CH637135A5 - Cephalosporin derivatives and a process for their preparation - Google Patents

Description

The invention relates to new cephalosporin derivatives that can be used as intermediates in the production of new cephalosporin derivatives with potent antimicrobial activity.

The invention relates to the cephalosporin derivatives which are represented by the following formula I in which R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or a monocyclic thioheterocycle, R2 carboxy or an ester, thioester or amide thereof, R3 is hydrogen or methoxy, and their salts.

The halogen atoms of the formula I represented by R1 are in particular fluorine, chlorine, bromine and iodine. Lower alkoxy means Cj-Cs-alkoxy such as methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy. Sulfonyloxy means Ci-Cs-alkylsulfonyloxy such as methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, i-propylsulfonyloxy, n-butylsulfonyloxy or Cö-Cs-arylsulfonyloxy such as benzenesulfonyloxy and toluenesulfonyloxy. Arylthio means substituted or unsubstituted Cc-Cio-arylthio such as phenylthio, toluylthio, methoxyphenylthio and dimethoxyphenylthio. Monocyclic thioheterocyclic groups are 5-membered rings with 1 to 4 heteroatoms (N, O or S), which can be represented by the formula -SQ, in which Q is a 5-membered heterocyclic group which comprises aza, oxa, Thia, Diaza, Dioxa, Dithia, Triaza, Trioxa, Trithia, Tetraza, Oxaza, Oxathia, Thiaza, Oxadiaza and Thiadiaza in the ring contains, for example furan, tetrahydrofuran, pyrrole, pyrrolidine, thiophene, tetrahydrothiophene, oxazole, thiazole, thiazole, thiazole, thiazole, Pyrazole, pyrazoline, imidazole, oxathiol,

2nd

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

637 135

Dioxol, dithiol, triazole, thiadiazoI, oxadiazole, dithiazole, dioxazole, oxathiazole, tetrazole, oxatriazole, thiatriazole, di-thiadiazole and others.

The S group located in the heterocycle can be present in any position of the heterocycle. The heterocycle can contain 1 to 4 substituents at any position, such as Ci-Cs-alkyl, hydroxy, Ci-Cs-alkoxy, halogen, nitro and amino.

For example, when R2 is an ester, R2 can be represented by the following formula: -COOR4, which means the 4-esters commonly used in the field of penicillin and cephalosporin. The symbol R4 includes Ci-Cs-alkyl (ie methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl), Ci-Cs-halogenated alkyl (e.g. chloromethyl, dichloromethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl), C7-C2o-arylmethyl (e.g. benzyl diphenylmethyl (benzhydryl), triphenylmethyl (trityl), p-methoxybenzyl, 3,4,5-trimethoxybenzyl, p-nitrobenzyl), C8-Ci2-acylmethyl (phenacyl), substituted silyl (e.g. dimethylsilyl, trimethylsilyl, triphenylsilyl), substituted stannyl (e.g. trimethylstannyl), adamantyl, 2-benzyloxy-phenyl, 4-methylthiophenyl, tetrahydropyran-2-yl 2-Cya-noethyl and others.

The compounds of the formula I can form acid addition salts on the 7-amino group. Examples of these are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and thiocyanic acid, and also organic acids, such as p-toluenesulfonic acid and naphthalenesulfonic acid. If R2 in the 4-position is a free carboxy group, i.e. -COOH, the compound of formula I can form salts with inorganic or organic bases.

The invention also relates to a method for

1. Reaction scheme 1

Preparation of compounds of formula I.

.3

(I)

wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or a monocyclic thioheterocycle, R2 carboxy, or an ester, thioester or amide thereof, R3 is hydrogen or methoxy, and their salts, characterized in that a compound of Formula Ib

R '

i

20 RNIi

25th

(Ib)

wherein R is benzyloxycarbonyl, is acid hydrolyzed. From a compound of the formula I obtained according to the invention, in which R3 is hydrogen, a compound of formula I in which R3 is methoxy can also be obtained by methoxylation 30 in the 7a position.

The compounds of formula I wherein R1 is halogen or sulfonyloxy can be prepared according to Reaction Scheme 1 below.

35

RNII

Stage a,

COOZ '

Stage b.

COOZ1

(II)

(III)

(Ia)

wherein R benzyloxycarbonyl, Z1 is a carboxy protecting group, duct in the above process is known and can be

X is halogen or sulfonyloxy and R3 has the meaning given above for example after the Japanese patent application. No. 51 -41385. It can also be prepared according to Reaction Scheme 2, which is represented by the starting formula represented by Formula II.

Reaction scheme 2

55 '

2 "

■ OCIUC ^ CII

HIGH2 = CH deoxidation

(1) COOZ1

COOZ

Introduction of the N-protecting group

(2)

637135

4th

RNH

(3)

COOZ '

partial

Hydrogenation

Peroxyacid ►

NaI04

RNH

\

f

■ 0 ^

hydrolysis

(5) z00zl

RisIU ~ CHO \

1) Oxidation CrOî

2) esterification *

RNH

OH

(6) coozl

OEI

RNH

COOZ '

Os

oxidation

RNH-

(9)

.COOZ '

r0,

COOZ

Zn-AcOH reduction

RNH 2 V JO ^ COOZ

ciK

-OH

(10) COOZ1

RNHv. .O ^ OOZ

Halogenation> J __ 1) PPI13

(SOCb)

«Rv ^

2) partial hydrogenation

(11)

COOZ '

RNH.

(II)

COOZ x wherein X 'and X "halogen, Z2 are an ester-forming group and Z1 have the meaning mentioned above.

In the following reaction scheme 2, each reaction can be carried out under known reaction conditions, corresponding to the respective reaction stages. The compounds Ia prepared by the process in reaction scheme 1 correspond to the compounds I in which R1 is halogen or sulfonyloxy, R2 has the same meaning and R3 is hydrogen. The reaction conditions in the individual stages in Reaction Scheme 1 are as follows.

Level a (II-III)

The hydroxy group in the 3-position of compound II is replaced by halogen or sulfonylated by treatment with a sulfonating agent to give the corresponding 3-halogen or 3-sulfonyloxy compound.

The halogenation of the hydroxyl group in the 3-position can also be carried out by other methods which are usually used in the halogenation of hydroxyl groups, for example using phosphorus halide, PX3 or thionyl chloride. With the invention

According to the process, the halogenation can preferably be carried out in a customary manner, in particular using oxalyl halide (i.e. oxalyl chloride), phosphorus oxyhalide (i.e. phosphorus oxychloride) or halogen (i.e. chlorine) triphenylphosphine.

The sulfonylation on the 3-hydroxy group can be carried out in the same way as the sulfonylation of conventional hydroxy groups. Examples of sulfonylating agents are alkylsulfonyl halides (i.e. methylsulfonyl chloride, ethylsulfonyl chloride), arylsulfonyl halide (e.g. benzenesulfonyl chloride, toluenesulfonyl chloride) and others. The reaction is carried out under conditions as in a conventional sulfonylation, for example by adding the above-mentioned halogenating agent in

Reaction scheme 3

637135

Presence of a tertiary amine such as pyridine or triethylamine.

Level b (III-Ia)

In this method, the 7-amino protecting group and, if necessary, the 4-carboxy protecting group are removed at the same time or gradually by hydrolysis or a reduction according to the kind of the protecting groups. The protective groups on the 7-amino and on the 4-carboxy are those which are generally used in the synthesis of penicillin and cephalosporine and can be easily removed in a known manner.

Compounds of formula I, except for those in which R1 is halogen or sulfonyloxy, can be prepared according to the following reaction scheme.

RNIK. JÛ

(III)

UNII

Stage c

COOZ1

Sufed ►

: ooz

1

(IV)

where R, Z \ R2 and X have the same meaning as above.

Compounds of formula I in which R1 is hydrogen can be prepared according to Reaction Scheme 3.

Combination of metals and acids, especially combination of zinc and acetic acid. The reaction can be carried out in the following known manner.

