IE45459B1 - Cephalosporin analogues - Google Patents

Abstract

PURPOSE:Cephalosporin analogs I(R<1> is H, halogen, lower alkoxy, sulfonyloxy, arylthio or monoheterocyclic thio;R<2> is COOH or its carboxyl derivatives; R<3> is H, or methoxy), e.g. 7beta-amino-3-chloro-1-oxa-1-dithia-3-cephem-4-carboxylic acid. [JP53018597A]

Description

I i * 11 M * " 1 —^^^ - - ---- I I 4 9 4 l> i> l\ I I * This invention relates to Important intermediates in I the preparation of novel cephalosporin analogues possessing I potent antimicrobial actions. Particularly, it relates to 7β- I amino-l-oxa-dothiacephalosporins.

I ^ Compounds in this Invention are represented by the I formula: r3 I R2 (I) I (wherein is hydrogen, halogen, lower alkoxy, sulfonyloxy, aryl- 2 thio or monocyclic heterocycle-thio; R is carboxy or derivatives H thereof at the carboxy group; RJ is hydrogen or methoxy).

The compounds (i) may be prepared according to the follow- ing reaction sequence.

RUN ? __ J | | Hydrolysis Alkoxylation ] 1 | I ^—N'^s^-'R1 > i1) 4 -N^ssiLjt1 I 12 3 (wlicrcin R i.s/ami noprotccting group; R , R and R^ are the same ns mentioned above) Halogen atoms represented by R1 in the above-mentioned 15 formula (l) arc, in particular, fluorine, chlorine, bromine and iodine. Ohrou^out the Specification lower alkoxy means - C5 alkoxy such as H methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy; sulfonyloxy means C,- Cj alkylsulfonyloxy r,~* *5153 , such as mothylsulfonyloxy, ethylsulfonyioxy, n-propylsulfonyloxy, 1-propylsulfonyloxy, n-butylsulforiyloxy or Cg - Cg orylsulfonyloxy . ( such ea bonzenesulfonyloxy and toluonesulfonyloxy.* arylthio means ' t ' · i aabatituted or unaubstituted Cg - C^q arylthio such as phenylthio, 3 tolylthio, methoxyphenylthio and dime thoxyphonylthioj and monocyclic heterocycle-thio groups are five-membered ones Involving 1-4 * • e hetero attorns O, or S).: which may be represented by the formula : -S-Q. Vherein 4 is, a five-membered heterocyclic group containing aza, oxa, this, diaza. diox?. dithia, triaza, trioxa, trithia, 10 tetroza, oxaza, otathla, thiaza, oxadiaza and thiadlaza in the ring. for example, furan, tetrohydrofuran pyrrole, pyrrolidine, thiophene, . ·> tetrahydroihiophene, oxazade, thiazolo, isoxazole, isothiazole,.· pyrazole, pyrazoline, imidazole, oXathiol, dioxole, dithiole, triazolb. thiadiazole, oxadiazole, dithiazole^dloxazole, oxathiazole, tetra- 15 sole, oxatriazole, thiatriazole or dithiadiazole.

The S group‘d connected to the heterocycle may be located at any possible position of the heterocycle· The heterocycle may involve 1-4 substituents such as alkyl, hydroxy, alkoxy, halogen, nitro and amino at an optional possible position or positions. *0 Tho derivatives at the carboxy group represented by R mean 2 esters, thioesterr and carbonamides. For example, when R 2 it la ester, R may be represented by the formula : -C00R , which means 4-ester usually used in the field of penicillin and cephalosporin chemistry. The symbol R4 includes alkyl (o.g. meci.yl, ethyl, 25 n-propyl, i-propyl, n-butyl, t-butyl), haiogenatcd alkyl (e.g. chloromethyl, dichloromethyl, 2,2-dichloroethyl, 2,2.2-tri-chloroethyl, 2,2.2-tribromoethyl), - C2o arylmethyl (e.g. benzyl, diphcnylmethyl(bcnzhydryl), triphenylmothyl(trityl), p-mothoxybenzyl, 3,4 ,5-trimothoxybenzyl, p-nitrobenzyl), Cg - c^2 acylmcthyl(phcnncyl)> 30 substituted silyl (c-g· dimethylsilyi, trimcthylsilyl, triphcnylsilv]), - 3 - I, » _ _ __ fc C 4 3 9 — ~ “ " ~ substituted stannyl (e.g. trimothylstannyl), adamantyl, 2-bonzyloxy-phenyl, ί»-methyl thiophcnyl, tetrahydropyran-2-yl and . 2-cyanoethyl. · The compounds of the formula (I) may form acid addition·. salts'at the 7-amino group· Representative of acids preferably used in acid salt formation are Inorganic acid such as hydrochloric acid, * h/drobromic acid, sulfuric acid, phosphoric acid, perchloric acid and thiocyanic acid and organic acids euch as p-toluenesulfonic acid and naphthalenosulfonic add. Yhen R at the k position is free 10 enrboxy group, i.e. -COOK, the compounds of the formula (l) may form sOts with possible inorganic or organic bases.

The compounds in this invention represented by the fofmdia (Z) may be prepared in a manner as shown in the following Reaction Schemes 1-8.

IS The compounds (la) of the formula (i), wherein R* is halogen or eulfonyloxy may be prepared in a manner as shown in Reaction Scheme 1.

Reaction Scheme-1 Step a o*J-— COOZ1 COOZ1 (H) (111) RΛ (la) (wherein R is amino protecting group ; Z1 is carboxy protecting groip ; X is halogen or sulfcnyloxy ; and R*is the same as mentioned above).

The starting materials represented by the formula (il) in 20 the above process are well-known and may be prepared, for example, in a manner described in Japanese Uiiexarained Patent Publication No.

I -* G J [>3 I 51-41385· They may also be prepared in a manner as shown in the I following Reaction Scheme - 2- I Reaction Scheme - 2 I HjN. JL' HJt>>CH2CeCH I Ύ j-p H0CH2csCH 7 I-[ N-protective I or"~deoxidizer (Γ reaction I COOZ1 φ COOZ1 I ffl I (5) (6) ^°0Zl I RNHw JOl ΛΒΟ RNHv JD^^COOZ2 I NalO. |-f ^ 1) oxidation ]-\ , i .—J-Lj- __, 0M^~ I COOZ1 2) esterification COOZ1 j 03 “γγ"^002' _Zn-ACOH I oxidation s^0 reduction I (9) cooz1 I X)^JCOOZZ HNIL^ O,____cooz2 I j-^ haiogenation ^ ^ ^ l) PPIu, I Cr~NV^0H (S0C12) (Γ~1ί>γχη 2)partial ^ I (10) COOZ1 (ll) COOZ1 hydrogenation I ««V I 00021 I *54ϋ0 I (wherein X' and X are halogen ; Z** is aster formative group 5 I R and Z1 ere the same as mentioned above).

I · In tho above-mentioned Reaction Scheme - 2, each reaction I may be carried out in veil-known reaction conditions which satisfy I S each reaction steps.

I Die compounds (Xa) prepared in the process shovn in I Reaction Scheme - 1 correspond to the compounds (l), wherein R1 I is halogen or sulfonyloxy, R^ has the same meaning and R3 is hydroeon.

I The reaction conditions in each step shown in Reaction Scheme » 1 I 10 are detailed as follows.

I Step a (IX—> JIX) I The hydroxy group at the 3 position of the compounds »(n) I are substituted by halogen or sulfonylated on treatment with I sulfonylating agent to yield tho corresponding 3-halogen- or 3“ I 15 sulfonyloxy compounds.

I Halogenetion of the hydroxy group at the 3-position I may also be carried out in manners ordinarily used in halogenation I of hydroxy group such as a m&.jier by means of phosphorus halogenide I PX^ or thionyl chloride. In this invention, the halogenation may I 20 preferably be effected in conventional manners, particularly I by means of oxalyl balogenidc (e.g. oxalyl chloride), phosphorus oxyhalogenide (e.g. phosphorus oxychloride) or halogen (e.g. chlorine)-triphenylphosphine.

The sulfonylation at the 3-hydroxy group may be carried 25 out in the same manner as sulfonylation of other hydroxy groups.

Representative of sulfonylating agents are alkylsulfonyl halogenides (e.g. methylsulfonyl chloride, ethylsulfonyl chloride) and atylsulfonyl halogenides (o.g. benzonesulfonyl chloride, toluonesulfonyl c lilori do). The reaction is carried out under conditions of 30 ordinary sulfonylation, for example, on addition of the above-mentionca - 6 - *0·1ϊ>9 sulfonylatlng agent in the presence of tertiary amine such as pyridine or triethylamine· i8tep to (HI—fla) In this process, the 7-amino protecting group and if ® required, the fc-carboxy protecting group are at the same time or stepwise removed by hydrolysis or reduction according to the properties of the protecting groups. The protecting group at the 7-amino and at the 4-carboxy are ones usually used in the field of penicillin and cephalosporin synthetic chemistry and can easily toe ) removed in a well-known manner.

