SU500754A3 - The method of obtaining the 7-substituted aminodesacetoxycephalosporan derivatives - Google Patents

Description

fi3i:; 6p, rTtH; t: - Qr;) Oi:.: iJTcg to gluesob 1O ,. iipoii3BOi; 4; A cef1 OsG1Orina from (; yjiiil:) K4 ::, ij, vj; -. lietH-ui.:-; HHia,, | sgge1-: SLOSOBAO ;; u - ini D - Cefalo ™ .f:; i p ;; tsch) O; n, ANI WITH PEGPoksiYYY PROIE siu / .i:;, ;; (; -. a;.,: 1-) NOVRI i iSU ;; n li n / .i is KiicnOH h :: rede, (.: -; 1.1-ЧГ:; ПЬЬ1 ГГ1 ;. f: JiOCO6a PASSED T |; y; 1, Og: -:; -; {usc п-1К Ptg.tzvodnyh Cephalo-ClMJ.; - Mi;: j L.:-: rBo6Oiii OU :: -G1Pi): CH11 1O 1 GruP- POP y ;-); 10): C;,: GI K Tari, dl 1К. :: 1УЧНИНЫ укизай;;.: С (к. д;: и} 5 и iiCAoaribiu sulfoxide (;, -Г:; а- 1. ..Ii .-: i «iai;: uni.i;:. iUOEOfl knslott Peoblid P.1: h, i-iiytibiUUillon-r:;:; v; .GDEL II-uKii: N:, fl srepiiy / ViuiiiJCHHjivJbm RDHK; and v; i4ijjaviu:; nopu OIii; ii: inif: i ..: .vit -. (a col g: g is deleted (JJi.oO:, - i.:;. Kav ijarf.:; K; i; v: i. 1Д,) И; 1ОваниаМв 3 ii ..; i: .i .-. V ,, c; fi: 0 1 SLOPE OF H - AMINOiiOOii-M :;. ./.- ;: (:;,; H: Gs; Yugl. KYKpgtoOK L UiipyRTCa D; f-; LO., Ksida penicillanic acids, in which I will avoid dec. arboxylation of sulfoxmda nenccyldonoic acid, with you :: o-sym Bichoce - O, HiiiOcpencTBt-HUo 7-oaMf-uibHHi: ix aCPSO-lezapethoxycephalosporin irii.RODES of the general formula i / -vs J-NXI with a nitrogen atom, a carbon or Sulfur carbon, which may be an emestape group; D1., Inert under the reaction conditions; H; j hydrogen, LOW ALKILNLP (} / ennl (R. from the high) alkyl, or R and I are in the bridge with the atom, nitrogen, to:) D ()) th oi aii Pr1 COH; -P.KYOYY, P dUdSTaYaLi G-, 1 p DIKLICOS:,; yu rjtViniy, HflTlpHSiOp С-. KiNIIMID,. f- | -alt1Md, ok (: azolidem1 yl ndi imidizole; w-, .HH; ibHyt6 group, which may have one or more substituents that are affected by the reaction; whether their salts, for example, sodium, potassium, calcium, or The method consists in the fact that the soup foxide of “b-mixed aminopenicillary acids of the general formula O J) N — CH — CH cCCH 1) u 1 j and R p have the indicated values are reacted with a compound of the general formula — the same or different each represents a n, from {and 7 "alkyl group, cycloalkyl radical with 5-8 carbon atoms, a phenylalkyl group with 1 to 2 carbon atoms in the alkyl radical, lower alkoxy, lower alkylthio or phenoxygroup? Pip or phenylalkoxy group / with 1 to 2 carbon atoms in the alkoxy; 1-radical, atom. - halo or 6-substituted aminopenicillanyl sulfoxide-3-carbonyloxy group or a 7-substituted aminodesacetoxycephalosporoyl-4-carbonyloxy group; or R and I 4 together represent the remainder of the ring, on (m, it is boron aluminum or phosphorus M, the same or different

And represent each lower alkyl, cycloalkyl with 5-8 carbon atoms, phenyl, phenylalkyl with 1-2 carbon atoms in the alkyl radical, and the lowest alko / UN)

) R, 3:

O xy, izishiy alkylthio or phenoxy, or phenylalkoxy group with 1-2 carbon atoms in the alkoxy radical, halogen atom or 6-substituted aminopenicillinyl sulfoxide-3-carbonyloxy group or 7-substituted amino-deacetoxycephalosporo-4-carbonyloxy group; or R k and R and together they represent a co5 including or Rr ring residue, (or 4g) and 1 together represent an oxygen atom or a sulfur atom, and M is silicon, sulfur, germanium or tin, or a carbon atom, if R, in Rg together are oxygen or sulfur; same or different. each represents a halogen atom or a lower alkylp, cycloalkyl with 5-8 carbon atoms, phenyl, phenylalkyl with 1-2 carbon atoms in the alkyl radical, lower alkoxy, lower alkylthio or phenoxy, phenylalkoxy with lv or 2 carbon atoms in the alkoxy radical , b-substituted aminocenylanilg-sulfoxide-3-carbonyloxy group, or 7-per-mezzenous and inodezacetoxy hercephalosporoyl 4-carbonyloxy group; same or different. each is a halogen atom, a 6-substituted aminopenicillanyl-sulfoxide-3-carbonyloxy, or a 7-substituted amino-deacetoxycephaloxy-sponyl-4-carbonyloxy group; or R and R together represent a ring residue, including M or together represent an oxygen (O) or sulfur atom), and Mn is phosphorus or vol 4ram; о R. „- lower alkyl, cycloalkyl with 5 carbon atoms, phenyl, or phenyl-alkyl, with 1–2 carbon atoms in the alkyl radical, lower alkoxy, lower alkylthio, phenoxy, or phenylalkoxy c. 1-2 carbon atoms in the alkoxy radical, M. - a sulfur atom; X is an anhydride group, for example, a halogen atom; followed by heating the resulting anhydride of the general formula Q

-de R, and H

. nmeut indicated sign

group CXXJR ,,, prepares to be a

rpymiy acid acids, where R, j has S values B - M. wn IX M -Md have in which the following values. In a dry inert organic solution jj Tejie at a temperature of not less than 160 ° C. equipment capable of causing - h rasipueiiib penamy ka & tda to D -pv femogo ring in the presence of a short-term compound, able to quickly remove the formed water and form cree hydrolysis of neural or ocHOBHbse products and then. 1 hydro; by lysing the obtained compound of general form., the mules X r – f 0 - / - 1 COOR where R; , R o and CO. , 2 have an indication of l- - I-JP (14. jH.i here applies to flni and chkogl- and alkylthio groups, coa 1 1.1,, 1 --- tj, g-atoms X; fenkl p .- 1 J41S parts in R - - p, j, 1g F, ,, 1 (1th PROTIEVOD -; BUT. OD bo.pep substituents in the form of atoms, naiigo alkyl, iiM ::: ii) ero alkox and yn (iuiaiJUT) apkilamia .

. The preferred coe / muennfi formula of unitary enterprise and CP are compounds when the rpytma - COOR is represented by

fight acid anhydride, where R) is the radius R.

 cal formula UE, where R

nmenet indicated by the value, M is phosphorus, aluminum or boron, or RjT of the formula X, where Yak Pu has the value, and M crackles, germanium or tin, or Р wdО {ш1И Р) n Р together is an oxygen atom (О), Mg1 is carbon; it is better that 1 be a plggl group. 6, If M is silicon, then it is better that R represents the silyl radical of the formula (X., X, X2) 5Si, where X. is Xd ,. 1L11 are rare, cary and represents a halogen atom, a lower alkyl cleoxy group or a phenylalkyl group with 1-2 carbon atoms in an alkyl radical, a cycloalkyl group with 5-8 carbon atoms or 6 substituted aminopenshylyl sulfoxide-3 - carbonypoxy or 7 3aMeiueiniyio amipod.zacetoxycephalosporan; l - 4-carboxyloxy, and X ..-- X „. if oai are not halide or alkyl, they are mixed with one or more haloids or lower alkyl, lower alkoxy or di (lower) alkylamino. A particularly preferred glutinous radical is the three (lower) alkylslylene group, especially the I trimethylsllyl group. To protect the carboxyl function of the starting materials of the general form. Y Y P, are the reagents of the general formulas Ш-У,. in which there are free bonds at the M atom on the desiccated by the anhydride group, luuie by the T atom,.,. haloqd These reagents and reactions i. sulfox and up to 6 m for the other place and i ncc nitsi la paw kksloty provides am; 1H1 hydrogen, which is combined with actqui-. a ruyushaya group (for example, a galondl atom) of the reagent, forming an acid. This knot serves as an acid for the expansion of the ring. Examples of compounds that are common for the group of the general formula U are .Mrv substances that can be paccMfTri / iirsi 11-. as, derivatives of acids,) IM- (1 BCi ,; BBf-, AiCl, AILV. ,, ,, BCl ,, 4H)., iKM, 7 (С Hg) AlCl. () MC1, CH PC1, I CHO-PC1 1 X PCI, CH-OOR1 i3 C HgOPCl, PCI. PCI, (,. C HgOPCl. CgHgOPC ClCHgCH CH OPCl, ClCH CHCCDCH OPCl, CH “CH (CHCH OCH1. CH“ OCH CH “O ol.f ,, iC. And S PC1”. 25JL Examples of compounds containing coarse Formula 1U, which can also be considered as derivatives of acids, can serve such substances as SOS. CSC1, C "H OSOVG, 2 25 SNOSOC1. C" N OSOVG, g and C, H CH OSOS1, CH-SOY, BfCOCOB about about 23 C.., C1, .. SSOVG, C1 "SOS1, oo CH, SOS1. CH ,, - C-OS about. CH 2. C H-COBr", f. about CH,. CCOCl, , o-D o Sici, C,., o o o h CH OSi Cl CH Sici CH OSiC 33 33 2 5 D CgHgPCl. OStCl SI of the CH OSi C1 axis 500754 l, .. Clg. (Cl, (C,) Qi Cl. (CH,) & (Ci, () 281 Clg, (, (CHQ) .QiCi, / Sici. SND / CH, Sici. (. () .IQt, () i Cl, (ClCH2CH20) 2Si Cl . (CH3 CH (Cl) CH20) 281 Cl, Cl. () H81Cl. ), jSi Cl. (CHd) z51 Cl. {CHg) Bt. () SiCl, 6 53 CH CH, SiCl CHDO Sici, cHg -. Sici, 3 gici, ci (cH CH o) S ici., (CHNCH ( C1) CH20) S SI Cl. 2 OHVG SnCl, SnBr, SOClg, Opr. 3 OCl., And CgHgOSOCl. In addition to the silicon-containing reagents used to protect the carboxylic acid reagents, use the protection of the carooxyl function of the starting material. and other reagents to remove the water formed during the expansion of the ring. Examples of reagents, containing a formula of formula Y, can be used for the production of phosphoric acid, Ha. p, PF3r, POC.L (С ,, Н, .0)., с and РОС 1., о, 2., optx: .i2. ; , .oros1 „.sn„ axes, cht it Sedo S. CgH gOPOC 1 ,, p P (X, 12 and Boli | ram content of compounds, I8lrimer Bfj ..