Level c (III-IV)

Halogen or sulfonyloxy in the 3-position of the compounds of the formula III are removed by reduction, 3-unsubstituted oxadethiacephem compounds being obtained. The reduction can be carried out, for example, by selective reduction of the halogen or sulfonyloxy in the 3-position without influencing other substituents or functional groups, for example by

Level d (IV-Ib)

This procedure, which is the same as in step b, is a hydrolysis or reduction which can be carried out in the usual manner as is customary in the synthesis of cephalosporin and penicillin.

On the other hand, the compound I can be prepared in this process step according to the following reaction scheme.

Reaction scheme 4

RNlk

acetone

RNEÏ

p-TsOH

COOZ

0

0-

RNIK S Zn-AcOH v

03 | [) r

oxidation

I 1

* V-i

COOZ

(14)

637 135

1) Partial halogenation

(SOCh) q N "vy5J? Ph3 hydrogenation

2) PPhs' 1

(16)

Oli ra '! - K

J —'Kf - pb3 Ni "0,. • 0j — i <Y ^ ph:

cooz1 COOZ1

(17)

3rd

Wittig's RNIL ^

->

reaction

»,

,, COOZ

(IV)

where R and Z1 have the same meaning as above.

The reactions according to the above reaction scheme 4 can be carried out under known conditions, corresponding to the requirements of the individual reaction stages.

Compounds of formula I in which R 'is arylthio or a monocyclic thioheterocycle can be prepared according to the following reaction scheme.

Reaction scheme 5

N £ X - r / ° X

Level f 1 [>

0

R

(III)

(V)

(Ic)

wherein R, Z1, R2 and X have the same meanings as above, and Y is arylthio or a monocyclic thioheterocycle.

weak bases are organic bases such as pyridine and triethylamine. The reaction generally proceeds well at room temperature.

Level e (III-V) 60

Halogen or sulfonyloxy in the 3-position of the compound stage f (V — Ic)

III is substituted by the desired arylthio group. This procedure, which is the same as that of step b and or the monocyclic thioheterocycle. This reaction d is a hydrolysis or reduction, which is carried out under the same conditions by the reaction of the starting product as described in steps b and d.

III can be performed with the corresponding arylthio compound or the 65.

monocyclic, heterocyclic thiol in the presence of an other hand, the compound Ic according to the following

weak base or with the appropriate salt. The above reaction scheme can be prepared.

7

637135

Reaction scheme 6

COOII

YH

(COCI2) (pyridine)

RNHO ^ COÏ

Y-n ^ -vph.

COOZ "

(12)

COOZ "

(19)

RNH

Wittig's

reaction

->

-> (IC)

COOZ "

(V)

where R, Y and Z 'have the same conditions as above. 2o Compounds I, in which R1 is lower alkoxy, can be The reactions according to the above reaction according to the following reaction scheme, scheme 6 can be carried out in a known manner under conditions that correspond to the respective reaction stages, reaction scheme 7

will.

RNH ^

COOZ1

RNII n ni12v ,,

^) XX * 3 ÌT? 1

COOZ1

(II)

cf

(VI)

CMy ^ oz;

R

(Id)

wherein R, R2 and Z1 have the meanings given above and Z3 is lower alkoxy.

Level g (II-VI)

This process is carried out under the conditions of the enol esterification of ketones or those conditions which are generally used in the action of agents such as diazoalkanes for the esterification of carboxylic acids. The enol esterification of ketones is carried out, for example, using trialkyl orthoformates (i.e. triethyl orthoformate) or alcohols and p-toluenesulfonic acid. The alkylation by the diazoalkanes (diazo methane, diazoethane) can be used according to the process of the invention.

3s These implementations can be carried out in a known manner.

Level h (VI-Id)

This procedure, which is the same as for levels b, d and f,. 40 is a hydrolysis and reaction which can be carried out under the same conditions as in the reaction stages mentioned.

Compounds I in which R3 is methoxy can be carried out in a known manner according to the following reaction scheme 45.

Reaction scheme 8

OCH

Process i

(If)

(le)

wherein R1 and R2 are the same as mentioned above.

Stage i

The starting product If corresponds to the corresponding compounds according to Reaction Scheme 7. The introduction of 7-methoxy shown in Reaction Scheme 8 can be carried out in a known manner by methods which are commonly used in penicillin and cephalosporin synthesis to introduce 7-methoxy. These procedures are described below.

60

Procedure 1

The 7-amino group of the starting product If is acylated according to the 7-acylamino derivatives, the latter 65 are reacted with methoxylithium (LÌOCH3) and t-butyl hypochloride (t-BuOCl) in an inert solvent at low temperature (Belgian patent application no. 817 836) and then the 7-acyl protecting group is removed.

637135

Procedure 2

The 7-amino group of the starting product If is treated with sodium nitrite to give the 7-diazo compound a; this compound is reacted with halogen azide (made from sodium azide and the corresponding halogen, e.g. BrN3, CIN3, IN3) to give the corresponding halogen azide compound b and this compound.

NaNCh (If) = *

2 ^,

1) MeOH>

a

<7

3-

(a)

R

(If)

dung is reacted with methanol, then the azide is added by reduction, the corresponding 7-amino-7-methoxy compound Ie being obtained.

The reaction scheme in this method is given by the following equation (Japanese Patent Application No. 47-931).

X '

X '"Well

2) Reduction wherein R1 and R2 are the same as mentioned above and X '"is halogen.

Procedure 3

The starting product If is reacted with p-hydroxybenzaldehyde (preferably those which have an extensive substituent or substituent adjacent to p-hydroxy, for example 3,5-di-t-butyl-4-hydroxybenzaldehyde), benzylidene derivatives (c ) can be obtained. The latter are oxidized by suitable oxidizing agents (e.g.

IfO- ^ CHO

Nickel, peroxide, lead tetraacetate), quinoid derivatives being obtained. The latter are reacted with methanol to give 7a-methoxy compounds (e) whose benzylidene group is hydrolyzed (generally by treatment with a Grignard agent) to give the corresponding 7β-amino-7a-methoxy compounds (Ie) . The reaction scheme in this method is given by the following equations (Japanese Patent Application No. 50-50394).

: h = n

(c)

oxidation

O

(d)

hydrolysis

R '

(Ie))

MeOH

OMe

HO— <\ CII = N: O

(e)

0 '

r

R

wherein R1 and R2 are the same as mentioned above.

Procedure 4

On the other hand, a method as shown in the following reaction scheme can be used. In this process, the 7-amino group of the starting product If is protected by an acyl protective group which has at least one hydrogen atom in the a-position, 7-acyla-

minoderivate (f) can be obtained. The latter are treated with a halogenating agent to give imino-halide derivatives (g), which are treated with a base for dehydrohalogenation, and to give ketenimine derivatives (h), which are halogenated to form dihalogenimine derivatives, which are reacted with alkali metal methoxide and then are hydrolyzed to remove the acyl group (Japanese Patent Application No. 50-126 692).

O

0 "

\ II

N: iicnìl,

/

(If)

(f)

^ Halogenating agent

»2

R

637135

-HX

^ x C = C = N 0

O '^

(H)

Xz '

q;

, ^ 'TN

0OCH3 hydrolysis> ^

(le)

wherein R1 and R2 are the same as mentioned above, Q 'and Q "are hydrogen or suitable substituents, X and X' are respectively halogen.

The compounds of formula I according to the invention are important intermediates for the preparation of new 1 1-oxadethiacephalosporins. The introduction of various acyl groups on the free 7-amino group of the compound I, as is known in the chemistry of penicillins and cephalosporins, gives very antimicrobially active compounds.

