The method of obtaining cephalosporin antibiotics

 

(57) Abstract:

Usage: in the pharmaceutical industry. The inventive method of receiving cephalosporin antibiotics of the formula I, where R Is H, t-Bu, gu(Ph)CH-carboxyamide group, Q-H, PhOCH2CO or PHCH2OCO-aminosidine group Z-S or-CH2-, R'-(C2-C3)-alkenyl. Reagent 1:3-sulfonylacetanilide derived cafema formula II, where Q and P have the above values, Z-persulfonic, 4-nitrobenzenesulfonate and 4 bromophenylacetonitrile. Reagent II: organistaion R Sn(R2)3where R' has the above meaning, R2is lower alkyl. Conditions: environment aprotic solvent, catalyst connection Pd (II) or PD (0) in an amount of 1-10 mol.% the reagent 1. 2 C.p. f-crystals, the structure of the compounds of formulas I and II.

n

The invention relates to a method for ceremony, carb(detya)ceremony and oxa(detya)SafeMove connections.

But Shi and others in the U.S. patent N 4520022 (28 may 1985) described cephalosporin antibiotics having a 1-propeciabuy group in 3-position and vpisivaushiesya the following formula, in which R1and R2mean H, HE, co3or CL:

< / BR>
1-propenyloxy group described Ious activity than (E)-configuration. These compounds are produced by the interaction of 3-galogenocyanogen with triarylphosphines education in phosphorylase intermediate compound, which is then treated with an aldehyde to obtain propenonovoi or substituted propenonovoi group.

When carrying out the above method produces a mixture of CIS(Z)- and TRANS(E)-isomers. Therefore, to obtain preferred, with a higher antibacterial activity of CIS(Z)-isomer is necessary to carry out costly separation or to create such conditions in which the target is formed isomer. The overall yield of the desired CIS(Z) isomer in the calculation of the original material is reduced due to the formation of TRANS(E)-isomer.

Recently, in order to prevent the formation of undesired isomer and increase thus the output was proposed catalyzed by palladium combination to enter alkenilovyh the substituents in the 3-position of the cephalosporin ring. Allyl combination of 3-galogenarenov with vinylstyrene initiated connections Pd (0), halides metallov and Tris-(2-furyl)phosphine, leads to the formation of new cephalosporins (S. R. Baker of soedineniya Pd (0) and LiCi combination of cyclohexanoltramadol with vinyltrimethylsilane was applied to obtain various 3((Z)-1-propenyl)ceph-3-volumes by reacting 3-triplexity-3-EMA with (Z)-1-propynylbutylcarbamate (S. R. Baker and others U.S. patent N 4870168, issued September 26, 1989).

Other research extending the range of reactions and optimization of process conditions for catalyzed by palladium combination of ventiltrieb and vinylstyrene reported in the works of Scott and Stille, J. Amer. Chem. Soc. 108, 3033-3040 (1986) and Stille and Groh. J. Amer.Chem, Soc. 109, 813-817 (1987).

The combination of 3-triplexity-3-EMA with tributylstannyl in the presence of PdCi2(CH3CN)2no phosphine or LiCi required in the case of the method described above W. J. Scott and others described G. K. Cook and J. H. McDonald III (196th American Chemical Society National Meeting, Los Angeles, CA Sept 25-30, 1988 Division of Organic Chemistry, Abstract N 32).

The subject of the invention is a method for cafemom, oxazepam and carbacephem with alkenylphenol, alkenylphenol, aryl or heterocyclic group in 3-position carambola kernel. The proposed method involves reacting 3-sulfonylmethane cafema, oxazepam or carbacephem with organosilanes in the presence of Pd (II) or Pd (0) catalyst, and the specified 3-sulfonyloxy group selected from persulfonic-, 4-nitrobenzenesulfonate - and 4-bromobenzonitrile groups. The proposed method is a modified version of the method described in our U.S. patent No. 48 is oxicet-3-EMA in the case of the method in accordance with the present invention are relatively cheap reagents.

