Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This invention relates to new antibacterials, 7~-
(fluorinated methylthioacetamido)-7-methoxy-3-(1-hydroxy
alkyl-5-tetrazolyl)thiomethyl-1-dethia-1-oxa-3-cephem-4-carb-
oxylic acids and their derivatives of the follo~ting formula :
OCH3
RSC~l2COMH~--O~
~ ~C~2 S~~ ~ ( I )
COOR2 p~l
wherein, R is FC~- or F2CH-;
Rl is R'O-substituted-alkyl, in which R3 is h~drogen or
a hydroxy-protectlng group; and
R2 is a hydrogen or light metal atom or a carboxy-
protecting group~
In the above formula (I), the hydroxyalkyl represented
by R~ can be hydroxyethyl, hydroxypropyl, hydroxyisopropyl, or
the like. The protecting group P~3 of this hydroxyalkyl can
contain 1 to 12 carbon atoms and form an aliphatic acid ester
(e.g~, chloroacetate, dichloroacetate), carbonate ester (e.g~,
butoxyformate, benzyloxyformate, alkylbenzylo;:yformate),
alkanoate ester (eOg. acetate, propionate, ben~oate), alkoxy-
alkyl ether (e.g.l methoxymethyl ether, ethoxyethyl ether,
tetrahyarofuranyl ether, tetrahydropyranyl ether), alkyl ether
(e.g., tert-butyl ether), aralkyl ether (e.g., diphenylmethyl
ether), silyl ether (e.g., trimethylsilyl ether, àimethyl-t-
butylsilyl ether~, stannyl ether (e.g., trimethylst2nnyl
- 2 -
~ 2~
ether), or ot~er equivalent protecting group.
The carboxy-protecting group for Compound (I) can be a
conventional carboxy deri~atlve includins, for example, an
inorganic salt (e.g., lithium, sodium, potassium, magnesium,
calcium, aluminum, or ammonium salt); organic base s21t
(alkylamine, e.g., ethylamine, ciiethylamine, triethylamine,
piperidine, morpholine, arorlatic amine, e.g., aniline,
dimethylaniline, naphthylamine, aromatic base, e.g., pyridine,
picoline, lutidine, quinoline, nicotinamide~; 1 to 8C
aliphatic ester (e.g., methyl, ethyl, propyl~ isopropyl,
butyl, isobutyl, t-butyl, hexyl ester), 7 to 15C aralkyl ester
(e.g., benzyl, p-methylbenzyl, di~ethylben~yl, methoxï~enz~l,
nitrobenzyl, diphenylmethyl ester~, 6 to 12C aromatic ester
(e.g., phenyl, trichlorophenyl, diisopropylphenyl ester), 3 to
12C silyl ester (e.g., trimethylsilyl, dir;ethylmethoxysilyl
ester), 3 to 12C stannyl ester (e.g., trimethylstannyl ester),
acid anhydride (iOe., syr~.etric ar.hydride or unsy~metric
anhydride with an inorganic acid~ e.g., carbonic acid,
sulfuric acid, phosphoric acid, sulfinic acid, or 1 to 12C
organic acid as a carboxylic acid, e.g., acetic acid,
propionic acid, v21eric acid, benzoic acid, 1 to 12C sl~lfonic
acid, e.g~, methanesulfonic acid, ethanesulfonic acid,
benzenesulronic acid, mesitylenesulfonic acid, or the li~e),
or an alride of an equivalent erfect.
The light rletal salt is a physiologically 2ccept2ble
- 3 -
~s~
salt of the carbo~y ~ith a light metal atom of 1st to 3rd
group, 2nd to ~th series or the Periodical Table, eOg.,
lithium, sodium, pc.assium, magnesium, calcium, aluminum.
The pharmacological esters of Compound (I) are oral or
parenteral antibacterials, including substituted alkyl esters
as 1-alkanoyloxyalkyl, e.g., acetoxymethyl, propion~loxy-
ethyl, pivaloyloY.ymethyl; 3 to 6C alkoxyformyloxyalkyl, e.g~,
l-ethoxycarbonyloxyethyl; and 4-methyl-2-oxo-1,3-dioxol-4-
en-4-ylmethyl ester; 7 to 15C substituted aralkyl esters,
e.g., phenacyl, phthalidyl ester, and 6 to 12C optionally
substituted aryl esters, e.y., phenyl, xylyl, indanyl ester.
Compounds (I) show antibacterial effects on contacting
with Gram-positive or Gram-nesative bacteria. They are userul
as bacterial growth inhibitors on human, anlmal, plant, or
perishable objects, or as growth-promoting additives in human
or animal feedstuf~s. For example, they are useful for
treating or preventing human, veterinary, or poultry infec-
tions caused by sensitive Gram-positive bacteria, e.g.,
Bacillus cereus~ Baclllus subtilis, Corynebacterlum
diphtheriae, StaPhYlococcus aureus, Stre~tococcus PVroqeneS,
Streptococcus Pneumoniae~ or enterococci, or Gram-negative
bacteria, e.g., Enterobacter cloacae, Escherichia coli,
Klebsiella Pneumoniae, Proteus mirabilis, Proteus mo~anii,
Proteus rettqeri, Proteus vulqaris, Salmonella paratyDhi,
_
Salmonella t~Jphi, Seratia marsescens, Shl~qella sonnei, or
some anaerobic bacteria, e.g., Bacteroides fraqills.
Compounds ~I) are also userul as starting materials for
synthesizing other antibacterials.
Compounds (I) are useful in various oral or p~renteral
dosage forms solely or with other coacting substances. The
pharmaceutical compositions contain 0.01 to 99 ~ of Compound
(I) aissolved, dispersed, or suspended in a solid or liquid
pharmaceutical carrier. They are solid preparations, e.gO,
tablets, powder, dry syrups, troches, granules, capsules,
pills, suppositorles, or the like: or liquid preparations,
e.g~, injections, ointements, dispersions, inhalants, suspen-
sions, solutions, emulsions, syrups, elixirs, or likeO They
can be 1avored or colored, and t2blets, granules, and caps-
ules may be coatedO They can be in a unit dosage form. The
carriers are harmless to both Compound (I) and patients and
include, for solids, binders, e.g., acacia, carboxymethyl-
cellulose, gelatin, glucose, polyvinylpyrrolidone, sodium
alginate~ sorbitol, s.arch, syrups, tragacanth; bulking
agents, e.50, bentonite, calcium carbonate, calcium phosphate,
glycine, kaoline, lactose, salt, sorbitol, starch, sugar,
talc; diluents, e.g.~ calcium carbonate, kaolin, lactose,
starch, sucrose; disirtegrators, e.g~, agar, carbonates, sod-
ium laurylsulfate, starch; lubricants, e.g., boric acid, C2C20
oil, magnesium stearate, paraffin, polyethylene glycol,
silica, sodium benzoate, stearic acid, tzlc; or wetting 2sent;
for solutions, solvents e.g., water, buffer, peanut oil,
sesa~le oil, methyl oleate; emulsifying agents e.s. acacia,
lethicin, sorbitan monooleate; suspending agents, e.gO,
carboxymethylcellulose, glucose, methyl cellulose, sorbitol,
sugar syrup, gelatin, hydroxyethylcellulose, carboxyMethyl-
cellulose, aluminum stearate gel, hydrogenated fats; buffers;
dispersins agents; or solubilizing agents; or for both, pre-
servatives, e.g., methyl or ethyl p-hydroxybenzoate, sorbic
acid; antioxidants; aromatic substances; analgesics; edible
coloring agents; stabilizing agents; a~sorption promoters,
e.g., glycerin mono or di-alkanoates; or the like
Compounds (I) are stable and effective against bacteria
resistant to other ~-lactams. They have better characters,
e.g., less Antabuse-like reaction, absorption, distriution,
metabolism, excretion, etc. than other ~-lactams. Usually,
their doses are 10 ~g to 1 mg topically or 1 to 2 g orally of
the pharmaceutical esters or free acids, and 0.2 to 5 g of
light metal salts or pharmaceutical esters intravenously or
intramuscularly daily for preventing or treating bacterial
infections. The dose and interval can be varied according to
the sort of bacteria and seriousness of the disease.