The following examples illustrate the invention.

example 1

7ß-Amino-3-chloro-l-oxa-1-dethia-3-cephem-4-carboxylic acid

(I: R '= C1; R2 = COOH; R3 = H) (Ia: R2 = COOH; X = C1)

1. To a solution of 1.5 g (3 mmol) of diphenylmethyl-7ß-benzyloxycarbonylamino-3-hydroxy-l-oxa-l-dethia-3-cephem-4-carboxylate (II: R = PhCH2OCO; Z '= CHPli2 ) in 30 ml of dimethylformamide, 0.03 ml (0.36 mmol) of pyridine are added with ice-cooling and then 0.31 ml (3.6 mmol) of oxalyl chloride are added dropwise. After stirring for three hours at room temperature, the reaction mixture is poured into 5% aqueous phosphoric acid solution while cooling with ice and then extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is chromatographed with 20 parts by volume of silica gel and eluted with benzyl / ethyl acetate (5: 1), 489 mg of the 3-chloro derivative in question, diphenyl-methyl-7β-benzyloxycarbonyl-amino-3-chloro-1-oxa-1-dethia -3-cephem-4-carboxylate can be obtained (III: R = PhCH20C0; Z1 = CHPh2; X = C1) 31.4% yield). Melting point 130 to 131 ° C.

IR: v ™ cl3 cm- ': 3450, 1805, 1725, 1620.

NMR: 5CDC13ppm: 4.32 (s, 2H), 4.98 (d, J = 4.0Hz, lH),

5.10 (s, 2H), 5.20-5.80 (m, 2H), 6.97 (s, 1H), 7.0 (m, aromatic H).

10 eluted, whereby 0.95 g of the 3-chloro derivative in question are obtained (III: R = PhCH> OCO; Z '= CHPh2; X = C1) (59.0% yield).

2. To a solution of 950 mg (1.83 mmol) of the 3-chloro derivative, which was prepared as described above 15 (III: R = PhCH20C0; Z '= CHPh2; X = C1) in 37 ml of methylene chloride, 1.78 ml (16.5 mmol) of anisole and a solution of 1.45 g (11 mmol) of aluminum chloride in 18 ml of nitromethane were added and the mixture was left to stand at room temperature overnight. The reaction mixture 20 is extracted with 15 ml of ice-cooled 2% hydrochloric acid, and the aqueous layer is washed with methylene chloride and then with ethyl acetate and evaporated under reduced pressure. The residue is chromatographed in a column of Diaion HP 20 (trademark of Mitsubishi Chemical Industries; 25 Hiporous Polymer) and eluted with hydrochloric acid (pH 3). The eluate is adjusted to pH 4.4 and concentrated under reduced pressure, giving 175 mg of the 3-chloro derivative in question (I: R1 = C1; R2 = COOH; R3 = H) (43.8% yield).

30th

IR: vJS cm-1: 3420, 1818, 1630, 1613.

Example 2

7β-amino-1-oxal-dethia-3-cephem-4-carboxylic acid ss (I: R '= R3 = H; R2 = COOH) (Ib: R2 = COOH)

1. To a solution of 1.98 g (3.96 mmol) of the 3-hydroxy derivative (II: R = PhCH20C0; Z '= CHPh2) in 20 ml of dimethylformamide, 0.62 ml (2 equivalents) of methyl sulfo nyl chloride and then 8.3 ml (1.5 equivalents) of triethylamine were added at -50 ° C. and the mixture was then stirred at the same temperature for 15 minutes, poured into ice-water, crystals precipitating out, which were separated off by filtration and 2.15 g of the 3-methylsulfonyloxyde-45 rivâtes: Diphenylmethyl-7ß-benzyloxycarbonylamino-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylate (III: R = PhCH2OCO; Z1 CHPI12; X = 0S02CH3) 94.0% yield).

so IR: v ™ cl3cm - ': 3420, 1810, 1730, 1510, 1365, 1165.

NMR: SCDC13 ppm: 2.96 (s, 3H), 4.46 (bs, 2H),

4.97 (d, J = 4.0Hz, 1H), 5.07 (s, 2H), 5.45 (dd, J = 4.0Hz, 1H).

55

This product can also be manufactured by the following procedure.

To a solution of 1.62 g (6.2 mmol) of triphenylphosphine in 20 ml of tetrahydrofuran are chlorine / carbon tetrachloride, a solution of 1.55 g (3.1 mmol) of 3-hydroxy derivatives «a (II: R = PhCH2OCO; Z '= CHPh2) in 10 ml of tetrahydrofuran and then 0.86 ml (6.2 mmol) of triethylamine with ice cooling and stirring. After stirring for 1.5 hours at room temperature, the reaction mixture is poured into ice water and then extracted with ethyl acetate. The «s

The extract is washed with water, dried and evaporated. The residue is chromatographed using 3 parts by volume of silica gel and with benzene / ethyl acetate (10: 1)

2. To a solution of 1.15 g (2 mmol) of the 3-methylsulfonyloxy derivative (III: R = PhCH20C0; X = 0S02CH3) in a mixture of methylene chloride (20 ml) and acetic acid (40 ml) are activated 3 g Zinc powder was added and the mixture was stirred at room temperature overnight, 3 g of zinc powder being added 2 and 3 hours after the start of the reaction. The zinc powder is filtered off and the filtrate is mixed in ethyl acetate. The organic layer is washed with water, dried, evaporated under reduced pressure and gives 913 mg of the relevant 3-deoxy derivative diphenylmethyl-7β-benzyloxycarbonyla-mino-1-oxa-1-ethia-3-cephem-4-carboxylate (IV: R = PhCH2OCO; Z1 = CHPh2) (94.2% yield) as powder.

637 135

10th

IR: CI ™ CI3 cm-1: 3450,1800,1730,1650.

NMR: 8cdc13 ppm: 4.41 (m, 2H), 4.95 (d, J = 4.0Hz, lH),

5.15 (s, 2H), 5.53 (dd, J = 4.0; 9.0Hz, 1H), 6.51 (m, lH), 6.99 (s, lH).

This product can also be manufactured in the following manner.

0.72 g of activated zinc powder is added to a solution of 240 mg of the 3-chloro derivative (III: R = PhCH20C0; Z '= CHPli2; X = C1) in a mixture of methylene chloride (4 ml) and acetic acid (8 ml) and the mixture was stirred at room temperature. A further 0.72 g of activated zinc powder are added three times, four hours to 9 hours after the start of the reaction, and the mixture is left to stand overnight with stirring. The zinc powder is filtered off and the filtrate is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue obtained is chromatographed in a column of silica gel and eluted with benzene / ethyl acetate (5: 1), 215 mg of the relevant 3-deoxy derivative (IV: R = PhCH20C0; Z '= CHPh2) (96.0% yield), be preserved.

3. To a solution of 913 mg (18.8 mmol) of the 3-deoxy derivative (IV: R = PhCH20C0; Z '= CHPh2) prepared according to the above method in 35 ml of methylene chloride, 1.85 ml (9 equivalents) of anisole and one Solution of 1.51 g of aluminum chloride (6 equivalents in 18 ml of nitromethane was added, the mixture was left to stand at room temperature overnight and then extracted with 2% hydrochloric acid while cooling with ice. The aqueous layer was washed with methylene chloride and then with ethyl acetate.

evaporates and the remaining organic solvent in the aqueous layer is removed under reduced pressure. The residue obtained is chromatographed in a Diaion HP 20 column (trademark of Mitsubishi Chemical Industries: High-power Polymer) and eluted with dilute hydrochloric acid (pH 3.0). The eluate is evaporated under reduced pressure and gives 291 mg of the relevant 3-oxacephem derivative (I: R '= R3 = H; R2 = COOH) hydrochloride (70.6% yield).

[a] n, s + 11.1 ° + 2.4 (c = 0.216, in methanol)

IR: v cm cm-1: 3500.2600, 1805, 1645, 1610, 1550.

NMR: 8CDC13 ppm: 5.37 (d, J = 4.0Hz, lH),

5.51 (d, J = 4.0Hz, 1H), 6.70 (m, lH).