If this is not specified or does not follow from the context under used in this description the expressions "alkyl", "alkenyl", "quinil", "alkanol", etc. refers to both straight and branched carbon chains. Compounds containing fragment

< / BR>
referred cefem if Z denotes a sulphur atom, "oxazepam if Z means oxygen atom, and carbacephem if Z denotes a methylene. Different asymmetric carbon atoms azabicycloalkanes system have the same stereochemical configuration as the asymmetric carbon atoms cephalosporin antibiotic, is widely used in medical practice, which corresponds to the product of the fermentation of the cephalosporin C.

According to the invention receive caremy, oxazepam and carbacephem formula I

< / BR>
in which Q, P and Z have the same definitions as in formula I. R1selected from the group consisting of H, C2-6-alanyl,2-6-quinil,2-6-alkadiene,6-10-aryl, substituted C6-10-aryl, unsubstituted and substituted heterocyclic residue, and these substituted aryl and a heterocyclic residue containing 1-3 groups selected from C1-3-alkyl, hydroxy-, WITH1-3-alkoxycarbonyl and cyano groups. Examples of the heterocyclic residue are predil, imidazolyl, thiazolyl, furyl, pyrrolyl, thienyl and isoxazolyl. The proposed method can be used, in particular, to obtain compounds of the formula I, in which R1means H, C2-6alkenyl or2-6-quinil, it is most preferable to obtain compounds in which R1means2-6alkenyl. In particular, the proposed method can be used to obtain cefprozil, i.e. 77-[D-2-amino-2-(4-hydroxy-phenyl)-acetamido] -3-[(Z)-1-propen-1-yl]ceph-3-em-4-carboxylic acid.

Thus, the compounds of formula I are obtained from the compounds of formula II according to the following scheme:

< / BR>
in which Q, Z and R have the above definition, and L is selected from the group consisting of persulfonic-, 4-nitrobenzenesulfonate - and 4-bromobenzonitrile groups. The compound of formula II is subjected to interaction with organotitanium formula R1-Sn-(R2)3in which R1has the above definition and R2means an organic group, which are often used in reactions combination of organostannic (R2may, for example, mean1-6-alkyl, in particular butyl), what="ptx2">

Used in the above reaction scheme, the starting material 3-(persulfonic)oxiclean connections receive the above-described manner. The original 3-[(4-nitrobenzenesulfonyl)oxy] cefem and 3-[(4-Brabanthal)sulfonyl)oxy] cefem obtained using the modified method described in U.S. patent N 3985737, issued October 12, 1976 Corresponding oxazepam and carbacephem derivatives can be obtained similarly.

To obtain the proposed method, compounds of formula I pick the aprotic organic solvent in which are dissolved playing the role of a catalyst compound of palladium and a compound of formula II. Catalytic process connection palladium, take in the amount of 1-10 mol. in the calculation of the compound of formula II. The less reactivity of the source material, the more (within these limits) is the catalyst. The reaction is carried out, carrying out a simple contact R1-substituted organostannic, palladium compounds and 3-sulfonylmethane reagent of formula II is dissolved or suspended in an aprotic organic solvent. The reaction spontaneously proceeds at room temperature is t 10 min to 1 h In adverse conditions, the reaction may proceed more slowly, up to 2 or 3 days. When carrying out the process on an industrial scale it is preferable that the duration of response was 1-4 hours Duration of reaction can be determined empirically on the basis of the analysis of the reaction mixture in the absence of the starting compound of formula II or by the maximum amount of product formed. For analysis it is possible to use thin-layer chromatography, high performance liquid chromatography, nuclear magnetic resonance or spectrophotometric methods.

Catalyzed by palladium combination of 3-sulfonylmethane cafema, oxazepam or carbacephem with organotitanium by the method in accordance with the invention is preferably carried out without using phosphine ligand or metal halide. Although phosphine ligand, for example triphenylphosphine, and a metal halide such as zinc chloride, and may be contained in the reaction medium, however, their presence does not provide any advantages in terms of yield of the target product.

