DE2735408A1 - 7 BETA-AMINO-1-OXADETHIACEPHALOSPORINE - Google Patents

Description

below: M 305

Case: P 3049 TW

SHIONOGI & CO., LTD.
Osaka, Japan
10

rs-amino-l-oxadethiacephalosporine "

The invention relates to those characterized in the claims Objects.

The compounds of the invention can be prepared according to the following reaction scheme getting produced:

^RIDi ^ i ^ O ^ ² ^ rO-

Hydrolysis kethoxylation

J-K ^

12 "5 R is an amino protecting group and R, R and R have the in

Claim 1 given meaning.
25th

Possible halogen atoms for the radical R are fluorine, chlorine, bromine and iodine atoms. The term lower alkoxy means a radical with 1 to 5 carbon atoms, such as the meth

"" 709886/0986

oxy, xthoxy, n-propoxy, isopropoxy and n-butoxy group, the term sulfonyloxy group means a C -Arylsulfonyloxy radical, such as the benzenesulfonyloxy and toluenesulfonyloxy groups. The term arylthio group denotes an optionally substituted Cg_ ₁₀ arylthio such as phenylthio, tolylthio, and methoxyphenylthio Dimethoxyphenylthiogruppe. The monocyclic heterocyclothio radicals include five-membered radicals with 1 to 4 heteroatoms (N, 0 or S), which can be represented by the general formula -SQ. Q denotes a five-membered heterocyclic radical which has an aza-, oxa-, thia-, diaza-, dioxa-, dithia-, trlaza-, trioxa-, trithia-, tetraza-, oxaza-, oxathia-, thiaza-, oxadiaza- or has thiadiaza moiety in the ring. Specific examples of such heterocyclic ring systems are furan, tetrahydrofuran, pyrrole, pyrrolidine, thiophene, tetrahydrothiophene, oxazole, thiazole, isoxazole, isothiazole, pyrazole, pyrazoline, imldazole, oxathiol, dioxole, dithiol, triazole, thiadiazole, oxadiazole, dioxazole, oxadiazole , Tetrazole, oxatriazole, thiatrlazole and dithiadiazole. The sulfur atom can be in any possible position on the heterocyclic ring. The heterocyclic ring can have 1 to 4 substituents, such as C, -, alkyl or alkoxy groups, hydroxyl groups, halogen atoms, nitro and amino groups. These substituents can be in the possible position or positions.

709886/0986

The functional derivatives of the carboxyl group R are for example the esters, thioesters and acid amides. " If the radical R is, for example, an ester, R can by the all-

Ii

common formula -COOR are reproduced. The usual ones come Esters in question, as they are in the penicillin and cepha-

Ii

losporin chemistry are known. The radical R is, for example a C ", - alkyl, such as methyl, ethyl, propyl, isopropyl, η-butyl and tert-butyl group, a C ₁ C ^- HaIogenalkylrest how the Chlorinethyl-, dichloromethyl -, 2,2-Dichloräthyl-, 2,2,2-trichloroethyl and 2,2,2-Tribromäthylgruppe, a C ₇ _ ~ Q ₂ ^Ar yl ^m ethyl radical, such as benzyl, diphenylmethyl, triphenylmethyl, p -Methoxybenzyl, 3 »^» 5-trimethoxybenzyl and p-nitrobenzyl group, a Cg.g-acylmethyl radical, for example a phenacyl group which is substituted by a silyl radical, such as a dimethylsilyl, trimethylsilyl or triphenylsilyl group, a substituted stannyl radical, such as a trimethylstannyl group, an adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydropyran-2-

yl or 2-cyanoethyl group.
20th

The compounds of the general formula I form salts with acids with the amino group in the 7-position. Examples of the acids that can be used for salt formation are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid and thiocyanic acid, and organic acids such as p-toluenesulphonic acid and naphthalene

p
sulfonic acid. If the radical R in the 4-position represents a free carboxyl group, the compounds of the general

L J

709886/0986

Γ -1

My formula I is based on inorganic or organic bases and salts form.

The compounds of the general formula I according to the invention can be prepared in the manner described in the reaction schemes below.

Compounds of the general formula Ia in which R is a halogen atom or represents a sulfonyloxy radical, can according to the following Can be prepared according to reaction scheme I:

Reaction scheme I.

^15th JtX

OH ^ Λ N-

1 "ι level a 0 *" T? Level b COOZ COOZ ¹

(III)

R is an amino protecting group, Z is a carboxyl protecting group, X is a halogen atom or a sulfony
meaning given in claim 1.

X is a halogen atom or a sulfonyloxy group and R has the

The starting compounds of the general formula II are known and can, for example, according to the method described in JA-OS IJI385 / 76 processes described or according to the process described in Reaction Scheme II.

70988R / 0986

1 Reaction scheme II

Η _Λ Ν ^> OCHpC == CH

Protection of the NH group

Pe ro xv acid.

15 RNH ^ Q ^^ CHO RNH

^NaI0 II ¹ ^ oxidation with

COOZ ¹ 2) esterification ( _g \ COOZ ¹

²⁰ Oxidation ^ ^N v ^ O Reduction

(a) cooz ¹

-N _n s O v ^ COO Z ²

TJ ^ D PPh ₃

25 (10)

, ^, 2) partial

COOZ ¹ _cooz l hydrogenation

(II) ^cooz 70988R / 0986

" ¹ ^" 2735A08

X * and X "are halogen atoms, Z is one capable of ester formation Group, R and Z have the above meaning and Ph represents a phenyl group.

In Reaction Scheme II above, each stage can be carried out in a manner known per se.

The compounds of the general formula Ia which can be prepared according to reaction scheme I correspond to the compounds of the general formula Formula I, in which R is a halogen atom or a sulfo

3 2

nyloxyrest and R represents a hydrogen atom and R represents has the above meaning.

The reaction conditions in each stage of Reaction Scheme I are illustrated below:

Level a (ΙΙ-ΐ * III)

The hydroxyl group in the 3-position of the compounds of the general Formula II is substituted by a halogen or sulfonylated by treatment with a sulfonylating agent. It becomes the corresponding 3-halogen or 3-sulfcnyloxy compounds obtain.

The halogenation of the hydroxyl group in the 3-position is carried out in the usual way, for example with a phosphorus trihalide or thionyl chloride. The halogenation is preferably carried out with an oxalyl halide, such as oxalyl chloride, a phosphorus oxyhalide such as phosphorus oxychloride, or

709B8R / 0986

a calogen, such as chlorine, together with triphenylphos-hin . '■ ■ ■

The sulfonylation of the 3-hydroxy group is in itself carried out in a known manner. Specific examples of sulfonylating agents that can be used are alkylsulfonyl halides such as Methyl sulfonyl chloride and ethyl sulfonyl chloride, aryl sulfonyl halides, Benzenesulfonyl chloride or toluenesulfonyl chloride. The reaction can, for example, in the presence of a tertiary Amine, such as pyridine or triethylamine, can be carried out.

Level b (III - * - Ia)

In this process, the protecting group is in the 7-position and optionally the protective group in the ^ position at the same time or split off gradually by hydrolysis or reduction, depending on the properties of the protective groups. as Protective groups in the 7-position and the ^ -position come the protective groups customary in the penicillin and cephalosporin chemistry in question, which can also be split off again in a manner known per se.

The compounds of general formula I, with the exception of those in which R is a halogen atom or a sulfonyloxy radical, can be prepared according to reaction scheme III will.

