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    • 专利摘要:
    This invention relates to 7-oxo-4-thia-1-aza-bicyclo-[3,2,0]-heptane derivatives, to processes for their synthesis from esters of penicillanic acid 1-oxide, and to intermediate compounds obtained in the synthesis. More particularly, the present invention relates to new and novel compounds of formula (1): <IMAGE> (1) wherein R is a hydrogen atom, an alkyl having from 1 to 5 carbon atoms, trichloroethyl, benzyl, p-nitrobenzyl, diphenylmethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl, trimethylsilyl or a group of formula <IMAGE> and R1 is -CH2OH, -CH2OCOR2, -CH2OR3, -COOR2, -CHO, -CH2SH, -CH2SR4, -CH2NH2, -CH2NHCOR2 in which R2 is an alkyl having from 1 to 5 carbon atoms, aryl, aralkyl or a five- or six-membered heterocyclic ring containing one or more heteroatoms; R3 is an alkyl having from 1 to 5 carbon atoms, benzyl, trityl, trialkylsilyl; and R4 is a five- or six-membered heterocyclic ring containing one or more heteroatoms, benzyl, trityl or trialkylsilyl; and to the synthesis of such compounds. Compounds of formula (1) (E+Z isomers) are endowed with antibacterial activity.
    公开号:SU942598A3
    申请号:SU792847112
    申请日:1979-11-23
    公开日:1982-07-07
    发明作者:Фольо Мауризио；Франчески Джованни；Скарафиле Косимо；Аркамоне Федерико
    申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    (5) METHOD FOR OBTAINING 7-OXO- -TIA-1-AZABICYCLO DERIVATIVES (3,2,0) HEPTAN (ITS OPTIONS)
    one
    The invention relates to a method for the preparation of new compounds of the penicillin series - derivatives of 7-oxo-4-thia-1-azabicyclo (3.2.0 heptane
    general formula
    i.
    (I)
    n
     COORi
    where R. is a hydrogen atom, alkyl with 1-5 carbon atoms, trichloroethyl, benzyl, I-nitrobenzyl or diphenylmethyl, RI group or -COOH 2, where Ra is alkyl with 1-5 atom f i: carbon, which are intermediate products in synthesis of substances with antibacterial activity.
    Known are -ox-analogs of the compounds of the formula (I) - clavulan Slot: EFC about Sietilenide) - 7-oxo-OX-1-azabicyclo (3,2,0) heptane-2-carboxylic acid or its H, N-disubstituted 3 (| -aminoethylidene) - or
    S-esters of 3- (f-thioethylidene) -derivatives, which have physiologically active properties.
    Clavulanic acid derivatives are obtained by reacting clavulanic acid ester with the corresponding amine or mercaptan ij.
    The purpose of the invention is to obtain new compounds expanding the arsenal of means of influencing a living organism.
    The goal is achieved by the fact that in the method of producing compounds of formula 1, the compound of the general formula
    ABOUT
    .
    PG,
    GP
    five
    0
    where R is alkyl with 1-5 carbon atoms, is subjected to interaction with allenova compound of the formula
    R500C-CH "C CH-COOT j where Cd - has the indicated values; in a toluene or benzene medium under reflux temperature, the compound of the general formula pY Y COOBj OV in n where R and Cc have the indicated values is subjected to isomerization in dich methane, at room temperature, the compound of the general formula v oJ ylcooB, Soon where Cs and R4 have the indicated values, is subjected to ozonation at temperatures from -20 to -78 ° C in dichloromethane, the compound formed of the formula: O, Y COORs, inn COOEi COOR4 where R n R. have the indicated meanings recover three with doped phosphorus in dimethylformamide formed compound of the general formula rY v 0, 500R4 where Rj and RA have the indicated values, are hydrolyzed in the presence of silica gel, the resulting compound of the general formula qfT (JoORj where RJ has the indicated values, condensation with the compound of the formula SNO -COOVd where Rj- is lower alkyl, trichloroethyl, benzyl, I-nitrobenzyl or diphenylmethyl, B. benzene at reflux temperature, the resulting compound of the general formula Ouo soovz COORg where R and R have the indicated meanings is subjected to orirovaniyu thionyl chloride in the presence of pyridine at 10 ° C, the resulting compound of general formula «k V COOBi R5- wherein Ra and are as defined above, is condensed with triphenylphosphine in the presence of pyridine with a compound of general ly 0 formuobrazuyuschees rPh COOTl5 (5 OCR 5 wherein. R and Rg have the indicated values and Ph is phenyl, ozonized in the presence of trifluoroacetic acid at a temperature of from -20 to the resulting compound of the general formula. COOR, D T (f where Rj, Rg- and Ph have the indicated values, are cyclized by heating at 100-120 ° C in toluene, and, if necessary, the final product, where RO is -COOR, is converted into the final product, where, reduction and / or the desired product, where R has the meanings indicated for R., is subjected to hydrolysis to obtain the desired product, where R is a hydrogen atom. The second method of producing compounds of general formula 1 coincides with the first method in the step of obtaining compounds of formula XI with the option MI that a compound of formula YI is converted to a compound of formula Y (1 at, and the compound of formula X. is converted to the compound of formula 1X1 at, then the resulting compound of general formula XI is ozonized at a temperature from -20 to the resulting compound of general formula f NyCi COORj where RJ and Rg- have the indicated values, condense with triphenylphosphine at room temperature in the presence of pyridine, the resulting compound of general formula XIU is further converted as in the first method. The third method of producing compounds of general formula I is the same as the second method in the stage of preparing compounds X, then forming The compound of the general formula X is ozonized at a temperature of from -20 to -78 ° C, the compound formed of the general formula r lf-COOBj COOR5 R and R have the indicated meanings, is chlorinated with thionyl chloride in the presence of pyridine, and the resulting compound of the general formula X1U is further converted as in the second way. The fourth method of obtaining compounds of general formula 1 coincides with the second method according to the stage of obtaining compounds of the formula UH, then the resulting compound of the general formula UH is ozonized at a temperature of from -20 to the resulting compound of the general formula Ichi D ± 0 1 Coax, where it has the indicated values condense with the compound of the general formula GC in benzene at the boiling point under reflux the resulting compound of the general formula D f "OOR3 (JOOBg where Rj and R have the indicated values are chlorinated. In the absence of pyridine, the formed compound of general formula XIV is further converted as B by the second method. The fifth method for preparing compounds of general formula 1 coincides with the first method in the step of preparing compounds of formula Y, then the resulting compound of general formula V is reduced by phosphorus tribromide at a dimethylforma 1 type formed The compound of the general formula G-V 100K4 0. COOB, where Ri | and R have the indicated values, is subjected to ozonation at a temperature from -2Q to -78 ° C in dichloromethane. the resulting compound of general form CG. COOB where Rfl and R have the indicated meanings, is subjected to hydrolysis in the presence of silica gel and the resulting compound of the general formula XY1 is further converted as in the fourth method. Example. Methyl (2R, 5R) -E-methoxycarbonylmethylene-7-oxo-β-thia-1-azabicyclo (3.2.0) heptane-2-carboxylate. The sequence of reactions: r V cooCH, f with l cnftflv СООСН,
    f ..
