CA1090336A - Cephalosporin analogues - Google Patents

Abstract

NOVEL CEPHALOSPORIN ANALOGUES
ABSTRACT

Cephalosporin analogues of the general formula:

Description

This invention relates to important intermediates in the pre-` paration of novel cephalosporin analogues possessing potent anti-microbial actions. Particularly, it relates to 7~-amino-1-oxa-dethiacephalosporins.
Compounds in this invention are represented by the formula:

:. R

R2 (I) .. `. 1 (wherein R iS hydrogen, halogen, lower alkoxy, sulfonyloxy, aryl-thio or monocyclic heterocycle-thio; R iS carboxy or derivatives thereof at the carboxy group; R3 is hydrogen or methoxy).
The compounds (I) may be prepared according to the following reaction sequence.

RHN i OH2~ o 1 Hydrolysis (I) < Alkoxylatlon ~ ~ 1 R R
,.'' (wherein R is aminoprotecting group; R , R and R are the same as - mentioned above) Halogen atoms represented by R in the above-mentioned formula (I) are, in particular, fluorine, chlorine, bromine and iodine.
Lower alkoxy means Cl - C5 alkoxy such as methoxy, ethoxy, n-,, .
propoxy, i-propoxy and n-butoxy. Sulfonyloxy means Cl - C5 alkyl-sulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, n-propyl-.,~, sulfonyloxy, i-propylsulfonyloxy, n-butylsulfonyloxy or C6 -C8 arylsulfonyloxy such as benzenesulfonyloxy and toluenesulfonyloxy.
Arylthio means substituted or unsubstituted C6 - C10 arylthio such as phenylthio, tolylthio, methoxyphenylthio and dimethoxyphenylthio.

,~
:

)33t;
Monocyclic heterocycle-thio groups are five-membered ones involving 1 - 4 hetero atoms (N, O, or S), which may be represented by the formula : -S-Q. Wherein Q is a five-membered heterocyclic group containing aza, oxa, thia, diaza, dioxa, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxathia, thiaza, oxadiaza and thiadiaza B in the ring, for example, furan, tetrahydrofuranlpyrrole, pyrroli-dine, thiophene, tetrahydrothiophene, oxazole, thiazole, isoxazole, isothiazole, pyrazole, pyrazoline, imidazole, oxathiol, dioxole, dithiole, triazole, thiadiazole, oxadiazole, dithiazole, dioxazole, oxathiazole, tetrazole, oxatriazole, thiatriazole, dithiadiazole and the like. The S group connected to the heterocycle may be located at any possible position of the heterocycle. The hetero-cycle may invole 1 - 4 substituents such as Cl - C5 alkyl, hydroxy, Cl - C5 alkoxy, halogen, nitro and amino at an optional possible position or positions.
The derivatives at the carboxy group represented by R mean esters, thioesters, carbonamides and the like. For example, when R2 is ester, R may be represented by the formula : -COOR , which ;~
means 4-ester usually used in the field of penicillin and cephalo-20 sporin chemistry. The symbol R includes Cl - C5 alkyl (e.g. -~
methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl), Cl - C5 halogenated alkyl (e.g. chloromethyl, dichloromethyl, 2,2-dichloro-ethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl), C7 - C20 aryl-methyl (e.g. benzyl, diphenylmethyl(benzhydryl), triphenylmethyl-(trityl), p-methoxybenzyl, 3,4,5-trimethoxybenzyl, p-nitrobenzyl), C8 ~ C12 acylmethyl(phenacyl), substituted silyl (e.g. dimethyl-silyl, trimethylsilyl, triphenylsilyl), substituted stannyl (e.g.
trimethylstannyl), adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydropyran-2-yl, 2-cyanoethyl and the like.
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, - hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and thiocyanic acid and organic acids such as p-toluenesulfonic acid and naphthalenesulfonic acid. When R at the 4 position is .- free carboxy group, i.e. -COOH, the compounds of the formula (I) may form salts with possible inorganic or organic bases.
The compounds in this invention represented by the formula (I) may be prepared in a manner as shown in the following Reaction ` 10 Schemes 1 - 8.
~; The compounds (Ia) of the formula (I), wherein R is halogen J or sulfonyloxy may be prepared in a manner as shown in Reaction ~!,,t,,, Scheme 1.

Reaction Scheme-l '. -RNH ~ O~ RNH ~ O

~ ~ N ~ H Step a 0 ~ ~ ~ X
,-~ COOZ 1 COOZ
~ (II) (III) ~"". H2N ~ O~ , ;~ 20 Step b o ~ ~ X

; (Ia) (wherein R is amino protecting group; Z is carboxy protecting group; X is halogen or sulfonyloxy ; and R is the same as mentioned above).
The starting materials represented by the formula (II) in the : above process are well-known and may be prepared, for example, in a manner described in Japanese Unexamined Patent Publication No.

~` 51-41385. They may also be prepared in a manner as shown in the .. . .
following Reaction Scheme - 2.

Reaction Scheme -2 .,.

..

~ ~5a() 3 3~

II2N Y' TI N OCH,-C-CII
~ IIOCII2C--CII 2 ~ ~ ~ NT-pro-tective O ~ ~ deoxidizer ~ N ~ reaction (l) coozl (2) 5 RNI-I ~ OCII2C-CHpartial RNH ~ O
~L hyd r o gella t i o n ~f L

(3) CoOZl (4) CoO~l l0 perox~ acid RNH o ~ hydrolysis RNfI O ~ OH

0~ ~L ~' ' :'. (5) COOZ (6) coozl RNH O CHO R~TH ,o CooZ2 15 NaIO4 ~ ~~~ 1) oxid~tion ~

2) esterificatlon (8) eoozl O3 o~COOZ2 Zn-~cOH
20~
oxidation O ~ ~ ~ O reduction (g) coozl ~.
RNH o~r,eooz2 RNII O Cooz ~~ halogenation ~ ~ 1) PPh3 2 5 \~oo z1 ( SOC12 ) ~ N~ 2 ) par tial (10) (11) coozl hydrogcllal~io RNH~O

~' - 0~ ~\011 :
(II) Z

.

.

':

- - : .

3 36 (wherein X' and X" are halogen; z2 is ester formative group; R and Z are the same às mentioned above).
In the above-mentioned Reaction Scheme - 2, each reaction may be carried out in well-known reaction conditions which satisfy each reaction steps.
The compounds (Ia) prepared in the process shown in Reaction ~; Scheme - l correspond to the compounds (I), wherein R is halogen or sulfonyloxy, R2 has the same meaning and R is hydrogen. The reaction conditions in each step shown in Reaction Scheme - l are detailed as follows:
Step a (II ~ III) The hydroxy group at the 3 position of the compounds (II) are substituted by halogen or sulfonylated on treatment with sulfonyla-` ting agent to yield the corresponding 3-halogen- or 3-sulfonyloxy ~-~
compounds.
Halogenation of the hydroxy group at the 3-pos~tion may also ; be carried out in manners ordinarily used in halogenation of hydroxy group such as a manner by means of phosphorus halogenide PX3 or thionyl chloride. In this invention, the halogenation may 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.
The sulfonylation at the 3-hydroxy group may be carried out in - 25 the same manner as sulfonylation of ordinal hydroxy group. Repre-sentative of sulfonylating agents are alkylsulfonyl halogenides - (e.g. methylsulfonyl chloride, ethylsulfonyl chloride), arylsulfonyl halogenides (e.g. benzenesulfonyl chloride, toluenesulfonyl chloride) and the like. The reaction is carried out under conditions of ordinal sulfonylation, for example, on addition of the above-., -. .

. .

16~ 33~;

mentioned halogenating agent in the presence of tertiary amine such as pyridine or triethylamine.
Step b (III--~Ia) In this process, the 7-amino protecting group and if required, the 4-carboxy protecting group are at the same time or stepwise removed by hydrolysis or reduction according to the properties of ,ç 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 be removed in a well-known manner.
Compounds (I), except those wherein R is halogen or sulfonyl-oxy, may be prepared in a manner as shown in the following Reaction ;~ Scheme.

