FI68838C - SOM MELLANPRODUKT VID FRAMSTAELLNING AV 7ALFA-METOXI-1-OXADETIACEPHALOSPORINER ANVAENDBARA (1R, 5S) -7-OXO-4-OXA-2,6-DIAZABICYCLO (3.2.0) HEPT-2-EN-FOERENINGAR - Google Patents

Description

1 68838 Intermediate (1R, 5S) -7-oxo- * J-oxa-2,6-diazabicyclo D.2.Ö used as an intermediate in the preparation of V'q-n.ctokci-1-oxadothiacephalosporins hept-2-ene compounds - Somellanproduct of a compound of 7c * -methoxy-i-oxadethiacephalosporin and 5 (1R, 3S) -7-oxo-z <-oxa-2,5-diazabicyclo (3.2. Ojhept) This invention relates to (1R, 5S) -7-oxo-1H-oxa-2,6-diazabicyclo [3.2.03] hept-2-ene compounds which are useful intermediates in the treatment of bacterial anti-bacterial compounds. hydrogen or for the preparation of 7α-methoxy-1-oxadethiacephalosporins.

The compounds of the invention can be represented by the following formula.

R

ie O

wri 1

^ ^ OH -NZCH

wherein R is methyl, benzyl, phenoxymethyl or phenyl, which may be substituted by halogen, methyl, methoxy, nitro or cyano, and Z is a divalent group of formula

CH_ CH

H 2 I 3 ^ -CHC- or -C = C-

COB iOH

wherein COB is carboxy or carboxy protected with benzyl, nitrobenzyl or diphenylmethyl.

Compounds of formula I may be prepared, for example, from compounds of formula II

R

-55 *. Z

”H -p- * H

^ -JJ-z ch2ic

II

2,68838 wherein X represents acyloxy, nitroxy, phenylsulfonyl, chlorine or bromine such that a compound in which X represents acyloxy or nitroxy is hydrolyzed to a compound in which X represents hydroxy; 5 a compound in which X represents phenylsulfonyl is treated with an oxidant, e.g. peracid, to produce a compound in which X represents phenylsulfinyl, followed by heat transfer to a compound in which X represents phenylsulphenyloxy, followed by reduction to a compound in which X represents hydroxy; or a compound in which X represents chlorine or bromine is treated with sodium iodide to prepare a compound in which X represents iodine, followed by treatment with heavy metal salts (e.g. silver nitrate, trifluoroacetate, copper acetate, lead acetate, copper nitrate), alkali metal perchlorate, thio compounds. thiourea, alkylthiourea) to give a compound in which X represents hydroxy or acyloxy (especially nitrooxy), the latter being hydrolysed with e.g. a base to remove the acyl group to give a compound in which X represents hydroxy.

During the above reactions, sometimes double bond transfer or isomerization can occur. This is also part of the invention.

Compounds II can be prepared from epipenicillin-1-oxides III by sequentially ring opening and re-ring formation according to the following reaction formula: RCO-1H? CH X f \ .S / 2X l.

'- ^ Y O

O'— «y 'CH3 - * - Menee; - ·: <o ^

35 COU

III ΓΙ

II

3,68838, provided that the bonds S + 0 and C-CH 2 of compound III are in the cis positions, and by optionally isomerizing compound II to compound IIa, T / UCH, IIa! h -) - pH, 3 -NCeCCH 2

COB

The starting compounds III can be prepared according to methods analogous to those described in the Journal of the Chemical Society, Perkin I, 1973, 932 and Tetrahedron Letters, 1973, 3001.

The preparation of the compounds of the formula 11 is described in detail in patent publication FI 67 531.

Compounds of formula II in which X is chlorine or bromine can also be prepared by halogenating compound II prepared in a manner analogous to the preparation of compound II.

20 R

* P i?

Hb

TT

25 O ** - ä-Z-CHj

The β-oxazolinoazetidinones of the formula I are previously known, for example, from DE 2 356 862 and J. Chem. Soc. Perkin I, 197 * 1, 181 and 1975, 883. However, from these compounds it is not possible to prepare optically pure 7α-hydrogen or 7α-methoxyoxadethiacephalosporins. Also from Can. J. Chem. The method known from 52 (197 * 1) 3996 is not very useful for obtaining these compounds in pure form.