- Compound ~I) are produced, e.g., as follows:
1) Amidation.
Compound ~I) can be produced by amidating the following
Amine (II) or its reactive derivative ~ith a fluorinated
~,f'~
~ 9 ~
methylthioacetic acid ~III) or its reactive derivative:
OCH3
~2~
~ H2S 1~ P~SCH2COO~ (III~ or its (I)
tII) COOR2 RL reactive derivative
wherein, R, R~, and R2 are as defined above,
Amine ~II) is preparable by the method o~ e.g., Japanese
Pztent Application Kokai 56-3~993. The reactive derivative
of Amine ~II) has 7-amino activated by, e.g., silyl (e.g.,
trimethylsilyl, methoxydimethylsilyl), stannyl te.g.,
trimethyl~tannyl), alkylene (a residue of e~amino fro~, e.g.,
acetone, acetylacetone, acetoacetate, acetoacetonitrile,
acetoacetanilide, cyclopentanedione, acetylbutanolide),
alkylidene (e.g., l-chloroethylidene, l-chlorobe~zylidene,
l-methoxyethylidene, l-butoxy-l-phenoxyethylidene, ?ropyll-
dene, benzylidene), or acid (forming a salt of the amino with
a mineral acid, e~g., hydrochloric acid, sul~uric acia;
carboxylic acid, e.g., acetic acid, succinic acid; sulfonic
acid, e.g~, methanesulfonic, ethanesulfonic, benzenesulfonic
acid); or the carboxy protected as referred to above.
The fluorinated methylthioacetic acid ~III) are produced
by reacting a fluoromethyl halide, an alcoholic alcoholate,
and a thioglycolate, e.g., 1 to ~C alkyl ester. The reac-
tive derivative or tne acid (III) to be preparea in z con-
ventional m2aner i;cluZes an acid anhydride, acid halide,
`~
reactive ester, reactive amide, azide, or the like.
The process of above acylation i., as follo~s:
a) ~ree acid (III) - One to t~lo molar e~uivalents of Acid
~III) is reacted with ~ine (II) preferably in the presence
of 1 to 2 molar e~uivalents of a condensing reasent (carbo-
diimide, e.g., NrN'-diethylcarbodiimide, N,M'-dicyclohexyl-
carbodiimide; carbonyl compound, e.g., carbonyldiimidazole;
isoxazolinium salt; acylamino compound, e.g., 2~ethoxy-1-
ethoxycarbonyl-1,2-dihydroquinoline; or the like) preferably
in a nonprotic solvent, e.g., halohydrocarbonr nitrile,
ether, amide, or the like solvent or a mixture thereof.
b) Acid anhydride - This includes a symmetric anhydride,
mixed anhydride (with mineral acid, e~g., phosphoric acid,
sulfuric acid, carbonic half ester; 1 to 5C alkanoic acid, 7
to 12C aralkanoic acid, 1 to 12C sulfonic acid); and intra-
molecular anhydride, e.g., ketene, isocyanate. Pre~erably,
~mine tII) or its reactive derivative is acylated with 1 to
molar equivalents of the acid anhyZride in the presence of 1
to lG molar equivalents OL an acid scavenger ~e.g., an
inorganic base, e.g., oxide, hydroxide, carbonate, or
hydrogen carbonate of alkali metal or alkaline earth metal;
organic base, e.g., 3 to 12C ~ertiary a~iner 4 to 12C
aromatic base; 2 to 12C oxirane, e.g., alkylene oxide,
aralkylene oxide; or the like), preferably in a nonprotic
solven~, e.g., halohydrocarbon, nitrile, ether, amide/ or the
~ L~5~
like solvent or a mi~ture thereo.
c) Acid halide - This is chloride, bromide, or iodide. One
to 2 molar equivalents of this acid halide is preferably
reacted with Amine (II) or its reactive derivative in the
presence of 1 to 10 molar equivalents of the acid scavenyer
of above b), in a halohydrocarbon, nitrile, ether, ketone,
water, dialkylamide, or the like solvent or their mixture.
d) Reactive ester - This includes 2 to 6C enol ester, e.g.,
vinyl ester, isopropenyl ester; 6 to 12C aryl ester, e.g.,
chlorophenyl ester, nitrophenyl ester; heterocyclic estert
e.~., ester with l-hydro~ybenzotriazole; or ester with
hydroxylamine or diacylhydroxylamine, and the like.
e) Reactive amide - This is an aromatic amide, e.g., amide
with imidazole, triazole, 2-ethoxy-1,2-dihydro-quinoline,
diacylanilide; or the like.
f) Formimino compound - e.g., M,M-dimethylformimino ester~
and g) Cther reactive derivatives.
The reactions from d) to g) are carried out by treating 1
molar equlvalent of Amine (II) or its reactive derivative
with 1 or more equivalents or the reactive derivative of
fluorinated ~ethylthioacetic acid (III) in a nonprotic
solvent, e.g~, halohydrocarbon, ether, ketone, amide, ester,
or the like solvent or a mixture thereof.
2) Introduction of the substituted tetrazolylthio
The objective Compound ~I) or its derivative can be
~ 5~9~.3~3
produced ~y treating a 1-dethia-1-oxacephe~ co~pound having
~-methyl su~stituted by a leaving group (I~) with Lhiol (V)
or its reactive derivative:
RSCH2CONH ~ O HS ~ ~ ~ (V)
~IV) O N ~ CH2Y R' (I)
COORZ or its xeactive deriv.
wherein Y is a leaving group replaceable with Thio-compound
(V) and R, ~1, and R2 are as defined above.
Halogen, phosphoryloxy, alkanesulfonyloxy, dichloroacet-
oxy, trichloroacetoxy or like acyloxy is representative o~ Y.
Salts of Compound (V) with alkali Metal, e.g., sodium,
potassium, magnesium, calcium; or organic base, e.g., tri-
ethylamine, are the representative reactive derivatives.
In this reaction, tne starting material ~IV) is brought
to contact with Thiol compound (V), if re~uired together with
a base, prererably in an inert solven~, e.g., halohydro-
carbon, ether, ketone, amide, or the like solvent.
3) ~lethoxylation
~ epresentative introduction of 7a-methoxy to the 7~-
hydrogen-7~-~fluorinated methylthioacetamido)-3-substituted
tetrazolyl-thiomethyl-l-dethia-l-oxa-3-cephem-4~carboxylic
acid or its derivative is as follo~s:
a) ~eacting the 7-hydrogen compound with an ~-halogenating
reagent, e.g., t-butyl hypochlorite; alkali metal methoxide,
-- 10 --
e.y., sodiu~l metnylate, potassium ~ethylate~ and a reducins
reagent in methanol.
b) ~eacting the 7~-hydrogen compound ~tith t-butyl hypo~
chlorite and methanol-base in a solvent, e.g., tetrahydro
furan, contairling phenyllithium.
S) Deprotection.
i) ~epresentative deprotections of protected carboxy to give
the corresponding ~ree carboxy are as follows:
a) Highly reactive esters, amides, and anhydrides are hydro-
lyzed with water containing an acid, base, or buffer
solution.
b) Haloethyl, benzyl, nitrobenzyl, methylbenzyl, dimethyl-
benzyl, diphenylmethyl, triphenylmetbyl, and the like esters
give the free acid by hydrogenating over e.g., platinum,
palladium, or nickel as catalyst; or mildly reducing ~tith an
acid and low valent metal, e.g., tin, zinc, divalent chromyl
salt; or sodium dithionite.
c) Benzyl7 methoxyben~yl, methylbenzyl, dimethoxybenzyl,
t-alkyl, trityl, diarylmethyl, cyclopropylmethyl, sulfonyl-
ethyl, cyclopropylethyl, and the like esters a,ford the free
acid by solvolyzing with an acid, e.g., miner~l acidr Lewis
acid, sulfonic acid, strong carboY.ylic acid; if required in
the presence of a cation scavenger, e.g., anisole.
d) Phenacyl, ethynyl, p hydroxy-3,5-di-t butylben~yl, and
the like esters give the free acid with a base.