709886/0986

Reaction scheme III

Al

O T ^ C

COOZ ^X

^ Stage c
COOZ ^X

(IH)

1 2
R, Z, R and X have the meanings given above.

Compounds of the general formula I ₁ in which R represents a hydrogen atom are prepared according to reaction scheme III.

Level c (III-5 ».IV)

The halogen atom or the sulfonyloxy radical in the 3-position of the Compounds of general formula III is made by reduction

! 5 split off. The corresponding ones are in the 3 position obtained unsubstituted oxadethiacephem compounds. the Reduction is carried out in such a way that the halogen atom or the sulfonyloxy radical in the 3-position is selectively split off becomes, for example, through the system metal and acid, in particular zinc and acetic acid.

Level d (IV-s ^ Ib)

The hydrolysis or reduction can be carried out in the same way as stage b.
25th

The compounds of the general formula Ib can also be prepared according to Reaction Scheme IV.

70988B / 0986

~ ¹³ ~

Reaction Scheme IV

acetone

(6) COOZ ¹

P-TsOH

(l3) COOZl

oxidation

COO Z ^J

'Halogenation (SOCl ₂ )

. ^ o

(15)

partial hydrogenation

OZ

^ PPh,

(l6) COOZ ¹

RNH

RNH,

Λ ^ CHO

Ph,

(i7) cooz ¹

(18)

^coozl

M Vittiss reaction

²⁰ »■

RNH

R, Z and Ph have the meaning given above,

²⁵ The compounds of general formula I ₁ wherein R represents an arylthio group or a monocyclic Heterocyclothiorest can Reaction Scheme V are prepared according to.

70988R / 0S88

Reaction scheme V

(Ic) ^r

1 2
R, Z, R and X have the meanings given above.

Y is an arylthio or monocyclic heterocyclothio radical,

Level e (III— = * ■ V)

The halogen atom or the sulfonyloxy radical in the 3-position of the compounds of the general formula III is replaced by the corresponding arylthio or monocyclic heterocyclothio radical replaced. For this purpose the connections of the all

^ common formula III with the corresponding aryl mercaptan or monocyclic heterocyclothiol reacted in the presence of a weak base or with the corresponding salt. Preferred weak bases are organic bases such as pyridine and triethylamine. The implementation usually takes place at room temperature.

Level f (V-s * Ic) '■

The hydrolysis or reduction can be carried out under the same conditions as in steps b and d.

The compounds of the general formula Ic can also be prepared according to Reaction Scheme VI.

709886/0986

Reaction Scheme VI

COOH

00Z ^J

- 15 -

YH

/ (COCl ₂ ) \ V n /

Pyridi

' BNlL ^ O ^^ COY

(19)

Wittig reaction

, γ and Z ^v have r *.

RNH

COOZ "(V) given in advance

The compounds of general formula I in which R * is a means lower alkoxy radical can according to the reaction scheme VII are produced.

Reaction scheme VII ¹⁵ RNH _x ^ O.

RNH

• Η level g

COO Z ^J

2 1 3

R, R and Z are as defined above and Z is a

²⁰ lower alkyl radical,

Level g (II - ^ VI)

This procedure is under the conditions of etherification enolizable ketones or the esterification of carboxylic acids with diazoalkanes carried out »The etherification of enolizable Ketones, for example, with a trialkyl orthoformate, such as triethyl orthoformate, or carried out with an alcohol and p-toluenesulfonic acid. As Di-

709886/0986

Γ "I.

azoalkanes can be used, for example, diazomethane and diazoethane will.

Level h (VI -is »Id)

The hydrolysis or reduction can be carried out according to stage b, d or f.

Compounds of general formula I, means a group in which R · methoxy · ⁵ may, according to Reaction Scheme VIII can be produced.

Reaction scheme VIII

QCH ₃

UU I f \ ' NH **

J Jt Λ St ·. I if » \

1 2
R and R have the meanings given above.

Stage i

The compounds of the general formula If correspond to the compounds which are prepared according to Reaction Scheme VII. The introduction of a methoxy group in the 7-position can be carried out according to the methods customary in penicillin or cephalosporin chemistry. These methods are described below.

70988B / 0986

Embodiment 1)

The amino group in the 7-position of the compounds of the general Formula If is reacted with an acylating agent to give the corresponding 7-acylamino derivative. This connection is made with methoxylithium (LiOCH,) and tert-butyl hypochlorite (t-BuOCl) in an inert solvent at low temperatures implemented according to BE-PS 817 836. Then the 7-acyl protecting group cleaved.

Embodiment 2)

The compound of the general formula If is reacted with sodium nitrite to give the corresponding 7-diazo compound (a). This compound is made with a haloazide, prepared from sodium azide and the corresponding halogen, such as BrN ,, ClN, or JN ,, converted to the corresponding haloazide (b). This compound is reacted with methanol and then the azido group is reduced. The corresponding 7-amino-7-methoxy compounds (Ie) are obtained. These Implementations are explained by the following reaction scheme (see JA-OS 931/72):

χι 1

NaNO, ° ^ '

2) Reduction 1 2
R and R have the meanings given above and

X is a halogen atom

709886/0986

For guidance form 3

The compounds of the general formula IX are substituted with a p-hydroxybenzaldehyde, which is preferably substituted by a bulky radical or bulky radicals in the o-position to the hydroxyl group, such as 3 »5-di-tert.-butyl- ⁱ l-hydroxybenzaldehyde, to the corresponding Benzylidene derivative (c) implemented. This compound is reacted with an oxidizing agent such as nickel peroxide or lead tetraacetate to form compound (d). This compound is reacted with methanol to give the 70 methoxy compound (e) and the benzylidene group is split off hydrolytically, usually by treatment with Girard reagent. The reactions are explained by the following reaction scheme (see JA-OS 50 39V75):

CHO

CH = N

(If)

(O)

oxidation

CH-N,

/ \ y-cii = N,

OCH

CH ₃ OH

(d)

Hydrolysis Ξ *

R and R have the above meanings.

Embodiment 4

The compounds of the general formula Ie can also according to

709886/0986

Γ Π

can be prepared using the reaction scheme below. For this purpose the amino group is in the 7-position of the compounds of the general formula If protected by an acyl radical with at least one hydrogen atom in the (X-position. There are

* the 7-acylamino derivatives (f) obtained with a halogenating agent to be converted to the corresponding iminohalides (g). These compounds are converted into hydrogen halide with a base cleaved. The corresponding ketenimines (h) are obtained, which give rise to the corresponding dihalogenimines (i) halogenated, then reacted with an alkali metal methoxide and then hydrolyzed to split off the acyl group will; see JA-OS 126 692/75. These reactions proceed according to the following reaction scheme:

Q ' I ^Q '

j ^ CHCNH ^ ^ ⁰ X Halo genie run

(If) Q "

OCH hydrolysis . >
i> (Ie)

R ¹ and R ² have the above meaning, Q ¹ and Q "are hydrogen atoms or any substituents which are inert under the reaction conditions, and X and X ¹ are halogen atoms»

709886/0986

The compounds of general formula I are valuable intermediates for the production of new 1-oxadethiacephalosporins, By introducing acyl residues of rare chain acids known from penicillin and cephalosporin chemistry into the amino group in the 7-position antibiotically active compounds are obtained%

The examples illustrate the invention.