The proposed method is preferably used as starting material 3-(persulfonic)oxiclean connection formular> Catalytic process connection palladium may be the connection of Pd (II) or Pd (0). Examples of suitable compounds of Pd (II) are palladium acetate, palladium chloride, palladium bromide, palladium iodide, dichloride, bis(acetonitrile) palladium dichloride, bis(phenylacetonitrile)palladium, palladium nitrate, acetoacetate palladium sulfate and palladium oxide. Examples of suitable compounds of Pd (0) are bis(dibenzylideneacetone) palladium, Tris(dibenzylideneacetone)palladium and tetrakis(triphenylphosphine)palladium. The preferred catalytic palladium compounds are palladium (II) acetate and Tris(dibenzylideneacetone) palladium (0).

Aprotic solvent used in the implementation of the proposed method can be selected from 1-methyl-2-pyrrolidinone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide, ethers such as diglyme and dioxane, hexamethylphosphoramide, acetone, nitromethane and nitrobenzene, as well as halogenated hydrocarbons such as methylene chloride. Preferred solvents are 1-methyl-2-pyrrolidinone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, methylene chloride and dimethylformamide. It is most preferable to use as the races/P> In a preferred variant of the proposed method as a 3-sulfonyloxy use 3-[(persulfonic)oxy]cefem, as organostannic-R1tributylstannyl, where R1means2-6alkenyl, as the palladium catalyst is a palladium (II) acetate or Tris(dibenzylideneacetone)-dipalladium (0); the reaction mix is carried out in an environment of 1-methyl-2-pyrrolidinone or methylene chloride without the addition of phosphine ligands and halides of metals.

The proposed method comprising catalyzed by palladium the reaction mix 3-sulfonyloxy with organotitanium, preferably, in particular, to use it to get cefprozil. Used for the synthesis of cefprozil original standan, Z-1-propyltriethoxysilane, can be obtained from CIS-1-bromopropene. Described below are developed effective way of obtaining pure (> 99; O)CIS-isomer of 1-bromopropane.

Obtain CIS-1-bromopropene.

In a flask with a capacity of 500 ml equipped with a stirrer, thermometer and addition funnel, was loaded crotonic acid (51,68 g to 0.6 mol, Aldrich) and 320 ml of heptane. The mixture was heated on a water bath until the reaction temperature 30oC in a protective atmosphere of dry nitrogen, and then add the using a cold water bath temperature 30oC. for 4-5 min after the addition of bromine was crystallization of the resulting product, Erythro-2,3-dibromsalan acid. To maintain the reaction temperature is about 34oWith the flask cooled in a water bath. After that, the mixture was allowed to cool to ambient temperature, stirred for another 16 h and cooled in an ice-water bath for 30 minutes Colorless crystals were sucked out on a filter, washed twice with heptane portions of 75 ml, and dried under vacuum to constant weight at ambient temperature. The result obtained 130 g (88%) of Erythro-2,3-dibromsalan acid so pl. 87-89oC. In a 2-l flask equipped with stirrer, thermometer and reflux condenser with mounted on it berroteran with mineral oil, downloaded 717,5 ml (3,71 mole, 4.13 equivalent) 89% of triethylamine (Aldrich). Under vigorous stirring to the flask was added in ten portions at intervals of 5 min 221,33 g (about 0.90 mole) of Erythro-2,3-dibromsalan acid. In the process of adding happened allocation of gas through the bubbler propulsively bubbles) and was observed warming the mixture to 40oC. the Reaction mixture was stirred for 3.4 hours at ambient temperature, then was heated to 40oC and cooled to ambient temperature and added to it 321 ml of water. The solid precipitate was washed and dissolved, after which the flask was added 230 ml of concentrated HCl (Fisher), maintaining a reaction temperature of 0oC. When the Department of the lower phase and the separation funnel was received 82,15 g (75%) of the crude CIS-1-bromopropene. The aqueous phase was retained for the extraction from it of triethylamine.

The crude product is washed with an equal volume of a saturated solution of NaHCO3and distilled at atmospheric pressure, resulting in the pure CIS-isomer of 1-bromopropane in the form of a colourless liquid. So Kip. 59-60oC.

An acidic aqueous phase was cooled to 0-5oC and added to it with vigorous stirring 750 ml of 25% aqueous solution of NaCH. After separation in a separating funnel, the upper phase was quantitatively extracted triethylamine.