Example 3

7β-Amino-3- (1-methyltetrazol-5-yl) thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid

(I: R '= 1-methyltetrazol-5-ylthio; R2 = COOH; R3 = H) (Ic: Y = 1-methyltetrazoI-5-ylthio; R2 = COOH)

1. 370 into a solution of 1.12 g (1.94 mmol) of the 3-methyl-sulfonyloxy derivative, prepared according to Example 2 (III: R-PhCHaOCO; Zl = CHPh2; X = OSChCH3) in 10 ml of dimethylformamide mg (3.2 mmol) of l-methyltetrazol-5-ylthio and 0.42 ml (3.0 mmol) of triethylamine were added with cooling to 0 ° C. and the mixture was stirred at room temperature overnight. After the reaction has ended, the mixture is poured into ice water. The yellow precipitate obtained is separated off by filtration, washed and dried, 1.007 g of the 3-tetrazolylthio derivative in question (V: R = PhCH2OCO; Z '= CHPh2; Y = l-methylte-

trazol-5-ylthio) is obtained as a yellow powder (86.7% yield.

IR: v ™ cl3 cm-1: 3450.1805.1730.

5 NMR: 5CDC13 ppm: 3.93 (s, 3H), 4.28 (ABq, J = 18Hz, 2H),

5.00 (d, J = 4.0Hz, 1H), 5.17 (s, 2H), 5.30-5.90 (m, 2H), 6.98 (s, lH).

10 2. To a solution of 137 mg (0.229 mmol) of the 3-tetra-zolylthio derivative, prepared as described above (V: R = PhCH2OCO; Z '= CHPh2; Y = 1-methyltetrazol-5-ylthio) in 4 ml of methylene chloride 0.223 ml (2.06 mmol) of anisole and a solution of 190 mg (1.4 mmol) of aluminum chloride

] 5 in 2 ml of nitromethane and the mixture was left to stand overnight, then mixed with 3 ml of 2% hydrochloric acid while cooling with ice. The aqueous layer is washed with methylene chloride, acetic acid is added and the mixture is concentrated. The concentrate is made up with sodium carbonate

20 'is adjusted to pH 2.5 and gives 24 mg of the 7β-amino-3-tetrazolylthio derivative in question (I: R' = 1-methyl-tetrazol-5-ylthio; R2 = COOH; R2 = H) as crystals.

Melting point greater than 200 ° C.

25 IR: cm-1: 1820, 1630, 1620.

Example 4

7ß-Amino-3-methoxy-l-oxa-l-dethia-3-cephem-4-carbon-30 acid

(I: R '= OCH3; R2 = COOH; R3 = H) (Id: R2 = COOH; Z3 = CH3)

1. A mixture of diazomethane and ether is added to a solution of 1.15 g (2.30 mmol) of the 3-hydroxy derivative (II: R = PhCH20C0; Z '= CHPh2) in 12 ml of methylene chloride and the mixture was stirred for 10 minutes at room temperature, then evaporated under reduced pressure. The soluble residue obtained is chromatographed in a column of 50 g of silica gel and eluted with benzene / ethyl acetate 40 (4: 1), 0.89 g of the relevant 3-methoxy derivative diphenylmethyl-7β-benzyloxycarbonylamino-3-meth-oxy- l-oxa-l-dethia-3-cephem-4-carboxylate can be obtained (75% yield).

45 IR: v ™ cl3cm-1: 3495, 1796, 1725, 1626, 1512.

NMR: 8cdc, 3 ppm: 3.70 (s, 3H), 4.23 and

4.54 (ABq, J = 18Hz, 2H), 4.96 (d, J = 4.0Hz, 1H), 5.18 (s, 2H), so 5.42 (dd, J = 10Hz; 4, 0Hz, lH),

5.81 (d, J = 10Hz, 1H), 7.02 (s, 1H), -7.4 (m, aromatic H).

2. To a solution of 1.06 g (2.06 mmol) of the 3-methoxy derivative (VI: R = PhCH2OCO;

Z '= CHPh2; Z3 = CH3) in 20 ml of methylene chloride, 3 ml of anisole and 3 ml of trifluoroacetic acid are added with cooling and the mixture is stirred for 15 minutes, mixed with 20 ml of toluene and then evaporated under reduced pressure. 60 The oily residue is dissolved in benzene and extracted with 5% aqueous hydrogen carbonate solution. The extract is washed with benzene, adjusted to pH 2 with 10% hydrochloric acid and then extracted again with ethyl acetate. The extract is washed with water and an aqueous sodium 65 chloride solution and evaporated under reduced pressure, 0.67 g of the free 4-carboxylic acid compound 7ß-benzyloxycarbonylamino-3-methoxy-1-oxa-1-dethia-3-cephem- 4-carboxylic acid can be obtained.

11

637135

IR: v ™ x 3 cm-1: 3430, 1793, 1725, 1630, 1510.

3. 200 mg (0.934 mmol) of the free 4-carboxylic acid compound are added to a suspension of 100 mg of 5% palladium / charcoal in 20 ml of a solution of ethyl acetate and methanol (1: 1) in which hydrogen has previously been absorbed. which was prepared as described above, added and the mixture stirred vigorously under a hydrogen atmosphere. The reaction mixture is stirred for two hours at room temperature and the catalyst is then filtered off. The filtrate is evaporated under reduced pressure and gives 65 mg of the 7β-amino compound in question (I: R '= OCH3; R2 = COOH; R3 = H) (53% yield).

IR: v ** cm-1: -3400, -2900.1785, 1679.1647.

The catalyst filtered off in the above process is washed several times with methanol / hydrochloric acid and the washing water is evaporated under reduced pressure, 65 mg of the hydrochloride of the 7β-amino derivative (I: R1 = OCH3; R2 = COOH; R3 = H) as white powdery crystals be preserved.

IR: v ££ cm-1: -3400, -3000,1787,1694,1619.

Example 5

p-nitrobenzyl-7ß-amino-3-chloro-7a-methoxy-l-oxa-l-dethia-3-cephem-4-carboxylate

(I: R '= C1; R2 = C00CH2C6H4-N02-p; R3 = OCH3) (Ie: R' = C1; R2 = C00CH2C6H4-N02-p)

3,5-di-t-butyl-4-hydroxybenzylidenamino) in a mixture of methanol (2.5 ml) and tetrahydrofuran (0.5 ml), 81 mg of Grignard reagent are added and the mixture is stirred for one hour at room temperature, 5 then poured into water and extracted with methylene chloride. The extract is washed with water, dried and evaporated under reduced pressure. The residue is chromatographed in a column with 3.5 g of silica gel and eluted with benzene / ethyl acetate (4: 1), where

10 35 mg of the corresponding 7-amino derivative (I: R '= C1; R2 = COOCH2. CsH4. NCh-p; R3 = OCH3) (43.8% yield).

IR: v ™ cl3 cm-1: 1790, 1740, 1520, 1350.

15 NMR: 8cdci3 ppm: 1.83 (bs, 2H), 3.53 (s, 3H), 4.54 (s, 2H), 5.01 (s, 1H), 5.47 (split, 2H) , 7.67 (d, J = 9Hz, 1H), 8.28 (d, J = 9Hz, 1H).

20 The following compounds can be prepared by one of the methods described above.

p-nitrobenzyl-7ß-amino-1-oxa-1-dethia-3-cephem-4-car-boxylate

25th

30th

50

1. To a solution of 141 mg (0.399 mmol) of p-nitro-benzyl-7ß-amino-3-chloro-l-oxa-l-dethia-3-cephem-4-carboxylate (I: R! = C1 ; R2 = COOCH2C6H4. NCh-p; R3 = H) (prepared from the free 3-chloro derivative derived from Example 1 (I: R '= C1; R2 = COOH; R3 = H) by esterification) in 112 mg (1.2 equivalents) of 3,5-di-t-butyl-4-hydroxy-benzaldehyde are added to a mixture of 7 ml of chloroform and 1 ml of benzene, and the mixture is heated with a molecular sieve for separation with heating in a reaction vessel of the water is treated at reflux. After 2.5 hours, the reaction mixture is mixed with a further 30 mg of the aldehyde compound and reacted for 3.5 hours. The mixture is cooled to -15 ° C, 45 mixed with 65 mg magnesium sulfate and 219 mg nickel peroxide and stirred for 30 minutes at the same temperature and then for 40 minutes at room temperature. The mixture is filtered and the filtrate mixed with 5 ml of methanol, stirred for 1.5 hours at room temperature and evaporated under reduced pressure. The residue is chromatographed in a column with 12 g of silica gel and eluted with benzene / ethyl acetate (19: 1), 125 mg of the 7-methoxy derivative in question p-nitrobenzyl-7β- (3,5-di-t-butyl-4-) hydroxybenzylidene) amino-3-chloro-7a-methoxy-l-oxa-l-dethia-3-cephem-4-carboxylate (e: R '= C1, R2 = COOCH2-C6H4.NCh-p; 7ß-side chain = 3 , 5-Di-t-butyl-4-hydroxy-benzylidenamino) can be obtained as a viscous product (52.2% yield).