The compounds of the invention may be used as intermediates in the preparation of antibacterial 1-oxa-i-detiacephalosporins of the following formula IV:

It 68838 OCHj r'cohhJ.

_ COOH

5 IV

wherein R'CO is a cephalosporin or penicillin side chain acyl Η; 10 X 'is hydrogen or is known in cephalosporin chemistry, the so-called a nucleophilic group as a substituent on the 3-methyl group. Several of these compounds are described, e.g., in U.S. Patents 4,013,653, 4,138,486, 4,183,928, 4,226,864, and 4,226,866.

From the compounds of formula I, compounds of formula IV can be obtained, for example, according to the following reaction formula: OCH-KVfN-- o ^ PvjXh-o ^ Yc, ^.

-NZCH-, ΟΗ COB * C00H

J £ IV

If necessary, the group R can be changed to R · at some suitable stage.

The compounds of the invention can be used to prepare the desired 1-oxadethiacephalosporins in high yield due to the fact that 6-epioxadethiacephem compounds are not formed in the reaction mixture as much as in known processes involving about 0.5 to 0.3 parts of epimer and due to the formation of lower amounts of other by-products compared to previous methods, for example those described in the above-mentioned publications.

The following examples illustrate the invention in more detail. Examples 1-3 show the preparation of compounds II and Example 4 their use.

5,68838 (1R, SS) -7-oxo-4-oxa-2,6-diazaticyclo [J. 2. The numbering used in the examples of the CTJ bept-2-ene backbone is shown below.

i 5 3 2 N 2 -P 11 1 H> 5 O * - \ ~ 10 7

Stereochemistry of carbon atom no. 1 is identical to the stereochemistry of 6-epipenicillin at position 6 and carbon atom no. Around 5, it is inverted relative to the penicillins at position 5 and the cephalosporins at position 6.

The stereochemistry around α-carbon bound to COBthen is essentially the same as that of penicillins, but is not limited to it.

The experimental errors in the IR spectrum are ± 10 cm -1 and in the NMR spectrum ± 0.2 ppm. Melting points are uncorrected.

The physical constants of the products are given in Table II.

25 The following abbreviations are used in the examples:

An acetone DMSO dimethyl sulfoxide

Ph phenyl rt room temperature 30 t- tertiary- 6 68838

Example 1

Ph Ph m ^ o> r ^ o

\ —I * 5H2 n ~ CPBA_ ^ \ / CH O

5 o ^ "NpCCH2SPh —NCHCCH2SPH

COOCHPh2 COOCH? H2

Ph ch3oh 1 10 Ph p ιτ> 3 W 9Η2

- ^ q <J-NCHCCH2OH

COOCHPh2

To a solution of 703 mg of diphenylmethyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl) -3 -phenylthiomethyl 3-butenoate in 14 ml of chloroform, a solution of 220 mg of m-chloroperbenzoic acid in 7 ml of chloroform is added dropwise and the mixture is stirred for 10 minutes, the mixture is stirred with 700 mg of triphenylphosphine and 70 with methanol and boiled under reflux with heating at 75 ° C. When the reaction is complete, the mixture is evaporated under reduced pressure. The residue is chromatographed on a 30 g column of silica gel deactivated with 10.55 g of water and eluted with a Bent-25 fungus containing 20-30% of ethyl acetate and the eluate containing the desired product is evaporated to give 401 mg of diphenylmethyl- ( 2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo (1,2,2,3hept-2-en-6-yl) -3-hydroxymethyl-3-butenoate in yield 68%.

30

Example 2

Ph Ph JL J.

