SU495841A3 - Method for preparing cephalosporin derivatives - Google Patents

Description

(54) METHOD FOR OBTAINING DERIVATIVES OF CEF.ALOS PORIN

3

benefit. The product obtained in this case, when necessary, is separated by an optical optical method: by processing an optically active Pg and IF; high carbon or sul15foxis; 10 () ;;,

o; l; oh like vinna, dibisislvipna, glutamic; a ;:, kam (5arsulfonic 11slot), followed by treatment of the mineral salt with mineral, L1 ogranpicheskom poem, such as hydrated potassium or sodium, triethylamine, and quality,; a threonzomer of formula II can be acouched as the following br, Amnnnsklotu vn formula

R; NHCH2CH2COOI-I

13al1model is subjected to bsnyl sputter in the presence of acid Ageite XH, where Ii has the indicated values, X is a halogen anion, sulfonic sulfuric acid; and ilochalot COMPLEX efnr (Lormu.chy

©

R, NH ClbC} l2COOCH, C6ll,

110. J

yf

ABOUT

where Ac is the acyl residue, which is subjected to acidic alcoholysis.

The corresponding mercaptan is obtained under the influence of the formula

Y-Cr

.OOR

where is II31NY alkl or ara.alkyl, Ymndonyl or acylamino-naphtha, in which anil is an organic residue: is carbonic acid. At the same time, we obtained y-lact m 2A "R - hydroxycarbonyl--1-met; l) - 5-am1}) yamstil-2, 3-digndro - KZ-thiazin-i - carbo; i) ioj; 1c ,; ogy (} 10rm ly

which is condensed with a: and: silt or ar-alkyl ester of n, avelic acid. The benzyl ester of 2,3-dnoxone rrolidium-4 — Carbopa KHc.ioTi) i, i of the enol form o6Hi, eii of the formula

COOOii CnHj;

but .1

which gndrogenolysis translates into the corresponding 4-carboxinron1 1, which is subjected to amnnomethyln1 a1; nude in the conditions of the reaction of Maniheh receive the corresponding 2,3-dpoxo-4- (R, 1) -iomyomethyl 1 pp () lead 1 in which m R, R-alkyl or aralcn, 11lp together - XRR group forms a heterocyclic residue. In the final report, ayut known P1 prnem: n; ;;. minogroup on tnolnuyu and get 2,3-dnoxo 4-acylthiomethylpyrrolidium obndium formulas

Y- tlC R O O Oh,

.

where R, RI and Y have the following values: e values, which is hot from treating them with hydrazine in xyx xyns,: o1o hydrolysis or in s, and) hydrogepolysis, resulting in 01st -; -. 1: - (R-oks; 1-1.3-thiazin-4 cannabis - Clrbon. To; LO) ORV is treated with KHCHIJIM agent: OM. At the same time, y-lactam 2- (7, -carbo; hs; | -a-amm11omet |; l) -o-ammogamel-2, o -) () - i, 3-71P13 in-4-carb (;; 1O1 of 11 kplssp p subject to ei about ipnTiKiHpOiiaHHio chlorn1) | p; With a heat of 3 oci: .OBHOi (; agent, HanpjiMep ii) ii-, i} i; iaMiiHa., getting a three-meter track meter 2- (a - |; arbo1cci-s - three GPA, i; ii "MeTi:; i ) -5-amnpoo e ellЛ2, o-; i, pgilpo-1, .i - - ca |) 6oHoBoii 1 ..: slice-B total cijopAiy; iiJ Ji. P; 1 is shown obn (and the scheme of synthesis.

