GB2166441A - Preparation of 2-thiacephems - Google Patents

Preparation of 2-thiacephems Download PDF

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GB2166441A
GB2166441A GB08528360A GB8528360A GB2166441A GB 2166441 A GB2166441 A GB 2166441A GB 08528360 A GB08528360 A GB 08528360A GB 8528360 A GB8528360 A GB 8528360A GB 2166441 A GB2166441 A GB 2166441A
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thiacephem
methyl
prepared according
group
carboxylate
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GB8528360D0 (en
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Marco Alpegiani
Angelo Bedeschi
Maurizio Foglio
Giovanni Franceschi
Ettore Perrone
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

<IMAGE> 2-Thiacephems II (R1=H or an organic group, R2=H or a carboxy protecting group and Y=H, halogen or an organic group) are prepared from azetidinones IV <IMAGE> (R1, R2 as above and Z represents various organic groups) by ozonolysis of the double bond, conversion of the hydroxy group to a halogen atom, an alkane sulphonyloxy group or an arene sulphonyloxy group, and cyclisation by reaction with a sulphide or hydrosulphide in the presence of a base to give II (Y=H). Halogenation, preferably after cyclisation, using N-bromosuccinimide or N-chlorosuccinimide in an inert organic solvent at 20-130 DEG C in the presence of a radical initiator and an acid scavenger, gives II (Y=halogen). The latter compounds may be converted to II (Y=organic group) by known reactions. The 2-thiacephems II are useful in the preparation of penems as described in Application No. 2131432, from which this Application is divided.

Description

SPECIFICATION Preparation of 2-thiacephems Description The invention relates to processes for the preparation of 2-thiacephems of the general formula II
wherein R, represents a hydrogen atom or an organic group, R2 represents a hydrogen atom or a carboxy protecting group and Y represents a hydrogen or halogen atom or an organic group. These 2-thiacephems are useful as starting materials for the preparation of penems of the general formula I
wherein R1, R2 and Y are as above defined. The conversion of the 2-thiacephems II to the penems I is described and claimed in our British Patent Application No. 2131432, from which this Application is divided.
Organic groups which R, may represent include optionally substituted aliphatic or cycloaliphatic groups. The aliphatic groups are preferably alkyl groups having from 1 to 12 carbon atoms and the optional substituents may be one or more hydroxy, amino, cyano and/or mercapto groups. The hydroxy, amino and mercapto groups may be free or protected. Particularly preferred alkyl groups are methyl and ethyl, especially the latter, and a preferred substituent for such a group is a hydroxy group, which may be free or protected. The 1-hydroxyethyl group in 6S, 8R or 6R, 8S configuration is most preferred. The cycloaliphatic groups are preferably monocycloalkyl groups having from 4 to 7 carbon atoms. Cyclopentyl and cyclohexyl groups are especially preferred.Optional substituents are preferably chosen from alkyl groups having from 1 to 6 carbon atoms, for example methyl or ethyl groups, hydroxy, amino and mercapto groups, the hydroxy, amino and mercapto groups being free or protected.
The carboxy protecting group R2 may be any group which, together with the -COO-moiety, forms an esterified carboxy group, Examples of carboxy protecting groups R2 are alkyl groups having from 1 to 6 carbon atoms, for instance methyl, ethyl or t-butyl; halo-substituted alkyl groups having from 1 to 6 carbon atoms, for example 2,2,2-trichloroethyl; alkenyl groups having from 2 to 4 carbon atoms, for example allyl; optionally substituted aryl groups, for example phenyl and p-nitro-phenyl; aryl substituted alkyl groups, the alkyl part whereof has from 1 to 6 carbon atoms and the aryl part whereof is optionally substituted, for example benzyl, p-nitro-benzyl and p-methoxy-benzyl; aryloxy substituted alkyl groups, the alkyl part whereof has from 1 to 6 carbon atoms, for example phenoxy-methyl; or groups such as benzhydryl, o-nitro-benzhydryl, acetonyl, trimethylsilyl, diphenyl-t-butyl-silyl, and dimethyl-t-butyl-silyl. The definition of R2 as a carboxy protecting group also includes any residue, such as acetoxymethyl, pivaloyloxymethyl or phthalidyl, leading to an ester group which is known to be hydrolyzed "in vivo" and to have favourably pharmacokinetic properties.