Connect and. , soda {.-., the stingy groups are abundant with U1, is Yugsk proivaroids. With acids {For example .. H. O S O C1, y2.

, CH ,,

 and, SN ./) AIA1.

Of the best protective reagents, it is more suitable to use three-halogenated compounds, a combined phosphorus compound, phosphorus compounds, three (lower) alkyl halondanes, di (lower, wider) alkyl diges O 4 Shsil 1 (carbohydrates, carboxylic acids, etc.). A content of a compound, for example, a three-bromide is a phosphorus and a silicon, a variety of other materials, such as three (Ni), and a yelbromilane, for example, triytilbromosilan, etc. ,

For example, Si6is- (trnmetsh1snlal) - shtyak.1yd

The best molecular ratio of the protective reagents of the carboxyl groups relative to su'foxy in 6 -mixed aminopenicillanic acid is 0, 25--4 cv. reagent, the advantage of 0.33-1 eq. By the term one equivalent is meant a colichsmithic theoretically required reagent

sewn up carboxyl group in 1 mole

sulfoxide benzyl vniik lanovoy acid.

Along the groups of the R f.-ioryr alkanoyl group with a 2O carbon 5) single AND aiowia of the nitrogen to which they are attached may represent a heterocyclic group (for example, a phthalmicide).

your group; Amy, represented by-singers-p.) Chi)

with 5e nzi loks ij n arba m oi l, fi nil tata m id,

phenoxy thiamide, 3-acetylureide, (3.5. 7-dichlorosypch.il) -amine, 2 phenoxy 1ropio 1.-.

5a CP-d, 2-phenox ibir imid, knox ife ni. I acetamide, 5 methyl 3 phenyl 4-isoxazolcar; boxamkd, 5 ... methyl-.3- (o-hlopfev and n)

-methyl.-3 (2,. Dix. Solkaroksemid.

.-chlorophenyl) .4 ™ nzoxazol carboxes; 1, 2, (G-diethoxyenzamide, 2 ethoxy- "1-naphtamide, (o.aminobenzamide) -phenylacetamide-N-methyl, 2- (2-iiMHHO-5-nitrobepzam1ts). .41 phenylamine 4 -methyl, N-benzylformamide, H-methyl-2-fanox) 1aigmpmide, H - Meg L-2- | benylacetamide, Vj-eti.n..2 j ..- 4 "nilayamide,. N isobuil-2, Pkg; ii aietamid, 2-bonzylmden-4,5 dioxo.3- (zksa ZOLIDINIL, 2 ™ BUTYL Succy1P-5MKD, 2, 2-.ZYM1: til-o-oke 0-4 -4 yl midaz ol i; pi and l4iTa l imide, 0 (α-amino, C1 - (X-cyclo-xa- / ..- dienyl) -acetamide, C (- "MHH t -HHJsaHtTam0d, C-amino-2-thienyl azg: cham1.a, 2- -the acidyl, amide, 3-thieyl .: pet; 1 1 .. 2-furcacetamide, 4- CHLO 1fen1,1l11 .-; tlm1sh, 3-bromphong paietamide, 3-NITEK ("L-iylactamide. 4 NKTrofe ylacetamide, 3-T if1 srglgptl phenylacetamide, 4 - cya1f li.1c;), and, 4-methylthioO. | «-1 Nlapetamide, i 1" iianian T amide, 2-byfluosulfiraniltstamipi, for example 4- | enil (iniouiHii).: I.-1, finoxi (lower) alkano l, folyl (msouinit) alknloxycarbonyl, (lower) alkaioipamproxy, (lower) alkoxy) alkanoiip, salicyl, optionally mixed with one or two halogen atoms, fbnox15 | enyl (lower) alkanoyl, izoylcarbonyl; , phenyl- 0 (-amino (lower) alkanoyl, gneiyl- or furyl (lower) alkanoyl, thie-NILE-: mk furyl-01 -amino (nszHIG alkanoyl, phenylthio (lower) alkanoyl, 2.bonzofuranyl (lower) alkanoyl, benzosulfonyl, or 1-piperidinsulfonyl. The phenyl and heterocyclic radicals of such groups can have substitutions, for example, halogen atoms and lower alkyl, closed carboxylic, phenyl (lower) alkoxy. substituted amino, ntro, cyan, trifluoromethyl and methylthio groups. R g can be, for example. ep, a hydrogen atom, or a methyl, ethyl, isobutyl or benzyl group. BtviecTe from that atom. Namid benzalsulfonylaminoacetamide, n f. -brambenzenesulfenamide and 1-pipericinsulfonamide. The best P. R. N - groups are phenylacetamide and phenoxyacetamide. Eeln need. ; to receive deacetoxycvfalo; spore derivative of general formula I,; Hz.E. R is (D-aminophenylacetic-; "m .: 1W | then the free group is appropriate;; HS; the original sulfoxide-in-substituted; ammoniaopenipylamine characteristics of general formula II must be protected during the expansion of the ring of Uii, for example, by the benyloxycarbonyl group which can then be easily removed and form a free amino group. The free carboxylic group in the 6-ac side chain can be protected, for example, by esterification, better by forming 1 -hydrous acid. acid anhydride of the carboxyl group attached to the thiazolidine ring; Silicon-containing compounds are required: .u.i to remove water formed during expansion of the penamic structure. Compounds of the general formulas are preferred.

X

(Xiil)

Xg-Si-N c-gi-Xg

I I I

X;

t

J

(x-iv)

-Si-N- with N-3i-Xg Xsx

Y. S

(LU)

X, St-N-C - X. -i I I

X 4

(xyiy

Si-N-P-O

h /

at

X

w / c .. w -X

(XU11)

Si-MI I

3% 50075

 /four

Si-N

(XXII) I

X

fO

(xxjiO

N

h

/

NH

where have the indicated meanings

l.o

In addition, these symbols represent: 6-substituted aminopenicillanyl sulfoxide-3-carbonyloxy or 7-substituted aminod9-acetoxycephalosporoyl-4-carbonyloxy groups,

, X.-X "each separately represent

with (. hydrogen or hydrocarbon fuppa without aliphatic non-saturation with 1-8 carbon atoms, 1 or X ,, and X together