    COOCH
    COOCHt
    COOCH
    r
    r - f Geenz 9 - "L
     Y OHj0% / COOCH,
    nnf.M
    0
    400 (JH, aj 0.185 g methylpenicillinate-1-oxide is dissolved in 3.7 ml of toluene. 0.270 g of glutamic acid dimethyl ester is added to the solution and the resulting solution is heated under reflux for k hours. The main reaction may be was purified on a xp matrix column using a benzene-ethyl acetate mixture, resulting in a 0.221 4 vinylthiocarbomethoxymethyl-2-methoxycarbonyl-l-methoxycarbonyl-2-methyl-2-propenyl G-azetidin-2-one-5-oxide. IR spectrum (CHCU), V ... C.KC 1770,. PMR spectrum (CDCla), (f: 2.00 (singlet, CH-jt -); 2.9 (double doublet, D, 0 and 5.0 Hz, sSS short circuit) H); 3.0 (double doublet,, 0 and .2, 0 Hz, (C (3) H); 3.88 (singlet, three CH-jO); 5.00 (broad singlet. 1 SOOS (NC) and one of the vinylidene protons); 5.2 (wide singlet, C () H); and one of the vinylidene protons); 6.60 (singlet, : TH COOiJlHs) b) 0.221 g of L-vinylthio-C1-carbomethoxymethyl-2-methoxycarbonyl-1-D-methoxycarbonyl-2-methyl-2-propenyl-azetidine-2-one-5-oxide is dissolved in 4 ml of dichloromethane and 0.04 ml of triethylamine is added to the solution. The solution is kept at room temperature for one night and then evaporated in vacuo twice from carbon tetrachloride. The residue consists of pure 4b-vinylthio-1 carbomethoxymethyl-2-methoxycar99 bonyl -1-1-methoxycarbonyl-2-methyl-1-propenyl-azetidin-2-one-5-oxide and correspond to the full calculated output of the IR spectrum (SSCS) , dAax cm 1775 PMR spectrum (CDCb), rf: 2.12 and 2.30 CX} 3.78 (xing two singlet,, Pglet, three CHjO); 5f11 {wide syn gle C () H); : 6.64 (singlet CH). 0.221 g of the compound obtained 4 1 b is dissolved in 12.3 ml of methylene chloride and cooled to -78 ° C. A stream of ozone in oxygen is passed through this solution until it turns blue. The resulting ozonide is reduced by agitating with an aqueous solution of sodium pyrosulfite. The organic phase is dried over anhydrous and evaporated in vacuo to give 0.172 g of 4 |% -vinylthio-1-carbomethoxymethyl-2-methoxycarbonyl3-1-methoxyoxoyl-azetidin-2-one-5-oxide. IR spectrum (CHClj ) ,, cM: 1830 1720. PMR spectrum (CDCl5), cf: 3.70 (singlet, two); 3.88 (singlet, CHjO); 5.27 (double doublet,, 5 and 2.5 Hz,; С () Н); . 6, B5 (. Singlet g) a solution of 0.172 g of Y-vinylthio-1-carbomethoxymethyl-2-methoxycarbonyl -1-methoxyoxoyl-azetidin-2-one - $ - oxide in 1.15 ml of anhydrous dimethylformamide is cooled before and to this solution with simultaneous stirring, 0.07 ml of phosphorus tribromide. After 10 minutes, the mixture was poured into ethyl acetate and washed twice with water. The organic layer is dried with anhydrous sodium sulfate and evaporated in vacuo, whereby 1 is obtained. 0.126 g of rgvinylthio-C1-carbomethoxymethyl-2-methoxycarbonylZ-1-methoxyoxoalkyl-azetidin-2-one. NMR spectrum (SOSTS): 3.7b (D (singlet two CHe, 0); 3.97 (D (singlet); 5.65 ((double doublet, 5 and 2.5 Hz, tCCjlH); 6 , 20 сГ singlet 0-Н1. E) a solution of 0.126 g of “ji-vinylthio-1-carbomethoxymethyl-2-methoxycarbonyl -1-methoxyoxoyl-azetidin-2-one in i ml of methanol is incubated overnight with intensive stirring I together with 0 g of silica gel. After filtering off the insoluble product, the methanolic solution is evaporated and the residual product is evaporated and subjected to separation in a chromatographic column using a mixture of benzene and these acetate for elution, which results in 0, OBD of p-vinylthio- | 1-carbomethoxymethyl-2-methoxycarbonyl -azetidin-2-one .. IR spectrum (СНС1,), 0 .. n-cm: 1780, 1715. PMR spectrum (CDCl5), (J: 3.70 {singlet, two); 3.83 (singlet -CHa-C C); 5.11 (broad singlet, C (t) H); 5.77 (singlet, - 0-H), e) O, and ml of methyl glyoxylate (freshly prepared by ozonolysis from dimethyl fumarate) are dissolved in + ml of benzene and the solution is heated under reflux for 30 minutes in a flask and stark. After cooling this solution, 0 is added to it, OBR g of compound prepared in accordance with IA ,. and the resulting solution is again heated under reflux at boiling point for 3 hours. After separation in a short chromatographic column filled with silica gel, to purify the product from an excess amount of methyl glyoxylate, 0.13 g / l-vinylthio is obtained. 1-carbomethoxymethyl-2-methoxy-carbonyl-1-methoxycarbonyl-1-hydroxymethyl-3-vazeidin-2-one as a mixture of its diastereoisomers. PMR spectrum (SOSTS): 3.75, 3.90, and 3.95 rf (three singlet, three); 5.38 cf (singlet, ir-CH-OlH) 5.0 cf (broad singlet, C () H); 6.00 сГ (singlet, С-Н). g) To a solution of 0.13 g of the compound prepared according to 1e in 2 ml of anhydrous tetrahydrofuran, cooled to 0 ° C, 0.032 ml of pyridine and 0.028 ml of thionyl chloride are added while stirring. The mixture is kept under stirring for 30 minutes. the insoluble product (pyridine hydrochloride) is filtered off and the resulting solution is evaporated in vacuo at 0 ° C. The residual evaporation product in an amount of 0.121 g is | 5-vinylthio-O carboxy methoxymethyl-2-methoxycarbonyl-1-G1-methoxy-carbonyl-1- chloromethyl} -azetidin-2-one in the form of a mixture of its diastereois. IR spectrum (CHCU), ii) (3, j. 1780,, 715. PMR spectrum (SOSTS), 3.7, 3.75 and 3.92 (three singlet, three CHjO); (broad singlet, C () H; 5.91 (singlet, CHC1); 6.10 (singlet, C-H}. H) A solution of 0.121 g of a compound prepared according to g, in 2.5 ml (, tetrahydrofuran and 2.5 ml dioxane with a content of 0.028 pyridine and 0.180 g of triphenylphosphine is heated at 5 ° C for 1 h. Cana through silica gel; the product yield is 0.133 g. frared spectrum (SNS C),) ... 1755 (large; 1715. PMR spectrum (SOSTS) O: 5.65 and 3.72 two singlet, two), 5.5 (broad singlet, C (t) H); 6.68 (singlet, &quot;C-H); 7.2-8.0 (multiplet, 3 C, AND groups). I) A solution of 0.133 g of a compound prepared according to 1 9 in 8 ml of dichloromethane The mixture is cooled at -20 ° C and 9.5 ml of trifluoroacetic acid and dichloromethane is added in. The ozone stream in oxygen is passed through for 1 min and the solution is degassed with nitrogen and 0.27 MP of trimethylphosphite is added to it. The resulting solution is spoiled with NaHCO solution.

    Mr. Mr.
     g SOOCH5
     - gtm
    0 Y 500CH5 JOOCH,
    SOOCH3 g
    U
    Xj iooCHj
    loOCHj
    V
    .one
    Q
    coaxial, and dried over anhydrous sodium sulfate, resulting in 0.080 g of p-methoxycarbonylacetyl, thio-1-f1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl-1-azetidin-2-one. IR spectrum (SNSC), 1755 (large). j) O, Od g 4rimethoxycarbonylacetylthio-1-1-methoxycarbonyl-1-triphenylphosphol-ylanidomethyl-J-azethidin-2-one, prepared according to 1i, dissolved in 3 mp of toluene and heated at 30 minutes. The product is purified from triphenylphosphine oxide by passing through a short chromatographic column. 0.036 g of a mixture of the desired product and its isomer are obtained. Purification of the main component (.E-isomer) is carried out by the method t.on layered chromatorraphy, /, E-isomer. IR spectrum (CHCb), l).,. Vr cm: 1792, 1750, 1700, PMR spectrum (COClS), (G: 3.31 (dyoy doublet, 5 and “. Hz, o {, C (6) Н); 3.86 (double doublet, J 16.5 and 2.0 Hz, | ЗС (6) Н); 3.91 and 3.92 Double bond of singlet, two СНЗО), 5.53 (. Double doublet,, 0 and 2.0 Hz, 0 (5) N); 5.64 (doublet, 0 Hz, C (2) H), 6.29 (doublet, 0 Hz, C – H). Mass spectrum: ha / e 257, 0355 (M. Calc. Calculated according to the formula, S 257, 0358); m / e 215, 0253 (M-CHjCO, calculated according to 215, 0252); m / e 15b, 0119 (M-CHa.CO-COOCH, calculated according to C FUNOeS 15b, 0119). EXAMPLE 2 Methyl (2R, 5R) -E-3-methoxycarbonylmethene-7-oxo -A-thia-1-azabicyclo (3,2,0) heptane-2-carboxylate. Reaction Scheme:
    SOOCH
    Y COOCfls
    coaxially
    sgt
    cooCHj w
    Q yon coocHj
    SOOSK5
    . . s soosch
    about
     -
     (5H5 COOCH,
    coodHs f
    rf Y COOCtt3
    xfСООСНз
    COOCHj
    .
