 ~1.90 (4H, m, CH2X2) 2.00~ 2.30 (2H, m, CH2), 3.67 (2H, br, 2-CH2), 3.93 (3H, s, N-CH3), 4.30 (2H, br, 3-CH2), 4.80~ 5.20 (4H, m, -CH2O-, `CH- &
C6-H), 5.63 (lH, q, J = 5 & 8Hz, C7-H) r 7.10~ 7.60 (m, 6H, ~ &- OCONH-), 8.78 (lH, d, J = 8Hz, -CONH-) 80a 24205~491D

Exam~le 19 Us;.ng 1~81 g oE 7~ -[D-5-(p-t-butylbenzamido)-5-carboxy-valerylamido]-3-hydroxymethyl-3 cephem-4-carboxylic acid ditri-n-butylamine salt ln place of 1.75 g oE 7 ~ -(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl~3-cephem-4-carboxylic ~.~

a3~0~

ditri-n-butylamine salt, -the procedure of Example 5 was repeated to give 1.18 g (yield 93.4%) of 7-[D-5-~p~-t-butyl-benzamido)-5-carboxyvalerylamido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

I R ( K B r j cm~l: 1 7 7 6, 1 7 2 7, 1 6 4 0 NMR ( d6~: ,S O ): o 1.2 8 ( 9H, 5, C~I3 ,<3 ), 1.7 0~2.2 1 ( 6H, CH2 x3 ), 3.5 4~3.7 7 ( 2H ,AB(l, J= 1 8Hz, 2--CH2 ), 3 9 1 ( 3H, s, N--CH3 ), 4.2 0 ~4.3 7 ( 2H, AB q, J= 1 3Hz, 3--CH2 ),4.3 9 (1 H , `CH-) . 5.0 2 ( 1H, d , J=~H% ,C~ - H) , 5.64( lH, q, J=~-~8H7, C7--H), 7.43~7.81 ( ~H ,~ ), 8.4 2 ( lH, ~l, J=8HZ, ~CONH), 8.7 9 ( lH, ~I, J= 8HZ,--CONH--) Example 20 In 2.ml of methylene chloride was dissolved 0.450 g of o-phenylene phosphorochloridate, and.at 0-5C, a solution of ~O437 g of tri-n-butylamine in 1 ml of methylene chloride and a solution of 76.0 mg of methanol in 2 ml of methylene chloride were added in that order. The mixture was stirred at room temperature for 20 minutes to make a methyl o~phenylene phosphate solution. This solution was added to a solution of 1.032 g of 7~-(D-5-carboxy-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt and 0.267 g of 2-mercaptobenzoxazole in 5 ml of methylene chloride under coolin~ at -20C to -25C
and stirring, and the reaction was allowed -to procced at -20C to -10Cfor ~Q minutes. To the reaction mixture was added 15 ml of water and, after phase separation, 15 ml of water was added to the organic layer. The pH was adjus-ted ~' - 82 - ~

to 9.0 with N-NaOH and, after phase separation, the organic layer was further extracted twlce with 5 ml of water. The were combined and washed with 5 ml oE methylene chloride. The aqueous layer was adjusted to pH 2 with 2 N
HCl and extracted with a 1:1 mixture of methylene chloride and THF. The organic layer was washed twice with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off and ether was added. The resulting powder was collected by filtration and dried to give 588 mg tyield 78.2%) of 7~-(D-5-carboxy-5-phthalimido-valeramido)~3-(benzoxazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid.

I R ( K B r ) cm~~ : 3 3 1 0, 2 9 3 0, l 7 7 5, 1715, 1530, 1500 N M R ( (i6--Dl~/I S O ): ~ 1.3 0~~.4 0 ( 6H, m, -C H2 C H2 C .~12--), 3. 6 8 ( 2 H, A B ~ , 2--C H ), 4.2 3 ~4.6 6 ( 2H, AP5 (I, J= 1 4Hz, 3--CH2 ), 4 73 ( I H, t, J = 7~1z, ,CH- ) , 5.0 4 ( 1 H, l1, J = 5Hz, C6--H ), 5.6 3 ( l H, ~, J= 5 ~ 8 HZ, C --H ) ,7.2 0 ^-7.7 7 ( 4I-I, m, ~ ), 7.8 7 ( 4 H, s ,~)~
8.78 ( lH. ~1, J=8~1z,--C ONH--) Example 21 Under cooling a-t-20C to-10C with stirring, a solutlon of 57.0 mg of methanol and 365 mg of tri-n-butylamine in 6 ml oE methylene chloride was added to a solu-tion of 376 mg of o-phenylene phosphorochloridate in 5 ml of methylene chloride and, then,at room temperature, the mi~ture was stirred Eor an hour -to make a me-thyl o-phenylene phosphate solu-tion~ On the other hand, 874 mg of 7 ~- (D~5-carbo~y-5-phthal--~2~ V~

i.midovaleramido)-3-hydroxymethyl--3-cephem-4-carboxylic acid ditri-n-butylamine salt was dissolved in 5 ml of methylene chloride and a solution of 158 mg of pyridine in 2 ml of methylene chloride was added at 5-O~C. Then, under cooling at -40C to 30C, the above-mentioned methyl o-phenylene phosphate solution was added and the mixture was stirred at -30C to -10C for 45 minutes and at 0-10C for 30 minutes.
The powdery precipitate was collected by filtration, washed with methylene chloride and dried to give 465 mg (yield 82.4%) of 7B-~D-5-carboxy-5-phthalimidovaleramido)-3-cephem 3-pyridlnium methyl-4-carboxylate.

I R ( K B r ) cm ~: 3 3 7 5, 3 0 2 0, 2 9 2 0, 1 7 72, 1 7 1 0 , 1 3 9 0 NMR ( D20+Na OD ): ~ 1.3 0~2.6 0 ( 6H, m, -CH2 CH2 CH2--) ~ 2.9 0 ~ 3.5 5 ( 2H, AB q, J= 1 8 H~, 2--CH2 ), 5.1 0 ( 1I-I, (1, J=5Hz, C6--H), 5.3 2 ~ 5.6 6 ( 2H, AB (1, J= 1 7 ~z, 3--CH2 ), 5. 6 3 ( l II , (1 . J = 5 Hz , C I--H ) , 7. 7 8 ( 4 H , s .
), 8.0 3~9.0 6 ( 5H, In,--~ ) Example 22 Under ice-cooling and stirring, a solution of 646 mg of 2,6-lutidine and 96.8 mg of methanol in 7 ml of methylene chloride was added to a solution of 528 mg of o-phenylene phosphorochloridite in 3 ml of methylene chloride and the reaction was allowed to proceed for 5 minutes to make a methyl o-phenylene phosphate solution~ To this solution was added 376 mg of isonicotinamide and the mixture was stirred for 10 minutes. Then, 923 mg of 7~-(D-S-carboxy-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid 2,6-lutidine salt was added and the mix-ture was stirred under ice-cooling for 2 hours and a-t room temperature for 5 hours.
The reaction mixture was allowed to stand a-t -20C to -10C
overnight. To this reaction mixture was added 15 ml of water and the mixture was adjusted to pH 7.0 with 1 N NaOH.
The aqueous layer was washed with methylene chloride, ad-justed to pH 6.0 and concentrated under reduced pressure.
The concentrate was subjected to Amberlite~ XAD-2 column chromatography, elution being carried out with water and water methanol. The ac-tive fractions were collected, con-centrated, and lyophilized to give 560 mg ~yield 63.1~)of 7~-(D-5~carboxy-5-phthalimidValeramido)-3-cephem-3-(4 carbamoyl-pyridinium )methyl-4-carboxylate sodium salt.

I R ( K B r ) cm~' : 3 3 5 0, 1 7 7 3, 1 7 0 8, 1 613, N M R ( D2 O ): ~ 1.3 0~ 2.6 0 ( 6 H, n~,--C H2 C H2 CH2--), 2.9 0 ~: 3.5 5 ( 2~-I, AB9, J= 1 8Hz, 2--CH2 ), 5.1 0 ( 1 H, d, J = 5 Hz, C6--H ), 5.3 4 ~
5.6 8 ( 2H, AB q, J = 1 4 HZ, 3--CH2 ), 5.6 0 ( lH, Cl , J = 5 Hz, C 7--H ) , 7. 7 9 ( '1 H, s , ~ ) , 8. 4 1 & 9. 1 4 ( 4 H, d ~1, --(~--CO~

