Note: Descriptions are shown in the official language in which they were submitted.
1 This invention relates to (1) compounds represented by
the formula: 2 3
y R ~ OR
A~ OCH2CCH2Z
lC = R
COB
hherein A is amino or substituted amino, COB is carboxy or
protected carboyx; R is =C~CH3)2, ~ CH3, = PR
~CH2
or~PO(OR )2
R is alkyl, aryl or aralkyl; OR and OR
independently or taken together represent a ketal; Y is
hydrogen or methoxy; Z is hydrogen or halogen and (2) a
process for preparing compounds represented by the formula:
y
A ~ ~ OCH2CXCH2Hal
O C=R
COB
by halogenating compounds represented by the formula:
_~ OCH2CXCH
A ~ 3
C=R
COB
wherein A, COB, R and Y are the same as mentioned above;
Hal is halogen, X is oxo or R o_~oR3 oR2 d oR3
are the same as mentioned above.
More particularly, it relates to reactions (2), (3),
and (4) and compounds ~III) and (IV) illustrated in the
following reaction sequence.
~tZ9F~7~
1 A ~ OCH2cOc~3 ~ OcH2cocH2~!al
o c=Rl halogenation ~ k ~c=~l
(I) I COs (II) I C'OB
(3) ~ ketalization (~) I deketali~ation
Y R2o oR3 y
A ~ CH2~CH3 halogenation~ A ~ OCH ~CH Hal
O ~C=Rl
~OB OB
(III) (IV)
wherein A, COB, Hal, R , OR , OR and Y are the same
as mentioned above.
In other words, this invention relates to
intermediates in the preparation of l-oxadethia-
cephalosporins and processes for preparing them, which
comprise tl) ketals tIII) of methyl ketones II) and ketals
tIV) of halomethyl ketones (II); t2) a process for preparing
halomethyl ketones ~II) or their ketals (IV) on halogenation
of methyl ketones (I) or their ketals tIII); (3) a process
for preparing ketals (III) on ketalization o~ methyl ketones
tI); (4) a process for preparing halomethyl ketones tlI) on
deketali~ation of ketals tIv); and t5) a process for
preparing halomethyl ketones tII) from methyl ketones tI) by
carrying out the aforementioned processes t3), t2), and (4)
successively.
1. Substituted-amino A
The substituted-amino A can be a side chain of natural
or synthetic penicillins or cephalosporins, which is stable
during the reaction, exemplified by an organic or inorganic
acylamino, diacylamino, hydrocarbylamino, sulfenylamino,
1 silylamino or acid addition salt of an amino group.
Representative of the acyl in the aforementioned
acylamino include:
1) (Cl - C10)alkanoyls;
2) (Cl - C5)haloalkanoyls;
3) azidoacetyls or cyanoacetyls;
4) acyl groups of the formula : Ar-CQQ'-CO-
wherein Q and Q' each are hydrogen or methyl; Ar is phenyl,
dihydrophenyl, or monocyclic heteroaromatic group involving
1-4 nitrogen atoms, oxygen atom and/or sulfur atom, which
may optionally be substituted by inert groups such as (C
- C5)alkyls, trifluoromethyl, cyano, aminomethyl,
protected carboxymethylthio, hydroxy, (Cl - C3)alkoxy,
(Cl - C10)acyloxy, chlorine, bromine, iodine, fluorine
and nitro;
5) 2-sydon-3-acetyl or (4-pyridone-1-yl)acetyl;
6) acyl groups of the formula : Ar-G-CQQ'-CO-
wherein Ar, Q and Q' are the same as mentioned above; G is
oxygen atom or sulfur atom;
7) acyl groups of the formula : Ar-CH-C0-
T
(wherein Ar is the same as mentioned above; T is i) hydroxy
or (Cl - C10)acyloxy; ii) carboxy (C2 - C7~alkoxy-
carbonyl, (C2 - C15)aralkoxycarbonyl, (Cl - C12)-
aryloxycarbonyl, (C1 - C7)alkanoyloxy, (C1 - C3)
alkoxy, cyano, carbamoyl; iii) sulfo or (Cl ~ C7)alkoxy-
sulfonyl;
8) acyl groups of the formula : Ar-CH-CO-
W-N-W'
wherein Ar is the same as mentioned above; h' and W' are
l respectively hydrogen or substituents on amino group (e.g.