I with atoms of Naota, to KO-ropONiy they are attached-N-C-W-Si-X, (XU111) i-N-С - OX,, X О O X, Xg Si. -Si - X. nonsens. ", Form o- or 6-4JieiUiyto gegero; ikk-shchuyu group, which may contain, the top hetero atom in the form of oxygen and nitrogen, provided that X and X „in. 5best contain no more than 18 carbon, and if X is an alkyl group with a tertiary carbon atom, nitrogen, to X - atom H№i X and Xp together with the nitrogen atom to which they are attached, and the carbonyl group complete the 5 or 6-hen heterocyclic group with an ethylene ring of trimethylene g-rupyuy in the ring; I XI and X, -, k-each represents Io Y a hydrocarbon group without an apiphatic O unsaturation (preferably alkyl) with 1-8 carbon atoms; X .., is a hydrogen atom or a hydrocarbon on a group without aliphatic unsaturation with 8 carbon atoms or a group SiCX.j, X, .. .. is an alkyl group with 1-8 ugnerSD UWNH of atom self; In an alkyl group with 3-18 carbon lii-iMi atoms with not less than 3 and no more ujNi 5 carbon aTOiviBMu aroMONi fiOCTa to the carbonyl group to which r | 1 compound; fl J. lUHs 2. Silicon-containing compounds of the general formulas Xlil-XXI can be, for example, N, O-bis-f, three l et ley li l) acetamide, N), O-bio (trimethylsilyl) -tri- fluoroacetamide, M, N bis- (grammethylsnlil) -carbodip MFA, H - trimmethy leu or .g) "acetamide, M" METTiL ™ C - (trimegil; 1. l: yl) acetamide, N. "MSCHIP ™ C" - (trimethylsi tl:) C) Op; amide, C - (t h of methyigam OO 2-. pyrolidene, M (triztilsilil) urea, f, H bis "- (trimetylcyl lil) urea, (tris { ) enylsnyl) “, etipcnrb mat, trimegtil force ul dm etyl pffoksimi /., N-trimeti ..:. sils- Lch. y, 1 methyltriftoran. yy1mide and make-up-> silimnd gmmg, .These KpfJMii} Ffic u; ep Kaiiu- e soo.p. results are given after reactivity with; Iodine neutrinsic C: oed11 Ioni, which are not sjjfuaioT in the course of reactivity or do not interfere with D-desataces (; ntsefalosporoleshvogo product. Kremp 1Y; oyderzhimi compounds of the general formulas XXII and XXiH ARE; ARE; M-Ethyl pi; -ethyl l and /) mi) 1, c - (trimethlks lg /) - diethylamine hexamethyldisyl, hexylmethyl diclotrnipazac and octamethyl, Eotetrasilg): 5nn, These silicon gifts and others. n |: n1 juicy water with organic products,; Preferred creams (1; sodol; any compounds of the general XXl-XXI formulas, the best cremium containing n compounds) enylmi are the N, O-6is- (trimethylsil5) -acetammd and H, M -bis (grimethylsipkp) - urine ( zina (te, compounds; formulas XII and, where X are methyl groups); which can quickly react with water, (The rings that form during paciuirpefiijH, with the formation of neutral compounds, for example, iep hexamide acetyl disiloxane and acetamide or / or acetamide or / or acetamide or acetamide or acetamide, can be reacted with water, for example thus: 1az udega.ch iabejatt-, decomposition of anhydride with water to the skin during the expansion of the ring. Number of KpeMiTi-itopraHiiHetJ KOro Compound ™ Nepi, added to the reaction of the mixture of the mixture, should be so that; to remove the water, formed by peaKunii, c. Also, in order to prepare the cytes Icrypus, to dig free caroxylose rtiynnn in the original cytopropychropycytes, in the same way, the syringes, the cymes, the syringes, the cymes, the gene, and the digesters. , if it comes from (b-zinchenmoy amylope-n-pilln: fuxide. acid; and iipHivsenHvuT KpeMiu-sevoy compound g g;: 1 Xy1.11 °, amount of HC. less than IjS ol -; ee. per 1 mole of sulfo ™ xpi nei "JiUTnj; aHOi: ioiT cyplot, T; I ijji mole tseiozukt G as sililoto TO doirp for carboxy. 1 ;; nd rijyuiibi, about octylyl for absorbing jujube X in:; | L ::, CJ / iuaK;, ecjts, the outcome of the NC is anni / tjiiiAa KnCJTO.-i- Sul; 4 C15.D6-C & A) by the solution of amypopeptpgglppor K; sdt5, then for Udlopp -: apt sweat; 1bet ;; {only 1 mole KGSMNIIO SOI / MPI CPI, RO / MUSHPTELPO KB KB / SUSH SULOXIDE PEN - I11LL; P-; A; p1 - 6Plot 2-4 okr kr; -: Bgio soyo shnepp, Dzholsno primsh h- acids 1, providing ;; 1 pii p9CiiJ, v: peHi e iisisaMncjrotioni iui, which is not ST1LiL1 :: y10GSYA HJvJ PMTT Not : I cracking and containing G soeedipo and MP; added with D leaks; a mixture under the conditions of iieaiiunib V. taak; 111K: lo-a, 1:; tpos g / slab); about MK ;. one; HLO (; ist5 and waterr ::: D ,, V04S - | - fl -sul: .foi;:; s..p1ggr; |; to 1-: hmm: ;; harle KPICJIOT ;. f-; i.-;; ; On: TMlvVXi: I,:.; I L iVi; Y O DIS; ib Ji hydrogen ::; d, :: ldl..t;) ii; .4; .iO: -ii viU; iiaOViiyio, HISRPOZi: yi ::;, PschlSgu'-, t.f; j; .-; i: V:. :: n;:, U:; iyeU-nbie yKcy (vi-ii /: Q, u-Oiiii. O) c;.) O -., syio: yc; o, rpi: j ::. io; .iyKcyonyi4i. / nyKcyoivyjOj forN; paie; iu, .iia .nioKti (.- a.:abi,, tiu x / yur-metChL, sulg;: o; s ;;; a ;; gu, .phuiVC ;;: -: psulsul; loo and kof. I / LIK. lb | „; To lslot, ii.-E;:,: t.;. VH: t. jiiiKPiHO Eyio. ..: - ii Ki; v-jijr -o. Uica.u i-ov; V:;. (ethn.chsulfochp / and vi;: ri3K, P -; - h iiU: nll iii; OiK r 0 gGy Mi UMnnOueii, G: 0: PG: .1P ; 11; n; ::;: LO;) H; 1TC / M: -.: S: i rinVi.tiaSf-iiHKO .Oni / lVi ;; /.,;,: -::}} - i;:, -i; iU: - ::.:.:; i: f-: i.; il / j-iHj; "groups. A strong acid is hydrogen bromide. Acid may be added as such to the reaction mixture. Advantageous acid; mix with a nitrogen-containing base, forming an acid addition salt. Such bases include -aliphatic, cycloaliphatic , aromatic or heterocyclic amines, for example hexamethylenetetra min, aniline, diphenylamine,., N-methylaniline, dimethylaniline pyridine and quinoline, or pyridine or quinoline; substituted by, for example, one or more lower alkyl, aralkyl, I aryl or mono- or di- (lower) alkylamino, e.g. picoline, 2-ethylpyridine, 2-propylpyridine, 2 3-dimethylpyridine, 2,5-dnmeGi pyridine, 2,6-dimethylpyridine, collidines, 2-dimethylaminopyridine, quinoline, isoquinoline, 3-metilizohinodan, as well as pyrazole, imidazole or N-methylimidazole. The best bases are pyridine, substituted pyridines, quinoline, substituted quinolines, imidazole, and substituted imidazoles. It is better to use an excess of: bases with respect to the acid. A complex of an acid and a nitrogen-containing base can be formed in situ in the reaction mixture by initially protecting the starting sulfoxide of 6-substituted aminopenicillanic acid in a dry inert solvent by reacting with an acid radical containing compounds such as a halogen-containing compound, for example, phosphorus chloride, phosphorus chloride, acetylbromide, propionylbromide, trimethylchlorosilane, dimethyldichlorosilane, trimethylbromosilane or triethylbromosilane. The resulting hydrogen halide in this initial stage is preferably bound to the base, since the formation of the acid anhydride proceeds more smoothly and the ring structure of penidillane sulfoxide is very sensitive to the strong acid in the free state. All bases, with the exception of bases with hydroxy groups, iX) Dna, for binding the 5th acid (e.g. potassium carbonate or amino-com- plex of the cyclohexylamine salt of penicillanic acid sulfoxide), but it is better to use nitrogen-containing bases that are soluble in organic (Dissolve Having a pKa of 4–10, Obrnzukchmiis with a gallopdvag genus, the genus may supply or contain a kyglot,}) the passage of torment. to expand the ring with penicillin ulfoxide, the ratios of the substances in the reaction mixture to 1 mol of 6-substituted penis-slanic acid sulfoxide are 0.25-4 moles of acid (preferably 0.33-1 mol), 0.25- 4 eq. a carboxyl group protection reagent (preferably 0.33-1 eq), at least 2 eq. a silicon-containing compound (preferably 3-7 eq.), or, if an acid-nitrogen-containing complex is used, then 0.1-10 moles of the complex (preferably O, 25-4 moles), 0.25-2 equivalents. protective reagent (preferably O, 33-1 eq.) not less than 2 eq. the silicon-containing compound (preferably 3-7 eq.) and more additions of the base itself, e.g. 1-10 moles. The amount of the additional base should increase in direct proportion to the amount of the acid-base complex. By the term one equivalent is meant the number of moles of the protective reagent for the carboxyl group or silyl compound that is theoretically necessary for the reaction with 1 mole of benzylpenicillanic acid. The formation of the acid anhydride and the ring expansion reaction are carried out in a dry inert organic solvent. These include acetonitrile, acetylene , carbon tetrachloride, dimethyl sulfoxide, methyl ethyl ketone, methyl or ethyl isobuty; w; eton, such haloalkanes as 1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1-chloroethane, 1,2,3-trichloropropane , methylene chloride and chloroform. The preferred solvent is dioxane. The process of expansion of the ring can be conducted at 50-16 ° C, preferably 60-13 ° C, more severe at 70-110 ° C. The reaction temperature should be kept below 160 ° C in order to minimize the formation of decomposition products. Typically, the reaction temperature and reaction time are interconnected for the by-product of good yields of deacetoxy-pephalosporane derivatives. Low temperatures require a longer reaction time, and at a higher temperature — more than 10 hours — anyone, HanpHMcv) at 8O, 00, and 11 ° C, the reaction time can be 24, 10, and 6 hours, respectively. On every Nrjii, sous / L) forc syda penitsllaHOBQi acid (for example, sulfoxide ben 17

znippen 1Cyl-gin) use 1-4 mop kggs / k; you are better than bromine hydrogen chloride, 1.5-15 mol-nitrogen-containing base, better than d-picoline, and the amount of base must always exceed the amount of acid, and 2- 4 mole; N 5O-bis- (trimethisilyl) atamide “Rectification is carried out at 80-1 in a dry inert organic solvent, preferably not in diox. .

It is also possible to apply 0: 3.3 1 eq, acetylbromide or sinbromisgy phosphorus, 1.5-15 moles of nitrogen-containing base, better than CX-picoline, for each-mole of penicillanic acid; acid, 1, ...; ole. H, (trnmetilsilkp) -detam yes il.y W, V - bks tvvgmet1shsssh1i) "" acetamida luiKftf - .. bio umetypsi yl urea

At the end of the co-expansion reaction, co .: P. p. D, desacetoxacephalic sporia B5 irod, will be treated in a recipe-juc mixture "; solids and desattaxyephapospores; equ: yu acid as such or in the form of a salt; | l south by conventional methods, for example, astraction and / or crystallization, So BS; l: -, the reaction is carried out in organic; dissolve. le, not miscible with water, then reaction. OHi-jyio mixture after cooling can

/ extracted with water at pH 7%., g; - :: gnym, for example, using dilute 9g-legs of an aqueous solution of caustic Cl4l1, and a.:; ; a solution is washed with an organic solvent, for example, butylagiomatomeLe Desacetoxycephalospore, a new cis; lot / (for example, .7-phenylacetamide production —O PPC its salt can be obtained;

a) by adding an aqueous solution of TxpoTbf by collecting the precipitated deacetoxicase / sporoic acid;

c) by extracting an organic solvent, with a pH below 4.5 and co1gce5gr {gr ;. by the formation of adssgracts to crystalline acid;

c) by the addition of n butanol, water deletion and to: increase of acid of the ki-ih salt; , lots of butanol solution; ,

e) extraction of organic solution.

 -. .,. ,: .-. .

at a pH below 4.5 with the addition of a salt: alkali metal, for example, anetate — mel; “. or a solution of alkali metal salt., for example, potassium 2-ethylhexanoate E n, tsh. for example, triethylamine or cyclohegssipy, in an organic solvent with: ::: gvv.v Io fflM collecting the precipitated alkaline tal salt or acid amine ;,

 e) extrusion with an organic solvent at a pH below 4.5 and precipitated-l dk- -.

acetoxy acetalyuraic acid; ibn; to a poor organic medium, for example; diegilic sffijipa or ng (klOlek (; ipa, if the reaction is carried out in an organic

 a solvent that mixes water with water, tp / v-decacetoxacephalosporneg-rijioHSvodnogo can be distinguished by pouring the mixture into water n adding organic dissolve.h ,. To separate the mixture, you need

 enough water and oranic pacTBOpi-ti- tel. The organic layer is again extracted with water. PH .7t. a-connection of single layers of industrial solvent, T1. with butyl acetate

S

treatment of items under paragraphs a-e discharge; ° distego, exoxidine, or algal acid; or acid; its salt It is also possible to evaporate organic slyup in vacuum, but the orth of the reaction, in the Bodoysme –– –– ke: o: cems solvent and add water, –– bring the pH to 7 organic phase; The Vagusum solution is washed with opygic vevvod and treated in accordance with the usual conditions. The lcecco reaction mixture is also released into a solution of Kislott R water at, i:) H OKojio /. ; in the case of the inter-mingen-i, vyvv; Shuyu lu aptok, siyefaposporg-iOuy kigjOTy P; tshp ;;

Bfcf 1: -d / t dea5 etoksidefyog; gop_pol yoolotglg MOJKsi vary depending on repg-enT .-. In s-f assay-loy react.shi, but usually

 t; -, | -y-С. .UD 45% tJO ОЯЯЬ БО о ЧС: IPU

; : - A: 1 -: - LL; - At the entrance of a "T", take up about 70% J- "JKO 90%.

