CA1065852A - PROCESS FOR PREPARING 7.beta.-ACYLAMINO-7.alpha.-ALKOXYCEPHALOSPORINS OR 6.beta.-ACYLAMINO-6.alpha.-ALKOXYPENICILLINS - Google Patents
PROCESS FOR PREPARING 7.beta.-ACYLAMINO-7.alpha.-ALKOXYCEPHALOSPORINS OR 6.beta.-ACYLAMINO-6.alpha.-ALKOXYPENICILLINSInfo
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- CA1065852A CA1065852A CA321,402A CA321402A CA1065852A CA 1065852 A CA1065852 A CA 1065852A CA 321402 A CA321402 A CA 321402A CA 1065852 A CA1065852 A CA 1065852A
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- carbon atoms
- cephem
- acid
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Abstract
A B S T R A C T
7.beta. -Acylamino-7.alpha. -alkoxycephalosporins and 6.beta. -acylamino-6.alpha. -alkoxypenicillins are prepared by hydrolysing a 6.alpha. - or 7.alpha. -alkoxy-keteneimine penicillin or cephalosporin compound.
7.beta. -Acylamino-7.alpha. -alkoxycephalosporins and 6.beta. -acylamino-6.alpha. -alkoxypenicillins are prepared by hydrolysing a 6.alpha. - or 7.alpha. -alkoxy-keteneimine penicillin or cephalosporin compound.
Description
06~8S~ ~ ~
Many cephalosporin and penicillin derivatives having antibiotic properties are known, the first of these to be dis-covered having various substituted acetamido chains at the 7 or 6~ positions and being unsubstituted at the 7~ or 6~ positions, respectively. More recently, however, it has been discovered that various 7~- or 6~-alkoxy derivatives of these compounds are also valuable antibiotic substances.
Of the known methods of introducing an alkoxy group into the 7- position of a cephem ring or the 6-position of a penam ring alkoxylation with t-butyl hypochlorite and lithium alkoxide is simplest to perform and gives best yields [R.A. Firestone and B.G.
Christensen, J. Org. Chem. 38, 1436 (1973); G.A. Koppel and R.E.
Koehler, J. Amer. Chem. Soc. 95, 2403(1973)]; however, this method has the disadvantage that it is not applicable to cephalosporins or penicillins which are sensitive to t-butyl hypochlorite, i.e.
which have an anion formation centre in the side chain at the 7-or 6- position.
We have now discovered a process for preparing certain 7~-acylamino-7~-alkoxycephalosporin or 6~-acylamino-6~-alkoxy-penicillin derivatives which are useful as antibacterial agentsand some of which may also be used as intermediates in the pre-paration of other, but more ~aluable, antibacterial agents.
~ ' ',.', :
~
,, ' ~ .
' -- 1 -- . .
1C1658S;~
The present invention relates to a process for the pre-paration of derivatives of the ~-lactam antibiotics i.e. the cephalosporins and penicillins, and specifically to the prepara-tion of 7~-acylamino-7a-alkoxycephalosporins 6~-acylamino-6a-alkoxypenicillins and certain intermediates in said process.
The cephalosporin derivatives referred to in the present specification are named with reference to cepham, which has the structure:
~ N
O ,~
as described in J. Amer. Chem. Soc. 84, 3400 (1962), the corres-ponding unsaturated compounds being referred to as "cephems" and the position of the unsaturation being indicated by a numeral e.g. 3-cephem.
The penicillin derivatives re~erred to in the present specification are named as derivatives of penicillanic acid, which has the formula:
\~CH3 ~6 15 2 ~ ~3 N4 ~
COOH
~ 2i~2 ~
The compounds which may be prepared by the process of the present invention have the formula (I):
R oR3 C - C NH - S ~ ~
R H O ~ ~ J ~ ~:
wherein Rl represents a hydrogen atom, a halogen atom, an alkyl : group having from 1 to 4 carbon atoms or an aryl group; R2 repre- ;.
sents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, and aryl group, an alkylthio group having from 1 to 4 carbon atoms, an alkynylthio group having from 2 to .
4 carbon atoms, an arylthio group, an azidoalkylthio group having ;
from 1 to 4 carbon atoms, a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety, an alkylsulphonyl group hav-ing from 1 to 4 carbon atoms, a 5- or 6-membered heterocyclic group, a 5- or 6-membered heterocyclic-thio group, or 1 5- or 6- .: :
membered heterocyclic-oxy group;. R3 represents an alkyl group having rom 1 to 4 carbon atoms; and Z represents a fragment of forrnula: ~ ~ CH3 :
~ or ~ CH3 ¦ CH2A R4 wherein R4 represents a carboxyl group, an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, a haloalkoxy- :
carbonyl group having from 1 to 4 carbon atoms in the alkyl moiety a benzyloxycarbonyl group which is ~:.
.:.
',''''"
_ 3 _ ~ 65~
unsubstituted or has one or more halogen, methoxy or nitro sub-I stituents, a diphenylmethoxycarbonyl group, a trialkylsilyoxy-¦ carbonyl group having from 1 to 4 carbon atoms in each alkyl moiety, a dialkylhalosilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiety a phenacyloxycarbonyl group which is unsubstituted or has one or more halogen or nitro sub-stituents, an acyloxycarbonyl group, a haloacyloxycarbonyl group, a dihalophosphinoxy-carbonyl group, a dialkylphosphinoxy-carbonyl group or an aminocarbonyl group; and A represents a hydrogen atom, an azido group or a group of formula -B-E wherein B represents an oxygen or a sulphur atom and E represents an acyl group, an alkyl group having from 1 to 4 carbon atoms or a substituted or unsub-stituted carbamoyl, thiocarbamoyl or heterocyclic group.
In this formula (I), Rl is a hydrogen atom; a halogen atom ~e.g. chlorine, bromide or iodine); an alkyl group having rom 1 to 4 carbon atoms (e.g. methyl~ ethyl, n-propyl, isopropyl or n-butyl); or an aryl group (e.g. phenyl or naphthyl). R is preferably: a hydrogen atom; a halogen atom (e.g. chlorine, bromide or iodine); or an alkyl group :
i 1~ E;5~35~
having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isohutyl or t-butyl); an aryl group (e.g.
phenyl or naphthyl); an alkylthio group having from 1 to 4 carbon atoms ~e.g. methylthio, ethylthio, n-propylthio or isopropyl-thio): an alkynylthio group having from 2 to 4 carbon atoms (e.g. propargylthio); an arylthio group (e.g. phenylthio); an azidoalkylthio group having from 1 to 4 carbon atoms (e.g. azido-methylthio or azidoethylthio); a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety (e.g. cyanomethylthio or cyanoethylthio); a 5- or 6- membered heterocyclic-thio group containing one or more sulphur and/or nitrogen and/or oxygen atoms in the ring and which may be substitutea by an alkyl group having from 1 to 3 carbon atoms (e.g. imidazolythio, thiadiazolyl-thio, triazolylthio, thienylthio, isoxazolylthio, methylisoxazolyl-thio, tetrazolylthio, methyl-tetrazolylthio, pyrimidinylthio or pyridylthio); a 5- or 6-membered heterocyclic-oxy group contain-ing one or more sulphur and/or nitrogen and/or oxygen atoms in the ring and which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. isoxazolyloxy methylisoxazolyloxy, imidazolyloxy, thiadiazolyloxy, triazolyloxy, thienyloxy, tetra-zolyloxy, methyltetrazolyloxy, pyrimidinyloxy, or pyridyloxy);
a 5-'':.,'-' ~365~3S2 ! or 6- membered heterocyclic group containing one or more sulphur and/or nitro~en and/or oxygen atoms in the ring and which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. thienyl, imidazol, thiadiazolyl, isoxazolyl, methylisoxa-zolyl, tetrazolyl, methyltetrazolyl, pyrimidinyl or pyridyl); or an alkylsulphonyl group having from 1 to 4 carbon atoms (e.g.
methylsulphonyl, ethylsulphonyl, or n-propylsulphonyl). R3 is an alkyl group having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl). R4 is a carboxyl group or a protected carboxyl group such as an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety ~e.g. methoxycar-bonyl, ethoxycarbonyl, n-propoxycarbonyl or n-butoxycarbonyl), a haloalkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety (e.g. dichloroethoxycarbonyl or trichloroethoxy-carbonyl), a benzyloxycarbonyl group optionally substituted with halogen, methoxy or nitro (e.g. benzyloxycarbonyl, ~ chloro-benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxy-carbonyl), a diphenylmethyloxycarbonyl group, a trialkylsilyloxy-carbonyl group having from 1 to 4 carbon atoms in each alkyl moiety (e.g. trimethylsilyloxycarbonyl or triethylsilyloxycar-bonyl), a dialkylhalosilyloxycarbonyl group having ~rom 1 to 4 carbon atoms in each alkyl moiety (e.g. dimethylchlorosilyloxy-carbonyl or dimethylbromosilyloxy~arbonyl), a phenacyloxycar-bonyl ~roup optionally substituted with halogen or methoxy (e.g.
~65~S2 ~-chlorophenacyloxycarbonyl, p-bromophenacyloxycarbonyl or ~-methoxyphenacyloxycarbonyl), an acyloxycarbonyl group (e.g.
acetoxycarbonyl or benzoyloxycarbonyl), a halo-acyloxycarbonyl group (e.g. chloroacetoxycarbonyl or bromo-acetoxycarbonyl), a dihalophosphinoxycarbonyl group (e.g. dichlorophosphinoxycarbonyl or dibromophosphinoxycarbonyl), a dialkylphosphinoxy carbonyl group (e.g. dimethylphosphinoxycarbonyl), or an aminocarbonyl group (e.g. 3-oxo-2,3-dihydro-s-triazoloE4,3-a]pyridon-3-ylcar-" bonyl. ~ is preferably: an acyl group (e.g. acetyl, propionyl or benzoyl); a carbamoyl group; or a 5- or 6- membered hetero-cyclic group, which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. tetrazolyl, l-methyltetrazolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, thienyl, thiadia-zolyl, methylthiadiazolyl, pyrimidinyl or pyridyl).
In accordance with the invention which is the subject of our application No. 222,728, compounds of formula (I) are pre-pared by reacting a halo-imine of formula (II):
.
Rl H
C C = N ~ ____-S
yl y O N V
"' .
: ' " ' . ' " :' -(in which Rl, R2 and Z are as defined above and yl and Y are the same or different and each represents a halogen atom) with an alkali metal alkoxide of formula (III):
R30M (III) (in which R3 is as defined above and M represents an alkali metal) to give an alkoxyketeneimine of formula (IV): -Rl OR
C = C = ~ (IV) N Z
0~
(in whi.ch Rl, ~2 and Z are as defined above) and/or a dialkoxy-imino compound of formula (V):
. ' 658~;i2 3~t oR3 R ¦ ~R3 f ~ IV) (in which Rl, RZ, R3 and Z are as defined above), and hydrolizing said alkoxyketeneimine (IV) and/or reac-ting said dialkoxyimino compound (V) wi-th a halo- ;
silane or an acid and treating the resul-ting product with water.
The process which is the subject of the present invention is the preparation of a compound o~ formula by the hydrolysis of an alkoxyketeneimine of 10 formula (IV). The al-ternatlve route to a compo~d o~
formula (I) via a dialkoxyim.ino compound (Y) is the ~ 1,403 sub~ec-t o~ our copending application~o:E even date.
~..
The first stage in the reaction of the halo-imine - (II) with the alkali metal alkoxide (III) to form the lS allcoxyketeneimine (lV) and/or the dialkoxyimino compound (V) is the dehydrohalogenation of halo-imine(II). This reaction must, therefore, be carried out in the presence of an acid-binding agent, i..e. a base. If desired, the , I . . . .. . .:
~ 8S 2 base may be provided by -the alkali me-tal alkoxide (IrI) or, alternatively, another base may be used. Preferably, the base is employed in an amount of at leas-t 1 equivalent per mole of halo-imine (II) and more 5 pre~erably about l equivalen-t is employed. The course o:E the subsequent reaction depends upon -the relative proportions of alkali metal alkoxide and halo-imine(II).
Where the amount of alkali metal alkoxide (excluding -tha-t, if any, employed as acid-binding agent in the preceding 10 stage) i~ about l mole per mole of halo-imine(II), the product o~ the reaction is predominantly the alkoxy-; keteneimine(IV) as recluired for use in the process o~ the present invention. On the other hand, if the amount of alkali metal alkoxide is about 2 moles per mole 15 of halo-imine(II), the dialkoxyimino compound(V) is the predominant produc-t. Wnlere the amoun-t of alkali metal alkoxide is between 1 and 2 moles per mole of halo-imine(II)~ a mixture of alkoxyketeneimine(IV) and dialkoxyimino compound(V) will be obtai~ed.
20 Although the presence o~ excess alkoxicle will have no adverse ef~ec-t, it is not bene~icial ancl, accordingly, we pre~er to employ about 1 mole of alkoxicle per mole of halo-imine(II) in order to produce predominantly alkoxyketeneimine(IV) (2 moles of alkoxide per mole of 25 halo-imine(II) will produce predominantly dialkoxyimino compound(V)).
~`
. , .
, 5~ 52 The halo~imines of fo.rmula (II) are themsel~Tes new compounds. They ma.y be prepared by reacting an acylamino compound of formula(VI) R/
~y~
~in which Rl, R2 and Z are as de~ined above and X
represents a hydroxy group or a halogen atom) with a halogenating agent.
The reactions of which the process of the present invention forms part may be illustrated by the 10 following reaction scheme:
.,, _ A. .
~6S~3152 R2/l 11 IIH j~ halog~na~e (Y~) . .
Rl H
(Il) \C--C
b~J'-- ~ 2~C= Ic_y~
(VII) 3 .
_~ \C~-~ N ~R ~ S~
(-MY) R2/ F 2 3 , ' ' (~Y) ~~
\C-C=~L~S\
/halosilan~ :
/ acid Rl OR~ ~ ~H20 R~ B o~ (I) 12- .
9 (;~65852 Thus9 in -the first step of -the overall process forming th* subject o~ our said a~plication No. 222728, halo~imine (I]:) is prepared by reacting acylamino compound(VI) wi-th a halogenating agent. Examples of haloge~ating 5 agents are: phosphorus pen-tahalides, e.g. phosphorus pentachloride or phosphorus pentabromlde; phosphorus trihalidesg e.g. phosphorus trichloride or phosphorus tribromide; phosphorus oxyhalides, e.g. phosphorus oxychloride or phosphorus oxybromide; and thionyl 10 halides, e.g. thionyl chloride or thionyl bromide.
