IE45459L

IE45459L - Cephalosporin analogues

Info

Publication number: IE45459L
Application number: IE771630A
Authority: IE
Original assignee: Shionogi & Co
Priority date: 1976-08-05
Filing date: 1977-08-04
Publication date: 1978-02-05
Also published as: FR2360594A1; CH637135A5; IE45459B1; NL7708722A; IL52668A; JPS5318597A; IL52668A0; CA1090336A; BE857482A; JPS609514B2; GB1552099A; DE2735408A1; FR2360594B1

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

4 S 4 t» i> * This invention relates to important intermediates in the preparation of novel cephalosporin analogues possessing potent antimicrobial actions. Particularly, it relates to 7P-amino-l-oxa-dothiacephalosporins. 5 Compounds in this invention are represented by the formula: r3 R2 (1) (wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, aryl- 2 thio or monocyclic heterocycle-thio; R is carboxy or derivatives thereof at the carboxy group; R is hydrogen or methoxy). 10 The compounds (i) may bo prepared according to the follow ing reaction sequence. r3 RUN ? h2N_ 1 I i Hvdrolvsis Alkoxvlation I I i i | nyaroiysis Aisoxyiaiion i i i ^> t1) * Q diphenylmethyl(benzhydryl), triphenylmothyl(trityl), p-methoxybenzyl. ,5-trimothoxybenzyl, p-nitrobenzyl), Cg - Cjl2 "tylmethyl (phcnncyl), 30 substituted silyl (e.g. dimethylsilyl, triracthylsilyl, triphcnylsijyl), - a - substituted stannyl (e.g. trimothylstannyl), adamantyl, 2-bonzyloxy-phenyl, 4-methylthiophenyl, tetrahydropyran-2-yl and 2-cyanoethyl. • Hie compounds of the formula (X) may form acid addition- . 5 salts at the 7-anri no group. Representative of acids preferably used in acid salt formation are inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and thiocyanlc acid and organie acids such as p-toluenesulfonic acid and naphthalenosulfonic add. When R2 at the 4 position is free 10 carboxy group, i.e. —COOH, the compounds of the formula (I) may form s»Ot8 with possible inorganic or organic bases.

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

IS The compounds (la) of the formula (i), wherein R1 is halogen or sulfonyloxy may be prepared in a manner as shown in Reaction Scheme 1.

Reaction Schcmc—1 "VQ- J—Step a 0 i 1 COOZ1 "MS C00ZJ (n> (in) h.

Step b D=a (la) (wherein R is amino protecting group ; Z1 is carboxy protecting groip ; o X is halogen or sulfonyloxy ; and R is the same as mentioned above).

The starting materials represented by the formula (II) in 20 the above proccss are well-known and may bo prepared, for example, in a manner described in Japanese Unexamined Patent Publication No. - 4 - 31-41385• They may also be prepared in a manner as shown in the following Reaction Scheme - 2.

Reaction Scheme - 2 JL% „ HJL ^OCHoOHCH j j H0CH2C5CH ^ • j | N-protective — deoxidizer CT >^7 ■ - j- . reaction (1) ^ (2) i00Zl mHYY0CRsrarcH ^ "YA^ J—K. J hydrocenation J—jl 1 (3) ®°°Zl (4) ®00zl m pcroxy acld^^**^——hydrolysis^ COOZ"" iooz1 NalO^ ron^_-CL^CHO RNHV JX X00Z2 1 T 1) oxidation > * oks 3 - 1 v ... >1 ^OOZ1 2) esterification ^ COOZ1 03 RNH^ ^O^yCOOZ2 ZnWV.cOH " /V (9) COOZ1 oxidation V^.° reduction ^'Hv O^^COOZ2 KNH^ ^Qv ^CQQZ2 I « halogenation ^ J | ^ i) pph^ » (S0C12) 0r ' >sj^*X 2)partial f COOZ / \ COOZ1 hvdrotrnr *34!>d V, ^ (wheroin X' and X are halogen ; Z4* is ester formative croup ; R and Z* are the same as mentioned above).

In tho above-mentioned Reaction Scheme - 2, each reaction Bay be carried out in veil-known reaction conditions which satisfy 5 each reaction steps.

Hie compounds (Xa) prepared In the process shown in Reaction Scheme - 1 correspond to the compounds (I), wherein R1 ia halogen or sulfonyloxy. R2 has the same meaning and R3 is bydrogon. The reaction conditions in each step shown in Reaction Scheme - 1 10 are detailed as follows.

Step a (II—»JXl) The hydroxy group at the 3 position of the compounds~^U.) are substituted by halogen or sulfonylated on treatment with •ulfonylating agent to yield tho corresponding 3-halogen- or 3-\5 sulfonyloxy compounds. .

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

Hie 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. mothylsulfonyl chlorido, ethylsulfonyl chlorido) an4 arylsulfonyl halogonides (o.g. benzonesulfonyl chlorido, toluonesulfonyl chlorido). The reaction ts carried out under conditions of 30 ordinary sulfonylation, for example, on addition of the above-mentioned - 6 - * S -J u aulfonylating agent in the presence of tertiary amine such as pyridine or triethylamine.

Stop b (HI—*la) In this process, tho 7-amino protecting group and if required, the 4-carboxy protecting group are at the same time or •tepviso 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 con easily be rescved in a well-known manner.

.Compounds (l), except those vhorein R1 is halogen or • A% m sulfonyloxy, may be prepared in a manner as shown in the following Reaction Scheme.

Reaction Scheme - 3 RNH^ RNH Step c iooz^ ioozi (m) (iv) Step d -> R2 (lb) (wherein R, Z , R and X are the same as mentioned above).

Compounds (l) wherein Rl 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-unsubdtitutod oxadetliiucephem structure. The reduction may bo carried out in such manners as selective reduction of halogen or - 7 - •* J 4 t»0 o sulfonyloxy at tho 3 position without any influence on other aubatituonts or functional groups, for example, combination of metals and.acids, particularly combination of zinc and acetic acid. Tho reaction may be carried out in the well-known manner.

Step d (IV—»Ib) This is a process of hydrolysis or reduction, the same as step b and may bo carried oat in the manner orulnarily used in the fiold of penicillin and cephalosporin synthetic chemistry.

Alternatively, Che objective compound (lb) in this step may be prepared in the nanner aa shown in the following Reaction Scheme.

Reaction Scheme - U ' r* OH acetone (6) COOZ1 RNH °N1.0 * (13) COOZ1 oxidation * o^y° <14 > coozl Zn^AcOH 1)haioeenation (S0C12> ^ o^~NVi>Ph3 2)PPh- J (16) COOZ1 ehhn_Y°v^-'0 _> J—'«yO" (13) k"*1 partial hydrogena ti on Naio. 4 0^ ^CHO Ph„ (17) COOZ Vittig reaction (18) 0- "3 iooz1 RWH^ JQ^ * -Mr1 (ib) (xv) ^oozl <45 J:>9 (wheroin R nnd 21 are the same as mentionod above).

The reactions shown in the above Reaction Scheme - 4 may be carried out under well-known reaction conditions which satisfy reaotion process as shown in each step. t Compounds (i) wherein R1 is arylthio or monocyclic hetero-cycle-thio may be prepared in a manner as shown in the following Reaction Schemo. % .

Reaction Scheme - 5 7Q ~=^ (Hi) Step f (1c) (wherein R, Z1, R2 and X are tho samo ss mentioned above ; T is arylthio or monocyclic heterocycle-thio).

Step e (HI—>V) Halogen or sulfonyloxy at the 3 position in compounds (III) 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 heterocycle-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—»Ic) Ibis is a process of hydrolysis or reduction, the seme as steps b and d, and may be carried out under the same conditions as in tho steps b and d. - 9 - 3 4'J9 Alternatively, the objective compounds (ic) may be prepared In a manner as shown in the following Reaction Scheme.