(C2 ~ C7)alkoxycarbonyl, (C3 - Cl0)cycloalkyl -
(C2 ~ C3)alkoxycarbonyl, (C5 - C8)cycloalkoxycarbonyl
(Cl - C4)alkylsulfonyl-(Cl - C4)alkoxycarbonyl, halo
(Cl - C3)alkoxycarbonyl, (Cl - C15)aralkoxycarbonyl,
(Cl - C10)alkanoyl or (C2 - Cl5)aroyl, which may
optiona].ly be substituted by inert groups such as hydroxy,
(Cl - Cl0)alkanoyloxy, halogen, (Cl - C5)hydroxy-
alkyl and trifluoromethyl, pyronecarbonyl, th.iopyrone-
carbonyl~ pyridonecarbonyl, carbamoyl, guanidinocarbonyl;substituted ureido carbonyls such as 3-methyl-2-oxoimidazo-
lidin-l-ylcarbonyl and 3-methanesulfonyl-2-oxoimidazolidine-
l-ylcarbonyl, substituted-amidooxalylcarbamoyls such as 4-
methyl-2,3-dioxopiperazin-1-ylcarbonyl and 4-ethyl 2,3-dioxo-
piperazin-l-ylcarbonyl, substituted-thioureidocarbonyls
corresponding to the aforementioned ureidocarbonyls; or W,
W' and nitrogen atom are, taken together, phthalimido,
maleinimido or enaminos derived from enolic carbonyl
compounds such as ~C5 - Cl0)acetoacetate, (C4 - Cl0)-
acetoacetamide, acetylacetone, acetoacetonitrile and 1,3-
cyclopentanedione;
9) acyl groups of the formula: Ar-C-CO-
NOE
wherein ~r is the same as mentioned above; E is hydrogen or
(Cl - C5)aklyl;
10) 5-aminoadipoyl; N-protected 5-aminoadipoyl (e.g. those
N-protected by (Cl - C10)alkanoyl, ~Cl - Cl0)-
aralkanoyl; (C2 - Cll)aroyl, (Cl - C5)haloalkanoyl,
(C2 ~ C10)alkoxycarbonyl or the like); carboxy-protected
5-aminodipoyl (those C-protected by (Cl - C5)alkyl,
~
(C2
- C21~aralkyl, (Cl - C10)aryl, and the like;
these protecting gro~ps each may be substituted by (C1 -
C5)alkyl, (Cl - C5)alkoxy, halogen, nitro or the like;
and
11) acyl groups of the formula: L-O-CO-
wherein L is a readily removable ~Cl - C10)hydrocarbon
group which may be substituted, for example, t-butyl, 1,1-
dimethylpropyl, cyclopropylmethyl, l-methylcyclohexyl,
isobutyl, 2-alkoxy-t-butyl, 2,2,2-trichloroethyl, benzyl,
naphthyl, p-methoxybenzyl, pyridylmethyl, diphenylmethyl.
A may be diacylimidos from (C4 - C10)polybasic
carboxylic acids.
The substituted amino A includes aminos substituted by
(Cl - C20)hydrocarbyl or hydrocarbylidene (e.g. methyl,
ethyl, propyl, t-butyl, trityl, methylidene, benzylidene,
l-halo-2-phenylethylidene, 1-alkoxy-2-phenylethylidene,
3-5,di-t-butyl-~-hydroxybenzylidene, o-hydroxybenzylidene)
and (C2 - C10)organo silyl aminos (e.g. trimethylsilyl-
amino).
The amino A also includes groups which may be
converted into amino or amido, such as azido, isocyanato,
and isocyano.
Two amino substituents of A, taken together, may form
a ring (e.g. 2,2-dimethyl-4-oxo-5-phenylimidazolidin-3-yl).
Reactive group A may be protected beforehand and,
after termination of the reaction, deprotected in the
conventional manner.
Most preferable group A is phenylacetamido and
phenoxyacetadimo.
3G 2. Protected carboxy group COB.
ze~
1 The group COB represents carboxy groups protected in
forms oE esters, amidos, acid halogenides, acid anhydrides,
salts and the ]ike.
Examples of the group B are oxygen functional groups
such as ~Cl - C10)alkoxy (e.g. methoxy, ethoxy,
t-butoxy), (C7 - C20)aralkoxy ~e.g. benzyloxy, methoxy-
benzyloxy, diphenylmethoxy, trityloxy), (C5 -
C15)aryloxy (e.g. phenoxy, naphthyloxy), ~Cl - C12)-
organo metallic oxy (e.g. trimethylstannyloxy, dimethyl-
chlorosilyloxy, trimethylsilyloxy), (Cl - C15)organic or
inorganic acyloxy, oxy of metal of I, II and III groups in
the Periodic Table (e.g. sodiumoxy, potassiumoxy,
magnesiumoxy), and (Cl - C12)ammoniumoxy; sulfur
functional groups (e.g. groups which may form (Cl - C12)-
thiolester, thiocarboxy and the like; nitrogen functional
groups [those form amides such as N-(Cl - C5)alkylamide,
N,N-di(Cl - C5)alkylamide, and amide with inidazole or
phthalimide; groups which may form hydrazide or azide]; or
halogen atom (e.g. chlorine, bromine).
These groups, if possible, may involve hetero atoms
such as oxygen, nitrogen and/or sulfur in the skeleton and
may have unsaturation or substituents (e.g. nitrogen-,
oxygen-, sulfur-, carbon-, phosphorus-functional group,
halogen atoms).