Of these, phosphorus pentachloride is most preferred.
The halogentation reaction is suitably carried out in an anhydrous iner-t organic solvent, with stirring, at a temperature from -50C to 40C. The reaction time is 15 not critical, but the reaction will normally be complete within a period from 15 minutes to 5 hours. Suitable inert organic solvents are chloroform, methylene chloride, benzene, die-thyl ether, tetrahydrofuran and dioxane.
The reaction is prePerably e~fected in the presence o~
20 a tertiary amine, such as quinoline, diethylaniline, dimethylaniline, pyridine, tri.ethylaminc or diazab:lcyclo-octane.
When the halogenation reaction is complete, the react;ion mixture, including compound (II), may be used 25 as such as the starting material in the next step;
alternatively, the compound(II) may be reco~ered and purified by conventional means.
: `:
~)6585;~
Where ~4 in the acylamino startin~ material(V) is a carboxyl group, it shouJ:cl:Lirst be protected, by metl1ocls which are well understood in -the art. I~ X
in the star-ting ma-terial represents a hydro~y group, the halogenation reaction causes it -to be replaced by a halogen atom.
Alkoxyketeneimine(IV) is prepared by reacting haloimine(II) with one mole o~ al~ali metal alkoxide(III) in the presence of one equivalent of base, per mole o~
10 halo-imine. Examples of alkali metal alkoxides inGlude: lithium methoxide, lithlum e-thoxide, sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide. The base employed may be, and pre~erably is, simply an excess o~ the alkali metal 15 alkoxide(III). Alternatively, it may be: an inorganic base, such as an alkali metal hydroxide te.g. sodium hydroxide or potassium hydroxide), an alkali metal carbonate (e.g. sodium carbona~e or potassium carbonate), or an alkali metal hydride (e.g. sodium hydride or 20 potassium hydr~.de), or a tertiary amln~, such as a t~ialkylamine (e.g. trimethylamlne or triethylamine), a dialkylaniline (e.g. dimethylaniline or diethylaniline), pyridine, quinoline or diazabicyclooctane. The reaction is preferably carried out in an inert organic 25 solvent at temperatures o~ from -78C to 20C and will normally require a reaction time of ~rom l to 60 minutes. Suitable inert organic solvents are chloro~orm, 14- `, .~
lOG5852 die-t'hyl e-ther, tetrahydrofuran, dioxane~ benzene and alcohols o:E ~ormula R30H in which R3 is as de~ined above. After completion o~ the reac-tion, the reaction mixture including compound (IV) may be 5 employed as such as the starting material for -the next step. Alternatively, the alkoxyketeneimines(IV), which are novel compounds and also ~orm par-t of the present invention, may be recovered and purified by conventional means; ~or example, the reaction mixture ~0 may be poured into ice-wa-ter~ the desired compound extracted with an appropriate organic solvent, the solu-tion washed with water and'dried and the solven-t then evaporated off. The residue obta med may be further puri~ied by recr~s-tallization or chromatography.
In a final step, compound(I) is prepared by hydrolysis o~ compound(IV), e.g. with a dilute mineral acid or an organic acid, which may be diluted. Examples of mineral acids include hydrochloric acid, hydrobrom.ic acid, sulphuric acid, phosphoric acid and perchromic acid.
20 Ex~mples o~ organic acids include tri~'luoroacetic acid, tri.chloroacetic acid and dich~oroacet~c acld. The reac-tion is preferably carried out in an aqueous oræanic solvent at a temperature from -20C to 40C, with ~tlrring. The reac-tion will normally take from 0.5 to 12 hours.
When the reaction is complete, the desired product(I) may be recovered by any conventional means.
One such recovery procedure comprises: evaporating the reaction mixture to dryness under re~uced pressure and .
.
~06S~352 add.ing lce~wa-ter to -the residue; extracting the mi.x-ture with an appropria-t organlc solvent; washing the extract wi-th water and then drying i-t; and finally evaporating o~f the solvent. The residue may then be 5 purified by recrystallization or chromatography.
. (Ins-tead of proceeding via alkoxyketeneimille(IV), - the overall process may proceed via dialkoxyimino compound (V), in accordance with the invention of our said copending application of even dateS the disclosure of 10 which is incorporated herein by re~erence.) .
Some of the acylamino oompounds(VI) employed a~ star-ting materials i.n the overall process are novel and may be prepared by known methods, for example those described in "Cephalosporins and Penicillins"
15 edited by E.H. Flynn, Academic Press, New York and London(1972j page 83. By way of example, they may be prepared by reacting the corresponding amino compolmd with a halide or anhydride of a carboxylic acid having the ~o~mula:
R~
~C -- COOH
X ,:
.
.
-~6-1~6S8S;2 (in which Rl, R2 and X are as defined above) or by reacting the corresponding amino compound with the carboxylic acid itself in the presence o~ a peptide coupling agent e.g. dicyclohexylurea. ;~
The process of the present invention has the advan-tages that is generally applicable to the preparation of cephalo-sporins and penicillins, even if they have an anion formation centre in the side chain, and that it can be carried out as part of a sequence without isolation of the intermediates produced during the reactions, i.e. in a "one-pot" reaction.
Certain of the compounds of formula (I) are new.
Examples of the new compounds are the following:
(1) 7~-chloroacetamido-7~-methoxy-3-methyl-3-cephem-4-carboxylic acid ~2) 3-carbamoyloxymethyl-7~-chloroacetamido-7~-methoxy-3-cephem-4-carboxylic acid ;~
(3) 7a-methoxy-3-methyl-7~-propionamido-3-cephem~4-carboxylic acid (4) 7a-methoxy-3-methyl-7~-phenoxyacetamido-3-cephem-4-carboxylic acid (5) 3-acetoxymethyl-7a-methoxy-7~-phenylthioacetamido-3-cephem-4-carboxylic acid (6~ 3-acetoxymethyl-7~-chloroacetamido-7a-methoxy-3-cephem-4-carboxylic acid.
1C~65~S2 (7) 7~-chloroacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (8) 3-carbamoyloxymethyl-7~-methoxy-7~-(1,2,4-triazol-4H-3- :
yl)thioacetamido-3-cephem-4~carboxylic acid (9) 3-carbamoyloxymethyl-7~-timidazol-2-yl)thioacetamido-7~-methoxy-3-cephem-4-carboxylic acid (10) 3-carbamoyloxymethyl-7~-methoxy-7~-(1,3,4-thiadiazol-2-yl) thioacetamido-3-cephem-4-carboxylic acid ~
(11) 3-carbamoyloxymethyl-7a-methoxy-7~-propargyl-thioacetamido- ::-.
3-cephem-4-carboxylic acid ~`:
(12) 3-carbamoyloxymethyl-7~-cyanomethylthioacetamido-7a- :
methoxy-3-cephem-4-carboxylic acid i (13) 3-carbamoyloxymethyl-7~-methoxy-7~-(5-methyl-1,2,4-triazo1- ..
4H-3-yl)thioacetamido-3-cephem-4-carboxylic acid (14) 3-carbamoyloxymethyl-7a-methoxy-7~-(2-pyridyl)-thioacet-amido-3-cephem-4-carboxylic acid :::
(15) 3-carbamoyloxymethyl-7~-methoxy-7~-(2-pyrimidyl)-thioacet- .
amido-3-cephem-4-carboxylic acid .`.
(16) 3-carbamoyloxymethyl-7~-methoxy-7~-(thiazolin-2-yl)-thio-acetamido-3-cephem-4-carboxylic acid (17) 3-carbarnoyloxymethyl-7~-methoxy-7~-(n-propyl-thioacetamido)-3-cephem-4-carboxylic acid :~
.. , ,. . . , ,, .~
(18) 3-acetoxymethyl-7~-cyanomethylthioacetamido-7~-methoxy-3 cephem-4-carboxylic acid (19) 3-acetoxymethyl-7~-(imidazol--2-yl)thioacetamido-7a-methoxy-3-cephem-4-carboxylic acid (20) 7a-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~
(1,3,4-thiadiazol-2-yl)thioacetamido-3-cephem-4-carboxylic acid -:
(21) 7~-(imidazol-2-yl)thioacetamido-7~-methoxy-3-(1-methyl-lH- : . .
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic ~cid (22) 7~-cyanomethylthioacetamido-7a-methoxy-3-(1-methyl-lH
tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (23) 7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~-propargylthioacetamido-3-cephem-4-carboxylic acid (24) 7~-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylic acid (25~ 6~-chloroacetamido-6~-methoxypenicillanic acid (26) 6a-methoxy-6~-phenylthioacetamidopenicillanic acid :.
(27) 6~-methoxy-6~-propargylthioacetamidopenicillanic acid -(28) 6~-methoxy-6~-(1,3,4-thiodiazol-2-yl)thioacetamido-penicillanic acid I ~065852 (29) 7a-benzyloxy-7~-chloroacetamido-3-methyl-3-cephem-4-car-boxylic acid (3P) 7~-(isoxazol-3-yl)oxyacetamido-7a-methoxy-3-(1-methyl-lH- ~:
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (31) 7a-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~
(5-methyl-1,3,4-thiodiazol-2-yl)thioacetamido-3-cephem-4- ; :
carboxylic acid (32) 3-carbamoyloxymethyl-7a-methoxy-7~-(5-methyl-1,3,4-thia-diazol-2-yl)thioacetamido-3-cephem-4-carboxylic acid -~
i 10 (33) 3-acetoxymethyl-7~-azidomethylthioacetamido-7a-methoxy-3-cephem-4-carboxylic acid I (34~ 3-acetoxymethyl-7a-methoxy-7~-(1,3,4-thiadiazol-2-yl)thio- .
acetamido-3-cephem-4-carboxylic acid :::
(35) 3-acetoxymethyl-7a-methoxy-7~-propargylthioacetamido-3-cephem-4-carboxylic acid :
(36) 3-acetoxymethyl-7~-(isoxazol-3-yl)oxyacekamido-7a-methoxy-3-cephem-4-carboxylic acid (37) 3-acetoxymethyl-7~~(isoxazol-3-yl)thioacetamido-7a-methoxy-3-cephem-4-carboxylic acid .
(3~) 7~-methoxy-7~-methylsulphonylacetamido-3-(1-methyl-lH-ketrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid :
.. . . .
~L11)6~852 Of the compounds in the above list, the following numbered compounds have particularly good antimicrobial activity against a wide range of pathogenic microorganisms: 8; 9; 10;
11; 12; 18; 19; 20; 21; 22; 23; 30; 31; 32; 33; 34; 35; 36; 37 and 38. The antimicrobial activities of ~hese compounds, in :
terms of their minimum inhibitory concentrations (mcg/ml) against various microorganisms, are summarized in the following Table in which the compounds are identified by the numbers given in the :~
above list. The microorganisms against which the compounds were tested were as follows:
IA: Staphylococcus aureus 209p IB: Staphylococcus aureus (CP and PC resistant) :
.
IIA: E. coli NIHJ
IIB: E. coli 609 (CER resistant) III: Shigella flexnerl Komagome IVA: Klebsiella pneumoniae 806 __ ... . . .
IVB: Klebsiella pneumoniae 846 (CER resistant) .:
' V: Proteus vulgaris VI: Salmonella entaritidis Gaertner .. . .
1~6~i~35;2 :
- Table ~
', Microorganism Compound _ ~ _ . IA IB IA IIB III IVA IVB V VI
~, 8 1.5 6.2 6.2 12.5 12.5 6.2 >400 25 6.2 9 <~.1 0.8 1.5 3.1 3.1 3.1~200 6.2 1.5 0.4 1.5 3.1 3.1 3.1 3.1>400 6.2 1.5 11 0.8 1.5 3.1 3.1 6.2 3.1>400 6.2 1.5 12 0.8 1.5 1.5 0.8 3.1 0.4~400 6.2 0.4 18 0.2 0.8 1.5 1.5 3.1 1.5>400 6.2 0.8 19 1.5 6.2 12.525 25 12.5 >400 25 6.2 0.~ 0.8 1.5 1.5 1.5 1.5>200 3.1 0.8 21 0.8 3.1 6.2 6.2 6.2 6.2>200 12.5 3.1 22 0.2 0.8 0.8 0.8 0.8 0.8~200 1.5 0.2 23 0.2 0.8 3.1 3.1 3.1 3.1400 3.1 0.8 0.2 0.8 3~1 3.1 3.1 3.1~400 6.2 1.5 31 0.4 1.5 12.512.5 6.2 12.5400 ~.1 1.5 32 0.8 3.1 6.2 6.2 ~12.5 6.2 >200 6.2 3.1 0.4 0.8 6.2 6.2 6.2 6.2>200 3.1 1.5 ;'''' - 22 - ~
. . , , , : . : . . : :. ... .. .. .. . .. . .
~65~5~ ~:
, Microorgani sm :
Compound _ No . IA IB IIA I IBII I IVA. IVB V VI
._. ~"'.
34 0.8 1.5 3.1 6.2 6.2 3.1 >400 6.2 3.1 350.8 3.1 3.1 6.;26.2 6.2 >4006.2 1.5 `~
36<0.1 0.8 6.2 6.212.5 6.2 >40012.5 3.1 . _ ., 370.2 0.8 3.1 6.26.2 3.1 >4003.1 1.5 380.8 3.1 1.5 1.51.5 0.8 40012.5 0.4 . , . .
~06S~3S2 Accordingly, -the cornpcunds produced by the process o~ the present inven-tion have excellent antimicrobial activi-ties against a wide range o~
pathogenic micro-organisms. The compounds may be administered orally or parenterally, :~or example as capsules, tablets or injections; they are most pre~erably administered by injection. The optimum dosage will var~ with the body weight, age and disease o~ the patient but the total daily dosage will 10 generally be ~rom lO0 to 3000 mg, administered i~ divided doses, three or four times a day, i~ necessary, however, more ~han this amoun-t may be used.