Cc: hp; 7th 1: g lfox 55Db) bb-aamRgtsepkoy 4M-; ta:; neiUijo; aH03Ou acid. LC} kt; o received, e6tsab: T; oh-i answer the l;:. b-eama- iUJiHHbiJi th, g :: popl gtsil inovo ;. KPLOT oxide: lg 1 slitsch and:; wesgg b; M siozobgl. For & GOI purpose-for-mHyd-dt-yu yminopogtstsiltsnoe protovodvodvodnom obrzbyytByu in inert organic; ;:; g; ohm pastp gogole smii water substances; OLb-dolg; -tag :: “l-pzpy oxygen, ijanpHiof p podi: -; m ttl-iiooo ::: G1T; s; k-th; ii; 4pa; ucoi-j Eodoro-ija 1o; -,; 5eoz: lop.-ь in kolichgggovo, dostptoch-. nooi r, io Oyislsoosh sulfur atom chkgaoo-l / s-o-;

:, GP}, 7 O, SHELF OF OUL.F; 1L: ND

viOKa0 g; -: with zydepyt yz) :: e0kt lopt; -. nd fmysv

: -0: 0: 1THY G.O-tg.dMI, AlGCHLRIDH; G: 1OT1L

chLoglouosads / b flr substituted yla-pgoi oeitsilla john 1;: nsl ;; tk: -; he; but nOlu-T; t ;;; - kitty: lot-; OHV ringing lbstsdy (ogluchim ™ o;; D) re-aaa-ts-tkalno-telno in i-ia8: ii-iOK: -roi is like, oooo / fLoyaw / i.

:, Ol .- VrOOCKifVO ;; re «1П5ЙСО1 ;; erZha :: L-; l

Gkluo. l; l-l; cl &; gb: x esk both zsb; oi1lchot: gth

 // l y / -; 0 Ll P of WATER; AbrE: ;; o ;; LG LSR

o; i, jao. .; iaSeH is. iSero- coltyda: OOr-vi with a bee Example 1, К .1.0,5 g (30 mmol) of sulphonic acid. benzylpenshllinp was sequentially added in succession to 195 ml of lyoxysh, 25 ml (102 mmol), N, O-bis (trimethylsilyl) acetamide, 6 ml. (61 mmol) 0 (picoln and 5.8 M solution of hydrobromnd (X-pixel lil in dichloromethane (5.2 ml, 30 mmol of hydrobromide 01-picoline). In situ a trimethylsilyl derivative of benzylpenicillin sulfoxide was formed. After coagulation the reaction mixture with reverse flow for 6 hours (102 ° C), the reaction mixture is cooled to 20 ° C and poured into 1500. ml of ice water. Then 650 ml of ethyl acetate and 5 O ml of butyl acetate are added and the pH is adjusted to 7 with stirring. , 4 with potassium hydroxide solution. The mixture is allowed to separate, after which the organic layer is separated. The aqueous layer is washed with 30 m ethyl acetate and 50 ml of butyl acetate. The resulting organic layer was combined with the first layer obtained earlier, and this mixture was extracted with 200 ml of a 0.75 M solution of potassium phosphate in water, buffered to pH 7, the extract was added to the main aqueous solution. contains 9.2 g of the potassium salt dZ 7-phenylacetamide-deacetoxycephalosporanic acid, t, e, D -benzyldezacetoxycephalosporin (yield 83%), as determined by microbiological analysis using the microorganism fseheriachca Colt

After 5 ml of butyl acetate was added to the aqueous solution, the mixture was stirred and the pH was adjusted to 2 with 4N sulfuric acid. The mixture was allowed to stand, and the organic layer was separated. The aqueous layer is again extracted with 250 ml of butyl acetate. United butyl acetate extracts

filtered on a water-repellent filter. The aqueous layer, still containing some amount of D-7-phenyl-acetamide-deacetoxycephalosporic acid, is discarded. To the buty-l acetate solution is added with rapid stirring.

2.65 g (27 mmol) of anhydrous finely dispersed acetate. After stirring for 3 hours at room temperature, the wrinkle is filtered off, washed with a small amount of butyl acetate, and dried in vacuum at 30 ° C to obtain 1O, 2 g of D-7-phenylacetamide-de-acetoxycephalosporanic acid potassium salt 85% pure, as shown by microbiological analysis (yield 23.5 mmol,

78%). I (H „0): 262 nm

max 2

(: 175),

1 cm

Structure 11.; dtpe.1 / cd.: 1K.t 1K and PDARs,

Anpiz PMR spectrum: 5 1.94 (S 3); 2.99 (d 1 18 Hz, 1); 3.44 (d 1 18 Hz, 1); 3.62 (S 2); 4.97 (d 1 - 4.5 Hz, 1); 5.58 (d 1 4.5 Hz 1); 7.27 (S 5).

Sodium salt of 2,2-dnmetnl-2-strong-5-sulfonate is used as internal ethanol.

Example 2, a) 1.05 g (3 mmol) of benzylienicillin sulfoxide is added to a mixture of 20 ml of solution 3, O mmol of hydrogen bromide in dioxane, N, O-bis- (trimethylsilyl) acetamide (2.5 ml) 10 mmol ). In Siiu: trimetisyl is formed; il-benzyl penicillin sulfoxide derivative. The reaction mixture is heated at 102 C. The reaction is followed by thin layer chromatography.

After 6 hours, no penicillin sulfoxide remains in the reaction mixture. I take samples of 5 ml each and add it to 35 m in 0.75 M potassium phosphate iodine solution with pH 7. The aqueous solution is washed with 10 ml of ethyl acetate and diluted with water to 50 ml. Potassium salt & -7-Phenylacetamide-deacetoxycephalosporanic cyt "lots in an aqueous solution are determined by direct microbiological analysis using microscopic organisms fsc / ie iftcb-O-coI

After 6 hours, the yield of D-7-phenylacetamide-deacetoxycephalosporanic acid is 47%.

c) The experiment from point a is repeated, but instead of 2O ml of dioxane, 18 ml of toluene and 2 ml of a 1.5 M solution of hydrogen bromide in dioxane are used. Yield of A-7 — phenyl acetamide-dycetoxycephalosporanic acid is 46%, as shown microbiological analysis.

c) Testing from point a is repeated, but an additional amount and-picoline (0.9 ml, 9 mmol) will be taken. The output of h -7-phenylacetamide-deacetoxycephalospore-. The amount of acid is 82%, as shown by microbiological analysis.

Example 3 To dioxane (20 ml), N jO-bis- (trimethylsilyl) acetamide (3.2 ml 13 mmol) and P-toluene sulfonic acid (O, 57 g, 3 mmol) are successively added to Ij05 g (3 mop) of benzylpenicillin sulfoxide. ). The trimethylsilyl benzyl-penenidillic sulfoxide derivative was formed in situ. After the reaction mixture was heated for 6 hours at 101 ° C, no sulfoxide remained. After processing the mixture according to example 2, the output L / -7-phenylacetate Mn-deacetoxycephalospore

21 new acids is 41%, as shown by microbiological analysis. EXAMPLE 4 a) A mixture of 2.1 g (6 mmol) of sul1: foxen benzylpenenitsnlin 20 ml of chloroform, 20 ml (200 mmol) of C (α-picoline, 8 ml (33 mmol) of N, O -bis- (trimethylsipyl) -acetamide and 1.6 m (5.8 mmol) of concentrated sulfuric acid are heated to a trimegyl derivative of sulfoxide: benzylpe {seemingly formed 1n Situ., After heating for 24 hours, the yield of D-7-phenylacetamide -dezethoxygüfalosporanic acid was 12%, as shown by microbiological analysis of 1 passed according to example 2. c). Repeat item a, but instead of 1.16 ml of concentrated sulfuric acid, 6.4 ml (26 mmol) of N, O-bis (trimethylsilyl) acetamide and 1.14 g (b mol) of fJ -toluene sulfoxide are taken. The yield of D 7-phenylacetamide-deacetoxycephalosporanic acid after heating for 24 hours at 83 ° C was 1-3%, as shown by microbiological analysis, according to the method of Example 2, c) Repeat the test of item a, but instead 1.6 ml sulfuric acid take 5 ml (20 mmol) of N, O-bis- (trimethylsilyl). -acetamide and 2 ml of a 3.3 - M solution of C hydrochloride (α-picoline (6.6 mmol) in dichloroethane. After heating for 24 hours at 85 ° C, exit -7-phenyl acet-amide-deacetoxycephalosporic acid was 53% , as shown by the microbiological analysis according to the method of Example 2, Example 5, Mixture of 1, O5 g (3 mmol) of benzylpenicillin sulfoxide, 10 ml of benzyl cyanide, 10 ml (100 mmol of Q-picoline, 3 ml of 3.3 -M hydrochloride solution ( X-picoline (10 mmol) in 152-dichloroethane and 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide are heated at 95 ° C. Trimethylsilyl derivative of sulfoxide b Enzylpenicillin formed 1 Sttu. After 6 hours, V-7-phenylacetamide-deacetoxycephalosporanic acid vyhozhd was 48%, as shown by microbiological analysis according to the method of example 2, Example 6. Repeat the experiment from example 5, but used 15 ml of benzyl cyanide and 5 ml (50 mmol) 0 (β-picoline. Trimethylsilyl derivative of benzyl perenielline sulfoxide formed in situ. Yield of D-7 phenyl acetyl amide-deacetoxycephalosporanic acid

