CS207653B2 - Method of preparation of thehalogenated 2-oxoazetidines - Google Patents

Abstract

7-Amino-3-hydroxy-3-cephem-4-carboxylic acid derivs of formula (I) are prepd. by (a) halogenating a 1-(2-Y-1-COX-1-propenyl)-3-amino-4-(protected mercapto)-2-azetidinone of formula (II), (b) deprotecting the resulting 1-(3-halo-2-Y-1-COX-1-propenyl) cpd. of formula (III), and (c) cyclising the product, (where Q is opt. substd. amino, pref. acylamino, and R is a protecting gp., or Q and SR together can form a -N=CR1-S- gp., whwe where R1 is a substituent capable of forming a COR1 acyl radical; X is OH or a carboxy-protecting gp.; Y is OH (opt. in ketonic form) or a disubstd. amino gp.).

Description

The present invention relates to a process for preparing compounds of formula Ia wherein a

B is hydrogen or phthalimido V

(Ia) is phenylacetamido, phenoxyacetamido,

R is hydrogen, methoxymmthyl, o-nitrophenyl phenyl ^lsul f ^e, 2-benzoothazolyl, cyklopropylmethoxykarboinfl, benzyloxycarbonyl or one silver atom,

Y is hydroxyl, methanesulfonyloxy, p-toluenesuffonyloxy, methoxycarbonyloxyskipina, cyclopropylmethoxycarbonyloxy, benzyloxycarboinyloxystaipina, 1-morpholinyl, 1-piperidinyl, chlorine, dialkylamino, such as diethylamino, e.g.

X 6 is hydroxyl, methoDQr 1, 2,2,2-tricycloxy, yy, benzyloxy, p-nitrobenzyloxy, or diferylmethoxy, and

Hal is a halogen atom, characterized in that a compound of formula IIa is reacted

wherein A, B, R, X and Y are as defined above with at least one molar equivalent of a molecular halogen, H-haloamide or N-haloimide, in halogenated hydrocarbons such as dichloromethane, chloroform, or carbon tetrachloride in an ether such as for example tetrahydrofuran, or in di-lower allyl-lower alkanoamides such as dimethylformamide no ^b ov mixtures thereof ^p M ⁰ temperature from -5 ° C to ⁺ 5 ⁰ ° C.

Compounds of formula Ia are novel compounds which are valuable meeiprodukty ^p ro ^{p at} pH rave AA-cephem (TV) ^p ccording nteledu jícího REA ^ ^é Raho sch matt:

removal ^ A \ B ^ ^N SH —M protecting T __N CHoHal groups cT C = c <^, 1 v cox

(III)

Cox (IV) wherein A, B, Hal, X and Y are as defined above and T is hydroxylová'sku ina ^p.

The preferred material, i.e., the 4-substituted thio-3- (amino or substituted amino) -2-oxo-alpha- (1-ethylidene) azetidine-1-acetic acid, or derivatives of their carboxyl groups of formula IIa may be prepared from: of peniniline-1-oxide by reaction with ε-easec®, acetic anhydride and the like to form alpha-ssopropenyl acetic acid and its derivatives, which are oxidized to give the starting material wherein the alpha substituent is 1-hydroxy or 1-isopropyl which, with acylating agents, amination agents, reactive nitrogen introducing agents and the like, provides a backlash of the starting materials. Furthermore, starting materials may also be prepared from the azetidin-4-one derivative and reactive acetoacetic acid derivatives.

The process of the present invention can be carried out by reacting a compound of formula IIa with a molecular halogen, an N-halide or an N-halide as a halogenating agent. Rerererative halogenating agents belong to the following categories:

1. Xg xg, BrCl, IBr, C ₆ H ₅ I.XX, C ₅ H ₅ N.NX \ X ', C ₆ H ₅ Jt (CC ₃ ) ₂ X'.Xg,

2. = NX '(alkyl) ₄ NC'x2, (acyl) NHX', (acyl) NX ', wherein alkyl or acyl contains up to 7 carbon atoms and X is chlorine, bromine or iodine.

When these halogenating agents are used as such, which act through a halogen radical, the reaction is carried out by the action of heat, light, peroxide, (peracids, peroxide, hydroperoxide and the like) and azo compound (tzoЪbsislbbyrrolirilil, etc.) or other free radical initiator.