Representative of CO~ are (Cl - C5)halo-
alkylesters, (C2 - C5)acylalkylesters, (C5 - C~)-
arylester, (C5 - C20~arylkylesters, esters of (Cl -
C12)oxime, (Cl - C5)-N-alkoxyamides, imides of dibasic
acids, N,N'-di(C3 - C5)alkylhydrazides, salts of alkali
or alkaline earth metals, salts of (Cl C5)alkylamines
~?~
1 and other equivalent groups. (The aforementioned carbon
number means that of B).
Preferable COB esters of carboxylic acids
(particularly methyl-, t-butyl-, 2,2,2-trichloroethyl-,
methanesulfonylethylpivaroyloxymethyl-, phenacyl-, benzyl-,
p-methoxybenzyl-, p-nitrobenzyl-, benzhydryl-, indanyl-,
benzaldoxime-, N,N-dimethylaminoethyl, and trimethylsilyl-
esters), and salts of alkali metals or alkaline earth metals
(e.g. lithium, sodium, potassium, magnesium and other
equivalent salts).
3. R
R is isopropylidene, isopropenyl, =PR
~PO(oR )2' 3
~ H R is alkyl such as methyl, ethyl,
cyanoethyl, ethoxyethyl, propyl, chloropropyl, isobutyl,
pentyl, cyclohexyl and octyl, aryl such as phenyl and tolyl
or aralkyl such as benzyl, phenethyl and pyridylmethyl.
Since Rl does not participate in the reaction, it can be
varied widely, e.g. possession of substituents.
4. OR , OR .
OR and oR3 are independently or taken together
ketal forming groups such as alkoxy (e.g. methoxy, ethoxy,
propoxy, isobutoxy, pentyloxy, cyclohexyloxy, aralkoxy (e.g.
benzyloxy, phenethyloxy, pyridylmethoxy, alkylenedioxy (e.g.
ethylenedioxy, propylenedioxy, trimethylenedioxy), and
aralkylenedioxy (e.g. phenylethylenedioxy,
phenyltrimethylenedioxy, diphenylpropylenedioxy). OR and
OR , since they are removed after termination of the
reaction, can be varied widely, e.g. possession of
substituents, so far as the reaction is not obstructed.
1 5. ~, Hal.
Z is hydrogen or halogen.
~ al is halogen such as chlorine, bromine and iodine.
6. Y.
Y is hydrogen or methoxy.
Cephalosporins derived from methoxylated derivatives
exhibit especially excellent antimicrobial action in many
cases.
[2] Starting Materials
i) Starting materials (I), for example, ~-(2f-aceton-
yloxy-3~-acylamido-4-oxoacetidin-1-yl)-~-isopropylidene-
acetate, may be prepared by reacting already well-known ~-(2
-chloro-3~-acylamido-4-oxo-azetidin-1-yl)-~- isopropylidene-
acetate with propargyl alcohol in the presence of silver
fluoroborate to yield ~-(2~-propargyloxy-3~-acylamido-4-oxo-
azetidin-l-yl)-~-isopropylideneacetate and hydrating the
later in the presence of mercury salts.
ii~ The isopropylideneacetates thus prepared are
subjected to cleavage reaction with ozone to yield ~2~-
acetonyloxy-3~-acylamido-4-oxoacetidin-1-yl)glyoxalates,
which are reduced and halogenated to yield ~-(2~-acetonyloxy-
3~-acylamido-4-oxoacetidin-1-yl)-~-chloroacetate; the latter
is heated in the presence of triethyl phosphite to yield the
other starting materials,~~(2~-acetonyloxy~3~-acylamido-4-
oxoazetidin-l-yl)-~-diethylphosphoroylacetates.
iii) The other starting materials,~-(2~- acetonyloxy-3~-
acylamido-4-oxoacetidin-1-yl)-~-triphenylphosphoranylidene-
acetates may be prepared from ~-(2~-acetynyloxy-3~-acylamido-
-4-oxoazetidin-1-yl)-~-chloroacetates prepared in the manner
as mentioned in ii), on reaction with triphenylphosphine.
1 The rest (I) may be prepared in the conventional
manners, for example, by modifylng the aforementioned
methods, the raw materials, reagents and the like or by
modifying the desired portion of the aforementioned other
starting materials (I).
These processes have been described in ~ritish Patent
Application No. 46759/1975, and Japanese Patent Application
Open to Public Inspection No. 49-133594.
[3] Prior Art
Halogenation of acetonyloxy groups of ~-(2~-acetonyl-
oxy-33-acylamido-2-oxoazetidin-1-yl)acetates is not known
yet. Halogenation usually takes place at the methyl and
methylene groups of acetonyloxy group, but the location and
influence on other reactive groups in the molecule have not
yet been eludicated.
The halogenation of the corresponding acetonylthio
derivatives is not known.
[4] Preparation
(A) ~alogenation (2)
The aforementioned halomethyl ketones (II) or their
ketals (IV) are prepared from methyl ketones (I) or their
ketals (III) on halogenation.