(

IR: v ™ xcl3 cm-1: 1780.1735,1680.1520.1345.

NMR: 8CDC13 ppm: 1.48 (s, 18H), 3.61 (s, 3H), 4.49 (s, 2H), 5.23 (s, 1H), 5.44 (aromatic H), 8 , 53 (s, 1H). ,

2. To a solution of 125 mg of the 7-methoxy derivative (e: R '= C1; R2 = COOCH2 • C6Ü4 • N 02-p; 7ß-side chain =

(I: R '= H; R2 = COOCH2-C6H4-NCh-p; R3 = H).

IR: v ™ cl3 cm-1: 3405.1772, 1726.1633, 1605.1517.1345.

NMR: 8CDC13 ppm: 1.74 (b, 2H), 4.61 (m, 2H),

5.05 (d, J = 4.0Hz, 1H), 5.42 (bs, 2H), 5.5 (m, lH), 6.61 (m, lH), 7.67 and 8.31 ( q, J = 9.0Hz, 4H).

p-nitrobenzyl-7ß-amino-3-methylsulfonyloxy-1-oxa-1-dethia-3-cephem-4-carboxylate

(I: R1 = 0S02CH3; R2 = C00CH2-C6H4-N02-p; R3 = H)

IR: v ™ cl3cm - ': 3420.1790.1735.1610.

NMR: Scdci3 ppm: 2.15 (bs, 2H), 3.23 (s, 3H), 4.52 (s, 2H), 5.02 (d, J = 4Hz, 1H), 5.30 (s , 2H), 5.33 (m, 1H), 7.48 and 8.10 (q, J = 8.0Hz, 4H).

7β-amino-3-phenylthio-l-oxa-1-dethia-3-cephem-4-car-bonic acid

(I: Rl = S-Ph; R2 = COOH; R3 = H).

Procedure 6

1. Diphenylmethyl-2- [2e- (2-propynyloxy) -3ß-amino-4-oxo-azetidin-1-yl] -2-isopropylidene acetate

55 (2: Z '= CHPh2)

To a solution of 0.95 g diphenylmethyl-2- (2e-chloro-3ß-amino-4-oxoazetidin-1-yl) -2-isopropylidene acetate (1: Z1 = CHPh2; Xi = C1) in a mixture of propargyl alcohol 60 (3 ml) and tetrahydrofuran (2 ml) 0.79 g (4 mmol) of silver tetrafluoroborate are added and the mixture is then stirred for three hours at room temperature, diluted with 50 ml of benzene, cooled to 0 ° C. and with a mixture of 100 ml of one aqueous 5% sodium bicarbonate solution and 5 ml of a saturated aqueous sodium chloride solution. The reaction mixture is stirred and filtered through Celite. The benzene layer is separated off, dried over Glauber's salt and under reduced pressure

637135

12

evaporated. The brown oily product obtained is purified by chromatography in a column with silica gel containing 10% water and eluted with benzene / ethyl acetate (1: 1), 268 mg of the 2e-propynyloxy derivative (2: Z1 = CHPh2) (134 mg of the 2a-propynyloxy derivative and 134 mg of the 2ß-propynyloxy derivative) can be obtained.

2a-propynyloxy derivative

IR: v ^ c, 3 cm-1: 3400,3320,2115,1767, 1723.

NMR: Scdc, 3 ppm: 1.83 (brs, 2H), 1.98 (s, 3H), 2.22 (s, 3H),

2.33 (t, J = 2.5Hz, 1H) 4.07 (d, J = 2.5Hz, 2H), approx.4.07 (m, lH), 4.93 (d, J = l, 0Hz, 1H), 6.90 (s, 1H), 7.32 (s, 10H).

2β-propynyloxy derivative

IR: v ™ cl3 cm-1: 3410.3320.2115, 1767.1720.

NMR: SCDC13ppm: 1.77 (brs, 2H), 2.00 (s, 3H), 2.23 (s, 3H), 2.27 (t, J = 2.5Hz, 1H), 4.12 ( d, J = 2.5Hz, 2H),

4.23 (d, J = 4.0Hz, 1H), 5.27 (d, J = 4Hz, 1H), 6.90 (s, 1H), 7.32 (s, 10H).

2. Diphenylmethyl-2- [2ß- (2-propynyloxy) -3β-benzyloxy-carbonylamino-4-oxoazetidin-l-yl] -2-isopropylidene acetate

(3: R = PhCH2OCO; Z ^ CHPha)

To a solution of 30.0 g (0.074 mol) of the 2β-propynyloxy derivative (2: Z1 = CHPh2) in 250 ml of dry methylene chloride, 14.07 g (0.0825 mol) of benzyloxycarbonyl chloride are cooled with ice and then dropwise one Mixture of pyridine (6.7 mmol, 0.0825 mol) and methylene chloride was added and the mixture was stirred under cooling for 30 minutes, poured into ice water and extracted with methylene chloride. The extract is washed with water and an aqueous sodium chloride solution, dried and evaporated under reduced pressure. The oily residue obtained is chromatographed over 1000 g of silica gel and eluted with benzene / ethyl acetate (5: 1), with 26.5 g of the relevant 3β-benzyloxycarbonylamino derivative (3: R = PhCH2OCO; Z '= CHPh2) (66.3% yield ) can be obtained.

IR: vSxcl3 cm-1: 3440.3300.2110.1774.1720.1630.1507.

NMR: 8CDC13ppm: 2.00 and 2.25 (s, 3Hx2),

2.17 (d, J = 3 Hz, 1H), 4.07 (d, J = 3 Hz, 2H), 5.10 (d, J = 4Hz, 1H), 5.17 (s, 2H), 5.33 (q, J = 8Hz, 4Hz, 1H),

5.55 (d, J = 8Hz, 1H), 6.98 (s, lH).

3. Diphenylmethyl-2- (2ß-allyloxy-3ß-benzyloxycarbonyl-amino-4-oxoazetidin-1-yl) -2-isopropylidene acetate

10th

filtered off and the filtrate evaporated under reduced pressure to give 26.3 g of the 3β-allyloxy derivative (4: R = PhCH2OCO; Z1 = CHPh2) (98.8% yield).

'IR: v ^ cl3 cm-1: 3440,1772,1720,1628,1505.

NMR: 8CDCI3 ppm: 2.00 and 2.25 (s, 3Hx2), 3.90 (m, 2H), 4.8-5.9 (m, 6H), 5.17 (s, 2H), 6, 95 (s, 1H).

4. Diphenylmethyl-2- [2ß- (2,3-epoxypropoxy) -3 ß-benzyloxoxycarbonylamino-4-oxoazetidin-1-yl] -2-isopropylidene acetate

(5: R = PhCH2OCO; Z1 = CHPh2)

15

15.3 g (0.071 mol) of m-chlorobenzoic acid are added in small portions to a solution of 25.6 g (0.047 mol) of the 2β-allyloxyde derivative (4: R = PhCH2OCO; Z [= CHPh2) in 260 ml of chloroform and the mixture was left to stand at room temperature (23 to 25 ° C) for two days and evaporated under reduced pressure. The residue is dissolved in ethyl acetate and washed with 5% aqueous sodium thiosulfate solution, 5% aqueous sodium hydrogen carbonate solution, water and then with an aqueous sodium chloride solution. The solvent is evaporated off under reduced pressure and gives an oily residue which is chromatographed in a column with 800 g of silica gel and eluted with benzene / ethyl acetate (5: 1), 21.25 g of the epoxy derivative in question (5: R = PhCH2OCO; 30 Z '= CHPh2) (81.2% yield) can be obtained.