When these halogenating agents are used as such which act through halogen cations, the reaction is optionally carried out in the presence of an acid scavenger (organic or inorganic bases, for example, sodium carbonate, pyridine, quinoline, lutidine, diethyltmine, triethylamine, and the like). The onion ion of the starting compound is easier to halogenate to give the desired compound in higher yield under mild conditions.

If these halogenating agents are used via the carbanions - starting compounds, then the starting compounds are reacted with an anionic reagent (alkali metal hydrides, alkali metal amides, alkali metal alkoxides, HUium, dialkylamine, alcohol hexialkyldisilazane, trialkylamine, Grignird reagents, etc.) formation of a carbanion, followed by reaction with a hilogenating agent. The reaction is carried out in a halogenated hydrocarbon, an ether or an amide as solvents at a temperature of from -50 ° C to +50 ° C, preferably from -25 ° C to 0 ° C, so as to avoid side reactions.

The surfactants include halogenated hydrocarbons (meth-enhihalide, chloroform, carbon tetrachloride, dichlorobenzene and the like), ethers (diethyl ether, ethylene glycol, dimethyl ether, tetrahydrofurine, tetrahydropyran, dioxane, morphine, inisol, etc.), amides (dimethylethyl). (dimethylacetimide, hexamethylphosphoricstriaeid, etc.) and mixtures thereof.

During the reaction, cis-trans isomerization at the substituent at the alpha-position of the geomeeric isomer may take place, which reaction is included within the scope of the present invention.

The halogenation of the compounds represented by the formula IIa, assuming that Y has a meaning other than nitric oxide, proceeds smoothly in some cases and difficult in other cases. The main bend is the position into which halogen atoms are introduced. In other words, the priority of the desired position relative to other positions in the hilogenation is rather small and cast from one compound to another. Another factor that limits Y to the above range is not in halogenation but in subsequent reactions, for example i) ease of deprotection to give a compound of formula III where Y * is hydroxyl and ii) ease of cyclization to give the desired cephem compound IV in high yield .

The cyclization can be carried out by reacting compounds of formula III with

i) acid ii) base or iii) solvent, optionally in the presence of a catalyst. The starting compounds tend to cyclize almost automatically and under various mild conditions, whereby the cephem compounds can be isolated in good yield.

The acids used include E ^ n ^ n ^ i ^^ CONSTANTS -například acid, hydrochloric acid, hydrobromic acid, sulfuric acid dusiř- к у • -slinu phosphoric acid chlorofyl _r Rist, sulfurous acid), sulfonic acids '-' (E.g., acetic acid, arylsulfonic acid), phosphonic acid, carboxylic acids (e.g. formic acid, acetic acid, hilogenic acid, phosphoric acid, phthalic acid) and other organic or inorganic acids, or their salts with weak bases (such as aromatic or aliphatic bases, γγ ^ πϊθϊ, alkaline earth metals, aluminum, silver) or salts of these acids with common bases including salts of metals. The Lewis acids may also be used, preferably in an apathic solvent.

Bases used for the basic medium preferably include these weak bases. Strong bases (e.g. alkali metal hydroxide, alkali metal carbonate, tertiary ammonium hydroxide) can be used under certain mild conditions as they break down the starting or final compounds, especially beta-lactams. Leiis bases may also be used.

The catalyst for cyclization can be non-mineral or alkaline silicigel, alumina, diatomaceous earth, florisil and other catalysts.

In some cases, cyclization may occur. by treatment with a solvent (for example, a high polarity solvent including amides such as hexamethylphosphoric triamide, dimethylformamide, formamide and the like, alcohols and water). In some cases, polar. solvents accelerate the reaction. Assuming. with that. the reaction is the result of catalysis with hydrogen halide produced by the initial reaction.

The reaction is preferably carried out in a solvent with heating or cooling or at a temperature of ιηίΞυτοοη. If necessary, the reaction medium is stirred under inert gas.

Preferred solvents are polar solvents, for example alcohols, carboxylic acids, amides, nitriles, nitrocarbons, sulfoxides, aqueous solvents and solvents capable of highly dissolving the starting materials, for example. esters, ethers,. halogenated hydrocarbon solvents that sometimes facilitate. reaction. The reactions generally proceed rapidly at room temperature and in high yields the desired cephem or cepham compounds are obtained.