. Compounds (l)» except those vhorein R^ is halogen or Φ sulfonyloxy, may be prepared in a manner as shown in the following Reaction Scheme.

Reaction Scheme - 1 RNH^ RNH. JQ XX -=t* X C0021 COOzl (IH) (IV) -=n- "X R2 (lb) (wherein R, Z*, R2 end X are the same as mentioned above).

Compounds (l) wherein R1 is hydrogen are prepared in the process described in Reaction Scheme - 3· Step c (III—>IV) Halogen or sulfonyloxy at the 3 position of the compounds represented by the formula (ill) is removed by reduction to yield 3-unsubstituted oxadethiucephem structure. The reduction may bo carried out in such manners as selective reduction of halogen or «S4U9 sulfonyloxy at tho 3 position without any influence on other aubetituonts or functional groups, for example, combination of metals and.adds, particularly combination of zinc and acetic acid· The reaction may bo carried out in the well-known manner.

Step d (IV—»Ib) . , This is o process of hydrolysis or reduction, the same 'as step b and may be carried out in the manner oruinarily used in tho field of penicillin and cephalosporin synthetic chemistry.

Alternatively, i>he objective compound (lb) in this step 10 may be prepared in the manner as shown in the following Reaction Scheme.

Reaction Scheme - ft * - ~ OH 0-\“ RNHx__-Ox/JLs/CH acetone RNH^ jq . j — p-TsOH ζΓ (6) COOZ1 (13) COOZ1 Bmrr°—0 “"wOk.o ., > <^"V - * Λν» (1ft) C00Z (15) io02^ «Λ 1) ha logena tion RNH>v^Okx0 partial (S0C12) Ph ^ ~ hydrogen a tion ^ 2) PFb3 (l6) COOZ1 NalO^ RNIk| (l?) COOZ1 (18) ^oozl RNH^^^O wittig ^ II I reaction > (lb) (IV) ^0021 - $ - AS 4 r>9 (wboroin R and 2*- are the same as mentioned above).

I The reactions shown in the above Reaction Scheme - k may be carried out under well-known reaction conditions which satisfy reaotion process as shown in each step.

Compounds (i) wherein R1 is axylthio or monocyclic hetero- cycle-thio may be prepared in a manner as shown in the following e Reaction Scheme. * ; Reaction Scheme - 5 JEifK St.p . jAA u (in) C0C21 (») 40021 sTT* yQ (Ic) R (wherein R, Z1, R2 and X are tho same is mentioned above ; T is arylthio or monocyclic heterocycle-thio). step e (HI—»V) Halogen or sulfonyloxy at the 3 position in compounds (Hi) is substituted by a desirable arylthio or monocyclic heterocycle-thio. This reaction is carried out by reacting tne starting materials (ill) with the corresponding arylthiol or monocyclic hetorocycle-5 thiol i:i the presence of a weak base or with the corresponding salt. Preferable weak bases are organic ones such as pyridine and triethyl-aoine. Ordinarily, the reaction proceeds well at room temperature.

Step f (v—yic) This is a process of hydrolysis or reduction, the seme 3 as steps b and d, and moy be carried out under the same conditions as in tho steps b and d. - 9 - « 434U9 I Alternatively, the objective compounde (ic) may be prepared I In a manner aa shown in the following Reaction Scheme* I Reaction Scheme - 6 I rkh^h^o^cooh . ra κηιγ_^0'ν^:οτ I /(coci2) \ (Λγ™3 I (l2) cooz1 VwrtoW (19) cooz1 I Vittijf reaction I -r —* (vj cooz1 I (wherein R, Y and Z* are the same as mentioned above). I The reactions in the above Reaction Scheme - 6 may be I oarrlcd out under well-known reaction conditions which satisfy * I each step. . I Compounds (l). wherein R1 is lower alkoxy, may be prepared I in a manner as shown in the following Reaction Scheme. I Reaction Scheme - f I HNHV-tx°vl I stop g > cX'X'ozl I (II) C00jl (VI) 0002 I _, “YT0; I Step h J^OZ^ (id) ** I (vheroin R, R~ and Z1 are the same as mentioned above ; Z^ is I lower alkyl). I 4S-1S9 Stop e (II—*vi) This process is curried out in a condition of enolothorification of ketones or on tho action of reagents as diazoalkane ordinarily employed in eetorification of carboxylic 5 adds. Enolothorification of ketonea is carried out· for example· by moans of trialkylorthoformates (e.g. triethylorthofornate) or alchols and p-toluenesulfonic add. Alkylation by diazoalkanes (e.g. diazometbane· dlazoethnne) may be employed in this invention. These roactions may be carried out in the well-known manner.

Stop h (VI—>Id) This Is a process of hydrolysis or reduction, the same as steps b. d and f, and may be carried out under the same condition as In those steps.

Compounds (i)· wherein R? is methoxy, may be prepared '5 in a manner as shown in the following Reaction Scheme· Reaction Scheme — 8 H 9CH3 IO^Y^rI ProCe8S 1 > V R2 R2 (If) (Ie) (wherein R* and R^ are the same as mentioned above).

Step i The starting material.'· (if) correspond to each objective compound prepared in the Reaction Scheme.' 7. Introduction of 20 the 7-methoxy as shown in Reaction Scheme - 8 may be carried out according to manners of introduction of the 7-methoxy ordinarily employed in the field of penicillin and cephalosporin chemistry.

These methods arc described as follows.

- U - 4Q4U0 I Method l I The 7-amino of the starting materials (if) is acylated I to corresponding 7-acylamiho derivatives, the latter are reacted I with nethoxylithium (LiOCH-j) and t-butyl hypochlorite (t-BuOCl) in I 5 an inert solvent at low temperature (Belgium Patent Application No· I 817836)» and then the 7-aoyl protecting group is removed.

I e I e I Method 2 I The -7-amino of the starting materials (if) is reacted with I codium nitrite to yield 7-diazo compounds (a), the latter reacted I 1C vith haloazide (prepared from sodium azide and the corresponding I halogen)(e.g. BrN^, CIN^, IN^) to yield the corresponding haloazide I <· I compounds (b), and the latter reacted vith methanol followed by* I reductive azide decomposition to yield the objective 7-amino-7- I methoxy compounds (Ie)· I 15 The reaction scheme in this process is represented as follows I (Japanese Unexamined Patent Publication No. 47-931)· (.) R (b) 1,2 l) MoOII --—> do) I 2) Reduction I (wherei*. R1 said R2 are the same as mentioned above ; X”' is halogen) .

I Method 3 The starting materials (if) are reacted with p-hydroxy-20 benzaldehydes (preferably those having a bulky substituent or I substituents adjacent to the p—hydroxy, for example, 3,5-di-t-butyl- I 4-hydroxybonzaldehyde) to yield benzylidene derivatives (c), the I latter oxidized by means of appropriate oxidating agents (e>g· nickel - 12 - I ϋϊ) I peroxide· load tetraacetate) to yield quiuoid type derivatives (d) , I the latter roacted with methanol to yield 7®-nethoxy compounds (o) I and benzylidene group of the latter hydrolyzed (ordinarily on the I treatment of Girard reagent) to yield the objective 7P-amino-7e- I 5 methoxy compounds (Ie)· The reaction scheme in this process is I represented as follovs(Japanese Vnexamined Patent Publication No.

I · * I 50-5039¾).

I * » I KO-^A-CHO nr-* I HO—')—CH=N o I \=J \-S oxidation ---> -* (o) R2 --- Λ (-) "'jr·*1 <·> hydrolysis -> (Ie) (wherein R^ and R2 are the same as mentioned above).

Method ^ Alternatively· a manner as shown in the following Reaction Scheme may also be utilized. In this method , the 7-amino group of the starting materials (if) is protected by acyl group having at least one hydrogen atom at the a position to yield 7-acylamino 15 derivatives (f), the lattor treated with a halogenating agent to yield iminobalide derivatives (g)· the latter treated with a base for dohydrohalogenation to yield keteneinine derivatives (h) , the latter halogenatcd to yield dihaloecnoimine derivatives (i), the latter reacted with alkali metal methoxide and then hydrolyzed - 13 - I to remove the acyl group (Japanese Unoxamlned Patent Publication I No. 30-126692). I I H I Q' | hologenating Q' I ' ^θηθΝΗν agent ^CH-C=NL yCL —I o*> R (») I I ® 0C1I- hydrolysis I I -->-> (Ie) I (vherein R1 and R^ aro the same as mentioned above ; 0' and Q" . I I 5 aro hydrogen or appropriate substituents ; X and X' are halogen, I I respectively). I I The compounds represented by the formula (i) in this H I invention are important intermediates in preparation of novel H I 1-oxadethiacephalosporlns. Introduction of various acyl groups H I 10 . used in the field of penicillin and cephalosporin chemistry to the H I free 7-amino group of the compounds (i) yields antimicrobially very active H I compounds as described and claimed in Patent Specification No. .- ' . I I The following examples 1 to 5 are provided to further illustrate H I this Invention; Examples 6*to B describe the preparation of H I 15 starting materials. H I Example 1 H I 2& —amino-*1—chloro-1—oxa-l-dn thia—3-cephcm-4-carborvlic acid H I (X : R*=C1 : R2=C00?I. lP=Il) (la ; R2=C00H ; X=Cl) I I i) To a solution of 1.5 g (3 mmoles) of diphenylmothyl 7β- H I 20 benzyloxycarbonylamino-3-hydroxy-l-oxa-l-dothia-3-cephem-4-carboxylate H I (XI : RsPhCI^OCO ; Z1=CIIPh2) in 30 ml of dimetliylformand.de is added H I ~ ~ .‘•si's9 I 0.03" ml (0.36 mmole) of pyridine under ice-cooling and then dropviso I addod 0.31 “1 (3*6 mmoles) of oxalyl chloride. After stirring I for 3 hours fit room tempcruturo, the reaction mixture is poured I into 5 % phosphoric acid oquoous solution under ice-cooling and I 5 oxtracted with ethyl acetato. The extract is washed with water» I dried and evaporated. The residue is chromatographed on 20 parts I by volume of silica gel and eluted with benzene-eIhyl acetate (5 : l) 1 to yield 489 mg of the objective 3-chloro derivative» diphenylmethyl I 7P**benzyloxycarbonylaminc·· <-chloro-l-oxa-l-dethia-3-cephem-4- I 10 earboxylate (HI : R=PbCH20C0 ; Z1=CHPh2 ; X=Cl) (31.4 $> yield).