IR: v ^ xcl3 cm-13445, 1778, 1724, 1632, 1508.

35

NMR: 8cdci3 ppm: 2.00 and 2.25 (s, 3H x2), approx.

2.2-3.9 (m, 5H), 5.18 (s, 2H), approx. 5.0-5.3 (m, 2H), 5.58 (d, J = 10Hz, 1H), 6.83 (s, 1H).

A small amount of the diepoxy derivative (2.15 g; melting point 40 118 to 120 ° C) are obtained as a by-product in this process.

5. Diphenylmethyl-2- [2ß- (2,3-dihydroxypropoxy) -3ß-ben-zyloxycarbonylamino-4-oxoazetidin-1-yl] -2-isopropylidena-4S acetate

(6: R = PhCH2OCO; Z '= CHPh2)

66 ml of 30% perchloric acid and 44 ml of water are added to a solution of 21.25 g (0.038 mol) of the epoxyderi-s0: vates, prepared by the above process (5: R = PhCH2OCO; Z '= CHPh2) in 220 ml of acetone added while cooling with ice and the mixture was stirred at room temperature for 2 to 3 hours and extracted with ethyl acetate. The extract is washed with 5% aqueous 5S sodium bicarbonate solution, water and then with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure, 20.6 g of the diol derivative in question being obtained (6: R = PhCH2OCO; Z '= CHPli2) (94.4% yield).

60

(4: R = PhCH20C0; Z '= CHPh2)

To a suspension of 6.6 g of 5% palladium / calcium carbonate in 170 ml of methanol, in which hydrogen gas has been adsorbed, a solution of 26.5 g (0.049 mol) of 3β-benzyloxycarbonylamino derivative (3: R = PhCH2OCO; Z '= CHPli2) in 100 ml of methanol and the mixture was stirred for 50 minutes under a hydrogen atmosphere. The catalyst will

IR: v ™ 3 cm-1: 3600.3445, 1778, 1725, 1632, 1508.

NMR: Scdci3 ppm: 1.97 and 2.22 (s, 3Hx2), 3.47 (m, 4H),

4.9-5.3 (m, 2H), 5.13 (s, 2H), 6.07 (m, lH), 65 6.97 (s, lH).

Similarly, the 2β-propionyloxy derivative (2: Z1 = CHPI12) is reacted with phenylacetyl chloride to give

13

637135

the 3β-phenylacetamide derivative (3: R = PhCH2CO; Z '= CHPh2) and the latter is successively subjected to hydrogenation, epoxidation and splitting of the epoxy ring,

whereby diphenylmethyl-2- [2ß- (2,3-di-hydroxypropoxy) -3ß-phenylacetamido-4-oxoazetidin-1-yl] -2-isopropylidene acetate is obtained (6: R = PhCH2CO; Z '= CHPh2).

Procedure 7

1. DiphenylmethyI-2- [2ß- (2,3-isopropylidenedioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-1-yl] -2-10 isopropylidene acetate

(13: R = PhCH2OCO; Z '= CHPh2).

To a solution of 2.5 g of diphenylmethyl-2- [2ß- (2,3-1S dihydroxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazeidin-l-yl] -2-isopropylidene acetate (6: R = PhCH20C0; Z '= CHPh2) in 50 ml of acetone, 5 mg of p-toluenesulfonic acid are added while cooling with ice and the mixture is stirred for three hours, mixed with a small amount of a 5% strength aqueous sodium hydrogen carbonate solution and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, washed with water, dried and evaporated. The residue obtained is chromatographed in a column with silica gel and eluted with benzene ethyl acetate 2S (2: 1), giving 2.26 g of the isopropylidene dioxy derivative in question (13: R = PhCH20C0; Z '= CHPh2) (84% yield) .

and

7.00 (s, lHx2), approx.7.3 (m, aromatic H).

3. Diphenylmethyl-2- [2ß- (2,3-isopropylidenedioxypro-s poxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-l-yl] -2-tri-phenyl-phosphoranidene acetate

30th

55

IR: v ™ cl3 cm-1: 34.50, 1780, 1725, 1635, 1600.

NMR: SCDC13 ppm: 1.28 (s, 6H), 2.00 (s, 3H), 2.25 (s, 3H), 3.25-4.20 (m, 5H), 4.90-5 , 77 (m, 5H), 6.95 (s, lH), approx.7.3 (m, 15H).

2. Diphenylmethyl-2- [2ß- (2,3-isopropylidenedioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-1-yl] -2-hydroxyacetate

(15: R = PhCH2OCO; Z '= CHPli2)

A solution of 2.2 g (3.58 mmol) of the isopropylidene dioxy derivative, prepared as described above (13: R = PhCH20C0; Z1 = CHPh2) in 40 ml of methylene chloride is introduced with cooling with ice / acetone until the mixture 45 changes to blue. The excess of ozone is removed and the mixture is mixed with 22 ml of methyl sulfide and left under cooling at the same temperature for one hour and then at room temperature for one hour. The mixture is mixed with a small amount of acetic acid, washed 50 with water, dried and evaporated, 2 g of the intermediate l-diphenylmethoxalyl-2ß- (2,3-isopropylidendioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidine (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 under ice cooling for two hours. The zinc powder is filtered off and washed with methylene chloride. The filtrate and the wash water are combined, washed with water, dried and evaporated to give 20 g of the 2-hydroxy derivative in question (15: R = PhCH2OCO; Z1 = CHPh2) (95% yield).

IR: v ™ cl3 cm-1: 3500.3430, 1780, 1740, 1720, 1600.

NMR: 5CDCI3ppm: 1.47 (s, 6H), 3.17-4.30 (m, 5-6H),

5.16 (s, 2H, 4.70-6.00 (m, 3-4H), 6.97

65

(16: R = PhCH2OCO; Z '= CHPh2)

1.3 ml (1.02 mmol) of dimethylaniline are added to a solution of 2.0 g (3.4 mmol) of the 2-hydroxy derivative (15: R = PhCH20C0; Z '= CHPh2) in 60 ml of dry methylene chloride while cooling with ice and 0.74 ml (1.02 mmol) of thionyl chloride was added dropwise, and the mixture was stirred at the same temperature for 30 minutes and then poured into ice water. The methylene chloride layer is separated off, washed with water, dried and evaporated, 2.3 g of the intermediate diphenylmethyl-2- [2β- (2,3-isopropylidenedioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoaze-tidin-l-yl ] -2-chloroacetate [IR: v ™ cl3 cm-1: 3436, 1785, 1750, 1720, 1595]. This product is dissolved in 40 ml of methylene chloride and mixed with 0.86 ml (6.8 mmol) of dimethylaniline and 1.8 g (6.8 mmol) of triphenylphosphine. The mixture is heated under reflux for 6 hours, a further 1.8 g of triphenylphosphine are added, the mixture is poured into a 5% strength aqueous sodium bicarbonate solution with cooling, washed with water, dried and evaporated. The residue is chromatographed in a column with silica gel and gives 1.6 g of the triphenylphosphorane derivative in question (16: R = PhCH2OCO; Z '= CHPh2) (56.6% yield).

IR: v ™ cl3cm - ': 3400.1760.1710.1620.1590.

4. Diphenylmethyl-2- [2ß- (2,3-dihydroxypropoxy) -3ß-ben-zyloxycarbonylamino-4-oxoazetidin-1-yl] -2-triphenyl-phos-phoranylidene acetate

(17: R = PI1CH2OCO; Z '= CHPh2)

To a solution of 417 mg (0.5 mmol) of triphenylphosphorane derivative (16: R = PhCH20C0; Z1 CHPI12) in 8 ml of methanol are added 1.6 ml of 10% hydrochloric acid and the mixture is stirred at room temperature for 40 minutes poured a cooled aqueous 5% sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is chromatographed in a column with silica gel and gives 172 mg of the free acetonide derivative in question (17: R = PhCH2OCO; Z '= CHPh2) (43.3% yield).