    J H doodHj g) 0.350 g of methyl penenicillin-1-oxide is dissolved in 7 ml of toluene. 0.573 g of glutinic acid dimethyl ester was added to the solution and the resulting solution was heated under reflux for 4 hours. The main product was purified by chromatography using a mixture of benzene and ethyl acetate. The result is 0 g of rgwiiylthio-EI-carbomethoxymethyl-2-methoxycarbonyl -1 -D-methoxycarbonyl-2-methyl-2-propenyl 3-azetidin-2-one-5-oxide. IR spectrum (SNSI),) ..... see: 17. PMR-cnei Tp (SOC), NW: 2.00 (synglet, CHj-fc-); 2.95 (double doublet, 0, 0 Hz, (G) H); 3, (double doublet, o, and 2.0 Gi pC (W) H); 3.88 (singlet, three); L (100С (Н 5,00 (wide singlet. And one of the vinylidene protons); 5,2А (broad singlet, C (t) H and one of the vinylidene protons); 6,60 (singlet, Н С iooC (H) b) 0, g of the compound prepared in accordance with 2a is dissolved in 7.5 MP of dichloromethane and 0.075 ml of triethylamine is added. The solution is kept at room temperature for 8 hours and then evaporated by vacuum in vacuum of carbon tetrachloride. pure 4p-vinylthio-p-carbomethoxymethyl-2-methoxycarbonyl -1-G1-methoxycarbonyl-2-methyl-1-propenyl -azetidin-2-one-5 oxide with quantitative you IR spectrum (CHGl,), l) Ox-cm: 1775, 1725. PMR spectrum (SOSTS), c5: 2, T2 and CjHj 2.30 (two singlet, CHj / 3.78 (singlet, three ); 5.11 (broad singlet, C (4) H); 6.6 (singlet, C — H). C) 0, A20 g of the compound prepared according to 26 is dissolved in 23 ml of methylene chloride and cooled-to. A stream of oooon in oxygen is bubbled through this solution until a blue color appears. The resulting ozonide is reduced, for which it is shaken with an aqueous solution of sodium pyrosulfite. The organic phase is dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.327 g of L-vinylthio-1-carbomethoxymethyl-2-methoxycarbonyl} -1-methoxyoxoyl-azetidin-2-one - $ - oxide. IR spectrum (), cm: Pl830, 1720. PMR spectrum (COCl 3), eG: 3.70 (cg, two CHiO); 3.86 (singlet, CHiO); 5.27 (double doublet, 5.5 and 5 Hz, CCijH); 6.65 Cinglet, C-H) i g} Solution of 0.327 g of compound prepared in accordance with 2c; in 22 ml of anhydrous dimethylformamide, cool before and add 0.13 ml of tribromide phosphorus with stirring. After 10 minutes, the mixture was poured into ethyl acetate and washed twice with water. The organic layer was dried over anhydrous sodium sulphate and evaporated in vacuo to give 0 g of 4p-vinylthio-C1-carbomethoxymethyl-2-methoxycarbonyl-methoxy-oxo-2o-azetidin-2-one. PMR spectrum (SOSTS),: 3.7b (syn, two); 3.97 (singlet, CHAO); 5.65 (double doublet,, 5 and 2.5 (4) H); 6.20 (singlet, CH). d. Solution 0, g of the compound prepared according to 2 g in 7.5 ml of methanol is incubated overnight with vigorous stirring together with 0.75 g of silica gel. After filtering off the insoluble product, the methanolic solution is evaporated and the residue is separated on a silica gel chromatography column using a mixture of benzene and ethyl acetate as an eluting solution. The result is 0.120 g of t f5-vinyl-thio-1-carboxomethoxymethyl-2-methoxycarbonyl -azetidine -2-one., IR spectrum (CHCL), ..Apie-cm: 1780, 1715. PMR spectrum (SOSTS) , and: 3.70 (synglet, two CH) 0); 3.83 (singlet, -CH2C C); 5.11 (broad singlet, C () H); 5.77 (singlet, CH). (e) 0.27 ml of methyl glyoxylate (freshly prepared by ozonolysis of dimethyl fumarate) is dissolved in 7.5 ml of benzene and the solution is heated under reflux in a Dean-Starc flask for 30 minutes. After cooling the solution to 50 ° C, 0.12 8. of the compound prepared according to 2D is added, and the resulting solution is again heated under reflux for 3 hours. To purify the product from the excess of methyl glyoxylate it is passed through a short silica gel column. and get 0,255 g / -vinylthio-n- | , 1-carbomethoxymethyl-2-methoxy.carbonyl -1 -1-methoxycarbonyl-1-6xymethyl 3-azetidin-2-one as a mixture of diastereoisomero PMR spectrum (SOSC), (G: 3.75, 3.90 and 3, 35 (three singlet, three); 5.38 (, singlet, 1 {-Ca-0 (H) 5.0 (broad singlet, C (4) H); 6.00 (singlet sn ;. g) To a solution of 0.255 g of the compound prepared in accordance with 2e, 3.8 MP of anhydrous tetrahydrofuran, cooled to 0 ° C, 0, OO ml of pyridine and 0.05 ml of thionyl chloride are added with stirring. The mixture is stirred for 30 minutes, the insoluble matter is filtered off (pyridine hydrochloride and the resulting solution is evaporated under vacuum at 30 ° C. The residue is 0.230 g of | b-vinylthio-tl -carbomethoxymethyl-2-methoxycarbonyl - - 1-methoxycarbonyl-1-chloromethyl-azetidin-2-one as a mixture of its diastereoisomers. IR spectrum ( sleep 1,), L) duox 1780,, 1715. PMR spectrum (SOSTS), c1: 3 ,, 3.75 and 3.92 (three singlet, three); 5.30 (broad singlet, C (4) H); 5.91 (singlet, CHC1); 6.10 (singlet C-H) h) A solution of 0.230 g of the compound prepared in accordance with 2g in 15 ml of dichloromethane is cooled to -78 ° C and oxygenated through it with ozone before staining the solution in blue. The mixture is then agitated with an aqueous solution of sodium pyrosulfite, dried over anhydrous sodium sulfate, evaporated in vacuo to give 0 g of rgmethoxycarbonylacetylthio-1-methoxycarbonyl-1-chloromethyl-azetidin-2-one. IR (CHCl1), 1 | (, cm 1785, 1750. NMR spectrum (CDCU), 0: 3.66 (lg, u, 3.85 and 3.92 (two singlet, two); 5, 75 (broad singlet, C (4) H); b, 08 ({Y- (H- (31) and) Rastyber 0, g of the compound prepared according to 2 in 5.5 ml of anhydrous tetrahydrofuran containing 0.025 ml pyridine and 0.1–7 g of triphenylphosphine are heated at room temperature for 8 hours after careful heating. After purification on silica gel, 0.080 g of 4p-methoxycarbonylacetylthio-1-Pmethoxycarbonyl-1-triphenylphosphoranylidenemethyl) -az tidin-2-one is obtained. IR spectrum (CHCIj), (c 1755 (large) PNR spectrum (COC1)), (G: 3.60 and 3.7 (d va); 5.80 (broad blue glut, C (4) H); 7.1-8.1 (multiplet, 3 CgH groups). k) 0.080 g 4 | g-methoxycarbonylacetylthio-1-l-methoxycarbonyl -1-trifeiylphosphoranylidenemethylZ-azetidin-2-one, prepared according to 2i, is dissolved in 3 ml of toluene and kept at 120 ° C for 30 minutes. The product is purified on a short p ± b and coaxial
    g. -h§h. (; nz COOCHH coaxial, L jL I TT0 J-Tj-1-; ооСНз # I-T "YP I,
    U (I
     (Jh,
    I
    (JOOCHi COOOH YoiT ooCH COOCH, COOCH coaxially from the triphenylphosphine oxide chromatographic column and get 0.036 g of the mixture of the target compound and its 2-isomer. Purification of the main component (E-isomer) is carried out by thin-layer chromatography / E-isomer ICH spectr ),), 1750, 1700. NMR spectrum (CDCl5) cf: 3.31 (double doublet 1 16.5 and i, O Hz, s {.C (6) H); 3.86 double doublet, J 16.5 and 2.0 Hz, (C (b) H); 3.91 and 3.92 (two single, two); 5.53 (double doublet, 0, and 2.0 Hz, C (5) H); 5, (doublet, J 1.0 Hz, C (2) H); 6.29 (doublet, J 1.0 Hz, C – H) .. Mass spectrum: m / e 257, 0355 (M, calculated for (. 257, 0358); m / e 215, 0253 (, calculated for CeH9N04 21570252; m / e 156, 0119 (M-CH iCO-COOCHi, calculated for 156, 0119). Example 3 Methyl I (2R, 5R) -E-3-methoxy carbonylmethylene-7 -oxo-4-thia-1-azabicycloSZ, 2,0j heptane-2-carboxylate Reaction Scheme fy v COOCHj СООСНз S .о СООЙНз ООdH, Hj with р-j - lf COOCHj СООСНз СООСНз Vci COpCHj
    a) g methylpenicillinate-1-oxide is dissolved in 7 ml of toluene. To the solution was added 0.513 g of dimethyl ester of glutinic acid, and the resulting solution was refluxed for k hours. The main product was purified by chromatography using a mixture of benzene and ethyl acetate. The result is 0, g {5-vinylthio-fl-carbomethoxymethyl-2-methoxycarbonyl -1 -1-methoxycarbonyl-2-methyl-2-propenyl 3-azetsdin-2-one-S-oxcd.