When Y represents a halogen atom, it is preferably a fluorine, chlorine or bromine atom.
When Y represents an organic group, it is preferably a) a free or protected hydroxy group; b) a formyloxy group or an acyloxy group having from 2 to 6 carbon atoms, optionally substituted by a halogen atom, by an acyl group having from 2 to 6 carbon atoms, or by an amino, hydroxy or mercapto group, the amino, hydroxy or mercapto group optionally being in a protected form; c) an unsubstituted or N-alkyl or N-acyl substituted carbamoyloxy group; d) an alkoxy group having from 1 to 12 carbon atoms or an alkylthio group having from 1 to 12 carbon atoms, either of which is optionally substituted by one or more halogen atoms, formyl groups, acyl groups having from 2 to 6 carbon atoms, and/or amino, hydroxy or mercapto groups, the amino, hydroxy or mercapto group optionally being in a protected form;; e) a 1-pyridinium group, unsubstituted or substituted in the meta or para position with the group CONY2; f) a heterocyclylthio group -S-Het wherein Het, denoting a saturated or unsaturated heterocyclic ring containing at least one oxygen, sulphur and/or nitrogen heteroatom, is preferably: A) a pentatomic or hexatomic heteromonocyclic ring, containing at least one double bond and at least one oxygen, sulphur and/or nitrogen heteroatom, unsubstituted or substituted by one or more a') alkoxy groups having from 1 to 6 carbon atoms, aliphatic acyl groups having from 2 to 6 carbon atoms, hydroxy groups andlor halogen atoms; b') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms; c') alkenyl groups having from 2 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms; d') groups of the general formula -S-R3 wherein R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, or groups of the general formula -S-CH2-COOR4 wherein R4 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy-protecting group; e') groups of the general formulae -(CH2)m-COOR4 or -CH=CH-COOR4 or -(CH2),,-CN or -(CH2)m-CONH2 or (CH2)m-SO3H wherein m is zero, 1, 2 or 3 and R4 is as defined above; f') groups of the general formula
wherein m is as defined above, and each of Rs and R6, which may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aliphatic acyl group or when one of R5 and R6 is hydrogen, the other may be also an amino protecting group; or B) a heterobicyclic ring, containing at least two double bonds wherein each of the condensed heteromonocyclic rings, being the same or different, is a pentatomic or hexatomic heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroatom, said heterobicyclic ring being unsubstituted or substituted by one or more substituents selected form a'), b'), c'), e') and f') as defined above.
In the above definitions A) and B) preferred halogen atoms are chlorine, bromine and iodine; preferred alkyl groups are methyl and ethyl; a preferred alkenyl group is allyl; a preferred aliphatic acyl group is acetyl; a carboxy protecting group may be any of the groups previously indicated for the R2 substituent; and the free sulpho and carboxy groups possibly present may be salified, e.g. as sodium or potassium salts. A heteromonocyclic ring of the above class A) may be, for example, an optionally substituted thiazolyl, triazolyl, thiadiazolyl, tetrazolyl or triazinyl ring.Preferred substituents on such rings are, for exam pie, ple, one or more substitutents chosen from amino, hydroxy, oxo and a Cl-C6-alkyl group, preferably methyl or ethyl, wherein the C1-C-alkyI group may be optionally substituted by a substituent chosen from carboxy, sulpho, cyano, carbamoyl, amino, methylamino or dimethylamino. A heterobicyclic ring of the above class B) may be for example, a tetrazolopyridazinyl radical optionally substituted by amino or carboxy.
In the above formula I the amino, hydroxy or mercapto protecting groups possibly present may be those usually employed in the chemistry of penicillins and cephalosporins for these functions. They may be, for instance optionally substituted, especially halo-substituted, acyl groups, e.g. acetyl, monochloroacetyl, dichloroacetyi, trifluoroacetyl, benzoyl orp-bromophenacyl; triarylmethyl groups, in particular triphenylmethyl; silyl groups, in particular trimethylsilyl, dimethyl-t-butyl-silyl, diphenyl-t-butyl silyl; or also groups such as t-butoxycarbonyl, p-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyl, pyranyl and nitro. When, in particular, the R1 substituent in formula (I) is a hydroxyalkyl group, preferred protecting groups for the hydroxy function are p-nitro-benzyloxycarbonyl; dimethyl-t-butyl-silyl; diphenylt-butylsilyl; trimethylsilyl; 2,2,2-trichloroethoxycarbonyl; benzyl; p-bromo-phenacyl; triphenylmethyl and pyranyl. All the alkyl and alkenyl groups, including the aliphatic hydrocarbon moiety of the alkoxy, alkylthio and acyloxy groups, may be branched or straight.