In addi-tion to their pharmaceu-tical use, the 7~-haloacetamidocephalosporin and 6~-haloacet~nldo-15 penicillanic acid deriva-tives, such as 7~-chloroace-tamido-7~-methoxy-3-(l-methyl-lH-tetrazo1-5-yl)-thiome-thyl-~-cephem-4-carboxylic acid and its esters, are use~ul intermediates, whioh can be tran~ormed into o-ther cephalosporin or penicillin derivatives having 20 valuable antimicrobial activity by replacing the halogen atom wi-th another radical.
Th~ inventLon i~ lllustrated b~ the following Examples:
EX~PLE 1 25 (A) M~ h ~ ) -3-cephem-4-carboxylate.
360 mg o~ phosphorus pentachloride were dissolved in 24 ml o~ chloro~orm, after which 0.2L~ ml o~ quinoline and ~40 mg o~ ~-dichloroacetamido-3--~4-65~52 methyl-~-cephem~L~-carboxylate were added at room temperature. The reaction mixture was s-tirred at roo~ temperature for 1 hour and then -the sol~en-t was evaporated o~f under reduced pressure. To -the 5 residue were added 40 ml of anhydrous te-trahydrofuran and precipitates were ~il-tered o~f. The resulting solution contained methyl 3-methyl-7~(1',2',27-trichloroe-thylidenimino)~3~cephem-4~carboxylate, which was used in the next stage of the reaction without 10 purifiaction.
', To determine the properties of this compound7 the above procedure was repeated and the compound was then isolatedas ~ollows: the tetrahydro~uran solu-tion was poured into a 10% w/v so]ution o~ dipotassium 15 hydrogen phosphate and extracted with eth~l acetate.
The extracts were washed with water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~f at 20C under reduced pressure, giving 320 mg of methyl 3-methyl-7~-(1',2',2'-trichloroethyli-20 denimino)-3-cephem-4-carboxylate, as an oil.
NMR spectrum (CDC13)~ ppm = 2.17 (3H, singlet), 3.27 & 3.50 (2H, AB quartet, J = 19 Hz), 3.83 (3H, singlet), 5.10 (lH, doublet, J = 5 Hz), 25 5 55 (lH, doublet, J = 5 Hz), 6.42 (lH, singlet).
.
, . .. , . , . . . ~ . ~
: ' . . ,... , :
1~)65i~3SZ
(B) ~ hlor~ac~eta~ivo-7~=rnetho;~ m ~
The c~de produc-t ob-tained above was dissolved in 30 ml of te-trahydrof.urc~n and, after cooling -to -70C,5 -this solution was stlrre~l at -the same ter.npe.ra-ture ~or 20 minutes wi-th a methanol solution of lithium methoxide, prepared from 15 mg o~ lithi~ an.d 1 ml of methanol. 0.1 ml o~ acetic acid was then added to the reaction mixture. The solution was poured into 10 water and extrac-ted w1th ethyl ace-tate. The extrac-ts were washed with water and dried over anhydrous sodium ..
sulphate; the solvent was evaporated of~ under reduced pressure. The residue was puri~ied by chromatography on silica gel, giving 80 mg of meth~l 15 7~~chloroace-tamido-7~-methox~-3-methyl-3-cephem~
carboxylate, m.p. 123 - 125C.
I.R. spectrum (Nujol - Trade Mark)?Jnaxcm 1= 3380, 1790,1730, NMR spect ~n (CDC13)S ppm - 2.25 (3H, singlet), 3.20 (2H, singlet), 20 3.53 (3H, singlet), 3.73 (3H, single-t)g 4~07 ~2H, singlet), ~.98 (lH, singlet), 7.43 (lH, ~nglct).
lOG5852 ?_(7~-~hloroace-ta ido-7~ metho~ m~ y~
riaz o~ ,3 a~Ey~ one A solution o~ 2-~[3-me-thyl-7-(l',Z',2'-5 trichloroethylidenimino)-3-cephem-4~carbonyl]triazolo r4,3-a~pyrido-3-one in 25 ml of -tetrahydrofuran was prepared from 221 mg of 2-(7-dichloroacetamido-3~
methyl-3-cephem-4-carbonyl)-triazolo[4,3-a~pyrido-3-one, 120 mg of phosphorus pentachloride, 0.8 ml of quinoline 10 and 10 ml of chloro~orm, fo~lowing -the procedure described in Example I~A). To this solution was added, at a -temperature o~ -78C, a methanol solu-tion o~
lithium methoxide prepared from 11 mg of lithium and 1 ml of methanol. The mixture was stirred at -78C
15 ~or 10 minutes and -then treated with 0.1 ml of acetic acid. The resulting solution was poured into a solution of sodium chloride and then extracted with ethyl ecetate. The ex-tracts were washed with wa-ter and dried over anhydrous sodium sulphate; the solvent 20 was then èvaporated off under reduced pressure. The resi~ue was chromatographed on silica gel, giving 50 mg o~ 2-(7~--chloroacetamido-7~-methoxy-3-methyl-3-cephem-4-carbonyl)-triazolor4,3-a~pyrido-3~one.
NMR spectrum (CD3COCD~)~ ppm = 2.0t3H, singl~t), ~5 3.25 & 3.53 (2H, AB quartet, j = 19 Hz), 3.42 (3H, single-t), 3.77 (2H, singlet), 5.20 (lH, singlet), 6.4 - 6.7 (lHt multiplet), 7.0 _ 7 4 (2H, multiplet) t 7.6 - 7.8 (lH, multiplet).
-~7-~-.!
~C)6Sl35Z
EXAMP~E 3 __ ___ (A) ~ h ~::5~$~C!_L~ae9aL~tte . .
A solu-tio-n of benæhydryl 7~-(2'-bromo~ chloro-
Many cephalosporin and penicillin derivatives having antibiotic properties are known, the first of these to be dis-covered having various substituted acetamido chains at the 7 or 6~ positions and being unsubstituted at the 7~ or 6~ positions, respectively. More recently, however, it has been discovered that various 7~- or 6~-alkoxy derivatives of these compounds are also valuable antibiotic substances.
Of the known methods of introducing an alkoxy group into the 7- position of a cephem ring or the 6-position of a penam ring alkoxylation with t-butyl hypochlorite and lithium alkoxide is simplest to perform and gives best yields [R.A. Firestone and B.G.
Christensen, J. Org. Chem. 38, 1436 (1973); G.A. Koppel and R.E.
Koehler, J. Amer. Chem. Soc. 95, 2403(1973)]; however, this method has the disadvantage that it is not applicable to cephalosporins or penicillins which are sensitive to t-butyl hypochlorite, i.e.
which have an anion formation centre in the side chain at the 7-or 6- position.
We have now discovered a process for preparing certain 7~-acylamino-7~-alkoxycephalosporin or 6~-acylamino-6~-alkoxy-penicillin derivatives which are useful as antibacterial agentsand some of which may also be used as intermediates in the pre-paration of other, but more ~aluable, antibacterial agents.
~ ' ',.', :
~
,, ' ~ .
' -- 1 -- . .
1C1658S;~
The present invention relates to a process for the pre-paration of derivatives of the ~-lactam antibiotics i.e. the cephalosporins and penicillins, and specifically to the prepara-tion of 7~-acylamino-7a-alkoxycephalosporins 6~-acylamino-6a-alkoxypenicillins and certain intermediates in said process.
The cephalosporin derivatives referred to in the present specification are named with reference to cepham, which has the structure:
~ N
O ,~
as described in J. Amer. Chem. Soc. 84, 3400 (1962), the corres-ponding unsaturated compounds being referred to as "cephems" and the position of the unsaturation being indicated by a numeral e.g. 3-cephem.
The penicillin derivatives re~erred to in the present specification are named as derivatives of penicillanic acid, which has the formula:
\~CH3 ~6 15 2 ~ ~3 N4 ~
COOH
~ 2i~2 ~
The compounds which may be prepared by the process of the present invention have the formula (I):
R oR3 C - C NH - S ~ ~
R H O ~ ~ J ~ ~:
wherein Rl represents a hydrogen atom, a halogen atom, an alkyl : group having from 1 to 4 carbon atoms or an aryl group; R2 repre- ;.
sents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, and aryl group, an alkylthio group having from 1 to 4 carbon atoms, an alkynylthio group having from 2 to .
4 carbon atoms, an arylthio group, an azidoalkylthio group having ;
from 1 to 4 carbon atoms, a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety, an alkylsulphonyl group hav-ing from 1 to 4 carbon atoms, a 5- or 6-membered heterocyclic group, a 5- or 6-membered heterocyclic-thio group, or 1 5- or 6- .: :
membered heterocyclic-oxy group;. R3 represents an alkyl group having rom 1 to 4 carbon atoms; and Z represents a fragment of forrnula: ~ ~ CH3 :
~ or ~ CH3 ¦ CH2A R4 wherein R4 represents a carboxyl group, an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, a haloalkoxy- :
carbonyl group having from 1 to 4 carbon atoms in the alkyl moiety a benzyloxycarbonyl group which is ~:.
.:.
',''''"
_ 3 _ ~ 65~
unsubstituted or has one or more halogen, methoxy or nitro sub-I stituents, a diphenylmethoxycarbonyl group, a trialkylsilyoxy-¦ carbonyl group having from 1 to 4 carbon atoms in each alkyl moiety, a dialkylhalosilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiety a phenacyloxycarbonyl group which is unsubstituted or has one or more halogen or nitro sub-stituents, an acyloxycarbonyl group, a haloacyloxycarbonyl group, a dihalophosphinoxy-carbonyl group, a dialkylphosphinoxy-carbonyl group or an aminocarbonyl group; and A represents a hydrogen atom, an azido group or a group of formula -B-E wherein B represents an oxygen or a sulphur atom and E represents an acyl group, an alkyl group having from 1 to 4 carbon atoms or a substituted or unsub-stituted carbamoyl, thiocarbamoyl or heterocyclic group.
In this formula (I), Rl is a hydrogen atom; a halogen atom ~e.g. chlorine, bromide or iodine); an alkyl group having rom 1 to 4 carbon atoms (e.g. methyl~ ethyl, n-propyl, isopropyl or n-butyl); or an aryl group (e.g. phenyl or naphthyl). R is preferably: a hydrogen atom; a halogen atom (e.g. chlorine, bromide or iodine); or an alkyl group :
i 1~ E;5~35~
having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isohutyl or t-butyl); an aryl group (e.g.
phenyl or naphthyl); an alkylthio group having from 1 to 4 carbon atoms ~e.g. methylthio, ethylthio, n-propylthio or isopropyl-thio): an alkynylthio group having from 2 to 4 carbon atoms (e.g. propargylthio); an arylthio group (e.g. phenylthio); an azidoalkylthio group having from 1 to 4 carbon atoms (e.g. azido-methylthio or azidoethylthio); a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety (e.g. cyanomethylthio or cyanoethylthio); a 5- or 6- membered heterocyclic-thio group containing one or more sulphur and/or nitrogen and/or oxygen atoms in the ring and which may be substitutea by an alkyl group having from 1 to 3 carbon atoms (e.g. imidazolythio, thiadiazolyl-thio, triazolylthio, thienylthio, isoxazolylthio, methylisoxazolyl-thio, tetrazolylthio, methyl-tetrazolylthio, pyrimidinylthio or pyridylthio); a 5- or 6-membered heterocyclic-oxy group contain-ing one or more sulphur and/or nitrogen and/or oxygen atoms in the ring and which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. isoxazolyloxy methylisoxazolyloxy, imidazolyloxy, thiadiazolyloxy, triazolyloxy, thienyloxy, tetra-zolyloxy, methyltetrazolyloxy, pyrimidinyloxy, or pyridyloxy);
a 5-'':.,'-' ~365~3S2 ! or 6- membered heterocyclic group containing one or more sulphur and/or nitro~en and/or oxygen atoms in the ring and which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. thienyl, imidazol, thiadiazolyl, isoxazolyl, methylisoxa-zolyl, tetrazolyl, methyltetrazolyl, pyrimidinyl or pyridyl); or an alkylsulphonyl group having from 1 to 4 carbon atoms (e.g.
methylsulphonyl, ethylsulphonyl, or n-propylsulphonyl). R3 is an alkyl group having from 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl or n-butyl). R4 is a carboxyl group or a protected carboxyl group such as an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety ~e.g. methoxycar-bonyl, ethoxycarbonyl, n-propoxycarbonyl or n-butoxycarbonyl), a haloalkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety (e.g. dichloroethoxycarbonyl or trichloroethoxy-carbonyl), a benzyloxycarbonyl group optionally substituted with halogen, methoxy or nitro (e.g. benzyloxycarbonyl, ~ chloro-benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxy-carbonyl), a diphenylmethyloxycarbonyl group, a trialkylsilyloxy-carbonyl group having from 1 to 4 carbon atoms in each alkyl moiety (e.g. trimethylsilyloxycarbonyl or triethylsilyloxycar-bonyl), a dialkylhalosilyloxycarbonyl group having ~rom 1 to 4 carbon atoms in each alkyl moiety (e.g. dimethylchlorosilyloxy-carbonyl or dimethylbromosilyloxy~arbonyl), a phenacyloxycar-bonyl ~roup optionally substituted with halogen or methoxy (e.g.
~65~S2 ~-chlorophenacyloxycarbonyl, p-bromophenacyloxycarbonyl or ~-methoxyphenacyloxycarbonyl), an acyloxycarbonyl group (e.g.
acetoxycarbonyl or benzoyloxycarbonyl), a halo-acyloxycarbonyl group (e.g. chloroacetoxycarbonyl or bromo-acetoxycarbonyl), a dihalophosphinoxycarbonyl group (e.g. dichlorophosphinoxycarbonyl or dibromophosphinoxycarbonyl), a dialkylphosphinoxy carbonyl group (e.g. dimethylphosphinoxycarbonyl), or an aminocarbonyl group (e.g. 3-oxo-2,3-dihydro-s-triazoloE4,3-a]pyridon-3-ylcar-" bonyl. ~ is preferably: an acyl group (e.g. acetyl, propionyl or benzoyl); a carbamoyl group; or a 5- or 6- membered hetero-cyclic group, which may be substituted by an alkyl group having from 1 to 3 carbon atoms (e.g. tetrazolyl, l-methyltetrazolyl, isoxazolyl, imidazolyl, thiazolyl, triazolyl, thienyl, thiadia-zolyl, methylthiadiazolyl, pyrimidinyl or pyridyl).
In accordance with the invention which is the subject of our application No. 222,728, compounds of formula (I) are pre-pared by reacting a halo-imine of formula (II):
.