For example

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

1) A solution of 1.5 g (3 mmol) of 7β-benzyloxycarbonylamino-3-hydroxy-1-oxa-1-dethia-3-cephem- ⁱ <-carboxylic acid diphenylmethyl ester (II: R = PhCH ₂ OCO; Z ¹ ^ = CHPh ₂ ) in 30 ml of dimethylformamide, 0.03 ml (0.36 mmol) of pyridine and, dropwise, 0.31 ml (3 »6 mmol) of oxalyl chloride are added while cooling with ice. After stirring for 3 hours at room temperature, the reaction mixture is poured into 5 percent aqueous phosphoric acid while cooling with ice and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is chromatographed on 20 parts by volume of silica gel and eluted with a mixture of benzene and ethyl acetate (5: 1). The eluate is evaporated. There are 489 mg (31% ¹ J

d. Th.) 7ß-Benzyloxycarbonylamino-3-chloro-1-oxa-1-dethia-3-cephem- ⁱ <-carboxylic acid diphenylmethyl ester from P. 130 to 131 ° C obtained.

70988 K / 0986

1 - 21 -

Max

1805, 1725, 1620.

NMR: 6 ^CDC1 3 ppm: 4.32 (s, 2H), 4-98 (d, J = U .0Hz, IH), 5.10 (s, 2H), 5.20 - 5-80 (m, 2H), 6.97 (s , lH), 7-0 (with aromatic H)

This compound can also be prepared as follows: A solution of 1.62 g (6.2 mmol) of triphenylphosphine in 20 ml of tetrahydrofuran is mixed with 6.2 mmol of a solution of chlorine in carbon tetrachloride and a solution of 1.55 g (3.1 mmol) of the 3-hydroxy derivative (II: R = PhCH ₂ OCO; Z ¹ SCHPh ₂ ) in 10 ml of tetrahydrofuran and then 0.86 ml (6.2 mmol) of triethylamine are added while cooling with ice and stirring. After stirring for 90 minutes at room temperature, the reaction mixture is poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated.

The residue is chromatographed on 30 parts by volume of silica gel and eluted with a mixture of benzene and ethyl acetate (10: 1). The eluate is evaporated. 0.95 g (59.0 % of theory ) of the corresponding 3-chloro compound are obtained.

2) A solution of 950 mg (1.83 mmol) of the 3-chloro derivative in 37 ml of methylene chloride with 1.78 ml (16.5 mmol) of anisole and a solution of 1.5 g (11 mmol) of aluminum chloride in 18 ml of nitromethane are added and the mixture is left to stand for 15 hours at room temperature. The reaction mixture is then mixed with 15 ml ice-cold 2 percent hydrochloric acid extracted. The aqueous phase is washed with methylene chloride and then with ethyl acetate and evaporated under reduced pressure. The residue is on a 400 g of a highly porous polymer (Diaion

709886/0986

γ -ι

273S4Ü8

HP 20) filled column chromatographiart and eluted with hydrochloric acid of pH 3. The eluate is adjusted to a pH of Ί.4 and evaporated under reduced pressure. 175 mg (43.8 % of theory ) of the corresponding 3-chloro derivative are obtained

(I: R ¹ SCl; R ² = COOH; R ³ = H).

, 1818, 163Ο, I613.

Example 2

7β-Amino-1-oxa-1 -de thia-3-cephem- ¹ * - carboxylic acid 10

1) A solution of 1.98 g (3.96 mmol) of the 3-hydroxy derivative (II: R = PhCH ₂ OCOj Z ¹ = CHPh ₂₎ in 20 ml of dimethylformamide at -50 ⁰ C with 0.62 ml (2 Equivalents) of methylsulfonyl chloride and then 0.83 ml (1.5 equivalents) of triethylamine. The mixture is stirred at the same temperature for 15 minutes and then poured into ice water. The resulting crystals are filtered off. 2.15 g ( 9.0% of theory ) of 7β-BenzyIoxycarbonylamino-3-methyIsulfonyIoxy-1-oxa-1-dethia-3-cephem-'J-carboxylic acid diphenylmethyl ester are obtained.

IR: v ^CHC1 3 cm " ¹ : 3 ^ 20, 1810, 1730, 1510, I365, H 65. max

NMR. 5CDCl ₃ p _prn . 2.96 (s, 3H). 4.46 (bs, 2H), h . 97 (d, J = ^ .0Hz, 1H), 5.07 (s, 2H), 5

2) A solution of 1.15 g {2mllol) of the 3-Ilethylsulfonyloxyderivats (III: R = PhCK ₂ OCO; Z ¹ = CHPh ₃ ; X = OSO ₂ CH ₃ ) in a mixture of 20 ml of methylene chloride and 40 ml of acetic acid is mixed with 3 g activated zinc dust and 15 hours

709886/0986

" ²³ " 273SA08

the stirred at room temperature. During this tent will be after

2 hours and after 3 hours from the start of the reaction, respectively

3 g zinc dust entered. After the reaction has ended, the zinc dust is filtered off and the filtrate is treated with ethyl acetate.

The organic phase is separated off, washed with water, dried and evaporated under reduced pressure. There are 913 mg (9 ^ »2 % of theory ) 7ß-Benzyloxycarbonylamino-l-oxa-l-de-

as powder thia-3-cephem- ¹ l-carboxylic acid diphenylme thy reads he / received.

IR: v ^ ¹ 3 cm " ¹ : 3 ^ 50, 1800, 1730, 1650. KMR : 6 ^CDC1 3 ppm: h.hl {m, 2H), k. 95 (d, J = ^ i.OHz, IH ), 5-15 (s, 2H), 5.53 (dd, J = 4.O, 9-OHz, lH), 6.5l (m, lH), 6.99 (s, lH).

This compound can also be prepared as follows: A solution of 240 mg of the chlorine derivative (III: R = PhCHpOCO; Z = CHPh ₂ >> X = Cl) in a mixture of ¹ l ml of methylene chloride and 8 ml of acetic acid is 0.72 g activated zinc dust was added and the mixture was stirred at room temperature. In the period from the fourth to the ninth hour after the start of the reaction, three additional 0.72 g of activated zinc dust are introduced. The reaction mixture is stirred for 15 hours. The zinc dust is then filtered off and the filtrate is poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is chromatographed on silica gel and eluted with a mixture of benzene and ethyl acetate (5: 1). 215 mg (96.0 % of theory ) of the compound mentioned are obtained.

3) A solution of 913 mg (18.8 mmol) of the L-709886/0986 -J obtained in (2)

Compound in 35 ml of methylene chloride is made with 1.85 ml (9 equivalents) anisole

and a solution of 1.51 g (6 equivalents) of aluminum chloride in 18 ml of nitromethane are added and the mixture is left to stand for 15 hours at room temperature. The reaction mixture is then extracted with 2 percent hydrochloric acid while cooling with ice. The aqueous phase is washed with methylene chloride and ethyl acetate and evaporated under reduced pressure . The residue is chromatographed on a column filled with a highly porous polymer (Diaion HP 20) and eluted with dilute hydrochloric acid (pH 3.0). The eluate is evaporated under reduced pressure. 291 mg (70.6 t of theory ) of the 3-Oxacepfce.m-Deri-

vats (I: R ¹ = R ³ = Hj R ² = COOH) obtained as the hydrochloride.