Reaction Scheme - 3 .- , ~ ~ X Step c o ~ ~
' COOZ COOZ
;~ (III) (IV) ,. ~H2 ~ ~

Step d O
(Ib) (wherein R, Z , R and X are the same as mentioned above).
- Compounds (I) wherein R is hydrogen are prepared in the ~:, ~ process described in Reaction Scheme - 3.

^~j 25 Step c (III -~IV) ~ Halogen or sulfonyloxy at the 3 position of the compounds :.~
; represented by the formula (III) is removed by reduction to yield 3-unsubstituted oxadethiacephem structure. The reduction may be carried out in such manners as selective reduction of halogen or - -sulfonyloxy at the 3 position without any influence on other sub-' `
,:,, .

3;~
stituents or functional groups, for example, combination of metals and acids, particularly combination of zinc and acetic acid. The 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 be carried out in the manner ordinarily used in the field of penicillin and cephalosporin synthetic chemistry.
Alternatively, the objective compound (Ib) in this step may be prepared in the manner as shown in the following Reaction Scheme.
Reaction Scheme - 4 OH o RNH ~ ~ acetone RN ~ O~ ~ O
O ~ p-TsOH O
(6) cloozl (13) coozl RNH~ O ~ RNH ~ o ~
3 ~ Zn~AcOH ~
. ~ ~ __~ O ' ~ ~--N OH
r`'~oxidation o~ ~ O~ ~
' ` COOZ COOZ 1 (14) (15) .
:....................................O~
1) halogenation RNH ~ O ~ partial (SOC12) ~ halogenation 2) PPh3 (16) CoOZ

OH
RNH ~ o ~ NaIO4 RNH ~ CHO
, 25 ~ ~ Ph3 O ~ PPh3 ` (17) COOZ (18) COOZl .,.
Wittig RNH ~ O~ (Ib) reaction o ~ ~ 1 COOZ
(IV) (wherein R and Z are the same as mentioned above).
The reactions shown in the above Reaction Scheme - 4 may be carried out under well-known reaction conditions which satisfy reaction process as shown in each step.
Compounds (I) wherein R is arylthio or monocyclic hetero-cycle-thio may be prepared in a manner as shown in the following Reaction Scheme.
Reaction Scheme - 5 10 RNH o RNH ~o ~ ~ ~ ` ~
o ~ - N~ ~ X step e o~ - N~ \ y (III) (V) lCOOZ

2` ~ ~

step f o ~ N ~ y (Ic) (wherein R, Z ~ R and X are the same as mentioned above ; Y is arylthio or monocyc:Lic heterocycle-thio).
Step e (III _ V) Halogen or sulfonyloxy at the 3-position in compounds (III) is substituted by a desirable arylthio or monocyclic heterocyclethio.
This reaction is carried out by reacting the starting materials (III) with the corresponding arylthiol or monocyclic heterocycle-thiol in the presence of a weak base or with the corresponding salt.
Preferable weak bases are organic ones such as pyridine and triethyl-amine. Ordinarily, the reaction proceeds well at room temperature.
t.~.
Step f (V ~Ic) This is a process of hydrolysis or reduction, the same as steps b and d, and may be carried out under the same conditions as in the steps b and d.

:' Alternatively, the objective compounds (Ic) may be prepared in a manner as shown in the following Reaction Scheme.
Reaction Scheme - 6 .

O COOH YH R~H o~OY

O~ PPh (COC12) O ~ - N~PPh3 1 pyridine I 1 (12) COOZ (19) COOZ
.

; Wittig reaction ~--f~ ~
; ¦ I - , (Ic) COOZ
(V) -: ~ -(wherein R, Y and Z are the same as mentioned above).
~` The reactions in the above Reaction Scheme - 6 may be carried ; out under well-known reaction conditions which satisfy each step.
Compounds (I), wherein R is lower alkoxy, may be prepared in a mannex as shown in the following Reaction Scheme.
: . i ` Reaction Scheme - 7 . .
: RNH ~ Ol RNH ~ ~

N ~ H steP g N ~ oZ3 - (II) CoOZl (VI) CZ

,~ ~H2 `n''~
Step h O ~ ~ OZ

. (Id) R

: 25 . ~ .
(wherein R, R2 and Z are the same as mentioned above ; Z is lower alkyl).

Step g (II-~VI) This process is carried out in a condition of enoletherifica-tion of ketones or on the action of reagents as diazoalkane ordin-''' ::
'., ()336 arily employed in esterification of carboxylic acids. Enoletheri-fication of ketones is carried out, for example, by means of tri-alkylorthoformates (e.g. triethylorthoformate) or alcohols and p-toluenesulfonic acid. Alkylation by diazoalkanes (e.g. diazome-thane, diazoethane) may be employed in this invention. Thesereactions may be carried out in the well-known manner.
Step 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 R3 is methoxy, may be prepared in a -manner as shown in the following Reaction Scheme.
Reaction Scheme - 8 , . .
: 15 H OCH3 NH2 ~ ~ 2 O ~ ~ R N
R

(If) (Ie) 20 (wherein R and R are the same as mentioned above). -- --~ Step i :;
~ The starting materials (If) correspond to each objective com-:
pound prepared in the Reaction Scheme - 7. Introduction of 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 manners are described as follows.

; Manner 1 The 7-amino of the starting materials (If) is acylated to corresponding the 7-acylamino derivatives, the latter are reacted ,, 10 :

. . .

~S~)336 .
with methoxylithium (LioCH3) and t-butyl hypochlorite (t-BuOCl) in an inert solvent at low temperature (Belgium Patent Application No.
817836), and then the 7-acyl protecting group is removed.
Manner 2 The 7-amino of the starting materials (If) is reacted with sodium nitrite to yield 7-diazo compounds (a), the latter reacted with haloazide (prepared from sodium azide and the corresponding . .
, halogen)(e.g. Br~3, ClN3, I~3) to yield the corresponding haloazide ;~ compounds (b), and the latter reacted with methanol followed by , .
reductive azide decomposition to yield the objective 7-amino-7-; methoxy compounds (Ie).

~ The reaction ccheme in this process is represented as follows , ~ (Japanese Unexamined Patent Publication No. 47-931).
~, X ' 2 ~ ~ X"'~3 3 ~ ~ -' 15 0 ~ R
R R
(a) (b) 1) MeOH ~ (Ie) 2) Reduction (wherein R and R are the same as mentioned above; X"' is halogen).

20 Manner 3 - The starting materials (If) are reacted with p-hydroxybenzalde-.
~; hydes (preferably those having a bulky substituent or substituents adjacent to the p-hydroxy, for example, 3,5-di-t-butyl-4-hydroxy-benzaldehyde) to yield benzylidene derivatives (c), the latter oxidized by means of appropriate oxidating agents (e.g. nickel peroxide, lead tetraacetate) to yield quinoid type derivatives (d), the latter reacted with methanol to yield 7a-methoxy compounds (e) and benzylidene group of the latter hydrolyzed (ordinarily on the treatment of Girard reagent) to yield the objective 7~-amino-7a-methoxy compounds (Ie). The reaction scheme in this process is '' 11 . ~

~.6~)33~;
represented as follows (Japanese Unexamined Patent Publication No.
50-50394) HO ~3 HO ~3CH=~
\~~ oxidation (If) --- ? O ~LN~ R 1 ( ) O ~CH-~ Ho~3CH=N
~~ MeOH O

(d) o ~ ~R
(e) hydrolysis (Ie) ~. :
(wherein R and R are the same as mentioned above).
Manner 4 Alternatively, a manner as shown in the following Reaction . Scheme may also be utilized. In this manner, 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 :
20 derivatives (f), the latter treated with a halogenating agent to ; yield iminohalide derivatives (g), the latter treated with a base ' for dehydrohalogenation to yield keteneimine derivatives (h), the .
latter halogenated to yield dihalogenoimine derivatives (i), the `. latter reacted with alkali metal methoxide and then hydrolyzed to . 25 remove the acyl group (Japanese Unexamined Patent Publication ~o.
:. 50-126692).
: Q' 1l Q' \ CE~C~H ~ agent ~