Reaction Scheme - 6 RKH^ JO ,COOH RNR. JO^^JCCH / (coeij) \ cr~KYPrhJ (12) I™1 . VpyTlrtW (»> I™*1 Vittig reaction ■» (Ic) Y COOZ1 (V) (wherein R, Y and Z1 are the same as mentioned above).

The reactions in the above Reaction Scheme - 6 may be 5 oarrlcd out under well-known reaction conditions which satisfy ' each step. .

Compounds (l), wherein R1 is lower alkoxy, may be prepared in a maimer as shown in the following Reaction Scheme.

Reaction Scheme - 7 RNHN__^°N HNVk ^0. rQ > „, 0r t>H Step g Cr 0Z-' ' „_1 COOZ1 (II) 0002 (\1) i—r i " St®P h > O^S^OZ^ (Id) ** (wherein R, R~ and Z1 are the same as mentioned above ; is 10 lower alkyl). - lO- * C J E> o Stop c (II—>VI) This procoss is carried out in a condition of enolothorification of ketones or on tho action of reagents as dlazoalkane ordinarily employed in estorification of carboxylic 5 acids. Enolothorification of ketones is carried out, for example, ^y moans of trialkylorthoformates (e.g. trlethylorthoformate) or alcbols and p-toluanesulfonic acid. Alkylation b/ diazoalkanes (e.g. diazomethane, diazoethane) may be employed in this invention. These roactions may be carried out in the well-known manner. 15 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 coni&Ltion as in those steps.

Compounds (i), wherein is methoxy, may be prepared In a manner as shown in the following Reaction Scheme.

Reaction Schotnc — 8 H QCH3 r2 r2 (If) (Ie) (vherein R* and R2 are the same as mentioned above).

Step i The starting material? (if) correspond to each objective compound prepared in the Reaction Scheme.' 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 are described as follows. - 11 - 4tS4l>0 Method 1 Tho 7-amino of the starting materials (if) la acylated to corresponding 7-'acylamino derivatives, the latter are reacted with methoxylithium (LiOCH^) and t-butyl hypochlorite (t-BuOCl) in 5 an inort solvent at low temperature (Belgium Patent Application No* 817836), and then the 7-aeyl protecting group is removed.

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

Method 3 The starting materials (if) are reacted vith p-hydroxy-20 bvnzaldeliydes (preferably those having a bulky substituent or substituents adjacent to the p-hydroxy, for example, 3,5-di-t-butyl-4-hydroxybcnzaldehyde) to yield benzylidene derivatives (c), the latter oxidized by means of appropriate oxidating agents (e.g. nickel - 12 - a poroxidc, load tetraacetate) to yield quiuoid type derivatives (d), tho latter roaoted with methanol to yiold 7<*-methoxy compounds (o) and benzylidene group of the latter hydrolyzed (ordinarily on the treatment of Girard reagent) to yield tho objective 7P-amino-7«-5 methoxy compounds (ie). The reaction scheme in this process is represented as ?ollovs(Japanese Unexamined Patent Publication No. 50-50394).

K°-Q-C oxidation -CHO HC "-Q {If) ^ I ] J — > (O) R2 O-^VciI-N ft H0-^~\-CItN ! 0 hydrolysis > (Ie) (wherein R1 and R2 are the same as mentioned above). lO Method 4 Alternatively, a manner as shown in the following Reaction Scheme may also be utilized. In this method , the 7-amino group of tho starting materials (if) is protectod by acyl group having at least one hydrogen atom at the a position to yield 7-acylamino 15 derivatives (f), the latter treated with a halogenating agent to yield iminohalide derivatives (g), the latter treated with a base for dohydrohalogenation to yield keteneimine derivatives (h), the latter halogenated to yield dihalogcnoimine derivatives (i), the latter reacted with alkali raotal methoxide and then hydrolyzed - 13 - A * ii»a to remove the acyl Group (Japaneso Unexamined Patent Publication No. 50-126692).

Q' a halogenatlus Q' 1 ^CIICNH. .0. agent ^CH-C=N. .,0>.

"I <*) * <±> * .

* ® OCll- hydrolysis 2> , > (Ie) (vherein R1 and R^ are the same as mentioned above ; Q1 and Q" . 5 aro hydrogen or appropriate substituents ; X and X' are halogen, respectively).

The compounds represented by the formula (l) in this invention are important intermeciictos in preparation of novel 1-oxadethiacephalosporins. Introduction of various acyl groups 10 . used in the field of ponlcillin and cephalosporin chemistry to the free 7—amino group of the compounds (i) yields antioicrobially very active compounds as described and claimed in Patent Specification No. ' " .

The following examples 1 to 5 are provided to further illustrate this Invention; Examples 6 to 8 describe the preparation of 15 starting materials.

Example 1 2fi —amino—1-chloro—l—oxa-1-dethia—l-cephem-fr-carboyvlic acid (I : R^-Cl ; R2=C00!I. 1^=11) (la ; R2=C00H ; X=Cl) 1) To a solution of 1.5 S (3 mmoles) of diphenylmothyl 7?— 20 benayloxycarbonylamino-3-hydroxy-l-oxa-l-dethia-3-cephem-4-carboxylate (II : RsPhCI^OCO ; Z^sCHPhg) in 30 ml of dimetliylformamide is added - 14 - <* 3 J J» 9 0.03' oil (0.36 mraole) of pyridine under ice-cooling and then dropviso addod 0.31 oil (3.6 mmoles) of oxalyl chloride. After stirring for 3 hours at room temporuture, the reaction mixture Is poured into 5 % phosphoric acid oquoous solution under ice-cooling and 5 extracted vith ethyl acetato. The extract is washed vith water, dried and evaporated. The residue is chromatographed on 20 parts by volume of silica gel and eluted vith benzene-eIhyl acetate (5 : l) to yield 489 mg of the objective 3-chloro derivative, dlphenylmethyl 7p-b*r\ zyloxyc arbonyl amine-•.<-chloro-l-oxa-1-de thia-3-c ephem-Jj-IO carboxylate (HI : R=PbCH20C0 ; Z1=CHPh2 } X=Cl) (31.4 56 yield). ■p. 130 - 131 °c m : e""X : 3450' 1805' 1725 • 1620' tCDCl- 'max KMR : 6CDCj-3 ppm s 4.32(s,2H), 4.98(d,J=4.0Hz,lH), 5.10(s,2H), 5.20 - 5.80(m,2H), 6.97(s,lH), 7.0(m,aromatic H). 15 This product pay also be prepared as the following manner.

To a solution of 1.62 g (6.2 mmoles) of triphenylphosphine in 20 ml of tetrahydrofuran are adeed 6.2 mmoles of chlorine-carbon tetrachloride, a solution of 1-55 g (3-1 oanoles) of 3-hydroxy derivatives (II : R=PhCH90C0 : Z^CIIPhg) in lO ml of tetrahydrofuran 20 and then 0.86 ml (6.2 mmoles) of triethylamine under ice-cooling while stirring. After stirring for 1.5 hours at room temperature, the reaction mixture is poured into'ice water and extracted vith •thylacetate. The extract is washed with water, dried and evaporated-The residue is chromatographed c*-. 30 parts by volume of silica gel 25 and eluted with benzene-ethyl acetate (lO : l) to yield 0.95 8 of the objective 3-chloro derivative (HI : n»PhCH20C0 ; Z1=CHPh2 ; X=C1) (59-0 56 yield). 2) To a solution of 950 mg (1.83 mmoles) of the 3-chloro derivative, prepared above (ill : R=PhCII20C0 ; Z^CHPl^ ; X^Cl) 30 din 37 nil of methylene chloride are added 1.78 ml (l6.5 mmoles) of - .15 _ 4tt 1^0 * # aniso.'.e and a solution of 1-45 g (ll raaoles) of aluminum chloride in 18 ml of nitromethane, and the mixture allowed to stand at room temperature overnight. The reaction mixture is extracted with 15 ml of ice-cooled 2 % hydrochloric acid, and the aqueous 5 layer vashed with methylene chloride and then ethyl acetate, and •vaporated under reduced pressure. The residue is chromatographed • • on a column of 400 g of Diaion HP 20 (Trade mark of Mitsubishi Chemical Industries ; Hi porous polymer) and eluted vith hydrochloric cold (pH 3). The eluate *3 adjusted to pH h•h and evaporated under IC reducod pressure to yield 175 mg of the objective 3-chloro derivative: (I : R^Cl ; R2=CC0H ; R3=H)(43.8 g yield).