C ⁰ Od + 11.1 ° ± 2.k (c = O.2l6, in methanol) IR: v _max cm-1: 3500, 2600, 1805, l6 * »5. 1610, 1550.

NMR: 6 ^CDCl 3 ppm: 5-37 (d, J = i ».OHz.lH), 5-5l (d, J = 4.OH _Z , 1H), 6th.

Example 3

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

1) A solution of 1.12 g (1.9 ^ mmol) of that in Example 2

prepared 3-methylsulfonyloxy derivative (III: R = PhCH ₂ OCO; Z ^ CHPh ₂ ; X = OSO ₂ CH,) in 10 ml of dimethylformamide is cooled with ice at O ⁰ C with 373 mg (3.2 mmol) of l-methyltetrazole -5-

^L 709886/0986

Γ Π

ylthiol and 0.42 πα (3.0 mMo " ¹ ) triethylamine are added. The mixture is stirred for 15 hours at room temperature. After the reaction has ended, the reaction mixture is poured into ice water. The yellow precipitate formed is filtered off, washed and dried. 1.007 g (86.7 % of theory ) of the corresponding 3-tetrazolylthio derivative were obtained as a yellow powder.

PITf ¹ I ι

IR: vj ^ x 3 cm- ¹ : 3 ^ 50, 1805, 1730.

NMR: 6 ^CDCl 3 ppm: 3-93 (s, 3H), 4.28 (ABq, J = ISHz, 2H), 5.00 (d, J = Jt-

IH), 5-17 (s, 2H), 5.30-5.9O (m, 2H), 6.98 (s, 1H). 10

2) A solution of 137 mg (0.229 mmol) of the 3-tetrazolylthio derivative obtained in 4 ml of methylene chloride is mixed with 0.223 ml (2.06 mmol) of anisole and a solution of 190 mg (1.4 mmol) of aluminum chloride in 2 ml of nitromethane and Left to stand at room temperature for 15 hours. Then the reaction mixture is treated with 3 ml of 2 percent hydrochloric acid while cooling with ice. The aqueous phase is washed with methylene chloride and then acetic acid and evaporated. The concentrate is adjusted to a pH of 2.5 with sodium carbonate. There are 24 mg of the corresponding 7.beta.-amino-3-tetra zolylthio derivative obtained in crystalline form, melting above 200 ⁰ C.

^{111: v} ma £ cm " ¹ : 1820, I630, 162Ο.

Example 4 7β-Amino-3-methoxy-1-oxa-1-dethia-3-cephem-4-carboxylic acid

709886/0986

27354Ü8

1) A solution of 1.15 g (2.30 mmol) of the 3-hydroxy derivative

(II: R = PhCH ₂ OCO; Z ¹ SCHPh ₂ ) in 12 ml of methylene chloride is mixed with a mixture of diazomethane and diethyl ether, stirred for 10 minutes at room temperature and then evaporated under reduced pressure. The oily residue obtained is chromatographed on a column filled with 50 g of silica gel and eluted with a mixture of benzene and ethyl acetate (4: 1). The eluate is evaporated. 0.89 g (75 % of theory ) of 7β-benzyloxycarbonylamino-3-methoxy-1-oxa-1-dethia-3-cephem- ¹ l-carboxylic acid diphenylmethyl ester are obtained.

IR: vSSS ¹ ^ cm " ¹ : 3 * 495, 1796, 1725, 1626, 1512.

NMR: 6 ^CDCl 3 ppm: 3-7O (s, 3H), 4.23 and U .5 ^ (A-Bq, J = 18Hz, 2H), J | .96 (d, J = it.OHz, 1H), 5.l8 (s, 2H), 5. * »2 (dd, J = IOHz; ^ .0Hz, 1H), 5-8l (d,

J = IOHz, IH), 7.02 (s, IH), -7.4 (m, aromatic H). 15th

2) A solution of 1.06 g (2.06 mmol) of the obtained 3-methoxy derivative in 20 ml of methylene chloride, 3 ml of anisole and 3 ml of trifluoroacetic acid are added while cooling, for 15 minutes stirred, mixed with 20 ml of toluene and then evaporated under reduced pressure »The oily residue is mixed with benzene dissolved and extracted with 5 percent aqueous sodium bicarbonate solution. The aqueous extract is washed with benzene, adjusted to pH 2 with 10 percent hydrochloric acid and then extracted again with ethyl acetate. The ethyl acetate extract is washed with water and aqueous sodium chloride solution and evaporated under reduced pressure. It will 0.67 g of 7ß-Benzyloxycarbonylamino-3-methoxy-l-oxa-l-dethia-3-

* - 709886 / 098S ^J

"I - 27 -

cephem- ¹ * -carboxylic acid obtained.

CHCl ι

^{331: v} _B ar ^{3 cm:} 3 * 30, 1793, 1725, 1630, 1510.

3) A suspension of 100 mg of 5 percent palladium-on-carbon in 20 ml of a mixture of ethyl acetate and methanol (1: 1) into which hydrogen has previously been introduced is ^{mixed with 200 mg (0.93 1} ^ mmol) of the obtained added free carboxylic acid. The mixture is shaken vigorously in a hydrogen atmosphere. The reaction mixture is then stirred for 2 hours at room temperature and the catalyst is filtered off. The piltrate is evaporated under reduced pressure. It
65 mg (53 % of theory ) of the 7β-amino compound
(I: R ¹ SOCH ,; R ² = COOHj R ⁵ sH).

do. v ^KBr _cm -l: -3400, - 2900, 1785, 1679, 16 * 7

The filtered catalyst is washed several times with a mixture of methanol and hydrochloric acid. The washing solutions are evaporated under reduced pressure. 65 mg of the 7β-amino derivative are obtained as the hydrochloride in white crystals.
IR: vJ ^ J cm " ¹ : - 3 ^ 00, - 3OOO, 1787,

Example 5

7ß-Amino-3-chloro-7C <-methoxy-l-oxa-l-dethia-3-cephem- ⁱ l
carboxylic acid p-nitrobenzyl ester

L-709886/0986

Γ ~ 1

1) A solution of 14 l mg (0.399 mmol) of 7β-amino-3-chloro-loxa-1-dethia-3-cephem- ¹ »-carboxylic acid p-nitrobenzyl ester (prepared by esterification of the 3-chloro compound obtained in Example 1) In a mixture of 7 ml of chloroform and 1 ml of benzene, 112 mg (1.2 equivalents) of 3-5-di-tert-butyl-4-hydroxybenzaldehyde are added and the mixture is heated under reflux. At the same time, the resulting water of reaction is separated off in a water separator using a molecular sieve. After 2 1/2 hours, the reaction mixture is treated with a further 30 mg of the aldehyde and refluxed for a further 3 1/2 hours. The reaction mixture is then cooled to -15 ° C., 65 mg of magnesium sulfate and 219 mg of nickel peroxide are added and the mixture is initially stirred for 30 minutes at -15 ° C. and for a further * »0 minutes at room temperature. The mixture is then filtered and the filtrate is treated with 5 ml of methanol, stirred for 90 minutes at room temperature and then evaporated under reduced pressure. The residue is chromatographed on a column filled with 12 g of silica gel and eluted with a mixture of benzene and ethyl acetate (19 I 1). The eluate is evaporated. There are 125 mg (52.2 % of theory ) 7β- (3,5-di-tert-butyl-4-hydroxybenzylidene) -amino-3-chloro-7C ^< -methoxy-1-oxa-1- dethia-3-cephem- ¹ <carboxylic acid p-nitrobenzyl ester obtained as a viscous substance.