22 after 6 hours of heating at s; ix-annay, carried out according to the method of example 2. Example 7. Repeat the test of prcNiepa 5, but take 17.5 ml of benzyl | Anda, 2.5 ml (25 mmol) of α-picoline and 2 ml of a 3.3 M solution of hydrochloride 0 (α-picoline (6.6 mmol) in 1,2-dichloroethane, TrimethylsilylP1 is a sulfoxide derivative; benzylpenicillin was formed. In. 5tiu. The yield of D-7-phenylacetamide-deacetoxycephalosporanic acid after 6 hours of heating at 95 was 48%, as shown by microbiological analysis according to the method of Example 2, Example 8. A mixture of 1 g (3 mmo, l) of benzyl perenielline sulfoxide, 15 ml of benzyl cyannd , 7.2 ml (72 mmol) of pyridine, 2.5 ml (10 mmol), N, O-bis- (trimethylsilyl) 1 acetoxide and 0.27 ml (1 mmol) of a 3.3 M solution x 0 (β-picoline organhydrate is heated at. Trime-) tsilsilyl derivative of benzylpenicillin was formed Situated after 6 h. Exit-7-phenylacet-, amide-deacetoxycephalosporoic acid was 38%, as shown by microbiological analysis according to the method of Example 2. Example 9, Mix from 38%. 1, O5 g (mmol) of benzylpennylcillium sulfoxide, 20 ml of benzyl cyanide, 2.5 ml (10 mmol) of N, O-bis- (trimethylsilyl) acetamide and 10.24 g (1.5 mmol) of the pyrcic hydrochloride are heated at 90 C. Trimethylsiloxane I derivative of benzylphenyl sulfoxide formed Situ Through 1 o hour; The yield of A-phenylacetamide-deacetoxycephalosporanic acid was 54% as shown by microbiological analysis according to the method of Example 2. Example 10 The experiment of Example 9 was repeated, but instead of 0.24 g of pyridine bromide O 4, 48 g (3 mmol) were added. 0.3 ml (3 mmol) 0 (β-picoln, trimethylsilyl derivative of benzylpenicillin sulfoxd formed In, Sliu, After heating for 10 hours at 9 ° C, the yield of L-7-phenylacetamide-deacetoxycephalosporanic acid was 59%, as shown by microbiological by analysis. Example 11. A mixture of 1.05 g (3 mmol) sul benzylpenicillin dioxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis- (trimethylsilyl) acetamide, 0.48 g (3 mmol) of pyridine bromohydrate and 0.3 ml (3 mmol) of Ot-picolin are heated at 85 C. Trimethylsilyl permeate benzylpenicillin sulfoxide obra23

was called in situ through

The right mixture of you sa tor in 15O ml O, 7S

A 0.7S M solution of potassium phosphate in water (pli 7) and washed with chloroform. The pH of the aqueous layer was adjusted to 2 in the presence of 50 ml of ethyl acetate. Ethyl acetate SLM is washed with water and dried over anhydrous sodium sulfate. After otoiki; ethyl acetate get 1 g of D-7 enylacetamine D-de-381 E1 - hydroxyfapospooric acid with a purity of 10 56% by PMR using as internal ethanol 2J6 dichloroacetophenone „

P jiv m er 12. A mixture of l, 0fe g (3 mmol) of benzylpenydipline sulfoxide,, | 20 ml of dioxane, ml (10 shley) P

N, O - bis- (trimethylsilyl) acetamnda, 0, (3 mop). 6 M solution of bromohydrate Q -. "". Picoline B dichloromethane and 0.6 ML (6 M MOU) C (- Ps olica is heated with ihpH stirring, T1 {methyl methyl): E, hydroxyl sulfoxide rungZippe Eshtsillina about “decomposed”: siiLt.After 6 hours, the reaction mixture is drunk in 200 O / 75 M water of a solution of potassium phosphate, with a pH of 7 ml of buffered acetate, buffered, a water layer is washed with 50 ml of ethyl acetate and after a pH of 2 days, the water layer is extracted twice 10 MP of ethyl acetate. After sci-si over f

sulg || atom of magnesium ethylmethate. distilled in vacuum. The residue (g) contains 7O%. DZ "7-feilacetamide-deacetoxy-phthalocopic spichoacidic acid, KS is shown by TuF-L LMPR analogue (yield mmol; / V%),

Example 13, 0.64 g (3.3 iviMOJin); triethylbromosilane supplemented with xc-lesi 1 (05 g NW mmol) benzylneggigi qi {1lina, dioxia | and 0.9 wui (E mmol) sulfoid (t-mixture of Flovijie mixed for 0.5 hour inSi u. three ethylene liln derivative benelyl succinyl sulfoxide, its presence was confirmed by PMR. Then 2s5 fefs (10 mmol) of N 5O-bio Strimethyl in 4-acetamide and CMecbs containing bromine are added. /, Rat I, -picolina, nygrevalyt 4 hours ripM I 102 C, After processing the mixtures as B. npiifvie-s re 2, the output is fi -7 fe1SylacetamD-dB. / anetoksnnefalosporeiovoy to slots amounted to / 73% e as shown by the nucrobiological analysis

Example 14a a) K mixtures ne 20m 0.15 M solution of chlorotute hydrogen | 3 mmol) in dioxaca ml (mmo, l) H, tIALETypsi a) -dedemiwadd

IjOS g (3 mmol) of benzylpesh 5y5llin o?: 5 was equivalent to In SUu,. After heating for 6 hours with a distillation distillation), the reaction mixture is treated as in Grade 2, Yield

24

D-7 ™ cbd and utamide-deza. Acetoxydephalosporeic acid was about 10%, as shown by microbiological analysis.

c) To a mixture of 2 ml (3 mmol) of a 1.5 M solution of hydrogen chloride in benzyldium

Nide, 2.5 ml (10 mmol) .. H (trimethylsi-t1l) ". Acetamide and 0.9 ml (9 mmol) d Picolica 1.03 g (3 mmol) sul: fokskda bepsi penidilline. The mixture is boiled at 95 ° C for 6 hours, Yield, 7 .. fequipacetamide-deacetoxic 4) spO-sporoic acid, which is 49%. determined according to example 2

Example. 15, a) Dioxane (18 ml) N 5O ™ 6is-Str methyls) lnl) acetamide C l-sh, 10 mmol) n O-picolin (0.9 ml, 9 mmol), a few minutes 2 ml of a solution of 1. hydrogen bromide C3 mmol) B dioxia are added, and the mixture is heated for 6 hours at 101 C. Trimetilsk, w-1l sulfoxnda benzyl derivative | yydiplina formed in situ,. After treatment of the reaction mixture, as in example, 2, the yield of -7 is feiiacetamide-de-acetoxyacephalosporic EOic acid amounting to 97%, as shown by migrobiological analysis,

c) CG mixture of IfOS g (3 mmol) of sulphaHyd benzylpenyl-5 ml-10.5 ml (10 mmol, N, .- (-grshtetilsilkl) -ad em amide / DjS ml (Z mmol) C (-p Colin and { 1.56) 6 M solution of hydrobromide O; Pkkolin in 20 ml of bioxane is heated by reverse distillation for one hour; 1 h; The composition is 82%, as shown by microbiological analysis,

c) Experiment from point to repeat the new "iCTO ml 0 (- picoline take 0.9 ml

With 9 ohmols) and instead of bromp dradus 0.. -Picolinv take ml (9 myopia). -and; instead of bromhydrate c-picoline take, 420 mg (3 mmo) 6pOMyKcychoii acid,; Trimethylsilane derivative sudfoxidy lZenzi.shansnitsilsha formed ift Situ. ; Vyrk.od 7 feralgalecetamide deacene xylated 11 alasporanic acid. sic: tavil 32%,: kyk is shown by Microscopic analysis, e) Repeat (according to ny tiKTy s, but Besto 6-fold acidic acid is taken 70O mg (3 mmol) of a picriton 1SLOTY .-. trimethylsylated or pendant sulfidic acid, sulfonate, 1% SLOW .-. , pyNypklina formed 1n siiu--.

3J4

d - / fe5 | y latseta.gi 15, "desks oksi iieij; ano-2526

| Sporapovay acid was 47%, as in the. -Exalyl bromide. In this c: part-and C-m-zhukazakoi; cpc biological analysis,: the exact product is excilyl

(e) The experiment on point c is repeated, but instead of sulfoxide anhydride, benzenex.

 one hundred bromoacetic acid take 875 mg; D-7-Phenylacetamind-doses; Squat. (3 mmol) Tris- (ethylsulfonyl) -, methane, 5 xsnacephaleesporanoic acid is

1t.e „(C H S O) CH, Trimethylsilyloyl and BE.

; benzylene-icillin sulfoxide derivative Repeat the experiment on item e, but

i formed In. situ ,. Output D — instead of dioxane, they take as solution1 -7-phenylacetamide-d8zatsetszhsicefalospore-: solvent 1O ml of toluene. Acetyl anhydride, acid, was 28%, as shown by benzeplenpenine sulfo sulphide, by microbiological analysis; Wels in Si fu,. Exit D -7-feiil. acetamide-deacetoxypefalosporanovic acid Example 16. a) 530 mg (1.5, is 76%. l) of benzylpenicillin sulfoxide are suspended in 10 ml of dioxane. After adding; i) Repeat the experiment from nyjiKTa e, according to BNie, 0.45 ml | 4j5 mmol) of d-picopin; one hundred dioxane take 10 ml of butyl acetate. The clear solution is cooled to 0 ° C. The yield of D-7-4) yenylacetamide-deacetox11I With vigorous stirring, the cephalosporanic acid is added, which is 78%, and 0.05 ml (Oj5 mmol) of 3-broth phos-Example 17. RDB 10.5 g j handicap The mixture is stirred at O G in temmole) bepzylpepncillin sulfoxide Gnekie SO min. Benzyl sulfoxide anhydride in 15 O ml of dpoxane and 7.2 i, n (00 mmolOGI i of penicillin and phosphorus tribromide phosphorus is cooled to 6 ° C. After the addition has been done in siiu .. Then add 0.9 ml of the solution to 1.4 to (l (18.5 mmo / c.th) (3j5 mmol) H, O-bis- (trimethylsilyl) -; adethyl bromide in 5O ml of dioxpane

: -acetamidvo After 4.5 hours, the reverse of the peg 25 is stirred for 30 min at which the race is controlled by an amount of 7 phenylanetamide-1 benzoylgunicyl sulfoxide anhydride. : Co-on-dezacetoxycephalosporanic acid was formed in situ,. l :: b; 1l 1 1