The halogenation is carried out as follows:
i) The starting materials, methylketones (I3 or their
ketals (III) are dissolved in a solvent (such as
hydrocarbon, halohydrocarbon, ether, ester, alcohol,
carboxylic acid, amide or like solvent or their mixtures);
ii) A halogenating agent (such as molecular halogens,
cupric halogen;des, mercury halogenides, molecular compounds
of hydrohalogenic acids, aromatic bases and halogens,
1 molecular compounds of phenyltrimethylammonium halogenides
and halogens, N-haloamides, N-haloimides, esters of
hypohalogenous acid, hypohalogenites and other halogenating
agents) is added; and
iii) The reaction is conducted preferably at room
temperature or under warming. Ordinarily, the reaction
terminates within a period of 0.5 - 10 hours, but sometimes
requires more than 20 hours at room temperature.
iv) The preferable solvents are those which may participate
in ketalization, such as primary alcohols, glycols, and
1,3-diols. These solvents promote the reaction accompanied
by ketalization oE methylketone (I~ in the presence of acids
or halogenating agents in the reaction medium.
v) Most preferable halogenating agents are cupric
halogenides (e.g. cupric bromide), and molecular compounds
of pyridinium hydrohalogenides and halogens (e.g. molecular
compound of pyridine hydrobromide and bromine), by which the
reaction proceeds mildly with formation of a minor quantity
of by-product.
vi) Preferable starting materials are ketals (III) of
methyl ketones; in this case, the reaction proceeds rapidly
with formation of very small quantity of by-product. The
yield of halogenation not through the ketals is 10-30%,
whereas that through the ketals is 50-100%.
vii) This reaction proceeds particularly smoothly under
ketalizable conditions (e.g. alcohol, in the presence of
mineral acid or Lewis acid) to give the objective compounds
in high yield (B) ketalization (3).
Methylketones (I) are ketalized to yield ketals (II)
of methylketones.
1 The ketalization is carried out as follows:
i) Methylketone (I) is dissolved in a solvent (such as the
alcohols halohydrocarbons, ethers, esters, amides or ~heir
mixtures containing a ketalizing agent ~such as primary or
secondary alcohols (e.g. methanol, ethanol, propanol,
secondary butanol, benzyl alcohol), glycols ~e.g. ethylene
glycol, propylene glycol, phenylethylene glycol), diols
(e.g. trimethylene glycol, 3-hydroxybutanol), ortho esters;
or other ketalizing agents].
ii) The reaction is conducted in the presence or absence of
a catalyst (e.g. mineral acids, sulfonic acids; mineral acid
salts with heavy metals, particularly cupric bromide, copper
sulfate; other ketalization catalysts).
iii) The reaction is conducted preferably at about -20 to
50 degrees C.
The aforementioned halogenating agents may also serve
as catalysts for ketalization.
(C) Deketalization (4)
The deketalization may be carried out as follows:
i) The ketals ~IV) of halomethylketones are dissolved in an
a~ueous solvent (such as halohydrocarbon, ether, ester,
amide, carboxylic acid, ketone or like solvents, or their
mixtures).
ii) The reaction is conducted in the presence of a catalyst
(such as mineral acids, organic acids, e.g. sulfonic acids).
iii) At -20 to 100 degrees C for 1 to 30 hours. The
objective compounds are easily obtained.
(D) Successive Process
Each reaction described above may be carried out
successively. For example, the halomethylketone ketals (IV)
1 may be prepared by halogenation immediately after the
aforementioned ketali~ation of methylketones in a reaction
vessel; the subsequent deketalization yields
halomethylketones (II); deketalization is carried out after
halogenation of ketals (III) of methylketones. When
ketalization, halogenation and deketalization are carried
out successively, halomethylketones (II) are usually
obtained from ~ethylketones (I) in more than 95% overall
yield. The yield is much higher than that of direct
halogenation (10-30% yield) not through the ketal.
l5] Products and Use
The products of each step may be purified in a
conventional manner such as recrystallization,
reprecipitation or chromatography after removal of the
starting materials remaining unchanged, reagents,
by-products and solvents in a conventional manner such as
extraction, washing, concentration and drying. It is
natural to pay attention to deketalization on the action of
acids during the treatment of ketals.
Halomethylketones (II) or their ketals (IV) are used
as intermediates in the preparation of antimicrobial agents,
l-oxadethia-3-cephem-4-carboxylic acids.
For example, halomethylketones (II) are reacted 1)
with aromatic heterocyclic thiol in the presence oE a base,
2) when R is isopropylidene or isopropenyl, it is
converted into phosphoroyl or phosphoranylidene in a manner
as mentioned in [2], and 3) the products are heated in the
presence of a base to yield antimicrobial agents,
l-oxodethia-3-substituted-thiomethyl-3-cephem-4-carboxylic
acid derivatives. In order to prepare potent antimicrobial
~Z9~
1 agents, it is appropriate to modify A, COB and Y in
well-known manners.
l`he following examples are provided to further
illustrate the products and processes of this invention.