. ~;
ii) ~epresent2tive deprotections of A hydroxy-protectins
group giving the correspondins free hydroxy are as follows:
a) ~ighly reactive ester-type protecting groups, e.g., halo-
alkanoyl~ are removed with an aqueous base.
b) Alkoxycarbonyl, aralkoxycarbonyl, t butyl, t-alkylsilyl,
and the like carbonate or ether"-type protecting group can be
removed with an acid, e.g., mineral acidt Lewis acid, strong
carboxylic acid, at -50C to 50C, optionally in the presence
of a cation scavengerO
c) Acetal, enol ether, trialkylsilyl, and the like ether
type protecting groups are removed with an acid.
6) Esteri~ication
The carboxy in Compound (I) or its reactive derivative
gives the corresponding ester with an alcohol or its reactive
derivative. ~Ihen esterified ~ith alcohol, it requires a
condensing reagent as cited for 1), b) above. ~ mild and
strong reagent is preferably used to avoid side reactions.
P~eactive derivative of the alcohol can be a ~iazo
compound or chloride, bromide, iodide, sulfonate, or the li~e
to be used with an acid scavenger as 1), b) above. Reactive
carboxy derivatives include salts and ~ixed anhydrides with a
carbonic acid, carboxylic acid, sulfonic acid, or ~iner~l
acid including hydrogen halides.
~ sterifications can be one of those described in, e.g.,
J. F. ~ lcO~ie Ed.~ "Protective Groups in Organic
~ ~r 9~
Chemistryn, pp. 1~3 (1973), Plenum Press, ~.Y.; S. Patai ~d.,
nmhe Chemistry of Carboxylic acids and Esters" in "'~he
Chemistry of ~unctionsl Groupsn, 2P ;05 (1969), Interscience
~ubl.~ John Wiley & Sons, Ltd., London; and various patents.
7) Salt formation
Compound (I) having free carboxy can form a salt by
treating witb an organic or inorganic base. The base can be
a hydroxide or a salt of weak acid, e.g., weak carboxylic
acid, carbonic acid~ or the like. The separation of the salt
from an organic solvent is preferable, as it is a simultane-
ous purification. Lyophilizing or concentrating a neutral
aqueous solution may be used for isolation.
Said reactions proceed at between --50C and 100C over a
0.1 to 20 hours period, optionally in dry or stirred medium.
The reaction solvent is one of hydrocarbon, e.g.,
pentane, hexane, octane, benzene, toluene, xylene; halohydro-
carbon, e.g., dichloromethane, chloroform, carbon tetra-
chloride, dichloroethane, trichloroetnane, chlorobenzene;
ether, e.g., diethyl ether, methyl isobutyl ether, dioxane,
tetrahydrofuran; ketone, e.g., acetone, methyl ethyl ketone,
cyclohexanone; ester, e.g., ethyl acetate, isobutyl acetate,
methyl benzoate; nitrohydrocarbon, e.g., nitromethane, nitro-
benzene; nitrile, e.g., acetonitrile, benzonitrile; amide,
e.g., formamide, acetamide, dimethylformamide, dimethylacet~
amide, hexamethyl phosphorotriamide; sulfoxice, e.g.,
.
.~
dimethyl sul~oxide; carbo::ylic acid, e.g., formic acidl
acetic acid, propionic acid; organic base, e.g., cietr;yl-
amine, triethylamine~ pyridine, picoline, collidine,
quinoline; alcohol, e.g., methanol, ethanol, propanol,
he~anol, octanol, benzyl alcohol; water; am~onia; or other
industrial solvent or a mixture thereof.
One obtains the product by removins impurities, e.g.,
unreacted starting materials, by-products, solvents; ~y e.g.,
concentrating, drying, evaporating, extracting, filtrating,
precipitating, washing; and purifying by usual work up, e.g.,
adsorbing, chromatographying, distillating, eluting, lyophil-
izing, precipitating, crystallizing.
The compounds (I) are safer antibacterials than the
structurally close compounds. For ex~lple, they have less
side effects~ e.g., disulfiram-like activityO
Test method: The test compound (1 g/kg each) was given
to a group of 4 rats. After 18 hours ethanol (2 g/~g each)
were given. After another 1 hour the rats ~ere autopsied and
the liver acetaldehyde dehydrogenase (ALDH) activity and the
blood level of acetaldehyde ~AC) were determined.
DISULFI.r'~l-LIKE ACTIVIT`~ =F2CH~ =CH2CH20H, i;~2=~i
_ _ _ _ _ . _ _____ _ , _
Test compound Liver ALDH activity Blood AC level
Control 16.16 + 0.88 unit 5.4 + 0.6 s/ml
Compound (I) 13.81 + 1.20 3.5 ~ 0~9
Disulfiram 3.53 ~ 0.22 213.4 ~ 25.6
- 14 -
Following examples illustrate this invention.
In the Examples, "volume" shows milliliter for 1 gram of
and "equivalent" sho~s molar equivalent for 1 molar equivalent of
the starting beta-lactam. The product is usually isolated, if
required after diluting ~ith a solven , e.g., dichloromethane,
adjusting pH, washing with water, drying, and concentrating.
Physicochemical constants are identical with that of the samples
produced by other routes. In the examples, AOii is for acetoxy-
methyl, Cbz is for carbobenzoxy, ECE i~ for ethoxycarbonyloxy-
ethyl, Ph is for phenyl, PO~I is for pivaloyloxymethyl, Tbz is for
p-methylca~bobenzoxy, and THP is for tetrahydropyran-2-yl.
Physical constansts are listed on Tables 1-1 to 2.
Example 1 (Amidation)
OCH3 loc~3
E~2N~0~ F2 CHSCE32CONH~0
O - - ~N - ~;LcH2slN - N ~ ~L C~ 2S~i
~2) COOR2 CH2 ~2CY.SC~2COO~ COOR2 lH2
R30C~2 t3) ~1) R30C~ 2
~1) R3=PhC~20CO-, R2=CHPh2
To a solution of 7~-amino-7~ ~methoxy-3~ (2-benzyloxy-
carbonyloxyethyl)~ tetrazol-5-yl]thiomethyl-1 dethia-l-oxa
3-cephem-4-carboxylic acid diphenylmethyl ester (2 millimoles;
* --1
IR(Nujol): ~340, 1785, 1758, 1720, 1632 cm ) in dichloromethane
~1 to 3 volumes) are added pyridine or collidine (1 to 2 equi-
* trademark
15 -
9~
valents) and difluoromethylthioacetyl chloride (1.0 to 1.5
equivalents) at 2 tem2erature between -2G~C and 0C, and the
mixture is stirred for a 0.2 to 1 hour period. The reation
mixture is diluted with ethyl acetate or dichloromethane,
washed with brine or water and aqueous sodium hydrogen
carbonate, dried and evaporated under reduced pressure. The
residue is recrystallized from ethyl acetate to give 7~-di-
fluoromethylthioacetamido-7-methoxy-3-[1-(2-benzyloxycarbon-
yloxyethyl)-lH-tetrazol-5-yl~thiomethyl-1-dethia-1-oxa~3-
cephem-4-carboxylic acid diphenylmethyl ester. Yield: 75%.