    IR spectrum (SNSI), T d s11ssSm: 1770,.
    NDP-spectrum (COCl3),: 2.00 (singlet, CH-C-); 2.93 (double doublet,, 0 and 5.0 Hz, ccc (H) H); 3.40 double doublet, o, and 2.0 Hz, RS (Z) N); 3.88 (singlet, three
    5.00 (wide singlet 1Г СООС (Нз
    P

    and one of the vinylidene protons, 5.24 (broad singlet, C (4) H, and one of the vinylidene protons): 6.60
    T1
    (singlet, (J I COOS (NC)
    b) 0.420 g of the compound prepared according to the above is dissolved in 7.5 ml of dichloromethane and 0.075 ml of triethylamine is added. The solution was kept at room temperature for 8 hours, and then evaporated twice in vacuo from carbon tetrachloride. The residue includes pure 4p-vinylthio-C1-carbomethoxymethyl-2-methoxycarbonyl -1-L1-methoxycarbonyl-2-methyl-1-propenyl-azethidin-2-on-5 OKCid with a quantitative yield ..
    IR Spectrum (СНС1а), 1IDd-cm: 1775, 1725.
    HMR spectrum (COCl3), O: 2.12, and
     5NZch
    2.30 (two blue blades,
    SNS /
    3.78 (singlet, three CH, 0) -, 5.11 (broad singlet, C (|) H); oh, 64 (singlet, С-Н).
    c) 0.420 g of the compound prepared according to 36 is dissolved in 23.4 ml of methylene chloride
    and cooled to -78 ° C. Through this; the solution is bubbled with a stream of ozone in oxygen until a blue color appears. The resulting ozonide is reduced, for which purpose it is stirred up with an aqueous solution of sodium pyrosulfite. The organic phase is dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.327 g of 4,0-vinylthio-1-carbomethoxy-2-v-methoxycarbonyl-3-methoxy oxoyl-azetidine-2-oH-S-oxide.
    IR spectrum (sleep 1 a), A ...-. ,,, 1830, 1720.
    5 PMR spectrum (COC), f: 3.70 (singlet, two CHjO); 3.88 Sslinglet (CHjO); 5.27 (double doublet, 5.5 and 2.5 Hz, C (4) H); 6.65 (singlet;
    d) A solution of 0.327 g of compound 0 prepared according to
    Sn, in 2.2 ml of anhydrous dimethylformamide is cooled before and 0.13 ml of phosphorus tribromide is added with stirring.
    After 1Q min, the mixture is poured into ethyl acetate and washed twice with water. The organic layer is dried over anhydrous sodium sulfate and evaporated.
    Q in vacuo to give 0.240 g of 4p-vinylthio-C1-carbomethoxymethyl-2-methoxycarbonylJ-1-methoxyoxoyl-azetidin-2-one.
    HMR spectrum (COCl3), cG: 3.76 (singlet, two CH3); 3.97 (singlet,
    CHjO); 5.65 (double doublet,, 5 and 2.5 Hz, С (4) Н); 6.20 (singlet, CH).
    e) A solution of 0.240 g of the compound prepared in accordance with 3g in 7.5 ml of methanol is incubated overnight with vigorous stirring together with 0.75 g of silica gel. After filtering off the insoluble product, the methanol solution is evaporated and the residue is separated on a silica hematography column using a mixture of benzene and ethyl acetate as an elution solution. The result is
    0 0.120 g 4p-vinylthio-E1-carbomethoxymethyl-2-methoxycarbonylZ-azetidin-2-one.
    cm 1780
    IR (SNSI), 1, ....-..- cm 1740, 1715. PMR spectrum (CDClj), cr: 3.70 (singlet, two CHdO); 3.83 (singlet, -SNg.); 5.11 (broad singlet, C (4) H); 5.77 (singlet, CH). 21 e) 0.27 MP of methyl glyoxylate (ozone-prepared dimethyl fumarate) is dissolved in 7.5 ml of benzene and the solution is heated under reflux in a Dean-Stark flask for 30 minutes. After cooling the solution, 0.120 g of the compound prepared in accordance with HL is added and the resulting solution is again heated under reflux for 3 hours. To purify the product from excess methyl glyoxylate it is passed through a short chromatographic column with silica gel and yield 0.255 g K-vinylthio-f1-acarboxymethyl-2-metoxycarbonyl - 1-f 1 -methoxycarbonyl -1-hydroxymethylazetidin-2-one in the form of a mixture of diastereoisomers. PMR spectrum (SOSTS), a: 3.75, 3.90, and 3.95 three singlet, three (singlet, -CH-0 (H); 5.0 (broad инг singlet, C (4) n); 6.00 (C-H singlet). G) A solution of 0.255 g of the compound prepared according to Ze in 17 ml of dichloromethane is cooled before and a stream of oxygen with ozone is bubbled through it until the solution is colored blue. The mixture is then agitated with an aqueous solution of sodium pyrosulfite, dried over anhydrous sodium sulfate, evaporated in vacuo, and 0.155 g of p-methoxycarbonylacetylthio-1-t1-methoxycarbonyl-1-oxymethyl-3-azethidine-2-one is obtained, and the PMR spectrum (SOS) is). : 3.76 (synglet, CO-CH2. -COOC (Hz); 3.90 and 3, (two singlets, two CH3); 5.60 (syn / o (nglet C5.72 (broad syn. N COOC (KS) glut, C (4) H). H) To a solution of 0.155 g of the compound prepared in accordance with G3, in 2.3 ml of anhydrous tetrahydrofuran cooled to OC, ml of pyridine and 0.032 ml of thionylchloride are added with stirring. The mixture is stirred 3 0 min, filtering off insoluble matter (pyridine hydrochloride) and the resulting solution is evaporated in vacuo at. Ostayuk is an AO g-vinylthio-Cl carbomethoxymethyl-2-methoxy822 carbonyl 1 -1-methoxycarbonyl-1-chloromethyl 1 -azetidine-2-one in the form of a mixture of its diastereoisomers. PMR spectrum (SOSTS): 3.76 (singlet, CO-CH2-SOOS (H)); 3.90 and 3.9 (two singlets, two CHSOs; 5.60 / o (n) singlet (J / SOOS (Hj), 5.72 (broad singlet, C (4) n). i} A solution of 0, g of the compound prepared in accordance with 3C, in 5.5 ml of anhydrous tertahydrofuran containing 0.025 ml of pyridine and O., 1b7 gtriphenylphosphine after being gently heated is maintained at room temperature for 8 hours. After purification on silica gel, 0.080 g is obtained p-methoxycarbonylacetyl-1-1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl3-azetidin-2-one. IR spectrum (СНС1з) .1) .. а.сг /. / VVQKC (large). PIR spectrum (), (G: 3.60 and 3.7 (two CH "0); 5.80 (broad singlet, C (4) HB 7.1-8.1 (multiplet, 3 C H groups ).) 0.080 g) U-methoxycarbonyl acetylthio-1-1-methoxycarbonyl-1-triphenylphosphoranylidenemethyl-azethidin-2-one, prepared according to SM, dissolved in 3 ml of toluene and kept at 120 ° C for 30 minutes. The product is purified on a short chromatographic column from triphenylphosphine oxide to give 0.036 g of a mixture of the intended compound and its Z-isomer. Purification of the main component (E-isomer) is carried out by thin layer chromatography. E-isomer “IR spectrum (СНС1з), -). Дс5Кс 792, 1750, 1700. PMR-spectrum (SOSTS), tf: 3.31 (double doublet, 5 and 0 Hz, s (.C (6 ) H); 3.86 (double doublet, 5 16.5 and 2.0 Hz, (6) H); 3.91 and 3.92 (two singlet, two CH-0); 5.53 (double doublet ,, 0 and 2.0 Hz, C (5) H); 5.64 (doublet, L-1.0 Hz, C (2) H); 6.29 (doublet, 5 1.0 Hz, C- o) Mass spectrum: m / e 257, 0355 (M ras. calculated for 257, 0358) 23 m / e 215, 0253 (M-CHB.CO, calculated for C8H9N04 215, 0252); m / e 156, (M-CH -CO-COOCHj, calculated for (HeNOj. 156, 0119). Rf, JL - -CooCHj r
    Mr & Y OOCHj
    COOCHj
    : 0
     C0 COOCHj
    .-xSSjX (JOOCH3
    Well
    (ZOOCHNO OP9, rj ixCOOCH5 N SOOSYag jVv 0 iJOOCHj Example p.Metil (2R, 5R) -E-3-Me7oxycarbonylmethylene-7-oxo-thia-1-azabicyclo {3, 2,0) heptane-2-carboxylate . Reaction scheme: $ 4. (JH5 SsX COOCHj ff 1 11 COOCHj COOCHj -jX Y OOCHj-K-s O COOCHj FOODWORK
    jL
    --Vci