IR : vj^£ cm-1 : 3*120, 1818, 1630, 1613.

Example? 2 2& -amlno-l-oxn-1-dcthia—"j-cephem—4-carboxvl ic acid (I ; Ri=R3=H : 15 R2-=C00H>(lb : R2=C00H) 1) To a solution of 1.98 g (3*96 mmoles) of the 3-hydroxy derivatives (II : R=PhCH20C0 ; Z^sCHPhg) in 20 ml of dimethyl-formamlde are added 0.62 ml (<£ equivalents) of methylsulfonyl chloride and then O.83 ml (1.5 equivalents) of triethylamine at 20 „ 50 °C, and the mixture stirred at the same temperature for 15 minutes and poured into ice vater to precipitate the crystals, vhich are collected by filtration to yield 2.15 g of the objective 3-methylsulfonyloxy derivative , diphenylmethyl 7P-benzyloxy-carbonylamino-3-methylsulfonyloxy-l-oxa-l-dethia-3-cephem-4-carboxylate 25 (HI : R=PhCH20C0 ; ZX=CHPh2 ; X=0S02CH3)( 9*1.0 £ yield).

IR : v^"^3 cm"1 : 3420, 1810, 1730, 1510, 1365. 1165.

WOA NMR s oCDCl3 ppm : 2.96(s,3H), 4.46(bs,2H), 4«97(d,J=4.0Hz,lH), 5.07(s,2H), 5.^5(dd,J=4.0Hz,lH). 2) To a solution of 1.15 g (2 mmoles) of the 3-methyl-30 sulfonyloxy derivatives (ill : RsPhCH^OCO ; Z1=CHPh2 ; X=0S02CH^) * S J 5' 9 in a mixture of mothylcne chloride (20 ml) and acotic acid (40 ml) is addod 3 g ot activated zinc powder, and the mixture stirred at room temperature overnight, during vhich time each 3 6 of zinc « . I powder is added aftor the lapse of 2 hours and after 3 hours from 5 the begining of the reaction. Zinc powdor is filtered off and the filtrate mixed viti ethyl acetate. The organic layer is washed vith water, dried and evaporated under reduced pressure to yield 913 ®£t of the objective 3~deoxy derivatives, di phenylmo thy1 ?P«>benzyloxycarbonylamino-l~oxa-l-dethia-3-cephem~4-carboxylate 10 (iv : R=PhCH20C0 ; Z1=CHPh2)(9'< .2 £ yield) as powder. IR : cm"1 : 3450, 1800, 1730, 1650.

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

This product may also be prepared in tho following manner. 15 To a solution of 240 mg of the 3-chloro derivative (IH : R=PhCH20C0 ; Z1=CHPh2 ; X=C1) in a mixture of methylene chloride(4 ml) and acetic acid (8 ml) is added 0.72 g of activated zinc powder, and the mixture stirred at room temperature.

Additional 0.72 g of activated zinc powder is added three times during a period after 4 hours up to 9 hours from tho begining of the reaction, and the mixture allowed to stand overnight with stirring. Zinc powder is filtered off, and the filtrate poured into water and extracted with ethyl acetate. The extract is washed vith v&ler, dried and evaporated. The obtained residue is chromato-25 graphed on a column of silica gel and eluted vith benzene-ethyl acetate (5 : l) to yield 215 mg of the objective 3-deoxy derivative (IV : R=PhCH20C0 ; Z^CHPhg) (96.0: yield). 3) To a solution of 913 (l8.8 mmoles) of the 3-dooxy derivatives prepared above (IV : R=PhClI20C0 ; Z1=CID,h2) in 35 ml 30 of mothylcne cliloritle are added 1.85 ml (9 equivalents) of anisolo - 17 - 4 S 4 !»9 \^. and a solution of 1*51 S of aluminum chlorido (6 equivalents) in s\ 18 sil of nitroraothane, and tho mixture allowed to stand at room temperature overnight and extracted with 2 $ hydrochloric acid under ice-cooling. The aqueous layer is washed with methylene 5 chloride and the ethyl acetate, and evaporated under reduced pressure in order to remove organic solvent remaining in tho • • aqueous layer. Tho obtained residue io chromatographed on a column of Diaion HP 20 (Trade park of Mitsubishi Chemical Industries ; Eighporous polymer) and eluted with dilute hydrochloric acid (pH 3.0). XO Tho eluate is evaporated under reduced pressure to yield 291 mg of the objective 3-oxaceohcra derivative (I : R*=r3=H ; R2=C00H) hydrochloride (70.6 £ yield). [.]?•' + 11.1® ± 2.4 (c=0.216, in methanol) IR : cm-1 : 3500 , 2600, 1805, 1645. l6l0, 1550. 15 NMR : 6CDC13 PPm : 5«37(d,J=4.0Hz,lH), 5.5l(d,J=4.0Hz,lH), 6-70 (m,lH).

Exacinl o 3 7a-amino-l-(l-motTiyltetrazol-5-yl) thio-l-oxa-l-dethia-'S-cephein-'t-carboxylic ncid (l ; R1=l-methyltetrazol~5-ylthio : R^COOH. 20 R3=HHlc : Y=l-methyltotrag:ol-5-ylthio ; R2^C00H) l) To a solution of 1.12 g (l.9*i mmoles) of th»» 3-mothyl-sulfonyloxy derivative prepared in Example 2 (ill : RsPhCHgOCO ; Z^sCIIPh,, ; X.-0S02CII-)) in 10 ml of dimothylformamide are added 373 mg 13»2 mntolos) of l-methyltetrazol-5-ylthiol and 0.42 ml 25 (3.0 mmoles) of triethylamine undor cooling at 0 °C and the mixture stirred ot room temperature overnight. After termination of the reaction, the mixture is poured into ice water. The obtained yellow precipitates are collected by filtration, washed and dried to yield 1.007 g of the objective 3-totrazolylthio derivative 30 (V : R=PhCH20C0 ; Z^sCHPI^ ; Y=l=methyltetrazol-5-ylthio) as yellow - ] 8 - povddr (86.7 1» yield).

IR » cn"1 : 3^50. 1805, 1730.

KMR I 6CDCI3 ppn. , 3.93(9,311), 4.28(ADq,J=l8Il2,2H), 5.00(d,J=4.01I 1H), 5.17(s,2H), 5.30 - 5.90(m,2H), 6.98(s,lll). 2) To a solution of 137 mg (0.229 mmoles) of the 3-tetrazolylthio derivative prepared above (V : R=PhCH20C0 ; CHPh2 ; Y=l-methyltetrazol-5-y» thio) in 4 ml of m~ thylcno chloride are added 0.223 ml (2.06 mmoles) of onisole and a solution of 190 (l.4 nmoles) of aluminum chloride in 2 ml of nitromethane, and the mixture allowed to stand at room temperature overnight and mixed vith 3 ml of 2 i» hydrochloric acid under ice-cooling. The aqueous layer Is washed vith methylene chloride and then acetic acidr and concentrated. The concentrate is adjusted to pH 2.5 vith sodium carbonate to yield 24 mg of the objective 7p-amino-3-tetrazolylthio derivative (i : R^l-methyltetrazol-5-ylthio ; R2=C00H ; R3=H) as crystals. mp. >200 6C IR : cm"1 : 1820, 1630, 1620.