; R (g) R

' 33~
-HX / C=C=N ~o X2\ Cl-IC=
O~ ~\R 7 Q~ X 'X ' (h) R (i) R

~ OCH3 hydrolysis ? , , (Ie) ~` (wherein R and R are the same as mentioned above; Q' and Q" are hydrogen or appropriate substituents ; X and X' are halogen, respectively).
The compounds represented by the formula (I) in this invention are important intermediates in preparation of novel l-oxadethiace-phalosporins. Introduction of various acyl groups used in the field of penicillin and cephalosporin chemistry to the free 7-amino group of the compounds (I) yields antimicrobially very active com-pounds.
The following examples are provided to further illustrate this invention.
Example 1 7~-amino-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : R =Cl ; R =COOH, R =H) (Ia : R =COOH ; X=Cl) 1) To a solution of 1.5 g (3 mmoles) of diphenylmethyl 7~-benzyloxycarbonylamino-3-hydroxy-1-oxa-1-dethia-3-cephem-4-carboxy-late (II : R=PhCH2OCO ; Z =CHPh2) in 30 ml of dimethylformamide is added 0.03 ml (0.36 mmole) of pyridine under ice-cooling and then ; 25 dropwise added 0.31 ml (3.6 mmoles) of oxalyl chloride. After stirring for 3 hours at room temperature, the reaction mixture is poured into 5 % phosphoric acid aqueous solution under ice-cooling and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is chromatographed on 20 parts by volume of silica gel and eluted with benzene-ethyl acetate (5 : 1) ~ 033~

to yield 489 mg of the objective 3-chloro derivative, diphenyl-methyl 7~-benzyloxycarbonylamino-3-chloro-1-oxa-1-dethia-3-cephem-