The final product is 3-hydroxy-3-cefer-4-carboxylic acid or 3-oxocapham-4-carboxylic acid of formula IV. In some cases, the substituents at the 3 or 7 position of the cephem ring vary during the reaction or processing and, as a result, the corresponding substituents in the starting and resulting materials are different. Optionally, these substituents can be converted back or converted to others by known methods.

Halogenation, deprotection and cyclization can be carried out in one step, namely without isolation of the intermediates and without removal of the reaction solvents.

Some starting raw materials are prepared by the following procedures.

Preparation 1

To a solution of Met-alpha l j- [4-3-rertapto ftalirido oxosjztidin-2-1-yl] -afja- (1HY _{(fdroxyethlliden)} -jcetátu (100 mg) in tetraiydrofuranu (3 mL) was added i b ^ (100 mg), and the mixture was cooled to -65 [deg.] C. To the solution was added triethylamine (60 mg), and the reaction mixture was stirred for one hour. The mixture was then purified by purifying the residue on silica gel to give methyl [4- (4-benzylsulfonylcarbonyl) -3-phenyl] -S-hexyetidin-1-yl] - [(1-benzylsilyl) thiamine ethyl acetate]. 94%. ^P roducts neotealhšje ^ Omer ^about half of alpha. ^IR: θ ^ ^ ^{3 1 79} 0 ^{1 780, 1730} ад ^- '. ^^ 8 ^ ° ^ ^{3 0} 8.00 - ^{7, 50, m} , 4H, 7.40 s, 5H, 7.30, s, 5H, 6.27, d, (5Hz), δ, 5.90, d, (5Hz), 1H, 5.27, s, 2H, 5.17, s, 2H, 3.70, s, 3H, 2.47, s, 3H.

Preparation 2

To a solution of methyl alpha- (4-rertapto- ^3- fluoro-2-soyl-thiazin-1-yl) -alpha-11-hydroxy-lithium) jeitate (50 mg) in tert-butylamine (2 mL) was added cyclopropylrethyl c. Loroformate (50 mg) was added and the mixture was cooled to -65 ° C, followed by the addition of triethylamine (30 mg) in Oehydrofuran (0.5 mL). After stirring for one hour, the mixture was slowly warmed to room temperature and evaporated. under reduced pressure and purified on silica chromaatorafií ^ l using benzene containing 5% ether to give methyl alťa- (4elyk0opoopylri0 oxykarboonllhio-3-ftalemido sχojZitidin-2-yl-1 ·] ^j> ajfa- (1lty01oorPlyame-Ooxytaríonyloxχli ^ hlLiien Acetate (61 mg) Yield 79%.

The product is ^ Гб! the geomeric isomers substituted in the alpha position (about 3: 2). IR: ³ ^ ™ ^1790, 1780,, 730 ^cm-first NMR: 5 ^CDC1 3 8.00 to ^7.60) m. 4H, 6 ⁾ 18, d, C5Hz), 3 / 5Щ 6.10, d, (5Hz), 2 / 5H, 5.85, d, (5Hz), 3 / 5H, 5.78, d, uH) , 2 / 5H, 4.30-3.80 / m, 4H, 3.87, s, 6 / 5H, 3.82, s, 9 / 5H, 2.53, s, 6 / 5H, 2.47 s, 9 / 5H, 1.60-0.90, m, 2H, 0.90-0.10, m, 8H.

·

Preparation 3

Acid chloride is added to a solution of 2,2,2-trichloroethyl alpha- (4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxo-azetidin-1-yl) -alpha- (1-hydroxyethylidene) acetate in tetrahydrofuran. and triethylamine ^{and the} mixture is reacted for 1 to 3 hours, processed in a conventional manner to give the following esters:

(1) 2,2,2-Trichloroethyl alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxo-azetidin-1-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate, IR: v 5J ^ 3 3,440, 1,795,

-1 nnri max

753, 1698, 1640, 1660 cm. NMR δ 3 2.70, s, 3H, 3.38, s, 3H, 4.6, m, 4H, 5.25, d, (5Hz), 1H, 5.78, d, (5Hz), 1H 6.8-8.0 m, 10H;

(2) 2,2,2-Trichloroethyl alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl-alpha- (1-toluene-p-sulfonyloxyethylidene) acetate, IR: v £ 52 ^ 3,420, 1,780, 1,770,