    fOOCttj a) 1.02 g of methic penicillinate-1-oxide a is dissolved in 30 ml of toluene. 1.5 g of glutinic acid dimethyl ester was added to the solution and the resulting solution was heated under reflux for an hour. The main product is purified chromatographically using a mixture of benzene and ethyl acetate. The result of 1.23 g of α-vinylthio-1 -carbomethoxymethyl-2-methoxycarbonyl - - 1-methoxycarbonyl-2-methyl-2-propenyl 3 -aze, tidin-2-one-5-oxide. IR spectrum (СНСЬ ), ... „,, cm: 177 IJijO. HMR spectrum (COCl3), (G: 2.00 (singlet, CH-Y-); 2.93 (double doublet, 0 and 5.0 Hz, sSS {3) H); 3.0 (double doublet, 9 "I, 9 and 2.0 Hz, RS (B) H); 3.88 (singlet, three); 5.00 (wide singlet K (100C (Hz) and one of the vinylidene protons); 5.2 (wide singlet, C C) H and one of the vinylidene protons); 6.60 singlet. (- HI COOCfHs) b) 123 g of the compound prepared according to a is dissolved in 22 ml of dichloromethane and 0.22 ml of triethylamine is added. The solution is kept at room temperature for 8 hours and the solvent is evaporated twice in vacuo from carbon tetrachloride. The residue includes pure p-vinylthio-p-carbomethoxymethyl -2-methoxycarbonyl -1 -1-methoxycarbonyl-2-methyl-1-propenyl 3-azetidIN-2-OH-5-OXID with a quantitative yield of the IR spectrum (CHC1), b HMR spectrum (COC1), cG: 2.12 and 2.3 3 3.78 (singlet sindwa, –1 "H5 / gl. Three CH2S); 5.11 (broad singlet, C (t) H); 6.6k (singlet, CH). c) 1.23 g of the compound prepared in accordance with 46 is dissolved in 68.5 ml of methylene chloride and cooled to -78 sec. Ozone in oxygen is bubbled through this solution until a blue color appears. The resulting ozonide is reduced, for which purpose it is agitated with an aqueous solution of sodium pyrosulfite. The organic phase is dried over anhydrous sodium sulphate and evaporated in vacuo to give 0.9 g of p-vinylthio-C 1 -carbomethoxymethyl-2-methoxycarbonyl 3-1-methoxyoxy-halo-azetidin-2-one-5-oxide. IR spectrum {as clear as Q), 0 Q cm: 1830 PMR spectrum (COCl 3), 0: 3.70 (singlet, two CH 2 O); 3.88 (singlet, 5.27 (double doublet, 5.5 and 2.5 Hz, C (4) H); 6.65 (singlet, C-H). G Solution 0.9 g of the compound, prepared in accordance with tB, 6, ml of anhydrous dimethylformamide is cooled to, and 0.38 ml of tribromic phosphorus is added with stirring.After 10 minutes, the mixture is poured into ethyl acetate and washed twice with water.The organic layer is dried over anhydrous sodium sulfate and evaporated in vacuum, obtaining 0.704 g of 4b-vinylthio-1-car6methoxymethyl-2-methoxycarbonyl -1-methoxyoxaloyl-azetidin-2-one. PMR spectrum (CST) O: 5.76 (singlet, two CH3); 3.97 ( singlet CH50 5.65 (dv oyun doublet, 5 and 2.5 Hz C () H); 6.20 (singlet, C-H). e) A solution of 0.70 g of the compound prepared according to g in 22 ml of methanol is incubated overnight at vigorous stirring with 2.2 g of silica gel. After filtration of the insoluble 8 product, the methanol solution is evaporated and the residue is separated on a chromatographic column with silica gel, using a mixture of benzene and ethyl acetate as an eluting solution. As a result, O, 352 g of p-v Inylthio-C1-carbomethoxymethyl-2-methoxycarbonyl 3 azetidyl-2-one is obtained. IR spectra.p (SNSI) ,, 1780, 1715. PMR-spectrum (CDCl3.), Cf: 3.70 (singlet, two CH3); 3.83 (singlet, -CH2.); 5.11 (broad singlet, C () H); 5.77 (singlet, CH). (e) A solution of 0.250 g of 3-8 vinylthio-1-carbomethoxymethyl-2-methoxycarbonyl-3-azetidin-2-one in Z ml of dichloromethane is cooled at -78 ° C and the ozone stream in oxygen is passed through this solution until it turns blue. The mixture is stirred together with an aqueous solution of sodium pyrosulfite and dried over anhydrous sodium sulfate. 0.282 g | -methoxycarbonylacetylthio-azetidin-2-one. HMR spectrum (COCl3), cG: 3.76 (singlet, CO-CH2. -COOC (H,); 3.81 (singlet, CH O); 5.35 (broad singlet, C () H); w ) A solution of 0.63 h of freshly prepared methylglyoxylate in k2 ml of benzene is boiled in a Dean and Stark flask for 30 minutes. 0.282 g of pU-methoxycarbonyl-acetylthio-azetidin-2-one prepared in accordance with E is added to this solution and the mixture is continued. It is heated at boiling point for 3 hours. After separation in a short chromatographic column to purify from excess methylglyoxylate, 0.155 is obtained. g 4 | Umetoxycarbonylacetylthio-1-l-methoxy carbonyl-1-hydroxymethyl 3-azetidine-3. HMR spectrum (SOSTS), G: 3.7b (singlet, CO-CH, j, -COOC (H-5)); 3.90 and 3.9 (two singlets, gsa CHjO); 5.60 (synIf / 0 (H) pet li COOS (NC) 5.72 broad singlet C (4) H). h) To a solution of 0.155 g of the compound prepared in accordance with 4g in ml of anhydrous tetrahydrofuran, cooled until, while stirring, add 0.036 ml of 27E pyridine and 0.032 ml of thionyl chloride. The mixture was stirred for 30 minutes, the insoluble matter was filtered off (pyridine hydrochloride) and the resulting solution was evaporated in vacuo at. The residue is 4-vinylthio-D carbometry, rxymethyl-2-methoxycarbonyl -1-Cl-methoxycarbonyl-1-chloromethyl 3-zetidin-2-one, 8 whole mixtures of its diastereoisomers. 1 H NMR spectrum (CDCl5), (f: 3.7b (singlet, CO-CH2-SOOS {H,)); 3.90 and 3.9 (two singlet, QB &amp;CHjO); ,, 0 (H) singlet / Ooe (ns}, 5.72 (broad singlet, C (4) H). I) A solution of 0.140 g of the compound prepared according to 4z in 5.5 ml of anhydrous tetrahydrofuran, containing 0.025 ml of pyridine and 0.1b7 g of triphenylphosphine after heating gently, kept at room temperature for 8 hours. After purification on silica gel, 9.080 g of 4 |% methoxycarbonylacetylthio-1-1-methoxycarbonyl-1-triphenylphosphoranylylidenemethyl-austidine- 2-she. IR (CHCL), 755 (large), PMR spectrum (COCl 3), cG: 3.60 and 3.74 (two); 5.80 (broad singlet, C (4) H); 7.1-8.1 (multiplet, 3 С Нр-groups). about rm ± b x „j -“ - jj -teodHj
    ioocHi e | -y at SOOSSH / k - --- cyoeh
    .. tO
    COOOHjCOOCHj
    YPPhj
    COOCH, Bc) 0.080 g of 4-methoxycarbonyl-acetylthio-1-1-methoxy-carbonyl-1-triphenylphosphoranylidenemethyl -azetidin-2-one prepared according to 4i is dissolved in 3 ml of toluene and held at 80 minutes. The product is purified on a short chromatographic column of triphenylphosphine oxide to give 0.036 g of a mixture of the desired compound {and its 2 isomer. Purification of the main component (E-isomer) is carried out by the method of hinge layer chromatography. 2 E-isomer, W-spectrum (CHeC), 1792, 1750, 1700. PMR spectrum (SOSC),: 3.31 (double doublet, 5 and 4.0 Hz, CCS (6) H); 3.86 (double doublet, 5, and 2.9 Hz; pC (6) H); 3.91 and 3.92 (two singlet, two); 5.53 double doublet, and 2.6 Hz, C (5) H); 5.64 (doublet, 0 Hz, C (2) H); 6.29 doublet, 0 Hz, C — H). . Mass spectrum: m / e 257, 0355 (calculated for 257, 0358); m / e 215, 0253 (M-CHg, CO, calculated for CgH9NG4 215, 0252); m / e 156, 0119 (M-CH CO-COOCH, calculated for C HgNOjj 156, 0119). PRI me R 5. Methyl (2R, 5R) -3-methoxycarbonylmethylene-7-oxo-4-thia-1-azabicyclo (3,2,0) heptane-2-carboxylate. Reaction scheme: rG-coaxial, OCH; Y COOCHj Hj COOCHj b COOCIlj COMHj a) 0.89 g of methyl penicyll-1-oxide is dissolved in 18 ml of toluene. 