(2) In a manner similar to above, the following compounds are
prepared from the corresponding 7~-amino-7~-methoxy-3-~1-(2-
protected hydroxyethyl)-l~-tetrazol-5-yl]thiomethyl-1-dethia-
l-oxa-3-cephem-4-carboxylic acid ester:
a) R 2 =t-C4Hg, R3=t-C4Hg,
b) R2=POM, R3=H
C) R2=-CE~2C6H40CH3-p, R3=PhCH20CO-
~d) R2=-C~Ph2, R3=H, mp. 170 - 172C.
e) R2=-CHPh2, R3=Cl2CHCO-,
f) R2=-CHPh2~ R3=PhCH2OCO-,
g~ R2=-CHPh2r R3=~-cH3c6H4c~2O
h) R2=-CHPh2, R3=tetrahydropyran-2-yl,
j ) R2=-CHPh2, R3 =Si ( CH3)2t-C4Hg,
(3) The same products can be obtained by acylating under
the following conditions:
i~ - 16 -
1) When COoP~2 of Amine t2) is carbo~y, this is aissolved
in aqueous (10 volumes) sodium hydrogen carbonate (2~5 e~ui-
valents) and the carboxylic acid (3) chloride 11.1 equivalent)
is dropwise added thereto~ The ~ixture is kept at a tempera-
ture between -5C and 40C over a 0.5 to 2 hours period.
2~ ~Ihen COOR2 is carboxy, the corresponding Amine ~2) is
treated with trimethylsilyl chloride and triethylamine (1.2
equivalents each) to O-silylate, and then treated with
pyridine ~4 equivalents) and the carboxylic acid ~3) chloride
(1.1 equivalents) at -30C over a 30 minutes to 2 hours
period, and the obtained silyl ester is hydrolyzed with acid.
3) A mixture of Amine (2), picoline ~4 equivalents),
trichloroethane, and the carboxylic acid ~3) chloride ~1.1
equivalent) is stirred at a temperature between 0C and -30C
over a 30 minutes to 3 hours period.
4) A mixture of Amine ~2), dimethylformzmide ~2
volumes), ethyl acetate ~10 volumes), triethylamine (1.1
equivalents), the carboxylic acid (3) chloride (1.2
equivalents), and dichloromethane (20 volumes) is stirred at
a temperature between 0C and -30C over a 30 minu~es to 2
hours period.
5) A mixture of Amine (2), chloroform (lC volumes~, di-
metho~yethane (10 volumes), pyridine (1.5 moles) J and a mixed
anhydride of the carboxylic acid (3) and isobutoxyformic acid
(1 to 2 e~uivalents) is stirred at a temperature between -5
znd 10C over a 30 minutes to 6 hours period.
6) A mixture of Amine ~2), ethyl acetate (lG volumes),
1,2-dichloroethane ~10 volumes), 4-methylmorpholine (1.5
equivalents), and the carboxylic acid ~3) symmetric anhydride
~1.1 equivalent) is refluxed over 10 minutes to 2 hours.
7) A mixture of Amine ~2), dichloromethane ~10 volumes),
pyridine ~1.5 equivalents), the mixed anhydride of the
carboxylic acid (3) and methanesulfonic acid ~1.1 equivalent)
at between 0C and 35C over a 1 to 3 hours period.
8) A mixture of Amine (2), dimethyl~ormamide (5 volumes),
dimethylaniline (1.3 equivalents), and the Vilsmeier reagent
consisting from the carboxylic acid t3) and dimethylformamide
~1.1 equivalent) is stirred at about 25C over 1 to 5 hours
period.
9) A mixture of Amine (2), ethyl acetate (10 volumes),
pyridine (1.5 equivalents), and the mi~ed anhydride of di-
ethyl hydrogen phosphate and the carboxylic acid ~3) is
stirred at between 0C and 10C over a 1 to 5 hours perio~.
10) A mixture of Amine (2), ethyl acetate (7 volumes),
dichloromethane ~10 volumes) r pyridine ~2 equivalents), and
the mixed anhydride of the carboxylic acid (3) and dichloro-
phosphoric acid (1.1 equivalent) is stirred over a 1 to 3
hours period at a temperature between 0C and 30C.
11) A mixture of Amine (2), lutidine (1.5 equivalents),
dichloromethane (10 volumes), and the mixed anhydride of the
~ 3
carboxylic acid ~3) and monochlorophosphoric acid dimethyl-
amiae is stirred over 1 to 4 hours at bet~een 0C and 30C.
12) A mi~ture of Amine (2), carbonyldiimidazole (1.1
equivalent~, tetrahydro~uran (10 volumes), aimethylacetamide
(5 volumes), and the carboxylic acid (3) (1.1 equivalent) is
stirred over a 1 to S hours period at between 0C and 35C.
13) A mixture of Amine (2), clichloromethane (10 volumes),
dimethylformamide (5 volumes), N,N-dicyclohexylcarbodiimide
tl.l equivalent), picoline (1.2 equivalents), and the carb-
oxylic acid (3) ~1.1 equivalent) is re~luxed over 5 hour.
14) A mixture of Amine (2), dichloromethane ~10 volumes),
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.1 equi-
valent), N,~ dicyclohexylcarbodiimide (1.1 esuivalent),
pyridine (1.5 equivalents), ana the carboxylic acid (3) (1.1
equivalent) is stirred over a 1 to 6 hours period at a
temperature bet~een 0C and 35C.
15) A mixture of Amine (2), dichloromethane (30 volumes),
cyanuric chloride (1.1 equivalent), pyridine S~ equivalents),
and the carboxylic acid (3) (1.1 equivalent) is stirred over
a 30 minutes to 2 hours period at between -30C to 20C.
16) A mixture of Amine (2), dichloromethane (3 volumes),
pnosphorus oxychloride (1.1 equivalent~, pyridine (1.5
equivalents), and the carboxylic acid (3) (1.1 equivalent) is
stirred over 20 minutes to 2 hours at between -10C to 0C.
17) Amine (2) is treated ~7ith trimethylsllyl chloride to
-- 1 9
~9~
~ ~ - ~
obtain the corresponding ~l-trimethylsil~l co~pound, and this
is treated with phosphorus oxychloride (1 5 equivalents), the
carboxylic acid ~3) ~1.2 equivalents), and pyridine (4 equi-
valents) in dichloromethane (5 weights) ~or 30 minutes to 2
hours at between 0C and room temperature.
18) A mixture of Amine (2), dichloromethane (8 volumes),
thionyl chloride (1.5 equivalents), pyridine t2.5 e~uival-
ents), and the carboxylic acid (3) (1.1 equiv.) is stirred
over 1 to 5 hours at a temperature between -30 and 0C.
19) A mixture of Amine ~2), dichloromethane ~20 volu~es),
l-hydroxybenzotriazole (2.1 equivalent), N,N'-dicyclohexyl-
carbodiimide (2.5 equivalents), and the carboxylic acid (3)
(2 equivalents) is stirred at 0C to 20C over 1 to 15 hoursO
20) A mixture of Amine ~2), dichloromethane (S volumes),
trifluoroacetic anhydride (1.5 equivalents), pyridine (3
equivalents), and the carboxylic acid (3) (1.5 equivalents)
is stirred over 3 hours period at between 0C and 50C.
21) A mixture of Amine (2), dichloromethane (lD volumes),
bromide of diethyl hydrogen phosphate (1.2 equivalents),
4-methylmorpholine (2.5 equivalents), and the carboxylic acid
(3) (1.2 equivalents) is stirred over a 1 to 3 hours period
at a temperature between GC and 3GC.
22) A mixture of Amine (2), ethyl acetate (10 volumes),
di-2-pyridyl disulfide (1.1 equivalent), triphenylphosphine
(1.1 equivalent), and the carboxylic acid (3) ~191 equival-
- 20 -
ent) is stirred over a 5 hours period at between 10 ana 50C.
23) A mixture of Amine (2), dichloromethane (3 volumes~,
1,3,5-tripyridiniumtriazine trichloride (4 equivalents), ana
the carboxylic acid t3) (1.1 equivalent) is stirred over a 1
to 5 hours period at a temperature between -10 and 10C.
24) A mixture of Amine ~2), t:etrachloride ~30 volumes),
g-methylmorpholine (1.5 equivalents), trisdiethylaminophos-
phine ~1.1 equivalent), and the carboxylic acid (3) (1.1
equivalent) .is kept at between -:20 and 10C over 2 hours.