xample 23 Under cooling at -50 to -40C and stirring,a solution of 0.455 g of tri-n-butylamine and 78.8 mg of methanol in methylene chloride was added to a solution of 0.469 g of o-phenylene phosphorochloridate in 5 ml of methylene chloride.
The reaction was allowed to proceed at room temperature for 20 minutes to make a methyl o-phenylene phosphate solution.
On the other hand, 0.339 g of tri-n-butylamine was added to a suspens:ion of 1.066 g of 7~ (D-5~carboxy~5-phthalimido-r ~
~f k valeramido)-3~hydroxymethyl-3-cephem 4-carboxylic acid ditri~n-butylamine sal-t and 0.322 g of ~,6-dimethyl-2-mercaptopyrimidine hydrochloride in 5 ml of methylene chloride to prepare a solution. Then, under cooling at -30C to -35C
and stirring, the above-mentioned methyl o-phenylene phosphate solution was added and the reactlon was allowed to proceed at 0-5C for an hour. ~o the reaction mixture was added 15 ml of water and the mixture was allowed to stand for phase separation. To the organic layer was added 15 ml of water and the mi~ture was adjusted to pH 6Ø After phase separation, 20 ml of water was added to the organic layer and the mix-ture was adjusted to pH 9.0 with 1 N NaOH. The aqueous layer was taken and washed twice with 5 ml portions of methylene chloride. To the aqueous layer was added 45 ml of methylene chloride-tetrahydrofuran (l:l) and the mixture was adjusted to pH 2.0 with 2 N HCl. After phase separation, the organic layer was ~ashed with saturated aqueous sodium chloride and dried over anhy~rous magnesium sulfGte. The solvent was then distilled off and ether was added to the residue. The powdery precipitate was collected by filtration and dried to give 0.630 g (yield 82.5%) of 7~-(D-5-carboxy-5-phthal-imidovaleramido)-3-(4,6-dimethylpyrimidin-2-yl)thiomethyl-3-cephem-~-carboxylic acid.
I R ( K B r ) cm~' : 3 29 0 .2 9 30 ,2 5 60 , 1 7 7 3 ,1 71 0 ,1 5 80 ,1 53 0 N M R ( ~6 - D M S O ) : ~ 1.3 0~ 2.~0 ( 6~, nl, -C H2C H2C H2 -) , 2.3 5 ( 6 H , S,CI~3x 2 ) ,3.55( 2 H ,2 -C M2 ) ,3.9 3-~ 4.3 6 ( 2 H ,~B~l, J= 1 4~1z.
-C~I2 ),~l.7 8 ( 1I-I~t ,J= 7~1z,-CI~ 1.99 ~
1 H ,~l ,J = 5~1z,C G - H ), 5~5 6 ( 1 H,(l,J =5 x 8 ~, C7 ~ ), 6 9 3 (1fl, s,~II ),7 8 ) , 8 2 2 ( lf~ J-= 8~ -C O Nl~

Example 24 1) In 5 ml of methylene chloride was dissolved 0.195 g of 5-mercapto-1-methyl-lH-tetrazole and the solution was cooled to -10C. Then, a solution o~ 0.268 g of o-phenylene phosphorochloridate i.n 5 ml of methylene chloride was added and~ under cooling at -20 to ~25C, a solution of 1.170 g of diphenylmethyl. 7~-t5-diphenylmethyloxycarbonyl-s-phtha imidovaleramido)-3-hydroxymethyl-3-cephem-4-car~oxilate in 8 ml of methylene chloride was added dropwise. The mixture was stirred at the same temperature for 20 minutes.
To the reaction mixture was added 10 ml of water and,then, the mixture was allowed to stand at room temperature for phase separation. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated and poured into 80 ml of ether. The powdery precipitate was colleceted by fil-tration and subjec-ted to silica gel column chromato-graphy (silica gel: 30 g, column height: 36 cm), elution ..
being carried out with ethyl acetate-n-hexane (4:1). The fractions were checked by TLC (developing solvent: the same as the above eluent) and the fractions (Rf: about 0.71~
containing the desired product were collected and concentrated.
To the concentrate was added ether to give diphenylmethyl 7~-(5-diphenylmethyloxycarbonyl-5-phthalimidovaleramido~-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate.
I R ( K B r ) cm~1: 3 3 5 O, 3 0 3 0, 2 9 3 0, 1 7 8 0 , 1 7 1 ~
NMR ( ~16--DM S O ): ~ l.3 0~2.4 0 ( 6I-1, m, --CII2CH2 CH2--), 3.6 8 ( 2H, bro;1(1 s, 2--CI-I2), 3.8 8 ( 3H, s,--N--CH3), 4.2~t ( 2H, I)ron(1 s, 3---CM2 ), ~1. 9 0~5.2 0 ( 21I, n1, C 6--l~f ~C: ~CH-), 5. 7 3 ( 1 1-I, (1 , J -- 5 (~: 8 1-1~ ), 6. 8 3 ~ 6. 9 0 ( 2 H, s, ---('OOC11~x2 ), 7.1 0~7.60 ( 2o~I"Il, ) C--x2 j, 7.9 1 ( ~II, s ,~ ), 8.87 ( 1 1~ "1, J - 8 ~ , - -C O1~ E~--) 2) In S ml oE methylene chloride were dissolved 0.182 g of 5-mercapto-1-methyl-1~l-tetrazoleand 0.~85 g of tri-n-butylamine and the solution was cooled to -10C.
A solution of 0.250 g of o-phenylene phosphorochloridate in S ml of methylene chloride was added and the mixture was cooled to -20 to -25C~ To this mixture was added 1.09 g of diphenylmethyl 7~-(5-diphenylmethyloxycarbonyl-5-phthal-imidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylate and the whole mixture was further treated in the same manner as described in 1) above to give the desired product, whose IR and NMR spectra were identical with those of the compound obtained in 1) Example 25 1) To 10 ml of ethyl acetate were added 0.540 g of 7~(2-thienylacetamido)-3-hydroxymethyl-3-cephem-4-carboxylic acid tri-n-butylamine salt and 0.175 g of 5-mercapto-1-methyl-lH
tetrazole and, under cooling at -20C and stirring, a solution of 0.370 g of methyl o-phenylene phosphorochloridate in 5 ml of ethyl acetate was added. The mixture was stirred under ice-cooling for 1.5 hours and 10 ml of water was added. After phase separation, 20 ml of water was added to the organic layer and the mixture was adjusted to pH 9Ø The aqueous layer was taken and washed with 5 ml of ethyl acetate. To the aqueous layer was added 20 ml o~ ethyl acetate and the mix-ture was adjusted to pH 2Ø After phase separation, the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodi~sulfate. The ethyl acetate was distilled off under reduced pressure and ether was added. The powdery precipitate was collected by filtration to give 0.380 g (yield 84.1%) of 7~-(2-thienylacetamido)-3-(l-methyl-lH-tetrazOl-5-yl)thiomethyl-3-cephem-4-carboxyIic acid. The IR and NMR spec-tra of this product were identical with those of the authentic sample.
2) Using 0.477 g of 7~-phenylace-tamido-3-hydro~y-methyl-3-cephem-~-carboxylic acid di-n-butylamine salt, the procedure of 1) above was repeated to give 0.361 g 88 ~ 6~

(yield 80.9%) of 7-phenylacetamido-3-(1-methyl-lH-te-trazol-S-yl)thiomethyl-3-cephem-4 carboxylic acid. The IR and NMR spectra of this product were identical with those of the authentic sample.
Example 26 To 180 mg of 5-mercapto-1-methyl-lH-tetrazole was added a solution of 271 mg of o-phenylene phosphorochloridite in 4 ml of methylene chloride, followed by addition of a solution of 157 mg of triethylamine in 3 ml of methylene chloride. Then, under cooling at -5C and stirring, 732 mg of 73-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylallline salt was added and the mixture was stirred at the same temperature for 5 minutes.
To the reaction mixture were added 10 ml of water and 7 ml of tetrahydrofuran and the mixture was adjusted to pH 2.
After phase separation, 20 ml or water was added to the organic layer and the mixture was adjusted to pH 7~0. The methylene chloride and tetrahydrofuran were distilled off under reduced pressure and 10 ml of methylene chloride was added. The mixture was adjusted to pH 9.0 with 1 N NaOH.
The aqueous layer was taken, washed with 10 ml of methylene chloride, and 20 ml of methylene chloride-tetrahydrofuran (1:1) added. The mixture was adjusted to pH 2.0 with 2 N
HCl. After phase separation, the organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. To the residue was added ether and the powdery precipitate was collected by filtration and dried to give 410 mg ~yield 65-7%) of 7~-~D-5-carboxy-5-phthalimidovaleramido)-3-~1-methyl-lH-tetrazol-5-yl)thlo-methyl-3-cephem-4-carboxylic acid. The IR and NMR spectra of this product were identical with those of the compound obtained in Example 1.
Example 27 (1) To a solution of 762 mg (~1 mM) of o-phenylene phosphorochloridate in 10 ml of methylene chloride was added 741 mg (4 mM) o~ tri-n-bu~ylamine and a solution o~

~$~

128 mg (4 m~) of methanol in 5 ml oE methylene chloride was added dropwise to make a methyl o-phenylene phosphate solution. On the other hand, 874 mg of 7~-(D-S-carbo~y-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt and 174 mg of 5-mercapto~1-methyl-lH-tetrazole were dissolved in 5 ml of methylene chloride and, under cooling at -15 to -10C, the solution was added dropwise to the above-mentioned methyl o-phenylene phosphate solution. The mixture was stirred at the same temperature for 40 minutes and the methylene chloride was distilled off under reduced pressure. The residue was dissolved in water-acetonitxile (3:2, v/v). The solutoin was assayed for 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(l-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid by high performance li~uid chromatography. The yield was 537 mg or 89.3%.
(2)-(18) In the reaction procedure described above in (1), 4 mM
of each hydroxy compound specifically given in Table 1 was employed in pIace of 128 mg of methanol for the preparation of a solution containing the corresponding o-phenylene phos-phorochloridate esterification product. Using this solution and following the above procedure (l), the reaction was carried out at a temperature of -15C to -10C and the reaction mixture was assayed. The reaction time and yield of 7~D-5-carboxy-5-ph-thalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid were as shown in Table 1.