ΠΉΠΊ Шал

685 cm NMR: ^.delta . 2.28, s, 3H, 2.50, s, 3H, 4.55, s, 2H, 4.63, ABq, (12Hz), 2H, 5.08, dd, ( 7.5Hz), 1H, 5.78, d, (5Hz), 1H, 6.65-8.22, m, 14H;

13) p-Nitrobenzyl-alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-cyclopropylmethoxycarboxyethylidene) acetate, IR: CHCl 3, 420, 1780 , 1,685, 1,640 cm ^-1 . NMR: δ ^CDCl 3 0.05 - 1.52, η, 5H, 2.47, s, 3H, 3.95 + 4.02, d, (2H), 4.50 + 4.58, s, 2H, 4.80-5.40, m, 4H, 6.67-8.13, m, 14H.

(4) 2,2,2-Trichloroethyl alpha- [4- (2-benzothiazolyl) dithio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-cyclopropylmethoxycarboxyethylidene) acetate, IR v _max 3 3 450 , 1 790,

690, 1650 cm ^-1 . NMR: δ ^CDCl 3 0.13-1.55, m, 5H, 2.52, s, 3H, 4.10, d, (7Hz), 2H, 4.53, ABq, (12Hz), 2H, 4 62, s, 2H, 5.11, dd, (7.5Hz), 1H, 5.75, d, (5Hz), 1H, 6.72-8.07, m, 10H.

Preparation 4

To a solution of ρ-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-hydroxyethylidene) acetate (904 mg) in a mixture (9.5 ml) of tetrahydrofuran and hexamethylphosphoric triamide (20 ml). 1) methanesulfonyl chloride (0.26 mL) and triethylamine (0.37 mL) were added. After two hours, the reaction mixture was poured into ice water and extracted with chloroform. The chloroform solution was washed with water and evaporated to give p-nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-methanesulfonyloxyethylidene) acetate (1.12 g). Yellow foam. ID No .: v 252 ^ 3 3 426, 1 785, 1 722 - 1 704br,

640, 1601, 1160, 1175, 986 cm -1. NMR: .delta. 0.32-1.25, m, 5H, 2.57, s, 3H, 2.72, s, 3H, 3.99, d, (7Hz), 2H, 4.55, s, 2H, 5.33-5.99, m, 4H, 6.82-7.62, m, 7H, 8.21, d, (8.5Hz), 2H.

The following compounds were prepared by similar acylation:

(1) p-Nitrobenzyl alpha- [4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-methoxycarbonyloxyethylidene) acetate, IR: v 1,780, 1,731, 1,643, i ΠΠΓΊ шах

612, 1601 cm. NMR: δ ^{υυυ ±} 3 ^0.2-1.33 , m, δ », 2.34, s, 3 / 2H, 2.50, s, 3 / 2H, 3.74, s, 3 / 2H, 3 , 83, s, 3 / 2H, 3.97, d, (7Hz), 2H, 4.52, s, 2H, 5.26, s, 2H, 5.53 -6.00, m, 2H, 6 , 79-8.24, m, 9H.

(2) 2,2,2-Trichloroethyl alpha- [4- (o-nitrophenyl) dithio-3-phenoxyacetamido-2-oxoazetidine- x CHCI

-1-yl] - .alpha .- (1-cyclopropylmethoxycarbonyloxyethylidene) acetate, IC: .delta.3.330, 1781, - 1 nm.

750sh, 1685, 1640 cm NMR: 6 ^? 3 ^0.2-1.4 , m, 5H, 2.50, s, 3H, 4.13, d, (8Hz), 2H, 4.53, ABq (12Hz), 2H, 4.56, s, 2H, 5.15, dd, (5.8Hz), 1H, 5.43, d, (5Hz), 1H, 6.8-8.4, m , 10H.