Example 4 7fl-amino-^-wothoyy-l-oxa-l-<1othia-T-cepliem-4-carbox>"lic acid (1 : R^OCHj : R2=C00II ; R3gH)(ld ; R2=C00H ; Z^^CHj) l) To a solution of 1.15 g (2.3O nmoles) of 3-hydroxy derivatives (U : RsPhCH20C0 ; Z1=CHPh2) in 12 ml of methylene chloride is added a mixture of >1jazomethane and ether, and. the 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 g of the objective 3-mothoxy derivatives, diphonylinethyl 7P-benzyloxycarbonylamino-3-methoxy-l-oxa-l-dethia-3-cephoia-4-carboxylate (75 £ yield). - 19 - 404li9 cm"1 : 3/195, 1796, 1725, 1626, 1512.

KMH s 6CDC13 ppm : 3.70(s,3H), 4.23 and 4.54(AJBq,J=18Hz,2H) , A.96(d,Js4.0Iiz,lH), 5.18(s,2U), 5.42(dd,J=10Hz;4.0IIz,lH), 5.8l(d, J.lOHz.lH), 7.02(s,lH)," -7.4(m,aromatic H).' 5 2) To a solution or 1.06 g (2.06 mmoles) of the 3-methoxy derivative prepared above (VI : RsPhCHgOCO } Z^-sCHPhg ; Z3=CH^j) in 20 ml of methylene chloride aie added 3 ml of ahi.?ole and 3 ml of trifluoroacetic acid under cooling, and the mixture stirred for 15 minutes, mixed vith 20 ml of toluene and then evaporated 10 under reduced pressure. The oily residue is dissolved in benzene e.n.1 extracted vith 5 i» sodium hydrogencarbonate aqueous solution. The oxtract is vashed vith benzene, adjusted to pH 2 vith 10 % „ hydrochloric acid and then extracted vith ethyl acetate again. The extract is vashed vith vater and sodi'jm chloride aqueous solution, 15 and evaporated under reduced pressure to yield 0.67 g of the free 4-carboxylic acid compound, 7p-benzyloxycarbonylamino-3-methoxy-1-oxa-l-d'*thia-3-cephem-4-carboxyllc acid. » : cm-1 : 3430, 1793, 1725. 1630, 1510. 3) To a suspension of 100 mg of 5 £ palladium - charcoal 'O in 20 ml of a mixture of ethyl acetate and methanol(l : l), on which hydrogen gas has preliminarily been adsorbed, is added 200 mg (0.91'^ aunole) of the free 4-carboxylic acid compound prepared above, and the mixture is vigorously stirred in hydrogen atmosphere. The reaction mixture is stirred a*, room temperature for 2 hours 25 and the catalyst filtered off. The filtrate is evaporatod under reducod pressure to yield 65 mg of the objective 7P-®niino compound (I : R^OQLj ; R2=C00H ; R3=ll)(53 i> yield).

IR : ciii-1 : - 3400, - 2900, 1785, 1679, 1647- The catalyst filtered off in the above operation is washed 30 vith methanol-hydrochloric acid several times and the washings are _ 20 _ >45 3'J evaporated under reduccd pressure to yield 65 mg of tho 7p-amino dorivativo hydrochloride (I : R^OCII^ ; R2=C00H ; r3=H) as white powdered crystals.

JR : vjjj cm"1 : - 3^00, - 3000, 1787. 169*», 1&L9-5 Bacample 5 pl.nltrobonzyl 73-amlno-T-chloro-7ot-mothoxy-l-oxa-? -dethi a-3-cephem-?i-carboxylato (i ; R1=C1 : R2=C00CH.jC/:H/, 'NO^-p; R^-QCH^) (Ie : R1=C1 : n^COOCH^CV.JTY• XO^-o) l) To a solution of 1^1 mg (0.399 mmole) of p-nitrobenzyl 10 7?-a^ino-3-chloroi-l-oxa-l—dQthia-3-cephom-4—carboxylato (i : Rl=Cl j R^-COOCI^C^H^•'SO^-p ; R"*=H)[prepared from the free 3-chloro derivative prepared in Example 1 (I : R^=Cl ; R2=C00H ; r3-h) on osterification] in a mixture of 7 ml cf chloroform and 1 ml of fconxeno is added 112 mg (l.2 equivalents) of 3,5-di-t-butyl-4-' 15 hydroxyberrzaldehyde and the mixture refluxed under heating in a reaction vessel equipped vith a watf>r separator containing molecular sieve. After 2-5 hours, tho reaction mixture is mixed with additional 30 rag of the aldehyde compounds and reactcd for 3.5 hours. The mixture is cooled to •• 15°C, mixed with 65 mg of magnesium 10 sulfate and 219 mg of nickel peroxide, and stirred at the same temperature for 30 minutes and at room temperature for kO minutes. The mixture is filtered and the filtrate is mixed with 5 ml of methanol, stirred at room temperature for 1.5 hours, and evaporated under reduced pressure. The residue is chromatographed on a column 25 of 12 g of silica gel and eluted vith benzene-ethyl acetate (19 t l) to yield 125 mg of the objective 7-methoxy derivatives, p-nitrobenzyl 7£-(3 »5-di-t-butyl-4-hydroxybenzylideno)amino-3-chloro-7 3 IR : cm-1 : 1780, 1735. 1680, 1520, 13'»5- HMR : 6CDC13 ppm : 1.48(s,18H), 3-6l(s,3H), 4.49(0,211), 5 23(». 1H), 5*44(aromatic H), 8.53(s,l II). 2) To a solution of 125 off of tho 7-methoxy derivative 5 (e : r!=C1 ; R2=C00CH2'C(jII1|'NO2-p ; 70-side chain=3,5-di-t-butyl-4-hydroxybenzylideneamino) in a ipixture of methanol (2.5 ml) and tetrahydrofuran (0.5 ml) is added 81 mg of Girard reagent, and the mixture stirred at room temperature for 1 hour, poured into vater and extracted vith methylene chlorido. The extract is iO vashed vith vater, dried «uid evaporated under reduced pressure.

The residue is chromatographed on a column of'3.5 g of silica gel and eluted vith benzene-ethyl acetate (4 : l) to yield 35 mg of* the objective 7-amino derivative (I : Rl=Cl ; R2=C00CH2*C(jH^«N02-p ; R^aOCII^) (43*8 £ yield). 15 IR : v^L3 cm-1 . 1790, 17I1O, 1520, 1350.

NMR : 6CDC13 ppm : 1.83(bs,2H), 3-53(s.3H), 4.54(s,2H), 5-0l(s. 1H), 5.i»7(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. >> p—nitrobenzyl 7p-o'uino-l-oxa-l-dethia-3-cephem-4-carboxylat (I : R1=Hj R2=CO0CIl2*C6H|j.N02-p ; R3=H) CHC1 1 IR : vmax 3 c : 3405, 1772, 1726, 1633, 1605, 1517, 13*»5. tCDCl« "max NMR : 6CDCa3 ppm : 1.74(b,2H), 4.6l(m,2H), 5.05(d,J=4.0Hz, 1H), 5.42(bs-2H), 5-5(m,lH), 6.6l(m,lH), 7.67 and 8.3l(q.J=9.0IIZ,4H). 25 p-nitrobenzyl 7p-araino-3-methylsulfonyloxy-l-oxa-l- dethia-3-cephera-4-carboxylato (I : r1=0S02CHj ; R2=C00CH2*C^H^-N02-p R3=H) IR : v^13 cm"1 : 3420, 1790, 1735, l6l0.