25) A mixture of ~mine (2), dioxane (10 volumes), N,N'-
dicyclohexylczrbodilmide t2 equivalents), and phthalimide of
the carboxylic acid ~3) ~2 equivalents) is stirred over a 2
to 8 hours period at a temperature between 10 and 50C.
26) A mix~ure of Amine (2), ~e~hyl isobutyl ketone (10
volumes), N,N'-dicyclohexylcarbodiimide (1.5 equivalents),
and succinimide of the carboxylic acid ~3) (1.5 equivalents)
is stirred over a 2 to 9 hours period at between 0 and 40C.
27) A mixture of Amine ~2), dichloromethane (20 volumes),
pyridine (3 equivalents), N,N'-dicyclohexylcarbodiimide (3
equivalents), and l-oxybenzotriazolyl ester of the carboxylic
acid (3) (3 equivalents) is stirred over a 5 to 10 hours
period at a temperature between 10 and 50C.
28) A mixture of Amine (2), chloroform (3 volumes),
toluene (1 volume), picoline (2 equivalents), oxalyl chloride
(1 equivalent), and the carboxylic acid (3) (1.1 equivalent)
- 21 -
~ 3.~
is stirred over a 10 minutes to 2 hours perioa at a
temperature between -SGC and lO~C.
~xample 2 ~Heterocyclic thio introduction)
,CH3 oc~3
F2CHSCH~CONH ~F2CHSC~2CONH
O=~----N ~ C~2Cl O M ~ CH ~ I
COOR~ COORZ C~2
R30CHz
~1) (R3=H, R2--CHPh~)
To a solution of 7~-difluoromethylthioacetamido-7a
methoxy-3-chloromethyl-1-dethia 1-oxa-3-cephem-4-carboxylic
acid diphenyl~ethyl ester (2 millimoles) in N,~-dimethyl
formamide (1 to 2 volumes) is added a solution of sodium
1-(2-hydroxyethyl~-lH-tetrazol-5-ylthiolate (1 to 2 equival-
ents) in N,N-dimethylformamide or methanol (1 to 2 volumes),
and the mixture is stirred at a temperature between -lGC and
50C over a 20 minutes to 5 hours period. ~he reaction
mixture is washed with water, dried, and concentrated to
dryness in vacuo. The residue is recrystallized from ethyl
acetate to give 7~-difluoromethylthioacetamido-7-methoxy-
3-[1-(2-hydroxyethyl)-lH-tetrazol-5-yl]thiomethyl-1-dethia-
l-oxa-3-cephem-4-carboxylic acid diphenylmethyl ester.
Yield: 80 to 95 %.
(2) In a manner similar to above, the reaction of tetrabutyl-
22 - `
3~;3~3
a~monium bromide (~.1 e~uivalent), 1-(2-hydroxyethyl)-5-
tetrazol-5-ylthiol (1~1 e~uivalent), sodium hydroxide (1.1
equivalent), and 7~-difluoromethylthioacetamido-7a metho;y-
3-chloromethyl-1-de~nia-1-oxa-3-cephem-4-carboxylic acid
diphenylmethyl ester in dichloromethane give the same
product. Yield: 70 to 84%.
In a manner similar to above, the following compounds are
produced from the corresponding 7~-difluoromethylthioacet-
amido-7a-methoxy-3-chloromethyl-:L-dethia-1-oxa 3-cephem-4-
carboxylate ester and the corresponding 1-(2 R3-protected
hydroxyethyl)-lH-tetrazol-5-ylthiol sodium salt:
a) R2at-C4~9, R3=t-C4Hg,
b) R2=-CHPh2, ~3=tetrahydropyran-2-yl,
c ) R 2 =-CHPh2 , R 3 =Cl2 CE~CO,
d) R2=-CHPh2, R3=PhCH20CO-,
e) R2=-cH2c6H40cH3-pt R =p CH3C6H4CH2
f) P~2=-C~I2CCl3, P3=H,
The starting ~aterials used here, 7~-dirluoromethylthio-
acetamido-7a-methoxy-3-chloromethyl-1-dethia-1-oxa-3-cephem~
4-carboxylic acid esters, can be produced as follows:
~CH3 ,OCH3
o~O P2CE~SCH2COMH~Ol
~CH2Cl o M ~CE~2Cl
COO~ 2 COOR 2
To a solution of 7~-amino-7a-methoxy-3-chloromethyl-1-
- ~3 -
dethia~l oxa-3-cephem-4 carboxylic acid ester in dichloro-
~ethane (5 to 10 volumes) are added yyridine or picoline (2
to 10 equivalents) and difluoromethylthioacetyl chloride (1
to 1.5 equivalents), and the mixture is stirred under
nitrogen over a 10 minutes to 2 hours period at a temperature
between -30C and 10C. The mixture is washed with aqueous
sodium hydrogen carbonate and wat:er, dried, and concentrated
in vacuum. The residue is the corresponding ester of 7~-di-
fluoromethylthioacetamido-7-methoxy-3-chloromethyl-1-dethia-
l-oxa-3-cephem-4-carboxylic acid~, Yield: 50 to 93%.
Example 3 (Deprotection)
,oc~3
F2C~SC~2CONH_ ~ l ~ - N
G--N_~CH2 S
COO~ 2 CH2CH2OR
O,CH3
F2CHSCH2CO~H ~ l N - N
_____________~ o=l~ ~ c~2s ~ ~j7
COOH H2CH20H
(1) Carboxy and hydroxy deprotections
(a) (R 2 =~C7IPh2 r R 3 =~
To a solution of 7~-difluoromethylthioacetamido-7a-methoxy-
3-el-(2-hydroxyethyl~-lH tetraæol-5-yl]thiomethyl-1-dethia-
l-oxa-3-cephem-4-carboxylic acid diphenylmethyl ester (1
- 24 -
equivalent) in dichloromethane (5 volumes~ are added anisole
(0 to 10 e~uivalents) and titaniu~ tetrachloride or alur,inum
chloride (1 to 5 equivalents), and the ~ixture is s~irred
over a ~0 J~inutes to 6 hours period at a temperature between
-45C and 10C. The reaction mixture is washed with diluted
hydrochloric acid and water, dried, and concentrated in
vacuum. The acid part i5 collected and crystallized from
ethyl acetate, acetone - dichloromethane, or methanol - ether
to give 7~-difluoromethylthioacet:amido-7a-methoxy-3-[1-(2-
hydroxyethyl)-lE~-tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3-
cephem-4-carbo.~ylic acid~ Yield: 95%.
~b) (R2=-CHPhz, P~3=H)
In place of aluminum chloride of preceding (a),
trifluoroacetic acid (0.3 to 3 weights) is used to give the
same compound in nearly quantitative yield.
(c) Substituting dichloro~ethane (2 to 5 weights) and
titanium tetrachloride or aluminum chloride with dichloro-
methane - nitromethane (5 to 1:1) mixture (12 weights) and
tin chloride respectively, the reaction of above ~a or b) is
repeated to obtain the same product in 85 to 98 % yield.
(d) Under the same condition as in (a) to (c) above, the same
compounds are prvduced from the compounds of the following
partial structure.
i) R2 =--C~IPh2, ~3 =PhCH20CO--
R C~2C6H4OC~-P~ R3=p-cH3c6H~cH
- 25 -
iii) ~.Z=t C~H9~ t-C4H9-
iv) R2--C~Ph2, P~'=tetrahydropyran-2-yl
V ) ~ 2 =-C~Ph2 ~ ~ 3 ~ S i ~ C~l 3)2t C4~Igr
~4) Removing tetrahydropyranyl
O,CH3
F2CHSCH2CO~3~ ~ O~ N - 2~7
o ~L CH 2S llij7~
OOCHPh2 CH2C:~I2Otetrahydropyran-2-yl
OCH3
~Cl ~2CHSCH2
O ~I~C112~
3 CJ~C.I~h2 CH C~ OH
To a solution of ~ -difluorometIIylthioacet2mido~7a-meth-
oxy-3-[1-(2-(tetrahydropyran-2-yloxy)ethyl)-lH-tetrazol-5-
yl]thiomethyl-l-dethia-1 oxa-3-cephem-~-carbo~ylic acid
diphenyl~ethyl ester (2 millimoles) in methanol (2 ml~ is
added lN-hydrochloric acid (0.1 ml), and the mixture is kept
at room temperature over a 1 to 2 hours period. The reaction
mixture is neutralized with aqueous sodium hydrogen carbonate
and concentrated. The residue is recrystallized from a
mixture of acetone and benzene to give a diphenylmethyl ester
identical with the product of E~a~ple 2
(5) RemoYing dichloroasetyl
.