According to the invention, the 2-thiacephems II in which Y represents a hydrogen atom, i.e. those of the general formula Ia
wherein R, and R2 are as above defined, are prepared from an azetidinone derivative of the general formula IV
wherein R2 and R2 are as above defined and Z represents (i) a group of the formula SR7 wherein R7 represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a heterocyclic group, (ii) a group of the formula SCOUR, wherein R8 represents an optionally substituted lower alkyl group, (iii) a group of the formula
wherein H9 and Rlo independently represent lower alkyl or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or (iv) a group of the formula
wherein R,1 represents an optionally substituted lower alkyl or aryl group, by a process comprising ozonolysing the carbon-carbon double bond, converting the hydroxy group in the resultant azetidinone to a halogen atom or an alkane sulphonyloxy group or an arene sulphonyloxy group and cyclising the resultant azetidinone by reaction with a sulphide or hydrosulphide in the presence of a base.
Also according to the invention, the 2-thiacephems Il in which Y represents a halogen atom, i.e. those of the general formula llb
wherein R, and R2 are as above defined and Hal represents a halogen atom, are prepared by the aforesaid process according to the invention and the further step of halogenating the methyl group either of the azetidinone IV prior to the steps of the aforesaid process or of the 2-thiacephem after the steps of the aforesaid process. The halogenation of the 2-thiacephem is effected by reaction with a halogenating agent in an inert organic solvent at a temperature of from 20"C to 130"C in the presence of a radical initiator and an acid scavenger.
This halogenation of the 3-methyl group of the 2-thiacephems Ila is most unexpected. Reasonable expectation would rule out the possibility of halogenating the 3-methyl group of the 2-thiacephems Ila owing to the presence of the disulphide moiety. Nevertheless, the halogention as described proceeds with high yields. Suitable halogenating agents are N-bromosuccinimide and N-chlorosuccinimide. The radical initiator may be azobisisobutyronitrile or benzoyl peroxide and the acid scavenger may be an epoxide (e.g. propylene oxide), an alkaline earth oxide (e.g. calcium oxide) or a molecular sieve. Suitable solvents are benzene, carbon tetrachloride and ethyl formate.
As stated, the halogenation may alternatively be effected on the azetidinone IV. This halogenation may be effected by methods known per se (allyl, ene-type, or electrochemical halogenation, see Tetrahedron Letters, 1980,71 and 351; 1981, 3193; 1982, 2187).
These processes are illustrated by the following reaction scheme wherein R1, R2, Z and Hal are as above defined and L represents a halogen atom, an alkane sulphonyloxy group or an arene sulphonyloxy group, preferably a methanesulphonyloxy group.
Compounds of the general formula IV, which are used as starting materials, are known compounds or can be obtained from known compounds by per se known procedures; the preparation of some representative entities is described in the Examples.
Following the right hand side of the reaction scheme, the compound of the general formula IV is first ozonolysed to give a compound of the general formula VI. The hydroxy group is then converted into a group L and the resultant compound of the general formula VIII is cyclised to give a compound of the general formula Ila. If desired, the methyl group may then be halogenated by the particular method above described to give a compound of the general formula Ilb.
Following the left hand side of the reaction scheme, the compound of the general formula IV may first be halogenated by one of the known methods above described. The resultant compound of the general formula V is then ozonolysed; the hydroxy group of the resultant compound of the general formula VII is then transformed into a group L and the resultant compound of the general formula IX is cyclised to give a compound of the general formula llb.
The transformation into a group L of the hydroxy group in the enol VI or VII, which may be in equilibrium with the corresponding keto-tautomer, is preferably a mesylation. We have surprisingly found that, when this reaction is carried out in tetrahydrofuran instead of the ubiquitously used halogenated hydro carbons, mesylates IX or VIII having Z alkene geometry, which are the most suitable ones for the subsequent cyclization, are almost exclusively obtained (similar transformation performed in dichloromethane usually affords a 1:1 mixture of E, Z isomers: see T.W. Doyle et al., Can. J. Chem., 1977, 55, 2873; M.J.