~2~

TabLe 1 No. Hydroxy _om~Reaction time Yield (min.) (mg) (%) (2) CH30H 35 493 82.0 (3) CH30H 40 511 84.9 (4) C H OH 60 505 84.0 (5) C2H5H 120 507 84.3 (6) 3CC 2 84.9 (7) BrCH2CH2OH 20 509 84.6 (8) 3 7 140 531 88.3

(9) i-C3H70H 180 434 72.1

(10) BrCH2CH(Br)CH2OH 20 475 79.0

(11) n~C4H9H 150 493 82.0

(12) i-C4HgOH 150 502 83.5

(13) sec-C4HgOH 210 513 85~3

(14) ~ OH 270 505 83.9

(15) ~ OH 10 495 82.3 (L6) ~ OH 5 509 84.6 (17) CH2=CH-CH2OH40 498 82.8 (18) CH2=C(CH3)CH2OH 40 490 81.5 ~2~

Example 28 Under cooling at -10C to 0C, 7~1 mg of -tri-n-butyl-amine was added to a solution or 762 mg of o-phenylene phos-phorochloridate in 12 ml of methylene chloricle and, then, at room temperature, 236 mg of n-propylamine was added. The reaction was allowed to proceed at the same temperature for 10 minutes to make an 2-oxo-2-propylamino-1,3,2-benzodi-oxaphosphole solution. Then, under cooling at -15C to -10C, a solution of 874 mg of 7~-(D-5-carboxy-5-phthalimidovaler-amido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt and 174 mg of 5-mercapto-1-methyl-lH-te-trazole in 5 ml of methylene chloride was added dropwise to the above-mentioned solution. The reaction was allowed to pro~
ceed at the same temperature for 150 minutes and the methylene chloride was distilled off under reduced pressure. The residue was treated and assayed in the same manner as Example 27 (1). The yield of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid was 45~ mg (75.5%).
Example 29 (1) To 5.5 g of pyrocatechol were added 110 ml of methylene chloride and 15.2 g of triethylamine. Then, under stirring at 10-20C, 7.29 y of phosphorus oxychloride was added dropwise to the above solu-tion over 10 minutes. The reaction mix-ture was filtered in a nitrogen gas stream and washed with a small amount of methylene chloride to give 124 ml of a substantially clear filtrate.
(2) Under cooling at -10C to 0C and stirring, 9.4 ml of the filtrate as obtained in (1) was added dropwise to a solution of 7~D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt ana 168 m~ of 5-mercapto-1-methyl-lH-tetrazole in 6 ml of me-thylene chloride and the reaction was allowed to proceed at the same temperature for 2 hours. The reac-tion mixture was left standing at 0-5C overnight. Then, under ice-cooling, 10 ml of 2 N ~ICl was added and the mix-ture was adjusted to pil2. To this mixture was added 18 ml of ~6~
- ~2 -tetrahydrofuran-water (1:1, v/v), and the insoluble matter was fi.ltered off and washed wi-th 2 ml of the above tetra-hydrofuran-water mixture. The filtrate and washings were combined and allowed to stand for phase separation. The organic layer was washed with 10 ml of water and the aqueous layer was extracted with 2 ml of methylene chloride.
The extract and the previous organic layer were combined, dried over anhydrous magnesium sulfate, conoentrated to about 5 ml, and poured into 70 ml of ether. The powdery precipitate was collected by filtration, washed with ether and dried to give 514 mg (yield 71.0%) of 7~-(D-5-carboxy-5-phthal-imidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid, the i~ and IR spectra of wnich were identical with those of the authentic sample.
Example 30 In 6 ml of methylene chloride were dissolved 849 mg of 7~-(D-5-carboxy-5 phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 194 mg c>~ ~-2-mercaptobenzothiazole and, under stirring at -10C to 0C, 9.4 ml of the filtrate as obtained in Example 29 (1) was added dropwise.
The reaction was allowed to proceed at room temperature for 40 minutes and the reaction mixture was left standing at 0-5C overnight. This reaction mixture was further treated in the same manner as Example 29 (2) to give 467 mg (yield 59.6~) of 7~D-5-carboxy-5-phthalimidovaleramido)-3-[(benzothiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid.
The IR and NMR spectra of this product were identical with those of the compound obtained in Example 12.
Example 31 (1) To 3.64 g of ethyl 3,4-dihydroxybenzoate were added 44 ml of methylene chloride and 6.06 g of triethyl-amine. Then, at 10-20C, 2.92 g o~ phosphorus oxychloride was addecl dror,wise to the above solution over 10 minutes. Th~ mix-ture was filtered in a nitrogen gas stream and -the residue on -the filter was washed wi-th 20 ml of me-thylene chloride. The filtrate and washings were ~ it~O~

combined and the solution-thusob-tained amounted to 62 ml.
(2) To 168 mg of 5~mercapto-1-methyl-lH-tetrazole was added 17.6 ml of the solution as obtained in (1). Then, under cooling at 0-5C and stirring, 849 rng of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt was added and the reaction was allowed to proceed at the same temperature for 2 hours. To the reaction mixture were added 10 ml of water and lb ml of methylene chloride and the mixture was adjusted to pH 2. After phase separation, the organic layer was washed with 5 ml of water. To the organic layer was added 20 ml of water and the mixture was adjusted to pH 8.5 with 1 N NaOH and allowed to stand for phase separation. The organic layer was washed with 10 ml of water. The aqueous layers were then combined and washed twice with 5 ml portions of methylene chloride. To the aqueous layer were added 15 ml of methylene chloride and 15 ml of tetra-hydrofuran and the mixture was adjusted to pH 2 with 4 N
HCl and allowed to stand for phase separation. The aqueous layer was washed with 10 ml of methylene chloride-tetrahydrofuran (1:1, v/v). The organic layers were com-bined, washed twice with 10 ml portions of saturated aqueous sodium chloride and dried over anhydrous ~agnesium sulfate.
The solventwas then distilled off and ether was added to the residue. The powdery precipitate was collected by filtration, washed with ether and dried to give 510 mg (yield 70.5%) of 7~-(D-5-carboxy-S-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR spectrum of this product was identical with that of the authentic sample.
Example 32 (1) To 3.27 g of 2,3-dihydroxynaphthalene were added 44 ml of methylene chloride and 6.06 g of triethylamine and, unde:r cooling at 10-20C and s-tirring, 2.92 g of phos-phorus oxychloride was added dropwise to -the resul-tant solution. The mixture was filtered in a nitrogen gas stream _ 94 _ '~2~

and the residue on the fil-ter was washed wi-th 20 ml of methylene chloride. The Eiltrate and washings were comhinecl and the solution thus obtained amounted to 56 ml.
(2) To 168 m~ of 5-mercapto-1--methyl-lH-te-trazole T~as added 15.9 ml of the solution as obtained in (1). To the resultant solution was added 849 mg of 7B-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt under coolin~ a-t 0-5C and stirring.
The reaction was allowed to proceed at the same temperature for 2 hours and then at room temperature for 5 hours. The reaction mixture was left standing at 0-5C overnight and further treated in the same manner as Example 31 (2) to give 7~D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR spectrum of this product was identical with that of the authentic sample.
Example 33 (1) To a mixture of ~ ml of methylene chloride and 6.06 g of triethylamine was added 2.20 g of pyrocatechol and, under ice-cooling, 2.61 g of phosphorus trichloride was added portionwise to the resultant solution. The mixture was further treated in the same manner as Example 32 (1) and the solution thus obtained amounted to 52 ml.
(2) Using 14.8 ml of the solution as ob-tained in (1) and followin~ the procedure of Example 32 (2), the reaction was carried out for 30 minutes. The reaction mixture was further treated in the same manner as Example 32 (2) to give 433 mg (60.0%) of 7~-(D-5-carboxy-5-phthalimidovaler-amido)-3-(1-methyl lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR spectra were identical with those of the authen-tic sample.
Example 34 (1) In a mix-ture oE 44 ml of methylene chloride and 10.1 g of triethylamine was dissolved 2.20 ~ o-f pyrocatechol and, under ice-cooling and stirrin~, 3.96 g of phosphorus pentachloride was added portlonwise. The mixture was further 9 5 ~2~3 03(~