_xample 1-1_ ______
(1) To a solution of 214 mg of benzyl~ -(2~-acetonyl-
oxy-33-phenylacetamido-4-oxoacetidin-1-y])-~-isopropylidene-
acetate in 5 ml of dry methanol is added 203 mg of cupric
bromide, and the mixture allowed to stand at room
temperature for 6 hours, poured into an aqueous sodium
hydrogencarbonate solution and extracted with ethyl
acetate. The extract is washed with water, dried over
magnesium sulfate and evaporated under reduced pressure to
yield 236 mg of ben7yl ~ [2~-(2,2-dimethoxypropoxy)-3~-
phenylacetamido-4-oxoazetidin-1-yl]-~-isopropylideneacetate
(100% yield).
IR ~ CHC13 3470, 1790, 1740, 1965 cm
max
NMR: ~ 3 1.10s3H, 1.92s3H, 2.25s3H, 3.05s3H, 3.08s3H,
3.28s2H, 3.57s2H, 5.27+5.00A~q(12Hz)2H,
5.13d(5Hz)lH, 5.23dd(5.8Hz)lH, 6.22d(8Hz)lH,
7.20s10H.
(2) To a solution of 213 mg of benzyl N- (2~-acetonyl--
oxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylidene-
acetate in 5 ml of dry methanol is added 320 mg of pyridine
hydrobromide - bromine complex, and the mixture stirred at
60 degrees C for 10 minutes to yield benzyl ~-[2~ (2,2-di-
methoxypropoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl)-a-
isopropylideneacetate and benzyl ~2~-~2,2-dimethoxypropoxy)-
3~-phenylacetamido-4-oxoazetidin-1-yl-~-isopropylideneacetate
~Læ~
1 and benzyl ~-[2~(2,2-dimethoxy-3-bromopropoxy)-3~-phenyl-
aceta mido-4-oxoazetidin-1-yl]-~-isopropylideneacetate.
Example 1-2
(1) To a solution of 1.15 y of benzyl ~-(2~-acetonyl-
oxy-3~-phenylacetamido-4-oxoazetidin-1-yl) a-isopropylidene-
acetate in 22 ml of dry ethanol is added 1.39 g of cupric
bromide and 1.5 ml of triethyl orthoformate~ and the mixture
stirred under heating at 60 degrees C for 15 minutes to
yield benzyl ~-[2~-(2,2-diethoxypropoxy)-3~-phenylacetamidc-
4-oxoazetidin-1-yl]-~-isopropylideneacetate [TLC : Rf=0.80,
ChH6+C2H5OCOCH (1:1) ; precoated silica gel plate
made by Merck Co.J.
Additionally, benzyl ~-[2 ~(2,2-diethoxy-3-bromopropoxy)-3~-
phenylacetamido-4-oxoazetidin-1-yll~ -isopropylideneacetate
(TLC : Rf=0.90, C6~6+C2H5OCOC~3 (1:1), precoated
silica gel plate may be Merck Co.~ is obtained as by-product.
Example 1-3
___ __.____
To a solution of 0.54 g (1 mmole) of diphenylmethyl
-(2~-acetonyloxy-3~-phenylacetamido~4-oxoazetidin-1-yl)~ -
isopropylideneacetate in 11 ml of dry methanol is added 0.56
g (2.5 mmoles) of cupric bromide, and the mixture stirred
under heating at 40 - 60 degrees C for 20 minutes to yield
diphenylmethyl ~-[2~-(2,2-dimethoxy-3-bromopropoxy)-3~
phenylacetamido-4-oxoazetidin-1-yl]-~-isopropylideneacetate
and diphenylmethyl ~-[2~-(2,2-dimethoxypropoxy)-33-phenyl-
acetamido-4-oxoa~etidin-1-yl]-~-isopropylideneacetate.
_xample 1-4_ _ _____
To a solution of 0.54 g (1 mmole) of diphenylmethyl
~-(2~-acetonyloxy-3~-phenylacetamido-4-oxoazetitin-1-yl)-
~-isopropylideneacetate in 11 ml of dry ethanol is added
14
~l~n
1 0.56 g (2.5 mmoles) of cupric bromide, and the mixture
stirred under heating at 40 - 60 degrees C for 10 minutes to
yield diphenylmethyl a-[23-(2,2-diethoxy~3-bromopropoxy)-3e-
phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylideneacetate
and diphenylmethyl a-[2~-(2,2-diethoxypropoxy)-3~-
phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylideneacetate
[TLC : Rf=0.55, C6~6+CH3CO~C2~l5 (2:1) precoated
silica gel plate made by Merck Co.~.
Exam~ 1-5
The following compounds may be prepared in the same
manner as mentioned in Examples 1-1 to 4.