Pearson, J. Chem. Soc., Chem, Comm. 1981, 947; P.C. Cherry et al., J. Chem. Soc., Chem. Comm. 1979, 663). Cyclisation of VIII or IX may be carried out in a single step, by reaction with a sulphide or hydrosulphide, such as Na2S, NaHS, Bu4NHS, or with H2S in the presence of a base such as triethylamine or pyridine. The cyclisation of IX or VIII wherein Z represents a group other than SR7 offers the clear advantage of releasing easily separable, usually water soluble by-products ZH (e.g. phenylsulphinic acid, succinimide), instead of by products R3SH (e.g. mercaptobenzthiazole) which usually require chromatographic separation or precipitation as heavy metal salts (Ag+, Pub2+).
Finally according to the invention, the 2-thiacephems II in which Y represents an organic group may be prepared by the further step of converting the halomethyl group introduced by the halogenation into a methyl group substituted by the desired organic group. This conversion may be effected at any point after the introduction of the halomethyl group, that is on any of the compounds V, VII, IX and llb. It is, however, preferably carried out on the compound llb. The conversion may be carried out by reactions known per se.
For example, 1) a compound lib can be converted into a compound II (Y = free or protected OH) by mild alkaline hydrolysis, or by reaction with cuprous oxide/dimethylsulphoxide/water or by reaction with a salt of a strong inorganic acid, e.g. a nitrate or a perchlorate, thus obtaining a labile ester with the said inorganic acid, which ester may be hydrolyzed, subsequently or in the same reaction medium, to the desired parent alcohol. Preferred salts of this type are Ag NO3, AgCIO4 and NaNO3.
2) a compound llb can be converted into a compound II (Y = an unsubstituted or N-alkyl substituted carbamoyloxy group) by conversion into a compound II (Y = OH) as described above followed by reaction with a suitable isocyanate; for example, trichloroacetyl isocyanate is a preferred reagent for obtaining compounds II (Y = OCONH2), following deprotection of the trichloroacetyl moiety on the first formed urethane adduct; 3) a compound llb can be converted into a compound II (Y = acyloxy) by reaction with a suitable salt of the corresponding carboxylic acid in a suitable solvent or under phase-transfer catalysis; or by conversion into a compound II (Y = OH) followed by a conventional acylation; 4) a compound llb can be converted into a compound II (Y = S-Het) by reaction with the corresponding HS-Het in the presence of a base, or with a preformed salt of HS-Het with a base, in a suitable solvent, such as tetrahydrofuran, acetone, acetonitrile or dimethylformamide. A suitable base is triethylamine; a suitable preformed salt is a sodium salt, e.g. sodium 1-methyl-1,2,3,4-tetrazole-5-yl-mercaptide.
Owing to the pronounced propensity of 3-hydroxymethyl-2-thiacephem-4-carboxylates to lactonize, it is preferable that in the process 1) described above R2 represents a somewhat bulky group, forming with the linked carboxy moiety an ester possessing a relative inertness towards nucleophilic attack by the neighbouring hydroxy group, e.g. a tert-butyl ester.
The following Example illustrate the invention. The abbreviations Me, But, Ph, Ms, pNB, THF, EtOAc, DMSO, MeCN, stand respectively for methyl, t-butyl, phenyl, methanesulphonyl, p-nitrobenzyl, tetrahydrofuran, ethyl acetate, dimethylsulphoxide and acetonitrile. NMR spectra were taken either on a Hitachi Perkin Elmer 60 MHz apparatus, or on a Brucker 90MHz; separation of inner lines of AB quartets are referred to spectra taken on the latter. "Hitachi" is a Trade Mark.
Example 1 Diphenylmethyl 6,6-dibromopenicillanate 90 g of 6,6-Dibromopenicillanic acid in 450 ml of acetonitrile was treated with a solution of 49 g of diphenyldiazomethane in 150 ml of acetonitrile. After 1 hour at 20"C the formed solid was collected by filtration and washed with small portions of cold diethyl ether, thus obtaining 116 g of the title product. A second crop (9 g) was obtained by evaporation of the mother liquors and trituration with diethyl ether.