4-carboxylate (III : R=PhCH20C0 ; Z =CHPh2 ; X=Cl) (31.4 % yield).
mp. 130 - 131C
IR : ~ m x 3 cm : 3450, 1805, 1725, 1620.
~MR : ~ 3 ppm : 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).
This product may 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 added 6.2 mmoles of chlorine-carbon tetrachloride, a solution of 1.55 g (3.1 mmoles) of 3-hydroxy derivatives (II : R=PhCH2OCO ; Z =CHPh2) in 10 ml of tetrahydro-furan and then 0.86 ml (6.2 mmoles) of triethylamine under ice-cooling while stirring. After stirring for 1.5 hours at room tem-perature, the reaction mixture is poured into ice water and extrac-ted with ethylacetate. The extract is washed with water, dried and evaporated. The residue is chromatographed on 30 parts by volume of silica gel and eluted with benzene-ethyl acetate (10 : 1) to yield 0.95 g of the objective 3-chloro derivative (III : R=
20 PhCH2OCO ; Z =CHPh2 ; X=Cl) (59.0 % yield)-2) To a solution of 950 mg (1.83 mmoles) of the 3-chloro :.
- derivatives prepared above (III : R=PhCH20CO ; Z =CHPh2 ; X=Cl) in 37 ml of methylene chloride are added 1.78 ml (16.5 mmoles) of anisole and a solution of 1.45 g (11 mmoles) 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 layer ~ washed with methylene chloride and then ethyl acetate, and evapora-- ted under reduced pressure. The residue is chromatographed on a ., 30 column of 400 g of Diaion HP 20 (Trade mark of Mitsubishi Chemical ' 33~j Industries ; Hiporous polymer) and eluted with hydrochloric acid (pH 3). The eluate is adjusted to pH 4.4 and evaporated under reduced pressure to yield 175 mg of the objective 3-chloro deriva-tive (I : R =Cl ; R =COOH ; R =H)(43.8 % yield).
~` 5 IR : ~ m cm : 3420, 1818, 1630, 1613.
Example 2 7~-amino-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : R =R =H ;
R =COOH)(Ib : R =COOH) 1) To a solution of 1.98 g (3.96 mmoles) of the 3-hydroxy derivatives (II : R=PhCH2OCO ; Z =CHPh2) in 20 ml of dimethylforma-mide are added 0.62 ml (2 equivalents) of methylsulfonyl chloride and then 0.83 ml (1.5 equivalents) of triethylamine at - 50DC, and the mixture stirred at the same temperature for 15 minutes and - poured into ice water to precipitate the crystals, which are col-lected by filtration to yield 2.15 g of the objective 3-methylsul-fonyloxy derivative, diphenylmethyl 7~-benzyloxycarbonylamino-3-methylsulfonyloxy-l-oxa-l-dethia-3-cephem-4-carboxylate (III :
~ R=PhCH2OCO ; Z =CHPh2 ; X=oSO2CH3)(94.0 % yield).
; IR :y 3 cm : 3420, 1810, 1730, 1510, 1365, 1165.
~MR :~ 3 ppm : 2.96(s,3H), 4.46(bs,2H), 4.97(d,J=4.0Hz,lH), 5.07(s,2H), S.45(dd,J=4.0Hz,lH).
2) To a solution of 1.15 g (2 mmoles of the 3-methylsulfonyl-oxy derivatives (III : R=PhCH2OCO ; Z =CHPh2 ; X=OSO2CH3) in a mixture of methylene chloride ~20 ml) and acetic acid (40 ml) is ~ 25 added 3 g of activated zinc powder, and the mixture stirred at room temperature overnight, during which time each 3 g of zinc powder is added after the lapse of 2 hours and after 3 hours from the beginning of the reaction. Zinc powder is filtered off and the filtrate mixed with ethyl acetate. The organic layer is washed - 30 with water, dried and evaporat;d under reduced pressure to yield '' ~ .
,,~ . . ', : : :

``` 1~()33~;
913 mg of the objective 3-deoxy derivatives, diphenylmethyl 7~-benzyloxycarbonylamino-l-oxa-l-dethia-3-cephem-4-carboxylate (IV :
R=PhCH20C0 ; Z =CHPh2)(94.2 % yield) as powder.
IR : Y ma 3 cm : 3450, 1800, 1730, 1650.
NMR : ~ 3 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), 6.51(m,lH), 6.99(s,lH).
This product may also be prepared in the following manner.
To a solution of 240 mg of the 3-chloro derivative (III :
R=PhCH2OC0 ; Z =CHPh2 ; X=Cl) 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 the beginning of the reac-tion, 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 with water, dried and evaporated. The obtained residue is chromatogra-phed on a column of silica gel and eluted with benzene-ethyl acetate (5 : 1) to yield 215 mg of the objective 3-deoxy deriva-tive (IV : R=PhCH20C0 ; Z =CHPh2)(96.0: yield)-3) To a solution of 913 mg (18.8 mmoles) of the 3-deoxy deri-vatives prepared above (IV : R=PhCH20CO ; Z =CHPh2) in 35 ml of :.-methylene chloride are added 1.85 ml (9 equivalents) of anisole and a solution of 1.51 g of aluminum chloride (6 equivalents) in 18 ml of nitromethane, and the mixture allowed to stand at room temperature overnight and extracted with 2 % hydrochloric acid under ice-cooling. The aqueous layer is washed with methylene chloride - and the ethyl acetate, and evaporated under reduced pressure in order to remove organic solvent remaining in the aqueous layer.
The obtained residue is chromatographed on a column of Diaion HP 20 ; ' , ' , ~ . : ' - : .. .

)33t;
. . , (Trade mark of Mitsubishi Chemical Industries ; Highporous polymer) and eluted with dilute hydrochloric acid (pH 3.0). The eluate is , evaporated under reduced pressure to yield 291 mg of the objective 3-oxacephem derivative (I : R =R =H ; R =COOH) hydrochloride (70.6 % yield).
[a]D + 11.1 ~ 2.4 (c=0.216, in methanol) IR : ~m cm : 3500, 2600, 1805, 1645, 1610, 1550.
NMR : ~ 3 ppm : 5.37(d,J=4.0Hz,lH), 5.51(d,J=4.0Hz,lH), 6.70 (m,lH)~
Example 3 7~-amino-3-(1-methyltetrazol-5-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : R =l-methyltetrazol-5-ylthio ; R =COOH, R -H)(Ic : Y=l-methyltetrazol-5-ylthio ; R =COOH) 1) To a solution of 1.12 g (1.94 mmoles) of the 3-methyl-sulfonyloxy derivative prepared in Example 2 (III : R=PhCH20C0 ;
Z =CHPh2 ; X=OSO2CH3) in 10 ml of dimethylformamide are added 373 mg (3.2 mmoles) of 1-methyltetrazol-5-ylthiol and 0.42 ml (3.0 mmoles) of triethylamine under cooling at 0C and the mixture stirred at room temperature overnight. After termination of the ; 20 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-tetrazolylthio derivative (V : R=PhCH2OCO ; Z =CHPh2 ; Y=l=methyltetrazol-5-ylthio) as yellow powder (86.7 % yield).
IR : ~ 3 cm : 3450, 1805, 1730.
~MR : ~ 3 ppm : 3.93(s,3H), 4.28(ABq,J=18Hz,2H), 5.00(d,J=4.0Hz, lH), 5.17(s,2H), 5.30 - 5.90(m,2H), 6.98(s,1H).
2) To a solution of 137 mg (0.229 mmoles) of the 3-tetrazolyl-thio derivative prepared above (V : R=PhCH2OCO ; Zl=CHPh2; Y=l-methyltetrazol-5-ylthio) in 4 ml of methylene chloride are added ':, l~S(~336 0.223 ml (2.06 mmoles) of anisole and a solution of 190 mg (1.4 mmoles) of aluminum chloride in 2 ml of nitromethane, and the mix-ture allowed to stand at room temperature overnight and mixed with 3 ml of 2 % hydrochloric acid under ice-cooling. The aqueous layer is washed with methylene chloride and then acetic acid, and concen-trated. The concentrate is adjusted to pH 2.5 with sodium carbo-nate to yield 24 mg of the objective 7~-amino-3-tetrazolylthio derivative (I : R =l-methyltetrazol-5-ylthio ; R =COOH ; R =H) as crystals.
mp.> 200C
; IR : ~ cm : 1820, 1630, 1620.
Example 4 7~-amino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : R =OCH3 ; R =COOH ; R3=H)(Id : R2=COOH ; Z3=CH~) ; 15 1) To a solution of 1.15 g (2.30 mmoles) of 3-hydroxy deri-vatives (II : R=PhCH20CO ; Z =CHPh2) in 12 ml of methylene chloride is added a mixture of diazomethane 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 ace-; tate (4 : 1) to yield 0.89 g of the objective 3-methoxy derivatives diphenylmethyl-7~-benzyloxycarbonylamino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylate (75 % yield).
IR : ~ 3 cm : 3495, 1796, 1725, 1626, 1512.
NMR : ~ 3 ppm : 3.70(s,3H), 4.23 and 4.54(ABq,J=18Hz,2H), :..
~ 4.96(d,J=4.0Hz,lH), 5.18(s,2H), 5.42(dd,J=lOHz;4.0Hz,lH), 5.81(d, -J=loHz~lH)~ 7.02(s,lH), -7.4(m,aromatic H).

2) To a solution of 1.06 g (2.06 mmoles) of the 3-methoxy derivative prepared above (VI : R=PhCH20CO ; Z =CHPh2 ; Z =CH3) - 30 in 20 ml of methylene chloride are added 3 ml of anisole .
. ~ . .
. ' ' ~ .

033~;