The compounds of formula I in which Q means carboxyaniline group known 7-allmilitarynews antibiotics are antibiotics that can be used for the treatment of infectious diseases caused by bacteria and other sensitive microorganisms. However, these antibiotics do not constitute the object of the invention, the object of which is the way and intermediates.

Those sedimentogenesis-antibiotics of the formula I by acylation or removal of first protective group and then acylation, carried out in a known manner.

The following examples illustrate various 3-R1-protected ceph-3-volumes of the formula I offered by way of the respective above-mentioned 3-sulfonyloxy-3-volumes. These examples, however, in no way limit the scope of the invention.

Example 1. Diphenylmethyl-7-phenoxyacetamide-3 [(4-nitrophenylacetylene] -3-cefem-4-carboxylate.

The solution 0,516 g (0,001 mol) diphenylmethyl-7-phenoxyacetamide-3-hydroxy-3-cefem-4-carboxylate in 5 ml of dry tetrahydrofuran was cooled to 0oC in nitrogen atmosphere, then added to it 0,040 g (0,001 mol) of sodium hydride (as a 60% solution in mineral oil), resulting in evolution of hydrogen. The reaction mixture was stirred for 5 min at 0oC and added to it 0,221 g (about 0.001 mole) of 4-nitrobenzenesulfonamide, was stirred for 1 h at 0oC for 19 h at room temperature. The solvent was then removed under reduced pressure and the residue was dissolved in 30 ml of ethyl acetate. The resulting solution was washed three times with water and the organic phase was concentrated in vacuum, obtaining the foamy residue. This residue was subjected to purification using chromatogr H-NMR (DCl3, 360 MHz): 8,15 (d, 2H); 7.7 (d, 2H); between 7.4 to 6.9 (m, N); 6,72 (s, 1H); 5,95 (LW.d, 1H); 5,3 (d, IH); 4,55 (s, 2H); 3.9 to (d, 1H); to 3.58 (d, 1H).

Example 2. Diphenylmethyl-7-phenoxyacetamide-3-(Z-1-propenyl)-3-cefem-4-carboxylate.

To a mixture of 1.75 (0,0025 mole) of the product in accordance with example 1 of 1.03 g (0,003125 mole) Z-1-propenyl-tri-n-butylstannane and 0.06 g (0,00025 mole) of 4-nitrobenzenesulfonamide and 17.5 ml of 1-methyl-2-pyrrolidinone at room temperature under nitrogen atmosphere was added 0.06 g (0,00025 mole) of palladium (II) acetate. The reaction mixture was stirred for 19 h at room temperature, then diluting 125 ml ethyl acetate and the organic phase is washed three times with water. An ethyl acetate solution was treated with charcoal, which was then filtered on brownmillerite. The solvent was removed under reduced pressure, and the residue was filtered through a layer of silica gel with 50% ethyl acetate in n-hexane. The crude product is recrystallized from 2-propanol, resulting in the 1,031 g (76%) of target compound.

The results of the analysis1H-NMR (DCl3, 360 MHz) d between 7.4 to 6.8 (m, 17H), or 6.1 (broad d, 1H); 5,85 (LW.d, 1H); of 5.55 (m, 1H); of 5.05 (d, 1H); 4,58 (s, 2H); 3.43 points (d, 1H); of 3.25 (d, 1H).

Example 3. Diphenylmethyl-7-phenoxyacetamide-3-(persulfonic)hydroxy-3-cefem-4-carboxylate.

A solution of 78oC in an inert atmosphere was added thereto dropwise over 2 min N, N-diisopropylethylamine (0,74 ml, 4.2 mmole, 1,1-equivalent). The resulting plenarily the solution was stirred for 5 min and then processed persulphate anhydride (0,77 g, 4.2 mmole, 1.1 equivalent). The reaction mixture was stirred for 30 min and then stopped the reaction by adding to a mixture of water (10 ml). After heating the reaction mixture to ambient temperature, the organic phase was dried over magnesium sulfate and filtered the solution through a thin layer of silica gel. The silica gel was washed with ethyl acetate (10 ml) and the combined organic fractions were concentrated, resulting in the pale yellow foamy mass. The crude product is recrystallized from diethyl ether and as a result was obtained 2.2 g (96%) of target compound as white needle crystals.