- - 26 -
e.
CCH3
F2CHSCH2COMH-~ ~ l N~
O~Crl2 ~1~
COOCHPh2 H2CH20COCHC12
oc~l3
Acetone F2CHSCH2COMH ~ O~ N~
--~ O ~ H2S--
NaHCO 3aq- COOCHPh2 CB2CH20H
To a solution of 7~-difluoromethylthioacetamido-7a-
methoxy 3-[1-~2-dichloroaceto~yethyl)-lH tetrazol~S-yl]thio-
methyl-l-dethia-1-oxa-3-cephem-4-carboxylic acid diphenyl-
methyl ester (4 millimoles) in acetone (10 ml) is added
aqueous lN-sodium hydrogen carbonate ~1 ml), and the mixture
is re~luxed for 30 minutes. The reaction mixture is
neutralized with acetic acid and concentrated to remove
acetone. The residue is extracted with ethyl acetate. The
extract is washed with water, dried~ and concentrated to give
a diphenylmethyl ester identical with the product ol Example
2(1). Yield: 76 %.
Example 4 (Salt formation)
OCH3
F2CHSCH2CON ~ ~ Nl ~ ~
- ~ ~ CH2 ~ ~ ----? Na-salt
~OOH ~H2CH2OH
~ 5~
(1) To a solution of 7~-difluoromethylthioacetamido-7~-
methoxy-3 ~ 2-hydroxyethyl)-lH-tetrazol-5-yl]thiomethyl-
l-dethia-l-oxa-3-cephem-~-carbo~ylic acid (2 millimoles) in
ethyl acetate is added a 3~1-solution of potassium 2-ethyl-
hexanoate (1 to 1.5 equivalents) in methanol, and the mixture
is stirred for 0.5 hours. The reaction mixture is concentr-
ated in vacuum. The residue is stirred in ether to give the
corresponding potassium salt. Yield: 81 ~.
~2) The starting carboxylic acid of above (1) ~1 equivalent)
is dissolved in aqueous l~l-sodium hydrvgen carbonate (1 e~ui-
valent) and conventionally lyophilized. This salt is given
intravenously as injection in water or orally as suspension
in glycerin monooctanoate at a dzily dose of 2 g to treat an
infection caused by sensitive Staphylococcus aureus.
E~1IC: Escherichia coli= ~ 0.1~g/m~.
Example 5 tPharmaceutically acceptable ester)
OCE13
FzCE3SC~2COM ~ ~ ~,
G= I ~ ~ CH2
COOK CH2CH20H
O,CH3
F 2CH S CH z C OMH r~
____________~ o ~ ~ CH2S
COOPOil CHzCE]20E3
- 28 -
/~s~9~
~1) To a solution of 7~-difluorc~ethylthloacet2mido-7a-
metho:sy-3-[1-(2-hydroxyethyl)-lH-tetrazol~ thiomethyl-l-
dethia-l-o~a-3-cephem-4-carboYylic acid potassium salt (1
millimole) in N,N-dimethylformamide (2 to 5 weights) is added
iodomethyl pivalate (1 to 2 equivalents) under ice cooling,
and the mixture is stirred for 1~4 to 2 hours. The reaction
mixture is diluted with ethyl acetate, washed with iced
aqueous sodium hydrogen carbonate, dried, and concentrated in
vacuum. The residue is recrysta:Llized from ethyl acetate to
give 7~-difluoromethylthioacetamido-7-methoxy-3-[1 (2-hydr-
oxyethyl)-lH-tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3-ceph-
em-4-carboxylic acid pivaloyloxymethyl ester. Yield: 67 %.
~2) Substitu~ing the potassium salt with the corresponding
sodium salt, the reaction of above (1) is repeated to afford
the same product. Yield: 72 ~.
(3) Substituting iodomethyl pivalate with iodomethyl acetate
or iodoethyl ethoxyformate, the reaction of above (1) is
repeated to arford the corresponding acetoxymethyl ester or
ethoxycarbonyloxyethyl ester(Polar and nonpolar isomersO
(4) In a manner similar to above (1), phthalidyl bromide is
reacted on the potassium salt of the carboxylic acid to
afford two stereoisomers at the ester group of the corres-
ponding phthalidyl ester(Polar and nonpolar isomers).
(5) 5-Indanol and methanesulfonyl chloride are reacted on the
- 29 -
~s~9~:~
carboxylic acid in the presence of pyriaine at -10C for 90
minutes in dichloromethane to obtain the correspondiny
indanyl ester.
(6) Pivaloyloxymethyl ester of (1) (250 mg), corn starch (150
mg), and magnesium s~earate (5 mg) are mixed, granulzted, and
filled in a gelatine capsule. One to three of this capsule
is orally administered thrice a day to a patient infected by
sensitive Staphylococcus aureus l:o treat the infection.
.
~7) Similarly, the acetoxymethyl ester or ethoxycarbonyloxy-
ethyl ester of (3) above is encapsulated and administered
orally to treat the same infection.
Example 6 (~iethoxylation)
E3
F~c~sCH2co~l ~
1~ CE~2
COOC~Ph2 CH2CEi2OCCCC-~P:^
OCH3
F2CHSCH2C~o
~2 1'
COOCElPh2 -CH2CEI2OCCOC~2Ph
To a solution of 7a-~ifluoror~lethylt~.ioacetamiao-3~ t2
benzyloxyc2rbonyloxyethyl)-lEI-tetrazol-5-yl]thiomethyl-l-de-
thia l-oxa-3-cephem-4-carboxylic acid diphenylmethyl ester (5
g) in dichloromethane (lC ml) are a~ded pyricine (1.1 equi-
- 30 -
~ 9
valent) and chlorine (2 equivalents) under ice coolin~
solution of lithium ~etho~ide (3 equivalents) in ~ethanol
is added to the mixture cooled at -5CC, and tne mixed
solution is let stand for 2 hours. The reaction r.lixture is
neutralized with acetic acid, washed ~ith water, dried, And
concentrated in vacuunl to afford 7~-difluoromethylthioacet-
amido-7-methoxy-3~ (2-benzyloxycarbonyloxyethyl)-lH-
tetrazol-5-yl] thiomethyl-l ~ethia-l oxa-3-cephem-4-
carboxylic acid diphenylmethyl ester (3.5 g).
Example 7 (~rotection)
,OCH3
F2C~SCH ~COMH~O
O N~CH2
COOC~Ph2 CH2C~ OH
oc~3
F2CHSCH2C~ ~o T
~ ~l~C~2 S~
cooCHPn2 H2CH20R3
1) (R3 = benzyloY.ycar'oonyl)
To a suspension of 7~-difluorsmethylthioacetamido-7a-
methoxy-3-[1-(2-hydro~yethyl)-lH-tetrazol-S yl]thiomethyl-1-
dethia-l-oxa-3-cephem-4-c2rboxylic acid diphenylmethyl ester
in dichloromethane (40 volumes) cooled at 0C is added
pyridine t5.6 equivalents) and benz~l chloroformate (1.5
- 31 -
equivalents). The mixture is stirred at 0C for 6 hours and
at 25C for 3 hours. ~sual ~tork up of the reaction r,li~ture
gives 7~-difluoromethylthioacetamido-7-methoxy-3-[1-t2-
benzyloxycarbonyloxyethyl)-l~-tetrazol-5-yl]thiomethyl-1-
dethia-l-o~:a-3-cephem-4-carboxylic acid diphenylmethyl ester.