V nH2 S1 ° 2 <1 / C „a 35 o ^ -M? HCCH2OCOCP, CH-Cl, -CH, OH O ^ HgHCCH ^ H COOCUPh2 * 3 COOCH? H2 11 ^ 68838

To a solution of 240 mg diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl) -3-trifluoroacetyloxymethyl -3-butenoate in 10 ml of a mixture of methanol and methylene chloride (4: 1), 4.8 g of silica gel containing 10% of water are added and the mixture is stirred for 30 minutes and filtered. The filter cake, silica gel, is washed several times with a mixture of methanol and methylene chloride. The combined filtrate and washings are evaporated under reduced pressure, the oily residue is chromatographed on 12 g of silica gel. Elution with a mixture of benzene and ethyl acetate (2: 1) gives 106 mg of diphenylmethyl- (2R) -2- (3'-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [j.2.2.0] hept. 2-en-6-yl) -3-hydroxymethyl-3-butenoate in 53 S yield and 90 mg of starting material in 35% recovery ·

Example 3

Diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oca-2,6-20-diazabicyclo [3.2.03] hept-2-en-6-yl) -3-iodomethyl-3-butenoate is obtained react with calcium carbonate and silver nitrate to give diphenylmethyl- (2R) -2- (3'-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.2] hept-2-ene-6- yl) -3-hydroxymethyl-3'-butenoate and diphenyl-methyl- (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.2] hept-2-ene-6 -yl) -3-nitroxymethyl-3-butenoate (1: 3) dissolved in 4.5 ml of methylene chloride. To the solution prepared above is added dropwise 0.5 ml of acetic acid and the mixture is stirred with 300 mg of zinc, stirred for 15 minutes at 0 ° C, diluted with methylene chloride, washed with water, dried and evaporated. The residue is purified by thin-layer chromatography to give 90 mg of diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.1] hept-2-ene-35 6- yl) -3-hydroxymethyl-3 ~ butenoate.

Similarly, other compounds of formula I may be prepared under the conditions set forth in Table I below.

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00 CJ CO. — S O M O r-N '-e CJ CJ O

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CO O, -. o O «« CJ O | M sr '—- 3 O O O CO m-n «

C - 'rM «· 00 ·» · »m-n» sr CO -— s— N— f'- r-i O

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O ON / -N

ON ιΛ · Λ σι M. O o / N ON ON 1/1 · »« M lo m m lo m * o o r-c

M N · _ M "N * ·» · MN N M / N ΛΝ CO N— NM NM

* M, M r-N> M O O O .M O O rM CO NM OO O

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M \\ I I (- »I 4J NM NM NM« nm NM MN -— 'NM NM NM Q NM NM NM NM MN ιΜ Λ NM

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MmnCOCSCSCSCSCSCSCNCS CSOlOOOOCOrHO 1 + · H HO ** ·· * ··· «« «« »« »« »» n

L — OOOOOOOOO O-MOOOOOCOO O

cs

H O

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M

CS I CS

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I I M

o j «! a je aa 3 · μ a = :::: = = = = = =: r :: aro rs aa, <s es 3 aa

cd CJ CJ

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3 w oo ^ ® # -i »« - · «o * -« O ^ H

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n X m X m · o X n X n X * o rs es X n X

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Sr M · «« k .O «k · · *» X

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S o o e n i - o m eo a * o m m p o o J

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Ps 5 — S Q “i, -Jn £ s s i rk ί! O! j S 3 j “δα n i i sF i l —1 ·“ * r

x x x x x xx x x X

X o o o o o oo o o o I I I I I T I I · 1

• U

I and J3 rs

Oi P »B. JC

x r * «^ SJ = = = = = = es u * δ 8 Ö

Xl I I I

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-¾ ^ - - * es ° «s x" X

—I 55 VO X X io n <0 * o 3 o4U. u ö G o O O u <D Xl I lllll H ______ 10 68838

Example 4 Ph

* H

»· *> PhCONH ..? _ {L

't-ι ·· * h2 —-—- »jcCl b 0 ^ -HCHCCH2OH -> COOCHPh2 COOCHPh- • · ^ OCH,

PhCOHK * ^ OCHj 2 = JJk c “” * 4- ^ 1 _ L:; r • '^ tvq

^ COOH

A. To a solution of 950 mg of crude diphenylmethyl (2R) -2- (3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [0.5.2] hept-2-ene- 6-yl) -3-hydroxymethyl-3-butenoate in 15 ml of methylene chloride, 20 μΐ of boron trifluoride etherate are added at room temperature and the mixture is stirred for 1.5 hours at the same temperature and evaporated. The residue is chromatographed on 30 g of silica gel.