1.3 g of glutinic acid dimethyl ester was added to the solution and the resulting solution was heated under reflux for k 4. The main product was purified by chromatography using a mixture of benzene and ethyl acetate. As a result, 1.07 g of PGI1-thio-1-carbomethoxymethyl-2-methoxycarbonyl-1-1-methoxycarbonyl-2-propenyl 3-azeticin-2-one - $ - oxide is obtained. IR spectrum (SNSC), cm-: 1770 PMR spectrum (SOSTS), 2.00 (singlet, CH, 2.93 (double doublet, O, and 5.0 Hz, obS (H) H); 3 , 0 (double doublet, 1, 0, and 2.0 Hz, (3) H) 3.88 (singlet, three CHjO); 5.00 (shIOOC (H5) and one and the same singlet to vinylidene protons}; 5 , 2 (broad singlet, C (4) H and one of the vinylidene protons); 6.60, (singlet. COOClHj) b 1.07 g of compound, prepared / leHHoro according to 5a, dissolved in 19 ml of dichloromethane and added 0.19 ml; triethylamine. The solution is kept at room temperature for 8 hours, and then evaporated "... twice in vacuum from carbon tetrachloride. Residue includes pure itp-vinylthio-C1-carboxymethyl-2-methoxycarbonyl-1-11-methoxycarbonyl-2-methyl-1-propenyl 3-azetidin-2-one-5-oxide with a quantitative yield of the IR spectrum (СНОа) (775 1725. c) 1.07 g-vinylthio-E1-carbometoc simethyl-2-methoxycarbonyl-1-1-label of sicarbonyl-2-methyl-1-propenyl 3-azetidine-2-OH-S-oxide obtained in accordance with 56, solution 16.4 ml of anhydrous dimethylformamide and cooled to -20 ° C. Phosphorus tribromide (ot t ml) is added to the solution and the mixture is kept under i stirring and cooling for 30 minutes. Ethyl acetate is added and the organic phase is washed twice with water and dried over anhydrous sodium sulfate. After evaporation of the vacuum under vacuum, 0.82 g of ify-vinylthio-1 1 -carbomethoxymethyl-2-methoxycarbonyl-1- | 1-methoxycarbonyl-2- -methyl-1-propenyl-azetidin-2-one. PMR spectrum (SOSTS), O: 2.03 (syn CG glut, ZN, H-2.26 (pinlet, 3H, ifWe; 3.32 (multiplet, J and 5 Hz, 2H, H-3); 3 , 70-3.80 II (СН2 СООСН СН-СООСНз, С1: coodHj 5.50 (doublet, doublet, 5 Hz, Ь 5.97 (singlet, 1H СН) g Solution of 0.820 g p-vinylthio- .1-carbomethoxymethyl -2-methoxycarbonyl 3-1-LI-methoxy carbonyl-2-methyl-1-propenyl 3-azetidin-2-one, obtained in 5c, in 90 ml of dichloromethane is cooled to -78 ° C and the ozone stream in oxygen is passed through this solution to as long as it does not turn blue, the ozonide is reduced by agitating the organic phase with sodium pyrosulfite solution. anhydrous sodium sulfate and evaporation in vacuo give 0.510 g of | -methoxycarbonylacetylthio-1-methoxyoxoyl-azetidine -2-one. PMR spectrum (COCl 3) (G: 3.08 (double doublet and H Hz, 1H, H ( Shl), 3.55 (double doublet, 5 and l Hz, F, H (6) P); 3.70 (singlet, 2H, .CHHCOSSH3); 3.80 (singlet, GH, CH2COOIJ), singlet, GH, CHOOSN ); 5.82 (.double doublet, J 5 and C Hz, 1H, C (h) H); e) To a solution of 0.510 g of methoxycarbonylacetylthio-1-methoxyoxy-haloazetidin-2-one prepared in accordance with 5g, in b7 ml of methanol was added 2.7 g of silica gel, the resulting mixture was kept under stirring for 60 minutes. After filtering off the insoluble matter, a residue is obtained by evaporation, containing 0.282 g of methoxycarbonate thio-a8ethidin-2-one; PMR spectrum (CDCU), d: 3.67 (singlet, CH-CH2-SOOS (Hz); 3.81 (singlet, CHio); 5.35 (broad singlet, C () H). 319 e) A solution of 0.63 g of freshly prepared methylglyoxylate in k2 ml of benzo ash is boiled in a Dean-Stark apparatus for 30 minutes. 0.282 g of methoxy-carbonyl acetylthio-azetidin-2-one prepared according to 5e is added, and the mixture is kept at boiling point for 3 hours. After removing an excess of methyl glyoxylate on a short chromatographic column, ijf-methoxycarbonyl acetylthio-1 - is obtained l-methoxycarbonyl-1-hydroxymethyl-3-azetidin-2-one. PMR spectrum (CDCl1): 3.7b (syn. Glat, CO-CH-COOC (Hz)); 3.90 and 3.9 (two singlet, two CH, 0); 5.60 Singlet 1 0 (H) 5.72 (Broad Singlet, / СООССНз) with (Mn). g) To a solution of 0.155 g of the compound prepared in accordance with 5e, in 2.3 ml of anhydrous tetrahydrofuran cooled to 0 ° C, 0.036 ml of pyridine and 0.032 ml of thionyl chloride are added with stirring. The mixture was stirred for 30 minutes, the insoluble matter was filtered off (pyridine hydrochloride) and the resulting solution was evaporated in vacuo at 30 ° C. The residue was α-vinylthio-C1-carbomethoxymethyl-2-methoxycarbonyl -1-t1-Methoxycarbonyl-1-chloromethyl 3-azetidine- 2-one / as a mixture of its diastereoisomers. PMR spectrum (COCl3), (G: 3, -7b (singlet, CO-CH-COOC (H ,,); 3.90 and 3.9 (two singlets, two CHjO), 5.60 (siglet i, f 0 (I) 5.72 (broad N COOS (H5), singlet, C (") H). 3 A solution of 0.140 g of a compound prepared in accordance with 5g in 5.5 ml of anhydrous tetrahydrofuran containing 0.025 ml of pyridine and 0.17 g of triphenylphosphine after careful heating is kept at room temperature for 8 hours. After purification on silica gel, 0.080 g of + 1, methoxycarbonylacetylthio-1-11-methoxycarbonyl-1-three phenylphosphenylidenemethyl-azethidin-2-one is obtained. IR -spectrum (SNS)) ,,,,, cm: 175 (large). 832 PMR-s ectr (CDClI), (f: 3.60 and 3.7 (two CHjO); 5.80 (broad singlet, C (4) H); 7.1-8.1 (multiplet, 3 Well groups). and ) 0.080 g of p-methoxycarbonyl-acetylthio-1-1-methoxy-carbonyl-1-triphenylphosphoranylidecmethyl-ase (Tidin-2-one prepared according to 5h is dissolved in 3 ml of toluop and kept at 30 minutes. The product is purified on a short chromatographic column from triphenylphosphine oxides and obtain 0.036 g of a mixture of the target compound and its Z-isomer. Purification of the main component (E-isomer) is carried out by the method of thin-film chromatography E-isomer V E-isomeo IR spectrum (SSCC), .. 1792, 1750, 1700. PMR spectrum (CDC1,), cG: 3.31 (double doublet, j 16.5 and 4.0 Hz, C (6) H); 3.86 (double doublet, J 1b, 5 and 2.0 Hz, (8) H); 3.91 and 3.92 (two single | two CHjO); 5.53 (double doublet, 2.0 Hz, C (5) H); 5.6 (doublet, 0 Hz C (2) H); 6.29, (doublet, 0 Hz, C – H). Mass spectrum: m / e 257, 03b5 (H, calculated for 257.03); m / e 215, 0253 (M-CH,., CO, calculated for SvNdM04 215, 0252); m / e 156, 0119 (M-CH / 2.CO-COOCH3, calculated for. 156, 0119). PRI me R 6. Benzyl (2R, 5) -E-3-methoxy carbonylmethylene-7-oxo-4-thia-1-azabicycloSZ, 2.0) heptane-2-carboxylate .. p - coaxes "- Nypphj coo (JH2- / O СООСИ5 n coaxial, 120 g itft-methoxycarbonylacetylthio-1-G1-benzyloxycarbonyl-1-trienylphosphoranylidenemethyl3-azetidin-2-one, prepared in accordance with paragraphs a and from 0, g meylpenenicillinate-g oxide and benzylglyoxylate instead of methylglyoxylate are dissolved in i ml of toluene and heated for 60 minutes at 100 ° C. The resulting desired compound is purified from POPhj, passed through a short chromatographic column, The result is an O.OtO g of pure final product. PMR spectrum {CDCl5), f: 3.22 (double doublet, Hz, 16 Hz, 1H, H-6 (J), 3.7 double doublet, 7 and
    SOOSNz
    SIG
    0 Tg oosnz-CHO