(1) Methyl a-(2~-acetonyloxY-3~-phenoxyacetamido-4-oxo~
azetidin-l-yl)-a-isopropenylacetate is reacted with cupric
chloride in dry ethanol at room temperature for 13 hours to
yield methyla -[2~-(2,2-diethoxypropoxy)-33-phenoxyacetamido-
4-oxoazetidin-1-yl)-~-isopropenylacetate.
(2) Similarly, 2,2,2-trichloroethyl a-(2~-acetonyloxy-3~-
benzyloxycarbonamido-3~-methoxy-4-oxoazetidin-1-yl)~ -tri-
phenylphosphoranylideneacetate is ketalized with propylene
glycol and p-toluenesul~onic acid to yield 2,2,2-trichloro-
ethyl a-[2~-(2,2,propylenedioxypropoxy)-33-benzyloxycarbo-
amido-3~-methoxy-4-oxoazetidin-1-yl]-a-triphenylphosphoranyl-
ideneacetate.
(3) Benzyl a-~2~-acetonyloxy-3~-~a-phenyl- a-benzyloxycarbo
nylacetamido)-3a-methoxy-4-oxoazetidin-1-yl)-~-diethylphos-
phoroylacetate is reacted with cupric bromide in proponal at
room temperature for 8 hours to yield benzyl a-[2~-(2,2-
dipropoxypropoxy-3~-(a-phenyl-a-benzyloxycarbonylacetamido)-
3a-methoxy-4-oxoazetidin-1-yl)-~-diethylphosphoroylacetate.
Example 2-1
~L~29æ~.
1 (1) To a solutio~ of 181 mg of benzyl ~-(2~-acetonyl-
oxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylid~ne-
acetate dissolved in a mixture of 0.2 ml of tetrahydrofuran
and 4 ml of t-butanol is added 640 mg of curpic bromide, and
the mixture stirred at 75 degrees C for 1.5 hours. I'he
reaction mixture is separated by thin layer chromatography
on silica gel to yield benzyl ~-[2~-(3-bromoacetonyloxy-3
-phenylacetamido-4-oxoazetidin-1-yl)-~- isopropylidene-
acetate (25% yield).
(2) To a solution of 75 m~ of benzyl ~-(2~-acetonyl-
oxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylidene-
acetate in 1 ml of t-butanol is added one drop of 25~
solution of hydrogen bromide in acetic acid and a solution
of 26 mg of bromine in 0.32 ml of chloroform, and the
mixture allowed to stand at room temperature overnight, then
poured into water, and extracted with ethyl acetate. The
extract is washed with water and dried over magnesium
sulfate. The residue is chromatographed on a column of 5 g
of silica gel c~ntaining 10~ water, eluted with ethyl
acetatebenzene, and evaporated to yield 13 mg of ~-~2
-(3-bromoacetonyloxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-
~-isopropylideneacetate (14.8~ yield).
(3) To a solution of 139 mg ~0.3 mmole) of benzyl
~-(2~-acetonyloxy-3~-phenylzcetamido-4-oxoazetidin-1-yl)-~-
isopropylidene acetate in 1.3 ml of dry t-butanol and 0.2 ml
of dry dichloroethane is added 192 mg t0.6 mmole) of
pyridinium hydrobromide-bromine complex, and the mixture
warmed at 45 - 50 degrees C for 1 hour. Then, an additional
91 mg (0.13 mmole) of pyridinium hydrobromide-bromine
complex is added, and the mixture heated for 1 hour.
16
1 Separation by thin layer chromatography yields u-12~-(3-
bromoacetonyloxy)-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-
isopropylideneacetate (33~ yeild). The products, prepared
in (1) - (3) described above, are identical and have the
following constants:
IR :~ 3 3420, 1780, 1730, 1685 cm
max
NMR:S D 3 1.98s3H, 2.25s3H, 3.62s2H, 3.68s2H, 4.12s2H,
5.1 - 5.5m4H, 6.73d(7Hz)lH, ca.7.4 - lOH.
Example 2-2__
(1) To a solution of 89 mg of benzyl ~-[2~-(2,2-
dimethoxypropoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-
isopropylideneacetate in 3 ml of methanol is added 85 mg of
cupric bromide, and the mixture refluxed under heating for 4
hours. The reaction mixture is worked up, and the extract
washed with water, dried and evaporated. The residue is
separated by thin layer chromatography to yield 49 mg of
benzyl ~[2~-(2,2-dimethoxypropoxy)-3-bromopropoxy)-3~-
phenylacetamido-4-oxoaæetidin-1-yl)-~-isopropylideneacPtate
(47.6% yield).
IR ~ CHC13 340, 1780, 1720, 1690 cm
max
NMR: ~ 3 1.97s3H, 2.25s3H, 3.13s6H, 3.23s2H,
3.42+3.73ABl(12Hz)2H, 3.63s2H, 5.03
5.66ABq(12Hæ)2H, 5.27d(5Hz~lH,
5.33dd(5;8Hz)lH, 6.23d(8Hæ)lH, 7.33s5H
7.40s5~.