treated in the same manner as Example 32 (1) and the solution thus obtained amounted to 48 ml.
(2) Using 13.7 ml of the solution as obtained in (1), the procedure of Example 31 (2) was repeated to give 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5~yl)thiomethyl-3-cephem-4-carboxylic acid. The IR spectrum of this product was identical with tha-t of the authentic sample.
Example 35 ~ 1) In a mixture of 40 ml of methylene chloride and 7.76 g of diisobutylamine was dissolved 2.20 g of pyro-catechol and, under ice-cooling, 2.92 g of phosphorus oxychloride was added portionwise over 10 minutes. The mixture was stirred at room temperature for 10 minutes and the red-brown solution thus obtained amounted to 50 ml.
(2) Using 14.2 ml of the reaction mixture as obtained in (1) and following the procedure of Example 31 (2), the reaction was carried out under ice-cooling fo 50 minutes and then at room temperature for 2.5 hours. The reaction mixture was further trea-ted in the same manner as Example 31 (2) to give 471 mg (65.2%) of 7~-(D-5-carboxy-5-phthalimido-valeramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The NMR specturm of this product was iden-tical with that of the authentic sample.
Example 36 (1) In a mixture of 40 ml of methylene chloride and 6.06 g of triethylamine was dissolved 2.20 g of pyrocatechol.
Then, under ice-cooling, 2.61 g of phosphorus trichloride was added por-tionwise and 4 ml of methylene chloride was further added. The mixture was stirred at room tempera-ture for 10 minutes and cooled again to 5C. On addition of 0.64 y of methanol, the temperature of the solution increased to 18C. The reaction mixture was stirred at room tempera-ture Eor 10 minutes and filtered in a nitrogen gas stream.
The residue on the filter was washed with methylene chloride and the filtrate and washings were combined. The solution ~L2~0 thus obtained amounted to 55 ml..
(2) To 168 mg of 5--mercapto-1-methyl-lH-tetrazole was added 15.6 ml of the solution as obtai.ned in (1). To the resultant solution was added 849 mg of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3~cephem-4-carboxylic acid ditriethylamine salt under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 2.0 hours. The reaction mixture was left standing at 0-5C overni~ht and the reaction was allowed to proceed at room temperature for ~ hours. The reaction mixture was further treated in the same manner as Example 31 (2) to give 482 mg (66.8%) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1 methyl-lH-tetrazol-5-yl)thio-methyl-3-cephem-~-carboxylic acid. The IR spectrum of this product was identical with that of the authentic sample.
Example 37 In 10 ml of methylene chloride were dissol~ed 450 mg of 5-mercapto-1-methyl-lH-tetrazole and 437 mg of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-carboxylic acid ditributylamine salt and, under cooling at -25C to -20C, 0.5 ml of 2,2-dihydro-4,5-dimethyl-2,2,2-trimethoxy l,3,2-dioxaphosphole was added dropwise over 5 minutes. The mixture was stirred at the same temperature for 5 minutes and 15 ml of water was added. After phase separation, the aqueous layer was washed with 5 ml of methylene chloride and the organic layers were combined.
Thenr 15 ml of water was added and the mixture was adjusted to pH 8.5 with 1 N NaOH and allowed to stand for phase separation. The aqueous layer was washed with 5 ml of methylene chloride,and 10 ml of tetrahydrofuran and 15 ml of methylene chloride were added. The mixture was adjusted to pH 2.8 wi-th 2 N HCl and allowed to stand for phase separati.on. The organic layer was washed with 5 ml of water and 5 ml of satura-ted aqueous sodium chloride in that order and dried ove:r anhydrous ma~nesium sulfate. The solvellt was then distilled off and a small amoun-t of acetone was - 97 ~ V ~

to the residue. To the resultant solution was added ether and the powdery precipltate was collec-ted by filtration, washed with ether and dried to give 215 mg (71.5%) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1 methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR
spectra of this product were identical with those of the authentic sample. ' Example 38 (1) To a solution of 1.86 g of triphenyl phosphite in 12 ml of methylene chloride was added a solution of 1.476 g of o-chloranil in 10 ml of methylene chloride at room temperature. The thus-obtained solution of 2,2-dihydro-4,5,6,7-tetrachloro-2,2,2-triphenoxy-1,3,2-benzodioxaphos-phole in methylene chloride amounted to 23 ml.
(2) Using 3.0 ml of the solution as obtained in (1) in place of 0.5 ml of 2,2-dihydro-4,5-dimethyl-2,2,2-tri-methoxy~l,3,2-dioxaphosphole, -the procedure of Example 37 was repeated to give 220 mg (73.1~) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid. The IR and NMR spectra of this product were identical with those of the authentic sample.
Example 39 In 15 ml of acetonitrile was suspended 0.173 g of 1-(2-dimethylaminoethyl)-5-mercap-to-lH-tetrazole, followed by addition o~ 0.152 g of triethylamine. Then, 0.874 g of 7~~(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt was added and the resultant solution was cooled to -25C.
Under cooling at -25C to 20C, a solution of 0 744 g of methyl o-phenylene phosphate in 5 ml of methylene chloride was added dropwise and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture was added 5 ml of water and the mix-ture was concentrated under reduced pressure. The residue was diluted to exac-tly 50 ml with water-acetonitrile (3:2, v/v) and the solution was assayed for 7~-(D-S-carboxy-5-phthalimidovaleramido)-3-[1-(2-dimethylaminoethyl)-1~-tetrazol-5-yl]thiome~hyl]-3-cephem-4-carboxylic acid by high performance liquid chromato-graphy. The yield was 0.593 g (90.0%). To a 45.0 ml portion of the above dilution (50 ml) was added 4.0 ml of 1 N HCl and the mixture was concentrated and lyophilized. The resultant syrupy solid was dissolved in ethanol, followed by addition of ether. The powdery precipitate was collected by filtration, washed with ether and dried to give 0.54 g of the hydrochloride of the above-indicated desired compound.
The NMR spectrum of -this product was identical with that of the compound obtained in Example 2.
Example 40 In a mixture of 4 ml of formamide and 6 ml of aceto-nitrile were dissolved 1.75 g of 7~D-5-carboxy-5-phthal-imidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-but~lamine salt and 0.293 g of isonicotinamide and the solution was cooled to -20C. Then, under stirring and ~oling at -20C to -15C, a solution of 0.74 g of methyl o-phenylene phosphate in 2 ml of methylene chloride was added dropwise and the reaction was allowed to proceed at the same tempera-ture for 30 minutes. The reaction mixture was warmed to 10C
and 50 ml of acetonitrile and 50 ml of ether were added.
The powdery precipitate was collec-ted by filtration, washed with acetonitrile and dried to give 1~04 g (yield 85.5%) of 7~D-5-carboxy-5-phthalimidovaleramido)-3-cephem-3-(4-carbamoylpyridinium)methyl-4-carboxylate.
NM~ (D2O + K2CO3): Identical with that of the compound obtained in Example 22 Example 41 Using a solution of 0.93 g of 2-phenyl-1,3,2-benzodi-oxaphosphole-2-oxide in 4 ml of methylene chloride in place of 0.74 g of methyl o-phenylene phosphate and following the procedure of ~xample 5, -the reaction was carried out for 10 minutes. The reac-tion mixture was Eurther treated in the same manner as Example 5 to c3ive 1.12 (yield 93.1~) ~z~
_ 99 _ of the desired product. The IR and NMR spectra of this product were iden-tic~ with those of the comFound obtained in Example 1.
Example 42 In 5 ml of water was dissolved 0.670 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid dipotassium salt-5H20, Eollowed by addition of 5 ml of tetrahydrofuran. The mixture was adjusted to pH 2.5 with 4 N HCl at 5C or below and :L0 ml of methylene chloride was added. After phase separation, the aqueous layer was extracted with 2.5 ml of tetrahydrofuran and 5 ml of methylene chloride and the organic layers were combined, dried over anhydrous magnesium sulfate and conoentrated under reduoed pressure~ To the concentrate were added 10 ml of tetrahydro-furan and 50 ml of methylene chloride and the mixture was concentrated. The residue was dissolved in 10 ml of tetra-hydrofuran, followed by addition of 0.174 g of 5-mercapto-l-methyl-lH--tetrazole. Then, at -15C to -10C, a solution of 0.744 g of methyl o-phenylene phosphate in 4 ml of tetra-hydrofuran was added and the mixture was stirred at the same temperature for 50 minutes and concentrated under reduced pressure. The residue was dissolved in a small amount of tetrahydrofuran and poured into 100 ml of ether.
The powdery precipitate was collected by fil-tration, washed with ether and dried to give 0.560 g (93.1~) of7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH-te-trazol-5-yl)thiomethyl 3-cephem-4-carboxylic acid. The NMR and IR spectra of this product were identical with those of the compound obtained in Example 1.
Example ~3 Using a solution of 0.65 g of 2-oxo-4,5-dimethyl-2,2-dihydro-2-methoxy-1,3,2-dioxaphosphole in 4 ml of methylene chloride in place of 0.74 g of methyl o-phenylene phosphate and following the procedure of Example 5, the reaction was carried out for 30 minutes. The reaction mixture was fur-ther treated in the same manner as Example 5 to give 0.95 g (79.0%) of -the desirecl product. The IR and NMR spectra of this procluct were identical with those of the compound ob-tained in Example 1.

Example 44 (1) Water (24 ml) was added to 8.78 g of deacetylcephalo-sporin C sodiu~ salt (purity; 90-1%) for dissolution of the later, followed addition of 8 ml of tetrahydrofuran (THF). To the mixture, there were added dropwise alternately 40% aqueous potassium carbonate solution and 3.76 g of phenyl chlorocarbonate while maintaining the mixture at pH 9.5-10.0 and at 15-20C.
After the addition, the mixture was stirred for 10 minutes, then 40 ml of THF was added, and concentrated hydrochloric acid was added dropwise with cooling at 3-5C until pH 2.5.
Following addition of 65 ml of methylene chloride, the whole mixture was allowed to stand for phase separation. Then the aqueous layer was further extracted with a mixture of 17 ml of THF and 34 ml of methylene chloride. The organic layers o~
101 24205-~9lD