: It is 85%, as shown by the microbiologist, 18 ml (7 O moles) N, (tI) 1 I: otll. chesky analysis. silyl-acetamide and the reaction mixture n / ib) PoEt ort or jbiT from point a, but instead JQjrpeearor with reverse distillation during

one hundred tribromide phosphorus take 0.05 ml 4.5 hours. After cooling

i (Of5 mmol) acetylbromide. In this case, 1 in 1 l of 0.2 L of an aqueous solution of phosphate potassium

the permeable product was acetyl, with a pH of 7. After ril-f was adjusted to 7 with ii: .v: beisyl peschilline sulfoxide anhydride, (using 4 n e.ojcoro KEL: dobailp solution; Yield of D-7-phenylacetamine D Dezacetoxy -), 600 ml of butyl acetate. The mixture) 1 x 11% cephalosporanic acid is 87%, and then in the funnel it is up to ;;;

as shown by microbiological analysis. The aqueous layer is washed with 00-l ovTiijiniu ;; c) Repeat the experiment on item c, but ad-; tat. United butylshutatchplo with: g) and

; tilbromide was added at room temp. - extracted with 500 ml of 0.75 L, per hundred

I mix the mixture. The output of D -7 phenylacetate-40IpacTBOpa potassium phosphate with jH 7:; ect |; -1kty

I amide-deacetoxycephalosporanic acid is added to the basic BO..V paoF-jv.niv.

ji.V1 -

| S3% j, as. d -: caeano microbiolo-i B of the combined aqueous: i .-. iax sadoi gichesky analzomozhits 9D g of potassium cojii; / l .oi {iijift) Repeat experimentally point b, but instead acetamide-desatoxification | 1 los11:; p |; Iovg-kpc hundred C (-pikoltsha added 0.36 ml (yield 82%), as fl;). enant: (4.5 mmol) pyridine. The output of D-7 is microbiolistic by analysis (.- n: M:) iHi, KJ: -phenylacetamide-deacetoxycephalospore- microorganism E.5ckeriuCh.i.n. ccli, Qulvic acid is 94%. Salt -7-pheny ga ga.ii1D-Df.zatsats- e) Repeat the experiment on point d, but toxicity F: cps parbDBE: t instead of 0.05 ml of acetychgbromide added 50. as in nphsefie 1; tea 1 0.07 ml (IjO mmol) of acetyl bromide. purity 67%, as n:; kaz "and move D - 7 phenylacetamide-deacetoxic-; analysis ((vyhai 7; phalosporic acid; my acid is 92%: Example 18,}

;. ) Repeat the experiment on item 3 but mom) SuLf :: KS Yes 6e 3tSJi: if

; BN-ecTO OjO5 ml of acetyl bromide is added (55 ml); they are collected in 10 ml of ai: x .-. If-;

OD4 ml (2.0 mmol) of acetyl bromide; You are 0.45 L (m: -. 1olp}

Move i 7 phenylg1cetamnd - deacetoxy-lin transparent paratBug

: pefalospzranova acid is 93% .; About S. At. M and Pi: .ie .. (;;;

 d.) experience on item d, but 0.05 l {O, 7 -.iMi-iiHi

0.05 ml was added instead of acetylb) OM11; 60 and a mixture of ner. | .-: 1I1v-gyug (mm

5OO754 27

Acetyl anhydride of benzylpenicillin drioxide was formed in sliu. Then 1.35 g (6.6 mmol} N, m-bis- (trimethylsilyl) -urea were added and, after 4.5 hours of refluxing, the amount of D-7-phenylacetate desicetoxy cephalosporanic acid determined by microbiological analysis, the yield is 54%.

fe) The experiment under point a is repeated, but instead of acetylbromide, 0, O5 ml (0.5 mmol) of tribromide 4k sphora is taken. In this case, an intermediate sample of benzylpenicillin sulfoxide and phosphorus tribromide is formed, D-7-phenylacetamide-deacetoxyacetate, and 33% by microbiological analysis.

c) Repeat the test (clause a), but instead of dioxane, take 10 ml of butyl acetate vi instead of 0.7 mmol take 0.12 ml (1.5 mmol) of acetyl bromide. The yield of -7 phenylacetamide-deacetoxycephalosporic acid is 54% ,

50O7

28

d) The experiment under point a is repeated, but instead of c-picoline 0.36 ml (4.5 mmo / w) of pyridine is taken and 0.22 ml (2.5 mmol) of trimethylbromosilane instead of apethyl bromide, a trimethylsilyl derivative is obtained benzylpenicillin sulfoxide. The yield of A-7 - acetyamide-dehydration aceticamide c1 oranic acid is 80%,

e) 525 mg (1.5 mmol) of sulfoxide benayl pepitsnllina and 760 mg (3.7 mmol)

N, N -bis (trimethylsilyl) urea, peed peidiruyut in 10 ml of toluene. Then 0.12 ml (1.5 mmol) of pyridine and 0.12 ml (1 mmol) of beisoyl bromide are added, and the mixture is heated for 5 hours at 1OO C, Benzyl anhydride benzylidene sulfoxide forms as an intermediate product, Vyg d D--7 ™ phenylacetamide-desRj-etoksitsefalosporoiovoy. acid is 57% by microbiological analysis,

f) Repeat the experiment on item e, but instead of benzoylbroms, take other productions of KHcjsoTbi. The results of the experiments are given in tab, p 1,

Derivative KIS / GOT

Tr 1chloroacetn bromide Trichloranetyl chloride

PRO PCL1ILBROM1 D

Phosgene Thionylchloride Thionipbromide P-Tol lsulfonyl loride Trehbr ohm boron Trehb1: 1Amum alumina Quad bromide silicon Gemfrommethy german - {. olio. phosphor bromide, phosphorus phosphorus TuoepONiiUi (H t brs mystic tungsten

Table 1

 Exit) enil

QUANTITY of ace t) li d ™ desad etoxy production ton

i ceflospranovoy acid,%

67

1.0 67 7S 31

1.0

1.0

0.5 32

0.55 67 21

0.65

1.0 81

0.37 4 O 73

0.34

o, as 82

0.25 26 82

0.2 75 0.33 74 56 0.37 0.2 It was established that trichloroacetyl (1,2), propionyl (3), carbonyl (4), thionyl (5, 6), P - are formed as intermediate products. tolylsulfonyl (7) sulfoxide anhydrides of benzyl penicillus; 1a and anhydride of benzyl penicillin sulfoxide and boron tribromide (8), trichromo alumina (9), chefhbromisty silicon (11), 4 bromide aluminum, (4), 4 bromide silicon, (4), germanium (11), 4 bromide aluminum, (4), germanium (11), 4 bromide aluminum, (4), germanium (11), 4) bromide, silicon, (4), germanium (11), 4 bromide aluminum, (4), germanium (11), 4 bromide aluminum, 9), 4 rd germanium (11), 4) bromide, silicon, (4), germanium (11), 4) bromide, silicon (11), 4 bromide germanium (11), 4) bromide, silicon (11), 4 bromide germanium (11), 4) bromide, silicon (11), 4 bromide germanium (11), 4) bromide, silicon (11); phosphorus tibromide (13), phosphorus oxybium (14), phosphorus thiobromide (15) and tungsten tibromide (16). . Example 19. 525 mg (1.5 mmol) of benzylpenicillin isosulfoxide and 1.4 g (7 mmol) of N, N-bis- (trimethysilyl) mocha are suspended in 10 ml of dioxane. 0.35 ml (2 mmol) of 6 M is added. a solution of bromine hydrate 0 (β-picoline in dichloroethane and the mixture is heated for 4 hours at 100. The trimethylsillene derivative of bevaylpenichene sulfoxide formed t sUu. The output of D-7-phenylacetamide-benzadetox 1 cephalosporic acid was 80%, as determined by the method of example 2. Example 20 ) 525 mg (1.5 mmo l) of benzylpenicidin sulfoxide and II, About g (5 mmol) of N, N-bis- (trime stilien lil) -urea suspension irate in 10 ml of idioxane. 0.25 ml (3 mmol) of pyridine and 0.15 ml (1.6 mmol) of trimej tilbromosilane are added, and the mixture is heated for 4.5 hours at 10 ° C. Trimethylsilyl derivatives of benzylphenncillin sulfoxide formed in Bitii. The output of L-7-feshsha-acetamide-dozacetoxydephalosporanic acid was 85%, by microbiological analysis. b) The experiment under point a is repeated, but instead of pyridine, 0.16 ml (1.6 mmol) of-picoline is taken. The yield was 85%. c) The experiment was repeated under point a, but instead of N, M-bis- (trimethylsilyl) urea, O, 83 ml (3.4 mmol) of N, O-b11c- (trimethylsilyl) -anetamide are taken. The yield of D-7-phenylacetamide-deacetoxycephalosporanic acid was 69% by microbiological analysis. ; Example 21. 525 mg (1.5 mmol) of benzylpenicillin sulfide and 1, O5 g I (5 thoughts) N, N - (trimethylsilyl). -Urea suspended in .O ml of butyl acetate. O, 23 ml (2.3 mmol) of p (α-picoline and O, 2 ml (2.2 mmol) of trimeliylbromosilane) are added. Trimethylsllene protzs aqueous benzylpennaillin sulfoxide is formed in sHu. After heating i at 1 ° C for 4 , 5 h, the yield of D; -7-phenylacetamide-deacetoxenecephalosporic acid is 78% by microbiological analysis. Example 22. A mixture of 1.05 g; (3 mmol) of benzylpenicyl sulfoxide, H, ml (15 mmol) of hexamethyldisilaza, 6 ml O, 5 M solution of methyl bromide in dioxane and 14 mp dioxane; warm for 4.5 hours at 100 ° C. Trimethyl silyl derivative with Benzyl ulfoxide j penicillin was formed ift.Output; I q3 7 phenylacetamide-desacetox cephalo; sporoic acid, was 48% of the PP I method of example 2.; Example 23. a) A mixture of 1.05 g i (3 mmol) of benzyl pepipiplinip , I 18 ml of dioxane, 0.9 ml (9 mmol) 0 (. Picolin, 2.6 g (10 mmol) K, 0-bis1 (tremitylsilyl) trifluorocetamide and 2 ml of 1.5 M solution of hydrogen bromide in dioxane After reflux for 4.5 hours, the trimethylsilyl derivative of benzylpenicillin sulfoxide is formed and situ. The yield of D-7-phenylacetamide-deacetoxycephalosporic acid was 73% by microbiological assay. b) The experiment under point a is repeated, but instead of N, O-bis- (trnmethylsilyl) trifluorodetamide, 1.8 g (10 mmol) N are taken. N (trimethylsilyl) -carbodiimida. Trimethylsilyl 1-derivative of benzylpenicillin sulfoxide formed tn Situ. The yield of D-7-phenylacetamide-deacetoxycephalch; paranoic acid was 14% by microbiological analysis. Example 24. 1, O5 g (3 mmol) of benzylpenicillip sulfoxide are suspended in 15 ml of dioxane. 2.5 ml (10 mmol) of N, O-bis- (trimethylsilyl) -acetamide, 1.2 ml (9 mmol) of 2-methylquinoline and 6 ML of a 0.5 M solution of brm hydrogen in dpoxane are added, and the mixture is heated when for 4.5 chag. The trimethylsilyl derivative of benzylfenicillin sulisfs1xid 1 formed l Situ, The yield of D-7-phenylacetamide-denopet xycephalosporanic acid was 49%, repeated with several foundations different from 2-mthylquinoline. The results are given in table. 2