KMR : 6CPC13 ppm 1 2- 15(br.,.?ll) , 3. 2j(s ,3») , •'« • 52(s.211) , 5-02(d, 30 J=4)la,lll), 5.30(M,2a), 5-33("'.lH), 7.;t3 and 8. jLo( Example 6 l) diphenylwc thyl 2-[2£-(2-propinyloxy)-3p-aniino-4-oxo-*zotidin-l-yl]-2-iaopropylideneac©tato (2 : z^sCHPh^) To a solution ol* 0.95 6 of diphenylmethyl 2-(2?-chloro-3fJ-ami.no- 4-oxoazetidin-l-yl)-2-isopropylideneacetato (l : z1oCHPh2 ; XjsCl) in a mixture of propargyl alcohol (3 ml) and tetrahydrofuran (2 ml) is added 0.79 g mmoles) of silver tetrofluoroborato, and the 10 mixture stirred at room temperature for 3 hours, dilut-d with 50 ml of benzene, coolcd to 0°C and mixed vith a mixture of 10 ml of 5 £ sodium hydrogencarbonate aqueous solution and 5 ml of saturated sodium chloride aqueous solution. The reaction mixture is stirred and filtered throuch Cellte (registered Trade Mark). The lb benzene layer is separated, dried over Glauber's salt and evaporated under reduced pressuro. The obtained brown oily materials are purified by chromatograpby on a column of silica gel containing 10 "f> water and eluted with benzene-ethyl acetaic yl : 1) to yield 268 mg of the 2o objective 25-propinyloxy derivative (2 : Zl=CHPh2)(134 mg of 2a-propinyloxy derivative and 134 mg of 2p-propinyloxy derivative). 2«t-propinyloxy derivative : ** '• v£a£l3 en"1 '• 3*»00, 3320, 2115, 176?, 1723-NMR j 6CDC13 ppm : 1.83(brs,2H), 1.98(s,3Jl), 2.22(3,3"). 2-33(t, 25 J=2.5Hz,1H), 4.07(d,J=2.5Hz,2H), ca4.07(m,lH), 4.93(d,J=1.0Hz,1H), 6.90(s,1H), 7.32(3,10H). 2p-propi»yloxy derivative : IR : v»^13 Cl*rl : 3^10, 3320, 2115, 1767, 1720.

NMR : 6CDC13 ppo, . 1.77(brs,2H), 2.00(s.3»), 2.23(s,3"). 2.27(t, ) J=2.5Hz,lH), 4.12(d,J-2.5Hz,2H), 4.23(d , Jr.4 .OHz.lIl), 5-27(d,J^4Ilz, 1H), 6.90(s,1H), 7.32(s,10H). - 23 - 404U9 w 2) diphenylmethyl 2-[2p-(2-propinyloxy)-3P-bcnzyloxy- carbonylamino-4-oxoazetidin-l-yl]-2-isopropylideneac 0 to te <3 t RsPhCHgOCO ; Z1=CHPh2) To a solution of 30.0 g (0.074 mole) of 2p-propinyloxy derivative 5 (2 : Z*=CHPh2) in 250 ml of dry methylene chloride is added 14.07 S (0.0825 mole) of benzyloxycarbonyl chlorido undor ice-cooling and .dropviso added a mixture of pyridine (6.7 mnolos ; 0-0825 molo) and methylene chloride, and the mixture stirred for 30 minutes undor cooling, poured into ice water and extracted with methylene 10 chloridc. The extract is wished with vater and sodium chloride equeous solution, dried-and evaporated undor reducod prosauro. The obtained oily residue is chromatographed on 1000 g of silica m gel and olutod with benzene-ethyl acetato (5 : l) to yield 26.5 g of tho objective 3p-benzyloxycarbonylamino derivative (3 : R= 15 PhCH20C0 ; Z^CHPhj) (66.3 * yield). 111 ! o"1 : 3^0 , 3300 , 2110, 1774, 1720, 1630, 1507* 0(Uf KMR s 6CDC13 ppm : 2.00 and 2.25(s,3H x 2), 2.17(d,J=3Hz,1H), 4.07(d,J=3Hz,2H), 5.10(d,J=4Hz,Ul), 5.17(s,2H), 5.33(q.J=8Hz,4Hz, 1H), 5.55(d,J=8Hz,lH), 6.98(s,IK). 20 3) diphenylmothyi 2-(2p-allyloxy-3P-benzyloxycarbonylamino- 4-oxoazetidin-l-yl)-2-isopropylideneacetate (k : R=PhCH20C0 ; Z1=C.tffb2) To a suspension of 6.6 g of 5 £ palladium-calcium carbonate in 170 ml of mothanol, to which hydrogen gos lias been adsorbed with 25 stirring, is added a solution of 26-5 6 (0.0'»9 molo) of 3p-benzyloxycarbonylamino derivative (3 : RsPliCH 0C0 ; Z*=CHPh2) in 100 ml of methanol, and the mixture stirred for 50 minutes under hydrocen atmosphere. The catalyst is filtered off and tho filtrate evaporated under reduced pressure to yield 26.3 g 30 of 2p-allyloxy derivative (•'« : R=PhCH20C0 ; z1=CHPh2) (98.8 ■£) 24 - * 5 J m » *2£l3 c""1 » 344o, 1772, 1720, 1628. 1505.

NMR : 6CDC13 ppm : 2.00 and 2.25(s,3H x 2). 3.90(n»,2H), 4.6 -5.9(0,611), 5-17(8,211), 6.95(a,lH) 4) dipJionylmotbyl 2-[2P-(2,3-«poxypropoxy)-3P-benzyloxy-carbonylnmino-4-oxoazetidin-l-yl]-2-isopropylideneacetate (5 : R=PhCH20C0 ; 21=CHRh2) ! To a solution of 25.6 g (0.047 mole) of tho 2P-aiiyioxy derivative (4 1 RsPhCHgOCO ; Z^sCHPh^) in 260 ml of chloroform ia added 15.3 g » • (0.071 mole) of m-chloroperbenzoic acid little by little, and the mixture allovod to stand at room temperature (23 - 25 °C) for 2 days and evaporated under reducod pressure. The residue is disaolvod in ethyl acetate, and vashod with 5 $ sodium thiosulfate aqueous* m solution, 5 % sodium hydrocencarbonate aqueous solution, vater and I thon aodium chlorido aqueous solution. - Tho solvent is evaporated undor rcduced pros sure to yiold oily residue, which is chroiuato-graphed on a column of 800 g of silica gel and eluted vith benzene-ethyl acetate (5 : l) to yield 21.25 g of the objective epoxy derivative (5 : R=PhCH20C0 ; Z1=ur?h2)(8l.2 £ yiold). IR : cm**1 : 3445, 1778, 1724, 1632, 1508.

NMR : 6CDC13 ppm : 2-00 and 2.25(s,3H x 2), ca 2-2 - 3-9(m,5H), 5.19(s,21!) , ca 5-0 - 5.3(m.2H). 5.58(d,J=10Hz,lH), 6.83(s,lH).

A small quantity of diepovy derivative (2.15 g , op. 118 -120 °C) is obtained as by-product in this process. 5) diphenylmethyl 2-[2P-(2,3-dihydroxypropoxy)-?,>-. benzyloxycarbonylainino-4-oxoazetidin-l-yl ]-2-isopropylideneace ta te (o : R=PhCH20C0 ; Z1=CHPh2) To a solution of 21.25 g (O.O38 mole) of the epoxy derivative proparod above (5 : R=PhCH20C0 ; Z^sCHPhg) in 220 ml of acetone are added 66 ml of 30 ^ perchloric acid and 44 jul of water wider ico cooling, and tho mixture stirred at room temperature for 2-3 ifllBO houra and oxtractod vith ethyl acetate. Tho oxtract is vashed vith 5 % aodium hydrogencarbonate aqueous solution, vator and then sodium chlorido aqueous solution, dried and evaporated under roduoed prossure to yield 20.6 g of tho objective diol 5 derivative (6 t R=PhCH20C0 ; Z*=CHPh2)(94.4 % yield). ** 1 *2?* co"1 1 3^00, 3445, 17781 1725, 1632, 1508.

NMR » 6CDC13 ppm j 1.97 and 2.22(s,3H x 2), 3.47(m,4H), -3.3(n.2H). 3-13(s.2H), 6.07(o,1H), 6.97(s,1H). .

In a similar manner, the 20-propionyloxy derivative lO (2 : Z*»CHrh2) is reacted vith phenylacetyl chloride to yiold the 3p-phenylacetamide derivative (3 : R=PhCII2C0 ; Z^CHPI^) 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-4-oxoazetidin-l-yl]-2-iso-15 propyl idenei^etato (6 : RsPhCHgCO } Z^CHPhj).