So pl. 131-132oC (decomposition).

The results of the analysis.

1H-NMR (CDCl3, 360 MHz); d 7,42-7,24 (complexes m, 13H); 7,03 (apparent t, 2H); 6.90 to (d, 2H, J 7.9 Hz); 5,97 (LW. d, 1H, J 5,0, 9,2 Hz); between 6.08 (d, 1H, J 5.0 Hz); 4,55 (s, 2H); 3,83 (A of AB, 1H, J 18.5 Hz); 3,51 (of AB, 1H, J 18.5 Hz).

13C NMR (90,5 MHz, CDCl3): d 168,63; 164,26; 157,62; 156,73; 139,94; 138,46; 138,28; 129,8

C28H23FN2O8S2< / BR>
Calculated C 56,17; N A 3.87; N 4,68.

Found, 55,88; N. Of 3.94; N 4,56.

Example 4. Diphenylmethyl-7-phenoxyacetamide-3-vinyl-3-cefem-4-carboxylate.

A solution of the palladium (II) acetate (3.6 mg, 0,0165 mmole, 0.1 equivalent) in 1-methyl-2-pyrrolidinone (2 ml) was treated with vinyl-tri-n-butylstannane (58,4 ml, 0.2 mmole, 1.2 equivalents) in an inert atmosphere and stirred the mixture for 3 minutes Resulting dark suspension was then processed diphenylmethyl-7-phenoxyacetamide-3-[(persulfonic)oxy] -3-cefem-4-carboxylate (100.0 mg, 0.16 mmole, 1.0 euivalent) and the reaction mixture was stirred for 10 minutes Then it was diluted with etiracetam and three times washed with water portions of 20 ml. Organic fraction was dried over magnesium sulfate and concentrated. The crude brown residue was subjected to purification via flash chromatography on silica gel (W. R. Grace, 951W), using first dichloromethane (50 ml) to remove the rest of stannane, and then 1% ethyl acetate in dichloromethane (75 ml). After concentration was received 74,8 mg (85%) of target compound in a solid white color.

The results of the analysis.

1H NMR (360 MHz, CDCl3: d 7,42-of 7.23) integrated. m, 14,55 (s, 2H); 3,62 (a of AB, 1H, J of 17.7 Hz); 3.46 in (of AB, 1H, J of 17.7 Hz).13C NMR (90,5 MHz, CDCl3): d 168,66; 164,19; 161,00; 156,82; 139,28; 139,01; 131,79; 129,77; 128,51; 128,39; 128,16; 128,04; 127,72; 127,54; 127,01; 126,48; 122,32; 118,07; 114,69; 79,37; 67,01; 58,47; 57,27; 24,09.

Example 5. Diphenylmethyl-7-phenoxyacetamide-3-(Z-1-propenyl)-3-cefem-4-carboxylate.

A solution of palladium (II) acetate (3.6 mg, 0.016 mmole, 0.1 equivalent) in dichloromethane (2 ml) was treated with Z-1-propenyl-tri-n-butylstannane (66,2 mg, 0.2 mmole, 1.2 equivalents) in an inert atmosphere and stirred the mixture for 3 minutes Resulting dark suspension was processed and then added one reception diphenylmethyl-7-phenoxyacetamide-3-[(persulfonic)oxy] -3-cefem-4-carboxylate (100.0 mg, 0.16 mmole, 1.0 equivalent) and the reaction mixture was stirred for 10 minutes Then it was diluted with dichloromethane and washed with 10 ml water. The organic fraction was dried over magnesium sulfate and subjected to purification via flash chromatography on silica gel (W. R. Grace, 951W), using first dichloromethane (50 ml) to remove traces of stannane, and then 10% ethyl acetate in dichloromethane (50 ml). After concentration was received 80.4 mg (89%) of target compound as a pale yellow solid, which was recrystallized from isopropyl alcohol. In achiev>/P>1H NMR (360 MHz, CDCl3): d 7,41-6,90 (the middle. m, 17H); 6,10 (d, 1H, J 11.7 Hz); 5,90 (LW, d, J 4,5, or 9.8 Hz); 5.56mm (m, 1H); 5,07 (d, 1H, J 4.5 Hz); 4,58 (s, 2H); 3,47 (A of AB, 1H, J 17.5 Hz); 3,28 (Il AB, 1H, J 17.5 Hz); 1.41 for (DV, d, 3H, J of 1.7 and 7.1 Hz).