IV

  H

VI

SNG $ AC

0. 0

L / i

Y

NA

 J, .J 4J

g

Ylp c criNii2

ROOCY;

iijNHCj N

BUT ABOUT

Ix

11 and

(C6H5) 3CHNIt should be noted that in this method, compounds V, VI, VII, VIII (see reaction scheme) have 2 asymmetric carbon atoms and therefore can exist as Treon Erythro isomers. In fact, these 2 isomers were obtained. On the other hand, depending on the conditions, it is possible to vary the threo / erythro ratio and even to obtain preferably one of the isomers or even almost exclusively one of them. This occurs during the formation of compound V, when it is possible to obtain almost exclusively the erythro isomer with appropriate treatment. However, it has been observed that the isomer of the erythro compound Y can be converted into a mixture of threo isomers and the erythro compound VI.

Thus, it is not necessary to convert V to VII and isolate them from compounds VI and VIII in each stage in pure form. A mixture of these isomers can also be used for the reaction. However, only the isomer of compound VIII is suitable for use in the further synthesis.

The reaction of the benzyl alcohol with the starting product of formula II is carried out in the presence of a sulfonic acid such as p-toluene or methanesulfonic acid, or in the presence of a mineral acid such as hydrochloric or sulfuric.

The condensation of an ester of formula III with alkyl or aralkyl oxalate is produced in. presence

.

J-nr

Ix

l m

tn ---- g

 one

about

.

an alkaline agent such as an alkaline alcohol, for example, tert, potassium or sodium butylate, potassium benzyl sulfate or sodium. Benzyl or ethyl ester should be used as oxalic acid ester.

The hydrogenolysis of the 2,3-D-yylosyl ester of the Yuxopyrrolidium-4-carboxylic acid of the enol form IVm is carried out in the presence of a palpasyl catalyst based on palladium platinum.

Minomethylation of the hydrogenolized product is carried out by the action of the formaldehyde: ia I hydrochloride of the selected amine in hydrochloric acid. Of the amines, one can take morpholine, pyrrolidine, dimstilamine, diethylamine, etc. for example.

Substitution of the amino group of thioligamide I occurs under the action of a thiocarboxylic acid — thioacetic or thioproxyl at the alkaline thiocarboxylate of an alkali metal such as sodium or potassium, resulting in a 2,3-dioxo-4a cyclothyrylpyrodine of formula 11.

A thiol-2,3-dioxo-4-acylthiomethylpyrrolidine of formula 1P is obtained by methanolysis in the presence of a miiera.tnogo acid, such as hydrochloric or sulfuric, or sulfonic acids such as o-toluenesulfonic acid or methylsulfonic acid. After the neutralization at a low temperature, add to the reaction lgassa, co.:transposing mercaptan of formula III

7

The diamin of formula IV, enalgin phthalimide malonaldehyde tert, butyl. The solution is evaporated to dryness in vacuo; The polluted residue is dissolved in dry senzens, heated under reflux or, if necessary, by azeotropic distillation of the water formed for 12 hours, and thus the thiazine of formula V is obtained, which under these conditions can be obtained mainly as the Erythro isomer.

The phthalimide group of the y-lic. Ta.zhg, 2- (rz-R-hydroxycarbonyl-a-phthalylhydro) -l-methyl 5-aminomethyl-2, 3-dihydro-1,3-thiazin-4-carboxylic acid forms is removed. V in the presence of hydrogenolysis in the presence of an organic solvent such as a disubstituted amide, such as dimethyl: 1 amide, or a cyclic ether, such as dioxap.

Saponification of the carboxyl group of y-lactam with 2- (aR-oxycarbonyl-a-amnnomethyl) -5-aminomethyl-2, 3-dihydro-1,3-thiazin-4-carboxylic acid of formula VI is carried out with mineral or organic acid , hydrobromic acid, toluene sulfonic acid, a mixture of hydrobromic acid and acetic acid, or trifluoroacetic acid in an anhydrous organic solvent, such as benzene, toluene, ether, dioxane, nitromethane, or a polyhalohydrocarbon, such as chloroform or methylene chloride.

Tritylation of the 2- ("- carboxy-aminomethyl) -5-aminomethyl-2,3-dihydro1, 3-thiazine-4-carboxylic acid formula VII is carried out by the action of trityl chloride in the presence of an alkaline agent, such as triethylamine.

The transformation of the formula Erythrou-lactam 2 (cc-carboxy-cc-tritylaminomethyl) -5-aminomethyl-2, 3-dihydro-1,3-thiazin-4-carboxylic acid of formula VIII into a threo form is carried out by treating an alkaline agent, such as hydroxide alkali metal, for example sodium hydroxide or lithium, in a medium such as methanol or ethanol.

Example 1. Preparation of yl ktam 6H, 7H-bg with-7-amio-3 - aminomethyl - cef-3 - i-4 carboxylic acid

Phase A. rt-Alanine benzyl ether toluene sulfonate.

In the apparatus, equipped with: With a device for separating the water formed during the reaction with an azeotropic solvent, the following mixture is refluxed for 5 hours:

(3-Alanin g 89

Monohydrate p-toluensulfonate, g210

Benzyl alcohol ml450

Carbon tetrachloride ml 500

During this time, about 45 ml of water is separated. Then the reaction mass is evaporated in vacuo, cooled and the resulting product is recrystallized from ether. Freeze, filter under vacuum, dry and collect 350 g (quantitative yield) of crystals s.t. square 142 ° C.

By, l The product is identical to the one described above.

Pha 3 a B. Benzyl 2,3-dioxopyrrolidine-4-carboxylic acid.

225 g of tert is added, potassium butylate in 900 s. M of anhydrous benzene is added 500 cm of benzyl alcohol, the mixture is cooled in an ice-methiol bath, and at a temperature not higher than 30 ° C, benzyl ester p is added. -alanine

300 g of oxalic benzyl ester is dissolved in 600CM of hot benzene, allowed to cool to room temperature, and the weakly acidic solution is neutralized by the addition of 0.4 cm of triethylamine. This solution is added to the mixture and kept in a cooling bath. Heated to room temperature, and then heated under reflux for 5 hours

The benzene is distilled off under vacuum, followed by successively adding 2 liters of water containing 15 cm of acetic acid, then 1.5 liters of isopropyl ether and, finally, PO cm of concentrated hydrochloric acid (until pH = 1). The resulting mass is cooled under non-placement for 2.5 h, sucked off, washed with water, isopropyl ether and non-recrystallized, the solution in dimethylformamide and precipitated in water. Obtain 130.5 g (i.e. 56%) of the product with so nl. 186 ° C, which is soluble in alcohols, ether and acetone, insoluble in benzene and water. Found,%: C 62; H 5.1; N 6.3

Ci2HnO4N (233.24)

Calculated,%: C, 61.8; H 4.76; N 6.01

P1 infrared spectrum:

Two maxima in the field of carbonyl 1729 and 1693 cm-.

Absorption in the region of united OH / NH.

Presence of monosubstituted aromatic compound. This compound is not described in the literature.

F a 3 a B: 2,3-dioxonirrolidin-4-carboxylic acid.

a) Preparation of a hydrogenation catalyst.

Under a hydrogen atmosphere, 0.8 g of the suspension of activated carbon in 4 cm 2% aqueous solution of palladium chloride is stirred.

After filling the catalyst, it is filtered without air and rinsed.

several times with anhydrous dimethylformamide.

b) Hydrogenation.

Dissolve 9.32 g of benzyl 2,3-dioxopyrrolidine 4-carboxylic acid in

50 cm of anhydrous dimethylformamide and the prepared catalyst is added. The laugh is placed in an atmosphere of hydrogen, then from time to time it is moved while it is cooled in order to avoid any noticeable increase in temperature. Filter, add

to the filtrate 500 cm-isopropyl ether, filter under vacuum and dry. 4,618 g (i.e. 96%) of the product are obtained, which is used without purification further in the synthesis. For analysis, they are redissolved in 6 volumes of dimethyl sulfoxide and 4 volumes of methanol. Filter and add 4 volumes of methanol. A white precipitate forms, which is sucked off and dried. Exit after cleaning 60%.

The product obtained as white crystals is not very stable due to decarboxylation. It is soluble in dimethyl sulfoxide and dimethylformamide, insoluble in isopropyl ether and in water.

Infrared spectrum (in vaseline oil). Absorption in the region of combined OH / NH.

Complicated and strong absorption in the carboxyl region: protrusion 1708 cm-max. 1677.

Paydeno,%: C 41.7; H 3.8; N 9.9

C5H504N

Calculated,%: C 41.96; H 3.52; N 9.79;

This compound is not described in the literature.

Phase G. 2,3-dioxo-4-morpholinomethylpyrrolidine hydrochloride.

Add 2 drops of hydrochloric acid to 10 cm of morpholine hydrochloride solution prepared by neutralizing 8.71 g of morpholine with concentrated hydrochloric acid and adding 50 cm of water. 2 cm of formaldehyde (30%) is added, then 2.83 g of 2,3-dioxopyrrolidine-4-carboxylic acid is added. The reaction mixture is heated to 60-65 ° C with stirring for 30 hours. Evaporated to dryness and the residue is recrystallized in ethanol. 2.986 g of product are obtained, which can be used directly to continue the synthesis.

For analysis, dissolve the product in the same volume of hot water and add three volumes of ethanol. Freeze, filter the node by disinfection, and obtain a product with a yield of 80%, in the form of white crystals, slightly soluble in ethanol and ether and soluble in water.

Found,%: C 45.8; H 6.4; N 11.8; C1 15.2.

CgHisOsNaCl: 234.7

Calculated,%: C 46.06; P 6,44; N 11.94; C1 15.11;

PNF | red spectrum (in vaseline oil).

Absorption bands at 3210 and from 3.6-4.1 microns.

A triplet in the field of carbonyl 1,711 cm1 691 cm -1 1 664 cm -1

This compound is not described in the literature.

2,3-Dioxo-4-morpholinomethylpyrrolidine hydrochloride can be obtained by starting from 2,3-dioxopyrrolidine-4-carboxylic acid benzyl ester without liberating the free acid as follows.

30.33 g of 2,3-dioxopyrrolidine-4-carboxylic acid benzyl ester B are added.

300 cm of dioxane with 10% water, slightly heated to dissolve the product, add 3 g of activated carbon and 1 cm of a 20% aqueous solution of palladium chloride, place in an atmosphere of hydrogen and mix very vigorously. After 1 h 40 min, 2700 cm of hydrogen are absorbed (the volume calculated theoretically is 2912 cm). Cool, purge with nitrogen and then add 130 cm of a mixture of the following composition, ml:

Morpholine, g 43,5

Water100

Concentrated hydrochloric acid40

Sol on acid 15

Formaldehyde50

Water Up to 500

The reaction mixture is heated to 50 ° C and 2325 cm of carbon dioxide is collected in 1 h. Theoretically, the amount of carbon dioxide released is equal to the amount of hydrogen initially absorbed in the reaction. Consequently, in the best case, it is necessary here to expect the release of 2700 cm — carbon dioxide. Within a few minutes, easily stirred, and

then filtered and evaporated to dryness in vacuo; - lee Residue can be used without

purification to continue the synthesis.

Phase D. 2,3-dioxo-4-acetylthiomethylcyrrolidine.

140 cm of water are introduced into a vessel cooled with an ice bath and methanol. 24 g of sodium hydrochloride, 60 cm t: 10} -acetic acid and 67.2 g sodium carbonate, are transferred within 5 minutes, and then 46.8 g of 2,3-dnoxo-4-morpholinomethylpyrrolidine hydrochloride are added. The reaction mixture was stirred at room temperature for 3.5 hours, added

in half an hour, small amounts of ether to destroy the yen generator. Then, by adding 80 cm of concentrated hydrochloric acid, it is acidified to RP 1, the excess tibuacetic acid is distilled off in vacuo,

filter and store 4Ziltrate. The product filtered on a Büchner funnel was flushed with water, dissolved in 150 cm of hot chloroform, the separated water was decanted and the aqueous layer was extracted with chloroform. The combined organic extracts of sHiaT are over sodium sulfate and evaporated in a vacuum. The residue is triturated in ether to a pasty state and 25 g (67%) of the product are obtained with a melting point. 136 ° C.

The resulting filtrate is extracted with chloroform, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in a mixture of 10 cm of ethyl acetate and 10 cm of ether. Leave a

overnight in the refrigerator, filtered under vacuum, and 2.5 g of product, identical to that obtained at the first discharge, is obtained. Overall yield 72.5%. The product can be used without further purification to continue the synthesis.

eleven

D ;; I analyze the product by recrystallization in ethyl acetate ester to a constant melting point. It is obtained, in the form of white crystals, soluble 3 pod and poorly soluble g; ether and ethyl ester of acetic acid.

Found,%: C 44.7; H 4.9; N 7.6; S 17.1.

CjHgOsNS (187.21)

Calculated,%: C 44.91; H 4.85; N 7.49; S 17.13.

Ultraviolet spectrum a) in ethanol — 0.1N hydrochloric acid. Maximum 225 mmkm E / L: 666

b) 3 ethanol - 0.1 and. caustic soda

Maximum 251 mkm Ej ° ,,: 564

Infrared spectrum (chloroform). Carbonyl Absorption - Max. 1689 NH thin band at 3 460. It is max, at 3210 cm.

Phase E: y-Lactau 2- (cc-tert. Butoxycarbopyl-a-phthalimidomethyl) -5-aminomethyl-2,3-dihydro-1, 3-thiazine-4-carboxylic acid.

18.72 g of 1,3-dioxo-4-adylthiomethyl-5H-nirrolidine is dissolved in 300 cm of a 5% methanol solution of g-toluenesulfonic acid and heated under reflux for 2.5 hours. Then the mixture is allowed to cool to at room temperature, cooled to -50 ° and 39.5 cm 2N of a solution of ammonium acetate in methanol are added dropwise. Then, in OTMoccjiepe nitrogen, priban / yut 30 g of anaminaphtholimnomaloalgsgid gret. butyl and allowed to stir ;; for several minutes at room temperature. The solvents are evaporated in vacuo by distillation, and the residue is dissolved in dry benzene and heated under reflux for 12 hours with separation of water. The residue, which consists mainly of the erythro isomer, is dissolved in 200 cm of methanol and the precipitated crystals are filtered off under vacuum. Ozone is posledate with lateral horses. It is etched in water, metaiol, ether, by elimination in dimethylformamide and by the addition of methanol.

Obtain 16.6 g (40%) of product with so pl. 250 ° in b :: ds white crystals, soluble in a mixture of methanol-chloroform, slightly soluble in pure methanol and insoluble in benzene and ether.

Found,%; C 57.7; H 5.4; N 9.9; S 7.9.

C.oHoiOsNaS (415.47)

Calculated,%: C 57.8; H 5.10. M0.11; S 7.72.

Phase W: Y-lactam hydrochloride 2- (a, -t-butoxycarbonyl-a-aminomethyl) -5-aminomethyl-2, 3-dihydro-1,3-thiazine-4-carboxylic acid.

16.6 g of y-lactam 2- (a-tert. Butoxycarbonyl-a-phthalimidomethyl) -5-aminomethyl 2, 3-dihydro-1,3-thiazine-4-carboxylic acid are added; 32 cm cm of methyl formamide. then, very slowly, with stirring under a nitrogen atmosphere, add 22 s:, g 2 and. solution hydrazineid12

mixed in dimethyl formamide and stirred for 30 minutes at room temperature. Then, for 30 min, 44 cm of hydrochloric acid is added, stirred for 10 min, then frozen (c s)). A bottle of salt is dried and the residue, dissolved in 30 cm of water, is treated with live coal. Filter, evaporate to dryness and crystallize the resulting product in methanol. The mixture is washed with ether and 12.5 g (97%) of the product is obtained, which, bearing the fact that it consists of a mixture of threo and erythro isomers, can be used in this form to continue the synthesis.

If necessary, the components of the mixture can be separated by fractional crystration from a mixture of methanol with 20% water, in which the meter is et | Both clepeoizo. Dimensional hydrochloride, threo- and erythro-, barely

we can distinguish them according to their mon (1) red or ultraviolet spectral characteristics, but the 3 chromatography in a thin layer makes the erythro form the most mobile (base Kieselgel gF 254 3/10 mm.

solvent for elution; mixture; ethyl vinegar C110Y acid 60%. ethanol 20%, hearth 20%).

At the same time, from each pure stereoisomeric hydrochloride (or their sm.xi) nri) ac-creation in a small amount of an aqueous solution of sodium hydrogen carbonate, a free base (or a mixture of free ocHOi; a)) can be extracted.

ETPLOVY.M ether acetic KIS.GG) YOU.

Phase 3: iJ-Lactam 2- (a-carboxy-a-tritylamino) -methyl-5-aminomethyl-2,3 - dihydro1.3-thiazine-4-carboxylic acid.

1.7Lactam 2- (a-box-a-amine mix. I) 5-amine methyl-2, 3-dihydro-l, 3-t 1 a: 5 - 1-carboxylic acid.

12.88 g of a mixture of isomers of threo and erythro, corresponding to; 2- {a-trsg y-lactam. b tox -.: -. (rbonylchlorohydrataminomethyl) - 5-a.minomet; l-2, 3-dihydro-1,3 - thiazin-4 - carboxylic

slots; add 320 cm of nitromethane, which is saturated with hydrochloric acid gas and cooled with a mixture of ice and methanol. Hydrochloric acid gas is passed into the resulting suspension for 50 minutes,

and then the hydrochloric acid is distilled into a snack. This compound is not described in the literature.

2.7Lectam 2- (oc-carboxy-cc-tritylaminomethyl) -5-aminomethyl-2,3-dihydro-1,3-thiazin-4-carboxylic acid.

The resulting mixture is stirred in a nitrogen atmosphere, cooled in an ice bath, and 28 cm of triethylamine and 24 g of trityl chloride are introduced into VO cm of methylene chloride. Allow to stand under nitrogen at room temperature overnight, and then evaporate to dryness under vacuum. The residue is dissolved in a mixture of 200 methanol and 200 cm of methylene chloride and 16 cm of acetic acid are added. Koi-center to the volume, stirred for half an hour at room temperature, filtered under vacuum, dried

collected 7,161 g (38%) tritylrosis of shock

product, almost purely threo.

This compound is not described in the literature.

3. Isolation of Erythro Isomer. The mother liquor obtained above is treated with activated carbon, filtered

and evaporated to dryness under vacuum in a water bath. The remaining oil is dissolved in 200 cm of ether, 20 cm of water are added dropwise and the mixture is stirred under nitrogen for 4 hours at room temperature. It is filtered under vacuum, washed with ether and then with water, and 8.368 g of the tritylated product is obtained (the form of erythro contains, and a little threo isomer). This compound is not described in the literature.

4. Isomerization of the erythro form into the threo form.

8.368 g of a tritylated derivative (erythro form) in 170 cm of methanol are suspended, cooled to 10 ° C, and 11.8 cm of aqueous lithium oxide hydrate 3.4 n. and incubated for 3 min at room temperature. Then, about 2.5 cm of acetic acid is added to obtain a slightly acidic pH, heated in a bath at 60 ° C for 10 minutes, filtered under vacuum, washed with methanol, and 4.728 g of tritylated derivative is collected (threo form).

The mother liquor is treated with activated carbon; the insoluble part is washed with methanol, added to the filtrate and evaporated to dryness in vacuo. The residue is dissolved in 10 cm of ether, 1 cm of acetic acid and 1 cm of water are added. It is left for 2 hours at room temperature, filtered under a vacuum, and 1.673 g of tritylaphenol derivative (erythro form) is obtained, which is isomerized, as described above, to obtain, thus, 0.887 g of threo derivative.

5. Clearing the threo isomer.

Different amounts of the threo product form are combined and 12.77 g are obtained; 10 cm of methanol is added and heated to reflux. The filter is filtered, after washing with ether, and 12.13 g (95%) of product is obtained, which can be used to continue the synthesis.

Get the product in the form of colorless crystals in m. PL. (dec) 240 ° C, the erythro isomer melts with decomposition at –220 ° C.

It is soluble in aqueous solution, slightly soluble in dimethylformamide and dimethyl sulfoxide, insoluble in organic hydrophobic solutions.

Paideno,%: C 69; N 8.6; S 7.1; H 5.3.

CavHssNsOsS (471.55)

Calculated,%: C 68.77; N 8.91; S 6.80; P 5.35.

Phase I; -Lactam DL-6H, 7H-cis-7-trtylamino-3-aminomethyl cephalosporanic acid.

Drive .- to the suspended state; 4.1B g | -alltam 2- (a-carbox-β-tritylamino) methyl-5-aminomethyl-2,3-digndro-1,3-thiazine-4-carboxylic acid in the form of greo -isomer 140 cm anhydrous pyridine, placed in a nitrogen atmosphere. 0., 2 g of dicyclohexylcarbodiimide is added, stirred for 5 minutes, li added 300 cm of benzyl chloride. and then 300 cm of anhydrous nitromethane. The resulting white suspension is left at room temperature, protected from light for 65 hours; Dicyclohexyl molesine as crystals is filtered under vacuum, the crystals are rinsed with chlorine: methylene, the filtrate and the washings are concentrated under vacuum to 1/4 of the volume, treated with animal charcoal, filtered and evaporated to dryness in vacuo. The residue is crystallized by trituration in ether, filtered off under vacuum, and the mother liquors are kept from washing.

The recrystallized product is dissolved in 30 cm-of ethyl acetate, precipitated by adding 2 cm of water, diluted with 35 cm-1 h and filtered to yield a 9.3 g of colorless crystals, salted with half of the water and melting at 200 ( with decomposition).

By adding water to the ethereal solution, KOToiJbn butt, above, another 0.18 g of 1; 1k Dumta is isolated, which is the same as that obtained by ii .; lIvvo i grown out.

The resulting product can be used to continue the synthesis.

For analysis, it is crystallized in acetic acid methyl ester to give an anhydrous sample with m.p. 240 ° C (decomposition).

Lalpz product, solvated with 1/2 water molecules.

%% C 69.9; H 5.5; X 9.1; S 0.8

C, 7P, C02Kz8-1 / 2H2O (462.5)

Calculated,%: C, 70.16; P 5.23; N 9.08; S 6.93.

Infrared spectrum in chloroform:

Free KP 3,440 + United Nn

R-Lactam 1777

-y-lactam 1698 cm C1663 cm-1

Aromatic

Ultraviolet spectrum ethanol

Bending around 226 mm E y: 42t

254 MiK.iE {..: 25

259-260 mmk.Ej j ,: 121

in ethanol with 0.1 i ;. sol yoG; kps, 1oto | ;

 . yy, 1cm-p1 . 1 .-, C.; (,,,,. I ..,. Loq Cj,.

ethanol with 0.1 n. caustic soda

MMK.

Ic