I mp. 130 - 131 °C I ** * carl : 31,50* 1805» 1725. 1620.

I NMR : 6CDC13 ppm s 4.32(s,2H), 4.98(d.J=4.0Hz,lH) , 5-10(s,2H), I 5*20 - 5.80(m,2H), 6.97(s,lH), 7.0(m,aromatic H).

I 15 This product may also be prepared as the following manner.

I To a solution of 1.62 g (6.2 mmoles) of triphenylphosphine I in 20 ml of tetrahydrofuran are adoed 6.2 mmoles of chlorine-carbon I tetrachloride, a solution of 1.35 g (3-1 mmoles) of 3-hydroxy I derivatives (II : RsPhCH^OCO : Z1=CHPh2) in IO ml of tetrahydrofuran I 20 and then 0.86 ml (6.2 mmoles) of triethylamine under ice-cooling I while stirring. After stirring for 1-5 hours at room temperature.

I the reaction mixture is poured into*ice water and extracted with I etbylacetate. The extract is washed with water, dried and evaporated.

I The residue is chromatographed on 30 parts by volume of silica gel I 25 and eluted with benzene-ethyl acetate (lO : l) to yield 0.95 g I of the objective 3-chloro derivative (ill : R=PhCH20C0 ; Z1=CHPh2 ; I X=Cl) (59-0 yield).

I 2) To a solution of 950 mg (1.83 mmoles) of the 3-chloro I derivative: prepared above (ill : RsPhCILjOCO ; Z*=CHPh2 ; X«Cl) I 30 in 37 ml of methylene chloride are added 1.7b ml (l6.5 mmoles) of I .· . · * _ 15 _ I ““-I—-*i™^—,—****J* 401¾0 I V · , I aniso.'.e and a solution of l·1*5 g (ll mmoles) of aluminum chloride I in 18 ml of nltromothane, and the mixture allowed to stand at I room temperature overnieht. The reaction mixture is extracted I with 15 ml of ice-cooled 2 % hydrochloric acid» and the aqueous 5 layer washed with methylene chloride and then ethyl acetate» and I evaporated under reduced pressure. The residue is chromatographed I on a coition of 400 g of Oiaion HP 20 (Trade mark of Mitsubishi I Chemical Industries ; Hiporous polymer) and eluted with hydrochloric noid (pH 5). The eluate la adjusted to pH 4.4 and evaporated under I 1C reduced pressure to yield 175 mg of the objective 3-chloro deriva tive: (X i R^eCl Ϊ R2=CC0H ; R3*H)(43*8 £ yield).

IR l v^ cm-1 : 3*20, 1818. 1630, 1613.

Etxamplo 2 2£ -arotno-l-oxa-3-dcthla-T-cephem—A-carhoxv3 ic acid (X : R^=R3=H ; 15 R2=C00HHTb : R2=C00H) 1) To a solution of 1.98 g (3*96 mmoles) of the 3-hydroxy derivatives (XX : RsPhCH20C0 ; Z*=CHPh2) in 20 ml of dimethyl-formamide are added 0.62 ml (2 equivalents} of metbylsulfonyl I chloride and then Ο.83 ml (1.5 equivalents) of triethyl amine at I 20 « 50 °C, and the mixture stirred at the same temperature for 15 minutes and poured into ice water to precipitate the crystals, I which are collected by filtration to yield 2.15 g of the objective I 3-methylsulfonyloxy derivative , diphenylmethyl 7β-benzyloxy- I carbonylamino-3-methylsulfonyloxy-l-oxa-l-dethia-3-cephem-4-carboxylate 25 (HI : R=PhCH2OCO ; Z1=CHPh2 ; X=0S02CH3)(9*«.0 £ yield).

IR : cm*·1 : 3¾ 20, 1810, 1730, 1510, 1365, 1165· I Μολ NMR : 0C0C13 ppo ; 2.96(s,3H), 4./»6(bs,2H) , 4.97(d,J=4-OHz,lH), 5·07(s,2H), 5*^5(dd,J=4.oHz,lH). 2) To a solution of 1.15 g (2 mmoles) of the 3-methyl- I 30 eulfouylox>* derivatives (ill : RsPhCH^OCO ; Z1=CHPh2 ; X=0S02CH3) - 16 - I » * I S 4 Si 9 I in a mixture of «ethylene chloride (20 ml) and acetic acid (*»0 ml) I la added 3 g of activated zinc powder, and the mixturo stirred at I room temperature overnight, during which time each 3 g of zinc I 1 . I I powder is added aftor the lapse r*f 2 hours and after 3 hours from I 5 the begining of tho reaction. Zinc povdor la filtered off and I tho filtrate mixed with ethyl acetato. The organic layer is washed I with water, dried and evaporated under reduced pressure to yield I 913 «g of the objective 3'“deoxy derivatives, diphenyl methyl I 7p-benzyloxycarbonylamino—1-oxa-l-dethia-3-cephem-4-carboxylste I 10 (iv : R=Phai20C0 ,* Z1=CHPh2)(9J!i.2 £ yield) as powder.

I IR : cm"1 : 3450, 1800, 1730, 1650.

I NMR : 6CDC13 ppm ; 4.4l(m,2H), 4-95(d.J=4.0Hz,lH), 5-15(s,2H); I 5.53(dd,J=4.0,9.0Hz,1H), 6.5l(m,lH), 6.99(a,lH).

I This product may also be prepared in tlio following manner.

I 15 To a solution of 240 mg of the 3-chloro derivative I (IH : RsPhCHgOCO ; Z^CHPhg ; X=Cl) in a mixture of methylene I chloride(4 ml) and acetic acid (8 ml) is added 0.72 g of activated I zinc powder, and the mixturo stirred at room temperature· I Additional 0.72 g of activated zinc powder is added three times I 20 during a period after 4 hours up to 9 hours from the bogining of I the reaction, and the mixturo allowed to stand overnight with I stirring. Zinc powder is filtered off, and the filtrate poured I into water and extracted with ethyl acetate. The extract is washed I with valer, dried and evaporated. The obtained residue is chromato- I 25 graphed on a column of silica gel and eluted with benzene-ethyl I acetate (5 : l) to yield 215 mg of the objective 3-deoxy derivative I (IV : R=PhCH20C0 ; Z^CHPhjj) (96.0: yield).

I 3) To a solution of 913 ®g (18.8 mmoles) of the 3-dooxy I derivatives prepared above (IV : RsPhCU^OCO ; Z^ClD’i^) in 35 ml I 30 of mothylcno chloride are added 1.85 ml (9 equivalents) of anisolo I - 17 - 1 4 S 4 ϊ> 9 I ^ I .

I and a solution of 1»51 g of aluminum chloride (6 equivalents) in I '· 18 ml of nitromothane» and the mixture allowed to stand at room I temperature overnight and extracted with 2 5» hydrochloric acid I under ice-cooling. The aqueous layer is washed with methylene I 5 chloride and the ethyl acetate· and evaporated under reduced I pressure In order to remove organic solvent remaining in tho I * t I aqueous layer. The obtained residue is chromatographed on a column I of Dial on HP 20 (Trade (nark of Mitsubishi Chemical Industries ; I Klghporous polymer) and eluted with dilute hydrochloric acid (pH 3*0).