were combined and dried over anhydrous magnesium sulfate and, following addition of 8.16 g of tri-n-butylamine, they were concentra-ted to dryness under reduced pressure. Methylene chloride was added to the residue and the solution was again evaporated to dryness. The residue was dissolved in methylene chloride and the solution was dropped into ether. The resulting powdery precipitate was collected by filtration to give 16.2 g of ditri-n-butylamine salt of 7~ -(D-5-carboxy-5-phenoxycarbonyl-aminovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm ; 3250, 2930, 1760, 1735, 1660, 1~00 NMR (d6-DMSO):~ 0.7~ 2.4 and 2.6 3.1 (m, (CH3CH2CH2CH2~3N & -(cH~)3co-) 3.45 (br, ~-CH2) r 3.95 (m, ,CH-), 4.15 (br, 3-CH2), 4.94 (d, J = 5Hz, C6-H), 5.52 (q, J = 5x8Hz, C7-H), 6.9~ 7.6(m, ~ ), 7.7~ 8.9(m, -O-CONH-, C-CON~, -COOH) (2) 7 ~-(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditri-n-butylamine salt (8.64 g) was dissolved in 100 ml of methylene chloride, 1.74 g of 5-mercapto-1-methyl-lH-tetrazole was added to and dissolved in the solution. Thereto was added dropwise wi-th cooling at -20~ to 25C a solution of 3.72 g of methyl o-phenylene phosphate in 10 ml of methylene chloride over 5 minutes. Thereafter, the whole mixture was stirred at 0 to -5C for 60 minutes. Cold water (80 ml) was added to the reaction mixture, the resulting mixture was adjusted to pH 8.5 with 1 N NaOH and, aEter phase separation, the aqueous layer was waslled with two 20-ml portions of methylene chlorlde. THF (50 ml) and 50 ml of methylene chloride were added to the aqueous layer, the mixture was adjusted to pH 1.5 by adding concentrated hydrochloric acid dropwise and, aEter phase separation, the aqueous layer was further extracted with a mixture of 15 ml of THF and 15 ml of methylene chlorideO The organic layers were combined, dried over anhydrous magnasium sulfate and concentrated until only a small amount of the solvent was remaining. The residue was added dropwise to 300 ml of ether and the powdery precipitate was collected by filtration, washed with ether and dried in vacuo to give 5.41 g (91.4% yield) of 7~ -(D-5-carboxy-5-phenoxycarbonylaminovaleramido)-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm ; 3270, 3020, 2920, 1780, 1725, 1530 NMR (d6-DMSO); ~ 1.4~ 2.4 (6H, m, -(CH2)3-), 3.69 (2H, br, 2-CH2), 3.94 (3H, s, N-CH3), 4.30 (2H, br, 3-CH2), 5.05 (lH, d, J = 5Hz, C6-H), 5.65 (lH, q, J = 5x8Hz, C7-H), 6.9 ~7.6 (SH, mr ~ ), 8.03 (lH, d~ J = 8Hz, -OCONH-)~
8.83 (lH, d, J = 8Hz, -CONH-) Example 45 (1) Water (25 ml) was added to 10.95 g oE deacetylcephalosporin C
sodium salt (purity: 90.1%) for dissolution of the latter, followed by addition of 7 ml of acetonitrile. 40% Aqueous potassium carbonate solution and 3.38 g of ethyl chlorocarbonate 103 ~6~ 2~205-491D

were added dropwise and alternately to the mixture with stirring and cooling at 15-70DC and maintalning the pH at 9.5-10. The reaction mixture was concentrated under reduced pressure, whereby the acetonitrile was distilled ofE. The residue was cooled to 0-5C and adjusted to pH 2.5 with concentrated hydrochloric acid.
The resulting precipitate was collected by filtra~ion, washed with cold water and then suspended in 200 ml of water. To the suspension was added 8 ml of triethylamine with stirring until dissolution. The mixture was then concentrated under reduced pressure. The residue was lyophilized and dried in vacuo in a desiccator containing phosphoric anhydride to give 15.2 g cf 7~ -(D-5-carboxy-5-ethoxycarbonylaminovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt.
IR (KBr) cm ; 3550 ~ 3150, 2930, 2840, 2670, 2480, 1762, 1710 ~1660, 1600, 1535 NMR (D2O): ~ 1.14 (3H, t, J = 7Hz, -CH3), 1.26 (18H, t, J = 7Hz, CH3x6), 1.5~-1.9 (4H, m, -CH2CH2-), 2.2~2.5 (2H, m, -CH2CO-), 3.19 (12H, q, J = 7Hz, CH2 x 6), 3.54 (2H, ABq, 2-CH2), 4.08 (2H, ~, J = 7Hz, -CO2CH2-), 4.26 (2H, s, 3-CH2), 5.08 (lH, d, J = 5Hz, C6-H), 5.59 (lH, d, J = 5Hz, C7-H) (2) Methylene chloride (15 ml), 5 ml of acetonitrile, 0.35 g of 5-mercapto-1-methyl-lH-tetrazole and 0.2 ml of tri-n-butylamine were added to 1.30 g of 7~ -(D-5-carboxy-5-ethoxycarbonyl-aminovaleramido) 3-hydroxymethyl-3-cephem-4-carboxylic acid ~1 104 ~ ~ ~O ~ O~ 24205-491D

ditrlethylamine salt. The resulting solution was cooled to -15C
to -10C and thereto was added a solution of 0.74 g of methyl o-phenylene phosphate in 2 ml of methylene chloride dropwise with stirring over 5 minutes. Thereafter, the mixture was stirred at 0-5C for 30 minutes and then concentrated under reduced pressure.
To the residue were added 20 ml of methylene chloride and 15 ml of water, the mixture was cooled to 0-5C and adjusted to pH 9.0 with 1 N NaOH and, after separation, the organic layer was washed with 3 ml of water. The aqueous layer and extract were combined and washed with 5 ml of methylene chloride. To the thus-obtained aqueous layer were added 10 ml of tetrahydrofuran and 20 ml of methylene chloride. The mixture was cooled to 0-5C and adjusted to pH 2 with 2 N HCl. The organic layer was separated, and 5 ml of tetrahydrofuran and ]0 ml of methylene chloride were added to the aqueous layer and the resulting mixture was allowed to stand for phase separation. The organic layers were combined~ dried over anhydrous magnesium sulfate and concentrated. Addition of ether to the residue and collection of the resulting powder by filtration gave 0.97 g (89.2% yield~ of 7~ -(D-5~carboxy-5-ethoxy-carbonylaminovaleramido)-3~ methyl-lH tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.

~;~6~

IR (KBr) cm ; 3350, 2950, 1775, 1710, 1530, NMR (d6-DMSO),~ 1.18 (3H, t, J = 7Hz, -CH3), 1-4 ~2.4 (6H! m, -CH2CH2CH2-), 3.93 (3H, s, N-CH3)~ 3 68 (2H, ABq~ 2-CH2), 3.97 (2H, q, J = 7Hz, -O-CH2-), 4.29 (2H, ABq, 3-CH2), 5.06 (lH, d, J - 5Hz, C6-H), 5.66 (lH, q, J =
5x8Hz, C7-H), 7.25 (lH, d, J = 8Hz, -OCONH~) 8.79 (lH, d, J = 8Hz, -CONH-).

Example 46 . ~
(1) In 20 ml of methylene chloride were dlssolved 3.53 ~ oE
7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditrie-thylamine salt and 0.87 g of 5-mercapto-1-methyl-lH-tetrazole. To this solution was added dropwise a solution of 1.50 y of ethyl o-phenylene phosphate in 3.8 ml of methylene chloride under stirring and cooling at -25C to ~20C and the mi~ture was stirred for 1 hour at -5C to 0C. To the reaction mixture were added 50 ml of water, 20 ml of THF and 20 ml of methylene chloride and the mixture was ad]usted to pH2 with 4N-hydrochloric acid. After phase separation, the aqueous layer was extracted with a mixture of 20 ml of methylene chloride and 10 ml of THF.
The organic layer and the extract were combined~ washed wi-th 20 ml of wa-ter, dried with anhydrous magne6ium sulfate/
concentrated under reduced pressure and the residue was dissolved-in ~0 ml of acetone. The solution was added dropwise into 300 ml of ether and the resultant precipitate was collected by filtration, washed with ether and dried in vacuo to give 2.86 g (yield 95.1 %) of 7~-(D-5-carboxy-5-phthalimidovaleramldo)-3-(l~methyl-lH-te-trazol-5-yl)thio-methyl-3-cephem-4-carboxylic acid. The IR and NMR spectra of this product were identical with those of the compound obtained in Example 1.
(2) In the above (1), methylene chloride solu-tion of ethyl o-phenylene phosphate was added dropwise at 23-27C and the mixture was stirred for about 39C for 5 minutes, cooled to ~ 107 ~

0C and treated thereaEter in the same method as descrlbed in the above (1) to give 2.72 g (yield 90.4 %) of a white powder. IR spectrum of this product was identical with that of the compound obtained in the above (1).
Example 47 (1) To the mixture of 1.10 g of pyrogallol and 1.30 g of methyl phosphorodichloridate was added 8 ml of methylene chloride. To the mixture was added dropwise 1.86 g of triethylamine under stirring and cooling at -35C to -30C, followed by stirring at 0-5C for 2 hours to afford the reaction mixture containing 4-hydroxy-2-methoxy-2-oxo-1,3,2-benzodioxaphosphole.
(2) In 20 ml of methylene chloride were dissolved 3.53 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 0.87 g of 5-mercapto-1-methyl-lH-tetrazole. The whole reaction mixture ob*ained in (1) was added to the solution under stirring and cooling at -25C to -20C, and the reaction mixture adhering to the reaction vessel was washed with 6 ml of methylene chloride and the washing was added.
I'he resulting suspension was stirred for 1 hour at -5-0C
and the reaction mixture was treated in the same method as in Example 46-(1) to give ~.76 g (91.8 %) of 73-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-methyl-lH--te-trazol-5-yl) thlomethyl-3-cephem-4-carboxylic acid. This product was identified by IR spectrum.

~ - 108 - ~2~0~4 (3) Using the reaction mixture of 5-ethoxycarbonyl-2-methoxy-2-oxo-1,3,2-benzodioxaphosphole obtained by the same procedure as (1) except using 1.59 g of ethyl 3,4-dihydroxy-benzoate in place of of pyrogallol, the same procedure as (2) was perfo~med to give 2.85 g (yield 94.7%) of the same product as obtained in (21. This product was identified by IR
spectrum.