31

Example 25 a) A mixture of 525 mg (1.5 mmol) of benzylpennyNillin supoxide 1 O ml of toluene, O, 12 ml (1.5 mmol) of pyridine, 1.45 ml (9 mmol) of N-methyl-N-trimethylsilyl-acetamide and Oi35 ml of 6 M d-picolin bromohydrate solution. in dichloromethia heated at 100 ° C for 5 hours. The trimethylsyl compound produced by sulfoxind benelpenenicnlin formed m. The yield of A 7 -phenylacetamide-deacetoxycephalosporanic acid is 58% by microbiological analysis,

B) Previous experience is repeated, but instead of N-methyl-N-trimethylsilylacetate, 1.7 ma (9.2 mmol) of W -me -til N-trn-methyl-silyl-tr iptopadetamide are taken, and d-7 phennacetamide-de-acetone y

32 Table 2

xycephalosporic acid was 86%.

Example 26, A mixture of 1.05 g {3 mmol) benzylpentine sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) -acetamide. p, 6 M (6 mmol) of CX -picolin and 0.5 ml of 6 M solution of bromine-, X-picoline hydrate in methylene chloride

About ml of dioxane is heated from back to:

at 2

distillation 4.5 hours. The trimethylsilyl derivative of benzylpentalline sulfoxide was formed in sUu - Yield of D-7-phenylacetamide-deaacetoxycephalosporanic acid composition:; 82% by microbiological analysis of Example 2.

The wash is repeated in solvent, which is different from dioxane. The results of rjpif are given in table. 3,

33

Solvent

1,2,3-Trichloropropane

Toluene

,, N-dimethylacetamide

Diethylmethylsulfonamide

Chlorobenzene

Isoamylacetate

Butyl acetate

Di ethylox alat

Anisole

1,2-Dimethoxyethane

Tetraethylene glyco dimethyl ether

Trimethyl glycol dimethyl ether Example 27. 1.3 g (3 mmol) sulfoxide .J 2-ethoxy-naphthylpvnicillin, 2.5m, (10 mmol) N, O-bis- (trimethylsilyl) -acetamide, O, 3 ml ( 3 mmol: 0 (α-picoline and 0.25 ml (1.5 mmol) of a 6 M solution of bromohydrate (X-picoline in methylene chloride is dissolved in 20 ml of dioxane. Trimethylsilyl derivative of sulfoxide 2-ethoxynaphthylpvnicillin) formed T n Situ The mixture is heated with reverse by distillation for 4.5 hours and drunk in a cold mixture of 2OO ml of 0.75 M aqueous potassium phosphate solution with a pH of 7 and 50 ml of ethyl acetate. After adjusting the pH to 7 using 4 n. The potassium hydroxide solution was transferred to a separatory funnel, agitated and allowed to stand. The aqueous layer was washed with 10 ml of ethyl acetate and, after adjusting the pH to 2 with 4N sulfuric acid, extracted with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was distilled off vacuum.The dry residue (490 mg) contains 80% D-7- (2-ethoxy-naphtamide) -desatsetxycephalosporanic acid by PMR using 2,6-dichloroacetophenone as internal ethanol. Exit 31%. Example 28. The experiment from Example 27 is repeated with 1.1 g (3 mmol) of phthalimidopenicillin sulfoxide, but instead of 0.25 ml of a solution of L-Picolin bromohydrate and 3 ml of Picolin take 0.5 ml (3 mmo) of 6 M a solution of hydrobromide 0 500754

34

(

Table 3

The output of U -7-phenylacetamide-deacetoxycephalosporanic acid,%

41 41 49 49 52 60 64 82 81 58 81 64 -Picoline in methylene chloride, Trimethylsilyl derivative of phthalimidopenipillin sulfoxide formed in Bit and. The river is mixed with a cirrne mixture as in Example 27, and 88O mg D -7-phash1m “g -“ deacetoxycephalospfanic acid with a purity of 64% is obtained. The yield of 72%. Example 29. The experiment from Example 27 was repeated with 1.3 g (3 mmol) of bvnolsulfonamide methylpenicillin sulfoxide. Trimethylsilyl benzyl sulfide sulfoxide benzenesulfonamidemethylpeniciplin was i / n. Obtain 1.3 g of 1 -7-benzenesulfonamide and decytoacetate in falospororanova acid with a purity of 63% and a yield of 66%. Example 30. a) To 1.1 g (3 mmol) of phenoxymethylphenyl sulfoxide of llin, add 2 O of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) / - acetamide, 0.6 ml ( 6 mmol) Of-pi: colin and 6 M solution of bromgs of I-41 nicoline dromide in methylene chloride (0.5 ml, 3 mmol). The trimethylsilyl derivative I of phenoxymethylenicillin sulfoxide was formed in situ. The mixture is heated with scorching distillation of 6 teMeHHe for 4.5 hours and; process in Example 2. By-pass 4. i I-7-phenoxyacetamide-deacetoxycephalospO of wound acid was 71%, as yet; hall direct microbiological analysis with the use of a microorganism.

fij but treatment mixture of gfimer 27 and nojr / tut 860 mg. -T-phenox-acetamnd-deaceoxtcephalosporanic acid;

, pot purity 85%, as shown by FlMPi-5

 spectra t; Primeionm as vut- /, ethnol 25b dnhloranetof8NO1 ,, Product yield 7O%,

Example 31, K. Suspension., 35 g | (3 mop) of cyclohexyl ammonium salt of sulfoxd benylpionncillin in 15 ml of dioxane 2.8 ml (11 mmol) of N, 0-bis - (trimethylsklil) ycetamide are added and in ml of a 0.5 M solution of hydrogen bromide j5 and dioxene, Trimethylsilane gives one sulfoxy and be a gcc lp and nilli; In situ, the mixture is heated by refluxing for 4.5 hours. BYCHO / D D-7 ™ -feylacetamide-dezatsoktstsefalloslora-20-th acid. is 55% by microbiological analysis.

Example 32. Getting smb1papvo1O aigi drn yes sulfseks and da fohn sym tee l p e: t cp lp on acetic acid.

a) Ras7vor Oj28 yl (Z mmo7sh) apet1; lbromida in ml of i, 2.-dphloretani1 n; zbavl added to rystvOru 1z1 (3 mmol) cyjfiDfjoKCTJAa fenoksimetilpe itsil.piia and G 7 2 ml of 19 mmol) piriS11; and; 1 to 20 1., 2-length: K gapa, After a crosshatch. Face for about an hour, the mixture is filtered and inserted into dosu: sa: Leaving yen (1.08 g 2., 6 µg) is em is a mixed feloxypenicillin anaptrnd and acetic acid

IR analysis; (in CHC1}; 1820., 1YOO

Claims (1)