Exairrpl r. 7 l) diphonylmethyl 2-[2p-(2,3-isopropylidenedioxypropoxy)-3P-benzyloxycarbonylamino-4 oxoazetidin-l-yl]-2-isopropylidenc- acetnto (13 : R^PhCJ^OCO ; Z1=CiIPh2) 20 To a solution of 2.5 g of diphenylmethyl 2-[2p-(2,3-dihydroxy-propoxy)-3P-l>e«7.yloxycarbonylamino-4-oxoazetidin-l-yl]-2-iso-propylidenoacetate (6 : R=PhCH2uC0 ; Z1=CIIPh2) in 50 ml of acetonc is added 3 og of p-tolucnesulfonic acid under ice-cooling, and the mixture stirred for 3 hours, mixed vith a small amount of " $ sodium 25 hydrogencarbonato aqueous solution and evaporated under rcduced pressure. The rosidue is dissolved in ethyl acetate, vashed vith vater, dried, and evaporated. The obtained residue is chromato-graphod on a column of silica gel and eluted vith benzene-etliyl acetate (2 : l) to yield 2.26 g of tho objective isopropylidencdioxy 30 derivative (13 : RrPhCH20C0 ; Z*=CHPh2)(84.£ yield). - 26 - J CHC1 i IR 1 v«ax 3 cra * ^50, 1780, 1725. 1635, 1600.

NMR l 6CDC13 ppm 1 1.28(s,6H), 2.00(s,3")» 2.25(s,3H), 3.25 - 4.20(m,5H), 4.90 - 5.77(m,5H), 6.95(s»lH)*: ca70(«»15H). 2) diphenylmethyl 2-[2p-(2,3-isopropylidenedioxy-propoxy) -30-benzyloxycarbonylamino-4-oxoazo tidin-1 -yl ] -2-hydroxyac e ta t e (15 s R^PhCJ^OCO ; Z1=CHPh2) — Into a solution of 2.2 g (3.58 mmoles) of the isopropylidonedioxy derivative prepared above (13 : RsPhCI^OCO ; Z1=CHPh2) in ko ml ot methyleno chloride is introduced ozone under ccalirig with dry lee-acetone until tho nixture turns blue. The sxcoss amount of ozone is removed, and the mixture mixed vith 22 ml of methyl sulfide and allowed to stand under cooling at the same tempoVdture for 1 hour and then at room temperature for 1 hour. The mixiura is mixed vith a small amount of acetic acid, vashed vith vater, dried and evaporated to yield 2 g of the intermediate, 1-diphenyl-methoxalyl-2p-(2,3-isopropylidenedioxypropory)-3p-benzyloxycarbonyl-amino-4-oxoazetidlne (14 : RsPhCH^OCO jZ^sCHPl^). This is dissolved in a mixturo of 20 ml of methylene chloride and 20 ml of acetic acid, mixed vith 2 g of activated zinc povder, and stirred for 2 hours under ice—cooling. Zinc povder is filtered off and vashed vith methylene chloride. The filtrate and the vaahinga aro combined, vasehd vith vater, dried and evaporated to yiold 20 g of the objective 2-hydroxy derivative (15 : R=PhCI^0C0 j Z^sCHPhg) (95 £ yiold). 18 1 v£?3 cm"1 : 3500, 3430. 1780, 1740, 1720, 1600.

KMR i 6CDC13 ppm : l.l»7(s,6H), 3-17-4.30(m,5-6H, 5.l6(s,2H), 4«70-6.00(m,3-4H), 6.97 and 7*00(s, 1H x 2), ca 7>3(m,aromatic H) . 3) diphenylmothyl 2-[2P-(2,3-ri«opropylidenodioxypropoxy)-3P-beiizyloxycarbonylamino-4-oxoazotidin-l-yl]-2-triplicnyl-phosphoranylidoneacetate (16 : RsPhCi^OCO ; Z1=Cia,h2) — - 27 To a solution of 2.0 € (3*4 nmoles) of 2-liydroxy dorivativo (l5 • RrJ>liai20C0 ; Z^sCHPhj) In 60 ml of dry methylene chloride is added 1.3 ml (l*02 mmoles) of dlmethylonllino under ice-cooling and dropviso added 0.74 ml (l.02 onolos) of thionyl chlorido, and the mixture stirred at the same temperature for 30 minutes, and poured into ice vater. The methylcno chlorido layer is separated and vashed vith vater, dried and evaporated to yield 2«3 6 of the intermediate, diphenylmethyl 2-[2p-(2,3-iso-propylidenedioxypropoxy)-30-benzyloxycarbonylamino-4-oxoazetidin-l*yl]-2-chloroacetate [iH j v^"^ cm~l : 3436, 1785, 1750, 1720, 1595*}• This is dissolved in 40 ml of methylene chlorido anij^ mixed vith 0.86 ml (6.8 mmoles) of dimethylaniline and 1.8 g (6.8 mmoles) of triphenylphosphine. The mixture is refluxed under heating for 6 hours, mixed vith additional 1.8 ? of triphenylphosphine, reacted for 12 hours, poured into 5 $ sodium hydrogen— oarbonato aqueous solution under cooling, vashed vith vater, dried and evaporated. Tho residue is chromatographed on a column of silica gel to yield 1.6 g of the obJocti\e triphenylphosphoran derivative (l6 : R=PhCHo0C0 ; Z^CHPhg) (56.6 £ yield). CHC1 ^ 111 : vmax cm : 3400, 1760, 1710, 1620, 1590. 4) diphenylmethyl 2-[2p-(2,3-d.ihydroxypropoxy)-3P-bonzyloxycarbonylamino-4-oxoazotidin-l-yl]-2-triphcnyl- phosphoranylideneacetate (17 : R=PhCH20C0 ; Z^sCKPh^) To a solution of 417 mg (0.5 mmole) of triphenylphosphorane derivative (l6 : R=PhCII20C0 ; Z^sCHPhg) 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 $> sodium hydrogoncorbonato aquoous solution and-oxtractod with othyl acotate. The extract is vashed vith vater, driod and ovaporatod.

The residuo is chroraatographed on a column of silica gol to yield - 28 - *« G i 172 ac of the objective acotonlde free derivative (17 : Ra PhCHgOCO } 21aCHPh2)t43.3 * yield).

IR t cm"1 : 3450 — 32OO, 1770, 1720,1630, 1600.

BaX 5) diphenylmethyl 70-benzyloxyearbonylamino-1-oxa-l-5 dethia-3-cephem-'i-carboxylate (IV : R=PhCH20C0 ; Z*=CHPh2) ——— To a solution of 139 mg (0.175 nmolo) of the ngetonide free derivative (l7 : R^hCH^OCO ; Z1=CHPh2) in 4 ml of tetrahydrofuran is added periodic acid consisting of sodium periodate (45 mg) and IN-sulfuric acid (2.2- ml) under ice-cooling, and the mixture 10 stirred at the same temperature for 3 hours and at room temperature for 1 hour, poured into ice water, and extracted with othyl acetate. The extract is washed with vater, dried and evaporated. Tbe residue is purified by chromatography on a column of silica gel to yield 15 mg of the objective protected oxacephom derivative 15 (IV : JUPhCH20C0 j Z1=CHPh2) (l7»7 % yield). this product is confirmed to be identical with an authentic specimen prepared by an alternative route in Example 2 in thin layer chromatography, IR spectrum and NMR spectrum.