The overall yield was 95%.
Analytical sample was obtained by crystallization from chloroform; mp 157-158"C; may (CHCI3 film) 1800, 1750 cm-'; 3 (CDCl3) 1.24 and 1.58 (each 3H, s, CMe2), 4.61 (1H, s, N.CH.CO), 5.80 (1H, s, N.CH.S), 6.91 (1H, S. OCH), and 7.30 ppm (10H, s. Ar).
Found: C, 47.80; H, 3.63; N, 2.64; S, 5.95; Br, 30.49%. C2lH19Br2NO3S requires C, 48.02; H, 3.64; N, 2.67; S, 6.10; Br, 30.43%.
Example 2 t-Butyl 6, 6-dibromopenicillanate Method A 100 g of 6,6-dibromopenicillanic acid in 1 litre of diethyl ether at 0 C was sequentially treated with 37 ml of triethylamine and 56 g of phosphorus pentachloride. After 1 hour stirring, the reaction mixture was evaporated under vacuum (dry benzene added and removed). The crude acyl chloride was dissolved in 200 ml of dichloromethane and stirred for 24 hours with 500 ml of t-butanol in the presence of 50 g of calcium carbonate. The suspended salts were then filtered off, and the solution was washed with aqueous sodium bicarbonate solution (some unreacted starting material could be recovered by back-extraction of the acidified aqueous washings), decoloured with charcoal and evaporated to afford the title product, which was then crystallized from diisopropyl ether.Yield 69 g (60%); mp 120-121"C, vmax (CHCI3 film) 1800 and 1740 cm-1; 5 (CDCl3) 1.98 (15H, s, But and CH3), 2.05 (3H, s, CH3), 4.38 (1H,S, N.CH.CO) and 5.70 ppm (1H, s, N.CH.S).
Method B 15 g of 6,6-dibromopenicillanic acid in 300 ml of dichloromethane was stirred overnight with 25 g of O- t-butyl-N,N-diisopropyl-isourea. The reaction mixture was filtered and the solution washed with aqueous sodium bicarbonate solution. Crystallization of the product from diisopropyl ether gave the title compound, 8 9 (47%).
Example 3 Diphenylmethyl 6&alpha;-bromo-6ss-(1R-hydroxyethyl)-penicillanate 120 g of Diphenylmethyl 6,6-dibromopenicillanate, prepared as described in Example 1, in 900 ml of dry distilled THF under nitrogen at -75 C was treated with 1 molar equivalent of a solution of ethylmagnesium bromide in diethyl ether. After 20 min at -75 C, 25.7 ml of acetaldehyde was added and the mixture was further stirred for 20 min at -75 C. After quenching with 400 ml of saturated aqueous ammonium chloride, partition between water and diethyl ether followed by removal of the solvent left the crude product.This was fractionated by silica gel chromatography (benzene:ethyl acetate) to afford the title compound, 67 g (60%), as a foam, crystallizable (diisopropyl ether) to a solid, mp 65-700C; vmax (film) 3450, 1785 and 1740 cm-1; 5 (CDCl3) 1.22 and 1.60 (each 3H, s, CMe2), 1.29 (3H, d, J=6Hz, CH3.CH), 2.90 (1H, d, OH), 4.17 (1H, m, CH3.CH.OH), 4.58 (1H, s, N.CH.CO), 5.49 (1H, s, N.CH.S), 6.90 (1H, s, OCHPh2) and 7.3 ppm (10H, s. Ar).
Using t-butyl-6,6-dibromopenicillanate, prepared as described in Example 2, and proceeding similar, there were obtained t-butyl 6&alpha;-bromo-6ss-(1R-hydroxyethyl)-penicillanate in 65% yield after crystallization from diisopropyl ether: hexane; m.p. 93-95"C with decomposition; 5 (CDCl3) 1.28 (3H, d, J=6Hz, CH3.CH), 1.54 (12H, s, But and CH3), 1.65 (3H, s, CH3), 2.65 (1H, s, CH.OH), 4.25 (1H, m, CH3.CH(OH).CH), 4.40 (1H, s, N- CH.CO) and 5.51 ppm (1H, s, N.CH.S).