I 10 Tho eluate is evaporated under reduced pressure to yield 291 mg of the objective 3-oxaceohcm derivative (I : R*sR3=H ; R^-COOH) hydrochloride (70.6 % yield). * ! + 11.1° ± 2.4 (c=0.2l6, in methanol) j IR ί cm“l : 3500 , 2600, 1805. 1645. l6l0, 1550. | 15 MMR : 6CDC13 ppm : 5.37(d,J=4.0H*,1H), 5.5l(d,J=4.0Hz,lH), 6.70 j (m.lH). t Sxemnlo 3 2ft -emino-*}-(l»mctltyltetraxol-5-vl)thio-l-oxa-l-dethia-^~cephem- 4-carboxylic ncid (X : R^=l-methyltetrazol-5-ylthio : R2gC00H. , 20 R^allHlc : Y=1-methyltetra7.ol-5-ylthio : R2^C00H) l) To a solution of 1.12 g (1.9¾ mmoles) of the 3-mothy1-sulfonyloxy derivative prepared in Example 2 (ill : R=PhCH2OCO ; Z^=CIEPh„ ; X.1OSO2CH3) in 10 ml of dimothylformamide are added 373 mg (3.2 mmoles) of l-methyltetrazol-5-ylthiol and 0.42 ml 25 (3*0 mmoles) of triethylamine under cooling at 0 °C and the mixture stirred at room temperature overnight. After termination of the reaction, the mixture is poured into ice water. The obtained yellow precipitates arc collected by filtration, washed and dried to yield 1-007 g of the objective O-totrazolylthio derivative 30 (V i R=PhCH20C0 ; Z^sCHPhj ; Y=l=methyltetrazol-5-ylthio) as yellow - J3 - 43459 powder (86.7 £ yield).' IR j ν2£Χ3 co-1 . 3ί>50§ l8o5, 1730.

NMR * 6CDC13 ppm j 3*93(s,3«), 4.28(ABq,J=l8Hz,2H), 5.00(d,J=4.01Iz, 1H), 5·17(β,2Η), 500 - 5.90(0,211), 6.98(a,l!l). 2) To a solution of 137 mg (0.229 ooolee) of the 3** tetrazolylthio derivative prepared above (V : RsPhCH^OCO ; Zjs CUPh2 » Y=l-oethyltetrazol-5-y·* thio) in 4 ml of methylene chloride are added 0*223 ®1 (2.06 mmoles) of aniaole and a solution of 190 off (1.4 mmoles) of aluminum chloride in 2 ml of nitromethane, and the 10 mixture allowed to stand at room temperature overnight and mixed with 3 ml of 2 % hydrochlorlo acid under ice-cooling. The aqueous layer is washed with methylene chloride and then acetic acidr and concentrated. The concentrate is adjusted to pH 2.5 with sodium carbonate to yield 24 mg of tho objective 7p-amino-3-15 tetrazolylthio derivative (l : Rl=l-methyltetrazol-5-ylthio ; R2=C00H ; R-*=H) as crystals, mp. >200 ®C IR : cra-1 : 1820, I63O, 1020.

Example 4 20 7B-amino-*l-CTothoxr-l-oxa-l-dcthia-3-cephem-4-carboxvlic acid (I : R^OCHj t Racoon : n3r-lO(ld i R2=C00H ; Z^CHj) 1) To a solution of 1.15 g (2.30 nmoles) of 3-hydroxy derivatives (H : RsPhCH^OCO ; Z^CHPhg) in 12 ml of methylene ohloride is added a mixture of >1j azomethane and ether, and. the 25 mixture stirred at room temperature for 10 minutes and evaporated under reduced pressure. The obtained oily residue is chromatographed on a column of 50 g of silica gel and eluted with benzene-ethyl acetate (4 : l) to yield 0.89 S of the objective J-mothoxy derivatives, diphonylroethyl 7P-henzyloxycarbonylamino-3-methoxy-30 l-oxa-l-dethia-3-ccphaia-4-carboxylatc (75 # yield). - 19 - 4041*9 ^ IR i cm”1 : 3*95, 1796, 1725, 1626, 1512.

KMR : 6CDC13 ppm : 3.70(s,3ll), 4.23 and 4.54(AJBq,J=l8Hz,2H) , A.96(d,J=4.Oil*, 1H), 5.18(8,211), 5.42(dd,J=10Hz;4.0IIz,lH), 5-8l(d, JbIOHz.IH), 7.02(s,1H),'-7.4(m,aromatic H).

I 5 2) To a solution of 1.06 g (2.06 mmoles) of the 3-mothoxy I derivative prepared above (VI : RsPbCHgOCO ; Z1=CMPh2 ; Z^sCH^j) I in 20 ml of methylene chloride aio added 3 el of anisole and 3 °1 I of trifluoroaeetie acid under cooling, and the mixture stirred I for 15 minutes, mixed vith 20 ml of toluene and then evaporated I 10 under reduced pressure. The oily residuo is dissolved in benzene I n.1 extracted vith 5 £ sodium hydrogencarbonate aqueous solution.

I The ox tract is washed vith benzene, adjusted to pH 2 vith 10 i .

I m I hydrochloric acid and then extracted vith ethyl acetate again.

I The extract is vashed vith vater and sodium chloride aqueous solution, I 15 and evaporated under reduced pressure to yield Ο.67 S of the free I 4-carboxylic sc id compound, 70-benzyloxycarbonyiamino-3-methoxy-l- I oxa-l>dcthia-3>ccphem-4-carboxylic acid.

I IR : cm”1 s 3430, 1793. 1725. 1630, 1510.

I 0luX I 3) To a suspension of 100 mg of 5 % palladium — charcoal I /0 in 20 ml of a mixture of ethyl acetate and methanol(l : l), on which I hydrogen gas has preliminarily been adsorbed, is added 200 mg I (0.934 mmole) of the free 4-carboxylic acid compound prepared above, I and the mixture is vigorously stirred in hydrogen atmosphere· I The reaction mixture is stirred at room temperature for 2 hours I 25 end the catalyst filtered off. The filtrate is evaporated under I reduced pressure to yield 65 mg of the objective 7?—amino compound I (I 5 R^OCH-j ; R2=C00H ; R3=II)(53 £ yield).

I IR * vS* cm-1 : - 3400, - 2900, 1785, 1679, 1647- max I The catalyst filtered off in the above operation is washed I jq with methanol-hydrochloric acid several times and the washings are I . 20 - 1 t · -I - 1 ·' » ~A a i ΰ d tmino obenzyl RleCl i . «.

H) on of 4-‘ n a ol ocular .5 hours. um mo nutes. of porated column ves, 3-chloro- ’ y- ^ IR : cm-1 s 1780, 1735. 1680, 1520. 13*5- KMR s 6CDC13 ppm : l.*8(s,l8H), 3·<»ΐ(β,3Η), .*».49(s,2H) . 5·23(·» 1H), 5.4*(aromatic H), 8.53U»111)· 2) To a solution of 125 me of the 7-mothoxy derivative 5 (· : R^-aCl ; R^sCOOCI^'C^lI^ *N02-p ; 7p>side cha in=3,5-di-t-butyl- 4-hydroxybenzylidencamino) in a mixture of methanol (2<5 ml) and tetrehydrofuran (o.5 ml) is added 81 mg of Girard reagent, and the mixture stirred at room temperature for 1 hour, poured into vater and extracted with methylene chloride. The extract is 10 vaehed with vater, dried ond evaporated under reduced pressure.

The residue is chromatographed on a column of'3.5 g of silica gel and eluted with benzene-ethyl acetate (4 : l) to yield 35 mg oP" the objective 7-amino derivative (I : R*=C1 ; R^sCOOCHg*C(jH^«NO^-p · R^sOCH-j )(43-8 yield). 13 : vmaxl3 cmml ! 1790, 17*0, 1520, 1350.

NMR : 6CDC13 ppm : 1.83(bs,2H), 3-53(s.3H), 4.54(s,2H), 5-0l(s. 1H), 5.47(split,2H), 7.67(d,J=9Hz,lH). 8.28(d,J=9Hz,lH).

The following compounds may be prepared in any of the manners as mentioned above. 22 p-nitrobenzyl 7P-omino-l-oxa-l-dethia-3-cepheni-4-carboxyiate (I : R^H; R2=C00CIl2*C6Hit.N02-p ; R3=H) IR ·’ νΞϋ?13 cm~X : 3*05» 1772, 1726, 1633, 1605, 1517, 13*5. max NMR : 6CI)C13 ppm : 1.7*(b,2H), 4.6l(m,2H), 5-05(d,J=4.0Hz, 1H) , 5.*2(bs-2H), 5.5(m,lH), 6.6l(m,lH), 7-6? and 8.3l(q,J=9-OHz,4H). p-nitrobenzyl 7p-amino-3-methylsulfonyloxy-l-oxa-l- dethia-3-cophom-4-carboxylato (i : R^OSO^CHj ; R2=C00CH2*-NOg-p . r3=H) IR : vJIaI^13 cm-1 : 3420, 1790, 1735, l6l0.