one and 1758 PMR: (in СДС1 „): 5 CJ (S 3), 1L4 (S 3), 2.32 C 3 3), 4.55 The amount of N (O-BLS - - (trimethylsilyl) ™) azotamnda mmol used (S a) 4.07 (3, 1) 5D7 {d 1., 1 -,. 4.5 Hz), 6.12 C0.1, 1-1.1 Hz and J 4.5 g), 6.98 (S 5). c) 2.2 g (5 simols) of anhydride of phenoxymethylenpenicillic acid and acetic acid anhydride are dissolved in a PO of mp miloxolite. After adding 3 mp. (11.7 mmol) of N, O-bis-Strimethylsi sh), acetamide, 1.1 m (15 mmol) of pyridine and 0.6 ml of dichloromethane containing mmol of bromine hydrate C (- picoline; the mixture is heated with non-reconversion for 4.5 hours, the F-exactant mixture is cooled to room temperature and mixed with 400 ml of 0.75 M aqueous solution of calz-w phosphate from pH 7 to 100 ml of ethyl acetate. pre-docking RP to 7 s. o 4 n, caustic feces) - the mixture is transferred to the ACJii teld rdOpOHKy, shaken to E. and given from-. one hundred, Water; the LAYER is separated, just a-FOT 10 O ml of ethyl acetate, pii to 2.4. With sulfuric acid, 200 each is extracted with ethyl acetate, ethyl (3 /) mol) to: 1pln. 1.and | M, ;;, i.pogS {: g Qi „ O, 9 ml (Q N-MOn l) Cd -rii:; xo.4Hlft: ijnCTj-opa 3.0 mmol methyl 3oncv o / iK and iaiperv: itOT diokeane with oonaiiibii. Ui-fKOM's hobby in TBseHoe 4j5 shs: coB-viem-sjo with iiaa, iup-ini MTi cnol r1E: tBak-c ;, St.PauliPy table,.-5 N (h} l) .that bloptda, (offense: and obg iiiO сse; to. case / x was paiQH 2f4 i-Ap}, B: -i:; to /: i &pm1-gd-Dbaatsetoy-:;5-;nave;;and; osphaic acidity; from 1Il from the path of microprobiol analysis, uOHytenjiKR) l-:;: G; -: 1 ng iped: :-: s and tab, 4., T i} Vigeod ft .7-fe clsez Pzd-de; zadetoksts | nbf lospor ikevoy 1a; slot.,% O Formula and recipe 1. Method for producing 7-substituted (as inolveatoxtox | aposoporanic derivatives of the general formula K R / CH, hydrogen atom, or g linked to the nitrogen atom of the sulfur ring, which can be substituted inert under the reaction conditions; p is hydrogen, is lower aggyl or (lower) alkyl, or R, and Rg together with the nitrogen atom to which they are attached represent a heterocyclic group, for example, oxazimide oxazolidinyl or imidazolidinyl, may have one or more inert under the reaction conditions, or their salts, characterized in that i ksid 6-am avmvschennyh 1 niiillinszhyh acids of general formula x-Sx CCCHj) gene with CH II C - N: n - COOH where R and are as defined above, -neni reacted with. by the general formula M.-X, identical or different, each is lower alkyl, cycloalkyl with 5-8 carbon atoms, phenylalkyl with 1-2 carbon atoms in alkyl, lower alkoxy lower alkylthio or phenoxy or 4enyllyloxy with 1-2 carbon atoms in the alkoxyl radical, a halogen atom or a 6-substituted amino-pet1icillanyl sulfoxide-3-carbonyloxy group, or a 7-substitution of an amino-dvayethoxycephalosporoyl-4-carbonyloxn group, or Kj and K 4 together M, where YT is the residue of M - boron , aluminum or phosphorus :, (- R. one each or different is each lower alkyl, cycloalkyl with 5-8 carbon atoms, phenyl, phenylalkyl, with 1-2 carbon atoms in alkyl, lower alkoxy, lower a; SiltyO or phenoxy, or phenylalkoxy with 1-2 carbon atoms in an alkoxy radical, a halogen atom or a 6-substituted amino-penicillanyl-sulfoxide-3-carbonyloxy group or a 7-substituted amino-deacetoxycephalosporo-4-carbonyloxy group, or R, and R together represent the residue of a ring, including M 2 Re. or ft. together pre 5, or P ichu (O), or they represent an oxygen atom, a sulfur atom (g) o, sulfur, germanium or tin, or a carbon atom. when R is together oxygen or sulfur; RQ and R. are the same or different, each is a halogen atom, lower alkyl, cycloalkyl with 5-8 carbon atoms, phenyl, phenylalkyl with 1-2 carbon atoms. in alkyl, lower alkyl-KS and, lower alkylthio or phenoxy, phenylalkoxy with 1-2 carbon atoms c. alkoxy, a 6-substituted aminopenicillanyl sulfoxide-3-carbonyloxy group, or a 7-substituted amino-deacetoxycephalosporane-4-carbonyloxy group; The C to R is the same or different 10 are each a halogen atom, a 6-substituted amino-penicillanyl-sulfox-3-carbonyloxy or 7-substituted amino-deaziotoxycephalospranic-4-carbonyloxy group, or R and R together are the remainder of the ring, including Mn, or together represent oxygen (O) or sulfur (S), M phosphorus or. tungsten: - lower alkyl, cycloalkyl with 5-8 carbon atoms, phenyl or phenyl plastic with 1–2 carbon atoms in alkyl, ai; most common alkoxy, lower alkylthis, f.coxy or 39 phenylalkoxy with 1–2 carbon atoms in alkoxy; YES - sulfur; X is an angi / cshdn group, for example, a halogen atom, followed by heating the resulting mixture; D) anhydride of general formula Q N —CH — CH - with about Rg have indicated R meanings the group is Vpymiy anhydride of the acid, where has the value of O 3 12, of which the indicated values, in a dry inert organic solvent or at a temperature of at least 160 ° C with an anhydrous acid capable of causing the expansion of the unsaturated ring to / (3-cephemic ring in the presence of a silicon-containing comd} able to quickly remove the formed; formed water and form neutral or BASIC products when hydrolyzed; followed by hydrolysis of) coaatf s Opinions of the general formula . N NN COOR M R, j n Sooya, have the R command, defined values; .: and the subsequent selection of the target; product in the form of kit / yuty or sobi, for example potassium, sodium & calcium, or. pmnn, izvnngngmi upneMaf-in. 4О f, X, X. С N -Si-X 2 20 X. X. X, X. X. ™ Si ... (j, o 80 X X. nx X / and -N but X. X, 60 2, Method p, 1, o tl and h and y and i with the fact that compounds of the general formulas are used as silicon-containing compounds. . -Si-Ni 3 H OX. | i Sj with .. X, X N with 4G X.O 111 x.-Si-N -c-x, where X, -X "are the same or different, each is halogen, lower alkyl or alkoxy, phenyl, phenylalkyl with 1-2 carbon and atoms in alkyl , cyclo a kil with 5-8 carbon atoms, besides X and XD, if it is not halide or alkyl, is optionally replaced by one or more halogen atoms, {lower alhyls, lower escoxy or di (lower) alkylamino groups; - each individually represents a hydrogen or hydrocarbon group without aliphatic unsaturation with y1 "ep | OD11 atoms ily X, h, and x". ". . together with the nitrogen atom to which they are attached I, form a 5- or 6-membered heterocyclic group in which a heteroatom can be & a form of oxygen | for nitrogen, provided that X and X tcT.e contain no more than 18 carbon atoms of UMOBs, and X is alkyl with a tertiary carbon atom j attached to. the atom, the veota to which they are attached, and the carbonyl group. ends with a 5- or 6-membered heterocyclic group with an egmme or trimethylene group in the ring; 8 9 each is a / hydrocarbon group without an aliphatic | non-rising (preferably alkyl) from 1-8 carbon 1 nym atomtam: - hydrogen atom or hydrocarbon group without alnfatiche sciens 42 U with 1-8 carbon atoms or the Si group (x, I 2 3 X is an alkyl group with 1-8 carbon atoms; Y is a hexylene group with 3-18 carbon atoms with no more than 5 and no less than I 3 carbon atoms between the azo-t atom in the carbonyl group to which it is attached; is joined; ft; 1 or 2. 3, the method according to paragraphs 1 and 2, distinguished by the fact that silicon-containing compounds are used in amounts of not more than 1, 5 mol. Eq., Per 1 mol of penydillanic acid sulfoxide or at least 1 mol. Eq. Per 1 mol of penicillanic acid sulfoxyd anhydride ..: 4, Method according to P (, 1, characterized in that an acid that is not silylated or not strongly silylated by a silicon-containing compound, which is added to the reaction mixture under the reaction conditions, is used as the anhydrous acid. 5, The method according to claim 4, the fact that hydrogen bromide, hydrogen chloride, toluene-ft-sulfonic acid, concentrated sulfuric acid, water iodide, genus, perchloric, iodic, nitric, hypochlorous, hypochlorous, selenium, substituted acetic acids, for example bromo acid, iodine acid, are used as the acid , trichloroacetic and LM trifluoroalkylsulite yulotes, substituted hypophosphorus, for example trichloromethylcyclophosphonic acid, to tri-; fluoromethlyl lophobic acid, naphthalene sulfonic acid, oxalic acid and pyric acid, trio-ji- (ethyl sulfonyl) methane, pentacyanpropene, tetracyanpropene, pentacyanocyclopentadienene, tetrashyne cyclopene mastic, amethystromethylenophenolmamine, amethystroxycarboxylic acid I: 6, The method according to p. 4. o tl l h ay | 1C i and c tem; that the acid is introduced into the reactive mixture as a low-pressure, in the form of sma sy with a nitrogen-containing ospill, form; He has to look after this: k: seggye} p. I w. k and with the fact that they use nitrogen-based priming, a solution dissolved in ergkichi solvent, and HMesoaiee rKp 4-I), I8, Method according to P, o tl 1 h: i KJI y i and so that as a rrofifp of the obspovayik, prim and kug -; 5th1th1: cue,; 1.MK.goa nyVTlveskie, fp aTiP oi. or, gvt (-; rocyclic amines, ippichl-l) sg-ksamyti-ne5 tetraam 1H, apilin-, difsmi-h; msh, D / g,; -mat tanipki, dimetglAnilin, -sijiiiji.iui, lil-golin, swept pyrid 1I11 lian chii, For example one or more echykpapy-lz aral1s m L1 X and aripnpugy ychm mono- HJSH; di (lower) alkilamiio grushkagn, nagfi; pnkolin measures ztishgyridi1 2% 2-propilpyri; -1 i ,, 253- wild dymetnlpiriding2vb Dimethylpyrich {g; div, ZaV-daglelipiridan, co-lidiny, 2-. j; -dimvgylaminopyridan, quinoline, ieohiiopii:: S-MeTHWjaoanHOrmHs and also pyrazole, they-; (daeol, -methylimideol,., I 9j The method according to p, 1e оt p and h and io jg u and u and s and TeMj that the mole of the sighed j 6 -mumborated amiko-foamy-1 linobyy sour; i you use 0,25--4 mol of acid:; 10,825-4 eq, carbo carboxy-reagent; xyl group, not less than 2 eq, silicon-containing | iig-containing compounds, or using complex acid-nitrogen compound from 0.1 to 10 moles of the base-case complex, 0.25-2 eq., protection reagent carboxyl group, at least 28 2 equiv., silicon-containing compounds, an additional amount of the base itself, such as moles, and the amount of the additional base, but be directly proportional to the amount of B used acid-base KO; UP1LEK " car, 10. The method according to p, 1, o tl and h and torn and and with TeMj that as a dry | 3rd organic inert solvent is acetonitrile, chlorobenzene, toluene, diagylmethylsul (}) onamide, dimethylformamide change; N, N Dimtylacetamide, 1,2-dimetszhsii. . ethane, Dioxan, triethypench diethyl ether . glycol, daethyl ester of tetraethylene glycol i, nitrobenzene, benethyl cyannd, butyl acetate, isoamylacetate, diatiloxalate, anisole (6aaa), carbon tetrachloride, dimethyl sulfonic acid, methyl ethyl ketone, methyl or eWft S66yfTijmet6Hr ™ HoHfla} TKaiirnSnpHM © p 1 2-dichloroethane, 1D-dichloro an, 1 bromine | 1 chloroethane, 1,2,3-trichloropropane, methylvay-, | loride and chloroform, I 11s The method according to p. 1, about tl and h; y; And And C I by the fact that the expansion reaction }). The loop is carried out at 50 60 C. Priority on the basis of 17 „08,71 R | 3 matters where Mg is silicon; R.J C is a hydrogen atom, low RS 6 - | broad alkyl, phenyl, phenylalkyl with 1-2 carbon atoms in alkyl, cycloalkyl with: 5-8 carbon atoms or 6 "- substituted aminopenicillanyl sulfoxide-3-carbonyloxy group or 7-a substituted amino-desatase: toxo-spore-sporaminyl- 4-carbonyloxy group | 21D2L, 1 other values of radical R