Rl H
C C = N ~ ____-S
yl y O N V
"' .
: ' " ' . ' " :' -(in which Rl, R2 and Z are as defined above and yl and Y are the same or different and each represents a halogen atom) with an alkali metal alkoxide of formula (III):
R30M (III) (in which R3 is as defined above and M represents an alkali metal) to give an alkoxyketeneimine of formula (IV): -Rl OR
C = C = ~ (IV) N Z
0~
(in whi.ch Rl, ~2 and Z are as defined above) and/or a dialkoxy-imino compound of formula (V):
. ' 658~;i2 3~t oR3 R ¦ ~R3 f ~ IV) (in which Rl, RZ, R3 and Z are as defined above), and hydrolizing said alkoxyketeneimine (IV) and/or reac-ting said dialkoxyimino compound (V) wi-th a halo- ;
silane or an acid and treating the resul-ting product with water.
The process which is the subject of the present invention is the preparation of a compound o~ formula by the hydrolysis of an alkoxyketeneimine of 10 formula (IV). The al-ternatlve route to a compo~d o~
formula (I) via a dialkoxyim.ino compound (Y) is the ~ 1,403 sub~ec-t o~ our copending application~o:E even date.
~..
The first stage in the reaction of the halo-imine - (II) with the alkali metal alkoxide (III) to form the lS allcoxyketeneimine (lV) and/or the dialkoxyimino compound (V) is the dehydrohalogenation of halo-imine(II). This reaction must, therefore, be carried out in the presence of an acid-binding agent, i..e. a base. If desired, the , I . . . .. . .:
~ 8S 2 base may be provided by -the alkali me-tal alkoxide (IrI) or, alternatively, another base may be used. Preferably, the base is employed in an amount of at leas-t 1 equivalent per mole of halo-imine (II) and more 5 pre~erably about l equivalen-t is employed. The course o:E the subsequent reaction depends upon -the relative proportions of alkali metal alkoxide and halo-imine(II).
Where the amount of alkali metal alkoxide (excluding -tha-t, if any, employed as acid-binding agent in the preceding 10 stage) i~ about l mole per mole of halo-imine(II), the product o~ the reaction is predominantly the alkoxy-; keteneimine(IV) as recluired for use in the process o~ the present invention. On the other hand, if the amount of alkali metal alkoxide is about 2 moles per mole 15 of halo-imine(II), the dialkoxyimino compound(V) is the predominant produc-t. Wnlere the amoun-t of alkali metal alkoxide is between 1 and 2 moles per mole of halo-imine(II)~ a mixture of alkoxyketeneimine(IV) and dialkoxyimino compound(V) will be obtai~ed.
20 Although the presence o~ excess alkoxicle will have no adverse ef~ec-t, it is not bene~icial ancl, accordingly, we pre~er to employ about 1 mole of alkoxicle per mole of halo-imine(II) in order to produce predominantly alkoxyketeneimine(IV) (2 moles of alkoxide per mole of 25 halo-imine(II) will produce predominantly dialkoxyimino compound(V)).
~`
. , .
, 5~ 52 The halo~imines of fo.rmula (II) are themsel~Tes new compounds. They ma.y be prepared by reacting an acylamino compound of formula(VI) R/
~y~
~in which Rl, R2 and Z are as de~ined above and X
represents a hydroxy group or a halogen atom) with a halogenating agent.
The reactions of which the process of the present invention forms part may be illustrated by the 10 following reaction scheme:
.,, _ A. .
~6S~3152 R2/l 11 IIH j~ halog~na~e (Y~) . .
Rl H
(Il) \C--C
b~J'-- ~ 2~C= Ic_y~
(VII) 3 .
_~ \C~-~ N ~R ~ S~
(-MY) R2/ F 2 3 , ' ' (~Y) ~~
\C-C=~L~S\
/halosilan~ :
/ acid Rl OR~ ~ ~H20 R~ B o~ (I) 12- .
9 (;~65852 Thus9 in -the first step of -the overall process forming th* subject o~ our said a~plication No. 222728, halo~imine (I]:) is prepared by reacting acylamino compound(VI) wi-th a halogenating agent. Examples of haloge~ating 5 agents are: phosphorus pen-tahalides, e.g. phosphorus pentachloride or phosphorus pentabromlde; phosphorus trihalidesg e.g. phosphorus trichloride or phosphorus tribromide; phosphorus oxyhalides, e.g. phosphorus oxychloride or phosphorus oxybromide; and thionyl 10 halides, e.g. thionyl chloride or thionyl bromide.
Of these, phosphorus pentachloride is most preferred.
The halogentation reaction is suitably carried out in an anhydrous iner-t organic solvent, with stirring, at a temperature from -50C to 40C. The reaction time is 15 not critical, but the reaction will normally be complete within a period from 15 minutes to 5 hours. Suitable inert organic solvents are chloroform, methylene chloride, benzene, die-thyl ether, tetrahydrofuran and dioxane.
The reaction is prePerably e~fected in the presence o~
20 a tertiary amine, such as quinoline, diethylaniline, dimethylaniline, pyridine, tri.ethylaminc or diazab:lcyclo-octane.
When the halogenation reaction is complete, the react;ion mixture, including compound (II), may be used 25 as such as the starting material in the next step;
alternatively, the compound(II) may be reco~ered and purified by conventional means.
: `:
~)6585;~
Where ~4 in the acylamino startin~ material(V) is a carboxyl group, it shouJ:cl:Lirst be protected, by metl1ocls which are well understood in -the art. I~ X
in the star-ting ma-terial represents a hydro~y group, the halogenation reaction causes it -to be replaced by a halogen atom.
Alkoxyketeneimine(IV) is prepared by reacting haloimine(II) with one mole o~ al~ali metal alkoxide(III) in the presence of one equivalent of base, per mole o~
10 halo-imine. Examples of alkali metal alkoxides inGlude: lithium methoxide, lithlum e-thoxide, sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide. The base employed may be, and pre~erably is, simply an excess o~ the alkali metal 15 alkoxide(III). Alternatively, it may be: an inorganic base, such as an alkali metal hydroxide te.g. sodium hydroxide or potassium hydroxide), an alkali metal carbonate (e.g. sodium carbona~e or potassium carbonate), or an alkali metal hydride (e.g. sodium hydride or 20 potassium hydr~.de), or a tertiary amln~, such as a t~ialkylamine (e.g. trimethylamlne or triethylamine), a dialkylaniline (e.g. dimethylaniline or diethylaniline), pyridine, quinoline or diazabicyclooctane. The reaction is preferably carried out in an inert organic 25 solvent at temperatures o~ from -78C to 20C and will normally require a reaction time of ~rom l to 60 minutes. Suitable inert organic solvents are chloro~orm, 14- `, .~
lOG5852 die-t'hyl e-ther, tetrahydrofuran, dioxane~ benzene and alcohols o:E ~ormula R30H in which R3 is as de~ined above. After completion o~ the reac-tion, the reaction mixture including compound (IV) may be 5 employed as such as the starting material for -the next step. Alternatively, the alkoxyketeneimines(IV), which are novel compounds and also ~orm par-t of the present invention, may be recovered and purified by conventional means; ~or example, the reaction mixture ~0 may be poured into ice-wa-ter~ the desired compound extracted with an appropriate organic solvent, the solu-tion washed with water and'dried and the solven-t then evaporated off. The residue obta med may be further puri~ied by recr~s-tallization or chromatography.
In a final step, compound(I) is prepared by hydrolysis o~ compound(IV), e.g. with a dilute mineral acid or an organic acid, which may be diluted. Examples of mineral acids include hydrochloric acid, hydrobrom.ic acid, sulphuric acid, phosphoric acid and perchromic acid.
20 Ex~mples o~ organic acids include tri~'luoroacetic acid, tri.chloroacetic acid and dich~oroacet~c acld. The reac-tion is preferably carried out in an aqueous oræanic solvent at a temperature from -20C to 40C, with ~tlrring. The reac-tion will normally take from 0.5 to 12 hours.
When the reaction is complete, the desired product(I) may be recovered by any conventional means.
One such recovery procedure comprises: evaporating the reaction mixture to dryness under re~uced pressure and .
.
~06S~352 add.ing lce~wa-ter to -the residue; extracting the mi.x-ture with an appropria-t organlc solvent; washing the extract wi-th water and then drying i-t; and finally evaporating o~f the solvent. The residue may then be 5 purified by recrystallization or chromatography.
. (Ins-tead of proceeding via alkoxyketeneimille(IV), - the overall process may proceed via dialkoxyimino compound (V), in accordance with the invention of our said copending application of even dateS the disclosure of 10 which is incorporated herein by re~erence.) .
Some of the acylamino oompounds(VI) employed a~ star-ting materials i.n the overall process are novel and may be prepared by known methods, for example those described in "Cephalosporins and Penicillins"
15 edited by E.H. Flynn, Academic Press, New York and London(1972j page 83. By way of example, they may be prepared by reacting the corresponding amino compolmd with a halide or anhydride of a carboxylic acid having the ~o~mula:
R~
~C -- COOH
X ,:
.
.
-~6-1~6S8S;2 (in which Rl, R2 and X are as defined above) or by reacting the corresponding amino compound with the carboxylic acid itself in the presence o~ a peptide coupling agent e.g. dicyclohexylurea. ;~
The process of the present invention has the advan-tages that is generally applicable to the preparation of cephalo-sporins and penicillins, even if they have an anion formation centre in the side chain, and that it can be carried out as part of a sequence without isolation of the intermediates produced during the reactions, i.e. in a "one-pot" reaction.
Certain of the compounds of formula (I) are new.
Examples of the new compounds are the following:
(1) 7~-chloroacetamido-7~-methoxy-3-methyl-3-cephem-4-carboxylic acid ~2) 3-carbamoyloxymethyl-7~-chloroacetamido-7~-methoxy-3-cephem-4-carboxylic acid ;~
(3) 7a-methoxy-3-methyl-7~-propionamido-3-cephem~4-carboxylic acid (4) 7a-methoxy-3-methyl-7~-phenoxyacetamido-3-cephem-4-carboxylic acid (5) 3-acetoxymethyl-7a-methoxy-7~-phenylthioacetamido-3-cephem-4-carboxylic acid (6~ 3-acetoxymethyl-7~-chloroacetamido-7a-methoxy-3-cephem-4-carboxylic acid.
1C~65~S2 (7) 7~-chloroacetamido-7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (8) 3-carbamoyloxymethyl-7~-methoxy-7~-(1,2,4-triazol-4H-3- :
yl)thioacetamido-3-cephem-4~carboxylic acid (9) 3-carbamoyloxymethyl-7~-timidazol-2-yl)thioacetamido-7~-methoxy-3-cephem-4-carboxylic acid (10) 3-carbamoyloxymethyl-7~-methoxy-7~-(1,3,4-thiadiazol-2-yl) thioacetamido-3-cephem-4-carboxylic acid ~
(11) 3-carbamoyloxymethyl-7a-methoxy-7~-propargyl-thioacetamido- ::-.
3-cephem-4-carboxylic acid ~`:
(12) 3-carbamoyloxymethyl-7~-cyanomethylthioacetamido-7a- :
methoxy-3-cephem-4-carboxylic acid i (13) 3-carbamoyloxymethyl-7~-methoxy-7~-(5-methyl-1,2,4-triazo1- ..
4H-3-yl)thioacetamido-3-cephem-4-carboxylic acid (14) 3-carbamoyloxymethyl-7a-methoxy-7~-(2-pyridyl)-thioacet-amido-3-cephem-4-carboxylic acid :::
(15) 3-carbamoyloxymethyl-7~-methoxy-7~-(2-pyrimidyl)-thioacet- .
amido-3-cephem-4-carboxylic acid .`.
(16) 3-carbamoyloxymethyl-7~-methoxy-7~-(thiazolin-2-yl)-thio-acetamido-3-cephem-4-carboxylic acid (17) 3-carbarnoyloxymethyl-7~-methoxy-7~-(n-propyl-thioacetamido)-3-cephem-4-carboxylic acid :~
.. , ,. . . , ,, .~
(18) 3-acetoxymethyl-7~-cyanomethylthioacetamido-7~-methoxy-3 cephem-4-carboxylic acid (19) 3-acetoxymethyl-7~-(imidazol--2-yl)thioacetamido-7a-methoxy-3-cephem-4-carboxylic acid (20) 7a-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~
(1,3,4-thiadiazol-2-yl)thioacetamido-3-cephem-4-carboxylic acid -:
(21) 7~-(imidazol-2-yl)thioacetamido-7~-methoxy-3-(1-methyl-lH- : . .
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic ~cid (22) 7~-cyanomethylthioacetamido-7a-methoxy-3-(1-methyl-lH
tetrazol-S-yl)thiomethyl-3-cephem-4-carboxylic acid (23) 7~-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~-propargylthioacetamido-3-cephem-4-carboxylic acid (24) 7~-bromoacetamido-3-carbamoyloxymethyl-7~-methoxy-3-cephem-4-carboxylic acid (25~ 6~-chloroacetamido-6~-methoxypenicillanic acid (26) 6a-methoxy-6~-phenylthioacetamidopenicillanic acid :.
(27) 6~-methoxy-6~-propargylthioacetamidopenicillanic acid -(28) 6~-methoxy-6~-(1,3,4-thiodiazol-2-yl)thioacetamido-penicillanic acid I ~065852 (29) 7a-benzyloxy-7~-chloroacetamido-3-methyl-3-cephem-4-car-boxylic acid (3P) 7~-(isoxazol-3-yl)oxyacetamido-7a-methoxy-3-(1-methyl-lH- ~:
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (31) 7a-methoxy-3-(1-methyl-lH-tetrazol-5-yl)thiomethyl-7~
(5-methyl-1,3,4-thiodiazol-2-yl)thioacetamido-3-cephem-4- ; :
carboxylic acid (32) 3-carbamoyloxymethyl-7a-methoxy-7~-(5-methyl-1,3,4-thia-diazol-2-yl)thioacetamido-3-cephem-4-carboxylic acid -~
i 10 (33) 3-acetoxymethyl-7~-azidomethylthioacetamido-7a-methoxy-3-cephem-4-carboxylic acid I (34~ 3-acetoxymethyl-7a-methoxy-7~-(1,3,4-thiadiazol-2-yl)thio- .
acetamido-3-cephem-4-carboxylic acid :::
(35) 3-acetoxymethyl-7a-methoxy-7~-propargylthioacetamido-3-cephem-4-carboxylic acid :
(36) 3-acetoxymethyl-7~-(isoxazol-3-yl)oxyacekamido-7a-methoxy-3-cephem-4-carboxylic acid (37) 3-acetoxymethyl-7~~(isoxazol-3-yl)thioacetamido-7a-methoxy-3-cephem-4-carboxylic acid .