^{IR! v} max ^{l3 emrl : 1780} ' ¹ ? 35, 1680, 1520,

NMR: 6 ^CDCl 3 ppm: 1.48 (8.1811), 3.6l (s, 3H), k.h9 (s, 2H), 5-23 (s, 25

IH), 5-V »(aromatic H) 8.53 (s, lH).

2) A solution of 125 mg of the 7-methoxy derivative obtained,

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in a mixture of 2.5 ml of methanol and 0.5 ml of tetrahydrofuran 8l mg Girard reagent are added, 1 hour at room temperature stirred, then poured into water and extracted with methylene chloride. The methylene chloride extract is mixed with water

washed, dried and evaporated under reduced pressure. The residue is chromatographed on a column filled with 3.5 g of silica gel and eluted with a mixture of benzene and ethyl acetate (4: 1). There are 35 mg (43 | 8 % of theory ) of the

corresponding 7-amino compound obtained,

CHCl
IR: v _max 3 cm -1: 1790, 17 ^ 0, 1520, 1350.

NMR: δ 3 ppm: 1.83 (bs, 2H), 3-53 (s, 3H), 4.54 (s, 2H), 5.0l (s,

, 8.28 (d, J = 9Hz, lH).

The compounds listed below can be based on the

can be produced in the manner described above:

1-7ß-Amino-l-oxa- & ethia-3-cephem- ¹ l-carboxylic acid-p-nitrobenzyl-

ester;

C ¹ WC ¹ I 1

IR: ^v _max ^{3 cm} : 3 ^ 05, 1772, 1726, 1633, 160 5, 1517, 13 ^ 5-NMR: 6 ^CDCl 3 ppm: 1.74 (b, 2H), k. 6l (m, 2H), 5-O5 (d, J = 4.0Hk,! Η), 5.42 (bs, 2H), 5 · 5 (ηι, 1Κ), 6.6l (m, lH), 7.67 and 8.3l (q »J = 9.0Hz, '» H).

^{7.beta.-Amino-3-methylsulfonyloxy-l-oxa-l-dethia-3-cephem-1} icarbonsäure p-nitrobenzyl ester;
IR: ν ^ ^Χ 3 cm " ¹ : 3 /» 20, 1790, 1735, 1610.

NMR: 0 ^CDCl 3 ppm: 2.15 (bs, 2H), 3-23 (s, 3H), 4.52 (s, 2H), 5-O2 (d,, 5.3O (s, 2H), 5 · 33 (πι , 1Η), 7Λ8 and 8.10 (q, J = 8.OHz, 4H).

7β-Amino-3-phenylthio-1-oxa-1-de thia-3-cephem-'l-carboxylic acid.

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Example 6

1) 2- / 2 §- (2-propinyloxy) -3ß-amino-4-oxo.azetidin-1-yl7-2-isopropylideneacetic acid diphenylmethyl ester

A solution of 0.95 g of 2- (2 | -chloro-3ß-amino-4-oxoazetidinl-yl) -2-isopropylideneacetic acid diphenylmethyl ester in a mixture of 3 ml of propargyl alcohol and 2 ml of tetrahydrofuran is mixed with 0.79 g of C * mmol) Added silver tetrafluoborate, stirred for 3 hours at room temperature, then diluted with 50 ml of benzene, ^{cooled to 0} ° C. and a mixture of 10 ml of 5 percent aqueous sodium bicarbonate solution and 5 ml of saturated sodium chloride solution, stirred and filtered through kieselguhr. The benzene solution is separated from the aqueous phase, dried over sodium sulfate and evaporated under reduced pressure. The brown oily residue obtained is purified by chromatography on 10% water containing silica gel and using a mixture of benzene and ethyl acetate (1: Oeluiert, The eluate is evaporated There are 268 mg of 2 £ -Propinyloxy derivative (13 ¹ I mg 2C * -. Propinyloxy derivative and 13 ^ mg 2ß-propinyloxy derivative) obtained.

The 2 (X-propinyloxy derivative has the following properties:

^{: V} ma _x ³ CB-I. ₃ 40O, 3320, 2115, 1767, 1723-NMR: 6 ^X 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), k. 93 (d, J = LOHz, 1H), 6.9O (s, 1H), 7-32 (s, 10H).

The 2ß-propinyloxy derivative has the following properties:

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CHCl ι

: V _103x 3 cm- ^x : 3Uo, 3320, 2115, 1767, 1720.

NMR: 6 ^CDCl 3 ppm: L77 (brs, 2H), 2.00 (s, 3H), 2.23 (s, 3H), 2.27 (t, J = 2.5Hz, 1H), i | .12 (d, J = 2.5 Hz, 2H), k . 23 (d, J = h .0Hz, IH), 5.27 (d, J = 4Hz, IH), 6.9O (s, lH), 7.32 (s, 10H).

2) 2- £ 2ß- (2-propynyloxy) -3ß-benzyloxycarbonylamino ^J »-oxoazetldin l-yl7-2-isopropylidenessigsäurediphenylmethylester

A solution of 30.0 g (0.07 ¹ J mol) of the 2β-propynyloxy derivative in 250 ml of anhydrous methylene chloride is mixed with 14.07 g (0.0825 mol) of benzyloxycarbonyl chloride and dropwise with a mixture of 6.7 ml ( 0.0825 mol) of pyridine and methylene chloride are added. The mixture is stirred for 30 minutes while cooling with ice, then poured into ice water and extracted with methylene chloride. The methylene chloride extract is washed with water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. The oily residue obtained is chromatographed on 1000 g of silica gel and eluted with a mixture of benzene and ethyl acetate (5: 1). 26.5 g (66.3 % of theory ) of the corresponding 3β-benzyloxycarbonylamino derivative are obtained.

IR: v ^CHCl 3 cm " ¹ : 3 ^ 0, 3300, 2110, 177 *», 1720, I63O, 1507-max

NMR: 6 ^CDC1 3 ppm: 2.00 and 2.25 (s, 3H χ 2), 2.17 (d, J = 3Hz, 1H), 4.07 (d, J = 3Hz, 2H), 5.1o (d, J = ^ Hz, lH), 5-17 (s, 2H), 5.33 (q, J = 8Hz IH), 5.55 (d, J = 8Hz, lH), 6.98 (s, IH).

3) 2- (2ß-Allyloxy-3ß-benzyloxycarbonylamino- ¹ »-oxoazetidine-

l-yl) -2-isopropylideneacetic acid diphenylmethyl ester L-

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A suspension of 6.6 g of 5: ~ percent palladium-on-calcium carbonate in 170 ml of methanol, into which hydrogen has been introduced while stirring, is mixed with a solution of 26.5 g (0.049 mol) of the 3β-benzyloxycarbonylaraino derivative added in 100 ml of methanol. The mixture is stirred in a hydrogen atmosphere for 50 minutes. The catalyst is then filtered off and the piltrate is evaporated under reduced pressure. 26.3 g (98.8 % of theory ) of the 2β-allyloxy derivative are obtained.