13C NMR (90,5 MHz, CDCl3): d 169,63; 164,28; 161,28; 156,83; 139.42; 139,10; 130,33; 130,33; 129,80; 129,74; 128,45; 128,28; 128,08; 127,79; 127,81; 127,18; 125,88; 122,37; 114,74; 78,99; 67,06; 58,45; 57,55; 28,50.

Example 6. Diphenylmethyl-7-phenoxyacetamide-3-[(4-brompheniramine)oxy] -3-cefem-4-carboxylate.

Specified target compound was obtained by modification of the method described in U.S. patent N 3985737. A solution of 0.51 g (0,001 mol) diphenylmethyl-7-phenoxyacetamide-3-hydroxy-3-cefem-4-carboxylate in 5 ml of acetonitrile was cooled to 0oC in nitrogen atmosphere and added to it 0,030 g (0,001 mol) of sodium hydride (80% solution in mineral oil), resulting in evolution of hydrogen. The reaction mixture was stirred at 0oC for 5 min and added to it 0,229 g (0,009 mole) of 4-bromobenzaldehyde. The cooling bath was removed and the reaction mixture was stirred at room temperature for 19 hours and Then it was filtered and the filtrate was treated with charcoal. The angle was filtered and then the solvent was removed, receiving the remainder in the form of foam, which per the analysis.

1H NMR (DCl3, 360 MHz): d 7.5 (d, 2H); 7,4 (d, 2BUT); 7,4-609 (m, N); 6,79 (s, 1H); 5,9 (LW. d, 1H); 5,1 (d, 1H); 4,55 (s, 2H); of 3.85 (d, 1H); 3,5 (d, 1H).

Example 7. Diphenylmethyl-7-phenoxyacetamide-3-(z-1-propenyl)-3-cefem-4-carboxylate.

To the mixture 0,184 g (0,00025 mole) of the product in accordance with example 6, 0,103 g (0,0003215 mole) Z-1-propenyl-tri-n-butylstannane and 0,0064 g (0,000025 mole) of 4-bromobenzaldehyde 2.5 ml of 1-methyl-2-pyrrolidinone in nitrogen atmosphere, at room temperature, was added 0,006 grams (0,000025 mole) of palladium (II) acetate. The reaction mixture was stirred at room temperature for 20 hours On the chromatogram high-performance liquid chromatography of the reaction mixture was observed peak of the target compounds with the same retention time as the retention time identical sample of the target compounds. The area of this peak was equal to 21.2%

Example 8. Diphenylmethyl-7-phenoxyacetamide-3-(z-1-propenyl)-3-cefem-4-carboxylate, obtained through Tris(dibenzylideneacetone)dipalladium ().

A solution of Tris(dibenzylideneacetone)diplegia (14.6 mg, 0.016 mmole, 0.1 equivalent) in dichloromethane (2 ml) or 1-methyl-2-pyrrolidinone (2 ml) was treated with Z-1-propenyl-tri-n-butylstannane (66,2 mg, 0.2 mmole, 1.2 equivalent) in an inert atmospherefor)oxy]-3-cefem-4-carboxylate (100.0 mg, 0.16 mmole, 1.0 equivalent). The reaction was controlled by high-performance liquid chromatography. When used as a solvent of dichloromethane, the reaction was ended after 3 h in the case of 1-methyl-2-pyrrolidinone duration it was 8 o'clock the yield of the target product, defined by high-performance liquid chromatography was more than 98% Identity obtained using both solvents products with the target compound was confirmed by NMR at 360 MHz.

Example 9. Getting diphenylmethyl-7-phenoxyacetamide-3-(Z-1-propenyl) -3-cefem-4-carboxylate via Tris(dibenzylideneacetone)dipalladium ().