and 3 ml of trifluoroacetic acid under cooling, and the mixture stirred for 15 minutes, mixed with 20 ml of toluene and ; then evaporated under reduced pressure. The oily residue is dis-solved in benzene and extracted with 5 % sodium hydrogencarbonate aqueous solution. The extract is washed with benzene, adjusted to pH 2 with 10 % hydrochloric acid and then extracted with ethyl ace-tate again. The extract is washed with water and sodium chloride aqueous solution, and evaporated under reduced pressure to yield 0.67 g of the free 4-carboxylic acid compound, 7~-benzyloxycarbonyl-10 amino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid.
IR : y 3 cm : 3430, 1793, 1725, 1630, 1510.
3) To a suspension of 100 mg of 5 % palladium - charcoal in 20 ml of a mixture of ethyl acetate and methanol (1 : 1), on which hydrogen gas has preliminarily been adsorbed, is added 200 mg 15 (0.934 mmole) of the free 4-carboxylic acid compound prepared above, and the mixture is vigorously stirred in hydrogen atmosphere.
The reaction mixture is stirred at room temperature for 2 hours - and the catalyst filtered off. The filtrate is evaporated under reduced pressure to yield 65 mg of the objective 7~-amino compound (I : R =OCH3 ; R =COOH ; R =H)(53 % yield).
; KBr -1 IR : ~ cm : - 3400, - 2900, 1785, 1679, 1647.
The catalyst filtered off in the above operation is washed with methanol-hydrochloric acid several times and the washings are evaporated under reduced pressure to yield 65 mg of the 7~-amino derivative hydrochloride (I : R =OCH3 ; R =COOH ; R =H) as white powdered crystals.
; IR : ~ cm : - 3400, - 3000, 1787, 1694, 1619.
Example 5 ., ~-nitrobenzyl 7~-amino-3-chloro-7a-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylate (I : R =Cl ; R =COOCH~C~H4 ~O2-p; R =OCH3)(Ie : R =Cl ;

' ~ ?()336 R2=COOCH2C~,H,~ ~ ~02 -P ) 1) To a solution of 141 mg (0.399 mmole) of p-nitrobenzyl - 7~-amino-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylate (I : R =Cl ;
R =COOCH2C6H4.NO2-p ; R --H)[prepared from the free 3-chloro deri-vative prepared in Example 1 (I : R =Cl ; R =COOH ; R =H) on esteri-fication] in a mixture of 7 ml of chloroform and 1 ml of benzene is "~ added 112 mg (1.2 equivalents) of 3,5-di-t-butyl-4-hydroxybenzalde-hyde and the mixture refluxed under heating in a reaction vessel -` equipped with a water separator containing molecular sieve. After 2.5 hours, the reaction mixture is mixed with additional 30 mg of ,....................................................................... .
the aldehyde compounds and reacted for 3.5 hours. The mixture is cooled to -15C, mixed with 65 mg of magnesium sulfate and 219 mg of nickel peroxide, and stirred at the same temperature for 30 ", ~; minutes and at room temperature for 40 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 of 12 g of ~ silica gel and eluted with benzene-ethyl acetate (19 : 1) to yield ,~ 125 mg of the objective 7-methoxy derivatives, p-nitrobenzyl 7~- -~i, 20 (3,5-di-t-butyl-4-hydroxybenzylidene)amino-3-chloro-7a-methoxy-1-~` oxa-l-dethia-3-cephem-4-carboxylate (e : R =Cl, R =COOCH2.C6H4.N02-p ;
7~-side chain=3,5-di-t-butyl-4-hydroxybenzylideneamino) as viscous material (52.2 % yield).
IR : ~ 3 cm : 1780, 1735, 1680, 1520, 1345.
25 ~MR :~ 3 ppm : 1.48(s,18H), 3.61(s,3H), 4.49(s,2H), 5.23(s, ~ç~ lH), 5.44(aromatic H), 8.53(s,1H).
.;, ~
2) To a solution of 125 mg of the 7-methoxy derivative (e :
R =Cl ; R =CoocH2-c6H4.~o2-p ; 7~-side chain=3~5-di-t-butyl-4-hydroxybenzylideneamino) in a mixture of methanol (2.5 ml) and tetrahydrofuran (0.5 ml) is added 81 mg of Girard reagent, and the , 20 033~;
mixture stirred at room temperature for 1 hour, poured into water and extracted with methylene chloride. The extract is washed with water, dried and 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 : 1) to yield 35 mg of the objective 7-amino derivative (I : R =Cl ; R =COOCH2-C6H4 N02-p ; R =OCH3)(43.8 %
yield).
IR :y 3 cm : 1790, 1740, 1520, 1350.
NMR :~ 3 ppm : 1.83(bs,2H), 3.53(s,3H), 4.54(s,2H), 5.01(s, lH), 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.
p-nitrobenzyl 7~-amino-1-oxa-1-dethia-3-cephem-4-carboxylate (I R =H; R =COOCH2-C6H4-N02-P ; R =H) IR : ~ 3 cm : 3405, 1772, 1726, 1633, 1605, 1517, 1345.
NMR :~ 3 ppm : 1.74(b,2H), 4.61(m,2H), 5.05(d,J=4.0Hz, lH), 5.42(bs,2H), 5.5(m,lH), 6.61(m,lH), 7.67 and 8.31(q,J=9.OHz,4H).
p-nitrobenzyl 7~-amino-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylate (I : R =OS02CH3 ; R =COOCH2-C6H4-N02-p ; R =H) IR : Y m x 3 cm : 3420, 1790, 1735, 1610.
NMR : ~ 3 ppm : 2.15(bs,2H), 3.23(s,3H), 4.52(s,2H), 5.02(d, J=4Hz,lH), 5.30(s,2H), 5.33(m,lH), 7.48 and 8.10 (q,J=8.0Hz,4H).
7~-amino-3-phenylthio-1-oxa-1-dethia-3-cephem-4-carboxylic acid (I : R =S-Ph ; R2=COOH ; R3=H).
ExamPle 6 1) diphenylmethyl 2-[2~-(2-propinyloxy)-3~-amino-4-oxo-azetidin-l-yl]-2-isopropylideneacetate (2 : z =CHPh2)----------To a solution of 0.95 g of diphenylmethyl 2-(2~-chloro-3~-amino-4-oxoazetidin-1-yl)-2-isopropylideneacetate (1 : z =CHPh2 ; X =Cl) in a mixture of propargyl alcohol (3 ml) and tetrahydrofuran (2 ml) : . - - : , , , . . , - . ' ~ 033~

is added 0.79 g (4 mmoles) of silver tetrafluoroborate, and the mixture stirred at room temperature for 3 hours, diluted with 50 ml of benzene, cooled to 0C and mixed with a mixture of 10 ml of 5 % sodium hydrogencarbonate aqueous solution and 5 ml of saturated sodium chloride aqueous soIution. The reaction mixture is stirred and filtered through celite. The benzene layer is separated, dried over Glauber's salt and evaporated under reduced pressure. The obtained brown oily materials are purified by chromatography on a column of silica gel containing 10 % water and eluted with benzene-ethyl acetate (1 : 1) to yield 268 mg of the objective 2~-propinyl-oxy derivative (2 : Z =CHPh2)(134 mg of 2a-propinyloxy derivative and 134 mg of 2~-propinyloxy derivative).
2a-propinyloxy derivative :
IR : y 3 cm : 3400, 3320, 2115, 1767, 1723.
NMR ~ 3 ppm : 1.83(brs,2H), 1.98(s,3H), 2.22(s,3H), 2.33(t, ,~; J=2.5Hz,lH), 4.07(d,J=2.5Hz,2H), ca4.07(m,lH), 4.93(d,J=l.OHz,lH), ~ 6.90(s,lH), 7.32(s,10H).
~.
2~-propinyloxy derivative :
IR : ~ 3 cm : 3410, 3320, 2115, 1767, 1720.

~MR :~ 3 ppm : 1.77(brs,2H), 2.00(s,3H), 2.23(s,3H), 2.27(t, - J=2.5Hz,lH), 4.12(d,J=2.5Hz,2H), 4.23(d,J=4.0Hz,lH), 5.27(d,J=4Hz, lH), 6.90(s,lH), 7.32(s,10H).

2) diphenylmethyl 2-[2~-(2-propinyloxy)-3~-benzyloxycarbonyl-~;; amino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (3 : R=PhCH20C0 ;

Z =CHPh2) ________________________ To a solution of 30.0 g (0.074 mole) of 2~-propinyloxy derivative (2 : Zl=CHPh2) in 250 ml of dry methylene chloride is added 14.07 g (0.0825 mole) of benzyloxycarbonyl chloride under ice-cooling and dropwise added a mixture of pyridine (6.7 mmoles ; 0.0825 mole) and methylene chloride, and the mixture stirred for 30 minutes under ;, ,.
'':

aO33ti coolingJ poured into ice water and extracted with methylene chloride.
The extract is washed with water and sodium chloride aqueous solu-tion, dried and evaporated under reduced pressure. The obtained oily residue is chromatographed on 1000 g of silica gel and eluted with benzene-ethyl acetate (5 : 1) to yield 26.5 g of the objec-tive 3~-benzyloxycarbonylamino derivative (3 : R=PhCH2oco ; Z =
CHPh2)(66.3 % yield).
IR : ~ 3 cm : 3440, 3300, 2110, 1774, 1720, 1630, 1507.
~MR : ~ 3 ppm : 2.00 and 2.25(s,3H x 2), 2.17(d,J=3Hz,lH), 4.07(d,J=3Hz,2H), 5.10(d,J=4Hz,lH), 5.17(s,2H), 5.33(q,J=8Hz,4Hz, lH), 5.55(d,J=8Hz,lH), 6.98(s,lH).
3) diphenylmethyl 2-(2~-allyloxy-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl)-3-isopropylideneacetate (4 : R=PhCH20CO ;
2) ~~~~~~~~~-~~~~~~~~--------------------To a suspension of 6.6 g of 5 % palladium-calcium carbonate in 170 :`"
l ml of methanol, to which hydrogen gas has been adsorbed with stir- ~ -"