Example 4 Diphenylmethyl 6&alpha;-(1R-hydroxyethyl)-penicillanate-1-oxide 52 g of Diphenylmethyl 6&alpha;-bromo-6ss-(1R-hydroxyethyl)-penicillanate, prepared as described in Example 3, in 400 ml of 95% ethanol was hydrogenated at 20700 pascals in the presence of 25 g of 10% by weight palladium-on-calcium carbonate and 11 g of calcium carbonate. The reaction mixture was filtered and evaporated to afford a residue which was partitioned between brine and dichloro-methane. Removal of the solvent left crude diphenyl-methyl 6cl-(1 R-hydroxyethyl )-penicillanate, which was oxidized with 17 g of 85% MCPBA in 500 ml of chloroform at 0-50C for 1 hour.The filtered solution was then washed with aqueous sodium bicarbonate solution and the solvent removed to leave 40 g (88%) of the crude title product as a foam, which can be used as such or purified by silica gel chromatography; vmax (CHCI3 film) 1790 and 1750 cm-1; 5 (CDCl3) 0.94 and 1.67 (each 3H, s, CMe2), 1.37 (3H, d, J=6Hz), 3.55 (1H, dd, J=2 and 6.5Hz, CH.CH.CH), 4.25 (1H, m, CH3.CH(OH).CH), 464 (1H, s, N.CH.CO), 4.98 (1H, d, J=2Hz, CH.CH.S), 6.98 (lH, s, OCHPh3) and 7.30 ppm (10H, s, Ar).
Using a similar procedure, but starting from t-butyl 6&alpha;-bromo-6ss-(1R-hydroxyethyl)-penicillanate, prepared as described in Example 3, there was obtained t-butyl 6&alpha;-(1R-hydroxyethyl)-penicillanate-1-oxide: yield 75%: may (film) 3440, 1785 and 1740 cm-1.
Example 5 Diphenylmethyl 6s iR-t-h utyldimeth ylsllyloxyethy)-peniclllana te- oxide 40 g of crude diphenylmethyl 6&alpha;-(1R-hydroxyethyl)-penicillanate-1-oxide, prepared as described in Example 4, was dissolved in 350 ml of DMF and stirred for 3 hours at 50-550C in the presence of 18.5 g of imidazole and 27 g of t-butyidimethylsilyl chloride. The reaction mixture was partitioned between diethyl ether and brine and the organic layer washed several times with water.Evaporation of the solvent and silica gel chromatography afforded the title product; yield 22 g; vmax (CHCI3 film) 1790 and 1755 cm-1; 5 (CDCl3) 0.06 (6H, s, SiMe2), 0.88 (13H, s, But and CH3), 1.3 (3H, d, J=6Hz, CH3.CH), 1.7 (3H, s, CH3), 3.4 (1H, dd, J=2 and 4.5Hz, CH.CH.CH), 4.40 (1H, m, CH3-CH.CH) 4.55 (1H, s, N.CH.CO), 4.88 (1H, d, J=2, CH.CH.S), 6.9 (1H,SOCH Ph3), and 7.25 ppm (10H, s. Ar).
By using a similar procedure, but starting from t-butyl 6&alpha;-(1R-hydroxyethyl)-penicillanate-1-oxide, prepared as described in Example 4, there was obtained t-butyl 6-(i'R-t-butyldimethylsllyloxyethyl)-peniclllan- ate-l-oxide in overall yield 55% from the 6a-bromoprecursor; vmax (CHCI3 film) 1785 and 1750 cm-1; 5 (CDCl3) 0.06 (6H, s, SiMe2), 0.88 (9H, s, SiBu'), 1.25 and 1.66 (each 3H, s, CMe2), 1.28 (3H, d, J=6Hz, CH3.CH), 1.45 (9H, s, OBu'), 3.5 (1H, dd, J=2 and 5Hz, CH.CH.CH), 4.4 (1H, s, N.CH.CO), 4.5 (1H, m, CH3.CH.CH) and 4.9 ppm (1H, d, J=2Hz, CH.CH.S) Example 6 Diphenylmethyl 6&alpha;;-(1R-p-nitrobenzyloxycarbonyloxyethyl)-penicillate-1-oxide Diphenylmethyl 6&alpha;-(1R-hydroxyethyl)-penicillanate-1-oxide, prepared as described in Example 4, was acylated with p-nitrobenzylchlorocarbonate by using N,N-dimethylamino-pyridine as a base and ethanolfree dichloromethane as solvent, according to a general method, thus obtaining the title product as a foam; 5 (CDCl3) 0.96 and 1.70 (each 3H, s, CMe2), 1.52 (3H, d, J=6Hz, CH3.CH), 3.83 (1H, dd, J=2 and 6Hz, CH.CH.CH), 4.66 (1H, s, N.CH.CO), 4.99 (1H, d, J=2Hz, CH.CH.S), 5.28 (2H, s, OCH2Ph), 5.35 (1H, m, CH3.CH.CH), 7.01 (1H, s, OCHPh2), 7.40 (10H, m, Ar), 7.55 and 8.26 ppm (each 2H, d, J=8Hz, Ar).