KMR : i-CPC13 ppm : 2-15(br.,.?ll), 3.2j(s,3U), 4.52(s,2H), 5-02(d, 30 J =4 Hz. HI) , 5-3^(^.211). 5-33 (m. Hi). 7-43 and B.n>(q,J=8.0Hz,4ll). - 22 - H-4C.Jb3 >-3-pl»onyl ίΜο-Ι-οχα-Ι-κΙοΙΜα^-ΟθρΙιοιβ-Ιι-Ε s R^S.Ph j R2bC00H ; R3sll). tnylmcthyl 2-[2ζ-(2-ρΓορ1η/1οχγ)-3β-ω»Χπο-4-οχο- sopro-pylideneacetate (2 : a^eCHPlbg) --—— >•95 g of diphenylmothyl 2-(2C-chloro-3p-amino- )-2-isopropylldeneacotate (l : Z^sCHPh^ > XjeCl) opargyl alcohol (3 ml) and tetrahydrofUran (2 ml) mmoles) of silver tetrafluoroborato, and the ; room temperature for 3 hours· diluted with cooled to 0°C and mixed with a mixture of 10 ml ogencarbonate aqueous solution and .5 ml of hloride aquoous solutiori. The reaction mixture tcred through Celite {registered Trade Hark). The ib benzene layer ie separated· dried over Glauber's salt and evaporated under reduced pressuro. The obtained brown oily materials are purified by chromatography on a column of silica gal containing 10 ή» water and elutod with benzene-ethyl acetate (i : l) to yield 263 mg of the 120 objective 25-propinyloxy derivative (2 : Z^sCHPhj){13¾ mg of 2a-propinyloxy derivative and 13¾ mg of 2p-propinyloxy derivative). 2a-propinyloxy derivative : 111 * vSaSl3 c®*1 i 3*100, 3320, 2115· 176?. 1723- NMR j $CDC13 ppm . i.83(brs,2li), 1.98(s,3!l), 2.22(s.3ll), 2.33(t# 25 J=2.5Hz.lH), i».07(d,J=2.5Hz,2H) , ca4.07(m.lH) , A.?3(d. Jsl-OHz,1H) . 6-90(s,1H). 7-32(s,10H). 2P-propinyloxy derivative ; 1IR : cm-1 : 3*10, 3320, 2115. 1767. 1720.

NMR : 6CDC13 ppo, . l. 77(brs ,2H), 2.00(s,3ll), 2-23(.-,.311). 2-27(t, ) J=2.5Hz,lH) , i».12(d,Ju2.5Hz,2H}, 1». 23(d , J*·’» .OHz.lll) , 5.27(d, 1H), 6.9θ(β,1H), 7-32(s,10H). - 23 - 4B4S9 2) diplienylmethyl 2-(2P-(2-propinyloxy)-30-bcnzyloxy-carbonylamino-4-oxoazetidin-l-yl]-2-isopropylideneac oto to (3 * RsPhCHgOCO ; ZX=CHPh2)---------------------- To a solution of 30.0 g (0.07¾ nolo) of 2p-propinyloxy derivative 5 (2 ϊ 2*=CHPh2) in 250 ml of dry methylene chloride is added 14.07 S (0.O825 mole) of benzyloxycarbonyl chloride undor ice-cooling and dropwiso added a mixture of pyridine (6.7 mmoles ; 0*0825 molo) and methylene chloride, and the mixture stirred for 30 minutes undor cooling, poured into ice water and extracted with methylene 10 chloride. The extract is washed with water and sodium chloride aqueous solution, dried-and evaporated undor reduced prossuro.

The obtained oily residue is chromatographed on 1000 g of silicA. gel and olutod with benzene-ethyl acetato (5 : l) to yield 26.5 8 of the objective 3P-benzyloxycarbonylamino derivative (3 : R= 15 PhCH20C0 ; Z1=CHPh2) (66.3 * yield). 111 5 ν®®*ι3 cmT* 5 3440 , 3300 , 2110, 1774, 1720, 1630. 1507· XQo> KKR s 6^^13 ppm : 2.00 and 2.25(s,3H x 2), 2.17(d, J=3Hz,lH) , 4.07(d,J=s3Hz.2H), 5«10(d,Js4Hz,lH), 5-l7(s,2H), 5.33(q,J=8Hz,4lfz, 1H), 5.55(d,J=8Hz,lH), 6.98(s,lK). 3) diphenylmethyl 2-(2p-allyloxy-3P-benzyloxycarbonylamino- 4-oxoazetidin-l-yl)-2-isopropylideneacctate (4 : RsPhCHgOCO ; Z1=0HFb2) --------------------------------------------- To a suspension of 6.6 g of 5 ί palladium-calcium carbonate in I70 ml of mothanol, to which hydrogen gos has boon adsorbed with 25 stirring, is added a solution of 26.5 g (θ·0·»9 mole) of 30-benzyloxycarbonylamino derivative (3 : R=PhCJI,,0C0 · zlsCHPhj) in 100 ml of methanol, and the mixture stirred for 50 minutes under hydrogen atmosphere. The catalyst is filtered off and tho filtrate evaporated under reduced pressure to yield 26.3 g 30 Of 20-allyloxy derivative (4 : R=PhCH20C0 ; z1=CHPh2) (98.8 4>) - 24 - I ·»5·1ΰ9 I 1 » I v2!Jl3 cm”1 : 3440, 1772, 1720. 1628, 1505· 1 MMR t 6CDC13 ppm s 2.00 and 2.25(s.3H x 2), 3«90(m,2H), 4.8 - I 5»9(«.6H), 5.17(s,2H), 6.95(o,m) 1 -·- 4) diphenylmethyl 2-[2β-(2,3-epoxypropoxy)-30-benzyloxy- Tll'-JwZ:··; \ ’ 4Ii^···'· carbonylamlno-4-oxoazetidin-l-yl]-2-isopropylideneacetate (5 ‘ I **i^fc*‘ 1 R=PhCH20C0 } Z1=CHPh2) · ---------------------- I To a solution of 25·6 g (0.047 mole) of tho 2p-allyloxy derivative 1 (4 t B=PhCH_0C0 ; Z^=CHPh_) in 26Ο ml of chloroform is added 13*3 6 I Λ . * 1 (0.071 mole) of m-chloroperbenzoic acid little by little* and the I xo mixture allowed to stand at room temperature (23 - 25 °C) for 2 1 days and evaporated under reduced pressure. The residue is dissolvod I in ethyl acetate* and washed with 5 £ sodium thiosulfate aqueous. 1 # 1 solution, 5 % sodium hydrocencarbonate aqueous solution, water and I 1 1 thon sodium chlorido aqueous solution. Tho solvent is evaporated 15 undor reduced prossure to ylold oily residue, which is chromatographed on a column of 800 g of silica gel and eluted with benzene-ethyl acetate (5 s l) to yield 21.25 g of the objective epoxy derivative (5 : R=PhCH20C0 ; Z1=ci3>h2)(81.2 1> yield).

IIR s cm”1 : 3445, 1778, 1724, 1632, 1508.

KMR ·. 6CDC13 ppm : 2.00 and 2.25(s,3H x 2), ca 2.2 - 3-9(m,5H), 5.l9(s,2H), ca 5-0 - 5-3(®.2H), 5-58(d,J=10Hz,lH), 6.83(s,lH).

A small quantity of diepovy derivative (2.15 S > ®P- 118 * 120 °C) is obtained as by-product in this process. ) diphcnylraethyl 2-[2β-(2,3-dihydroxypropoxy)-?,»·· 25 benzyloxycarbonylamino-4-oxoazetidin-l-yl]-2-isopropylideneacetate (6 : RePhCH^OCO ; Z1=CHPh2) ---------------------------- To a solution of 21.25 g (Ο.Ο38 mole) of the epoxy derivative proparod above (5 : R=PhCH20C0 ; Z1eCHPh9) in 220 ml of acetone 1 . are added 66 ml of 30 $ perchloric acid and 44 ml of water wider 20 ice cooling, and the mixture stirred at room temperature for 2-3 i I - 25 - I*aiso ·-,ν-» hours and extracted vith ethyl acetate. The oxtract is washed Vith 5 % sodium hydroffencorbonate aqueous solution, water and then sodium chloride aqueous solution, dried and evaporated under reduced pressure to yield 20.6 g of the objective diol 5 derivative (6 t ftaPhCH20C0 ; % yield).

X» i vjjjjjb cm"1 » 3600, 3hk5, 1778» 1725. 1632, 1508.

HMR t 6CDC13 ppa j 1.97 and 2.22(s»3H x 2). 3·47(β.ί»Η), 4-9 -5.3(m,2H), 5·13(β,2Η), 6.07(m,lH), 6.97(s,lH). .