    o a) Di-isobutyl aluminum hydride (2 equivalents from a 1.2 M solution in toluene) is added dropwise to a solution of benzyl (2R, 5R) –E-3-methoxycarbonylmethylene-7-oxo-2-thia-1-azabicyclo (3.2.0) heptane-2-carboxylate (00 mg prepared according to Example 6, but using 2.3 g of methylpenicillinate-1-oxide, in dry tetrahydrofuran (25 ml) under nitrogen atmosphere. The mixture is stirred for 1 h. The solution is taken at room temperature and treated with aqueous hydrochloric acid. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated. A 60 mg product is obtained by purification on a silica gel chromatographic column using a mixture of dichloromethane and ethyl acetate (80:20) as the eluting liquid. The IR spectrum, V 1795. b) 60 mg benzyl (2 R, 5 R) -E -3 (p) -oxyethylidene) -7-oxo-4-thia-1-azabicyclo (3.2.0) heptane-2-carboxylate was dissolved in 10 ml of ethyl acetate, 10 ml of a saturated solution of sodium bicarbonate and 100 mg were added 5% palladium on coal; the mixture is stirred (when hydrogen is supplied for 30 minutes. The aqueous phase is washed twice with ethyl acetate, acidified with 10% water. 9
    CHjOH
    n
    ABOUT
    CHgOH
    权利要求:
    Claims (3)
    [1]
    n soon 83 16 Hz, 1H, H-6oL); 3.77 (singlet, SN,); 5.18. (Singlet, 2H,); 5.36 (double doublet, t and 2 Hz, 1H, H-5); 5.51 (doublet, 5 Hz, 1H, H-2); 6.12 (doublet, 1 1.5 Hz, 1H CH); 7.33 (multiplet, 5H, Ph). EXAMPLE 7 Benzyl (2R, 5K) -E-CCP-hydroxyethylidene-7-oxo - "- thia-1-azabicyclo (3.2.0) heptane-2-carbonacetic acid solution of citric acid and twice extracted with methylene chloride. After drying over sodium sulfate and evaporation of the solvent, 22 mg of the desired product are obtained. IR spectrum, 1 1795, 1b95. Claims 1. Method for producing 7-oxo-β-thia-1-azabicyclo (3.2.0) Heptane derivatives of the general formula 1 | 2 j 0 Ir COOBj where R is a hydrogen atom, alkyl with 1-5 carbon atoms, trichloroethyl, benzyl, I-nitrobenzyl or diphenylmethyl; RZ or -COOR, where R is alkyl with 1-5 carbon atoms, which is a compound with a general formula. M. o - V-COOE4 where Bd is alkyl with 1-5 carbon atoms, is reacted with an allene compound of general formula III R, OOd-CH (} CH-COObx n where R has the indicated values, in toluene or benzene at boiling point with a reflux condenser forming a compound of the general formula; JV, SLF, 0.fxS (IOOR5 and COOR. where RI and R have the indicated values is subjected to isomerization in dichloromethane, the compound of the general formula for O is, where K- and R have the indicated values are subjected to ozonation at a temperature of from -20 to the dichloromethane formed compound The first form of LU1. xv COORj 1 COOR, where R- and R have the indicated values, is reduced with trichromic phosphorus at -40 ° C in dimethylformamide, the resulting compound of the general formula VII, dOOR where R and R4 have the indicated values, are hydrolyzed in the presence of silica gel, which forms compound of general formula Vtll rfY (JOORj L N. COOlls 9. de R has the indicated values, is subjected to condensation with the compound of the formula IX where CHO-COOB5 where Rf is lower alkyl, trichloroethyl, benzyl, p-nitrobenzyl or diphenylmethyl, in benzene at boiling point with reflux cooling its compound of the general formula X T SOOEz COOBs where R and RC have the indicated meanings, is chlorinated with thionyl chloride in the presence of pyridine with the resulting compound of the general formula XI I COOH 5 COOK 5 where R and Rg have the indicated meanings, is condensed with triphenylphosphine in the presence of pyridine The compound of the general formula XII GT 0 ypPhScoO ypPhs COORj COOK 5, where Rj and Rj have the indicated values and Ph is phenyl, is ozonated in the presence of trifluoroacetic acid at a temperature of -20 to form a compound of the general formula XIII gGT. COOEs where RO, Ph im are as defined above, is cyclized by heating at 100-120 C in toluene and, if necessary, the desired compound where R-
    [2]
    2. - -COOR, converted to the desired product, where Ra.-, by reduction and / or the desired product, where R has the values indicated for R 5, is hydrolyzed to obtain the desired product, where R / f is a hydrogen atom.
    2 "Method for producing derivatives where 7-ca co-thia-1-azabicyclo (3.2, o) heptane of the general formula I where RJ is a hydrogen atom, alkyl with 1 carbon atoms, trichloroethyl, bisyl, I-nitrobenzyl or diphenylme Rj .- or -COORj, where til; 1-5 carbon atoms, alkyl with 10 Д D and with the fact that l and h of general formula II are O ин CH Г GT И -COOH 4 where R is alkyl with 1 5 carbon atoms is reacted with allelic compound of general formula III ( 5H-COOV3 where R "has the indicated values, toluene or benzene at reflux temperature, forming the compound of general formula IV XX XX. One H soy where R and R have the indicated values is subjected to isomerization in dichloromethane, forming the compound of general formula V P CR soovz 0 f COOEs СООЕ4 - where R and R have the indicated meanings are ozonated at that from -20 to dichlormeth formed compound of general formula VI COOBj (loi, -СООВз СООВ4
    Rg and R. have the indicated values; they restore phos-20 C three-bromide.
    odds at -20 ° C in dimethylformamide, the compound formed is the general form of GGT COOBj СООКз соов where R and R4. have the indicated values, undergo hydrolysis in the presence of silica gel, which forms the compound of the general formula y III rr Y COORj H where K has the indicated values, is condensed with the compound of the formula IX CHO-COOBg - lower alkyl, trichloroethyl, where R h is nitrobenzyl or diphenylbenzyl, methyl, in benzene at a temperature Ki: reflux condenser, a decomposable compound of the general formula X, Q COOKj where R and Rg. have the indicated values, undergo chlorination, with thionyl chloride in the presence of pyridine with the compound formed: general form / s XI Q ЯуС1 СООВ5 (JOOB5 where RJ and Rg. have the indicated values, ozonate at -20 to-yS C, the compound being formed; where R and Ry have the indicated values, condense with triphenylphosphine at room temperature in the presence of pyridine, the resulting compound of the general formula XIII, where Rj and R have the indicated values and Ph is phenyl, is cycled by heating at 100-120 volts inert races the solvent, preferably toluene, and, if necessary, the target product, where RJ. - -COORj, is converted to the target n, where, by reduction and / or the target product, where RJ has the values indicated for R, is hydrolyzed to obtain the target product, where R is a hydrogen atom.
    3. The method of obtaining the derivatives of 7 oxo-α-1-β-ablation of (3,2,0) heptane of general formula I. 0 (ZOOVd where R is a hydrogen atom, alkyl with 1 carbon atoms, trichloroethane, benzyl, nitrobenzyl or diphenylmethyl R is —CHiOH or —COORj, where R is a. Kil with 1–5 carbon atoms, because The compound of the general formula fl, o 1H - COOB4, where Rd is alkyl with 1-5 carbon atoms, is reacted with an allene compound of the general formula iU R500C-CH C CH COORj where RI has the indicated values, in toluene or benzene at boiling point with reflux, forming a compound of common foriula IV
    [3]
    1-j lf «OOR5
    Loook,
    H COOR4
    . $.