^{111: v} ma £ ^{l3 cnrl:} 3 ^ 0, 1772, 1720, 1628, 1505-NMR: 6 ^CDC1 3 ppm: 2.00 and 2.25 (s, 3H χ 2), 3 9θ (ηι, 2Η), 4.8 5 9 (πι, 6Η), 5.17 (s, 2H), 6.95 (s, 1H)

4) 2- £ 2ß- (2,3-epoxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-1-yiy ^ -isopropylidenessic acid diphenylmethyl ester

A solution of 25.6 g (0.047 mol) of the 2β-allyloxy derivative in 26Ο ml of chloroform is used in small portions of 15 »3 g (0.071 mol) m-chloroperbenzoic acid added and 48 hours

left to stand at room temperature (23-25 ° C). The reaction mixture is then evaporated under reduced pressure. Of the The residue is taken up in ethyl acetate, and the ethyl acetate solution with 5 percent aqueous sodium thiosulfate solution, Washed 5 percent aqueous sodium bicarbonate solution, water and brine. After that the solvent is taking distilled off under reduced pressure. An oily residue is obtained which is chromatographed on 800 g of silica gel and eluted with a mixture of benzene and ethyl acetate (5: 1)

L _l

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will. The eluate is evaporated. 21.25 g (81.2 % of theory ) of the corresponding epoxy compound are obtained. IR: v ^ _x ^X 3 cm " ¹ : 3W, 1778, 172 ^, 16 ₃ 2, 1508. NMR: 6 ^CDC1 3 ppm: 2.00 and 2.25 (s, 3H x 2), about 2.2 - 3-9 ( m, 5H), 5.18 (s, 2H), ca 5.0-5-3 (". 2H), 5-58 (d, J = IOHz, IH), 6.83 (s, lH).

2.15 g of diepoxide with a melting point of 118 ° to 120 ° C. are obtained as a by-product.

5) Diphenylmethyl 2-Z2β- (2,3-Dihydroxypropoxy) -3β-benzyloxycarbonylamino- ¹ l-oxoazetidin-1-yl7-2-isopropylideneacetate

A solution of 21.25 g (0.038 mol) of the epoxy derivative obtained in 220 ml of acetone is admixed with 66 ml of 30 percent perchloric acid and ¹ l of ¹ l ml of water while cooling with ice. The mixture is stirred for 2 to 3 hours at room temperature and then extracted with ethyl acetate. The ethyl acetate extract is washed with 5 percent aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. There are (* 9 ^{1 1} "% d. Th.) Was obtained 20.6 g of the corresponding diol.

IR: ν ™ χ ¹ 3 cm " ¹ : 36ΟΟ, 3 ^ 5, 1778,. 1725, 1632, 1508. NMR: 6 ^CDC1 3 ppm: 1.97 and 2.22 (s, 3H χ 2), 3- ^ 7 (m , 4H), k-9 5.3 (n ,, 2H), 5-13 (s, 2H), 6.07 (m, 1H), 6.97 (s, 1H).

Similarly, the 2ß-propionyloxy derivative is made with phenylacetyl chloride converted to the 3ß-phenylacetamido derivative.

L J

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The compound is first hydrogenated, then epoxidized and the epoxy ring is split. The 2- / 2ß- (2,3-dihydroxypropoxy) -3ß-phenylacetamido- ¹ »-oxoazetidin-1-ylJ-2-isopropylideneacetic acid diphenylmethyl ester is obtained»

Example 7

1) 2-Z2ß- (2,3-Isopropylidendioxypropoxy) -3ß-benzyloxycarbonylamino ⁱ l-oxoazetidin-l-yl7-2-isopropylidenessigsäurediphenylmethylester

A solution of 2.5 g of 2- / 2ß- (2,3-dihydroxypropoxy) -3ß-benzyloxy carbonyl ami no- ¹ I -ο xoazetidin-1 -yl7-2-isopropyl idenessigsäurediphenylmethylester in 50 ml of acetone with ice cooling with 5 mg of p-toluenesulfonic acid are added. The mixture is stirred for 3 hours, then a small amount of 5 percent strength aqueous sodium bicarbonate solution is added and the mixture is evaporated under reduced pressure. The residue is taken up in ethyl acetate, the ethyl acetate solution is washed with water, dried and evaporated. The residue obtained is chromatographed on silica gel and eluted with a mixture of benzene and ethyl acetate (2: 1). 2.26 g (84 % of theory ) of the corresponding isopropylidenedioxy derivative are obtained.

^{IR: v} max 3 cm " ¹ : 3 ^ 50, 1780, 1725, I635, I600.

CDCl NMR: δ 3 ppm: 1.28 (s, 6h), 2.00 (s, 3H), 2.25 (s, 3H), 3.25 -

i ».20 (m, 5H), k.90 - 5.77 (m, 5H), 6.95 (s, lH),

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2) 2- £ 2ß- (2,3-Isopropylidenedioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoazetidin-1-yl7-2-hydroxyacetic acid diphenylmethyleeter

A solution of 2.2 g (3 »58 mmol) of the isopropylidenedioxy derivative obtained in 40 ml of methylene chloride is passed in ozone with cooling in a dry ice-acetone bath until the mixture has taken on a blue color. Excess ozone is then separated off and the mixture is mixed with 22 ml of methyl sulfide, left to stand for 1 hour at -60 ° C and a further hour at room temperature. The reaction mixture is then treated with a small amount of acetic acid, washed with water, dried and evaporated 2 g of 1-diphenylmethoxalyl-2ß- (2,3-isopropylidenedioxypropoxy) -3ß-benzyloxycarbonylamino-4-oxoacetldine were obtained. This compound is dissolved in a mixture of 20 ml of methylene chloride and 20 ml of acetic acid, 2 g of activated zinc dust are added and the mixture is stirred for 2 hours while cooling with ice. The zinc dust is then filtered off and washed out with methylene chloride. The filtrate and the washing solutions are combined, washed with water, dried and evaporated. 2.0 g (95 % of theory ) of the corresponding 2-hydroxy derivative are obtained *

CHCI 1

^{331: v} max 3 ^cm s 3500, 3 ^ 30, 1780, 17 ^ 0, 1720, l6oo. NMR: 6 ^CDC1 3 ppm: 1./au7(s.6H), 3 · 17- ^ 3θ (πι, 5-6Η, 5-16 (s, 2H), 4.7O-6.OO (m, 3-4H), 6.97 and 7.00 (s, IH χ 2), ca 7 · 3 («aromatic H).

3) 2- / 2ß- (2,3-isopropylidenedioxypropoxy) -3ß-benzybxycarbonyl-

amino-4-oxoazetidin-l-yl7-2-triphenylphosphoranylideneacetic acid-L. acid diphenylmethyl ester _j

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A solution of 2.0 g (3.4 mmol) of the 2-hydroxy derivative obtained in 60 ml of anhydrous methylene chloride is mixed with 1.3 ml (1.02 mmol) of dimethylaniline and, dropwise, with 0.74 ml (1, 02 mmol) of thionyl chloride were added. The mixture is stirred at the same temperature for 30 minutes and then poured into ice water. The methylene chloride phase is separated off, washed with water, dried and evaporated. There are obtained 2.3 g of 2- £ 2ß- (2,3-isopropylidenedioxypropoxy) -3ßbenzyloxycarbonylamino- ⁱ <-oxoazetidin-1-yl7-2-chloroacetic acid diphenylmethyl ester.