In a similar manner, the 2P-propionyloxy oerivative IO (2 : Z1oCHrh2) is reacted vith phenylacetyl chloride to yield the 3p-phenylacetamide derivative (3 ’ R=PhCII2C0 ; Z^CHPl^) and the latter is subjected successively to hydrogenation, epoxydation and cleavage of epoxy ring to yield diphenylmethyl 2-[2p-(2,3-di-hydroxypropoxy)-3P*-phenylacetamido-ii*-oxoazetidin-l-yl3-2-iso-15 propylideneaoetoto (6 : RsPhCH^CO ; Z^-CHPhg)· Example 7 1) diphonylmethyl 2-[2β-(2,3-isopropylidenedi oxypropoxy)-3P-benxyloxycarbonylamino-4 oxoazotidin-l-yl ]-2-isopropylideiie- aoetato (13 : R-PhClI20C0 ; Z1=CiIPh2) ------------------------ 20 To a solution of 2.5 g of diphenylmethyl 2-[2p-(2,3-dihydroxy-propoxy)-3P-bonzyloxycarbonylamino-4-oxoazetidin-l-yl]-2-iso-propylidonoacetate (6 : RsPhCHgUCO ; Z*=CHPh2) in 50 ml of acotone is added 5 mg of p-tolucnesulfonic acid under ice-cooling, and the mixture stirred for 3 hours, mixed with a small amount of 3 % sodium 25 hydrogencarbonato aqueous solution and evaporated under reduced pressure. The rosidue is dissolved in ethyl acetate, washed with vster, dried, and evaporated. The obtained residue is chromato-graphed on a column of silica gel and eluted with benzene-ethyl acetate (2 : l) to yield 2.26 g of tho objective isopropylidenedioxy 30 derivative (13 : R*PhCH20C0 ; zl=CHPh2)(84.# yield).

J - 26 - >v * 3 J ϋ 9 :/ι IR i v2?3 e™”1 * 3*50, 1780, 1725· 1<»35. 1&>0.

HHR I 6CDC13 ρρβ , 1.28(β,6Η), 2.00(β,3«). 2·25(β»3Η), 3.25 - ^ 4.20(m,5H), *.90 - 5.77(m,5H), 6.95(e,lll), ca7.3(m,l5H)· 2) diphenylmethyl 2-[2β-(2,3-lsopropylidenodioxy- 5 propoxy)-3P“benzyloxycarbonylamino-4-oxoazotidin-1 -yl]-2- hydroxyacetate (l5 : RsPhCHgOCO ; Z1=CHPh2) —----------- • » Into a solution of 2.2 ( (3.38 mmoles) of the isopropylidenedioxy derivative prepared above (l3 : RsPhCttjOCO ; Z^-aCHPhj) in ml of methylene chloride is Introduced ozone under celling with dry 10 lee-acetone until the nixture turns blue. The sxcoss amount of ozone is removed, and the mixture mixed with 22 ml of methyl sulfide and allowed to stand under cooling at the sane tespoVAture for 1 hour and then at room temperature for 1 hour. The mixture Is mixed with a small amount of acetic acid, washed with water, 15 dried and evaporated to yield 2 g of the intermediate, 1-diphenyl- nethoχalyl-2ί^-(2,3-isopropylidenedioxypropoxy)-3β-ben^yloxycaΓbonyl- amino-4-oxoazetidine (l4 : RaPhCH^OCO jZ^sCHPl^)· This is dissolved in a mixture of 20 ml of methylene chloride and 20 ml of acetic acid, mixed with 2 g of activated zinc powder, and stirred for 2 20 hours under ice-cooling. Zino powder is filtered off and washed with methylene chloride. The filtrate and the washings are combined, wasehd with water, dried and evaporated to yield 20 g of the objective 2-hydroxy derivative (15 : RsPhCH^OCO j zI=CHP1>2) (95 * yield).

CHC1 25 I® * vmax 3 cn 5 3500, 3*30, 1780, 17*0, 1720, 1600.

NHR s 6CDC13 ppm : 1.47(s.6H), 3.17-4.30(m,5-<>H, 5.l6(s,2H), 4>70-6.00(m,3-4H), 6.97 and 7·00(β, 1H x 2), ca 7·3(®,aromatic H). 3) diphenylmothyl 2-(2p-(2,3-risopropylidenodioxypropoxy)-33-bei»zyloxycarbonylamino-4-oxoazotidin-l-yl]-2-tripJienyl- 30 phosphoranylidoneacetate (l6 : RaPhCH20C0 ; Z1=Cia,h2)---------— - 27 - ι To a solution of 2.0 g (3*4 mmoles) of 2-liydroxy dorivativo (l5 : RsPhCHgOCO ; Zl=Cl£Ph2) in 60 ml of dry methylene chloride is added 1.3 ml (l.02 mmoles) of dimethylanilino under ice-cooling and dropwiso added 0.74 ml (l»02 snolos) of thionyl chlorido, 5 and the mixture stirred at the same temperature for 30 minutes· and poured into Ice water. The methylcno chloride layer is separated and washed with water» dried and evaporated to yield 2*3 g of the intermediate, dlphenylmethyl 2-[2(l-(2,3-iso- propylidonedioxypropoxy)-30-benzyloxycarbonylaoino-4-oxoazetidin- 10 1-yl3-2-chloroocetate [iR : cm“l : 3436, 1785· 1750, 1720, 1595*3* This is dissolved in 40 ml of methylene chlorido an4v * mixed with 0*86 ml (6.8 mmoles) of dimethylaniline and 1.8 g (6.8 mmoles) of triphenyiphosphine. The mixture is refluxed under heating for 6 hours, mixed with additional 1·8 p of triphenyl-15 phosphine, reacted for 12 hours, poured into 5 % sodium hydrogen-oarbonato aqueous solution under cooling, washed with water, dried and evaporated. Tho residue is chromatographed on a column of silica gel to yield 1.6 g of the objectse triphenylphosphoran dorivativo (16 : R=PhCHo0C0 ; Z*=CHPh2)(56.6 yield).

IR .♦ cm"1 : 3400, 1760, 1710, 1620, 1590. 4) dlphenylmethyl 2-[2p-(2,3-dihydroxypropoxy)-38-bonzyloxycarbonylamino-4-oxoazotidin-l-yl]-2-triphcnyl- phosphoranylldeneacetote (l7 s RsPhCHgOCO ; Z*sCKPh2) -------— To a solution of 417 mg (0.5 mmole) of triphenylphosphorane 25 derivative (16 ; R=PhCH20C0 ; Z*=CHPh2) in 8 ml of methanol is added 1.6 ml of 10 hydrochloric acid,and the mixture stirred at room temperature for 40 minutes, poured into cooled 5 ί> sodium hydrogoncarbonato aquoous solution and-oxtractod with othyl acetate. The extract is washed with water, dried and ovaporated.

' The residuo is chromatographed on a column of silica gol to yield - 28 - I ·« ΰ 1 1» i> I w I 172 mg of the objective acotonlde free derivative (17 : R= I PhCHjOCO j Z^CHPh^^O * yield).

I JR t vC0!lh cm”1 : 3450 — 3200, 1770, 1720,'1630, l600.

I 5) dlphenylaethyi 7P-benzyloxycarbonyiamino-l-oxa-l- I 5 dethia-3-cephem-4-carboxylate (XV : R=PhCH20C0 ; Z1sClQ?h2) “ I To a solution of 139 mg (0.175 mmole) of the aqetonide free I derivative (17 : RsPhCHjOCO ; zl=CHPh2) in 4 ml of tetrahydrofuran I ia added periodic acid consisting of sodium periodate (43 mg) I and ΙΝ-aulfuric acid (2*2 ml) under ice-cooling, and the mixture I 10 stirred at the same temperature for 3 hours and at room temperature I for 1 hour, poured into ice water, and extracted with ethyl I * .

I acetate. The extract is washed with water, dried and evaporated.

I The rosidue is purified by chromatography on a column of ailica I gel to yield 15 mg of the objective protected oxacephom derivative I 15 (IV : JUPhCHgOCO ; Z1«CRPb2) (17·7 % yield).

I This product la confirmed to be identical with an authentic I specimen prepared by an alternative route in Example 2 in thin I layer chromatography, XR spectrum and NMR spectrum.

I Example 8 20 1) diphcnylmethyl 2-[2p-(2-oxoethyloxy)-3P-bonzyloxy- carbonylamino-4-oxoazetidin-l-yl]-2-ieopropylideneacetato (7 s ItsPhCHgOCO J z!=CHPh2) --------------------- To a solution of 11.3 g (0.02 mole) of diphenylmethyl 2-Γ2β- (2,3-dihydroxypropoxy)~3p-ben 2yloxycarbonylamino-4-0X08zetidin- 25 l-yl]-2-isopropylideneacetate (6 : R=PhCH20C0 ; Z^CHPhg) in 200 ml of ethanol is added a solution of 5-14 g (0-024 mole) of sodium periodate in 210 ml of IN’-sulfuric acid, and the mixture stirred at room temperature for 30 minutes, poured into ice-water, and extracted with ethyl acetate. The extract is washed with 30 water and sodium chloride aqueous solution dried and evaporated - 29 - «ΰ4!>0 I Under reducod prossuro to yield 10.8 g of the objective formyl derivative (7 : R=PhCU?OCO ; Z^CHPhj). B IR , vCHC13 cm"1 : 3445, 1778, 1725, 1632. 1508. B max 2) diphenylmethyl 2-(2P-methoxycurbonylmothoxy-3d- B toenxyloxycarbonylomino-J»-oxoazeti (8 j R=PhCH20C0 ; Z^CHPhgj Z^CH^)---- B To a solution of 10.8 g of the formyl derivative (7‘- R=PhCH20C0 ; Z^sCIlPhj) in 100 ml of acetone is added 14 ml of* Jones reagent B at a temperature below 15 "C undor ice-cooling with stirring. H After 30 minutes, the reaction mixture is mixed with isopropanol H and an oxcess amount of the reagent decomposed. Tho insoluble^ materials are filtered Off, and the filtrate is poured into ice H water and oxtracted with ethyl acetate. The extract is washed with water and sodium chloride aqueous solution and evaporated under 15 reduced pressure to yield 11.1 g of the carboxylic acid compound I (8 s R=J>faCH20C0 i Z^CHPhg, Z2=H) as crude product. B This is dissolved in 150 ml of methylene chloride and mixed with I diazomethane-ether for esterification, and evaporated.