    nt
    dOOR:
    - YOH iOORj
    0 COORs where RJ and R have the indicated values, is isomerized in dichloromethane, the compound of the general formula for O is formed, y1c, where R and R have the indicated values, are ozonated at a temperature from -20 to. in dichloromethane, the compound formed by the general formula VI sGT / X Y CHOOSA COOR4 where Rj. and R. have the indicated values, is reduced by phosphorus tribromide in dimethylformamide, the compound formed by the general formula UI SvX (500B. Dni СООВ where R and RA have the specified values subjected to hydrolysis in the presence of silica gel, forming a compound of the general formula YIII R $ CHC COOK5 n. IL / LT where RJ has the indicated values, is subjected to condensation with the compound of the formula IX CHO-O-OOBj where R is lower alkyl, trichloroethyl, benzyl, I- nitrobenzyl or {diphenyl-methyl, in benzo e at reflux, the resulting compound of formula X
    one
    Where R and R5- have the indicated values, ozonate at a temperature from -2Q to -78 ° C, which forms the compound of general formula XV
    COOK:
    - wow
    0 where R and R have the indicated values are chlorinated with thionyl chlorine in the presence of pyridine with the resulting compound of general formula XIV, COOKg where R and Rc have the indicated values are condensed with triphenylphosphine at room temperature in the presence of pyridine to form the compound of general formula XIII . where R and Rg- have the indicated values and Ph is phenyl, is cyclized by heating at 100-120 ° C in an inert solvent, preferably toluene, and, if necessary, the final product, where R is -COORj, is converted into the final product, where, reduction and / or the desired product, where R is as defined for RC, is hydrolyzed to obtain the target product, where R is a hydrogen atom. k. The method of producing 7-oxo-D-thia-1-azabicyclo (, 0) heptane derivatives of the general formula I r-rV m LH Lt1 (ooBi where R is a hydrogen atom, alkyl with 1-5 carbon atoms, trichloroethyl, benzyl, i-nitrobenzyl or diphenylmethyl Rj.CHjOH or -COOR, where R is alkyl with J-5 carbon atoms, o tl
    942598 “2
    due to the fact that the compound of general formula II
    p -Vo where R is alkyl with 1-5 carbon atoms, is reacted with an allene compound of the general formula W - CH CH SI —COOR-, where R has the indicated values, at reflux temperature in toluene or benzene, the compound formed of the general formula W (-H-Cyr oov, where R and R. have the indicated meanings, is isomerized in dichloromethane, the resulting compound of the general formula Y S -. "oB, Y JOORs COOR where R and R have the indicated meanings, is subjected to ozonation at a temperature from -20 to dichloromethane, forming a compound of the general form Y1 .Lu. .G CoORj where Rj or R has the indicated values, is reduced by phosphorus tribromide with dimethylformamide, the compound of the general formula yit YN; o (where R-j and 4 are indicated values) is hydrolyzed in the presence of 3
    silica gel formed by the general formula YIU
     SOOKch where R has the indicated values, is ozonized at a temperature of from -20 to the resulting compound of a compound of the formula XY1 rfT COOS3 where R3 has the indicated values, is subjected to condensation with a compound of the general formula IX CHO-COOR5 where Rg- is lower alkyl , trichloroethyl, benzyl, and-nitrobenzyl or diphenylmethyl, in benzene at the boiling point under reflux, the compound of the general formula XV — o - V “S COOK 5 Ra and R — is formed, has been given an chlorophyll chlorine, in the presence of pyridine thionyl at the compound formed total Formulas XU S g 5 - coo: kz -Nycio where Ra and R have the indicated values Q, condense with triphenylphosphine at room temperature in the presence of pyridine, the compound of the general formula XIII, COOEj, Rj and R5 have the indicated values Ph - phenyl is cyclized by heating at 100-120 ° C in an inert solvent, preferably toluene, and, if necessary, the desired product, where R, j is -COOR, is converted to the desired product, where RO is CH2PH, reduced, and / or the target product, where R - has the values indicated for Ry, subject to 25981, c.
    Hydrolysis is carried out to obtain the desired product, where R is a hydrogen atom.
    5. The method of obtaining the derivatives of S 7-oxo | -4-ia-1-azabicyclo (3.2.0) heptane of the general formula 1 where is atom, kilo ldine where is it, leno where is the rate of lead, where is chlorine, is chlorine common, is there no phosphorus, forms CUt W lp COORi R; | - hydrogen atom, alkyl with 1-5 ami of carbon, trichloroethyl, bin -nitrobenzyl or diphenylmethyl; -CH2.0N or -COORo ,; where R is alc with 1-5 carbon atoms, o, so that the general formula II is O. $ vx "ttv fT pcn. 3, m O P COOKf RJ - alkyl with 1-5 carbon atoms, reacts with an alky compound of the general formula W -CH-C -CH-COOR j R has the indicated values toluene or benzene, the compound of the total formIV cf; C ° ™ OOR4 R and R have the indicated values, isomerization in dimethane formed by the compound of the formula V, III, COOR4 R and R j have the indicated three bromide restore lO with the dimethyl forms forming the compound XV total ( 1 (COOV where I and R have the indicated meanings, subject ozonization with a temperature of –20 to –78 ° C in dichloromethane, the compound of the general formula Cush V V JooBs о D COOR where Yaz and the indicated values are hydrolyzed in the presence of silica gel, the compound of the general formula XYI lf:, - BUT where R, MMeisT are the indicated values, it is condensed with a compound of the general formula IX CHO-COORy, where Rp is lower alkyl, trichloroethyl benzyl, I-nitrobenzyl or diphenylmethyl, in benzene at reflux temperature, a compound of the general formula XV pY Y ioo "3 o Y ° COOBj where I and Rj have the indicated values are chlorinated with thionyl chloride in the presence of pyridine at the resulting compound of the general formula, o - Vei COORg where R and Rj have the indicated values, condense with triphenylphosphine at room temperature in the presence of pyridine, resulting in the reduction of the general formula XBI VPBftj СООВ where Rg and R have the indicated meanings and Ph is phenyl, is cyclized by heating at 100-120 ° C in an inert solvent, preferably pyridine, and, if necessary, the desired product, where Rj. -COORg, translated into the target product, where Ra. - -CH, OH, reduction and / or the desired {product, where R has the values indicated for Ry, is hydrolyzed to obtain the desired product, where R is a hydrogen atom. Sources of information taken into account in the examination 1. Patent of the USSR V 645583, cl. C 07 O 498/04, 1976.
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    同族专利:
    公开号 | 公开日
    CA1139745A|1983-01-18|
    SE446339B|1986-09-01|
    DE2947118A1|1980-06-04|
    IT7927509D0|1979-11-23|
    IE49874B1|1986-01-08|
    ATA736879A|1981-06-15|
    FR2449092A1|1980-09-12|
    IL58750A|1983-07-31|
    AU5301979A|1980-05-29|
    JPS5573685A|1980-06-03|
    BE880153A|1980-05-20|
    IT1209143B|1989-07-10|
    CH644128A5|1984-07-13|
    DE2947118C2|1984-03-08|
    FR2449092B1|1983-06-03|
    SE7909667L|1980-05-25|
    AT365594B|1982-01-25|
    NL7908464A|1980-05-28|
    GB2093839B|1983-06-02|
    DK495879A|1980-05-25|
    IE792222L|1980-05-24|
    NO793791L|1980-05-28|
    IL58750D0|1980-02-29|
    AU529597B2|1983-06-16|
    YU287779A|1982-10-31|
    ZA796333B|1980-11-26|
    GB2093839A|1982-09-08|
    US4331677A|1982-05-25|
    引用文献:
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    US4110165A|1974-04-20|1978-08-29|Beecham Group Limited|Process for the production of clavulanic acid|
    US4207323A|1975-11-21|1980-06-10|Merck & Co., Inc.|6-Substituted methyl penicillins, derivatives and analogues thereof|
    US4076826A|1976-04-12|1978-02-28|Merck & Co., Inc.|3--6--7-oxo-4-oxaazabicyclo[3.2.0]heptene-2-carboxylic acid and derivatives thereof|
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    GB2014574A|1978-02-16|1979-08-30|Glaxo Group Ltd|Lactam Compounds|
    US4182711A|1978-04-27|1980-01-08|Bristol-Myers Company|Antibacterial agents of the β-lactam type|
    US4244965A|1978-06-15|1981-01-13|Beecham Group Limited|Azetidinoyl ethers|
    JPS5559193A|1978-09-20|1980-05-02|Glaxo Group Ltd|Bblactam compound|
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    NO831160L|1982-04-08|1983-10-10|Erba Farmitalia|PREPARATION OF SUBSTITUTED PENEM DERIVATIVES|
    JPS6124396B2|1982-06-21|1986-06-10|Taiho Pharmaceutical Co Ltd|
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    US5104862A|1991-03-20|1992-04-14|Merck & Co., Inc.|Bethalactam elastase inhibitors containing phosphorous acid derivatives at the 4-position of the 2-azetidinone|
    US5100880A|1991-03-20|1992-03-31|Merck & Co., Inc.|Novel betalactam elastase inhibitors containing phosphorous acid derivatives at the 4-position of the 2-azetidinone|
    US5348953A|1991-06-25|1994-09-20|Merck & Co., Inc.|Substituted azetidinones as anti-inflammatory and antidegenerative agents|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7845966|1978-11-24|
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