(2) To a solution of 97 mg of ~-[2~-(2,2-dimethoxy-
propoxy)-3~ phenylacetamido-4-oxoazetidin-1-yl)-~-isopropyl-
ideneacetate in 2 ml of dry methanol is added 140 mg of
1 pyridinium hydrobromide-bromine complex, and the mixture
refluxed under heating for 30 minutes, then poured into
water, and then extracted with ethyl acetate. I'he ex~ract
is washed with water, dried over magnesium sulfate, and then
evaporated. The residue (132 mg) is chromatograyhed on a
column of 4.5 9 of silica gel containing 10~ water, and
eluted with 15~ ethyl acetate-benzene. The eluate is
concentrated to yield 56 mg of benzyl ~-[2~-(2,2-dimethoxy-
3-bromopropoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl)~ -
isopropylideneacetate (50.~ yield). This product isidentical with that prepared in (1) described above.
_xample 2-3_ _ _ ___
The reaction mixture of Example 1-2(3) is further
heated with stirring, and after termination of the
bromination, cooled to room temperature. The mixture is
then poured into 5% aqueous sodium hydrogencarbonate
solution, the precipitate removed off by filtration and the
filtrate extracted with ethyl acetate~ The extract is
washed with an aqueous sodium chloride solution, dried over
sodium sulfate and evaporated under reduced pressure to
yield 1.62 g of crude benzyl a-[2~-(2,2-diethoxy-3-bromo-
propoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl)-~- isopropyl-
ideneacetate (106% yield).
IR ~CHC13 3420, 1775, 1720, 1680 cm
~MR J 3 1.13t(7Hz)6H~ 1.98s3H~ 2.25s3H~ 3.2-3.7mlOH,
5.50-5.5m4H, 6.52d(8Hz)lH, ca. 7.4-lOH.
Exam~le 2-4
The reaction mixture of Example 1-3 is further heated
with stirring, and after termination of the bromination,
poured into 5% aqueous sodium hydrogencarbonate solution.
18
2~l
1 The resulting insoluble material (cuprous bromide) is
filtered off, and the filtrate extracted with ethyl
acetate. The extract is washed with water, dried and then
evaporated to yield diphenylmethyl ~-12~-~2,2-dimethoxy-3-
hromopropoxy-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-
isopropylideneacetate as crystals.
Exam~le_2-5
The reac~ion mixture of Example 1-4 is ~urther heated
with stirring, and after termination of the bromination,
poured into 5% agueous sodium hydrogencarbonate solution.
The resulting insoluble material (cuprous bromide) is
filtered off, and the filtrate extracted with ethyl
acetate. The extract is washed with water, dried and
evaporated to yield diphenylmethyl~-[2 ~(2,2-diethoxy-3-
bromopropoxy-3~-phenylacetamido-4-oxoazetidin-1-yl)~ -
isopropylideneacetate (64.6% yield).
NMR : ~ 3 l.OSt(7Hz)6H, 1.93s3H, 2.18s3H, 3.0-3.8m8H,
3.57s2H, 5.20d(~Hz)lH, 5.37dd(4;3Hz)lH,
6.32d(8Hz)lH, 6.95slH, ca. 7.3ml5H.
Exam~le 2-6
The following compounds may be prepared in the same
manner as in Examples 2-1 to 5.
(1) The reaction mixture of Example l-S(l) is
refluxed under heating for 6 hours to yield methyl ~-[2~-
(3-chloro-2,2-diethoxypropoxy)-3~-phenoxyacetamido-4-oxo-
azetidin-l-yl) -~-isopropenylacetate.
(2) A solution of 2,2,2-trichloroethyl ~-[2~-(2,2-
propylenedioxypropoxy)-3~-benzyloxycarbonylamino-3~-methoxy-
-4-oxoazetidin-1-yl)-~-triphenylphosphoranylideneacetate in
dioxane is reaction with cupric bromide to 60 degrees C ~or
19
~Z9~
1 5 hours to yield 2,2,2~trichloroethyl ~-[2~-(3-bromo-2,2-
propylenedioxypropoxy)-3~-benzyloxycarbonylamino-3a-methoxy-
-4-oxoazetidin-1-yl)-~-triphenylphosphoranylideneacetate.
(3) The reaction mixture of Example 1-5(3) is
refluxed under heating for 6 hours to yield ben~yl ~-[2~
-(3-bromo-2,2-dipropoxy)-3~-( ~phenyl-a-benzyloxycarbonyl-
acetamido)-3a-methoxy-4-oxoazetidin~l-yl]-~-diethylphos-
phoroylacetate.
Example 3-1
To a solution of 12 mg of benzyl ~-12~-(2,2-dimethoxy-
3-bromopropoxy(-3~-phenylacetamido-4-oxoazetidin-1-yl)-~-
isopropylideneacetate in 1 ml of acetone is added 0.2 ml of
water and one drop of 60% perchloric acid, and the mixture
kept at room temperature for 3 hours and then at 70 degrees
C for 30 minutes. The mixture is poured into water, dried
over magnesium sulfate and evaporated to yield 9 mg of
residue, which is separated by thin layer chromatography on
silica gel to yield ~-12~-(3-bromoacetonYloxy)-3~-phenyl-
acetamido-4-oxoazetidin-1-yl]-~-isopropylideneacetate (50
yield). The product is identical with that prepared in
Example 2-1.