Yield: 95 ~. This product is the same to that of Example 1
~2), f).
2) tR3 = t-butyldimethylsilyl~
To a solution o~ 7~-difluoromethylthioacetamido-7~-
methoxy-3-[1-~2-hydroxyethyl)-lH-tetrazol-5-yl]thlomethyl-1-
dethia-l-oxa-3-cephem-4-car~o~ylic acid diphenylmethyl ester
in ~I,N-dimethylformamide (3 volumes) cooled at 0C is added
4-methylmorpholine (1.4 equivalents) and t-butyldimethylsilyl
chloride (1.4 equivalents). The mixture is stirred at 0C for
1.5 hours, diluted with brine, and extracted ~ith ethyl
acetate. The extract is washed with brine, dried over
magnesium sulfate, and concentrated to give oily material.
This is purified by silica gel chromatosraphy to give 7~-di-
fluoromethylthioacetamido-7-methoxy-3-[1-(2-t-butyldimethyl-
silyloxyethyl)-lH-tetrazsl-5-yl~thiomethyl-1-dethia 1-oxa-3-
cephem-4-carboxylic acid diphenylmethyl ester. Yield: 95 ~.
This product is identical with that of EYample 1 (2), j).
Similarlyl the products a) to j) of ~xample 1 t2) can be
prepared accordins to a conventional mannez ir. the art.
- 32 -
~2~
Exa~ple 8 (~1=2-hydroxypropyi)
,OC~13 oc~3
H21~1 ~ O~ r~l - N F2 S 2 ~ ~ ~J
o~ ~ CH2 ~ ~ ~ ~? O-I .1 ~ CH2SJ~
(2) COOC~IPh2 ~H2 COOCHPh2 1~2
HO HC~3 F2CHSCH2COOH (1~ HOCHCH3
(1~ Amidation
Substituting the 7~-amino-7a-methoxy-3~ (2-hydroxy
ethyl)-lH-tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3 cephem-
4-carboxylic acid diphenylmethyl ester with 7~-amino-7a-
methoxy-3-[1-~2-hydroxypropyl)-lH-tetrazol-5-yl]-thio~ethyl-
l-dethia-l-oxa-3-cephem-4-carboxylic acid diphenylmethyl
ester, Example 1 (2) is repeated to afford 7~difluoromethyl-
thioaceta~ido-7a-methoxy-3-[1-(2-hydro~ypropyl)~lH-tetrazol-
5-yl~thiomethyl-1-dethia-1-oxa-3-cephem-4-carboxylic acid
diphenylmethyl ester.
The Amine ~2) is treated ~ith the side chain carboxylic
acid (3) or its reactive derivative under a condition ol
Example 1, (3), 1) to 28) to give a product of ~xample 8(1).
(2) ~etS introduction
o,c~3 O,CH3
F2CHSC~2C~ ~ Ol F2CHSCH2CMH F l N
O ~ C~I2Cl ~ O ~ ~Lc~. 2S ~
COOc~lPh2 CoocHph~ C~21~C~13
33
~ 9 ~
Substi~uting 1-12-hydroxyeth~ lH-tetr2zol-5-ylthiol
sodium salt with l-t2-hydroxypropyl)-lH-tetrazol-5-ylthiol
sodium salt, Example 2, (1) is repeated to give the product
identical witn that of Exa~ple 8(1).
(3) Deesterification
oc~3
2 2 ~ N -
O M ~ CH ~ ~
COOCHPh2 C~2CH(OH)CH3
oc~3
COOH CE12CH(OH)C~
Substituting 7~-difluoromethylthioacetamido-7a-methoxy-
3-[l-(hydroxyethyl)-lH-tetr2zol-5-yl]thiomethyl-l-dethia-l-
oxa-3-cephem-4-carboxylic acid diphenylmethyl ester with 7~-
difluoromethylthioacetamido-7a-methoxy-3-[1-(2-hydroxypropyl
propyl)-1~-tetrazol-5-yl]thiomethyl-1-dethia-1-oxa-3-cepher,-
4-carboxylic acid diphenylmethyl ester, Exa~ple 3, (1) (a) is
repeated to give 7~-difluoromethylthioacetar,;ido-7a-methoxy-
3-~ hydroxypropyl)-lH-tetrazol-5-yl]thiomethyl-1-dethia-
l-oxa-3-cephem-4-carbo~ylic zcid.
4) (Salt formation and pivaloyloxy~ethyl ester)
- 3~ -
8~
,CCH 3
F 2CHS(::H2 CO~lH~ ~
O M ~C~12 ~'
COOH CH2C~ ( OH) CH 3
OCH3
F2C~SCH~CO~IH~_~o~ N~
______ ____ o 1 _ ~ CH2 ~ ~
COOPO~I CH2cH(oH)cH3
Substituting 7~-difluoromethylthioacetamido-7a-methoxy-
3~ (2-hydroxyethyl)-lH-tetrazol-5-yl)thiomethyl-1-dethia-
l-o:ca-3-cephem 4-carboxylic acid ~lith 7~-di~luoromethylthio-
acetamldo~7~-metboxy-3-[1-(2-hydroxypropyl)-lH-tetrazol-S-
yl3thiomethyl-1-dethia-1-o~:a-3-cephe~ 4-carboxylic acid,
Example 4 is repeated to give 7~-difluoro~ethylthioacetamido-
7-metho~y-3-[1-(2-nydroxypropyl)-lH-tetrazol-5-yl]thio-
methyl~l-dethia-l-oxa-3-cephem-~-carbo~yllc acid ~otassiur.
salt, and this product is esterified by the method of E,;a~ple
5 to afford the correspondins pivaloyloxymethyl ester.
- 35 -
~L~25.~
~2,~cc~~LI l S,~ irl
O ;~ a32 L~
C(X~ 2 G~2 ca2cL ~
~o~ R2 p3 IR(ChC13) cm ~(CDC13 ~
H H 3440, 1780, (CD3SOCD3): 3.42(s, 3H), 3.63(s, 2H), 3.75
179G, 1710, ~t, J=6Hz, 2H), 4.21(s, 2E~), 4.33(t, J=6
1680(!~r). Hz, 2H), 4.53(s, 2H), 5.07(s, lEI), 7.03(t,
J=56Hz, lH), 9.22(s, lH).
2 Na H 3400, 1766, (D2O): 4.00(s, 3E~), 4.18~s, 2E~, 4.47~t,
1687, 1610 J=6Hz, 2ED, 4.57, 4.74(l~Eq, J=7.5i1z, 2''.),
(~r). S.Ol(t, J=6Hz, 2H), 5.01(s, 20, 5.13~s9
lH), 7.58(t, J=56Hz, lH).
3 CE~2CC13 H 3390, 1792, (CDC~+CD3SOCD3~ 3.4G(sr 3E~), 3-59
1738, 1696. ~s, 2H~, 3.83 (t, J=5.8Hz, 2H), 4.2 - 4.9
(m, 8~D, 5.01(s, lO, 7.15(~, J=5s~Elz, lH),
9.13(s, 1~.
4 t-C4H9 t-C4Hg msO 1700.
FIB ~z 3300, 1792,
1716.
6 P~ Cbz 1790, 1755,
1709.
Tbz = p-me~hyl~enzyloxycarbonyl~.
-- 36 --
3~3
2 CCI~
F2 c~ co~ i f~
o=--~3~2S~
2 c~l2~
NO~ R2 R3 IR(CHCl3) Cm ~(CDC13) ~m~
7 ~Ph2 H ~P~ 170 ~ 172C-
8 C~h2C12C~CO- 1780, 1721q
9 C~Ph2 PhC~2OCO - 3375~ 17a5~ 3~53~S/ 5~ 4~19(5~ 2~ 4-37(Sr 4J.),
1746/ 1703~ 4~57(S~ 2V ~ 5-03(Sr lTl), 5-07(S~ 2H)
1624~ 13g1~ 6~89(S~ 6~89(~ ~=5O~/ 1~,
7~07 ~ 7~75(~ p~ 134 136C~
10 C~Ph2 ~PhC~2OC0- ~ 3375~ 1787~ 2~30 ~S~ 3~, 3.53 (s, 5F~ ~ 4.20(s,
1746r 1708~ 2~, 4.38 (s, 4~, 4~57 (S~ 2.~, 5~02
1630, 1~98~ (S~ 3P~, 6~87 (S~ 10 ~ 6~7 (t, J=56
1262, 1078O ~Zr 1~ ~ 7~03 ~ 7.63 (rur 15~ ~
11 CHPh2 T9æ 3400r 1785
1705.