To the mixture 0,175 g (0,00025 mole) of the product in accordance with example 1 0,099 g (0,0003 mole) Z-1-propenyl-tri-n-butylstannane in 1.0 ml of 1-methyl-2-pyrrolidinone in nitrogen atmosphere, at room temperature, was added 0,014 g (0,000025 mole) of Tris(dibenzylideneacetone)diplegia (About). The reaction mixture was stirred at room temperature for 17 h, then diluted it with ethyl acetate and the organic phase is twice washed with water. An ethyl acetate solution was treated with charcoal, which was then filtered, passing the mixture through a layer of armor is the site using chromatography on silica gel. The result has been to 0.060 g (44%) of target compound, the identity of which was confirmed by NMR.

Example 10. Tertbutyl-7-(benzyloxycarbonylamino)-3-persulfonic-1-carb(1 detya)-3-cefem-4-carboxylate.

1.35 M solution persulfonic anhydride in methylene chloride (665 μl, 0,906 mmole) was added dropwise to a stirred, cooled in a bath with a mixture of dry ice and acetone to a solution tertbutyl-7-(benzyloxycarbonylamino)-3-hydroxy-1-carb(1 detya(-3-cefem-4-carboxylate (158 μl, 0,906 mmole) in methylene chloride (5 ml). The solution was stirred at -78oC for 0.25 h, then the cooling bath was removed and continued to stir at ambient temperature for 0.25 hour. The solution is then washed three times with water and dried over sodium sulfate. After removal of solvent in vacuo received a viscous resin, which was subjected to purification using chromatography on SiO2(20 g), using as eluent a mixture of methylene chloride and ethyl acetate in the ratio 95:5. As a result received 139 mg (yield 30%) of target compound in the form of a viscous resin, which was recrystallized from a mixture of ethyl acetate and hexane, obtaining colorless crystals (56 mg) with so pl. 118oC (decomposition),65 (m, 2H); 2.13 in (m, 1H); 1,68 (m, 1H); 1,53 (s, N).

Mass spectrum: (positive ion FA, N OVA) m/z 471 (M+1).

1. The method of obtaining the cephalosporin antibiotics of the formula I

< / BR>
where P is hydrogen, tert-bucilina or diphenylmethylene carboxyamide group;

Q is hydrogen, phenoxyacetyl or benzyloxycarbonyl aminosidine group;

Z is sulfur or methylene;

R1C2C3alkenyl,

by reacting 9-sulfonylacetanilide derived cafema with organotitanium formula

R1Sn(R2)3,

where R1has the specified values;

R2lower alkyl,

in the environment aprotic solvent in the presence as catalyst compounds of Pd (II) or Pd (0) in an amount of 1 to 10 mol. per 3-sulfonylacetanilide derived cafema, characterized in that the quality of the derived 3-sulfonylacetanilide derived cafema use the connection formula II

< / BR>
where Q and P have the above meanings;

Z persulfonic, 4-nitrobenzenesulfonate and 4 bromophenylacetonitrile.

2. The method according to p. 1, characterized in that compounds of Pd (II) using palladium (II) acetate.

3. The method according to p. 1, wherein tanakam:

21.11.89 when Z is sulfur or methylene group, Q is hydrogen, phenoxyacetyl group, P is hydrogen, diphenylmethylene group;

31.10.90 when Z is sulfur or methylene group, Q benzyloxycarbonyl group, P-tert-bucilina group.

 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): wherein R1 represents para-nitrobenzyl or allyl; X represents halogen atom. Method involves: (1) interaction of compound of the formula (IVa): wherein R1 represents para-nitrobenzyl or allyl, and R2 represents benzyl or substituted benzyl with P(OR3)3 in a solvent medium to yield compound of the formula (III): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl; R3 represents (C1-C6)-alkyl and (2) the following heating compound of the formula (III) in a solvent in the presence of LiCl and organic soluble base to form compound of the formula (II): wherein R1 represents para-nitrobenzyl or allyl; R2 represents benzyl or substituted benzyl, and (3) interaction of compound of the formula (II) with R4-OH and PX5 to form compounds of the formula (I) that is an intermediate compound in synthesis of cephalosporin.

EFFECT: improved method of synthesis.

14 cl, 5 ex

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