(3~) 7~-methoxy-7~-methylsulphonylacetamido-3-(1-methyl-lH-ketrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid :
.. . . .
~L11)6~852 Of the compounds in the above list, the following numbered compounds have particularly good antimicrobial activity against a wide range of pathogenic microorganisms: 8; 9; 10;
11; 12; 18; 19; 20; 21; 22; 23; 30; 31; 32; 33; 34; 35; 36; 37 and 38. The antimicrobial activities of ~hese compounds, in :
terms of their minimum inhibitory concentrations (mcg/ml) against various microorganisms, are summarized in the following Table in which the compounds are identified by the numbers given in the :~
above list. The microorganisms against which the compounds were tested were as follows:
IA: Staphylococcus aureus 209p IB: Staphylococcus aureus (CP and PC resistant) :
.
IIA: E. coli NIHJ
IIB: E. coli 609 (CER resistant) III: Shigella flexnerl Komagome IVA: Klebsiella pneumoniae 806 __ ... . . .
IVB: Klebsiella pneumoniae 846 (CER resistant) .:
' V: Proteus vulgaris VI: Salmonella entaritidis Gaertner .. . .
1~6~i~35;2 :
- Table ~
', Microorganism Compound _ ~ _ . IA IB IA IIB III IVA IVB V VI
~, 8 1.5 6.2 6.2 12.5 12.5 6.2 >400 25 6.2 9 <~.1 0.8 1.5 3.1 3.1 3.1~200 6.2 1.5 0.4 1.5 3.1 3.1 3.1 3.1>400 6.2 1.5 11 0.8 1.5 3.1 3.1 6.2 3.1>400 6.2 1.5 12 0.8 1.5 1.5 0.8 3.1 0.4~400 6.2 0.4 18 0.2 0.8 1.5 1.5 3.1 1.5>400 6.2 0.8 19 1.5 6.2 12.525 25 12.5 >400 25 6.2 0.~ 0.8 1.5 1.5 1.5 1.5>200 3.1 0.8 21 0.8 3.1 6.2 6.2 6.2 6.2>200 12.5 3.1 22 0.2 0.8 0.8 0.8 0.8 0.8~200 1.5 0.2 23 0.2 0.8 3.1 3.1 3.1 3.1400 3.1 0.8 0.2 0.8 3~1 3.1 3.1 3.1~400 6.2 1.5 31 0.4 1.5 12.512.5 6.2 12.5400 ~.1 1.5 32 0.8 3.1 6.2 6.2 ~12.5 6.2 >200 6.2 3.1 0.4 0.8 6.2 6.2 6.2 6.2>200 3.1 1.5 ;'''' - 22 - ~
. . , , , : . : . . : :. ... .. .. .. . .. . .
~65~5~ ~:
, Microorgani sm :
Compound _ No . IA IB IIA I IBII I IVA. IVB V VI
._. ~"'.
34 0.8 1.5 3.1 6.2 6.2 3.1 >400 6.2 3.1 350.8 3.1 3.1 6.;26.2 6.2 >4006.2 1.5 `~
36<0.1 0.8 6.2 6.212.5 6.2 >40012.5 3.1 . _ ., 370.2 0.8 3.1 6.26.2 3.1 >4003.1 1.5 380.8 3.1 1.5 1.51.5 0.8 40012.5 0.4 . , . .
~06S~3S2 Accordingly, -the cornpcunds produced by the process o~ the present inven-tion have excellent antimicrobial activi-ties against a wide range o~
pathogenic micro-organisms. The compounds may be administered orally or parenterally, :~or example as capsules, tablets or injections; they are most pre~erably administered by injection. The optimum dosage will var~ with the body weight, age and disease o~ the patient but the total daily dosage will 10 generally be ~rom lO0 to 3000 mg, administered i~ divided doses, three or four times a day, i~ necessary, however, more ~han this amoun-t may be used.
In addi-tion to their pharmaceu-tical use, the 7~-haloacetamidocephalosporin and 6~-haloacet~nldo-15 penicillanic acid deriva-tives, such as 7~-chloroace-tamido-7~-methoxy-3-(l-methyl-lH-tetrazo1-5-yl)-thiome-thyl-~-cephem-4-carboxylic acid and its esters, are use~ul intermediates, whioh can be tran~ormed into o-ther cephalosporin or penicillin derivatives having 20 valuable antimicrobial activity by replacing the halogen atom wi-th another radical.
Th~ inventLon i~ lllustrated b~ the following Examples:
EX~PLE 1 25 (A) M~ h ~ ) -3-cephem-4-carboxylate.
360 mg o~ phosphorus pentachloride were dissolved in 24 ml o~ chloro~orm, after which 0.2L~ ml o~ quinoline and ~40 mg o~ ~-dichloroacetamido-3--~4-65~52 methyl-~-cephem~L~-carboxylate were added at room temperature. The reaction mixture was s-tirred at roo~ temperature for 1 hour and then -the sol~en-t was evaporated o~f under reduced pressure. To -the 5 residue were added 40 ml of anhydrous te-trahydrofuran and precipitates were ~il-tered o~f. The resulting solution contained methyl 3-methyl-7~(1',2',27-trichloroe-thylidenimino)~3~cephem-4~carboxylate, which was used in the next stage of the reaction without 10 purifiaction.
', To determine the properties of this compound7 the above procedure was repeated and the compound was then isolatedas ~ollows: the tetrahydro~uran solu-tion was poured into a 10% w/v so]ution o~ dipotassium 15 hydrogen phosphate and extracted with eth~l acetate.
The extracts were washed with water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~f at 20C under reduced pressure, giving 320 mg of methyl 3-methyl-7~-(1',2',2'-trichloroethyli-20 denimino)-3-cephem-4-carboxylate, as an oil.
NMR spectrum (CDC13)~ ppm = 2.17 (3H, singlet), 3.27 & 3.50 (2H, AB quartet, J = 19 Hz), 3.83 (3H, singlet), 5.10 (lH, doublet, J = 5 Hz), 25 5 55 (lH, doublet, J = 5 Hz), 6.42 (lH, singlet).
.
, . .. , . , . . . ~ . ~
: ' . . ,... , :
1~)65i~3SZ
(B) ~ hlor~ac~eta~ivo-7~=rnetho;~ m ~
The c~de produc-t ob-tained above was dissolved in 30 ml of te-trahydrof.urc~n and, after cooling -to -70C,5 -this solution was stlrre~l at -the same ter.npe.ra-ture ~or 20 minutes wi-th a methanol solution of lithium methoxide, prepared from 15 mg o~ lithi~ an.d 1 ml of methanol. 0.1 ml o~ acetic acid was then added to the reaction mixture. The solution was poured into 10 water and extrac-ted w1th ethyl ace-tate. The extrac-ts were washed with water and dried over anhydrous sodium ..
sulphate; the solvent was evaporated of~ under reduced pressure. The residue was puri~ied by chromatography on silica gel, giving 80 mg of meth~l 15 7~~chloroace-tamido-7~-methox~-3-methyl-3-cephem~
carboxylate, m.p. 123 - 125C.
I.R. spectrum (Nujol - Trade Mark)?Jnaxcm 1= 3380, 1790,1730, NMR spect ~n (CDC13)S ppm - 2.25 (3H, singlet), 3.20 (2H, singlet), 20 3.53 (3H, singlet), 3.73 (3H, single-t)g 4~07 ~2H, singlet), ~.98 (lH, singlet), 7.43 (lH, ~nglct).
lOG5852 ?_(7~-~hloroace-ta ido-7~ metho~ m~ y~
riaz o~ ,3 a~Ey~ one A solution o~ 2-~[3-me-thyl-7-(l',Z',2'-5 trichloroethylidenimino)-3-cephem-4~carbonyl]triazolo r4,3-a~pyrido-3-one in 25 ml of -tetrahydrofuran was prepared from 221 mg of 2-(7-dichloroacetamido-3~
methyl-3-cephem-4-carbonyl)-triazolo[4,3-a~pyrido-3-one, 120 mg of phosphorus pentachloride, 0.8 ml of quinoline 10 and 10 ml of chloro~orm, fo~lowing -the procedure described in Example I~A). To this solution was added, at a -temperature o~ -78C, a methanol solu-tion o~
lithium methoxide prepared from 11 mg of lithium and 1 ml of methanol. The mixture was stirred at -78C
15 ~or 10 minutes and -then treated with 0.1 ml of acetic acid. The resulting solution was poured into a solution of sodium chloride and then extracted with ethyl ecetate. The ex-tracts were washed with wa-ter and dried over anhydrous sodium sulphate; the solvent 20 was then èvaporated off under reduced pressure. The resi~ue was chromatographed on silica gel, giving 50 mg o~ 2-(7~--chloroacetamido-7~-methoxy-3-methyl-3-cephem-4-carbonyl)-triazolor4,3-a~pyrido-3~one.
NMR spectrum (CD3COCD~)~ ppm = 2.0t3H, singl~t), ~5 3.25 & 3.53 (2H, AB quartet, j = 19 Hz), 3.42 (3H, single-t), 3.77 (2H, singlet), 5.20 (lH, singlet), 6.4 - 6.7 (lHt multiplet), 7.0 _ 7 4 (2H, multiplet) t 7.6 - 7.8 (lH, multiplet).
-~7-~-.!
~C)6Sl35Z
EXAMP~E 3 __ ___ (A) ~ h ~::5~$~C!_L~ae9aL~tte . .
A solu-tio-n of benæhydryl 7~-(2'-bromo~ chloro-
2'-phenylethylidenirnino)~3-methyl-3-cephem 4-carboxylate in tetrahydro~uran was prepared ~rom 1.7 g of benzhydr~l 7~-(2'-bromo-2'-phenylacetamido)--3-methyl-3-cephem-4~7~-~2'-bromo-2'phenylacetamido)-3-methyl 3-cephem-4-carbo~ylate, 0.81 g o~ phosphorus pentachloride and 0.6 ml of ~uinoline7 follo~ing the procedure described in Example I(A). To this solution was added, at a temperature of -70C, a solution of lithium methoxide in methanol prepared ~rom 160 mg of lithium and :L5 ml - of methanl. The resul-ting mixture was stirred a-t -70C
~or 30 minutes, quenched with 1.~ ml of acetic acid, poured into water and then ex-tracted with eth~l acetate.
The e~tracts were washed with water and dried over sodium sulphate. The solvent was evaporated off under reduced pressure and the residue was purified by silica gel chromatography to af~ord 0.9 g of benzhydryl 7~-methoxy-
~or 30 minutes, quenched with 1.~ ml of acetic acid, poured into water and then ex-tracted with eth~l acetate.
The e~tracts were washed with water and dried over sodium sulphate. The solvent was evaporated off under reduced pressure and the residue was purified by silica gel chromatography to af~ord 0.9 g of benzhydryl 7~-methoxy-
3-methyl 7~-phenylketenimino-3-cephem~ carboxylat~. ;
I~ spectrum (Nujol ~ Trade Mark)~maxcm 1 = 2000,1780,1730.
NMR spectrum (CDC13)Sppm - 2.20 (3H, singlet), 2.93 & 3.13 (2H, AB quartet), 2S 3 70 (3H, singlet)~
5.00 (lH, singlet), 5.22 (lH, singlet), 6.87 (lH, singlet), 7,0 - 7.6 (15H, multiplet).
~3~) ~Jnetb~ 4 bo~ _r a~id.
0.2 ml o~ -tri~luoroacetic acid was added to a solution o~ 50 mg of -the benzhydryl 7~-methoxy~3-methyl-7~-phenylketenimino-3-cephem-4~carboxyla-te prepared above in 1 ml of chloro~orm. The solution was stirred at room temperature for 1 hour, and then the solvent was evaporated off under reduce~ pressure. The residue was dissolved in ethyl acetate and extracted with a 10 10% w/v aqueous solution of dipotassium hydrogen phosphate.
~he aqueous extracts were acidi~ied wi-th dilute hydrochloric acid to pH 2.2 and then extracted with ethyl acetate.
The extracts were washed with water`and dried over sodium sulphate; the solvent was then evaporated off, 15 giving 27 mg o~ 7~-methoxy-3-met~lyl~7~-phenylacetamido-3-cephem-4-carboxylic acid.
IR spectrum (Nujol - Trade Mark)~ maxcm = 325011770,1700.
NMR spectrum (CDC13) 6 ppm = 2.20 (3H, singlet), 3.17 (2H, single-t), 20 3.38 (3H, singlet), 3.63 (2H, singlet),
I~ spectrum (Nujol ~ Trade Mark)~maxcm 1 = 2000,1780,1730.
NMR spectrum (CDC13)Sppm - 2.20 (3H, singlet), 2.93 & 3.13 (2H, AB quartet), 2S 3 70 (3H, singlet)~
5.00 (lH, singlet), 5.22 (lH, singlet), 6.87 (lH, singlet), 7,0 - 7.6 (15H, multiplet).
~3~) ~Jnetb~ 4 bo~ _r a~id.
0.2 ml o~ -tri~luoroacetic acid was added to a solution o~ 50 mg of -the benzhydryl 7~-methoxy~3-methyl-7~-phenylketenimino-3-cephem-4~carboxyla-te prepared above in 1 ml of chloro~orm. The solution was stirred at room temperature for 1 hour, and then the solvent was evaporated off under reduce~ pressure. The residue was dissolved in ethyl acetate and extracted with a 10 10% w/v aqueous solution of dipotassium hydrogen phosphate.
~he aqueous extracts were acidi~ied wi-th dilute hydrochloric acid to pH 2.2 and then extracted with ethyl acetate.
The extracts were washed with water`and dried over sodium sulphate; the solvent was then evaporated off, 15 giving 27 mg o~ 7~-methoxy-3-met~lyl~7~-phenylacetamido-3-cephem-4-carboxylic acid.
IR spectrum (Nujol - Trade Mark)~ maxcm = 325011770,1700.