- 109 - ~2~

~4) Using the reaction mixture of 2-methoxy-5-methyl-2-oxo-l,3,2-benzodioxaphosphole obtained by the same procedure as (l) except using ].09 g of 3,4-dihydroxytoluene in place of pyrogallol, the same procedure as (2) was repeated to give 2.83 g (yield 94.1 %) of the product. IR spectrum of this product was identical with that of the compound obtained in (2).
Example 48 To the mixture of 87 mg of 5-mercapto-l-methyl-lH-tetrazole and 216 mg of sodium 7~-[2-(2-aminothiazol-4-yl)-2-(syn~-methoxyiminoacetamido~-3-hydroxymethyl-3-cephem-4-carboxylate were added 1 ml of ~ormamide and 1 ml of aceto-nitrile and the mixture was stirred to obtain a clear solution.
To this solution was added a solution of 280 mg of methyl o-phenylene phospha-te in 0.75ml ofmethylene chloride under stirring and cooling on an ice bath and the mixture was stirred for 0.5 hour under cooling with ice bath. After addition of 1 ml of cold water, the reaction mixture was concentrated under reduced pressure. To the residual solution was added 2 ml of water and the pH of the solution was adjusted to 2.5.
The resulting precipitate was collected by filtration, washed with 1 ml of cold water and dried in vacuo to give 210 mg (yield 82.6 90) of 7~-[2-(2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamido]-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-9-carboxy1ic acid.
NMR (DMSO-d6)~: 3.67 (211, br, 2-CE12) 3.83, 3.~3 (6H, t~o singlets~ N-C113, O-C~13), 9.27 (2H, br, 3-CIi2), 5.09 (11-l, d, J=51-1z, C6-1l), 5.76 (lH, q, J=5x8~1z, C7-H), 6.73 (11l, s, S~-H),~.55 (11-1, d, J=8Hz, CONII) - llo ~2~0~

Example 49 . .
To the mixture of 230 mg of 7~-amino-3-hydroxymethyl-3-cephem-4-carboxylic acidr 174 mg of 5-mercapto-1-methyl-lH-tetrazole, 4 ml of formamide and 1 ml of acetonitrile was added 253 mg of triethylamine under stirring and cooling with ice bath. To the resulting solution were added a solution of 650 mg of methyl o-phenylene phosphate in 2 ml of methylene chloride and 5 ml of acetonitrile under stirring and cooling at -10C to 0C, followed by stirring for 0.5 hour at 0C to 5C.
The resulting precipitate was collected by filtration, washed with 5 ml of acetonitrile and suspended in a mixed solution of 6 ml of water and 2 ml of acetonitrile. To this suspension was added about 0.1 ml of 35 % hydrochloric acid to obtain a clear solution. ~fter adjusting the pH of the solution to 4 by addition of 25 % ammonia-water under cooling with ice bath, the resulting crystals were collected by filtration, washed with 2 ml of cold water and dried in vacuo to give 280 mg (yield 85.3 %) of 7~-amino-3-(1-methyl-lH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 1790, 1615, 1535, 1410 NMR (D2O + CF3COOD)~: 3.71 (2EE, s, 2-CH2), 3.9~ (3H, s, N-CH3), 4.22 (2H, s, 3-CH2), 5.06 (lH, d, J=5Hz, C6-H), 5.17 (lH, d, J=5Hz, C7-H) Exrample 50 ____ To the mixture of 0.954 g of 7~-(D-5-carboxy-5-benzamido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid and 0.244 g of l-methyl pyrrole were added 2 ml of formamide and it3~

4 ml of acetonitrile. To the resulting solution was added a solution of 0.744 g of methyl o-phenylene phosphate in 2 ml of methylene chloride under stirring and cooling at -5-0C
and the mixture was stirred for 0.5 hour at -5-0C. To the reaction mixture were added 24 ml of methylene chloride, 12 ml of THF and 20 ml of water and the pH was adjusted to 2 by 4N-hydrochloric acid. After phase separation, the aqueous layer was extracted with 15 ml of methylene chloride-~HF (2:1).
The organic layer and the extract were combined and treated by the similar method as described in example 46-(1) to give 0.944 g (yield 87.3 %) of 7~-(D-5-carboxy-5 benzamidovaleramido)-3-(1-methylpyrrol-2-yl)methyl-3-cephem-4-carboxylic acid.
IR (KBr) cm : 1770, 1725, 1645, 1530 NMR (D2O + NaHCO3)~: 1.5-2.7 (6H, m, -(CH2)3-), 2,80, 3.16 (2H, ~Bq, J=18Hz, 2-CH2), 3.44, 3.90 (2H, ABq, J=14Hz, 3-CH2), 3.46 (3H, s, N-CH3), 4.42 (lH, m, ~CH-), 4.96 (lH, d, J=5Hz, C6-H), 5;53 (lH d, J=5Hz, C7-H), 5.8-6.2, 6.6-6.8 (3H, m, ~ ), 7.2-8.0 (5H, m, ~ ) Example 51 (1) To the mixture of 0.430 g of 2-methyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-as-triazine, 4 ml of formamide and 4 ml of-acetonitrile was added 0.416 ml of triethylamine. To the resulting solution was added 1.15 g of dipotassium salt of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid. To the mi~ture was added a solution of 1.12 g of methyl o-phenylenephosphate in 3 ml of methylene chloride under stirring and cooling at -20C to -15C followed by stirrin~ for 0.5 hour at 0-5C. The reaction mixture was concentrated under reduced pressure and 80 ml of cold water was added to the residual solution. The resulting precipitate was collected by filtration, washed with 10 ml of cold water and dried in vacuo to give 1.14 g (yield 90.7%) of 7~-(D-5-carboxy-5-phtalimidovaleramido)-3-(2,5-dihydro-2-methyl-5-oxo-as~triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid.
IR ~KBr) cm 1 1775, 1715, 1645 NMR (D2O + NaOD)~: 1.3-2.6 (6H, m, -(CEl2)3-), 3.04, 3.60 (2H, ABq, J=18Hz, 2-CH2), 3.86 (3H, s, N-CH3), 4.02, 4.39 (2H, ABq, J=13Hz, 3-CH2), 4.99 (lH, d, J=
5Hz, C6-H), 5,55 (lH, d, J=5Hz, C7-H), 7.75 (lH, s, triazin-H), 7.80 (4H, s, ~ ) (2) Using 0.384 g of 2-thiouracil in place of triazine the same procedure as in (1) afforded 1.10 g (yield 89.6 ~) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(4-hydroxypyrimi-din-2-yl)thiomethyl-3-cephem-4 carboxylic acid.
IR (KBr) cm 1 1770, 1710, 1530 NMR (D2O ~ NaOD)~: 1.3-2.6 (6H, m, -(CH2)3-), 3.02, 3.50 (2H, ABq, J=18Hz, 2-CH2), 3.97, 4.33 (2H, ABq, J=13Hz, 3-CH2), 5.01 (lH, d, J-5Hz, C6-H), 5.54 (lH, N H
d~ J=SHz, C7-H), 6.23, 7.84 (2H, dd, J=7Hz, -~7.82 (4H, s, ~ ) Example 52 -To the mixture oE 0.195 g of 2-mercaptobenzimidazole and 0.580 g of dipotassium salt of 7~-(D-5-carboYy-5-phthalimidovaleramido) -3-hydroxymethyl-3-cephem-4-carboxylic L2~0~

acid were added 2 ml of formamide and 2 ml of acetonitrile.
To the resulting solution was added a solution of 0.558 g of methyl O-phenylene phosphate in 1.5 ml of methylene chloride was added under stirring and cooling at -10C to -5C, followed by stirring at 0-5C for 1 hour. The reaction mixture was treated in a similar manner as described in Example 51-(1) to give 0.560 g (yield 88.1 %) of 7~-tD 5-carboxy-5~phthalimidovaleramido)-3-(benzimidazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 1785, 1770, 1710, 1640, 1390 NMR (D2O-NaHCO3)~: 1.3-2.6 (6H, m, -(CH2)3-), 2.96 3~23 (2H, ABq, J=18Hz, 2-CH2), 3.84, 4.40 (2H, ABq, J=13Hz, 3-CH2).
4~57 (lH, m, _CH-), 4.92 (lH, d, J=5Hz, C6-H), 5.52 (lH, d, J=5Hz, C7-H), 6.9-7.8 (8H, m, Example 53 (1) To the mixture of 1.637 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 0.53 g of 2-mercaptobenzoic acid were added 14 ml of methylene chloride and 7 ml of T~F.
To the resulting solution was added a solution of 0.863 g of methyl o-phenylene phosphate in 2.3 ml of methylene chloride under stirring and cooling at -20C to -15C, followed by stirring at 0-5C for 0.5 hour. The reaction mixture was treated in a similar method to Example 46-(1) to give 1.36 g (yield 91.7 %) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(2-carboxyphenyl)thiomethyl-3-cephem-4-carboxylic acid.