* ¹⁷⁸⁵ » ¹⁷⁵ °» ¹⁷² ° » ¹⁵⁹⁵ '

The compound obtained is dissolved in 40 ml of methylene chloride, and 0.86 ml (6.8 mmol) of dimethylaniline and 1.8 g (6.8 mmol) of triphenylphosphine are added. The mixture is refluxed for 6 hours, then 1.8 g of triphenylphosphine are added, the mixture is refluxed for a further 12 hours and, after cooling, poured into cold 5 percent aqueous sodium bicarbonate solution. The methylene chloride phase is separated off, washed with water, dried and evaporated. The residue is purified by chromatography on silica gel. 1.6 g (56.6 % of theory ) of the corresponding triphenylphosphorane derivative are obtained * IR: ν Jj "^ cm- ¹ : 3 * 100, 176Ο, 1710, I620, 1590.

4) 2- / 2ß- (2,3-Dihydroxyprcpoxy) -3ß-benzyloxycarbonylamino-Ί-oxoazetidine-l-yU ^ -triphenylphosphoranylidenessigsäurel_ diphenylmethyl ester _j

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A solution of 417 mg (0.5 mmol) of the triphenyiphosphorane derivative obtained in 8 ml of methanol is mixed with 1.6 ml of 10 percent hydrochloric acid, ^{stirred for 1} JO minutes at room temperature and then poured into cold 5 percent sodium carbonate solution poured. The mixture is then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel. There are 172 mg of C »3.3 % d. Th.) Obtain the corresponding acetonite-free compound.

v _fflax 3 cm " ¹ : 3 ^ 50 - 3200, 1770, 1720, I630, I600.

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

A solution of 139 mg (0.175 mmol) of the compound obtained in 4 ml of tetrahydrofuran is treated with a mixture of 45 mg of sodium periodate and 2.2 ml of 1N sulfuric acid while cooling with ice. Then the mixture is stirred for 3 hours at 0 ⁰ C and 1 hour at room temperature, then poured into water and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and evaporated. The residue is purified by chromatography on silica gel. 15 mg (17.7 i of theory ) of the title compound are obtained.

This compound is in the thin layer chromatogram, IR and

NMR spectrum identical to an authentic sample produced according to Example 2.

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Example 8

1) 2- £ 2ß- (2-oxoethyloxy) -3ß-benzyloxycarbonylamino- ¹ l-oxoazetidin-ly} 7-2-isopropylideneacetic acid diphenylmethyl ester

A solution of 11.5 g (0.02 mol) 2-Z. "2ß- (2,3-dihydroxypropoxy) ^{-3ß-benzyloxycarbonylamino-1} IO xoazetidin-1-y-1.7-2 isopropylidenessigsäurediphenylmethylester in 200 ml of ethanol with a solution of 5.1 ¹ l g (0.024 mol) of sodium periodate in 210 ml of sulfuric acid, the mixture is stirred for 30 minutes at room temperature, then poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is washed with water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. 10.8 g of the corresponding formyl derivative are obtained,

ir: _V CHC1 _{3 cm} -l. ₃ kk5, 1778, 1725, I632, 1508. max

2) 2- (2β-Methoxycarbonylmethoxy-3β-benzyoxycarbonylamino-4-oxoazetidin-1-yl) -2-isopropylideneacetic acid diphenylmethyl ester

A solution of 10.8 g of the formyl derivative in 100 ml of acetone is at a temperature below 15 ° C with ice cooling and Stirring mixed with 1Ί ml Jones reagent. After 30 minutes it will Isopropanol is added to the reaction mixture in order to decompose excess oxidizing agent. Be insoluble substances filtered off, and the filtrate is poured into ice water and extracted with ethyl acetate. Der.ätthylacetatextrakt is with Washed with water and aqueous sodium chloride solution and reduced

L _j

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evaporated under the current pressure. 11 »1 g of the crude carboxylic acid are obtained. This compound is dissolved in 150 ml of methylene chloride dissolved and treated with a solution of diazomethane in diethyl ether. The solution is then evaporated. The residue (11 g) is chromatographed on 200 g of silica gel and eluted with a mixture of benzene and ethyl acetate (5 ' 1). The eluate is evaporated. 9 »2 g (80.3 % of theory ) of the corresponding methyl ester are obtained.

IR: vj ^ ¹ 3 cm " ¹ : 3 ^ 5, 1780, 1725, 1635, 1510.

NMR: 6 ^CDC1 3 ppm: 2.00 and 2.25 (s, 3H χ 2), 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

3) 1-Diphenylmethoxalyl-ß-methoxycarbonylmethoxy-ß-benzyloxycarbonylamino-ß-oxoazetidine

A solution of 9 »2 g (0.016 mol) of the methyl ester obtained in 230 ml of methylene chloride is treated at -78 ° C with ozone. After about 30 minutes, the reaction mixture turns blue. Then nitrogen is introduced to remove excess ozone to separate. The mixture is at -78 ° C with 10 ml of dimethyl sulfide added, 1 hour at the same temperature and one Stirred for a further hour at room temperature, then mixed with methylene chloride and 2 to 3 drops of acetic acid, washed with water and aqueous sodium chloride solution, dried and evaporated. 8.9 g of the corresponding methoxalyl derivative are obtained as an oil.

cm- ¹ : 345Ο, I830, 1756, 1720, 1509

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4) 2- (2β-Methoxycarbonylmethoxy-3β-benzyloxycarbonylamino-4-oxoazetidin-1-yl) -2-hydroxyacetic acid diphenylmethyl ester

A solution of 8.9 g of the methoxalyl derivative obtained in a mixture of 90 ml of methylene chloride and 90 ml of acetic acid is admixed with 9 g of activated zinc dust while cooling with ice and stirring. After 15 to 30 minutes, the zinc dust is filtered off and the filtrate is treated with methylene chloride, washed with water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. 8.4 g (95.2 % of theory ) of the corresponding hydroxyacetic acid derivative are obtained.
IR: ν ° " ⁰¹ 3 cm" ¹ : 3500 - 3 * 00, 3 ^ 5. 1796, 17 ^ 7, 1512-

OaX

5) 2- (2β-Methoxycarbonylmethoxy-3β-benzyloxycarbonylamino-4-oxoazetidin-1-yl) -2-chloroacetic acid diphenymethyl ester

A solution of 8.4 g (0.015 mol) of the hydroxyacetic acid derivative obtained in 100 ml of anhydrous methylene chloride is added dropwise with 3.34 ml while cooling with ice and stirring (0.046 mol) thionyl chloride and 1.46 ml (0.018 mol) pyridine were added. After that, the mixture is taking another 30 minutes Stirred with ice cooling, then diluted with the appropriate amount of methylene chloride, with water and aqueous sodium chloride solution washed, dried and evaporated under reduced pressure. There are 8.9 g of the corresponding monochloroacetic acid derivative obtain.

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cra-l: 3435, 1790, 17 '·· 8, 1725, 1502.

6) Diphenylmethyl 2- (2β-carbomethoxy-3β-benzyloxycarbonylamino-4-oxoazetidin-1-yD-2-triphenylphosphoranylideneacetate

A solution of 8.9 g (0.015 mol) of the resulting monochloroacetic acid derivative in 100 ml of methylene chloride, 8.0 g (0.03 mol) of triphenylphosphine is added and 90 minutes under Heated to reflux. An additional 2.0 g (7.5 mmol) of triphenylphosphine are then added entered, and the mixture is refluxed for a further hour. After cooling, the reaction mixture becomes Poured into 5 percent aqueous sodium bicarbonate solution, neutralized and extracted with methylene chloride.