; ring, is added a solution of 26.5 g (0.049 mole) of 3~-benzyloxy-.~ carbonylamino derivative (3 : R=PhCH20CO ; Z =CHPh2) in 100 ml of methanol, and the mixture stirred for 50 minutes under hydrogen - 20 atmosphere. The catalyst is filtered off and the filtrate evapora-ted under reduced pressure to yield 26.3 g of 2~-allyloxy deriva-tive (4 : R=PhCH2oco ; z =CHPh2) (98.8 % yield).
IR : ~ m 3 cm : 3440, 1772, 1720, 1628, 1505.
NMR : ~ 3 ppm : 2.00 and 2.25(s,3H x 2), 3.90(m,2E), 4.8 -5.9(m,6H), 5.17(s,2H), 6.95(s,lH) 4) diphenylmethyl 2-[2~-(2,3-epoxypropoxy)-3~-benzyloxycar-bonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (5 :
=PhCH2OC0 ; Z 2) ~~~~~~~~~~~---------------_____ To a solution of 25.6 g (0.047 mole) of the 2~-allyloxy derivative (4 : R=PhCH2OC0 ; Z =CHPh2) in 260 ml of chloroform is added 15.3 g 1~ )33~;
(0.071 mole) of m-chloroperbenzoic acid little by little, and the mixture allowed to stand at room temperature (23 -25 C) for 2 days and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, and washed with 5 % sodium thiosulfate aqueous solution, 5 % sodium hydrogencarbonate aqueous solution, water and then sodium chloride aqueous solution. The solvent is evaporated under reduced pressure to yield oily residue, which is chromato-graphed on a column of 800 g of silica gel and eluted with benzene-ethyl acetate (5 : 1) to yield 21.25 g of the objective epoxy ~ 10 derivative (5 : R=PhCH20CO ; Z =CHPh2)(81.2 % yield).
; IR : ~ 3 cm : 3445, 1778, 1724, 1632, 1508.
NMR : ~ 3 ppm : 2.00 and 2.25(s,3H x 2), ca 2.2 - 3.9(m,5H), 5.18(s,2H), ca 5.0 - 5.3(m,2H), 5.58(d,J=lOHz,lH), 6.83(s,1H).
` A small quantity of diepoxy derivative (2.15 g ; mp. 118 -120 C) is obtained as by-product in this process.
5) diphenylmethyl 2-[2~-(2,3-dihydroxypropoxy)-3~-benzyloxy-carbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (6 :
2) ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
To a solution of 21.25 g (0.038 mole) of the epoxy derivative pre-r 20 pared above (5 : R=PhCH20CO ; Z =CHPh2) in 220 ml of acetone are added 66 ml of 30 % perchloric acid and 44 ml of water under ice : cooling, and the mixture stirred at room temperature for 2 - 3 .-hours and extracted with ethyl acetate. The extract is washed with 5 % sodium hydrogencarbonate aqueous solution, water and then sodium chloride aqueous solution, dried and evaporated under redu-ced pressure to yield 20.6 g of the objective diol derivative -(6 : R=PhCH20CO ; Z =CHPh2)(94.4 % yield)-IR : y 3 cm : 3600, 3445, 1778, 1725, 1632, 1508.

NMR : ~ 3 ppm : 1.97 and 2.22(s,3H x 2), 3.47(m,4H), 4.9 -5.3(m,2H), 5.13(s,2H), 6.07(m,lH), 6.97(s,lH).

:' ,` :

33bi In a similar manner, the 2~-propionyloxy derivative (2 : Z =
CHPh2) is reacted with phenylacetyl chloride to yield the 3~-phenylacetamide derivative (3 : R=PhCH2C0 ; Z =CHPh2) and the latter is subjected successively to hydrogenation, epoxydation and cleavage of epoxy ring to yield diphenylmethyl 2-[2~-(2,3-dihydroxy-propoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl]-2-isopropylidene-` acetate (6 : R=PhCH2C0 ; Z =CHPh2).
Example 7 1) diphenylmethyl 2-[2~-(2,3-isopropylidenedioxypropoxy)-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (13 : R=PhCH20C0 ; Z =CHPh2) ------ _--___________________ '- To a solution of 2.5 g of diphenylmethyl 2-[2~-(2,3-dihydroxypro-poxy)-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropyli-deneacetate (6 : R-PhCH20C0 ; Z =CHPh2) in 50 ml of acetone is added 5 mg of p-toluenesulfonic acid under ice-cooling, and the ;~ mixture stirred for 3 hours, mixed with a small amount of 5 %
sodium hydrogencarbonate aqueous solution and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried, and evaporated. The obtained residue is --~
; 20 chromatographed on a column of silica gel and eluted with benzene-ethyl acetate (2 : 1) to yield 2.26 g of the objective isopropyl-; idenedioxy derivative (13 : R=PhCH20C0 ; Z =CHPh2)(84.% yield).
IR : y 3 cm : 3450, 1780, 1725, 1635, 1600.
NMR :~ 3 ppm : 1.28(s,6H), 2.00(2,3H), 2.25(s,3H), 3.25 -25 4.20(m,5H), 4.90 - 5.77(m,5H), 6.95(s,lH), ca7.3(m,15H).
2) diphenylmethyl 2-[2~-(2,3-isopropylidenedioxypropoxy)-3~-benzyloxycarhonylamino-4-oxoazetidin-1-yl~-2-hydroxyacetate (15 :
R=PhCH20C0 ; z 2) ~~~~~~~~----------____ - Into a solution of 2.2 g (3.58 mmoles) of the isopropylidenedioxy 30 derivative prepared above (13 : R=PhCH20C0 ; Z =CHPh2) in 40 ml of .
.

Q33~;

:
methylene chloride is introduced ozone under cooling with dry ice-` acetone until the mixture turns blue. The excess amount of ozone is removed, and the mixture mixed with 22 ml of methyl sulfide and allowed to stand under cooling at the same temperature for 1 hour and then at room temperature for 1 hour. The mixture is mixed with a small amount of ecetic acid, washed with water, dried and evapora-ted to yield 2 g of the intermediate, 1-diphenylmethoxalyl-2~-(2,3-isopropylidenedioxypropoxy)-3~-benzyloxycarbonylamino-4-oxoazeti-dine (14 : R=PhCH20C0 ; Z =CHPh2). 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 hours under ice-, cooling. zinc powder is filtered off and washed with methylene . ,.
chloride. The filtrate and the washings are combined, washed with water, dried and evaporated to yield 20 g of the objective 2-... 1 ` 15 hydroxy derivative (15 : R=PhCH20C0 ; Z =CHPh2)(95 % yield).

IR : y 3 cm : 3500, 3430, 1780, 1740, 1720, 1600.

NMR :~ 3 ppm : 1.47(s,6H), 3.17-4.30(m,5-6H, 5.16(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) diphenylmethyl 2-[2~-(2,3-isopropylidenedioxypropoxy)-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-triphenylphosphoranyl-ideneacetate (16 : R=PhCH20C0 ; Z =CHPh2) -------------------To a solution of 2.0 g (3.4 mmoles) of 2-hydroxy derivative (15 :

R=PhCH20C0 ; Z =CHPh2) in 60 ml of dry methylene chloride is added 1.3 ml (1.02 mmoles) of dimethylaniline under ice-cooling and drop-.; .
wise added 0.74 ml (1.02 mmoles) of thionyl chloride, and the mix-ture stirred at the same temperature for 30 minutes, and poured into ice water. The methylene chloride layer is separated and '.`"
- washed with water, dried and evaporated to yield 2.3 g of the intermediate, diphenylmethyl 2-[2~-(2,3-isopropylidenedioxypropoxy)-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-chloroacetate . .
,;
:'~

CHCl3 ~ S~l3 36 [ ~ max : 3436, 1785, 1750, 1720, 1595.]. This is dis-solved in 40 ml of methylene chloride and mixed with 0.86 ml (6.8 mmoles) of dimethylaniline and 1.8 g (6.8 mmoles) of triphenyl-phosphine. The mixture is refluxed under heating for 6 hours, mixed with additional 1.8 g of triphenylphosphine, reacted for 12 hours, poured into 5 % sodium hydrogencarbonate aqueous solution under cooling, washed with water, dried and evaporated. The resi-due is chromatographed on a column of silica gel to yield 1.6 g of the objective triphenylphosphoran derivative (16 : R=PhCH20C0 ;
Z =CHPh2)(56.6 % yield).
IR : ~ 3 cm : 3400, 1760, 1710, 1620, 1590.
4) diphenylmethyl 2-[2~-(2,3-dihydroxypropoxy)-3~-benzyloxy-carbonylamino-4-oxoazetidin-1-yl]-2-triphenylphosphoranylidene-acetate (17 : R=PhCH20C0 ; Z =CHPh2) --------------------------To a solution of 417 mg (0.5 mmole) of triphenylphosphorane deriva-tive (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 % sodium hydrogen-carbonate aqueous solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is chromatographed on a column of silica gel to yield 172 mg of the ; objective acetonide free derivative (17 : R=PhCH20C0 ; Z =CHPh2) (43.3 % yield).
IR Ymax 3 cm : 3450 _ 3200, 1770, 1720, 1630, 1600.
5) diphenylmethyl 7~-benzyloxycarbonylamino-1-oxa-1-dethia-3-cephem-4-carboxylate (IV : R=PhCH20C0 ; Z =CHPh2) -------------To a solution of 139 mg ~0.175 mmole) of the acetonide free deri-vative (17 : R=PhCH20C0 ; Z =CHPh2) in 4 ml of tetrahydrofuran is added periodic acid consisting of sodium periodate (45 mg) and lN-sulfuric acid (2.2 ml) under ice-cooling, and the mixture stirred . . ~ . , .
- : ' , . ' : lQ~1~)33~;