~z~

IR (KBr)cm : 1770, 1710, 1535, 1465, 1390 NMR (DMSO-d6)~: 1.2-2.4 (6H, m, -(CH2)3-), 3.55 (2H, br, 2-CH2), 4.06 (2H, br, 3-CM2), 4.75 (lH, t, J=7Hz, `CH-), 5.06 (lH, d, J=5Hz, C6-H) t 5.61 (lH, q, J=5 & 8H2, C7-H), 7.0-7O7 (4H, m, ~-coo), 7.89 (4H, m, ~ _), 8.79 (lH, d, J=8Hz, CONH) (2) Using 0.443 g of 2-mercaptopyridine N-oxide in place of 2-mercaptobenzoic acid, the same reaction as (1) was performed. The reaction mixture was concentrated under reduced pressure and the residual mixture was dissolved in 50 ml of water-acetonitrile (1:1). After evaporating acetonitrile, the resulting precipitate was collected by filtration, washed with 10 ml of cold water and dried in vacuo to give 1.31 g (yield 92.3 %) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(N-oxidopyridin-2-yl)thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm l: 1775, 1715, 1530, 1470, 1390 NMR (D2O ~ NaOD)~: 1.3-2.6 (6H, m, -(CH2)3-), 2.99, 3.53 (2H, ABq, J=18Hz, 2-CH2), 3.90, 4.25 (2Hr ABq, J=14Hz, 3-CH2), 4.95 (lH, d, J=5Hz, C6~H), 5.53 (lH, d, J=5Hz, C7-H), 7.1-8.5(8H, m, ~ , ~ ) Example 54 To 0.288 g of 1-carboxymethyl-5-mercapto-lH-tetrazole and 0.363 g of triethylamine was added 6 ml of methylene chloride. To the resulting solution was added 0.847 g of 7~-~D-5-carboxy-5-phthalimido~aleramido)-3-hydroxymethyl-3-cephem-4~carbo~ylic acid ditriethylamine salt. To the ~26~

mixture was added a solution of 0.450 mg of methyl O-phenylene phosphate in 1.2 ml of methylene chloride under stirring and cooliny at -20C to -15C. The rnixture was s-tirred at -5~C
to 0C for 1 hour and the reaction solution was treated in a similar method to Example 46-(1) to ~ive 0.711 g (yield 91.8 %) of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-(1-carboxymethyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
IR (KBr) cm 1 1770, 1710, 1530 NMR (DMSO-d6)~: 1.3-2.4 (6H, m, -(CH2)3), 3.62 (2H, br, 2-CH2), 4.17, 4.47 (2H, ABq, J=14Hz, 3-CH2), 4.71 (lH, t, J=6Hz, ~CH-), 4.99 (lH, d, J=5Hz, C6-H), 5.28 (2H, s, NCH2COO), 5.62 (l~,q~ J=5 & 8Hz, C7-H), 7.89 (4H, s, ~'), 8.77 (lH, d~ J=8Hz, CONH) Example 55 (1) To the solution of 0.975 g 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 0.172 g of ethanethiol in 10 ml of methylene chloride was added a solution of 0.514 g of methyl O-phenylene phosphate in 1.3g ml of methylene chloride under stirring and cooling at -20C to -15C, followed by stirring for 1 hour at 0-5C. To the reaction mixture were added 20 ml of water and 20 ml of THF and the pH was adjusted to 2 by 35% aqueous hydrochloric acid.
To the mixture was added 30 ml of methylene chloride.
After phase separation, aqueous phase was extracted with 15 ml of methylene chloride-TE~F(2:1, v/v). The organic layer and the extract were combined, washed with -two 10 ml portions of water and 10 ml oE water was added. The pH of the mixture was adjusted to 7 e After phase separation, organic layer was extracted with S ml of water. The water phase and extract were combined and concentrated under reduced pressure. The concentrated solution was subjected to Amberlite XAD-2 column chromatography (XAD-2 of 100-200 mesh,: 70 ml, column height: 40 cm) and eluted with water and then with water-acetone ~20:1, v/v). The fractions were checked by TLC (developing solvent: acetonitrile 40:
water 2: 99 ~ formic acid 0.1) and the fractions(Rf: about 0.16) containing the desired product were combined, concentrated under reduced pressure and lyophilized to give 0.515 g (yield 63.0 ~) of 7~-(D-5-carboxy-5-phthal-imidovaleramido)-3-ethylthiomethyl-3-cephem-4-carboxylic acid disodium salt.
IR (KBrl Cm : 1760, 1710, 1610, 1390 NMR (D2O)~: 1.18 (3H, t, CH3), 1.4-2.7 (8H, m, -(CH2)3~, -CH2CH3), 2.93, 3.55 (2H, ABq, J=18Hz, 2-CH2), 3.23, 3.81 (2H, ABq, J-14Hz, 3-CH2) r 4.98 (lH, d, J=SEIz, C6-H), 5.48 (lH, d, J=5Hz, C7-H), 7.88 (4H, s, ~
(2) To the mixture of 0.580 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid dipotassium salt and 0.165 g of thiophenol were added 2 ml of formamide and 2 ml of acetonitrile.
To the resultant solution was adcled a solution of 0.558 g ;~ rl'o-~/e,~l'c of methyl O-phenylene phosphate in l.S ml of methylene chloride under stirring and cooling at -30C to -20C, followed by stirring for 45 minutes at 0-5C. The reaction mixture was concentrated under reduced pressure and 40 ml of cold water was added to the cocentra~e. The resultant precipitate was collected by filtration, washed with 10 ml of cold water and dissolved in 20 ml of 50 ~ aqueous acetonitrile. The solution was adjusted to pH 7 and concentrated under reduced pressure to remove acetonitrile.
The concentrate was subjected to XAD-2 column chromatography ~Rf of the desired product: about 0 36) in the sarne method as in above (1) to give 0.397 g (yield 62.1 ~) of 7~-tD-5-carboxy-5-phthalimidovaleramido)-3-phenylthio-3-cephem-4-carboxylic acid disodium salt.
IR (KBr) cm 1 1765, 1710, 1605, 1390 NMR (DMS0-d6+D20)~. 1.2-2.S (6H, m, -(CH2)3-), 3.11, 3.49 (2H, Asq~ J=18Hz, 2-CH2), 4.36 (lH, m, `CH-), 4.81 (lH, d, J=5Hz, C6-H), 5.42 (lH, d, J=5Hz, C7-H), 7.34 (5H, br,-~ ), 7.84 (4H, s, ~ ) ~6~

Example 56 In 25 ml of methylene chloride were dissolved 3.53 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-~-carboxylic acid dikriethylamine salt and 0.76 g of triethylamine. To this solution were added dropwise a solution of 2.79 g of methyl o-phenylene phosphate in 7.5 ml of methylene chloride under cooling at -45C to -40C with stirring and the mixture was stirred for 30 minutes at the same temperature. To this reaction mixture was added 50 ml of ether and the mixture was allowed to stand at 20C to 25C for 20 minutes. The resultant powderly precipitate was collected by filtration and washed with ether and dried.
The resulting powder was dissolved in a mixture of 10 ml of water and 20 ml of acetonitrile and the mixture was ad~usted to pH 7.0 with lN-NaOH and acetonitrile was distilled off under reduced pressure. The concentrate was subjected to Amberlite XAD-2 column chromatoyraphy (XAD-2 of 100-200 mesh:
150 ml, column hight: 45 cm), elution being carried out with water. The eluate was checked by TLC (developing solvent:
acetonitrile 80: water 15: 99% formic acid 2) and the fractions (Rf: about 0.12) containing the desired product were collected.
The resultant solution was concentrated, adjusted to pH 6.0 with lN NaOH and lyophilized to give 2.76 g (yield 90.7%) of sodium 7~-(D-5-carboxylato-5-phthalimidovaleramido~-3-cephem-3-trie-thylammoniomethyl-~-carbo.Yylate.
IR(KBr) cm 1 3~50, 1775, 1710, 1612, 1~65 NMR(D2O)~: 1.3~ (9H,t,~=7Hz, (-CH3) x 3), 1.30-2.60 ~ ~o~

(6H, m, -(CH2)3-), 2.9-4.3 (lOH, m, 2~CM2, 3-CH2, N(CH2CH3)3) 5.13 (lH, d, J=5Hz, C6-H), 5.61 (lH, d, J=5Hz, C7-H), 7.88 (4H, s, ~ ) -_ ample 57 In 25 ml of methylene chloride were dissolved 3.53 g of 7~-(D-5-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 1.33 g of 1-(2-dimethyl-aminoethyl)-lH-tetrazole and 0.76 g of triethylamine. To this solution were added dropwise a solution of 2.79 g of methyl o-phenylene phosphate in 7.5 ml of methylene chloride under cooling at -45C to -40C with stirring and the mixture was stirred for 30 minutes at the same temperature. And then, the mixture was allowed to stand at 20C to 25C for 20 minutes.
The resultant powdery precipitate was collected by fil-tration and washed with methylene chloride and dried in vacuo.
The above product (Rf; about 0.17) was fur-ther treated as in Example 56 to give 2.67 g (yield 82.3%) of sodium 7~-(D-5-carboxylato-5-phthalimidovaleramido)-3-cephem-3-[dimethyl[2-(1,2,3,-4-tetrazol-1-yl)]ethylammonio methyl-4-carboxylate.
IR(K~r) cm : 3450, 1770, 1710, 1613, 1390 NMR(D20) ~: 1.30-2.60 (6H, m, -(CH2)3-), 3.00-4.30 +/CH3 (lOH, m, -N ~ , 2-CH2, NCH2), -NCH2, C6-H), 5.53 (lH, d, J=5llz, C7-H), 7.82 (4H, s, ~ ), 9.37 (lH, s, HC~ ~) ~o~