Example 8 20 l) diphenylmethyl 2-[20-(2-oxoethyloxy)-30-bonzyloxy- carbonylamino-4-oxoazetidin-l-yl]-2-isopropylideneacctato (7 : JUPhCH20C0 ; Z1=CHPh2) To a solution of 11-5 g (0.02 mole) of diphenylmethyl 2-f20-(2i3-dihydroxypropoxy)-3p-benzyloxycarbonylamino-4-oxoazetidin-25 l-yl]-2-isopropylideneacetate (6 : R=PhCH20C0 ; Z1=CHPh2) in 200 ml of ethanol is added a solution of 5-14 g (0.024 mole) of sodium periodato in 210 ml of IN-sulfuric acid, and the mixture stirred at room temperature for 30 minutes, poured into ice-yater, and extracted vith ethyl acetate. The extract is vashed vith 30 vater and sodium chloride aqueous solution dried and evaporated - 29 - Under reducod pressuro to yield 10.8 g of tlio objective formyl derivative (7 : R=PhCIL,0C0 ; Z1=CHPh2). 111 : V£US13 cm"1 ; 3445, 1778, 1725. 1632, 1508. max 2) diphenylmethyl 2-(20-«nethoxycurbonylmathoxy-30-benzyloxycarbonylamino-4-oxoazetidin-l-yl)-2-isopropylideneacetate (8 : R=PhCH20C0 ; Z^CHPhgj , To a solution of 10.8 g of the formyl derivative (7: R=PhCH20C0 ; Z^aiPhg) in 100 ml of acetone is added 14 ml of Jones reagent at o tooporature below 15 "C undor ice-cooling with stirring.

After 30 minutes, the reaction mixture is mixed with isopropanol and an oxcess amount of the reagent decomposed. Tho insoluble • materials are filtered•off, and the filtrate is poured into ice water and oxtracted with ethyl acetate. The extract is washed with water and sodium chloride aqueous solution and evaporated under reduccd pressure to yield 11.1 g of the carboxylic acid compound (8 s R=.PhCHg0C0 ; 21=CHPh2, Z2=H) as crude product.

Ibis is dissolved in 150 ml of methylene chloride and mixed with diazomethane-ether for esterification, and evaporated.

The residue (ll g) is cbronatographed on a column of 200 g of silica gel and oluted with benzene - othyl acetate (5 : l) to yield 9«2 g of the objectivo methyl carboxylatc compound (8 : R=PhCH20C0 ; Z^CHPhg ; Z2=CH3)(80.3 £ yield). 111 : cn~1 : 3445, 1780, 1725, 1635, 1510.

NMR : 6CDC13 ppm : 2.00 and 2.25(s, 3H x 2), 3-58(s,3»)» 3-97(s, 2H), 5.0-5.40(m,2H), 5.13(*,2H), 5.77(d,J=8Ilvs,lH), 6.93(s.lH). 3 ) 1-d iphcnylma tlio xalyl -2p -mo thc>yc ji rbonylmc tho xy-3P-bonzyloxycarbonylamino-4-oxoazetidinc (9 : R-i'liCIIgOCO ; Z1 = CftPh2 ; Z2sCII ) To a solution of 9.2 g (0.016 mole) of tlic methyl carboxylate prepared above (8 : R=PhClI20C0 ; Z1=aU'h2 ; Z2=CH^) in 23O t:il of methylene - 30 - w ' A3 4U9 5 chlorido is introducod ozono under cooling at -78 °C. The roaction mixture) turns bluo aftor about 30 minutos, nnd then nitrogen gaa la Introducod to remove on excoas amount of ozono. The mixture !• mixed vith 10 ml of dimethylsulfide undor cooling - 78 °C, stirred at the same temperature for 1 hour and then at room temperature 10 for 1 hour, mixed vith methylene chloride and 2-3 drops of acotic acid, vashed vith vater and sodium chloride aqueous solution, dried and evaporated to yield 8.9 g of the objective me'thoxalyl derivative (9 : RaPhCHjOCO j Z*»CHPh2 ; Z2=CH^) as oily material. IR : cm"1 j 3*50, 1830, 1756, 1720, 1509- ^ 4) diphenylmethyl 2-(20-methoxycarbonylmethoxy-3P-benzyl- oxycarbonylamino-4-oxoazetidin-l-yl)-2-hydroxyacetate (lO : R=PhCH20C0 ; Z1=CHPh2 ; zKcUj) To a solution of 8.9 g of the methoxalyl derivative prepared above (9 : R=PhCH20C0 ; Z^ssCHPh^ ; Z2=CH^) in a mixture of 90 ml of methylene 20 chloride and 90 ml of acetic acid is added 9 g of activated zinc povder under ice-cooling vith stirring. After 15 - 30 minutes, zinc povder is filtered off, and the filtrate is mixed vith methylene chloride, washed vith vater and sodium chloride aquaous solution, driod and evaporated vinder reduced pressure to yield 8.4 g of the 25 objective hydroxyacetlc acid derivative (lO : R=PhCH20C0 ; Z1=CHPh2 ; Z2=CH^)(95•2 * yield).

QYOI « IR 1 vmax 3 cm 5 3500 - 3600' 34Z>5» 1796' 17*7» 1512• 5) diphenylmethyl 2-(20-methoxycarbonylmethoxy-3P-benzyl-oxycarbonylamino-4-oxoazetidin-l-yl)-2-chloroacetate (ll : R= 30 PhCHgOCO ; Z^CHPhjj ; Z^Oi^ ; X«=Cl) To a solution of 8.4 g (0.015 mole) of the hydroxyacetic acid prepared above (lO : RsPhCHgOCO ; Z1=CHPh2 ; Z2=CHj) in 100 ml of dx*y methylene chlorido are dropvise added 3-34 ml (0-046 mole) of thionyl chloride and 1.46 ml (0.018 mole) of pyridino under ice- - 31 - J5»0 ooolliu: with stirring, and tlio mixturo stirred for 30 minutca under ice-cooling, mixed with an appropriate amount of methylene chloride, washod with water and sodium chlorido aqueous solution, dried and evaporated under reducod pressure to yield 8.9 C of tlio objective 3 monochloroacetic acid derivative (ll : R=PhCII2OCO ; Z*=CHPh2 ; 22=CH3 ; X"=Cl). 1* •.VmJ?3 cm-1 ; 31,35, 1790, 1748, 1725, 1502. 6) diphenylmethyl 2-(2p-carbomethoxy-3p-benzyloxycarbonyl-emino-4-oxoazetidin-l-yl)-2-triphcnylphosplioranylidcneacetate 10 (\2 : R=PhCH20C0 ; Z1=CIIP]i2) Ye a solution of 8.9 S (0.015 mole) of tho monochloro dcrivntivo prepared above (ll : n=Phai20C0 ; Z1=ClD?h2 ; Z2=CH-}, X-^Cl) in*-* 100 ml of methylene chloride is added 8.0 g (0.03 mole) of tri-phenylpliosphine and the mixture refluxed under heating for 1.5 15 hours, mixed with additional 2.0 g (7*5 nsnoles) of Iriphenylphospliine and refluxed under heating again for 1 hour. The reaction mixturo is poured into 5 i» sodilun hydrogencarbonate aqueous solution, neutralized, and extracted vith -ethylene 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 acetatc (4 : 1 - 1 s l) to yiold 10.2 g of tho objective methyl triphenylphosphoranate derivative, diphenylmethyl 2-(2P-methoxy-carbonylmethoxy-3P-benzyloxycarboriyla.,nino-4-oxoazetidin-l-yl)-2-25triphenylphosphoranylideneacetate (84.1 £ yield).

• IR : vmi^13 cm~1 : 3',f,5. 1790, 1723, I630, 1512.

NMR : 6CDC13 ppm : 3-58(s,3H), 3.6 - 5.2(m,^K), 5.07(s,2H).