IR: v ™ cl3 cm-1: 3450-3200, 1770, 1720, 1630, 1600.

5. Diphenylmethyl-7ß-benzyloxycarbonylamino-1-oxa-1-dethia-3-cephem-4-carboxylate

(IV: R = PhCH2OCO; Z '= CHPh2)

To a solution of 139 mg (0.175 mmol) of the free acetonide derivative (17: R = PhCH20C0; Z '= CHPh2) in 4 ml of tetrahydrofuran, periodic acid consisting of sodium periodate (45 mg) and IN sulfuric acid (2.2 ml) was added while cooling with ice and the mixture was stirred at the same temperature for three hours and at room temperature for one hour, poured into ice water and extracted with ethyl acetate. The extract is washed with water, dried and evaporated. The residue is in a column

637135

14

Chromatograph silica gel and yield 15 mg of the protected oxacephem derivative in question (IV: R = PhCH2OCO; Z1 = CHPh2) (17.7% yield).

It was demonstrated by thin layer chromatography, IR spectrum and NMR spectrum that this product is identical to an authentic sample which was produced by an alternative method from Example 2.

Procedure 8

1. Diphenylmethyl-2- [2ß- (2-oxoethyloxy) -3ß-benzyloxy-carbonylamino-4-oxoazetidin-1-yl] -2-isopropylidene acetate

(7: R = PhCH2OCO; Z '= CHPh2)

To a solution of 11.5 g (0.02 mol) of diphenylmethyl-2- [2ß- (2,3-dihydroxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-l-yl] -2-isopropylidene acetate (6: R = PhCH2OCO ; Z1 = CHPh2) in 200 ml of ethanol, a solution of 5.14 g (0.024 mol) of sodium periodate in 210 ml of IN sulfuric acid is added and the mixture is stirred at room temperature for 30 minutes, poured into ice water and extracted with ethyl acetate. The extract is washed with water and an aqueous sodium chloride solution, dried and evaporated under reduced pressure, giving 10.8 g of the formyl derivative in question (7: R = PhCH2OCO; Z '= CHPh2).

IR: v ™ cl3 cm- ': 3445,1778,1725,1632,1508.

2. Diphenylmethyl-2- (2ß-methoxycarbonylmethoxy-3ß-benzyloxycarbonylamino-4-oxoazetidin-1-yl) -2-isopropylidene acetate

(8: R = PhCH2OCO; Z '= CHPh2; Z2 = CH3)

Z '= CHPh2; Z2 = CH3) in 230 ml methylene chloride is introduced with cooling to -78 ° C ozone. The mixture turns blue after about 30 minutes and then nitrogen gas is introduced to remove the excess ozone. The mixture is mixed with 10 ml of dimethyl sulfide with cooling to -78 ° C, stirred at the same temperature for one hour and then at room temperature for another hour, mixed with methylene chloride and then with 2 to 3 drops of acetic acid, with water and with an aqueous sodium chloride -ioid solution washed, dried and evaporated to give 8.9 g of the methoxalyl derivative in question as an oily product (9: R = PhCH2OCO; Z1 CHPhj; Z2 = CH3).

15

IR: v ™ cl3cm - ': 3450, 1830, 1756, 1720, 1509.

4. Diphenylmethyl-2- (2ß-methoxycarbonylmethoxy-3ß-benzyloxycarbonylamino-4-oxoazetidin-l-yl) -2-hydroxy-acetate

20 (10: R = PhCH2OCO; Z '= CHPh2; Z2 = CKb)

To a solution of 8.9 g of the methoxalyl derivative, prepared as described above (9: R = PhCH2QCO; Z '= CHPh2; Z2 = CH3) in a mixture of 90 ml of methylene chloride and 2s 90 ml of acetic acid, 9 g of activated zinc powder are cooled with ice and stirring added. After 15 to 30 minutes, the zinc powder is filtered off and the filtrate is mixed with methylene chloride, washed with water and an aqueous sodium chloride solution, dried and evaporated under reduced pressure to obtain 8.4 g of the hydroacetic acid derivative in question (10: R = PhCH2OCO ; Z '= CHPh2; Z2 = CH3) (95.2% yield).

IR: vs cm-1: 3500-3600, 3445, 1796, 1747, 1512.

35

To a solution of 10.8 g of the formyl derivative (7: R = PhCH2OCO; Z '= CHPh2) in 100 ml of acetone, 14 ml of Jones reagent are added at a temperature below 15 ° C. with ice cooling and stirring. After 30 minutes, the reaction mixture is mixed with isopropanol and the excess of the reagent is decomposed. The insoluble material is filtered off and the filtrate is poured into ice water and extracted with ethyl acetate. The extract is washed with water and an aqueous sodium chloride solution and evaporated under reduced pressure, 11.1 g of the carboxylic acid being obtained as a crude product (8: R = PhCH2OCO; Z '= CHPh2, Z2 = H).

This product is dissolved in 150 ml of methylene chloride and mixed with diazomethane ether for esterification and evaporated. The residue (11 g) is chromatographed in a column with 200 g of silica gel and eluted with benzene / ethyl acetate (5: 1), 9.2 g of the methyl carboxylate in question being obtained (8: R = PhCH2OCO; Z! CHPI12;

Z2 = CHs) (80.3% yield).

55

IR: vSaxC13 cm-1: 3445, 1780, 1725, 1635, 1510.

5. Diphenylimethyl-2- (2ß-methoxycarbonylmethoxy-3ß-benzyloxycarbonylamino-4-oxoazetidin-l-yl) -2-chloroacetate

(11: R = PhCH2OCO; Z '= CHPh2; Z2 = CHs; X "= C1)

To a solution of 8.4 g (0.015 mol) of the hydroacetic acid red derivative, prepared as described above (10: R = PhCH2OCO; Z '^ CHPhs; Z2 = CH3) in 100 ml of dry methylene chloride, 3.34 ml ( 0.046 mol) of thionyl chloride and 1.46 ml (0.018 mol) of pyridine are added with ice cooling and stirring, and the mixture is stirred for 30 minutes with ice cooling, mixed with a sufficient amount of methylene chloride, washed with water and an aqueous sodium chloride solution, dried and evaporated under reduced pressure, whereby 8.9 g of the relevant monochloroacetic acid derivative are obtained j (l 1: R = PhCH2OCO; Z1 = CHPh2; Z2 = CH3; X "= C1).

IR: v ™ cl3 cm-1: 3435, 1790, 1748, 1725, 1502.

6. Diphenylimethyl-2- (2β-carbomethoxy-35b-benzyloxy-carbonylamino-4-oxoazetidin-l-yl) -2-triphenylphosphora; nylidene acetate

NMR: 8CDC13 ppm: 2.00 and 2.25 (s, 3Hx2), 3.58 (s, 3H),

3.97 (s, 2H), 5.0-5.40 (m, 2H), 5.13 (s, 2H),

5.77 (d, J = 8Hz, 1H), 6.93 (s, 1H).

3. l-Diphenylmethoxalyl-2ß-methoxycarbonylmethoxy-3ß-benzyloxycarbonylamino-4-oxoazetidine

(9: R = PhCH20C0; Z> = CHPh2; Z2 = CH3)

In a solution of 9.2 g (0.016 mol) of the methyl carboxylate, prepared by the above method (8: R = PI1CH2OCO; place and again for one hour while heating at reflux fio (12: R = PhCH20C0; Z '= CHPh2)

To a solution of 8.9 g (0.015 mol) of the monochloro derivative, prepared as described above (11: R = PhCH2OCO; iZ1 = CHPh2; Z2 = CH3, X "= C1) in 100 ml of methylene chloride 65, 8.0 g (0.03 mol) of triphenylphosphine were added and the mixture was refluxed with heating for 1.5 hours, mixed with a further 2.0 g (7.5 mmol) of triphenylphosphine

treated. The reaction mixture is poured into an aqueous 5% sodium hydrogen carbonate solution, neutralized and extracted with methylene chloride. The extract is washed with water and an aqueous sodium chloride solution, dried and evaporated under reduced pressure. The residue is chromatographed in a column with 300 g of silica gel and eluted with benzene ethyl acetate (4: 1-1: 1), 10.2 g of the methyltriphenylphosphoranate derivative in question diphenylmethyl-2- (2β-methoxycarbonyl-methoxy-3ß-benzyloxycarbonylamino- 4-oxoazetidin-l-yl) -2-triphenylphosphoranylidene acetate (84.1% yield) can be obtained.