Preparation 5

To a solution of 2,2,2-trichloroethyl alpha- [4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl] -alpha- (1-hydrorojethoxide) acetate (695 mg) in hexamethyltylphosphoramide (8 mL) was added to a solution of silver salt. Add a mixture of cyclopropylmethyl chloroformate (480 mg) and triethylamine (180 mg) and stir the mixture for one hour. The reaction mixture was poured into ice water and extracted with benzene. The extract was PROMEA water, dried and evaporated to give product which was purified alpha chromac ^ ^r ^ rai: í silikagtlu to give 2,2,2-iriahlartih1l alpha- [4clkk0prappyletthoxekarbanyl4 thia43-fenaxyacetamidia2 oχoxalZiiin-1-YLE-4lfa - (14cyklaprapylmethoχyealbonn1laχ1tih ^г 1idβn) 4 acetate (650 mg). Yield 64.4%.

The product is a mixture (about 4: 3) of the alpha-isomeric substituent isomers.

Ičsv ™ ^X ° 3 3440, ^1785, 720 cm I ^first N ‰: δ ^CDCl 3 0 ^, 1 - 1 ^ _m> 10H, 2,4, 3H,

4.0, m, 3H, 4.60, s, 2H, 4.83, s, 2H, 5.2-6.1, m, 2H, 6.8-7.5, _m , 6H.

Preparation 6

To a solution of 4-nitrobenzyl-11 - [- cyclopropylaptyl-methoxycarbonyl-alcohol-3-phenoxy-octamido-24-oxoaletidin-1-41] -alpha- (1-methaleulphinyl) thiidine) (1.12 g) in benzene (11 ml) was added molar benzene (11 ml). (26 mL) with cooling and the mixture was kept at 10 ° C overnight. The reaction mixture was washed with water, dried and evaporated under reduced pressure. Purification of the obtained residue (1 g) on silica (10 g) with benzene / ethyl acetate (1: 2) afforded p-edtrobeeeel alpha- [4-glycopropelmethaxyeaaroaeltiiOaЗ-pheoxylcetamido-4-o-aaaeeidia-4-o-aaaeeidia-4-1-1a] (1-marfalieattheliite) acetate (602 mgg. Foam.

ΐδ: ^ν ° ^{X X} 3 3 430, 1 '774 ^, 1 69461½ 1 604 ^, 1 150 cm ^- '. NMR ^: δ ^CDCl 3 0.22 µm, δ 4 2.27 + 2.40, s, 3H, 3.43, m, 4H, 3.77, m, 4H, 4.02, d, (6, 4Hz), 2H, 4.57, s, 2H, 5.05-5.27, m, 3H, 5.89, d, (5.4Hz), 1H, 4.12-7.65, m, 7H , 8.23, d, (8.4Hz), 2H.

The following compounds are similarly obtained from the de-methanesulfonate reagent as described above.

(1) 2,2,2-Trichlartthyl4l1fa- [4- (eenzathlazaly) idithaaзf-feaxeyacelamdda 24Oxaolieti4-diethyl-1- _C ll ^- llfa - (^ - ^y piSer6Hln ^at 4h lii ^te) Hce3á3. lc: s £ ^ 3 3340 ¹ H73 1 -95, 1600 _H m '. NMR 6 1.68 ^{CDČ1 3,} 6H, 2 ^ brs, 3H, 3.36, br s, 4H, 4.63, ш, 4H, 5.0 to 5.7, ш, 2H,

6.8 - 8.0, m, 10H.

(2) p Nitrobteeyl llfl- [4- (2-beeeathiaealylidithaaзf feax1yacelaшiia424axaazztiiie41-y1] -alfl- ^(1-n paperidi ee't ^ ^h У.iien) ^ecetιát, NM: δ ^CDC1 3 ^1.63, br ^ [Delta] 2.33 ^, br .fwdarw.3 ^, 3.3, brs, 4H, 4.53, s, 2H, 5.0-5.5, m, 4H, 6.8-8.2, m, 14H.

Similarly, the successor of the compound is prepared from adpaidoid chloride.

(1) 2 _> 2,2-Trichlartthel llfa- [4-1ykapapaapylmtthaxykarboeylihio-3-phenoxyctamido4

-24axxaleti ^d in- ^1-41] -4 ^l alpha- ⁽¹ -piperidinyl ieaethy ^{i 1} i ^{i en)} acetate. IR: v® ^X 3 ³ 440 ^{1 780} _t ^{1 71} 0 1 695 ^cm-1 . NMR: 0 ² - - ³ m, 5H -, 67 ^{bi-6H 2} 40 or 2 ^ p. 3 ^ ^3, 35 ^ br 4H,

3.98, d, (7Hz), 1H 4.57, s, 2H, 4.73, s, 2H, 5.13-6.07, m, 2H, for dsamers.