To a solution of lb. 23 C (20.5 mmoles) of the methyl trjphc.iylphosphoranato in 2'i0 ml of tetrahyuroi'uran is tiropwiso added 30118 ml (22.5 mmoles) of sodium hydroxide aqueous solution (0.19 mrnolo/ - 32 - 5 ml) under cooling ot 2 - 5°C in a period of 30 minutea, and the mixture stirred for 15 Kinutos, neutralized vith 44 ml (23 mmoloa) of 2 £ hydrochlorio ucid and extracted vith ethyl acetate. .Tho extract is vashed vith vater and sodium chloride aqueous solution, driod and evaporated to yield 15.8 g ot the objective 10 triphenylphosphorono' derivative (12 t R=PhCH20C& | Zl=CHPh2) • IR : vSSX3 cm-1 , 3^0, 1775. 1725, 1625, 1510. 7) diphenylmethyl 7p-benzyloxyearbonylamino-3-hydroxy-l-oxa-l-dothia-3-cephem--<-cnrboxylate (ll : R=PhCH20C0 ; Z^= CHPh2) ! IS To a solution of 15- 8 g (20.3 mmolos) of triphenylphosphorane darivativo prepared abOve (12 : R=PhCH20C0 ; Z1=CIIPh2) in 300 ml pt dry toluene aro added 4l.4 g (406 mmoles) of acetic anhydride and 8.87 6 (102 mmoles) of N,N—dimethylacetamide, and the mixture heated at -lOO - 105 °C (bath temperature) for 16 hours. 20 Aftor coolinc. the reaction mixture is mixed with benzene, vashed vith vater, sodium chloride aqueous solution and then vater, driod and evaporatod undor roduced pressure. The residue (ca 20 g) Is chroma tographed on a column of 600 g of silica gel and eluted vith benzene-ethyl acetate-acetic acid (9:1: O.OOl) to yield 25 5.08 g of the main product, diphenylmethyl 3-acetoxy-70-benzyloxy-carbonylamino-l-oxa-l-dethia-3-cephem-4-carboxylate (hereinafter abbreviated to 3-acotoxy compound)(48 yield) and 3.25 g of byproduct, diphenylmethyl 2-(2-benzyloxycarbonyl-3,8-dioxo-5-oxa-2,7-diazabicyclo [4•2•0j octan—7-yl)-2-triphenylphosphoranylidene-30 acetate (21.5 £ yield).

Physical constant of 3-acetoxy compound : IR s vjax13 cm-1 : 3445, 1800, 1785, 1725, 1656, 1508. mm : 6CDC13 ppoi : 2.00(s,3ll), 4.32(s,2H), 5-05(d,J=4Hz,lH)', 5.13(s,2ll), 5.38(q,J=4!lz;10Hz,lll), 5-68(d,J=10Hz,1H) , 6.95(s,lH). - 33 - 4'i4r-i9 Physical constant of by-product : IR : cm-1 : 1790, 1778, 17k0, 1628.

NMR j ppm : 3-4(m,211), 4-5(m,2H), 5.27(s,2H). lbs 3-acetoxy compound (3*2 e ; 5*9 nmoles) prepared 5 above is dissolved in a mixture of 60 ml of pyridine and 12 ml of water under cooling, stirred at room temperature for 1.75 hours, poured into ice vater and extracted vith ethyl acetate.

The ethyl acetate layer is vashed vith 10 £ phosphoric acid, vater, and then sodium chloride aqv.eous solution, dried and evaporated lO under rcducod pressure to yield 3•05 g ot the objective 3-hydroxy compound (ll : R=PhCHgOCO ; Z^sCHPl^) as vhito foamy material._ IR : vJ^X3 cm"1 : 3440, 1795, 1725. 1675, 1510.

NMR : 6CDC13 ppm : 4.37(s,2H), 5-05(d,J=4Hz,lH), 5.l8(s,2ll), 5.45(q,J=10H2,lH), 5.72(d,J=10Hz,lH), 7.00(s,lH), 10.83(s,lH). ^5 This product may also be employed as tho starting material in Example 1. 34 -

Claims

CLAIMS:- .

1. A compound of the formula: wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or monocyclic heterocycle-thio; R^ is carboxy or 3 * **■ a derivative thereof; and R is hydrogen or raethoxy.

2. A compound of the formula: in claim 1.

3. A compound of the formula: 2 wherein R is as defined in claim 1 4tM9D

4. A compound of the formula wherein Y Is arylthio or monocyclic heterocycle-thio 2 and R is as defined in claim 1.

5. A compound of the formula H Ny ^ 2 rT oz- 3 2 wherein Z is lower alkyl and R is as defined in claim 1.

6. A compound of the formula OCH. I 3 10 1 2 wherein R and R are as defined in claim 1. - 36 -

7. 7p -amino- 3-chloro-l-oxa-l-dethia-3-cephem-4-carboxylic acid.

8. 7p-amino-l-oxa-l-dethia-3-cephem-4-carboxylic acid.

9. 70-ami no-3- (l-methyltetra20l-5-yl) thio-l-oxa-1-dethia-3-cephem-4-carboxylic acid.

10. 7(3-amino-3-methoxy-l-oxa-l-dethia-3-cephem-4- ^ carboxylic acid.

11. p-ni trobenzyl -amino- 3-chloro- 7* -methoxy-l-oxa"-l-da thi'a-3-cephem-4-carboxy late.

12. A compound as claimed in claim 1, wherein R1 is a group as listed hereinbefore in exemplification of R1.

13. A compound as claimed in claim 1 or claim 12/ 2 wherein R is a group as listed hereinbefore in exemplfication of R2.

14. A salt of a compound as claimed in any one of claims 1 to 13.

15. A salt as claimed in claim 14 which is an acid addition salt at the 7-amino group. - 37 - >43 4 59

16. A process for preparing a compound =\s claimed in claim 1 which process comprises deprotecting the amino group of a compound of the formulat- S wherein R is an amino protecting group.

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

18. A process as claimed in claim 16 or claim 17, wherein r' is halogen or sulfonyloxy in the product 10 compound as claimed in cl = lm 1.

19. A process as claimed in claim 18, wherein 3 • 2 R is hydrogen, and R is protected carboxy in the starting compound.

20. A process as claimed in claim 19, wherein the 15 starting compound has been prepared by halogenation or sulfonylation of a compound of formula (II) - 38 - *54 53 COOZ' , Z" being a carboxy protecting group.

21. A process em claimed in claim 20, wherein halogenation has been effected by the use of a phosphorus trihalide, a 5 thionyl halide, a halogen, an oxalyl halide or a phosphorus oxyhalide.

22. A process as claimed in claim 20, wherein sulfonylation has been effected by the use of em alkyl-sulfonyl halide or an arylsulfonyl halide. 10

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

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

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. A process as claimed in claim 25, wherein TV* is 2 hydrogen, and R is protected carboxy in the starting compound.

27. A process as claimed in claim 26, wherein r' in the starting compound is hydrogen.

28. A process as claimed in claim 27, wherein the starting compound has been prepared by reduction of a compound of formula (III) , 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 (II) as defined in claim 20 by a method as defined in any one of claims 20 to 23. - 40 - -45 4 b9

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.

31. A process uj 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.

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

33. A process as claimed in claim 32, wherein R3 is hydrogen, R1 being arylthio or monocyclic heterocycle- 2 thlo 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 conpound 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 -

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.

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. • . m

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

38. A process as coined in claim 16 or claim 17, wherein R* is lower alkoxy In the product compound as claimed in claim 1.

39. A process as claimed in claim 38, wherein R3 1 2 is hydrogen, R being lower alkoxy and R being protected carboxy in the starting compound.

40. A process as claimed in claim 39, wherein the starting compound has been prepared by etherification of a compound of formula (II) as defined in claim 20. - 42 - W 3 J £»9

41. A process as claimed in claim 40, wherein the etherlfication has been effected by reaction of the compound of formula (II) with a trialkylorthoformate or an alcohol and p-toluenesulfonic acid or by alkylation usiqg a diazoalkane.

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. — j** .

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

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

45. A process as claimed In claim 4j or claim 44, whorein 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?.

46. A process for preparing a compound as claimed in claim 1 and substantially as hereinbefore described.

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

48. A compound as claimed in claim 1 or a salt thereof which has been prepared in a process as claimed in any one of claims 16 to 47. F. R. KELLY S CO. AGENTS FOR THE APPLICANTS. - 44 -