NMR spectrum (CDC13) 6 ppm = 2.20 (3H, singlet), 3.17 (2H, single-t), 20 3.38 (3H, singlet), 3.63 (2H, singlet),
4.~5 (lH, singlet), 6.92 (lH, singlet), 7.22 (5H, singlet).
[I~.35c~e-th xy-~-m ~ C enimino-3-Following the ~rocedure described in Example l(A), benzhydryl-7~-(1',2'-dichloro-2'-phenylethylidenimino)-3 methyl-3-cephem-4-carboxyla-te was prepared ~rom 1.06 g of benzhydryl ~ (2'-chloro 2'-phenylacetamido)-3-me-thyl-3-cephem~4-carboxylate, 0.54 g of phosphorus pentachloride and 0.4 ml of quinoline and was then ~ dissolved in 40 ml o~ tetrahydrofuran. To this solution was addedj a-t a tempera-ture o~ -70C, a solution of lithium me-thoxide in methanol prepared from lO0 mg o~ lithium and lO ml o~ methanol. The reaction mixture was stirred at -70~ for 30 minutes, treated with 1 ml o~ acetic acid, poured into water and extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous sodium sulphate and the solven-t was then evaporated of~. The residue was chromatographed on silica gel, giving 0.7 g o~ benzhydryl 7~-methoxy-3-methyl-7~-phenylketenimino-3-cephem-4-carboxylate.
Following the procedure dcscribed in Example 3(~), ~his was convertecl to 7~-methoxy-3-methyl-7~-phenyl-lacetamido-3-cephem-4-car~oxylic acid.
, . .~ . . . . . . . . . .
.: .: . , . . i ,. . . . .. . . .
;, , , , , , . . . , : . . . .
1~6585Z
EXA~PLE 5 ~3 _ -~ 5 l.L= __x~late Benzhydryl 7~-(1',2'-dichloro-2' phenylethylide-nimino)-3-methyl-3-cephem 4-carboxyla-te was prepared from 257 mg of benzhydryl 7~--(2'-hydroxy-2'-phenylacet-amido)-3-meth~1-3-cephem-4-carboxylate, 360 mg of phosphorus pentachloride and ~.26 ml of quinoline, following -the procedure described in Example l(A), and was then treated as described in Example 4 -to give 120 mg of benzhydryl 7~-methoxy-3-methyl--7~-phenylketenimino-3-cephem-4-carbo~ylate.
EXAMP~E 6 . .
(A) ~-Bromophenacyl 3-ace-toxymethyl-7~-me-thoxy-~ -15 phenylketenimino-3-cephem-4-carboxylate Following the procedure descr:ibed in Example l(A), ~-bromophenacyl 3-acetoxymethyl-7~-(1',2'-dichloro-2'-phenylethylidenimino)-3-cephem-4-carboxylate was prepared from 0.62 g of ~-bromophenacyl 3-acetoxymethyl-20 7~-(2'-chloro-2'-phenylacetamido)-3-cephem-4-carbox~late, 0.~ g o~ phosphorus pen-tachloride and 0.2 ml of quinoline.
The compound was then dissolved in ~0 ~1 o~ tetrahydro~uran.
To thi~ solu-tion was added, at a tempera-ture of -70C, a solu-tion of lithium methoxide in methanol prepared from 25 40 mg oP lithium and 3 ml o~ methanol. The reaction '., ', .; :~ :- ' ,'': .; ' '"' .i ,' .: : '' ;' ' :';, " :', :' ' .
mixture was stirred at ~70~ for 30 minutes and then treated with 0.5 ml o~ aceti.c acid. The solut.ion was then poured into wa-ter and extracted wi.th ethyl aceta-l;e.
The extracts were washed wi-th water and dried over
[I~.35c~e-th xy-~-m ~ C enimino-3-Following the ~rocedure described in Example l(A), benzhydryl-7~-(1',2'-dichloro-2'-phenylethylidenimino)-3 methyl-3-cephem-4-carboxyla-te was prepared ~rom 1.06 g of benzhydryl ~ (2'-chloro 2'-phenylacetamido)-3-me-thyl-3-cephem~4-carboxylate, 0.54 g of phosphorus pentachloride and 0.4 ml of quinoline and was then ~ dissolved in 40 ml o~ tetrahydrofuran. To this solution was addedj a-t a tempera-ture o~ -70C, a solution of lithium me-thoxide in methanol prepared from lO0 mg o~ lithium and lO ml o~ methanol. The reaction mixture was stirred at -70~ for 30 minutes, treated with 1 ml o~ acetic acid, poured into water and extracted with ethyl acetate. The extracts were washed with water and dried over anhydrous sodium sulphate and the solven-t was then evaporated of~. The residue was chromatographed on silica gel, giving 0.7 g o~ benzhydryl 7~-methoxy-3-methyl-7~-phenylketenimino-3-cephem-4-carboxylate.
Following the procedure dcscribed in Example 3(~), ~his was convertecl to 7~-methoxy-3-methyl-7~-phenyl-lacetamido-3-cephem-4-car~oxylic acid.
, . .~ . . . . . . . . . .
.: .: . , . . i ,. . . . .. . . .
;, , , , , , . . . , : . . . .
1~6585Z
EXA~PLE 5 ~3 _ -~ 5 l.L= __x~late Benzhydryl 7~-(1',2'-dichloro-2' phenylethylide-nimino)-3-methyl-3-cephem 4-carboxyla-te was prepared from 257 mg of benzhydryl 7~--(2'-hydroxy-2'-phenylacet-amido)-3-meth~1-3-cephem-4-carboxylate, 360 mg of phosphorus pentachloride and ~.26 ml of quinoline, following -the procedure described in Example l(A), and was then treated as described in Example 4 -to give 120 mg of benzhydryl 7~-methoxy-3-methyl--7~-phenylketenimino-3-cephem-4-carbo~ylate.
EXAMP~E 6 . .
(A) ~-Bromophenacyl 3-ace-toxymethyl-7~-me-thoxy-~ -15 phenylketenimino-3-cephem-4-carboxylate Following the procedure descr:ibed in Example l(A), ~-bromophenacyl 3-acetoxymethyl-7~-(1',2'-dichloro-2'-phenylethylidenimino)-3-cephem-4-carboxylate was prepared from 0.62 g of ~-bromophenacyl 3-acetoxymethyl-20 7~-(2'-chloro-2'-phenylacetamido)-3-cephem-4-carbox~late, 0.~ g o~ phosphorus pen-tachloride and 0.2 ml of quinoline.
The compound was then dissolved in ~0 ~1 o~ tetrahydro~uran.
To thi~ solu-tion was added, at a tempera-ture of -70C, a solu-tion of lithium methoxide in methanol prepared from 25 40 mg oP lithium and 3 ml o~ methanol. The reaction '., ', .; :~ :- ' ,'': .; ' '"' .i ,' .: : '' ;' ' :';, " :', :' ' .
mixture was stirred at ~70~ for 30 minutes and then treated with 0.5 ml o~ aceti.c acid. The solut.ion was then poured into wa-ter and extracted wi.th ethyl aceta-l;e.
The extracts were washed wi-th water and dried over
5 anhydrous sodium sulphate; the solvent was then evaporated off under reduced. pressure. The residue was purified by silica gel chromatography~ giving 0.3 g of ~-bromophenacyl 3-acetoxymethyl-7~-methoxy- -7~-phenylketenimino-3-cephem-4-carboxylate.
10 IR spectrum (liquid)~maxcm 1 = 2000,1780,1740,1700 NMR spectrum (CDCI3)6 ppm = 2.00 (~H, singlet), 3~22 & 3.40 (2H, AB quartet, J = 15 Hz), 3.60 (3H, singlet), 4.97 (lH, singlet), 15 4.90 & 5.18 (2H, AB quarte-t, ; .- 16 Hz), i 5.18 (lH, singlet), ! 5.40 (2~I, single-t), 7.0 - 7.4 (5H), 7-4 - 7.9 (4Ho.
.
20 (B) ~-Bromophenacyl 3-acetoxymethyl-7~-methoxy-7~-phenyl-~9~b~ox~
. .
2 ml of trifluoroacet;i.c acid was adcled to a ~olu tio~ of 500 mg o~ th~ bromophenacyl 3-acetoxymethyl-7~-methoxy-7~-phenylketen.imino-~-cephem-~-carboxylate 25 prepared above i.n lO ml of chloroform. The solution was stirred at room temperature for 2 hours and then ~ lal658~2 evaporatcd to dryness ~der reduced pressure. The residue was dissolved in e-thyl ace-ta-te and washed wit.h a 10% w/v dipo-tassium hydrogen phospha-te solu-tion and water, and was dried over sodium sulphate; the sol~e~t 5 was then evapora-ted off, giving 470 mg o~ ~bromophenacyl 3 acetoxymethyl-7~-methoxy-7~-phenylacetamido-3~cephem--4-carboxylate.
¦ NMR spectrum (CDC13j~ ppm = 2.07 (3H, singlet), 3.35 & ~.55 (2H, AB quartet, J =17 Hz), 10 ~.40 (3H, singlet), 3.67 (2H, singlet), 5.03 (2H, AB quartetS~J = 13 Hz), 5.07 (lH, singlet), 5.40 (2H, singlet), 15 7.32 (5H)~
7-5 7-9 (4H).
`.
~-Bromophenacyl 3-acetox_methyl-7~-methoxy-7~-phen~lacet-amido 3-cephem-4-carbox~late A solution o~ 100 mg of ~-bromophenacyl-3-acetoxy-methyl-7~-methoxy-7~-phenylketenimino-3-cephem-4-carboxylate in tetrahydro:Euran~preparecl as descrlbed in E~ampl~ 6(a)~ wa~ adjusted to pH 3.0 ~y addition o~
dilute h~drochloric acid. The reaction mixture was 25 then stirred at 10C overnight, a~ter which it was poured lnto water and ex-tracted with ethyl acetate.
, .. ~ . ' ~33- ~
~65~352 The extracts were washed with water and dried over anhydrous sodium sulphate;. the solvent was then evaporated o~ under reduced pressure. The residue was chromatographed on silica gel, giving 20 mg o~
~-bromophenacyl 3-ace-toxymethyl--r~~methox~-f~phenylacet amido~3-cephem-4-carboxylate.
(A) Benzhydry~7~-methox~-3-methyl- ~ -methy]ketenimino-3-~4~
Following the procedure described in ~xample l(A), benzhydryl 7~-(2'-bromo-1'-chloropropylidenimino)-3-methyl-3-cephem-4-carboxylate was prepared ~rom 515 mg o~ benzhydryl 7~-(2'-bromo~ropionamido)-3-me-thyl-~-cephem-4-carboxylate, 270 mg o~ phosphorus pentachloride and 0 2 ml o~ ~uinoline, and was then dissolved in 40 ml o~
tetrahydro~uran. To this solution was added, at a temperature of -70C, a me-thanol solution o~ lithium methoxide prepared ~rom 50 mg o~ lithium and 4 ml o~
methanol. The reaction mixture was stirred at -70C
for 30 minutes and 0.4 ml of acetic acid was then added.
; The solution was then poured into water and extracted with ethyl acetate. The extracts were washed wlth water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~ under reduced pressure, giving 480 mg of crude benzhydryl 7~ methoxy-3-methyl-7~-methylketenimino-3-cephem-4-carboxyla~e.
IR spectrum (liquid)~ maxcm 1 _ 2020,1770,1710.
:IL065~52 5~G~L~ b_~Y=~ h~ ~7~=
ce~m-4-carbox~la~e .
The benzhydryl 7~-methoxy-3-methyl-7~-me-thylketen-imi.no-3 cephem-4-carboxylate obtained above was dissolved in 20 ml of chloro~orm containing 1 ml o*
tri.~luoroacetic acid. The solution was stirred for 20 hours at room température, and the solvent was then evaporated o~f under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solu-tion was washed with water and then dried over anhydrous sodium sulphate. To this ethyl acetate solution was added an excess of diphenyldiazomethane ; and the mixture was maintained at room temperature overnight. The solvent was then evaporated o:E* under reduced pressure and the residue was washed with n-hexane and chromatographed on silica gel, giving 90 mg o~ pure benzhydryl 7~-methoxy-3-rnethyl-7~-propionamido-3-cephem-4-carboxylate, as an oil.
IR spectrum (liquid)~ cm 1 = 3350,1780,1725,I690. ~;
NMR spectrum (CDC13)~ ppm = 1.15 (3H, triplet; J = 6 Hz), 2.10 (3H, singlet), Z.30 (2H, quartet, J = 6 Hz), 3.13 (2H, ~inglet), 3.~3 (3H, singlet), 4.97 (lH, singlet)
10 IR spectrum (liquid)~maxcm 1 = 2000,1780,1740,1700 NMR spectrum (CDCI3)6 ppm = 2.00 (~H, singlet), 3~22 & 3.40 (2H, AB quartet, J = 15 Hz), 3.60 (3H, singlet), 4.97 (lH, singlet), 15 4.90 & 5.18 (2H, AB quarte-t, ; .- 16 Hz), i 5.18 (lH, singlet), ! 5.40 (2~I, single-t), 7.0 - 7.4 (5H), 7-4 - 7.9 (4Ho.
.
20 (B) ~-Bromophenacyl 3-acetoxymethyl-7~-methoxy-7~-phenyl-~9~b~ox~
. .
2 ml of trifluoroacet;i.c acid was adcled to a ~olu tio~ of 500 mg o~ th~ bromophenacyl 3-acetoxymethyl-7~-methoxy-7~-phenylketen.imino-~-cephem-~-carboxylate 25 prepared above i.n lO ml of chloroform. The solution was stirred at room temperature for 2 hours and then ~ lal658~2 evaporatcd to dryness ~der reduced pressure. The residue was dissolved in e-thyl ace-ta-te and washed wit.h a 10% w/v dipo-tassium hydrogen phospha-te solu-tion and water, and was dried over sodium sulphate; the sol~e~t 5 was then evapora-ted off, giving 470 mg o~ ~bromophenacyl 3 acetoxymethyl-7~-methoxy-7~-phenylacetamido-3~cephem--4-carboxylate.
¦ NMR spectrum (CDC13j~ ppm = 2.07 (3H, singlet), 3.35 & ~.55 (2H, AB quartet, J =17 Hz), 10 ~.40 (3H, singlet), 3.67 (2H, singlet), 5.03 (2H, AB quartetS~J = 13 Hz), 5.07 (lH, singlet), 5.40 (2H, singlet), 15 7.32 (5H)~
7-5 7-9 (4H).