12 CEPh2 Si(C~)Zt-C4F~3365~ 1784~ 0~10 (S~ 3~i), 0-17 (s, 3iV, 0~7B (St
1720, 1700, 9H), 3.53 (s, 53, 3.90 (t, J=5~5 8z,
1624, 1600. 2Y.), 4.05- 4.38 (m, ~F,), 4.60 (br s,
1390, 1250, 2Y.), 5.03 (s, lF), 6.9C (s, 13, 6.90
1123, lG66A (t, J=56.4 Ei~, lF.), 7.20-7.6 (m, 11~).
-- 37 --
~BLE 1-3 CCH3
F2~cc~F~
c~ 2 C:~2C~ 2C23
~lo. ~2 R~ HC13) cm L ~ C13) ~
13 P~ 3400~ 1790, (~C13+~39OCD3(2~ 2.13~s, 3ED, 3.51
1780, 1740~ (s~ 3EI), 3.56(s, 2H), 3993(t, J=6Elz,
1700, 1632. 2~), 4.2g(t, J=6E~, 2~), 4.351s, 2H),
4.61(s, 2H), 5.06 ~s, lED, 5.83, 5.98(~,
J=6E.z, 2El) ~ 7.09(t, J-56Elz, lED, 9.11~s,
lE3~ .
14 PO~I H 3392, 1790, 1.22(s, 9I~)~ 3O50(sr 3F.), 3.55(s, 2Ei),
1751, 17C0~ 4.05(t, J=4.5Hz~ 2H), 4.21(s, 2H), 4.37
1632. (t, J=4.5Hz, 2El), 4.57~s, 2H), 5.03(s,
lEl), 5.82, 5.~5 ~q, J=6E~z, 2H), 6.92~t,
J=56 Y~ 3), 7.34(s, lE~).
15 PO~I El 3392, 1792, 1 .13(s, 3EI), 1021(s~ 3Ei) ~ 2.57, 2.66(q,
1756, 1700, J=6Hz, lH) ~ 3O53~s, 3E~), 3.56~s, 2H),
1631. 4.03 ~t, 4.5E3z, 2H), 4.23 (s, 2ED, 4 .37 (t,
J=4.5Hz, 2ED, 4.59(s, 2ED, 5.04(s~ lH),
5.33, 5.95(.~q, J=6Eiz, 2EJD, 6.93(t, J=56
~z, lE~), 7.43 (s, lE~) .
-- 3~ --
~, ,
7~
I~BLE 1~' GC~3
F~CHS 2 ~ ~ ! S~
CCOP~2 C~2~l2C~3
No~ R2 R3 IR(CHC~) c~ ~(CCCl ~ pprl.
16 Phthalidyl ~ 338~, 1794, ~CDC13+CD39OCD3(1:1)) : 3.39(sl 3~7~, 3.53
~Polar isomer) 1736t 1700. (s, 2~ , 3.7 - 4.5(m, 6~), 4.60(s, 2~ ,
5.01(s, 1~ , 7.C8~t, J=56 ~lz, lY.), 7.55
(s, lH), 7.6 - 8.0 (m, 5~, 9.15(s, lID.
17 (Monpolar is~er) 3381, 1795, (CDC13~CD39CCD3(1:1)) : 3.41(s, 3~ , 3.56
1739, 1705. (s, 2Y~, 3.93(t, J=5.8Hz, 2ED, 4.30(s,
2Y~, 4~36(tr J=5~8 ~2r 2~ 4~65(5~ 2
S.Ol(s, ~, 7.08~t, J=56 I~, lII), 7.~6
~s, lP~, 7.55 - ~.O(m, SF~, 9.C6(s, 1~ .
18 ~CE H 3400, 1793, 1.29(t, J=7.;~z, 3~ , l.oO(d, J=6~, 3~ t
(Polar isor,~r) 1765~ 1702. 3.51(sl 3~ , 3.69(s, 21~, 3.8 - 4~5(m,
8~ ~ 4 ~60 (s, 2Y~, 5 nO6 ~s, lY~, o.83, 6.95
, J=5.6E.z, 10, 6.96 (t, J=55~iz, lY~,
7.55 (s, lE~
- 39 -
~ ~r~
m~LE 1--5
F2CE~5G3 CCL~H`rrO1 Il l
o~1~2~`Ll~
c~2 Ca2Crl2Q~3
No. R2 p~ L~(CHC13 ) cr; ~iP~(CDC~ ) E~m.
19 (Monpolar isaner) 3395, 1790, 1.30(t, J=7.5HZ, 3P.), 1.60(d, J=6~.Z, 30,
1760, 1702. 3.53 (s, 3Y.), 3.60(s, 2H), 3.9 - ~5(m,
8E~, 4.63(S, 2H), 5.06~S, 1E1), 6.83, 6.95
~ABq, J=5.6HZ, lH), 6 ~96 ~t, J= 56HZ, 1H),
7 .53 (S, 1}~ .
20 indanyl H 3400, 179C, 1.9 - 2.3~r., 2~3), 2.75 - 3.15~r., 4H),
1731, 1700. 3.53~S, 50, 4.02(br s, 2H), 4.2 - 4.5(rl~
4H), 5 .12 ~s, lH), 6.91 (t, J=56Hz, lH),
6.95-7.3(~;, 3Y~, 7.63(s, lO.
21 4-carbo~ )3): 3.11 ~s, 3H), 3 .42 ~S, 2~,
~htha1i~1 3.71(t, J=5.8Hz, 2Y.), 3.~ - 4.4(m, 4E~),
~l-m~xture 4 .46 (s, 2H), 4 .;3G (S, 1H), 6 .96 (t, J=56HZ,
l~D, 7.4- ~.4(}n, 5YA).
- 40 -
5~BL~ 1 -6 S~rtiny s-.lnes
~ 2S~
cco~,2 a~2c;'2C~3
~0. E~2 R~ IR(CHC1~3 ) cm
22 ~P}~ C~2 334C~ 1785~ . 112.5 ~ 114.5~C.
1758~ 1720~ 3.13~br s, 2Y) ~ 3.44~s, 3E~), 4~22(5~ 2E~),
4.49(s~ ~Y.)~ ~.63(~;~ 2I~)r ~.89~s, l~D~
5.05~s, 2E), 6.~3~s, 1~) r 7.1 ~ 7.~(i;1t
150 .
23 OE~Ph2 Tb~. 3410, 334G~ m,~?. 135 - 138~5~Co
17S0t 1754~ 2.17(br s, 2EI), 2.31(5~ 3EI), 3~5Ci~s~ 3
1721~1ujol). ~'.24~s, 4~, 4.41~s, ~ .61(~ 2Ei)~
d..84~s, lEJ, 5.05~s, 2I~), 6.S2~s, lX),
7 .05 ~ 7 . 7 (~
~A
~5
T~EI~ 2 (n~ rcr~yl)
C~.3
F2C~SCH2CC~'EI~ l ¦ W
C~ U ~1-12 sl ,j~,
C OCr;2 G12CEI (C?~3 ) CH3
l~o~ R2 ~ pl IR(CHC13) cm 1 ~(CDC13) FFm
24 H 13 1762, 1680,
1605~ ujol).
PO~l E~ 338û, 3130,
1792, 1751,
1700 .
26 C~Ph2 H 3370, 1785,
1715, 1703.
27 ~h2 PHCH2OC~ 3498, 3282,
1768, 170~,
1673~ 1626.
-- 42 -