Example 58 In 4 ml of fo~lamide and 8 ml of acetonitrile were dissolved 1.20 g o~ dipotassi~n7B-(D-5-carboxylato-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylate monohydrate and 312 mg of 4-cyanopyridine. To this solution were added dropwise a solution of 1~12 g o~ methyl o-phenylene phosphate in 3 ml of methylene chloride under cooling at 0-5C and stirring,and the mixture was stirred for 30 minutes at the same temperature. To this reaction mixture was added 3.5 ml of lN NaOH and methylene chloride and acetonitrile were distilled off under reduced pressure. The concentrate was subjected to silica gel columnchromatography (50 g of silica gel was packed into a column with acetonitrile-water-formic acid ~80:15:2), col~mn hei~ht: 38 cm~, elution being carried out with acetonitrile-water (2.5:1). The eluate was checked by TLC ~developing solvent: acetonitrile 80: water 15:99% formic acid2) and the fractions (Rf: about 0.22) containing the desired product were collected. The resultant solution was concentrated, adjus-ted to pH 6.0 with lN NaOH
and lyophil1zed to give 1.08 g (yield 88.3%) o~ sodium 7~-(D-5-carboxylato-5-phthalimidovaleramido)-3-cephem-3-(4-cyanopyridinium)methyl-~-carboxylate.
IR(KBr) cm : 3420, 1770, 1710, 1613, 1395 NMR(D2O)~ 0-2.70 (6EI, m, -(CH2)~- ), 3.04 & 3.68 (21-l, ABq, J=18Hz, 2-CH2), 5.13 (lH, d, J=SHz, C6-H), 5.~ & 5.70 (2EI, ABq, J=15Hz, 3-CH2), 5.63 (lH, d, J=5Hz, C7-H), 7.82(~1EI, s, ~ ), 8.57 & 9.36 (~EI, dd, - ~ CN) - 12\ -Example_59 In 4 ml of formamide and 8 ml of acetonitrile were dissolved 1.20 g of dipotassium 7~-(D-5-carboxylato-5-phthalimido-valeramido)-3-hydroxymethyl-3-cephem-4-carboxylat_ monohydrate and 411 mg oE methyl nicotinate. To this solution were added dropwise a solution of 1.49 g of methyl O-phenylene phosphate in 4 ml of methylene chloride under cooling at -10C to -5C with stirring and the mixture was stirred for 30 minutes at the same temperature. The above reaction mixture (Rf: about 0.23) was further treated as in Example 58 to give 1.18 g (yield 91.5%) of sodium 7~ 5~carboxylato-5-phthalimidovaleramido)-3-cephem-3-(3-methoxycarbonylpyridinium)methyl-4-carboxylate.
IR (KBr) cm 1 3445, 1770, 1708, 1613, 1395 NMR (D2O)~: 1.30-2.60 (6H, m, -(CH2)3-), 2.95 &
3.62 ~2H, ABq, J=18Hz, 2-CH2), 4.10 (3H, S, -CH3), 5.12 (lH, d, J=5Hz, C6, H), 5.36 ~ 5.72 (2H, ABq, J=15Hz, 3-CH2), 5.62 (lH, d, J=5Hz, C7-H), 7.79 (4H, s, , ~ ), 8.0-9.8 (4H, m, - ~ ) ` CO

~26~-3¢~
~, - 121~-E ample 60 In 50 ~1 of methylene chloride were dissolved 7.06 g o~ 7~-(D-S-carboxy-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid ditriethylamine salt and 1.~7 g of 3-dimethylamino propionitrile, To this solution were added dropwise a solution of 3.72 g of methylo-phenylene-phosphate in 10 ml of methylenechloride under cooling at -45C to -40C with stirring and -the mixture was stirred for 30 minutes at the same temperature. And, then, the mixture was warmed ~nd stirred at 20 - 25C for 20 minutes.
The resultant powderly precipitate was collected by filtration and washed with methylene chloride. The resulting powder was dissolved in a mixture of 12 ml of water and 24 ml of acetonitrile and the mixture was adjusted to pH 3.4 with 4N hydrochloric acid. The resulting solution was poured into 310 ml of acetonitrile with stirring and the mixture was cooled to about 5C~ And, then, the solvent was removed by decantation arld 90 ml of acetonitrile was added to the residual viscous oil with stirrlng. The -resultant powderly precipitate was collected by filtration and washed with acetonitrile and dried in vacuo to give 4.78 g (yield 81.9~) of 7~-(D-5-carboxy-5~phthalimidovaleramido)-3-(2-cyanoethyldimethylammonio)methyl-3-cephem-4-carboxylate IR(KsrJcm 1 3400, 2247 ! ]-777~ 1715, 1617, 1392.
NMR (D2O + NaOD) ~: 1 30-2.60 (6H, m, -(CEI2)3-), 2 8-4 4 (14H~ m~ `~(CEl3)2' 2-CH2' 3-CH2' C 2 2 5.20 (lH, d, J=5Hz, C6-H), 5.61 (lH, d, ~=5Hz, C7-H), 7.86 ~4~I, s, ~ ) Example 61 In 20 ml of water was dissovled 6.70 g of dipotassium 78-(D-5-carboxylato-5-phthalimidovaleramido)-3-hydroxymethyl-3-cephem-4-carboxylate 5 hydrate. To this solution was added 30 ml of TEIF and the mixture was adjusted to pH 2.0with 4N

~ 26E~
-121b-hydrochloric acid at 0-5C. To this mix-ture was added 35 ml of methylene chloride and the mixture was allowed to s-tand for phase separation, The aqueous layer was extracted with two portions of a mixture of 6 ml of THF
and 10 ml of methylene chloride. The organic layer and the e~tract were combined, dried with anhydrous magnecium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of formamide and 40 ml of acetonitrile and 2.93 g of diethylamine was added.
To this solution was added dropwise a solution of 3.72 g of methyl o-phenylene phosphate in 10 ml of methylene chloride under cooling at -35~C to -30C with stirring and the mixture was stirred under cooling at -35C to -30C for 10 minutes and at -5C to 0C for 30 minutes. To the reaction mixture was added 100 ml of ether and the solvent was removed by decantation and the residual viscous oil was dissolved in the mixed solution of 7 ml of water and 14 ml of acetonitrile and adjusted to pH2.5with 4N hydrochloric acid at 0-5C. The resultant solution was adjusted to pH6.0 with 4N NaOH at 0-5C and ace-tonitrile was distilled off under reduced pressure.
The concentrate wad subjected to silica gel column chromato-graphy (250 g of silica gel was packed into a column with acetonitrile-water-~ormic acid (80;15:2), column height:
63 cm), elution being carried out with acetoni-trile-water (3:1). The eluate was checked by TLC (developing solvent:
acetonitrile 80: water 15: 99 ~ formic acid 2) and the fractions containing the desired product (Rf=about 0.27) were collected. The resul':ant solution was conclentrated under reduced pressure, adjusted to pH6.0 with lN NaOH and lyophilized to give 4.81 g (yield 32.8 ~) of sodium 7~-(D-S-carboxy-S-phthalimidovaleramido)-3-diethylaminomethyl-3-cephem-4-carboxylate lc--IR(KBr)cm 1 1766~ 170'" 1607, 1391 NMR ~D2O) ~; 1.2_2t7 (12H, m, ~CH3~2, -(CH2)3-), 2.8-3.6 (6H, m, -CH2CH3x2, 2-CH2), 3-75 ~ 4-08 ~2H, ABq, J=14Hz, 3-CH2), 5.07 (lH, d, J=511z, C6-H), 5.58 (lH, d, J=5Hz, C7-H), 7.86 (4H, s, ~ )

Claims (10)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of producing a 1,3,2-dioxaphosphole of the formula [I]B

[I]B

wherein represents a benzene ring which may be substituted and R represents an aryl, alkoxy or aralkyloxy group which may be substituted, which comprises reacting a catechol compound of the formula [II]B

[II]B

wherein is as defined above, with a compound of the formula [III]B

[III]B

wherein X is a halogen atom and R is as defined above, at a temperature not hig-her than about 30°C in the presence of a base.

2. A method according to claim 1, wherein represents an unsubstitu-ted benzene ring.

3. A method according to claim 1, wherein in the starting materials represents an unsubstituted benzene ring and R is ethoxy, to obtain the compound ethyl o-phenylene phosphate.

4. A method according to claim 1, wherein R represents an alkoxy group having one to six carbon atoms.

5. A method according to claim 1, wherein X represents a chlorine atom.

6. A method according to claim 1, wherein the base represents a trialkyl-amine in which the alkyl component has one to six carbon atoms.

7. A method according to claim 1, wherein the reaction is carried out in an inert solvent.

8. A method according to claim 1 or 7, wherein the reaction is carried out at a temperature within the range of 30°C to -100°C.

9. A method according to claim 1, wherein is a benzene ring unsub-stituted or substituted by one to four substituents, each independently selected from a straight or branched C1-C6 lower alkyl group, a straight or branched C1-C6 lower alkoxy group, a straight or branched C1-C6 lower alkylthio group, a C2-C6 lower acyl group, a C2-C6 lower acyloxy group, a C2-C6 lower acylamino group, a di-lower (C1-C6) alkylamino-lower (C1-C6) alkyl group, a C1-C6 lower alkoxycar-bonyl or C6-C10 aryloxycarbonyl group, nitro, halogen (Br, Cl, I, F), cyano, car-boxy, or hydroxy, or a divalent substituent selected from methylenedioxy, ethyl-enedioxy or , which divalent substituent may further be substituted by halogen, cyano, nitro, oxo or carboxyl.

10. A method according to claim 1 or 9, wherein R is unsubstituted or sub-stituted phenyl, tolyl, xylyl, biphenylyl, naphthyl, a straight or branched C1-C6 lower alkoxy group, benzyloxy, phenethyloxy, phenylpropyloxy or naphthyl-methyloxy, wherein the substituent is selected from halogen, nitro, cyano, oxo, C1-C6 lower alkoxy, C1-C6 lower alkylthio, alkoxycarbonyl, a C1-C6 lower alkyl-sulfonyl group and allylsulfonyl.