Following the same experimental procedure, there was obtained t-butyl 6O-{1Rp-nitrobenzyloxycarbon- yloxyethyl2-penicillanate- oxide Following the same experimental procedures, but using trichloroethylchlorocarbonate instead of p-nitro-benzylchlorocarbonate, there were also obtained: t-butyl-6&alpha;-(1R-trichloroethyloxycarbonyloxyethyl)-penicillanate-1-oxide diphenylmethyl 6a-( iR-trichloroethyloxycarhonyloxyethyl)-peniclllanate- i-oxide Example 7 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-methoxy-carbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one A mixture of 5 g of methyl 6O-(1 R-hydroxyethyl)-penicillanate-1-oxide and 3.04 g of 2-mercaptobenzthiazole was refluxed for 2 hours in dry toluene.The solvent was removed in vacuo and the crude product used as such for the next step.
Using similar procedures, there were obtained: 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)azetidin-2-one, starting from methyl 6&alpha;-(1R-t-butyl-dimethylsilyloxyethyl)-penicillanate-1-oxide, and prolonging the reaction time up to 6 hours; may (CHCI3 film) 1770 and 1744 cm-1, 5 (CDCl3) 0.02 and 0.04 (each 3H, s, SiMe2), 0.84 (9H, s, SiBut), 1.23 (3H, d, J=6Hz, CH93.CH), 1.91 (3H, s, =C.CH3), 3.38 (1H, dd, J=2 and 3.5 Hz, CH.CH.CH), 3.69 (3H, s, OCH3), 4.23 (1H, m, CH3.CH.CH), 4.82 (1H, s, N.CH.CO), 5.07 (2H, m.CH2=C), 5.42 (1H, d, J=2Hz, CH.CH.S) and 7.2-7.9 ppm (4H, m, Ar); 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one, starting from diphenylmethyl 6&alpha;-(1R-hydroxy-ethyl)-penicillanate-1-oxide; AmaX (CHCI3 film) 3400, 1765 and 1740 cm-1; 8(CDCI3) 1.22 (3H, d, J=6Hz, CH3.CH), 1.60 (3H, s, =C.CH3), 2.78 (1H, Br s, OH), 3.42 (1H, dd, J=2 and 6Hz, CH.CH.CH), 4.18 (1H, m CH3. CHOH.CH), 4.93 (1H, s, N.CH.CO), 4.90-5.10 (2H, m, CH2=C), 5.38 (1H, d, J=2Hz, CH.CH.S), 6.89 (1H, s, OCHPh2) and 7.15-7.90 ppm (14H, m.Ar); 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzothiazolyl-dithio-1-(1-t-butoxycarbonyl-2-methyl-1-prop-2enyl)-azetidin-2-one, starting from t-butyl 6&alpha;-(1R-t-butyl-dimethylsilyloxyethyl)-penicillanate-1-oxide; reaction time 6 hours; 3 (CDCl3) 0.06 (6H, s, SiMe2), 0.9 (9H, s, SiBu'), 1.26 (3H, d, J=6Hz, CH3.CH), 1.48 (9H, s, OBut), 1.95 (3H, s, =C.CH3), 3.40 (1H, dd, J=2 and 4Hz, CH.CH.CH), 4.20 (1H, m, CH3.CH.CH), 4.71 (1H, s, N.CH.CO), 5.1 2H, br s, CH2=C), 5.42 (1H, d, J=2Hz, CH.CH.S) and 7.2-7.9 ppm (4H, mAr); 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-diphenylmethoxycarbonyl-2-methyl-1prop-2-enyl)-azetidin-2-one, vmax (film) 1722 and 1743 cm 1;; 5 (CDCl3) 0.05 (6H, s,SiMe2), 0.80 (9H, s, SiBut), 1.29 (3H, d, J=6Hz, CH3.CH), 1.95 (3H, s, =C.CH3), 3.45 (1H, dd, J=2 and 4Hz, CH.CH.CH), 4.26 (1H, m, CH3.CH.CH), 4.95 (1H, s, N.CH.CO), 5.08 (2H, ABq, separation of inner lines 