`.
~-Bromophenacyl 3-acetox_methyl-7~-methoxy-7~-phen~lacet-amido 3-cephem-4-carbox~late A solution o~ 100 mg of ~-bromophenacyl-3-acetoxy-methyl-7~-methoxy-7~-phenylketenimino-3-cephem-4-carboxylate in tetrahydro:Euran~preparecl as descrlbed in E~ampl~ 6(a)~ wa~ adjusted to pH 3.0 ~y addition o~
dilute h~drochloric acid. The reaction mixture was 25 then stirred at 10C overnight, a~ter which it was poured lnto water and ex-tracted with ethyl acetate.
, .. ~ . ' ~33- ~
~65~352 The extracts were washed with water and dried over anhydrous sodium sulphate;. the solvent was then evaporated o~ under reduced pressure. The residue was chromatographed on silica gel, giving 20 mg o~
~-bromophenacyl 3-ace-toxymethyl--r~~methox~-f~phenylacet amido~3-cephem-4-carboxylate.
(A) Benzhydry~7~-methox~-3-methyl- ~ -methy]ketenimino-3-~4~
Following the procedure described in ~xample l(A), benzhydryl 7~-(2'-bromo-1'-chloropropylidenimino)-3-methyl-3-cephem-4-carboxylate was prepared ~rom 515 mg o~ benzhydryl 7~-(2'-bromo~ropionamido)-3-me-thyl-~-cephem-4-carboxylate, 270 mg o~ phosphorus pentachloride and 0 2 ml o~ ~uinoline, and was then dissolved in 40 ml o~
tetrahydro~uran. To this solution was added, at a temperature of -70C, a me-thanol solution o~ lithium methoxide prepared ~rom 50 mg o~ lithium and 4 ml o~
methanol. The reaction mixture was stirred at -70C
for 30 minutes and 0.4 ml of acetic acid was then added.
; The solution was then poured into water and extracted with ethyl acetate. The extracts were washed wlth water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~ under reduced pressure, giving 480 mg of crude benzhydryl 7~ methoxy-3-methyl-7~-methylketenimino-3-cephem-4-carboxyla~e.
IR spectrum (liquid)~ maxcm 1 _ 2020,1770,1710.
:IL065~52 5~G~L~ b_~Y=~ h~ ~7~=
ce~m-4-carbox~la~e .
The benzhydryl 7~-methoxy-3-methyl-7~-me-thylketen-imi.no-3 cephem-4-carboxylate obtained above was dissolved in 20 ml of chloro~orm containing 1 ml o*
tri.~luoroacetic acid. The solution was stirred for 20 hours at room température, and the solvent was then evaporated o~f under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solu-tion was washed with water and then dried over anhydrous sodium sulphate. To this ethyl acetate solution was added an excess of diphenyldiazomethane ; and the mixture was maintained at room temperature overnight. The solvent was then evaporated o:E* under reduced pressure and the residue was washed with n-hexane and chromatographed on silica gel, giving 90 mg o~ pure benzhydryl 7~-methoxy-3-rnethyl-7~-propionamido-3-cephem-4-carboxylate, as an oil.
IR spectrum (liquid)~ cm 1 = 3350,1780,1725,I690. ~;
NMR spectrum (CDC13)~ ppm = 1.15 (3H, triplet; J = 6 Hz), 2.10 (3H, singlet), Z.30 (2H, quartet, J = 6 Hz), 3.13 (2H, ~inglet), 3.~3 (3H, singlet), 4.97 (lH, singlet)
6.65 (lH~ broad singlet), 6.82 (lH, singlet),
7.1 - 7.6 (lOH, multiplet).
,~~r, ~ ~
lOI~iS8Si2 EXA~PLE ~
M~ acetor_cl~7 meth(?xy~3--me-th~1-3~ce~hem-4-carbo~ate , .
Follow:Lng the procedure described in Example i(A), metkyl 7~-(2'-bromo-1'-chloroethylidenimino)-3-me-thyl-3-cephem-LI-carboxyla-te was prepared ~rom 1.34 g o~ methyl 7~-bromoace-tamido-3-methyl-3-cephem--4-carboxylate~
1.5 g of-phosphorus pentachloride and 1 ml o~ quinoline.
The compound was then dissolved in 80 ml o~ tetrahydrofuran and a methanol solution of lithivm methoxide (prepared ~rom 200 mg of lithium and 20 ml of methanol) was added at -70 C. The reaction mixture was stirred a-t -70C for 30 minutes and then 2.5 ml o~ trifluoroacetic acid were added and stirring was continued at room temperature ~or 10 minutes. The mixture was -then poured into water and ?
extracted with ethyl acetate. The extracts were washed with a 10% w/v dipotassium hydrogen phospha-te solution and water and dried over anhydrous sodium sulphate.
The solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel, giving 250 mg o~ methyl 7~-acetamido-7~rmetho~y-3-methyl-3-cephem-~-ca.rboxylate.
IR spect~1m ~liquid)~maxcm ~ - 3220,1770, 1730,1690-NMR spectrum (cDcl3)6 ppm = 2.13 (6H, singlet), 25 3.20 & 3.37 (2H, AB quarte-t, J = 17 Hz), 3 .
3~55 (3H~ singlet)~
3.83 (3H, singlet), 5.07 (lH, singlet), 7.52 (lH, singlet).
,.-........... 1.
, 1~16585Z
3-Acetoxyme-thyl-7~- th~_y-7~ thienylace-tamido)-3-_ hem~ carboxylic acid _, Following the procedur~ described in ~xample l(A), benzhydryl 3-acetoxymethyl 7~-(1',2'-dichloro-2'-~-thienylethylidenimino3-3-cephem-4-carboxyla-te was prepared from 597 mg of benzhydryl 3-acetoxymethyl~7~-(chloro-~thienylacetamido)-3~cephem-4 carbox~late, 360 mg o~ phosphorus pentachloride and 0.2~ ml of quinoline. To the resulting solution was added, at a ; 10 temperature of -70C, a methanol solution of lithium methoxide prepared from 12 mg o~ lithium and 2 ml of me-thanol. The mix-ture was stirred at -70C for 40 minu-tes after which 5 ml o~ trifluoroacetic ~cid were added. Stirring was continued at room temperature for 40 minutes and the solvent was then evaporated off under reduced pressure. The residue was dissolved i in ethyl acetate and extracted with a pH 7.5 buffer (an aqueous solution of disodium hydrogen phosphate ~
potassium dihydrogen phosphate). The a~ueous extracts were adjusted to pH 2.0 with dilute hydrochlorlc acid and then ex-tracted with ethyl acetate. The combi~ed extract~ were washed with water and dried over anhydrous magnesium sulphate and the solven-t was then evapora-ted o~f, giving 85 mg of 3-acetoxyme-thyl-7cL-metho~y-7~ thienylacetamido)-3-cephem-4-carboxylic acid.
NMR spectrum (CD~SOCD3 ~ D20)~ ppm = 2.01 (3H, single-t), 3.20 (lH, do~blet, J = 18 Hz), 3.33 (lH, doublet, J = 18 Hz), 3.40 (3H, singlet), 3.85 (2H, singlet) 4.88 (2H, almost singlet), .`
~1065852 5.04 (lH, singrle-t);
6.go - 7.45 (3H, multiplet).
FX~MPLE 11 s ~-cephem-4-carbo~lic ac.id - Following the procedure described in Example l(A)~
benzhydryl 3-carbamoyloxymethyl-7~ ,2'-dlchloro-2'-~-thienylethylidenimino) 3-cephem-4-carboxylate was prepared from 597 mg of benzhydryl 3-carbamouloxymethyl lo 7~(chloro-~--thienylacetamido)-3-cephem-4-carboxylate, 220 mg of phosphorus pentachloride and 0.15 ml of quinoline and the produc-t was dissolved in l~o ml of tetrahydrofuran. To this solu-tion was added, a-t a temperature of ~70C, a methanol solution o~ thium lS methoxide prepared from 12 mg of lithium and 4 ml of methanol. The reaction mixture was stirred at -70C
for 30 minutes. After adding 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 40 minutes. The solvent was then evaporated off under reduced pressure and the residue was extracted with ethyl acetate. The resulting solution was re-ex-trac-ted ....
wlth a pH 7.5 buffer (a~ueous solution Q~ disodium hydrogen phosphate ~ po-tasslum dihydrogen phosphat~
The aqueous extracts were acidified to pH 2.0 with dilute hydrochloric acid and -then extracted with ethyl ace-tate. The combined extracts were washed wi-th wa-ter and dried over anhydrous magnesium su].pha-te; the solvent was then evaporated off, giving 60 mg of 3-carbamoyloxymethyl-7~,-methcxy-7~ thienylacetamido)- '' 3-cephem-4-carboxylic acid.
-3~-.. ~
- - \
~ ~ 6 ~ ~5 Z
IR spectrum (Nujol - Trade Mark)~maxcm 1 = 3420~3~30,32~0, 17~3,17~.5,16~0,1665.
NMR spectrum ~CD3CN)~ ppm - 3.53 (3H, singlet), ~.38 (lH, double-t, J = 18 Hz), 3.60 (lH, doublet, J = 18 Hz), 3.90 (2H,single-t), 4.88 (2H, single-t), 5.07 (lH, singlet), 6.95 - 7.40 (3H, mul-tiplet).
.''.
EXAMP~E 12 Following the procedure described in Example 1(~), methyl 6-(1',2'-dichloro-2' phenylethylidenimino)-perlicillanate was prepared ~ro~ 300 mg o~ me-thyl 6-(2'-chloro-2'-phenylacetamido)-penicillanate, 300 mg o.
lS phosphorus pentachloride and 0.2 ml of quinoline;
the product was di.ssolved in 30 ml o~ te-trahydrafuron.
To this solution was added, at a temperature of -70C, a methanol solu-tion of lithium methoxide, prepared ~rom 40 mg o~ lithium and 3 ml o~ methanol. The reaction mixture was s-tirred at -70C for 30 mlnutes and -then treated with 0.5 ml o~ acetic acid. The x~sultin~
solution was poured into water and extracted with ethyl acetate. The extracts were washed wit~h water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~ uncler reduced pressure. The relsl~ue was purified by silica gel chromatography, giving 1~0 mg o~ methyl 6~-methoxy-6~-phenylketenimino -39~
~ ~ 6 S~ S 2 penicillinate, m.p. 80C f IR spec-trum (Nujol - Trade Mark)~maxcm 1 = 2000,1765517l~0.
NMR spectrum (CDCl~) ppm - 1.35 ~6~'L~ single-t), 3.36 ~3H, slngle-t), 3.61 ~2H~ singlet) 7 3.72 (3H, sing~et), 4.34 (lh~ singlet), 5.52 (lH, singlet),-7.25 (5H, singlet).
_..
(A) Meth~l 7~-diphen~lketenimino~ methox~-3-meth~1-3-cephem-4-carboxylate 720 mg of phosphorus pen-tachloride were dissolved lS in 32 ml of anhydrous chloroform and then 0.52 ml of quinoline was added.' To this mixture, whils-t cooling with ice, were added 480 mg of methyl 7-(2'-hydroxy-2', 2'-diphenyl-acetamido)-3-methyl-3-cephem-4-carboxylate.
The reaction mixture was stirred, whilst cooling with : 20 ice, for 40 minu-tes at the end of which -time the solvent was distilled off under reduced pressure. To the residue were added 40 ml of anhydrous tetrahydrofuran and the resulting crystalline substances were ~iltered o~:~. A~ter coollng to -78C, the filtrate was stirred 2~ at a temperature from -70C to -78C for 20 minutes with a methanol solutlon of lithium methoxide prepared from 48 mg of lithium and 6 ml of methanol. 0.5 ml of acetic acid were then added and the reaction mixture was poured into water, and ex-trac-ted with ethyl acetate.
The extracts were washed with water and dried and the solvent was then evaporated off. The residue was purified by chromatography on silica gel, giving 65 mg of methyl 7~-diphenylketenimino-7~ me-thoxy-3-methyl-3--~0-' " ~ ' ~ ` , ;
.~,, ,;. .
~1~)65~5Z
c~phem~ carboxylate.
IR spectrum (li~uid film)~ maxcm 1 = 1997,1775,1730 N~R spec-trum (CDC13) ppm = 2.16 (3Hg singlet)~
2~80 (2H, singlet), 3.56 (3H, singlet), 3.82 (3H, singlet), 4.92 (lH, single-t) 7.2 - 7.5 (lOH).
(B) M
cephem-4-carbox~late . .
85 mg o~ me-thyl 7~-diphenylketenimino-7~-methoxy-3-methyl-3-cephem-4-carboxylate, prepared as described above, were dissolved in 3 ml of chloroform and 0.3 ml o~ trifluoroacetic acid was added. The mix-ture was stirred at room tempera-ture ~or 30 minutes and the solvent was then distilled o~f under reduced pressure, Water was added to -the residue and the mixture was then extracted with ethyl acetate, washed with water and dried, giving 83 mg of me-thyl 7 ~ diphenylacetamido-7 -me-thoxy-3-methyl-3-cephem-4-carboxylate, IR spectrum (Nuj~l - Trade Mar~)~ maxcm = 3350,1785, ~ 1730,1690.
.
.
. .
,
,~~r, ~ ~
lOI~iS8Si2 EXA~PLE ~
M~ acetor_cl~7 meth(?xy~3--me-th~1-3~ce~hem-4-carbo~ate , .
Follow:Lng the procedure described in Example i(A), metkyl 7~-(2'-bromo-1'-chloroethylidenimino)-3-me-thyl-3-cephem-LI-carboxyla-te was prepared ~rom 1.34 g o~ methyl 7~-bromoace-tamido-3-methyl-3-cephem--4-carboxylate~
1.5 g of-phosphorus pentachloride and 1 ml o~ quinoline.
The compound was then dissolved in 80 ml o~ tetrahydrofuran and a methanol solution of lithivm methoxide (prepared ~rom 200 mg of lithium and 20 ml of methanol) was added at -70 C. The reaction mixture was stirred a-t -70C for 30 minutes and then 2.5 ml o~ trifluoroacetic acid were added and stirring was continued at room temperature ~or 10 minutes. The mixture was -then poured into water and ?
extracted with ethyl acetate. The extracts were washed with a 10% w/v dipotassium hydrogen phospha-te solution and water and dried over anhydrous sodium sulphate.
The solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel, giving 250 mg o~ methyl 7~-acetamido-7~rmetho~y-3-methyl-3-cephem-~-ca.rboxylate.
IR spect~1m ~liquid)~maxcm ~ - 3220,1770, 1730,1690-NMR spectrum (cDcl3)6 ppm = 2.13 (6H, singlet), 25 3.20 & 3.37 (2H, AB quarte-t, J = 17 Hz), 3 .
3~55 (3H~ singlet)~
3.83 (3H, singlet), 5.07 (lH, singlet), 7.52 (lH, singlet).
,.-........... 1.
, 1~16585Z
3-Acetoxyme-thyl-7~- th~_y-7~ thienylace-tamido)-3-_ hem~ carboxylic acid _, Following the procedur~ described in ~xample l(A), benzhydryl 3-acetoxymethyl 7~-(1',2'-dichloro-2'-~-thienylethylidenimino3-3-cephem-4-carboxyla-te was prepared from 597 mg of benzhydryl 3-acetoxymethyl~7~-(chloro-~thienylacetamido)-3~cephem-4 carbox~late, 360 mg o~ phosphorus pentachloride and 0.2~ ml of quinoline. To the resulting solution was added, at a ; 10 temperature of -70C, a methanol solution of lithium methoxide prepared from 12 mg o~ lithium and 2 ml of me-thanol. The mix-ture was stirred at -70C for 40 minu-tes after which 5 ml o~ trifluoroacetic ~cid were added. Stirring was continued at room temperature for 40 minutes and the solvent was then evaporated off under reduced pressure. The residue was dissolved i in ethyl acetate and extracted with a pH 7.5 buffer (an aqueous solution of disodium hydrogen phosphate ~
potassium dihydrogen phosphate). The a~ueous extracts were adjusted to pH 2.0 with dilute hydrochlorlc acid and then ex-tracted with ethyl acetate. The combi~ed extract~ were washed with water and dried over anhydrous magnesium sulphate and the solven-t was then evapora-ted o~f, giving 85 mg of 3-acetoxyme-thyl-7cL-metho~y-7~ thienylacetamido)-3-cephem-4-carboxylic acid.
NMR spectrum (CD~SOCD3 ~ D20)~ ppm = 2.01 (3H, single-t), 3.20 (lH, do~blet, J = 18 Hz), 3.33 (lH, doublet, J = 18 Hz), 3.40 (3H, singlet), 3.85 (2H, singlet) 4.88 (2H, almost singlet), .`
~1065852 5.04 (lH, singrle-t);
6.go - 7.45 (3H, multiplet).
FX~MPLE 11 s ~-cephem-4-carbo~lic ac.id - Following the procedure described in Example l(A)~
benzhydryl 3-carbamoyloxymethyl-7~ ,2'-dlchloro-2'-~-thienylethylidenimino) 3-cephem-4-carboxylate was prepared from 597 mg of benzhydryl 3-carbamouloxymethyl lo 7~(chloro-~--thienylacetamido)-3-cephem-4-carboxylate, 220 mg of phosphorus pentachloride and 0.15 ml of quinoline and the produc-t was dissolved in l~o ml of tetrahydrofuran. To this solu-tion was added, a-t a temperature of ~70C, a methanol solution o~ thium lS methoxide prepared from 12 mg of lithium and 4 ml of methanol. The reaction mixture was stirred at -70C
for 30 minutes. After adding 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 40 minutes. The solvent was then evaporated off under reduced pressure and the residue was extracted with ethyl acetate. The resulting solution was re-ex-trac-ted ....
wlth a pH 7.5 buffer (a~ueous solution Q~ disodium hydrogen phosphate ~ po-tasslum dihydrogen phosphat~
The aqueous extracts were acidified to pH 2.0 with dilute hydrochloric acid and -then extracted with ethyl ace-tate. The combined extracts were washed wi-th wa-ter and dried over anhydrous magnesium su].pha-te; the solvent was then evaporated off, giving 60 mg of 3-carbamoyloxymethyl-7~,-methcxy-7~ thienylacetamido)- '' 3-cephem-4-carboxylic acid.
-3~-.. ~
- - \
~ ~ 6 ~ ~5 Z
IR spectrum (Nujol - Trade Mark)~maxcm 1 = 3420~3~30,32~0, 17~3,17~.5,16~0,1665.
NMR spectrum ~CD3CN)~ ppm - 3.53 (3H, singlet), ~.38 (lH, double-t, J = 18 Hz), 3.60 (lH, doublet, J = 18 Hz), 3.90 (2H,single-t), 4.88 (2H, single-t), 5.07 (lH, singlet), 6.95 - 7.40 (3H, mul-tiplet).
.''.
EXAMP~E 12 Following the procedure described in Example 1(~), methyl 6-(1',2'-dichloro-2' phenylethylidenimino)-perlicillanate was prepared ~ro~ 300 mg o~ me-thyl 6-(2'-chloro-2'-phenylacetamido)-penicillanate, 300 mg o.
lS phosphorus pentachloride and 0.2 ml of quinoline;
the product was di.ssolved in 30 ml o~ te-trahydrafuron.
To this solution was added, at a temperature of -70C, a methanol solu-tion of lithium methoxide, prepared ~rom 40 mg o~ lithium and 3 ml o~ methanol. The reaction mixture was s-tirred at -70C for 30 mlnutes and -then treated with 0.5 ml o~ acetic acid. The x~sultin~
solution was poured into water and extracted with ethyl acetate. The extracts were washed wit~h water and dried over anhydrous sodium sulphate; the solvent was then evaporated o~ uncler reduced pressure. The relsl~ue was purified by silica gel chromatography, giving 1~0 mg o~ methyl 6~-methoxy-6~-phenylketenimino -39~
~ ~ 6 S~ S 2 penicillinate, m.p. 80C f IR spec-trum (Nujol - Trade Mark)~maxcm 1 = 2000,1765517l~0.
NMR spectrum (CDCl~) ppm - 1.35 ~6~'L~ single-t), 3.36 ~3H, slngle-t), 3.61 ~2H~ singlet) 7 3.72 (3H, sing~et), 4.34 (lh~ singlet), 5.52 (lH, singlet),-7.25 (5H, singlet).
_..
(A) Meth~l 7~-diphen~lketenimino~ methox~-3-meth~1-3-cephem-4-carboxylate 720 mg of phosphorus pen-tachloride were dissolved lS in 32 ml of anhydrous chloroform and then 0.52 ml of quinoline was added.' To this mixture, whils-t cooling with ice, were added 480 mg of methyl 7-(2'-hydroxy-2', 2'-diphenyl-acetamido)-3-methyl-3-cephem-4-carboxylate.
The reaction mixture was stirred, whilst cooling with : 20 ice, for 40 minu-tes at the end of which -time the solvent was distilled off under reduced pressure. To the residue were added 40 ml of anhydrous tetrahydrofuran and the resulting crystalline substances were ~iltered o~:~. A~ter coollng to -78C, the filtrate was stirred 2~ at a temperature from -70C to -78C for 20 minutes with a methanol solutlon of lithium methoxide prepared from 48 mg of lithium and 6 ml of methanol. 0.5 ml of acetic acid were then added and the reaction mixture was poured into water, and ex-trac-ted with ethyl acetate.
The extracts were washed with water and dried and the solvent was then evaporated off. The residue was purified by chromatography on silica gel, giving 65 mg of methyl 7~-diphenylketenimino-7~ me-thoxy-3-methyl-3--~0-' " ~ ' ~ ` , ;
.~,, ,;. .
~1~)65~5Z
c~phem~ carboxylate.
IR spectrum (li~uid film)~ maxcm 1 = 1997,1775,1730 N~R spec-trum (CDC13) ppm = 2.16 (3Hg singlet)~
2~80 (2H, singlet), 3.56 (3H, singlet), 3.82 (3H, singlet), 4.92 (lH, single-t) 7.2 - 7.5 (lOH).
(B) M
cephem-4-carbox~late . .
85 mg o~ me-thyl 7~-diphenylketenimino-7~-methoxy-3-methyl-3-cephem-4-carboxylate, prepared as described above, were dissolved in 3 ml of chloroform and 0.3 ml o~ trifluoroacetic acid was added. The mix-ture was stirred at room tempera-ture ~or 30 minutes and the solvent was then distilled o~f under reduced pressure, Water was added to -the residue and the mixture was then extracted with ethyl acetate, washed with water and dried, giving 83 mg of me-thyl 7 ~ diphenylacetamido-7 -me-thoxy-3-methyl-3-cephem-4-carboxylate, IR spectrum (Nuj~l - Trade Mar~)~ maxcm = 3350,1785, ~ 1730,1690.
.
.
. .
,
Claims (3)
AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED
AS FOLLOWS:
1. A process for preparing a compound of formula (1):
(1) wherein R1 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms or an aryl group; R2 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group, an alkylthio group having from 1 to 4 carbon atoms, an alkynylthio group having from 2 to 4 carbon atoms, an arylthio group, an azidoalkylthio group having from 1 to 4 carbon atoms, a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety, an alkyl-sulphonyl group having from 1 to 4 carbon atoms, a 5- or 6- membered heteorocyclic group, a 5- or 6- membered heterocyclicthio group, or a 5-or 6- membered heterocyclic-oxy group; R3 represents an alkyl group having from 1 to 4 carbon atoms; and Z represents a fragment of formula:
or wherein R4 represents a carboxyl group, an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, a haloalkoxycarbonyl group having from 1 to carbon atoms in the alkyl moiety, a benzyloxycarbonyl group which is unsubstituted or has one or more halogen, methoxy or nitro substituents, a diphenylmethoxy-carbonyl group, a trialkylsilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiety, a dialkylhalosilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiet, a phenacyloxycarbonyl group which is unsubstituted or has one or more halogen or nltro substituents, an acyloxycarbonyl group, a haloacyloxycarbonyl group, a dihalophosphinoxycarbonyl group, a dialkylphosphinoxy-carbonyl group or an aminocarbonyl group; and A represents a hydrogen atom, an azido group or a group of formula B-E wherein B represents an oxygen or a sulphur atom and E represents anacyl group, an alkyl group having from 1 to 4 carbon atoms or a substituted or unsubstituted carbamoyl, thiocarbamoyl or heterocyclic group which process comprises:
hydrolysing an alkoxyketeneimine of forumla (IV):
/
(IV) (in which R1, R2, R3 and Z are as defined above).
(1) wherein R1 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms or an aryl group; R2 represents a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an aryl group, an alkylthio group having from 1 to 4 carbon atoms, an alkynylthio group having from 2 to 4 carbon atoms, an arylthio group, an azidoalkylthio group having from 1 to 4 carbon atoms, a cyanoalkylthio group having from 1 to 4 carbon atoms in the alkyl moiety, an alkyl-sulphonyl group having from 1 to 4 carbon atoms, a 5- or 6- membered heteorocyclic group, a 5- or 6- membered heterocyclicthio group, or a 5-or 6- membered heterocyclic-oxy group; R3 represents an alkyl group having from 1 to 4 carbon atoms; and Z represents a fragment of formula:
or wherein R4 represents a carboxyl group, an alkoxycarbonyl group having from 1 to 4 carbon atoms in the alkyl moiety, a haloalkoxycarbonyl group having from 1 to carbon atoms in the alkyl moiety, a benzyloxycarbonyl group which is unsubstituted or has one or more halogen, methoxy or nitro substituents, a diphenylmethoxy-carbonyl group, a trialkylsilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiety, a dialkylhalosilyloxycarbonyl group having from 1 to 4 carbon atoms in each alkyl moiet, a phenacyloxycarbonyl group which is unsubstituted or has one or more halogen or nltro substituents, an acyloxycarbonyl group, a haloacyloxycarbonyl group, a dihalophosphinoxycarbonyl group, a dialkylphosphinoxy-carbonyl group or an aminocarbonyl group; and A represents a hydrogen atom, an azido group or a group of formula B-E wherein B represents an oxygen or a sulphur atom and E represents anacyl group, an alkyl group having from 1 to 4 carbon atoms or a substituted or unsubstituted carbamoyl, thiocarbamoyl or heterocyclic group which process comprises:
hydrolysing an alkoxyketeneimine of forumla (IV):
/
(IV) (in which R1, R2, R3 and Z are as defined above).
2. A process as claimed in claim 1, wherein said alkoxyketeneimine (IV) is hydrolysed by an aqueous mineral acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
3. A process as claimed in claim 1, wherein said alkoxyleteneimine (IV) is hydrolysed by an organic acid selected from the group consisting of acetic acid, trichloroacetic acid, tribromoacetic acid and trifluoroacetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA321,402A CA1065852A (en) | 1974-03-22 | 1979-02-13 | PROCESS FOR PREPARING 7.beta.-ACYLAMINO-7.alpha.-ALKOXYCEPHALOSPORINS OR 6.beta.-ACYLAMINO-6.alpha.-ALKOXYPENICILLINS |
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3239174A JPS5512036B2 (en) | 1974-03-22 | 1974-03-22 | |
| JP3239274A JPS5512034B2 (en) | 1974-03-22 | 1974-03-22 | |
| JP3973074A JPS5519235B2 (en) | 1974-04-08 | 1974-04-08 | |
| JP4153074A JPS5720957B2 (en) | 1974-04-13 | 1974-04-13 | |
| CA321,402A CA1065852A (en) | 1974-03-22 | 1979-02-13 | PROCESS FOR PREPARING 7.beta.-ACYLAMINO-7.alpha.-ALKOXYCEPHALOSPORINS OR 6.beta.-ACYLAMINO-6.alpha.-ALKOXYPENICILLINS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1065852A true CA1065852A (en) | 1979-11-06 |
Family
ID=27508134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA321,402A Expired CA1065852A (en) | 1974-03-22 | 1979-02-13 | PROCESS FOR PREPARING 7.beta.-ACYLAMINO-7.alpha.-ALKOXYCEPHALOSPORINS OR 6.beta.-ACYLAMINO-6.alpha.-ALKOXYPENICILLINS |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1065852A (en) |
-
1979
- 1979-02-13 CA CA321,402A patent/CA1065852A/en not_active Expired
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