(2) 2,2,2-irichlorotin-11α- [4- (bee-thiazalylidithaazz-feaxeyacelamide-24-oxazazolin-1-yl) -alpha- (1-pleryleaethylene) acetate above.

These products are also new and chipped next face

(IIc) wherein A, B, R and X are as defined above, Y 'is a carbon acyloxy group containing up to 12 carbon atoms, a disubstituted amino group having 2 to 30 carbon atoms or an aromatic or aliphatic sulfonyl group having 1 to 20 carbon atoms.

Compounds IIc where i is a disubstituted amino group can be prepared by the following conventional reactions. the ways outlined in the preparations above:

acylation with sulfonyl acceptor cox

^X O-sulfone ^{y |}

AND

wherein A, B, R and X are as defined above at a temperature of from -30 ° C to 0 ° C.

The process can be carried out in a single vessel, in particular, it is not necessary to isolate the intermediate products and remove the reaction solvents at any of the steps for preparing the enamine.

The preparation of enamines by the above process and the halogenation, deprotection of toluene and cyclization can also be carried out in a single vessel, namely without isolation of any intermediate or even without removal of any solvent during the reaction, yielding up to 80% or more of the cephem compound IIc. hydroxyl. In other words, the reaction can be carried out simply as one reaction. In the case of solvents, a solvent is selected which is suitable for all reactions. Typical examples are ethereal solvents (for example tetrahydrofurto, tetraldropyrto and dioxane), amide solvents (for example dimethylformamide, dimethylacetamide and hexammthulfovfortriamide) and halogenated hydrocarbon solvents (for example chloroform, rid and di-acetyl).

As mentioned above, the present invention is a simple process starting from inexpensive penisants for the preparation of key 3'-hydroxy-3-formyl compounds in high yield.

The present invention is illustrated in more detail in the following examples.

Example 1

P-oitrobeosyl tl - [- Methoxymethylthio-3-phenoxyacetamide-2-oxo-trididio-1-yl] tert-11-hydroxyethylvideoideoacetate (1.06 g) in tetrahydrofuran (10 ml) was added and the solution was diluted with acetone (10 ml). -4 to ⁰ ° C under nitrogen, ^f e ^r e nitrogens BC ^ Å. ^t ry ^u ^ ^y l ^{α i} am o ^{(489 mg) of p} uštěný extended in tetrahytčjjofuranu (1 mL) and methuaoulfonolchlorid (252 mg) dissolved in tetrahydrofuran ydrvfurtou ^ (1 mL)

207653 8.

and the reaction mixture was stirred at -40 ° C for 30 minutes and at 0 ° C for 45 minutes. To this solution is added morpholine (209 mg) dissolved in tetrahydrofuran (1 ml), the reaction mixture was maintained for two ^hours Odin to 0 ° C, ^gives N-bromsukcinimM ⁽³ 92 mg) rea ^to protrude mixture is kept 1 5 hours at 0 ° C, water is added, the oily material is separated and extracted with ethyl acetate. The extract and the separated oily oil were combined, dried (MgSO4) and evaporated. Purification of the residual oil obtained (1.4 g) by chromatography on 5% water (20 g) afforded p-nitrobenzyl tl- [4-ethoxymethyllhio-3-hexhoxyphoxide-o2-oro-azetidin-1-yl]. (11-methyl-11-methyl-2-bromomethylidene) acetate (700 mg, 52% yield) and p-nitrobenzyl alf- [4-methyl-4-methyl-3-oxenoxy] -3-oxo-2-oxo-ethoxy-1-y- ] -aalaa ^{(1-morpholinyl,} orinoorlhfl · ylidene) tcetát (170 mg, yield 14%).

Stir the first product (100 mg) with 10% hydrochloric acid (0.3 mL) in a mixture of methanol (2 mL) and tetrahydrofuran (1 mL) at 0 ° C for 90 minutes and then isolate by diluting with water, evaporating, dissolving in chloroform, washing water, dried over magnesium sulphate and evaporated to give p-nitrobenzyl .alpha .- [4-morphomethylthio-3-phenoxyacetamido-2-oxo-azetidine-1 &lt; 11 &gt; -138- (1-methoxy-2-boomethylidene) tetrate (70 mg). ). Yield 78%.