" at the same temperature for 3 hours and at room temperature for 1 hour, poured into ice water, and extracted with ethyl acetate. The extract i5 washed with water, dried and evaporated. The residue is purified by chromatography on a column of silica gel to yield 15 mg of the objective protected oxacephem derivative (IV :
R=PhCH20CO ; Z =CHPh2) (17.7 % yield).
This product is confirmed to be identical with an authentic speci-men prepared by an alternative route in Example 2 in thin layer chromatography, IR spectrum and NMR spectrum.
ExamPle 8 .
1) diphenylmethyl 2-[2~-(2-oxoethyloxy)-3~-benzyloxycarbonyl-amino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (7 : R=PhCH2OCO ;

Z =CHPh2) -------------------_______ To a solution of 11.5 g (0.02 mole) of diphenylmethyl 2-[2~-(2,3-dihydroxypropoxy)-3~-benzyloxycarbonylamino-4-oxoazetidin-1-yl]-2-isopropylideneacetate (6 : R=PhCH20CO ; Z =CHPh2) in 200 ml of -ethanol is added a solution of 5.14 g (0.024 mole) of sodium periodate in 210 ml of lN-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 water and sodium chloride aqueous solution dried and evaporated under reduced pressure to yield 10.8 g of the objective formyl derivative (7 : R=PhCH20C0 ; Z =CHPh2).
IR : ~ 3 cm : 3445, 1778, 1725, 1632, 1508.
. 25 2) diphenylmethyl 2-(2~-methoxycarbonylmethoxy-3~-benzyloxy-`- carbonylamino-4-oxoazetidin-1-yl)-2-isopropylideneacetate (8 :
R=PhCH20CO ; Z =CHPh2; Z =CH3) -_____________________________ To a solution of 10.8 g of the formyl derivative (7 : R=PhCH2OC0 ;
z =CHPh2) in 100 ml of acetone is added 14 ml of Jones reagent at a temperature below 15 C under ice-cooling with stirring. After 30 minutes, the reaction mixture is mixed with isopropanol and an excess amount of the reagent decomposed. The insoluble materials are filtered off, and the filtrate is poured into ice water and extracted with ethyl acetate. The extract is washed with water and sodium chloride aqueous solution and evaporated under reduced pressure to yield 11.1 g of the carboxylic acid compound (8 :
R=PhCH20C0 ; Z =CHPh2, Z =H) as crude product. This is dissolved in 150 ml of methylene chloride and mixed with diazomethane-ether for esterification, and evaporated. The residue (11 g) is chroma-tographed on a column of 200 g of silica gel and eluted with benzene - ethyl acetate (5 : 1) to yield 9.2 g of the objective methyl carboxylate compound (8 : R=PhCH20C0 ; Z =CHPh2 ; Z =CH3) (80.3 % yield).
IR : Y 3 cm : 3445, 1780, 1725, 1635, 1510.
15 NMR ~ 3 ppm : 2.00 and 2.25(s,3H x2), 3.58(s,3H), 3.97(s, 2H), 5.0-5.40(m,2H), 5.13(s,2H), 5.77(d,J=8Hz,lH), 6.93(s,lH).
3) 1-diphenylmethoxalyl-2~-methoxycarbonylmethoxy-3~-. benzyloxycarbonylamino-4-oxoazetidine (9 : R=PhCH20C0 ; Z =CHPh2 ;
z =CH3) ------~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
,.~
20 To a solution of 9.2 g (0.016 mole) of the methyl carboxylate pre-pared above (8 : R=PhCH20C0 ; Z =CHPh2 ; Z =CH3) in 230 ml of methylene chloride is introduced ozone under cooling at -78C.
The reaction mixture turns blue after about 30 minutes, and then nitrogen gas is introduced to remove an excess amount of ozone.
The mixture is mixed with 10 ml of dimethylsulfide under cooling -78 C, stirred at the same temperature for 1 hour and then at room temperature for 1 hour, mixed with methylene chloride and 2 - 3 drops of acetic acid, washed with water and sodium chloride aqueous -solution, dried and evaporated to yield 8.9 g of the ob]ective 30 methoxalyl derivative (9 : R=PhCH20C0 ; Z =CHPh2 ; Z =CH3) as oily .

~ ()33~;
material.
IR : ~m 3 cm : 3450, 1830, 1756, 1720, 1509.
4) diphenylmethyl 2-(2~-methoxycarbonylmethoxy-3~-benzyloxy-! carbonylamino-4-oxoazetidin-1-yl)-2-hydroxyacetate (10 : R=PhCH2OCO
Z =CHPh2 ;Z =CH3) ______________________________ To a solution of 8.9 g of the methoxalyl derivative prepared above (9 : R=PhCH2OCO ; Z =CHPh2 ; Z =CH3) in a mixture of 90 ml of methylene chloride and 90 ml of acetic acid is added 9 g of acti-vated zinc powder under ice-cooling with stirring. After 15 - 30 minutes, zinc powder is filtered off, and the filtrate is mixed with methylene chloride, washed with water and sodium chloride aqueous solution, dried and evaporated under reduced pressure to yield 8.4 g of the objective hydroxyacetic acid derivative (10 :
R=PhCH2OCO ; z =CHPh2 ; z =CH3)(95.2 % yield)-15 IR : ~ 3 am : 3500 - 3600, 3445, 1796, 1747, 1512.
5) diphenylmethyl 2-(2~-methoxycarbonylmethoxy-3~-benzyloxy-carbonylamino-4-oxoazetidin-1-yl)-2-chloroacetate (11 : R-PhCH20CO ; Z =CHPh2 ; Z2=CH3 ; X"=Cl) ---------________________ To a solution of 8.4 g (0.015 mole) of the hydroxyacetic acid 20 prepared above (10 : R=PhCH2OC0 ; Z =CHPh2 ; Z =CH3) in 100 ml of dry methylene chloride are dropwise added 3.34 ml (0.046 mole) of ;~; thionyl chloride and 1.46 ml (0.018 mole) of pyridine under ice-cooling with stirring, and the mixture stirred for 30 minutes under -- ice-cooling, mixed with a proper amount of methylene chloride, washed with water and sodium chloride aqueous solution, dried and evaporated under reduced pressure to yield 8.9 g of the objective - monochloroacetic acid derivative (11 : R=PhCH2OCO ; Z =CHPh2 ;
z =CH3 ; X"=Cl) IR : ~ 3 cm ; 3435, 1790, 1748, 1725, 1502.

6) diphenylmethyl 2-(2~-carbomethoxy-3~-benzyloxycarbonyl-'' 033~

amino-4-oxoazetidin-1-yl)-2-triphenylphosphoranylideneacetate (12 : R=PhCH20C0 ; Z =CHPh2) -------------______________ To a solution of 8.9 g (0.015 mole) of the monochloro derivative ~` prepared above (11 : R=PhCH20C0 ; Z =CHPh2 ; Z =CH3, X"=Cl) in 100 ml of methylene chloride is added 8.0 g (0.03 mole) of tri-phenylphosphine and the mixture refluxed under heating for 1.5 hours, mixed with additional 2.0 g (7.5 mmoles) of triphenylphos-phine and refluxed under heating again for 1 hour. The reaction mixture is poured into 5 % sodium hydrogencarbonate aqueous solu-tion, neutralized, and extracted with methylene chloride. The extract is washed with water and sodium chloride aqueous solution, dried and evaporated under reduced pressure. The residue is chromatographed on a column of 300 g of silica gel and eluted with . benzene-ethyl acetate (4 : 1 - 1 : 1) to yield 10.2 g of the objec- -,~
; 15 tive methyl triphenylphosphoranate derivative, diphenylmethyl 2-(2~-methoxy-carbonylmethoxy-3~-benzyloxycarbonylamino-4-oxoaze-tidin-l-yl)-2-triphenylphosphoranylideneacetate (84.1 % yield).
IR : Y m 3 cm : 3445, 1790, 1725, 1630, 1512.
!~ ~MR :~ 3 ppm : 3.58(s,3H), 3.6 - 5.2(m,4H), 5.07(s,2H).
~; 20 To a solution of 16.23 g (20.5 mmoles) of the methyl triphenyl-phosphoranate in 240 ml of tetrahydrofuran is dropwise added 118 :*.
' ml (22.5 mmoles) of sodium hydroxide aqueous solution (0.19 mmole/
ml) under cooling at 2 - 5~C in a period of 30 minutes, and the mixture stirred for 15 minutes, neutralized with 44 ml (23 mmoles) of 2 % hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and sodium chloride aqueous solution, dried and evaporated to yield 15.8 g of the objective triphenyl-phosphorane derivative (12 : R=PhCH20C0 ; Z =CHPh2).
IR : ~ 3 cm : 3440, 1775, 1725, 1625, 1510.

7) diphenylmethyl 7~-benzyloxycarbonylamino-3-hydroxy-1-oxa-, , ~ O;~

l-dethia-3-cephem~4-carboxylate (II : R=PhCH20CO ; Z =CHPh2) ----To a solution of lS.8 g (20.3 mmoles) of triphenylphosphorane derivative prepared above (12 : R=PhCH20CO ; Z =CHPh2) in 300 ml of dry toluene are added 41.4 g (406 mmoles) of acetic anhydride and 8.87 g (102 mmoles) of ~,N-dimethylacetamide, and the mixture heated at 100 - 105 C (bath temperature) for 16 hours. After cooling, the renction mixture is mixed with benzene, washed with water, sodium chloride aqueous solution and then water, dried and evaporated under reduced pressure. The residue (ca 20 g) is chromatographed on a column of 600 g of silica gel and eluted with benzene-ethyl acetate-acetic acid (9 : 1 : 0.001) to yield 5.08 g of the main product, diphenylmethyl 3-acetoxy-7~-benzyloxycarbonyl-amino-l-oxa-l-dethia-3-cephem-4-carboxylate (hereinafter abbrevia-- ted to 3-acetoxy compound)(48 % yield) and 3.25 g of by-product, diphenylmethyl 2-(2-benzyloxycarbonyl-3,8-dioxo-5-oxa-2,7-diaza-bicyclo [4.2.0] octan-7-yl)-2-triphenylphosphoranylideneacetate (21.5 % yield).