_xample 3-2_ _ _ _ _
To a solution of 1.62 9 of benzyl ~-[2~-(2,2-diethoxy-
3-bromopropoxy)-3~-phenylacetamido-4-oxoazetidin-1-yl]-~-
isopropylideneacetate in 50 ml of acetone is added 15 ml of
water and 7 ml of 30~ perchloric acid, and the mixture
stirred at 50 degrees C for 4 2/3 hours. Acetone is
evaporated under reduced pressure, and the residue is
extracted with ethyl acetate. The extract is washed with 5~
aqueous sodium hydrogencarbonate solution, an aqueous sodium
l chloride solution and then water, dried over sodium sulfate,
and evaporated to yield 1.26 g of benzyl u-(2~-bromoacetonyl-
oxy-3-phenylacetamido-4-oxoazetidin-1-yl)-~-isopropylidene-
acetate as crude crystals ~93.6% yield). This product is
identical with that prepared in Example 2-l.
Example 3-3_____
To diphenylmethyl ~-[2~-(2,2-dimethoxy-3-bromopropoxy-
3-phenylacetamido-4-oxoazetidin-l-yl]-~-isopropylideneacetate
is added acetone, water and 30% perchloric acid, and the
mixture stirred at 50~ for 6 hours. Acetone is evaporated
and the residue is extracted with ethyl acetate. Ihe
extract is washed with an aqueous sodium hydrogencarbonate
solution and water, dried, and evaporated to yield
diphenylmethyl ~-[2~-(3-bromoacetonyloxy)-3-phenylacet-
amido-4-oxoazetidin-l-yl]~ -isopropylideneacetate. The
product is idential with that prepared in Example 3-4.
Example 3_4_
To a solution of 0.123 g (0.18 mmole) of diphenyl-
methyl ~-[2~-(2,2-diethoxy-3-bromopropoxy-36-phenylacet-
amido-4-oxoazetidin-l-yl]-~-isopropylideneacetate in 3.6 ml
of acetone is added 1.2 ml of water and 0.6 ml of 30%
perchloric acid, and the mixture stirred at 50 degrees C for
6 hours. Acetone is evaporated and the residue is extracted
with ethyl acetate. The ethyl acetate layer is washed with
an aqueous sodium hydrogencarbonate solution and then water,
dried and evaporated to yield 0.95 g of diphenylmethyl
~-[2~-(3-bromoacetonyloxy)-3-phenylacetamido-4-oxoazetidin-1-
yl]-~-isopropylideneacetate (85.2% yield).
IR ~C~Cl3 3430, 1780, 1690 cm
max
9~
1 NMR :~ 3 1.97s3H, 2.25s3H, 3.60s4H, 4.02s2~,
5.12d(4Hz)lH, 5.30dd(4;8Hz)lH, 6.72d(8Hæ)lH,
6.97sl~l, 7.3ml5H.
Exam~le_3-5
The following compounds may be prepared in the same
manner as in Example 3-1 to 4.
(1) ~ethyl ~-[2~-(3-chloro-2,2-diethoxypropoxy)-3~-
phenoxyacetamido-4-oxoaæetidin-1-yl]-~-isopropenylacetate is
hydrolyzed with perchloric acid in an a~ueous acetone to
1~ yield methyl~-[2~-(3-chloroacetonyloxy)-3~-phenoxyacet-
amido-4-oxoazetidin-1-yl]-~-isopropenylacetate~
(2) A solution of 2,2,2-trichloroethyl ~-12~-(3-
bromo-2,2-propylenedioxypropoxy)-3~-benzyloxycarbonyl-
amino-3~-methoxy-4-oxoazetidin-1-yl]-~-triphenylphosphoranyl-
ideneacetate in 50% formic acid is heated with
toluenesulfonic acid at 80 degrees C for 2 hours to yiel~
2,2,2-trichloroethyl ~[2~-(3-bromoacetonyloxy)-3~-benzyl-
oxycarbonylamino-3~-methoxy-4-oxoazetidin-1-yl]-~-triphenyl-
phosphoranylideneacetate.
(3). Benzyl ~-[~ -(3-bromo-2,2-dipropoxypropoxy)-3~-
( ~phenyl-~-benzyloxycarbonylacetamido)-3~-methoxy-4-oxoazet-
idin-l-yl]- ~diethylphosphoroylacetate is hydrolyzed with
perchloric acid in an aqueous acetone to yield ~-12~-(3-
bromoacetonyloxy)-3~ -phenyl-~-benzyloxycarbonylacetamido)-
3 ~methoxy-4-oxoazetidin-1-yl]-~-diethylphosphoroylacetate.
22