The methylene chloride extract is washed with water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. The residue is chromatographed on 300 g of silica gel and eluted with a mixture of benzene and ethyl acetate (4: 1 to 1: 1). The eluate is evaporated. There are obtained 10.2 g (8 ¹ 1.1% d. Th.) Of 2- (2ß-methoxycarbonylmethoxy-3ßbenzyloxycarbonylamino- ¹ l-oxoazetidin-l-yl) -2-triphenylphosphoranylidenessigsäurediphenylmethylester.

** '· ^ ¹ S c " ¹ " ¹ : 3 ^ 5, 1790, 1725, I63O, 1512. NMR: 6 ^CDC1 3 p _pm . 3.58 (5.3 * 1), 3.6-5.2 (m, i | H), 5-07 (s, 2H). 25th

A solution of 16.23 g (20.5 mmol) of the triphenylphosphoranate obtained in 240 ml of tetrahydrofuran is with cooling at 2 to 5 ° C within 30 minutes with II8 ml dropwise

L · -I

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(22.5 ir.Mol) sodium hydroxide solution (0.19 mmol / ml) were added. The mixture is then stirred for 15 minutes, then neutralized with M ml (23 mmol) of 2 percent strength hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and aqueous sodium chloride solution, dried and evaporated. 15.8 g of the corresponding triphenylphosphorane derivative are obtained.
IR: vgS ¹ ^ cm-1: 3W0, 1775, 1725, 1625, 1510.

7) Tß-Benzyloxycarbonylamino ^ -hydroxy-l-oxa-i-dethia ^ - cephem-'l-carboxylic acid diphenylmethyl ester

A solution of 15.3 g (20.3 mmol) of the triphenylphosphorane derivative obtained in 300 ml of anhydrous toluene is admixed with 111.1 g (406 mmol) of acetic anhydride and 8.87 g (102 mmol) of Ν, Ν-methyl acetamide. The mixture is heated at a bath temperature of 100 to 105 ° C. for 16 hours. After cooling, the reaction mixture is diluted with benzene and washed with water, aqueous sodium chloride solution and water again, dried and evaporated under reduced pressure. The residue (about 20 g) is chromatographed on 600 g of silica gel and eluted with a mixture of benzene, ethyl acetate and acetic acid (9: 1: 0.001). The eluate is evaporated. There are 5.08 g ( ¹ per % of theory ) of 3-acetoxy-7ß-benzyloxycarbonylamino-loxa-1-dethla-3-cephem-il-carboxylic acid diphenylmethyl ester (hereinafter referred to as 3-acetoxy compound for short) and 3, 25 g (21.5 % of theory ) 2 -. (2-Benzyloxycarbonyl-3,8-dioxo-5-oxa-2,7-diazabicycloiC ¹ 1.2.Q7octan-7-yl) -2-triphenylphosphoranylidene-

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Acetic acid diphenylmethyl ester obtained as a by-product.

The 3-acetoxy compound has the following properties: IR: v ^ ¹ 3 cm " ¹ : -3445t 1800, 1785, 1725, 1656, 1508.

NMR : 6 ^CDCl 3 ppm: 2.00 (s, 3Il), 4.32 (s, 2H), 5-05 (d, J = / »Hz, 1H), 5.13 (s, 2H), 5.38 (q, J = 4Hz ; 10Hz, lH), 5-68 (d, J = IOHz, IH), 6.95 (s, lH).

The by-product has the following properties: cm " ¹ : 1790, 1778, 1740, 1628.

CDCl
NMR : δ 3 ppm: 3-4 (m, 2H), 4-5 (m, 2H), 5-27 (s, 2H).

3.2 g (5.9 mmol) of the 3-acetoxy compound obtained will be dissolved in a mixture of 60 ml of pyridine and 12 ml of water with cooling. The mixture is 1 3 / Ί hours at room temperature stirred, then poured into ice water and extracted with ethyl acetate. The ethyl acetate extract is treated with 10 percent phosphoric acid, Washed with water and aqueous sodium chloride solution, dried and evaporated under reduced pressure. It will 3.05 g of the corresponding 3-hydroxy compound were obtained as a white foam.

IR: v ^ ax ¹³ cm " ¹ : 3M0, 1795, 1725, 1675, 1510. NMR : 6 ^CDCl 3 ppm: 4.37 (sJ2H), 5-05 (d, J = 4Hz, 1H), 5.18 (s , 2H), 5 x 45 (q, J = IOHz, IH), 5 x 72 (d, J = IOHz, IH), 7.00 (s, 1H), 10.83 (s, 1H).

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

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Claims (1)

vossius ^ ossiijs · η; L τ L PATENTS ^- LAWYERS SIEBERTSTRASSE 4 8ΟΟΟ MUNICH ββ - RHONE: (Οθβ) 47 «Ο 7S CABLE: BENZOLE PATENT MUNICH ■ TELEX 5- · -> β453 VOPAT D u.z .: M 305 (Vo / ko) August 5, 1977 Case: P 30 * 19 TW SHIONOGI & CO., LTD.
Osaka, Japan "yß-Araino-l-oxadethiacephalospcrine ⁿ Priority: 5.8.1976, Japan, No. 93 809/76 Claims 1. 7β-Amlno-1-oxadethiacephalosporine of the general formula I. X ^ »2 in which R is a hydrogen or halogen atom, a lower one Alkoxy radical, a sulfonyloxy or arylthio group or a ρ monocyclic heterocyclothio radical, R a carboxyl group or their functional derivative and R ^ is a hydrogen atom or a methoxy group, and their salts. 2. Compounds according to claim 1 of the general formula 709886/0986 in which X represents a halogen atom or a sulfonyloxy group and R has the meaning given in claim 1, and its salts 3 · Compounds according to claim 1 of the general formula in which R has the meaning given in claim 1, and its salts *
15th 4, compounds according to claim 1 of the general formula .0. in which Y is an arylthio group or a monocyclic hetero- represents rocyclothiorest and R has the meaning given in claim 1, and their salts. 5 * Compounds according to claim 1 of the general formula 25th 3 2 in which Z represents a lower alkyl radical and R represents in 709886/0986 Claim 1 has the meaning given, and its salts. 6. Compounds according to claim 1 of the general formula 1 2 in which R and R have the meaning given in claim 1, and their salts.
10 7 «7 [beta] -amino-3-chloro-1-oxa-1-dethia-3-cephem- ¹ <-carboxylic acid 8. 7.beta.-amino-l-oxa-l-dethla-3-cephem-l-carboxylic acid ^i. 9. 7β-Amino-3- (1-methyltetrazol-5-yl) -thio-1-oxa-1-dethia- ¹ »-carboxylic acid. 10. 7β-Amino-3-methoxy-1-oxa-1-dethia-3-cephem- ¹ 1-carboxylic acid. 11. 7.beta.-amino-3-chloro-'itx-niethoxy-l-oxa-l-dethia-3-carboxylic acid cephein- ⁱ l-p-nltrobenzylester. 12. A process for the preparation of the compounds according to claim 1, characterized in that it is known per se ter way either a) a compound of the general formula 7098BR / 0986 RNH 12th In which R represents an amino protecting group and R, R and R the have the meaning given in claim 1, which subjects to hydrolysis or b) for the production of 7o (-Me thoxy compounds of the general formula 1 in which R and R have the meaning given in claim 1, a compound of the general formula R ² methoxylated. ^L 7098BB / 0986