Example 2

The azetidineacetic acid derivatives are dissolved in a solvent, optionally an additive is added, a brominating agent is added, and allowed to react at the indicated temperature for the indicated time. The solution is washed with water, dried and evaporated.

Purification of the obtained residue by chromatography on silica containing 10% water and evaporation of the fractions containing the desired compounds afforded brominated tin-3-urine acid derivatives.

The reaction conditions are given in Table I and the physical constants are given in Table II.

OJ XD - P b

CM m

χθ

ř- 00 ο ο Μ * 00 c ~~ ο ο σ> <Ο Μθ

XO χο

CM ο со cm со αχ Γ— C- C- αχ Γ- αχ ΓΩ ο αχ ΓΩ χο со χο - CM LCX

3 β ο аз ο > Ή 03 ο β Ρ • β κ> ο Ρ • Λ • Η , Μ Η 9 • 9 ο оз and ω • Η and and ο φ α> co * Η • • ο Ή ρο CX ΧΟ Ρ - Ρ m ο what Ό 00 ω ζ-> and I I AND AND AND ή δθ Η Ρ * Η S CQ C0 4d

ο β ο ο β ο · Η ο ο • Η 9 and Ο Α ο ο and ο ο Χ5 CM ΙΓΧ χο m ο (Μ I - F CM AND Η- ο - AND and ιτχ and ΧΟ Ο X (X AND 1 AND AND I I

AND

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ΓΩ rH o 'Φ

AND

Ό I -Η - > ο β bÏ φ · η and S XO'— LfX ο ω o 00 ΐΧ ω ιγχ ω - CM · ω <л hH o § lx ffl αχ § ΓΩ § 2 й 2 § о § S PQ β Η and cm 2 - а - а - 2 - and их а го

ω οο § £

ΓΩ O XO CM CM O X0 αχ ф O O- O ΓΩ M * xo M- XO - CM · "

CM

XD c—

what

what «

O and o

AND

CM 0a * 4a

XO

O

CM a o t

ΓΩ rH o K o

AND

CM a

Ma xo o

CM et al

I <M o a

M and xo o

CM a o t

ΓΩ rH O o

CM a o t

CM o and xO O

CM a o r

ΓΩ rH O O

CM a o t

v and vY

CM CM CMCM and aa o o o o o o

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I I II

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со X! Ж > 1 О 04 / н · - Ж 1 ж 0-0 я II ж Х5 1 со ел ЕЧ KJ

XÍ ж ж Hj ж о о ж си СМ ем эд 1 Ж 1 ЭД 1 о- о о-о о- о II II II ж 1 Ж ж 1 о ОО ел

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Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of halogenated 2-oxoazetidines of the general formula Ia (Ia) cox wherein A A and B are hydrogen atoms or N- is 1-ethylacttamido.a, phenoxyactamidoB ^X , phthiimido, R is a hydrogen atom, 1-nitolytnylsulphonyl, 2- (2-methylsulfonyl), cyclopropylmethoxycarbonyl, benzoyloxycarbonyl or silver, Y is hydroxyl, methanesulphinyl, o-chlorosulphonyl, C 1 -C 4 -minomethyl, C 1 -C 4 -cyclopentyl, C 1 -C 4 -cyclopentyl, C 1 -C 4 -cyclopentyl, C 1 -C 4 -cyclopentyl, C 1 -C 4 -cyclopentyl, C 1 -C 4 -cyclopropane such as dlethylamino, X is hydroxyl, methoxy, 2 2 2-trichloroCloxy, benzyloxy, p-nitlobeneylloy, n-biphenylrthC10oy, and Hal is a halogen atom, characterized in that a compound of formula IIa is reacted COX (HA) people A, B, R, X and Y have the above meanings with at least one molecular equivalent of molecular halogen, N-halide, or N-halimide, in halogenated hydrocarbons such as ClCl chloroform, or chloride for example, in the ether and the ether there is tertiary tertiofuran or in the di-loweralkyl-lower alkanamide such as dimethylformamide or in their networks at a temperature of from -50 ° C to +50 ° C. 2. A process according to claim 1, wherein Y is a dialkylamino group having from 2 to 20 carbon atoms and A, B, R, X are as defined in point 1.