The residue (ll g) is chromatographed on a column of 200 g of H silica gel and oluted with benzene - ethyl acetate (5 : l) to yield 9>2 g of the objective methyl carboxylatc compound (8 : B R=PhCH20C0 ; Z^CHPhg ; Z2=CH3) (80.3 yield). B Π» : wSS1^ cm*1 : 3kk5, 1780, 1725, 1635. 1510. B MMR : 6CDC13 ppm : 2.00 and 2.25(s, 3» x 2), 3-58(s,3H). 3-97(s, B 2H), 5.0-5.40(m,2H), 5<13(a,2H), 5.77(d,J=8IU,lH), 6-93(s.1H). B 3) l-diphcnylmcthoxalyl-2p-iuethcxyc.-irbonylmcthoxy-3P- B bonzyloxycarbonylamino-A-oxoazetidine (9 : R-PliCIlgOCO ; Z^sCUPhj ; I Z2aCH3) ---------------------------------------------------- B To a solution of 9.2 g (0.0l6 mole) of the methyl carboxylate prepared H above (8 : R=PhCH2OCO ; Z*=CllPh2 · Z2=CH3) in 230 ml of methylene H AZlliQ I v 5 chlorldo in Introduced ozono under cooling at -78 °C. The roaction mixturo turns bluo aftor about 30 minutos, and thon nitrogen gas I - is Introduced to remove an excoss amount of ozono· The mixture I is mixed with 10 ml of dimethylsulflde under cooling - 78 °C, I stirred at the same temperature for 1 hour and then at room temperature I 10 for 1 hour, mixed with methylene chloride and 2-3 drops of acotic I acid* washed with water and sodium chloride aqueous solution, dried I and evaporated to yield 8.9 g of the objective me'thoxalyl deriva tive (9 s RsPhCHgOCO J Z^sCBPhg ; Z2aCHj) as oily material. 3» s v°”C13 cm"1 : 3*50, I83O, 1756. 1720, 1509- I OBX I 15 4) diphenylmethyl 2-(2β-methoxycarbonylmathoxy-3P-benzyl- I oxycarbonylamino-4-oxoazetidin-l-yl)-2-hydroxyacetate (10 : I RxJhCIl^OCO ; Z1=CHPh2 ; zKcHj)------------ I To a solution of 8.9 g of the methoxalyl derivative prepared above I (9 : R=PhCH2OCO ; Z1«CHPh2 ; Z2=CH^) in a mixture of 90 ml of methylene I 20 chloride and 90 ml of acetic acid is added 9 g of activated zinc I powder under ice-cooling with stirring. After 15 - 30 minutes, I sine povder is filtered off, and the filtrate is mixed with methylene I chloride, washed with water and sodium chloride aqueous solution, I dried and evaporated under reduced pressure to yield 8.4 g of the I 25 objective hydroxyacetlc add derivative (10 : R=PhCH20C0 ; Z1=CHPh2 ; I 2^(3^)(95.2 * yield).

I IR * VS?3 cm~1 s 3500 - 3600 , 3445. 1796, 1747. 1512.

I 5) diphenylmethyl 2-(2p-methoxycarbonylmethoxy-3P-benzyl- I orycarbonylamino-4-oxoazetidin-l-yl)-2-chloroacetate (ll : R= I 30 PhCHgOCO ; Z1=CHPh2 ; Z^CH^ ; X-=01) -------------------- I To a solution of 8.4 g (0.015 mole) of the hydroxyacetlc acid I prepared above (10 : R=PhCH20C0 ; Z1sCHPh2 ; ZZ=CH^) in 100 ml of I dry methylene chloride are dropwise added 3.34 ml (0.046 mole) of I thionyl chloride and 1.46 ml (0.018 mole) of pyridino under ice- 1 I - 31 - ISO ^ cooling with stirring, ond tlio mixturo stirred for 30 minutes under Ice-cooling, nixed with an appropriate amount of methylene chloride, washod with water.and sodium chloride oquoous solution, dried and evaporated under reduced pressure to yield 8.9 £ of tho objective 5 monochloroacetic acid derivative (ll : RsPhCI^OCO ; Z^sCHP^ ! Z2=CH3 i X"=Cl).

IB :ν®ϊ?3 cm-1 : 3^35. 1790, 17*8, 1725, 1502. 6) diphonylmethyl 2-(rp-carbomethoxy-3P-benzyloxycarbonyl-eaino-4-oxoazetidin-l-yl)-2-triphcnylphosplioranylidcneacetate 10 (»2 j R=PhCH20C0 ; Z1=CHPh2) ------------------------- Tc a solution οΓ 8·9 β (0.015 mole) ol’ tho monocbloro derivative prepared above (ll : U=Phai20C0 ; Z1=ClIPh2 ; Z2=CH3, X"=Cl) in*-* 100 ml of methylene chloride is added 8.0 £ (0.03 mole) of triphenyl phosphine and the mixture refluxed under heating for 1.5 15 hours, mixed with additional 2-0 £ (7*5 mmoles) of Iriphonylphosphine and refluxed under heating again for 1 hour. The reaction oiixturo is poured into 5 sodium hydrogencarbcnate aqueous solution, neutralized, and extracted with -othylcno chloride. The extract is washed with water and sodium chloride aqueous solution, dried and 20ovaporated under reduced pressure. The residue is chromatographed on a column of 300 g of silica gel and eluted with benzene-ethyl acetate (k : 1 - l : l) to yioid 10.2 e of tho objective methyl trlphenylphosphoranate derivative, diphenylmethyl 2-(23-mothoxy-carbonylme tho xy-3p-benzyloxycarhoriylamino-i»-oxoazetidin-l-yl )-2-25triphcnylphosphoranylideneacetatc (84.1 # yield). • 111 ! vmU£l3 c“"1 : 3^5. 1790, 1725, I630, 1512.

NMH : 5CDC13 pprn . 3.58(5,311), 3.6 - 5·2(ιτ.,4κ), 5.07(s,2Il).

To a solution of llS.23 g (20.5 mmoles) of the methyl triphcnylphosphoranato in 240 ml of tctrahydroi'uran is dropwiso added 30118 ml (22.5 mmoles) of sodium hydroxide aqueous solution (θ·19 mmole/ - 32 - . 4ί>ίί>3 5 ml) under cooilng at 2 - 3°C in a period of 30 minutes· and the mixture stirred for 15 nilnutos, neutralized with 44 ml (23 mmolos) of 2 £ hydroehlorio acid and extracted vith ethyl acetate· . Tho extract la washed vith water and sodium chloride aqueous solution, driod and evaporated to yield 15.8 g of the objective 10 trlphenylphosphorono' derivative (12 t R=PhCH20CQ. j Z1=CHPh2). » * v2SA3 cm-1 * 3440, 1773» 1725, 1625, 1510· 7) diplienylmethyl 7β-benzyloxycarbonylamino-3-hydroxy- l-oxa-l-dothia~3-cephem-4-carboxylate (il : R=PhCH20C0 ; Z^= CHPh2)---------------------- 15 To a solution of 15· 8 g (20.3 mmolos) of triphenylphosphorane * derivative prepared abdve (l2 : RsphCHgOCO ; Z^sCIIPh2) in 300 ml qf dry tolueuo aro added 4l.4 g (406 mmoles) of acetic anhydride and 8.87 g (102 nmoles) of Ν,Ν-dimethylacetamide» and the mixture heated at >100 - 105 °C (bath temperature) for 16 hours.

Aftor coolinc, tho reaction mixture is mixed with benzene, washed with vator, sodium chloride aqueous solution and then water, driod and evaporatod under reduced pressure. The residue (ca 20 g) is chromatographed on a column of 600 g of silica gel and eluted vith benzene-ethyl acetate-acetic acid (9 : 1 5 0.00¾ to yield 25 5.08 g of the main product, diptoenylmothyl 3-acetoxy-7p-benzyloxy- carbonyiamino-l-oxa-l-dethia-3-cephem-4-carboxylate (hereinafter abbreviated to 3-acotoxy compound)(48 $> yield) and 3.25 g of byproduct, diphenyliuothyl 2-(2-benzyloxycarbonyl-3,8-dioxo-5-oxa- 2,7-diazabicyclo [4.2.0] octan-7-yl)-2-triphenylphosphoranylidene-30 acetato (21.5 £ yield).

Physical constant of 3-acetoxy compound : IR : vCIIC13 cm”1 : 3445. 1800, 1785, 1725, 1656, 1508.