IR: v ™ cl3 cm-1: 3445, 1790, 1725, 1630, 1512.

NMR: 5CDCI3 ppm: 3.58 (s, 3H), 3.6-5.2 (m, 4H), 5.07 (s, 2H).

118 ml (22.5 mmol) of an aqueous sodium chloride solution (9.19 mmol / ml) are added to a solution of 16.23 g (20.5 mmol) of the methyltriphenylphosphoranate in 240 ml of tetrahydrofuran with ice cooling at 2 to 5 ° C. added dropwise over 30 minutes and the mixture stirred for 15 minutes, neutralized with 44 ml (23 mmol) of a 2% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and an aqueous sodium chloride solution, dried and evaporated to give 15.8 g of the triphenylphosphorane derivative in question (12: R = PhCH20C0; Z '= CHPh2).

IR: cm-1: 3440.1775, 1725, 1625.1510.

7. Diphenylmethyl-7ß-benzyloxycarbonylamino-3-hydroxy-1-oxa-1-dethia-3-cephem-4-carboxylate

(II: R = PhCH20C0; Z ^ CHPha)

41.4 g (406 mmol) of acetic anhydride are added to a solution of 15.8 g (20.3 mmol) of the triphenylphosphorane derivative, prepared according to the above method (12: R = PhCH20C0; Z '= CHPh2) in 300 ml of dry toluene and 8.87 g (102 mmol) of N, N-dimethylacetamide were added and the mixture was heated at 100 to 105 ° C (bath temperature) for 16 hours.

After cooling, the reaction mixture is mixed with benzene, washed with water, an aqueous sodium chloride solution and then with water, dried and evaporated under reduced pressure. The residue (approx.

15 637135

20 g) is chromatographed in a column with 600 g of silica gel and eluted with benzene / ethyl acetate / acetic acid (9: 1: 0.001), whereby 5.08 g of the main product are obtained: Diphenyimethyl-3-acetoxy-7β-benzyloxycarbonylamino-1-

5 oxa-l-dethia-3-cephem-4-carboxylate (hereinafter abbreviated as 3-acetoxy compound) (48% yield) and 3.25 g of a by-product: diphenylmethyl-2- (2-ben-zyloxycarbonyl-3, 8-dioxo-5-oxa-2,7-diazabicyclo (4.2.0) octan-7-yl) -2-triphenylphosphoranylidene acetate (21.5%

10 loot).

Physical constants of the 3-acetoxy compound IR: v ™ cl3cm-I: 3445,1800, 1785,1725,1656,1508.

1S NMR: 8CDC13 ppm: 2.00 (s, 3H), 4.32 (s, 2H),

5.05 (d, J = 4Hz, 1H), 5.13 (s, 2H), 5.3 8 (q, J = 4Hz; 10Hz, 1H),

5.68 (d, J = 10Hz, 1H), 6.95 (s, lH7).

2 °

Physical constants of the by-product IR: v "" xCl3 cm-1: 1790, 1778, 1740, 1628.

2S NMR: 5CHCl3 ppm: 3-4 (m, 2H), 4-5 (m, 2H), 5.27 (s, 2Hz).

The 3-acetoxy compound (3.2 g; 5.9 mmol) prepared according to the above procedure is dissolved in a mixture of 60 ml pyridine and 12 ml water with cooling, 1.75

Stirred for 30 hours at room temperature, poured into ice water and then extracted with ethyl acetate. The ethyl acetate layer is washed with 10% phosphoric acid, water and then with an aqueous sodium chloride solution, dried and evaporated under reduced pressure,

35 whereby 3.05 g of the 3-hydroxy compound in question are obtained as a white foamy material (II: R = PhCH20C0; Z '= CHPh2).

IR: v ™ cl3 cm "1: 3440.1795.1725, 1675.1510.

40

NMR: Scdci3 ppm: 4.37 (s, 2H), 5.05 (d, J = 4Hz, lH),

5.18 (s, 2H), 5.45 (q, J = 10Hz, 1H),

5.72 (d, J = 10Hz, 1H), 7.00 (s, lH), 10.83 (s, lH).

45

This product can also be used as the starting material in Example 1.

B

Claims (14)

637135 PATENT CLAIMS 1. Cephalosporin derivatives of the formula I wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, arylthio or a monocyclic thioheterocycle, R2 carboxy or an ester, thioester or amide thereof, R3 is hydrogen or methoxy and their salts. 2. Cephalosporin derivatives according to claim 1 of formula I. H N. in which R1 is halogen or sulfonyloxy and R3 is hydrogen. 3. cephalosporin derivatives according to claim 1 of formula I, in which R1 is hydrogen and R3 are hydrogen. 4. Cephalosporin derivatives according to claim 1 of formula I, in which R1 is arylthio or a monocyclic thioheterocycle and R3 are hydrogen. 5. Cephalosporin derivatives according to claim 1 of formula I, in which R1 is lower alkoxy and R3 are hydrogen. 6. Cephalosporin derivatives according to claim 1 of formula I, in which R3 is methoxy. 7. 7ß-amino-3-chloro-l-oxa-l-dethia-3-cephem-4-carboxylic acid, 7ß-amino-l-oxa-dethia-3-cephem-4-carboxylic acid, 7ß-amino- 3- (1-methyl-tetrazol-5-yl) thio-1-oxal-dethia-3-cephem-4-carboxylic acid, 7β-amino-3-methoxy-1-oxa-1-dethia-3-cephem -4-carboxylic acid or 7ß-amino-3-chloro-7a-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid according to claim 1. 8. Process for the preparation of a compound of formula I. H 2nd (I) wherein R1 is hydrogen, halogen, lower alkoxy, sulfonyloxy, Arylthio or a monocyclic thioheterocycle, R2 carboxy or ester, thioester or amide thereof, R3 are hydrogen or methoxy, and their salts, characterized in that a compound of formula Ib RNHv: wherein R is benzyloxycarbonyl, is acid hydrolyzed. 9. The method according to claim 8 for the preparation of a compound of the formula I in which R3 is methoxy, characterized in that a compound of the formula I obtained in which R3 is hydrogen is methoxylated in the 7a position. 10. The method according to claim 8 for the preparation of a compound of formula I in which R1 is halogen or sulfonyloxy and R3 is hydrogen. 11. The method according to claim 8 for the preparation of a compound of formula I in which R1 is hydrogen and R3 are hydrogen. 12. The method according to claim 8 for the preparation of a compound of formula I in which R1 is arylthio or a monocyclic thioheterocycle and R3 is hydrogen. 13. The method according to claim 8 for the preparation of a compound of formula I in which R1 is lower alkoxy and R3 are hydrogen. 14. The method according to claim 8 or 9 for the preparation of a compound of formula I in which R3 is methoxy. 15. The method according to claim 8 for the preparation of 7ß-amino-3-chloro-l-oxa-l-dethia-3-cephem-4-carboxylic acid, 7ß-amino-l-oxa-dethia-3-cephem-4-carboxylic acid , 7β-amino-3- (1-methyl-tetrazol-5-yI) thio-1-oxa-1-dethia-3-cephem-4-carboxylic acid, 7ß-amino-3-methoxy-1-oxa-1-dethia -3-cephem-4-carboxylic acid or 7β-amino-3-chloro-7a-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid.