DK141966B - Analogous process for the preparation of penicillin compounds or salts or hydrated forms thereof. - Google Patents

Description

OD OUTPUT 6 ELS PRINT H1 966 (& V * £ 8

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DENMARK (81), ntcl · 3 c 07 0 ^ 39/60 (21) Application No. 270/72 (22) Filed on 19 · Jan. 1972 (23) The bill Ί9 · Jan · 1972 (44) The claim submitted and

presented as published on 28 Jul. I96O

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Priority requested from it

Jan 20 1971 # 848/71 »CH

(71) F. HOFFMANN-LA ROCHE & CO. AKTIENGESELLSCHÅFT, Grenzacherstrasse 124-184, Postfach, CH-4002 Basel, CH.

(725 Inventor: Andre Furienmeler, Wettsteinallee 119, Basel, CH: Peter Quitt, Ml11lerer ~ 40 Rainweg, Puelllnsdorf, CH: Karl Vogler, Wenken * street 69, Riehen, CH: Paul Lanz, 16 Freldorfweg, Muttenz, CH.

(74) Plenipotentiary in the proceedings:

Plougmann & Vingtoft Patent Office.

(54) Analogous procedures for the preparation of penicillin compounds or salts or hydrated forms thereof.

The present invention relates to an analogous process for the preparation of novel acyl derivatives of 6-aminopenicilanoic acid, which acyl derivatives have the general formula I

A-OOO-CH-CO-SH-CH - OH C

i I | X0H, j

H - OH OH-COOH

Wherein T represents an alkyl or alkenyl group having 2-5 carbon atoms, or a cyclopropylmethyl, cyclobutylmethyl or cyclopentyl group, and A represents furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-Thiadiazolyl, imidazolyl, pyrazolyl, pyridyl, 1-oxidopyridyl, tetrahydro-pyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, cinchoninyl, quinolyl or isoquinolyl, wherein the radicals A may be mono or halo oxo, hydroxy, amino, C1-6 alkyl, C1-6 alkoxy, C1-2 alkoxycarbonyl and / or C2-2 alanoylamine and / or salts or hydrated forms thereof.

Fluorine, chlorine and bromine in particular are considered as halogen substituents. C1-6 alkyl, -alkoxy, -alkoxyearbonyl and -alkanoylamino groups are those in which the alkyl moiety contains 1-3 carbon atoms. An alkyl or alkenyl group in the substituent T may be straight or branched. Examples of such groups include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, neopentyl, vinyl, allyl, methallyl, butenyl and pentenyl, respectively.

Due to the good pharmacological properties of the compounds thus produced, a preferred aspect is that compounds are prepared in which A is 2-methyl-4-pyridyl, 2-oxo-2-pyrro-lidinyl, pyrazinyl, tetrahydro-2-furyl, 2-acetamido-4-thiazolyl, 1,5-dimethyl-3-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3-thiadiazol-4-yl or 2-furyl.

Other preferred classes of the compounds of the invention prepared are those in which T is an alkyl or alkenyl group having 4 or 5 carbon atoms. In addition, preferred compounds are those listed in the table below, and because of the particularly good pharmacological properties of the compounds prepared, a particularly preferred aspect of the present invention is that the compound of formula I is prepared wherein A is 2-furyl and T is 2-methylpropyl, i.e. [1- (2-Furoyloxy) -3-methylbutyl] -penicillin, especially the R-form, and its salts.

For the formation of salts, such bases which have already been used for salting with other penicillins may be used. Examples of pharmaceutically valuable salts include the alkali metal salts such as the sodium and potassium salts, the ammonium salts, the alkaline earth metal salts such as the calcium salts, and salts with organic bases such as amines, e.g. E-ethylpiperidine, procaine, dibenzylamine, h, ′'-dibenzyl ether = ethylenediamine or mono-, di- or trialkylamines.

141966

The salts of the compounds of general formula I may also be hydrated. The hydration can occur during the manufacturing process or little by little due to the hygroscopic properties of an initially anhydrous salt of a compound of the general formula I.

The compounds of general formula I and their salts may be present as optically pure isomers and as diastereomer mixtures.

The process of the invention is characterized in that 6-amino-penicillanic acid, whose carboxyl group is in protected form, is reacted with an acid of the general formula II

A - COOCH - COOH II

wherein A and I have the meaning given above, or with a reactive functional derivative thereof, the protecting group is cleaved and, if desired, the reaction product is converted to a salt.

The carboxyl group of 6-aminopenicillanic acid may e.g. be protected by conversion to a readily cleavable ester, e.g. the benzyl ester, or a silyl ester, e.g. the trimethylsilyl ester, or by salt = formation with an inorganic or tertiary organic base, e.g. tri = ethylamine.

As reactive functional derivatives of acids of general formula II, e.g. are mentioned halides, dve. chlorides, bromides and fluorides; azides; anhydrides (especially mixed anhydrides with stronger acids); reactive esters, e.g. N-hydroxysuccin = imid esters; and amides, e.g. imidazolides.

The reaction of 6-aminopenicillanic acid with a compound of the general formula II or a reactive functional derivative thereof can be carried out according to the usual methods of peptide chemistry. So = led one can e.g. condensing the free acid of the general formula II with one of said esters of 6-aminopenicillanic acid by means of a carbodiimide such as dicyclohexylcarbodiimide in an inert solution = 4 U19 solvent, e.g. ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the cleaved ester group. Instead of carbodiimides, oxazolium salts, e.g. Methyl 5 = phenylisoxazolium 3'-sulfonate.

In another embodiment, a salt of 6-aminopenicilanoic acid, e.g. a trialkylammonium salt, with a reactive functional derivative of an acid of the general formula II in an inert solvent, e.g. one of the above solvents.

The reaction of the protected 6-aminopenicillanic acid with a compound of the general formula II or a reactive functional derivative thereof may conveniently be carried out at temperatures between ca. + 5 ° C and -40 ° C, e.g. at about. 0 ° C.

Once the turnover is completed, the protection group is split off. Mr protecting group is a benzyl group (benzyl ester), it can be cleaved off by catalytic hydrogenation, e.g. using a precious metal catalyst such as palladium / coal. If the protecting group is a silyl group (silyl ester), this group can be very readily decomposed by treating the reaction product with water. Finally, if the carboxyl group in 6-aminopenicillanic acid is protected by salt formation (eg with triethylamine), the cleavage of this salt-forming protecting group can be effected by treatment with acid at a relatively low temperature, e.g. at about. 0 - approx. 10 ° 0th As acid can be used here e.g. hydrochloric, sulfuric, phosphoric or citric.

The acids of general formula II can be used in optically pure form or as racemates. Preferably, the R-enantiomers are used.

The compounds of general formula II and their reactive functional derivatives are novel compounds which can be prepared by, in a compound of general formula III,

A - GOOCH - B III

rp * where A and I have the meaning given above and B represents a protected carboxyl group, the group B transfers into a free carboxyl group.

The protected carboxyl group B may be a readily cleavable ester = group, e.g. a benzyl or tert.butyl ester group. The conversion of the protected carboxyl group B to the free carboxyl group can, in the case of the benzyl ester, be by catalytic hydrogenation using a precious metal catalyst, e.g. palladium / coal, and in the case of tert.butyl ester by treatment with acid, e.g. with a mineral acid such as hydrochloric acid, or with trifluoroacetic acid.

The possible conversion of the acids thus obtained of the general formula II into functional derivatives, e.g. halides, azides, anhydrides, esters or amides can be made by methods known in the art.

The compounds of the general formula III can be prepared in a manner known per se by protecting the carboxyl group in a compound of the general formula IV

COOH

CHOH IV

T

eg. by forming the benzyl ester or tert-butyl ester, and reacting the resulting compound with a compound of formula A-COOH, e.g. while providing benzene hydrochloric acid chloride.

The compounds of general formula I, their salts and their hydrates have antibiotic, especially bactericidal activity. They have a broad spectrum of action against gram-positive and gram-negative microorganisms. Also advantageous are their stability to gastric acid. The compounds can be used as therapeutics.

For adult humans, single doses of 200 - 1000 mg are considered. It is particularly preferred to administer the subject compounds orally.

The antimicrobial effect of the compounds of the invention is shown in the following table: 6 141966

Table -1 --- 1 ------

Compound from Minimum Inhibitory Concentration = CD ™ in Mice, (mg / kg orally) Example No., Tration ^ µg / ml)

Staphylo = Escherichia Staphylococ = Escherichia coccus coli 1346 cus aureus coli 1346 aureus EDA (Scho ch) 1 0.073 73 0.7 16 2. 0.156 19 1.1 18 3 0.312 0.625 2.0 37 14 0.312 10 7.2 93 15 1 , 25 19 3.1 27 16 0.625 78 2.9 42 17 1.25 10 2.4 47 18 1.25 10 1.6 55 21 0.312 2.5 1.1 47 25 0.625 1.25 1.4 41 26 0.312 5 0.8 27 27 0.312 2.5 2.8 52 57_0.312 19 1 4.8. 23___

Minimum inhibitory concentrations in vitro have been determined using dual dilution rows in broth.

From Danish Patent Application No. 3500/71 and British Patent No. 900,666, related penicillin compounds containing a benzoyloxy or phenoxycarbonyloxy group are known, but these known compounds have a higher minimum inhibitory concentration, expressed in CD in vivo by subcutaneous administration to mice, as shown in Table A below, in which the effect of some of the present compounds is similar to that of some of the patents produced in accordance with Danish Patent Application No. 3500/71. Table B below, and of Table B below, which gives the results of a comparison experiment in which the minimum inhibitory concentration, expressed in CD5Q value in mg / kg, by oral administration to mice is given for some of the the compounds of this invention and a compound prepared in accordance with British Patent Specification No. 900,666.

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The process according to the invention is further illustrated by the following examples:

Example 1.

22.6 g of (R) -2- (2-furoyloxy) -isocaproic acid, 80 ml of absolute benzene and 36 ml of thionyl chloride are heated for 2.5 hours, after which the mixture is evaporated and dried. 24.5 g of (R) -2- (2-furoyloxy) -isocaprone = acid chloride are obtained. This product is dissolved in 70 ml of methylene chloride and the solution is dropped at 0 ° C with stirring to a solution of 21.6 g of 6-aminopenicillanic acid in a mixture of 150 ml of methylene chloride and 23 ml of triethylamine. The reaction mixture is stored for 20 hours at 0 ° 0 and then evaporated at 20 ° C under reduced pressure. The residue is dissolved in 150 ml of ice water and extracted twice with 50 ml of ether each time. The aqueous phase is adjusted to pH 2 with 3H sulfuric acid at 0 ° C and extracted three times with 80 ml of ethyl acetate each time. The ethyl acetate solutions are washed three times with 20 ml of ice-cold 5 # sodium chloride solution each time, dried over magnesium sulfate and evaporated under reduced pressure at 20 ° C. The residue is dissolved in 300 ml of absolute ether and the solution is filtered and added with stirring 50 ml of 2F sodium 2-ethylcaproate solution in ethyl acetate. The precipitated [(R) -1- (2-furoyloxy) -3-methylbutyl] penicillin sodium is aspirated, washed with absolute ether and low boiling petroleum ether, dried and recrystallized from water / isopropanol. Melting point 182 -183 ° C (dec.). [α] D = + 221.5 ° (c = 2.0 in water).

The (R) -2- (2-furoyloxy) -isocaprone acid used as the starting material can be prepared as follows: 55.5g of (R) -2- (2-furoyloxy) -isocaproic acid benzyl ester in 400ml of ethanol is hydrogenated after addition of 5 g of 5 $ * palladium / coal, in = to the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated at 40 DEG C. under reduced pressure.

The oil obtained as the residue is dissolved in 250 ml of 8 $ sodium bicarbonate solution and washed twice with 80 ml of ether each time. Bi = 141966 The carbonate solution is adjusted to pH 2 with concentrated salt = acid and extracted three times with 100 ml of ethyl acetate each time. The ethyl acetate solutions are washed twice with 50 ml of water each time, dried with magnesium sulfate and evaporated under reduced pressure at 45 ° C. The (R) -2- (2-furoyl = oxy) -isocapronic acid obtained in the form of an oily residue is dried for 2 hours at 0.4 mm Hg and a temperature of 40 ° C. [α] D = + 7.0 ° (c = 4.0 in ethanol).

(B.) - 2- (2-Euroylo: xy) -isocaproic acid benzyl ester can be prepared as follows: In a three-neck flask equipped with a stirrer, thermometer and reflux condenser with calcium chloride tube, dissolve 264 g (R) -2-hy = droxy-isocaproic acid in 1.8 liters of absolute dioxane, first adding 285 ml of triethylamine and then 236 ml of benzyl chloride, and then heating the mixture for 20 hours with stirring in an oil bath at internal temperature 100 ° 0. After cooling, the resulting triethylamine hydrochloride which is washed with 500 ml of ethyl acetate is filtered off. The 3 µl = trate is evaporated at 50 ° C under reduced pressure and the oil recovered as the residue is dissolved in 800 ml of ethyl acetate and washed twice with 150 ml of 3N hydrochloric acid twice, twice with 100 ml of 5i each time. sodium chloride solution, twice with 150 ml of IOfe's potassium bicarbonate solution twice and twice with 100 ml of 5 $ sodium chloride solution each time. After each of these washes, 200 ml of ethyl acetate is then washed. The ethyl acetate solutions are dried over magnesium sulfate and evaporated under reduced pressure at 50 ° C. The crude product thus obtained is distilled at 0.3 mm Hg (112-115 ° C). There is obtained (R) -2-hydroxy-isoeapronic acid benzyl ester, [a] -jp = + 18.0 ° (c = 1 in methanol); n | p = 1.498.

To a solution of 23.6 g of furan-2-carboxylic acid in 100 ml of pyridine is added at 25 ° C with stirring over 20 minutes dropwise 27 ml of benzenesulfochloride. Then stir for 25 minutes at 25 °. Then, 44.4 g of (R) -2-hydroxy-iso = capric acid benzyl ester is added dropwise with stirring. The solution is either heated for 2 hours at 60 ° C or stirred for 20 hours at 25 ° C.

The pyridine is distilled off under reduced pressure at 30 - 50 ° C. The residue is dissolved with the addition of ice in 600 ml of 3 T hydrochloric acid and extracted twice with 250 ml of ethyl acetate each time, Ethylapetate = the solutions washed with 100 ml of 3H hydrochloric acid, twice with 100 ml of water each time, twice with each time 100 ml of 5 # sodium bicarbonate = solution and twice with 100 ml of water each time and dried with magnesium sulfate. The ethyl acetate is distilled off under reduced pressure at 40 ° C and the oil obtained as the residue is dried for 60 minutes under reduced pressure at 60 ° C. R - 2- (2-furoyloxy) -ieocaproacetic acid benzyl ester, [α] D = + 9.0 ° (c = 4.0 in ethanol) is obtained.

Example 2.

A mixture of 23.7 g of R-2- (isonicotinoyloxy) isocapronic acid, 80 ml of absolute benzene and 36 ml of thionyl chloride is heated for 2 hours, then evaporated and then evaporated three times with 30 ml of absolute benzene under reduced pressure at 45 ° C and then dried. 25.6 g of R-α- (isonicotinoylozy) -isopapronic acid chloride hydrochloride are obtained, which are dissolved in 80 ml of chloroform. The solution is dropped at 0 ° C with stirring to a solution of 21.6 g of 6-aminopenicillanic acid in a mixture of 150 ml of chloroform and 42 ml of triethylamine. The reaction mixture is stored at 0 ° C for 20 hours and then evaporated under reduced pressure at 20 ° C. The residue is dissolved in 200 ml of ice water and extracted twice with 70 ml of ethyl acetate each time.

The aqueous phase is adjusted to pH 2.5 with citric acid at pH 2.5 and extracted three times with 100 ml of ethyl acetate each time. The ethyl acetate solutions are washed three times with 30 ml of ice = cold 5 $ sodium chloride solution each time, dried with magnesium sulfate and evaporated under reduced pressure at 20 °. The residue is dissolved in 100 ml of ethyl acetate and 50 ml of 2H sodium = -2-ethylcaproate solution in ethyl acetate and 200 ml of absolute ether are added with stirring. The precipitated [(R) -1- (isonicotinoyloxy) -3-methylbutyl] pep nicillin sodium is aspirated, washed with absolute ether and low boiling petroleum ether and recrystallized after drying water / isopro = panol. Melting point 197 - 198 ° C (dec.). [α] 25 D = + 227 ° (c = 1.0 in water).

The starting R-2- (isonicotinoyloxy) -iso = capric acid, m.p. 138-139 ° C, [α] Dβ = + 22.3 ° (c = 3 in ethanol), can be obtained via its benzyl ester in by analogy with that given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 3

9.2 g of 6-aminopenicillanic acid are stirred in 100 ml of absolute chloroform at 0 ° C for 1 hour with 12.0 ml of triethylamine. Simultaneously, 5.2 g of pivaloyl chloride are added to a solution of 10.4 g of (R) -2 - [(S) -pyrogluta = moyloxy] isocaproic acid and 6.0 ml of triethylamine in 100 ml of absolute chloroform at -10 ° C, and stir for 20 minutes at -10 ° C. It is then cooled to -40 ° C and the above-mentioned 6-aminopenicillanic acid solution is added and the mixture is left at 0 ° C for 16 hours.

Then it is evaporated under reduced pressure at a bath temperature of 20 ° C and the residue is taken up in water and extracted twice with ethyl acetate. After washing the ethyl acetate extract with water and saturated sodium chloride solution and drying over sodium sulfate, they are evaporated in vacuo at a bath temperature of 20 ° C to a volume of 80 ml and stirred in 800 ml of petroleum ether. After decantation, this procedure is repeated, using chloroform instead of ethyl acetate. Decant the residue up into 100 ml of acetone and add 20 ml of 2M sodium 2 = ethylcaproate in ethyl acetate and precipitate with petroleum ether and decant. Of methanol / isopropyl ether, (R) -3-methyl = -1 - [(S) -pyr o glutamoyloxybutyl] -p enin cillin sodium crystallizes, m.p. 180 ° C (dec.), [A] jp = + 187.0 ° (c = 1.0 in water).

The starting compound (R) -2 - [(S) -pyroglutamoyloxy] = isocaproic acid can be prepared as follows: 14.2 g (S) -pyroglutamic acid is suspended in 60 ml of dimethylformamide and brought to solution with 15.4 ml of triethylamine. At -60 ° C, with stirring over 20 minutes, 52 ml of a 5.2M solution of phosgene in toluene is added, and after a further 5 minutes, with vigorous stirring, one is added to a temperature between -40 and -50. Cooled solution of 22.2 g (R) -2-hydroxyisocaproic acid = benzyl ester in 80 ml of pyridine. The mixture is then left for 16 hours at 2-4 ° C, then evaporated under reduced pressure using a dry ice-cooled master. The residue is taken up in ether and washed three times with IR hydrochloric acid, three times with water, three times with 10O's potassium bicarbonate solution and three times with water, dried over sodium sulfate and evaporated under reduced pressure. The residue containing (R) -2 - [(S) -pyroglutamoylo: xy] -iBoeapronic acid benzyl ester is hydrogenated in glacial acetic acid / water (95: 5) using 5 $ pal = ladium / coal until no longer absorbed hydrogen. The catalyst is then filtered off and the filtrate is evaporated under reduced pressure. After crystallization of the residue of ethyl acetate / petroleum ether, 11 g of (R) -2 - [(S) -pyroglutamoyloxy] isocaproic acid is obtained, m.p. 148-150 ° C (after conversion at 80 ° C), [a] -jp = +20 , 4 ° (c = 1.0 in methanol).

Example 4 · In analogy to Example 1, there is obtained with (R) -2- (5-bromo-2-furoyloxy) -isocaprone = the acid compound ([(RS) -1- (5-bromo-2-furoyl) -oxy] -3-methyl-butyl) = -penicillin sodium, m.p. 205 - 206 ° C (dec.).

[α] D = + 189 ° (c = 1 in water).

The (R) -2- (5-bromo-2-furoyloxy) -iso = capric acid used as the starting compound can be prepared via its tert-butyl ester in analogy to the information contained in Example 14 for the preparation of the starting material used in Example 14.

Example 5 * In analogy to Example 1, there is obtained the (R) -2- (2,6-dimethoxyisonicotinoyl = oxy) -isocapronic acid compound [(R) -1- (2,6-dimethoxyisonicotinoyl) * -oxy] -3-methylbutyl ] -penicillin sodium, melting point from 170 ° 0 (son = partition), [a] -jp = + 157 ° (c = 2 in water).

The starting compound used, m.p. 79 - 81 ° C, [α] D = + 12.2 ° (c = 2 in ether), can be prepared via the corresponding benzyl ester by analogy with the information given in Example 1 regarding the preparation of the Starting material used in Example 1.

Example 6

By analogy to Example 1, the (R) -2- (5-methyl-2-furoyloxy) -iso = capronic acid compound ([(R) -3-methyl-1- (5-methyl-2-furoyl) is obtained) -oxy] = -butyl) -penicillin sodium, m.p. 204 ° C (dec.), = + 211.3 ° (c = 1 in water).

The (R) -2- (5-methyl-2-furoyloxy) = isoeapronic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 7

By analogy to Example 1, there is obtained the (R) -2- (2-benzofuroyloxy) -isoea = pronic acid compound [(R) -1- (2-benzofuroyloxy) -3-methylbutyl] -piperolinium sodium, m.p. 197 ° C, [oc] -jp = + 183.3 ° (c = 1 in water).

The (R) -2- (2-benzofuroyloxy) -iso = capric acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 8.

By analogy to Example 1, there is obtained the (R) -2- (3-methyl-5-isoxazolyl-carbonyloxy) -isocaproic acid compound ((R) -1 - [(3-methyl-5-isoxazolyl) -c arbonyloxy] -3-methylbutyl) -pheni cillin sodium, m.p. 185 ° C (dec.), [α] D = + 214.3 ° (c = 2 in water).

The starting compound (R) -2- (3-methyl-5-isoxazolyl = 25-carbonyloxy) -isocaproic acid, m.p. 59 - 62 ° C, [α] D = + 13 ° (c = 2 in ethanol), can via its benzyl ester is prepared by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 9

In analogy to Example 1, there is obtained the (RS) -2- (3-furoyloxy) -isocaproic acid compound [(RS) -1- (3-furroyloxy) -3-methylbutyl] -penicillin-sodium = m.p. 208 ° C (dec.), [Α] D = + 210.6 ° (c = 0.5 in water).

The (RS) -2- (3-furoyloxy) -isocaprone acid used, m.p. 85-87 ° C, can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of Example 1. starting material used.

Example 10.

By analogy to Example 1, there is obtained the (S) -2- (2-furoyloxy) -isocaproic acid compound [(S) -1- (2-furoylozy) -3-methylbutyl] -penicillin sodium, m.p. from 150 ° C (dec. ). [<x] jp = 3 + 216 ° (c = 2 in water).

The (S) -2- (2-furoyloxy) -isocaprone acid used as the starting compound, [a] jp = -7 ° (c = 4 in ethanol), can be prepared via its benzyl ester by analogy to those of Example 1 given information regarding the preparation of the starting material used in Example 1.

Example 11.

By analogy to Example 1, the (R) -2 - [(1,2,3,6-tetrahydro-2,6 = -dioxo-4-pyrimidinyl) -arbonyloxy] -isocaproic acid compound is obtained from the [[R] -3- methyl 1 - ([(1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinyl) = -carbonyl] -oxy) -butyl] -penicillin sodium, m.p. from 220 ° C ( = [162] = + 162.5 ° (c = 1 in water).

The starting compound used (R) -2 - [(1,2,3,6-tetrahydro-2,6 = -dioxo-4-pyrimidinyl) carbonyloxy] isoeapronic acid, m.p. 94-96 ° C, [α] p = + 15.5 ° (c = 2 in methanol), can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 12.

By analogy to Example 1, there is obtained the (R) -2- (1-methyl-4-imidazolylcarbo = nyloxy) -isocaproic acid compound [(R) -3-methyl1-1- ([(1-methylimi = dazole-4) -yl) -carbonyl] -oxy) -butyl] -penieillin sodium, m.p. 150 ° C (dec.), [α] D = + 182.8 ° (c = 1 in ethanol).

The (R) -2- (1-methyl-4-imidazolyl = carbonyloxy) isocaproic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 13

By analogy to Example 1, there is obtained the (R) -2- (4-isoquinolylcarbonyloxy) = -isocaproic acid compound [(R) -1 - [(4-isoguinolylcarbonyl) -oxy] -3 = -methylbutyl] -peneillin sodium, m.p. 136 ° 0, [cc] jp = + 192.7 ° (c = 1 in ethanol).

The (R) -2- (4-isoquinolylcarbonyloxy) = -isocapronic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 14 · In analogy to Example 1, the (R) -2- (1,2,3-thiadiazol-4-yl = -carbonyloxy) -isocaproic acid compound [(R) -3-methyl-1 - [(1, 2,3 = -thiadiazol-4-ylcarbonyl) -oxy] -butyl] -penicillin sodium, melt = point 210 ° C (dec.), = +240.2 (c = 1 in water).

The (R) -2- (1,2,3-thiadiazol-4-yl = -carbonyloxy) -isocaproic acid used as the starting compound can be prepared as follows: 13.0g, 2,3-thiadiazole-4-earboxylic acid is suspended in 100 ml of pyridine, and dropwise 12.8 ml of benzene sulfochloride at 25 - 35 ° C dropwise and with stirring over 20 minutes. Stir for 1/2 hour at room temperature to form a clear solution. Then, with continued stirring, 17.9 g of (R) -α-hydroxyisovalerianic acid tert.butyl ester is added over 20 minutes = where the temperature rises to approx. 40 ° C. After stirring for 2 hours at 60 ° C, the reaction mixture is evaporated under reduced pressure and the evaporation residue is suspended in 200 ml of ethyl acetate and subjected to suction filtration. The precipitate is washed twice with ethyl acetate, and the combined filtrates are washed three times quickly with ice-cold dilute hydrochloric acid, once with ice water and three times with 10 $ potassium bicarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue containing (R) -2- (1,2,3-thiadiazole-4 = -yl-carbonyloxy) -isocaproic acid tert-butyl ester is poured over 100 ml of trifluoroacetic acid and after 1/2 hour evaporating under reduced pressure pressure. The residue is taken up in ether and extracted with the 10 M potassium bicarbonate solution. The combined bicarbonate extracts are simulated for Congo acid reaction and extracted three times with ethyl acetate. After washing, drying and evaporating the solvent, 19 g of a crystallizing oil is obtained. Of isopropanol is obtained 12 g of (R) -2- (1,2,3-thiadiazol-4-yl-carbonyloxy) -isocaproic acid, m.p. 104 - 105 ° 0, [α] D = + 20.0 ° (c = 1 in methanol).

Example 15

By analogy to Example 1, there is obtained the (R) -2- (tetrahydropyran-4-ylcar = bonyloxy) -isocapronic acid compound [(R) -3-methyl-1- ([(tetrahydro-dropyran-4-yl) carbonyl] -oxy) -butyl] -penicillin sodium, mp 183 ° C (dec.), [α] D = + 218.5 ° (c = 1 in water).

The (R) -2- (tetrahydropyran-4-ylcar = bonyloxy) -isocaproic acid used as the starting compound can be prepared via its benzyl ester in analogy with the information given in Example 22 regarding the preparation of the starting material used in Example 22.

Example 16.

By analogy to Example 1, there is obtained the (R) -2- (1,5-dimethyl-3-pyrazolyl = carbonyloxy) -isocaproic acid compound [(R) -1 - ([(1,5-dimethylpy = razol-3-yl) ) -carbonyl] -oxy) -3-methylbutyl] -penicillin sodium, m.p. = 205 ° C (dec.), [α] D = + 196.7 ° (c = 1 in water).

18 U19B6

The starting material used can be prepared as follows: 19.2 g of 1,5-dimethylpyrazole-3-carboxylic acid are heated together with 80 ml of thionyl chloride for 20 minutes to reflux, after which excess thionyl chloride is removed under reduced pressure. Evaporate two more times with toluene under reduced pressure, then take up the residue in 100 ml of toluene and drop at 0 ° C with stirring to 22.4 g of (R) -α-hydroxyisocaproic acid tert-butyl ester in 80 ml of pyridine. After stirring for 2 hours at room temperature, the mixture is evaporated under reduced pressure and the residue is taken up in ether and washed three times with water and three times with 10 µl of potassium bicarbonate solution. After drying and evaporation of the solvent, a residual crystallizing residue of 25.5 g was obtained, m.p. 69-71 ° C. This residue containing (B.) -2- (1,4-dimethyl = pyrazole-3 Ylcarbonyloxy) -isocaproic acid tert.butyl ester is left for 30 minutes at room temperature with 50 ml of trifluoroacetic acid, and after evaporation in vacuo, the residue is dissolved in ether and extracted with IOFO's potassium bicarbonate solution. After acidification of the bicarbonate extracts for Congo acid reaction, extract with ether and remove the ether under reduced pressure after washing and drying. The residue is recrystallized from ethyl acetate. 16 g of (R) -2- (1,5-dimethylpyrazol-3-ylcarbonyloxy) -isocaproic acid, m.p. = 155 DEG-161 DEG C., [α] D = + 13.1 ° (c = 1.0) in methanol).

Example 17. In analogy to Example 3, there is obtained the (R) -2- (2-acetamido-4-thiazolyl = carbonyloxy) -isocapronic acid compound [(R) -1 - ([(2-acetamido-4 = -thiazolyl) -carbonyl] -oxy) -3-methylbutyl] -penicillin sodium, m.p. = 220 DEG C. (decomposition), [cc] .jp = + 151.5 ° (c = 1 in water).

The starting material used can be prepared as follows: 14.4 g of 2-acetamido-4-thiazole carboxylic acid, suspended in 200 ml of dimethylformamide, are dissolved with 11.9 ml of triethylamine.

At -60 ° C and vigorous stirring, slowly 38.1 ml of a 2.86 µl solution of phosgene in toluene is slowly added, one to approx. -50 ° C cooled solution of 14.6 g of (R) -2-hydroxyisocaproic acid tert.butyl = 19 1A1986 ester in 50 ml of pyridine is added at once. The reaction mixture has been allowed to warm to room temperature, evaporated under reduced pressure, and the residue is taken up in ether and washed three times with water and three times with 10 # potassium bicarbonate solution, dried and evaporated under reduced pressure. The residual 26 g of crystalline mass is obtained which contains (R) -2- (2-acetamido-4-thiazolecarbonyloxy) -isocaprone = acid tert-butyl ester. This mass is left for 30 minutes at room temperature with 100 ml of trifluoroacetic acid. After removing the solvent under reduced pressure, the residue is taken up in ether and extracted exhaustively with 10 $ potassium bicarbonate solution. After acidifying the aqueous solution to pH 3, it is extracted three times with ethyl acetate and the extract is evaporated under reduced pressure after washing with water and drying over sodium sulfate. (R) -2- (2-Aeetamido-4-thiazolecarbonyl: xy) -isocaproic acid is obtained as a non-crystallizing resinous residue.

Example 18.

By analogy to Example 1, the (R) -2 - [(RS) -tetrahydro-2-furoyl = oxy] -isocaproic acid compound gives the [(R) -3-methyl-1 - [[(RS) -tetrahydro = -2 -Furoyl] -oxy) -butyl] -penicillin sodium, m.p. 170 DEG-185 DEG C. (decomposition), [α] D = + 200 DEG (c = 1 in water).

The starting compound (R) -2 - [(RS) - (tetrahydro-2-fluoro) -oxy] -isocapronic acid, [a] | p = -7 ° (c = 4 in ethanol), benzyl ester is prepared by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 19.

By analogy to Example 1, the (RS) -2- (2-furoyloxy) valerian = acid compound [(RS) -1- (2-furoylozy) -butyl] -penicillin sodium, m.p. 165-170 ° C ( decomposition), [α] jp = + 209 ° (c = 1 in water).

20

U196S

The (RS) -2- (2-furoyloxy) -valeric acid used as the starting compound, m.p. 53-56 ° C, can be prepared via its benzyl ester by analogy with the information given in Example 35 on the preparation of the Example 35 starting material used.

Example 20

By analogy to Example 1, the (RS) -2- (1,6-dihydro-6-oxonicotinoyl = oxy) -isocaproic acid compound [(RS) -1 - [(1,6-dihydro-6-oxonico = tinoyl) oxy] -3-methylbutyl] -p enicillin sodium, m.p. 200 ° C (dec.), [α] Dβ = + 191 ° (c = 1 in water).

The (RS) -2- (1,6-dibydro-6-oxonicotyl-noyloxy) -isocaproic acid, m.p. 167-170 ° C, can be prepared by analogy with its benzyl ester by analogy to those listed in Example 35. information regarding the preparation of the starting material used in Example 35.

Example 21.

By analogy to Example 3, there is obtained the (R) -2- (pyrazinylcarbonyloxy) -iso = capric acid compound [(R) -3-methyl-1 - [(pyrazinylcarbonyl) -oxy} = -butyl] -penicillin potassium, m.p. ° 0 (decomposition), [a] + = + 186.5 ° (c = 1 in water).

The (R) -2- (pyrazinylcarbonyloxy) = -isocaproic acid used as the starting compound can be prepared via its tert-butyl ester by analogy with the information given in Example 17 regarding the preparation of the starting material used in Example 17.

Example 22.

By analogy to Example 1, the (R) ~ 2- (nieotinoyloxy) -isoeaprone = acid-R-oxide compound [(R) -3-methyl-1 - [(1-oxidonicotinoyl) = -oxy] -butyl] is obtained. penicillin sodium, m.p. 175 ° C (dec.), [α] D = + 168.3 ° (c = l water).

21 161966

The starting compound (R) -2- (nicotinoyloxy) -isoca = pronic acid N-oxide can be prepared as follows: 17.8 g of nicotinoyl chloride hydrochloride are dissolved in 150 ml of pyridine and 50 ml of dimethylformamide and stirred into the solution. at a maximum of 15 ° C, 22.2 g of (R) -2-hydroxy-isovalerianic acid benzyl ester (prepared by reaction of (R) -2-hydro: xy-isovaleric acid and benzyl chloride in analogy to the corresponding information in Example 1). After stirring at room temperature for 2 hours, the mixture is evaporated under reduced pressure. The residue is taken up in ether, washed three times with water and extracted 6 times with ice-cold 3R hydrochloric acid. The hydrochloric acid phases are immediately added to saturated potassium bicarbonate solution and the base thus released is extracted three times with ether. After washing and drying, evaporated under reduced pressure to give 27 g of a resin containing (R) -2- (nicotinoyloxy) = -isoeapronic acid benzyl ester. This is hydrogenated in 200 ml of ethanbi un = using 2 g of 5 $ palladium / carbon until two equivalents of hydrogen are taken up. After suction filtration and evaporation, the residue is taken up in 10 $ potassium bicarbonate, washed twice with ether and adjusted with citric acid to pH 3. After extraction with ether, washing, drying and evaporation of the extract, a crystallizing oil is obtained. Of ethyl acetate / petroleum ether, 14 g of (R) -2 = - (nicotinoyloxy) isocaproic acid crystallize with mp 101 - 103 ° C, [α] D = + 18.8 ° (c = 1.0 in methanol).

The E-oxide is obtained from 26.4 g of the acid in 70 ml of glacial acetic acid by 3 hours of treatment with 11 ml of 30 $ hydrogen peroxide at 70 - 80 ° C. After further addition of 8 ml of 30 $ hydrogen peroxide, the mixture is left overnight at the same temperature. Gently evaporate under reduced pressure and evaporate twice with 50 ml of water each time, evaporating to dryness at no time. The residue is taken up in chloroform, washed four times with water, dried and evaporated under reduced pressure. Of ethyl acetate, 19 g of (R) -2-nicotinoyl = oxy-isocaproic acid H-oxide crystallize, mp 132-134 ° C, [α] D = + 20.8 ° (c = 1.0 in methanol).

Example 23

By analogy to Example 3, there is obtained the (R) -2- (4-chloropicolinoyloxy) -iso = capric acid compound [(R) -1- [(4-chloropieolinoyl) -oxy] -3-methyl = butyl] -penicillin sodium, m.p. 140 ° C (dec.), [<x] jp = +146.70 (e = 1 in water).

The (R) -2- (4-cIHorpicolinoyldxy) = -isocaproic acid, m.p. 120-122 ° C, used as the access compound, can be prepared via its tert.butyl = ester by analogy with the information given in Example 17 regarding the preparation of the starting material.

Example 24.

By analogy to Example 1, there is obtained the (R) -2- (2,6-dichloroisonicotinoyl = oxy) -isocaproic acid compound [(R) -1 - [(2,6-dichloroisonicotinoyl) = -oxy] -3-methylbutyl] -penicillin sodium, melting point from 162 ° C (son = partitioning), [α = + 164.6 ° (c = 2 in water).

The (R) -2- (2,6-dichloroisoneotinoyl = oxy) -isocaproic acid, m.p. 79-81 ° C (decomposition), can be prepared via its tert-butyl ester by analogy with the information given in Example 16 of the starting material.

Example 25

By analogy to Example 1, there is obtained the (R) -2- (4-oxazolylcarbonyloxy) = -isocapronic acid compound [(R) -1 - [(4-oxazolylcarbonyl) -oxy} -3 = -methylbutyl] -penicillin sodium, m.p. 173 ° C (decomp.), [Ccd] p = + 150.8 ° (c = 1 in ethanol).

The (R) -2- (4-oxazolylcarbonyloxy) = -isocaproic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 26

In analogy to Example 1, there is obtained the (R) -2- (2-methylisonicotinoyloxy) = -isocapronic acid compound [(R) -3-methyl-1 - [(2-methylisisonicotinoyl) = -oxy] -butyl] -penicillin sodium, m.p. 195 - 200 ° C (decomposition = division), [α] D = + 188 ° (c = 1 in water).

The (R) -2- (2-methylisonicotinoyl = oxy) -isocaproic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 22 regarding the preparation of the starting material used in Example 22.

Example 27

By analogy to Example 1, there is obtained the (R) -2- (3-isoxazolylcarbonyloxy) = -isocapronic acid compound [(R) -1 - [(3-isoxazolylcarbonyl) oxy] = -3-methylbutyl] -penicillin sodium, m.p. 188 ° 0 (dec.), [Ct] · + = + 209.6 ° (c = 1 in ethanol).

The (R) -2- (3-isoxazolylcarbonyloxy) = -isocapronic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 28.

By analogy to Example 1, there is obtained the (R) -2- (3-indolylcarbonyloxy) -isocyanic acid compound [(R) -1 - [(indol-3-yl-carbonyl) -oxy] -3-methylbutyl ] = -penicillin sodium, mp 175 ° C (dec.). = + 131.2 ° (c = 1 in ethanol).

The (R) -2- (3-indolylcarbonyloxy) = -isocaproic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 29 · In analogy to Example 2, the (S) -2- (isonicotinoyloxy) -isoca = pronic acid hydrochloride compound [(S) -1- (isonicotinoyloxy) -3-me = thylbutyl] penicillin sodium, m.p. 177 ° is obtained. 0 (decomposition), [oc] + p = +225 (c = 2 in water).

24 141966

The starting compound used is obtained by treating (S) -2- (iso = nicotinoyloxy) -isocaproic acid with thionyl chloride. The acid used for this (m.p. 138 - 139 ° C, [oc] jp = + 22.3 °, (c = 2 in ethanol)) can in turn be obtained via its benzyl ester in analogy with the information given in Example 1 of the starting material used in Example 1.

Example 30.

In analogy to Example 2, there is obtained the (RS) -2- (2,6-dimethylisonicotyl Noyloxy) -isocaproic acid hydrochloride compound [(RS) -1 - [(2,6-di = methylthioniso tinoyl) -osyl] -3-methylthylbutyl] -p enicillin sodium, [α] jp = + 159 ° (c = 2 in water).

The starting material used is obtained by treating (SS) -2- (2,6 = -dimethylisonicotinoyloxy isocaproic acid with thionyl chloride. This acid (m.p. 95 - 96 ° G) is obtained via its benzyl ester in analogy with the information given in Example 35). of the starting material used in Example 35.

Example 51.

I analogy of Example 1 is obtained with (R) -2- (cinchoninoyloxy) -isoca = pronic acid compound [(R) -1- (cinchoninoyloxy) -3-methylbutyl] -pe = nicillin sodium, m.p. 143 ° C (dec. ), [α] D = + 208.7 ° (c = 1 in ethanol).

The (R) -2- (cinchoninoyloxy) -iso ca = pronic acid used as the starting compound is obtained via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 32.

By analogy to Example 1, there is obtained the (R) -2- (7-chlorocinchoninoyloxy) = -isocaproic acid compound [(R) -1 - [(7-chlorocinchoninoyl) -oxy] -3 = -methylbutyl] -penicillin sodium, m.p. 135 ° C (dec.), [Α] 20 D = + 196.4 ° (c = 1 in ethanol).

The (R) -2- (7-chlorocinchoninoyloxy) = -isocaproic acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 33

By analogy to Example 1, there is obtained the (R) -2- (2-chloronicotinoyloxy) -iso = capric acid compound [(R) -1 - [(2-chloronicotinoyl) oxy] -3-methyl =

O C

butyl] -penicillin potassium, m.p. 120 ° C (dec.), [α] D = + 167.3 ° (c = 1 in water).

The (R) -2- (2-chloronicotinoyloxy) = -isocaproic acid, m.p. 64-67 ° C, [α] D = + 17.5 ° (c = 1 in methanol), can be via its tert.butyl ester are prepared by analogy with the information given in Example 16 regarding the preparation of the starting material used in Example 16.

Example 34.

By analogy to Example 1, the (R) -2- (quinaldoyloxy) -isocapron = acid compound is obtained [(R) -3-methyl-1- (quinaldoyloxy) -butyl] -penicillin = sodium, m.p. 170 ° C (dec.) ), [oc] | p = + 119.3 ° (c = 1 in ethanol).

The (R) -2- (quinaldoyloxy) -isocaprone acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 22 regarding the preparation of the starting material used in Example 22.

Example 35 · In analogy to Example 1, is obtained with (RS) -2- (isonicotinoyloxy) -isocaprone = the acid compound [(RS) -1- (isonicotinoyloxy) -3-methylbutyl] -penicil = lin sodium, [a]. + 197.5 ° (c = 2 in water).

26 161966

The starting compound used can be prepared as follows:

To a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml of dimethylformamide and 14.8 ml of triethylamine is added at 60 ° C with stirring over 15 minutes dropwise 29.5 g of (RS) -α-bromoisocaprone = acid benzyl ester . The reaction mixture is stirred for 5 hours at 90 ° C. The triethylamine hydrobromide is aspirated and the filtrate is evaporated at 60 ° C under reduced pressure. The residue is dissolved in 100 ml of ethyl acetate and filtered, and the filtrate is washed three times with 15 ml of 1ΪΤ potassium bicarbonate solution three times and twice with 20 ml of water each time. The ethyl acetate solution is dried over magnesium sulfate and evaporated at 45 ° C under reduced pressure. RS-2- (Isonicotinoyloxy) -isocaproic acid = benzyl ester is obtained in the form of an oil.

For purification, this ester is dissolved in 10 ml of ethyl acetate, mixed with a solution of 19 g of p-toluenesulfonic acid in 35 ml of ethyl acetate and the mixture is left for 2 hours at 0 ° C for crystallization. The (RS) -2 = - (Isonicotinoyloxy) isocaproic acid benzyl ester p-toluenesulfonate is aspirated, washed with 100 ml of ether and dried at 60 ° C under reduced pressure. Melting point 136 ° C. The p-toluenesulfonate is dissolved in 30 ml of water and the solution is adjusted to pH 9 with potassium carbonate and extracted twice with 50 ml of ethyl acetate each time. Ethyl acetate = the solution is washed twice with 10 ml of water each time, dried with magnesium sulfate and evaporated at 40 ° C under reduced pressure. The oil gives, after crystallization of low boiling petroleum ether (RS) = -2- (isonicotinoyloxy) -isocaproic acid benzyl ester, m.p. 49 -50 ° C.

8.2 g of (RS) -2- (isonicotinoyloxy) -isocaproic acid benzyl ester are hydrogenated in 50 ml of ethanol after addition of 800 mg of 5 $ palladium / carbon until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated at 45 ° C under reduced pressure. The oil is dissolved in excess sodium bicarbonate solution and extracted twice with 20 ml of ether each time, and the bicarbonate solution is adjusted to pH 2.5 with 3 $ T hydrochloric acid. The acidic solution is extracted twice with 70 ml of ethyl acetate each time. After two washes with 20 ml of 5 M sodium chloride solution each time, the ethyl acetate solution is dried over magnesium sulfate and evaporated under reduced pressure at 45 ° C and the ether-petroleum ether crystallized from the residue. (RS) -2- (isonyotinoyloxy) = -isocaproic acid, m.p. 98-100 ° C is obtained.

27 141966

Example 36.

By analogy to Example 2, with (RS) -2- (isonicotinoylo: xy) -valeric acid compound [(RS) -1- (isonicotinoyloxy) ~ butyl] -penicillin = sodium, [a] | p = +222 ° (c = 2 in water).

The (RS) -2- (isonicotinoyloxy) = valeric acid used (m.p. 152 - 153 ° C) can be prepared via its benzyl ester by analogy with the information given in Example 35 for the preparation of the starting material used in Example 35.

Example 37.

By analogy to Example 1, there is obtained the (R) -2- (nicotinoylozy) -isocaprone acid compound [(R) -1- (nicotinoyloxy) -3-methyl-butyl] -penicillin =-potassium, m.p. 195 ° C (dec. ), [α] jp = + 210.4 ° (c = 1 in water).

The (R) -2- (nicotinoyloxy) -isocaprone acid used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 22 for the preparation of the starting material used in Example 22.

Example 38

By analogy to Example 1, the (R) -2 ~ (2-thienoyloxy) -isocaprone acid compound [(R) -3-methyl-1- (2-thienoylozy) -butyl] -penicillin = sodium, [o ] + = 103 ° (c = 1 in water).

The (R) -2- (2-thienoyloxy) -isoca = pronic acid [[oc] jp = + 13.7 ° (c - 2 in ethanol)] used as its starting compound can be prepared by analogy with its tert.butyl = ester. the information given in Example 16 regarding the preparation of the starting material used in Example 16 = material.

Example 39

By analogy to Example 3, 2- (2-pyrrolylcarbonyloxy) -isoea = 28 U19S6 pronic acid compound [3-methyl-1 - [(pyrrol-2-ylcarbonyl) -oxy] = -butyl] -penic illine sodium is obtained in the form of a diastereomer mixture, mp 208 ° C (dec.), [α] D = + 187.5 ° (c = 1 in ethanol).

The starting compound used for 2- (2-pyrrolylcarbonyloxy) -iso = capric acid can be prepared via its benzyl ester in analogy with the information given in Example 35 regarding the preparation of the starting material used in Example 35.

Example 40.

By analogy to Example 1, there is obtained the (R) -2- (1-oxidoisonicotinoyloxy) = -isocaproic acid compound [3-methyl-1 - [(1-oxido-isonicotinoyl) = oxy] -butyl] -penicillin sodium, m.p. 195 ° C (decomposition), [cc] jp = + 187 ° (c = 2 in water).

(S) -2- (1-oxido-isonicotinoyl = oxy) -isocaproic acid (m.p. 168 - 169 ° C, [α] D = + 4.2 ° (c = 2 in ethanol)) is obtained via its benzyl ester in analogy with the information given in Example 22 regarding the preparation of the starting material used in Example 22. -

Example 41 · In analogy to Example 3, there is obtained the (R) - 2- (2,4-dimethyl-5-pyrimidinyl = carbonyloxy) isocaproic acid compound [(R) -1 - [(2,4-dimethyl-5 = - pyrimidinylcarbonyl-oxy] -3-methylbutyl] -p enicillin sodium, [oc] jp = +225 (c = 1 in water), mp 185 ° C (dec.).

starting compound used (R) -2- (2,4-dimethyl-5-pyrimidinylcarbonyloxy) -isocaproic acid, an oily substance, can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 42

By analogy to Example 3, there is obtained the (R) -2- (5-pyrimidinylcarbonyloxy) = -isocaproic acid compound [(R) -1 - [(5-pyrimidinylcarbonyl) oxy] = -3-methylbutyl] -penicillin sodium = + 237 ° (c = 1 in ethanol), m.p. 205 ° C (dec.).

The starting compound (R) -2- (5-pyrimidinylcarbonyl = oxy) -isocaproic acid, an oily substance, can be prepared via its benzyl ester by analogy with the information given in Example 1 regarding the preparation of the starting material used in Example 1.

Example 43 · In analogy to Example 3, there is obtained the (R) -2- (2-methoxycarbonyl-nicoti-noyloxy) -isocaproic acid compound [(R) -1- (2-methoxycarbonyl-ni = cotinoyloxy) -3-methylbutyl] - penicillin sodium, which melts above 145 ° C with decomposition, [a] -jp = + 195 ° (c = 11 water).

The (R) -2- (2-methoxycarbonyl-nico = nc tinoyloxy) isocaproic acid (m.p. 63-65 ° C, [cc] + = + 27.1 ° (c = 1 in methanol)) can be via its benzyl ester is prepared by analogy with the information given in Example 3 regarding the preparation of the starting material used in Example 3.

Example 44 · In analogy to Example 1, there is obtained the (R) -2- (5-methoxymethyl-2-furoyl = oxy) -isocapronic acid compound [(R) -1- (5-methoxymethyl-2-furoyl = oxy) -3 -methylbutyl] -penicillin sodium, m.p. 173 ° C (decomposition = division), [α] D = + 203 ° (c = 1 in water).

The (R) -2- (5 "methoxymethyl-2-fu = royloxy) isocaproic acid (m.p. 73-74 °) used as the starting compound can be prepared via its benzyl ester by analogy with the information given in Example 1 for the preparation of starting material.

Example 45 · In analogy to Example 1, we get with (R) -2 - [(S) -5-oxotetrahydro-2 =

Claims (2)

14-1966 -Furoyloxy] -isocaproic acid compound [(R) -3-methyl-1 - [(S) -5-oxo = thea trahydro-2-furoyloxy] -butyl] -penicillin sodium, m.p. 216 ° C (decomposition), [a] .jp = + 235 ° (c = 1 in water). The starting compound (R) -2 - [(S) -5-oxotetrahydro = -2-furoyloxy] -isocaproic acid (m.p. 115 - 116 ° C, [α] D + - + 23.4 ° (c = 0, 5 in dioxane)) is obtained via its benzyl ester by analogy with the information given in Example 22 regarding the preparation of the starting material used in Example 22. Example 46. In analogy to Example 1, the (R) -2- [(R) -5-oxotetrah, ydro-2-fu = royloxy] -isocapronic acid compound [(R) -3-methyl-1- [ (R) -5-oxo = tetrahydro-2-furoyloxy] -butyl] -penicillin sodium, m.p. 215 ° C (dec.), [Α] D = + 196 ° (c - 1 in water). The (R) -2 - [(R) -5-oxotetrahydro-2 = -fur oyloxy] -iso capric acid, an oily substance used as starting material, is obtained via its benzyl ester by analogy with the information given in Example 22 regarding the preparation of the starting material. Claims. An analogous process for the preparation of penicillin compounds of the general formula I / CH5 A-COO-CH-CO-NH-CH-CH Cf p I II I ch3 in T-N-: CH-C00H 0 wherein T represents an alkyl or alkenyl group having 2-5 carbon atoms or a cyclopropylmethyl, cyclobutylmethyl or cydopentyl group, and A represents furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-thiadiazolyl, pyrazolyl, pyridyl, 1-oxidopyridyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indoly1, cinchoninyl, quinolyl