CA1129871A - Azetidine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Azetidine derivatives of the formula:

wherein A is amino or substituted amino; COB is carboxy or protected carboxy; R1 is =C(CH3)2, , =PR43 or

Description

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 ~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.

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.

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 ~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.

Claims (34)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing compounds represented by the following formula:

wherein A is amino or substituted amino; COB is carboxy or protected carboxy; R1 is =C(CH3)2, ,=PR43 or (R4 is alkyl, aryl or aralkyl); Y is hydrogen or methoxy; X is oxo or (OR2 and OR3 independently or taken together represent a ketal); and Hal is halogen; which comprises halogenating compounds represented by the following formula:

(I) wherein A, COB, R1, X and Y are as defined above with a halogenating agent selected from the group consisting of molecular halogens, cupric halogenides, mercury halogenides, molecular compounds of phenyltrimethylammonium halogenides and halogens, N-haloamides, N-haloimides, esters of hypohalogenous acid and hypohalogenites.

2. A process as claimed in claim 1, wherein the reaction is conducted at room temperature or under warming.

3. A process as claimed in claim 1, wherein the reaction is conducted in a solvent selected from the group consisting of primary alcohols, glycols and 1,3-diols.

4. A process as claimed in claim 1, wherein the halogenating agent is cupric bromide.

5. A process as claimed in claim 1, wherein the halogenating agent is a molecular compound of pyridine hydrobromide and bromine.

6. A process as claimed in claim 1, wherein R1 is isopropylidene and A, COB, Y, X, and Hal are as defined in claim 1.

7. A process as claimed in claim 1, wherein R1 is and A, COB, X, Y and Hal are as defined in claim 1.

8. A process as claimed in claim 1, wherein R1 is triarylphosphoranylidene and A, COB, X, Y and Hal are as defined in claim 1.

9. A process as claimed in claim 1, wherein R1 is dialkylphosphoroyl and A, COB, X, Y and Hal are as defined in claim 1.

10. A process as claimed in claim 1, wherein B is C7-C20 aralkoxy and A, R1, X,Y and Hal are as defined in claim 1.

11. A process as claimed in claim 1, wherein B is 2,2,2-trichloroethoxy and A, R1, X, Y and Hal are as defined in claim 1.

12. A process as claimed in claim 1, wherein OR2 and OR3 are independently alkoxy and A, COB, R1, Y and Hal are as defined in claim 1.

13. A process as claimed in claim 1, wherein OR2 and OR3, taken together, represent an alkylenedioxy and A, COB, R1, Y
and Hal are as defined in claim 1.

14. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a bromo halogenating agent and A
is phenylacetamido, B is benzyloxy, R1 is isopropylidene, Y is hydrogen, R2 and R3 are methyl and Hal is bromo, for the preparation of benzyl .alpha.-[2.beta.-(2,2-dimethoxy-3-bromopropoxy)-3.beta.-phenylacetamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate.

15. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a bromo halogenating agent and A
is phenylacetamido, B is benzyloxyr R1 is isopropylidene, Y is hydrogen, R2 and R3 are ethyl and Hal is bromo, for the preparation of benzyl .alpha.-[2.beta.-(2,2-diethoxy-3-bromopropoxy)-3.beta.-phenylacetamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate.

16. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a bromo halogenating agent and A
is phenylacetamido, B is diphenylmethoxy, R1 is isopropylidene, Y is hydrogen, R2 and R3 are methyl and Hal is bromo, for the preparation of diphenylmethyl .alpha.-[2.beta.-(2,2,-dimethoxy-3-bromopropoxy)-3.beta.-phenylacetamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate.

17. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a bromo halogenating agent and A
is phenylacetamido, B is diphenylmethoxy, R1 is isopropylidene, Y is hydrogen, R2 and R3 are ethyl and Hal is bromo, for the preparation of diphenylmethyl .alpha.-[2.beta.-(2,2-diethoxy-3-bromopropoxy)-3.beta.-phenylacetamido-4-oxoazetidin-l-yl]-.alpha.
-isopropylideneacetate.

18. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a chloro halogenating agent and A
is phenoxyacetamido, B is methoxy, R1 is isopropenyl, Y is hydrogen, R2 and R3 are ethyl and Hal is chloro, for the preparation of methyl .alpha.-[2.beta.-(3-chloro-2,2-diethoxypropoxy)-3.beta.-phenoxyacetamido-4-oxoazetidin-l-yl]-.alpha.-isopropenylacetate.

19. A process as claimed in claim 1, wherein a compound of formula I is halogenated with a bromo halogenating agent and A
is benzyloxycarbonylamino, B is 2,2,2-trichloroethoxy, R1 is triphenylphosphoranylidene, Y is methoxy, OR2 and OR3 taken together are 2,2-propylenedioxy and Hal is bromo, for the preparation of 2,2,2-trichloroethyl .alpha.-[2.beta.-(3-bromo-2,2-propylenedioxypropoxy)-3.beta.-benzyloxycarbonylamino-3.alpha.-methoxy-4-oxoazetidin-l-yl]-.alpha.-triphenylphosphoranylideneacetate.

20. Compounds of the following formula:

wherein A is amino or substituted amino; COB is carboxy or protected carboxy; R1 is =C(CH3)2, , =PR43 or (R4 is alkyl, aryl or aralkyl); Y is hydrogen or methoxy;
OR2 and OR3 independently or taken together represent a ketal; and Hal is halogen; when prepared by the process of claim 1.

21. A compound as claimed in claim 20, wherein R1 is isopropylidene and A, COB, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 6.

22. A compound as claimed in claim 20, wherein R1 is and A, COB, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 7.

23. A compound as claimed in claim 20, wherein R1 is triarylphosphoranylidene and A, COB, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 8.

24. A compound as claimed in claim 20, wherein R1 is dialkylphosphoroyl, and A, COB, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 9.

25. A compound as claimed in claim 20, wherein B is C7-C20 aralkoxy and A, R1, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 10.

26. A compound as claimed in claim 20, wherein B is 2,2,2-trichloroethoxy and A, R1, Y, R2 and R3 and Hal are as defined in claim 20, when prepared by the process of claim 11.

27. A compound as claimed in claim 20, wherein OR2 and OR3 are independently alkoxy and A, COB, R1, Y and Hal are as defined in claim 20, when prepared by the process of claim 12.

28. A compound as claimed in claim 20, wheren OR2 and OR3, taken together, represent an alkylenedioxy and A, COB, R1, Y and Hal are as defined in claim 20, when prepared by the process of claim 13.

29. Benzyl .alpha.-[2.beta.-(2,2-dimethoxy-3-bromopropoxy)-3.beta.-phenyl-acetamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate, when prepared by the process of claim 14.

30. Benzyl .alpha.-[2.beta.-(2,2-diethoxy-3-bromopropoxy)-3.beta.-phenylace-tamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate, when prepared by the process of claim 15.

31. Diphenylmethyl .alpha.-[2.beta.-(2,2,-dimethoxy-3-bromopropoxy)-3.beta.-phenylacetamido-4-oxoazetidin-l-yl] a-isopropylideneacetate, when prepared by the process of claim 16.

32. Diphenylmethyl .alpha.-[2.beta.-(2,2-diethoxy-3-bromopropoxy)-3.beta.
phenylacetamido-4-oxoazetidin-l-yl]-.alpha.-isopropylideneacetate, when prepared by the process of claim 17.

33. Methyl .alpha.[2.beta.-(3-chloro-2,2-diethoxypropoxy)-3.beta.-phenoxyacetamido-4-oxoazetidin-l-yl]-a-isopropenylacetate, when prepared by the process of claim 18.

34. 2,2,2-trichloroethyl .alpha.-[2.beta.-(3-bromo-2,2-propylenedioxy-propoxy)-3.beta.-benzyloxycarbonylamino-3.alpha.-methoxy-4-oxoazetidin-l-yl]
-.alpha.-triphenylphosphoranylideneacetate, when prepared by the process of claim 19.