Physical constant of 3-acetoxy compound :
IR : ~ 3 cm : 3445, 1800, 1785, 1725, 1656, 1508.
NMR : ~CDC13 ppm : 2.00(s,3H), 4.32(s,2H), 5.05(d,J=4Hz,lH), 5.13(s,2H), 5.38(q,J=4Hz;lOHz,lH), 5.68(d,J=lOHz,lH), 6.95(s,lH).
Physical constant of by-product :
IR : r 3 cm : 1790, 1778, 1740, 1628.
NMR : ~ 3 ppm : 3-4(m,2H), 4-5(m,2H), 5.27(s,2H).
The 3-acetoxy compound (3.2 g ; 5.9 mmoles) prepared 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 water and extracted with ethyl acetate. The ethyl acetate layer is washed with 10 % phosphoric acid, water, and then sodium chloride aqueous solution, dried and evaporated under reduced 33~;
pressure to yield 3.05 g of the objective 3-hydroxy compound (II :
R=PhCH20CO ; Z =CHPh2) as white foamy material.
IR : ~ 3 cm : 3440, 1795, 1725, 1675, 1510.
NMR :~ 3 ppm : 4.37(s,2H), 5.05(d,J=4Hz,lH), 5.18(s,2H), ; ~ 5 5.45(q,J=lOHz,lH), 5.72(d,J=lOHz,lH), 7.00(s,lH), 10.83(s,lH).
This product may also be employed as the starting material in Example 1.

.. .

. . : -.-.

. ., ~ ' .

. -- .

.

": , ~ ` , '

Claims (23)

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

1. A process for the preparation of the compounds of the formula:

wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, C6 to C10 arylthio or a five-membered heterocycle-thio group having aza, oxa, thia, diaza, dioxa, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxathia, thiaza, oxadiaza and thiadiaza contained in the heterocycle, optionally substituted at any position or positions on the heterocycle by 1 to 4 substituents selected from the group consisting of C1 to C5 alkyl, hydroxy, C1 to C5 alkoxy, halogen, nitro or amino; R2 is carboxy or derivatives thereof selected from the group consisting of esters, thioesters or carbonamides; R3 is hydrogen or methoxy; and pharmaceutically acceptable salts thereof, comprising a process selected from the group of processes consisting of:
(i) hydrolyzing a compound of the formula:

wherein R is an amino protecting group; or (ii) where a compound of the formula:

is required, methoxylating the 7.alpha.-position of a compound of the formula:

2. A process according to claim 1, wherein R3 is hydrogen and R1 is halogen or sulfonyloxy.

3. A process according to claim 1, wherein R3 and R1 are hydrogen.

4. A process according to claim 1, wherein R3 is hydrogen and R1 is C6 to C10 arylthio or a five-membered heterocycle-thio group having aza, oxa, thia, diaza, dioxa, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxathia, thiaza, oxadiaza and thiadiaza contained in the heterocycle, optionally substituted at any position or positions on the heterocylce by 1 to 4 substituents selected from the group consisting of C1 to C5 alkyl, hydroxy, C1 to C5 alkoxy, halogen, nitro or amino.

5. A process according to claim 4, wherein the five-membered heterocycle in the heterocycle-thio group is selected from the group consisting of furan, tetrahydrofuran, pyrrole, pyrrolidine, thiophene, tetrahydrothiophene, oxazole, thiazole, isoxazole, isothiazole, pyrazole, pyrazoline, imidazole, oxa-thiol, dioxole, dithiole, triazole, thiadiazole, oxadiazole, dithiazole, dioxazole, oxathiazole, tetrazole, oxatriazole, thiatriazole, dithiadiazole, optionally substituted at any posi-tion or positions on the heterocycle by 1 to 4 substituents selected from the group consisting of C1 to C5 alkyl, hydroxy, C1 to C5 alkoxy, halogen, nitro or amino.

6. A process according to claim 1, wherein R3 is hydorgen and R1 is lower alkoxy.

7. A process according to claim 1, wherein R3 is methoxy.

8. A process according to claim 2 for the preparation of 7.beta.-amino-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R1 is chlorine and R2 is carboxy.

9. A process according to claim 3 for the preparation of 7.beta.-amino-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R2 is carboxy.

10. A process according to claim 4 for the preparation of 7.beta.-amino-3-(1-methyltetrazol-5-yl)thio-1-oxa-1-dethia-2-cephem-4-carboxylic acid, wherein R1 is (1-methyltetrazol-5-yl)thio and R2 is carboxy.

11. A process according to claim 6 for the preparation of 7.beta.-amino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, wherein R2 is carboxy and R2 is methoxy.

12. A process according to claim 7 for the preparation of p-nitrobenzyl-7.beta.-amino-3-chloro-7.alpha.-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylate, wherein R1 is chlorine and R2 is p-nitro-benzylcarboxylate.

13. Compounds represented by the formula:
wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, C6 to C10 arylthio or a five-membered heterocycle-thio group having aza, oxa, thia, diaza, dioxa, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxathia, thiaza, oxadiaza and thiadiaza contained in the heterocycle, optionally substituted at any position or positions on the heterocycle by 1 to 4 substituents selected from the group consisting of C1 to C5 alkyl, hydroxy, C1 to C5 alkoxy, halogen, nitro or amino; R2 is carboxy or derivatives thereof selected from the group consisting of esters, thioesters or carbonamides; R3 is hydrogen or methoxy; and the pharmaceutically acceptable salts thereof, when prepared by the process of claim 1.

14. Compounds according to claim 13, represented by the formula:
wherein X is halogen or sulfonyloxy and R2 is carboxy or deriva-tives thereof selected from the group consisting of esters, thioesters or carbonamides, and pharmaceutically acceptable salts thereof, when prepared by the process of claim 2.

15. Compounds according to claim 13 represented by the formula:

wherein R2 is carboxy or derivatives thereof selected from the group consisting of esters, thioesters or carbonamides, and the pharmaceutically acceptable salts thereof, when prepared by the process of claim 3.

16. Compounds according to claim 13 represented by the formula:
wherein Y is C6 to C10 arylthio or a five-membered heterocycle-thio group having aza, oxa, thia, diaza, dioxa, dithia, triaza, trioxa, trithia, tetraza, oxaza, oxathia, thiaza, oxadiaza and thiasiaza contained in the heterocycle, optionally substituted at any position or positions on the heterocycle by 1 to 4 sub-stituents selected from the group consisting of C1 to C5 alkyl, hydroxy, C1 to C5 alkoxy, halogen, nitro or amino; R2 is carboxy or derivatives thereof selected from the group consisting of esters, thioesters or carbonamides; and pharmaceutically acceptable salts thereof, when prepared by the process of claim 4.

17. Compounds according to claim 13 represented by the formula:
wherein Z3 is lower alkyl and R2 is carboxy or derivatives thereof selected from the group consisting of esters, thioesters, or carbonamides, and pharmaceutically acceptable salts thereof, when prepared by the process of claim 6.

18. Compounds according to claim 13 represented by the formula:
wherein R1 and R2 are as defined in claim 13, and pharmaceuti-cally acceptable salts thereof, when prepared by the process of claim 7.

19. A compound claimed in claim 13, namely 7.beta.-amino-3-chloro-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 8.

20. A compound claimed in claim 13, namely 7.beta.-amino-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 9.

21. A compound claimed in claim 13, namely 7.beta.-amino-3-(1-methyltetrazol-5-yl)thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 10.

22. A compound claimed in claim 13, namely 7.beta.-amino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid, when prepared by the process of claim 11.

23. A compound claimed in claim 13, namely p-nitrobenzyl-7.beta.-amino-3-chloro-7.alpha.-methoxy-1-oxa-1-dethia-3-cephem-4-carboxy-late, when prepared by the process of claim 12.