NMR : 6CDC13 ppm : 2.00(s,3Il). 4.32(s,2H). 5-05(d,J=4Hz,1H)\ 5.13(s,2H), 5O8(q,J=4Hz;10Hz,lll), 5·68(d,J=10Hz,1H), 6.95(s,lH). - 33 - I v-sati# I Physical constant of by-product : I XR j VC,,C13 cm"1 : 1790, 1778, 1740, 1028.

I max I KMR : ppm : ‘3-4(m,2H), 4-5(m,21l), 5;27(s,2H).

I Hie 3-acctoxy compound (3*2 g i 5*9 nmoles) prepared I 5 above is dissolved in a mixture of 60 ml of pyridine and 12 ml of I water under cooling, stirred at room temperature for 1.75 hours, I poured into ice water and extracted with ethyl acetate.

I The ethyl acetate layer is washed with 10 £ phosphoric acid, water, I pnri then sodium chloride aqueous solution, dried and evaporated I lo under reduced pressure to yield 3*05 S of the objective 3-hydroxy I compound (II ; RsPhCHgOCO ; 21=CHPh2) as whito foamy material._ _ I XR : cm"1 : 3440, 1795, 1725. 1675,. 1510.

I NMR ; 6CDC13 ppm : 4.37(s,2H), 5-05(d,J=4Hz,lH), 5.l8(s,2H)« I 5.45(q.J=10H2,lH), 5.72(d,J=10Hz,lH), ?.00(s,lH), 10.83(s,1H).

I 15 This product may also be employed as the starting material I in Example 1. « - 34 -

Claims (32)

1. 2. A compound of the formula: B2N o l2 wherein X Is halogen or sulfonyloxy and R2 Is as defined 10 In claim 1.

2. 3. A compound of the formula: H2N \_/ ° 0J—Νγ^ R2 2 wherein R is as defined In claim 1 - 35 - w 40490

3. 4. A compound of the formula:- 'XX R2 wherein Y is arylthio or monocyclic heterocycle-thio 2 and R is as defined in claim 1. 5 5. A compound of the formula:- οA-νΑ023 i2 3 2 wherein Z is lower alkyl and R is as defined in claim 1.

4. 6. A compound of the formula:- OCH —XXv R2 1 2 10 wherein R and R are as defined in claim 1. - 36 - 4ί$4!>9 7. "Jp-amino-3-chloro-l-oxa-l-de thia-3-cephem-4-carboxylic acid. 8« 7p-amino-l-oxa-l-dethia-3-cephem-4-carboxylic acid. 9. 7p-amino-3- (l-methyltetrazol-5-yl) thio-l-oxa-1- S dethia-3-cephem-4-carboxylic acid. 10. 7P-amino-3-methoxy-l-oxa-l-dethia-3-cephem-4- _ ^ carboxylic acid. 11. p-nitrobenzyl t* -amino-3-chloro-7*-methoxy-l-oxa-l-de thi'a-3-cephem-4-carboxyl ate. 10 12. A compound as claimed in claim 1, wherein ia a group as listed hereinbefore in exemplification of R*.

5. 13. A compound as claimed in claim 1 or claim 12« 2 wherein R is a group as listed hereinbefore in exemplfication of R2. 15 14. A salt of a compound as claimed in any one of claims 1 to 13.

6. 15. A salt as claimed in claim 14 which is an acid addition salt at the 7-amino group. - 37 - >43 4 5 9 I

7. 16. A process for preparing a compound as claimed in claim 1 which process comprises deprotecting the amino group I of a compound of the formula:- I ? I ςτ "vyA'· R1 I 6 wherein R is an amino protecting.group. I

8. 17. A process as claimed in claim 16, wherein the H deprotection is effected by hydrolysis or reduction.

9. 18. A process as claimed in claim 16 or claim 17, I wherein is halogen or sulfonyloxy in the product I 10 compound as claimed in cl Mm 1. H

10. 19. A process as claimed in claim 18, wherein I R^ is hydrogen, and R2 is protected carboxy in the H starting compound. H

11. 20. A process as claimed in claim 19, wherein the H 15 starting compound has been prepared by halogenation or sulfonylation of a compound of formula (II):- H „ *5459 ,RNH\__✓ 0\ cooz* , 2' being a carboxy protecting group.

12. 21. A process as claimed In claim 20, wherein halogenatlon has been effected by the use of a phosphorus trihalide, a 5 thionyl halide, a halogen, an oxalyl halide or a phosphorus oxyhalide.

13. 22. A process as claimed In claim 20, wherein sulfonylatlon has been effected by the use of an alkyl-sulfonyl halide or an arylsulfonyl halide.

14. 23. A process as claimed in claim 20 or claim 22, wherein sulfonylatlon has been effected in the presence of a tertiary amine.

15. 24. A process as claimed in any one of claims 20 to 23, wherein the compound of formula (XI) has been made by 15. method substantially in accordance with Reaction Scheme 2 starting at the beginning thereof or at any intermediate stage. - 39 - V-- <·5·1!»0

16. 25. A process as claimed in claim 16 or claim 17, wherein R* is other than halogen or sulfonyloxy in the product compound as claimed in claim 1. '26. λ process as claimed in claim 25, wherein R3 is 2 5 hydrogen, and R is protected carboxy in the starting compound.

17. 27. A process as claimed in claim 26, wherein R* _ in the starting compound is hydrogen.

18. 28. A process as claimed in claim 27, wherein the 10 starting compound has been prepared by reduction of a compound of formula (III) :- \γ—r"°N 0J— COOZ' , X being as defined in claim 2 and z' and R being as defined in claim 20. ^ 29. A process as claimed in claim 28, wherein the compound of formula (III) has been prepared from a compound of formula (XI) as defined in claim 20 by a method as defined in any one of claims 20 to 23. - 40 - <454 ί»9 %».

19. 30. A process as claimed In claim 29, wherein the compound of formula (II) has been made by a method as defined In claim 24.

20. 31. A process &j claimed in claim 27, wherein the 5 starting compound has been made by a method substantially In accordance with Reaction Scheme 4 starting at the beginning thereof or at any intermediate stage.

21. 32. A process as claimed in claim 16 or claim 17, . Φ wherein R* is arylthio or monocyclic heterocycle-thio 10 in the product compound as claimed in claim 1.

22. 33. A process as claimed in claim 32, wherein R^ is hydrogen, R* being arylthio or monocyclic heterocycle-2 thio and R being protected carboxy in the starting compound. 15 34. A process as claimed in claim 33, wherein the starting compound has been prepared from a compound of formula (III) as defined in claim 28 by reacting the compound of formula (III) with the corresponding arylthiol or monocyclic heterocycle-thiol in the presence of a weak 20 base or with the corresponding salt. - 41 - 1 *’ *

23. 35. A procc^j as claimed in claim 34, wherein the compound of formula (III) has been prepared from a compound of formula (II) as defined in claim 20 by a method as defined in any one of claims 20 to 23. 5 36. A process as claimed in claim 35, wherein the compound of formula (II) has been made by a method as defined in claim 24. • Α» . t

24. 37. A process as claimed in claim 33, wherein the starting compound has been made by a method substantially 10 in accordance with Reaction Scheme 6 starting at the beginning or at the intermediate stage.

25. 38. A process as claimed in claim 16 or claim 17, wherein R* is lower alkoxy in the product compound as claimed in claim 1. 15 39. A process as claimed in claim 38, wherein R^ 1 2 is hydrogen, R being lower alkoxy and R being protected carboxy in the starting compound.

26. 40. A process as claimed in claim 39, wherein the starting compound has been prepared by etherification of 20. compound of formula (II) as defined in claim 20. - 42 - ^ ----- »3di>9 41. λ process as claimed In claim 40, wherein the etherification has been effected by reaction of the compound of formula (II) with a trialkylorthoformate or an alcohol and p-toluenesulfonic acid or by alkylation 5 using a diazoalkane.

27. 42. A process as claimed in claim 40 or claim 41, wherein the compound of formula (II) has been made by a method as defined in claim 24. — . Φ

28. 43. A process for preparing a compound of the formula :- qoj3 R2 1 2 10 wherein R and R are as defined in claim 1, which process comprises methoxylating the 7α-position of a compound of the formula:- H2N j-

29. 44. A process as claimed in claim 43, wherein the methoxylation is effected substantially in accordance with - 43 - 40 4·*»* »A any one of the aforementioned methods of 7-roethoxylation . herein designated 1 to 4/starting at the respective beginning or at an intermediate stage thereof.

30. 45. A process as claimed in claim 4j or claim 44, 5 wherein the starting compound has been prepared in a process as claimed in any one of claims 19 to 24, 26 to 31, 33 to 37, or 39 to 4?.

31. 46. A process for preparing a compound as claimed in claim 1 and substantially as hereinbefore described. 10 47. λ process for preparing a compound as claimed in claim 1 and substantially as hereinbefore described in any one of the Examples 1 to 5.

32. 48. A compound as claimed in claim 1 or a salt thereof which has been prepared in a process as claimed in any one 15 of claims lb to 47. F. R. KELLY S CO. AGENTS FOR THE APPLICANTS. - 44 -