Elution with a mixture of benzene and ethyl acetate (4: 1) gives 0.686 g of diphenylmethyl 7a-benzamido-3-exomethylene-1-oxadethiacepham-4a-carboxylate as a foam in a yield of 8%.

(This can, if desired, be isomerized with triethylamine-30a to give diphenylmethyl 7a-benzoylamino-3-cephem-4-carboxylate) B. To a solution of 101 mg of diphenylmethyl-7a-benzamido-3-exomethylene-1-detia-1- oxacepham-4α-carboxylate in 1 ml of dichloromethane cooled to -25 ° C, 0.84 ml of a 0.8 M solution of chlorine in carbon tetrachloride are added and the mixture is stirred for 120 minutes. To the reaction mixture containing the diphenylmethyl-7α- (N-chlorobenzamido) -3-exomethylene-1-detia-1-oxacepham-4α-carboxylate thus formed is added 0.52 ml of 2 M lithium methoxide. a solution in methanol and the whole mixture is cooled to -50 to -60 ° C with stirring for 10 minutes, 0.2 ml of acetic acid are added, poured into ice water and extracted with dichloromethane. The extract is washed with dilute aqueous sodium hydrogen carbonate and water, dried and evaporated to dryness. The residue contains 95 mg of diphenylmethyl 7β-benzamido-7α-methoxy-3-chloromethyl-1-detia-1-oxa-3 'k-10 femi-β-carboxylate, yield 83% · C. Diphenylmethyl 7B prepared according to B p-Benzamido-7a-methoxy-3-chloromethyl-1-detia-1-oxa-3-cephem-1-carboxylate is dissolved in 3 ml of dichloromethane with stirring with 50 mg of sodium 1-methyltet-15 Razole-5-mercaptide and 30 mg of tetrabutylammonium bromide in 3 ml of water for 1 hour at room temperature The reaction mixture is poured into ice water, extracted with dichloromethane, washed with water, dried and evaporated to give about 100 mg of pure silica gel column chromatography. 7β-Benzamido-7α-methoxy-3- (1-methyltetrazol-5-ylthio) methyl 1-detia-1-oxa-3-cephem-U-carboxylate.

Claims (4)

68838 12 1. (1R, 5S) -7-Oxo-4-oxa-2,6-diazabicyclo [3.2.2] octab-2-ene compounds used as intermediates in the preparation of antibacterial 7α-methoxy-1-octadeacephalosporins, known for the formula R -f- * io. ¢ 0-HZCH2 ° H wherein R is methyl, benzyl, phenoxymethyl or phenyl which may be substituted by halogen, methyl, methoxy, nitro or cyano, and Z is a divalent group of formula CH2 5M3 -Ch {1 - or - C * C-COB COB 20 wherein COB is carboxy or carboxy protected with benzyl, nitrobenzyl or diphenylmethyl. A process for the preparation of compounds of formula I wherein R is methyl, benzyl, phenoxymethyl or phenyl which may be substituted by halogen, methyl, methoxy, nitro or cyano, and Z is a divalent group of formula CH 8 CH 12 I 3 -CHC- or -C * C-COB tOB 68838 13 characterized in that either a) a compound of formula R 5 N. ^ ~ 9 II • · • _ · oJJH3-Z-CH2> t wherein R and Z have the meaning given above, and 10 X is acyloxy, preferably trifluoroacetyl, or an inorganic acid residue, preferably nitro, or that b) a compound of formula R 15 • · m ANZ-CH 3 PS 2 20 in which R and Z have the meanings given above, is preferably oxidized with peracid, first to the corresponding phenylsulfinyl compound and then converted by heating to the corresponding phenylsulphenyloxy compound which is reduced. ν 'ΐ4 6 8 8 3 8