5Hz, CH2=C), 5.55 (1H, d, J=2Hz, CH.CH.S), 6.93 (1H, s, OCHPh2) and 7.1-8.0 ppm (14H, m, Ar); 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2enyl)-azetidin-2-one, starting from methyl 6a-( 1 R4richloro ethoxyca rbonyloxyethyl)-penicillanate-1 -oxide: v (CHCl3) 1775 and 1745 cm-1; 5 (CDCl3) 1.48 (3H, d, J=6Hz, CH3.CH), 1.91 (3H, s, =C.CH3), 3.69 (3H, s, OCH3), 3.70 (1H, dd, CH.CH.CH), 4.68 (s, 2H, OCH2), 4.76 (1H, s, N.CH.CO), 5.03-5.30 (2H, m, CH2=C), 5.23 (1H, m, CH3.CH.CH), 5.32 (1H, d, J=2Hz, CH.CH.S) and 7.10-7.96 ppm (4H, m, Ar); and, in a likewise fashion, starting from the corresponding t-butyl and diphenylmethyl penicillanates, 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-t-butoxycarbonyl-2-methyl-1-prop-2enyl)-azetidin-2-one; 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-diphenylmethoxycarbonyl-2-methyl i-prop-2-enyl)-azetidin-2-one; and starting from methyl 6ss-(1R-t-butyldimethylsilyloxy-ethyl)-penicillanate-1-oxide, 3R-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-methyl-1-prop-2-enyl)azetidin-2-one.
Example 8 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio- 7-/7-methoxy-carbonyl-2-hydroxy- i-prop- 1-enyl)-azetidin-2- one The crude 3S-(1 R-hydroxyethyl)-4R-benzthiazolyldithio-1-( -(1 -methoxycarbonyl-2-methyl-1 -prop-2-enyl)- azetidin-2-one obtained in Example 7 was dissolved in 300 ml of dry dichloromethane and treated with a stream of ozone at -70 C until TLC showed that all the starting material had reacted. The solution was purged with nitrogen and then 10 g of sodium metabisulphite was added at -30 C. The mixture was allowed to rise to room temperature under vigorous stirring, and then filtered.The solution was washed with 4 % aqueous sodium bicarbonate solution, dried over anhydrous sodium sulphate and evaporated.
The residue was taken up in diethyl ether, the undissolved matter was filtered off and the solution was evaporated to give the crude title product. An aliquot was purified by flash chromatography over silica gel (ethyl acetate:cyclohexane as eluant); 5 (CDCl3) 1.35 (3H, d, J=7Hz, CH3.CH), 2.11 (3H, s, CH3), 2.75 (1H, Br s, OH), 3.44 (1H, dd, J=2.0 and 5.0Hz, CH.CH.CH), 3.79 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.29 (1H, d, J=2.0Hz, CH.CH.S) and 7.25-7.95 ppm (4H, m, Ar).
By using a similar procedure, there were obtained: 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1enyl)-azetidin-2-one, starting from crude 3S-(1R-t-butyldimethyl-silyloxyethyl)-4R-benzthiazolyldithio-1-(1methoxy-carbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one; v , (film) 3350, 1770 and 1660 cm-1; 5 (CDCI3) 0.05 and 0.07 (6H, each s, SiMe2), 0.87 (9H, s, SiBut), 1.27 (3H, d, J=6.5Hz, CH3.CH), 2.07 (3H, s, =C.CH3), 3.33 (1H, dd, J=2.2 and 4.2Hz, CH.CH.CH), 3.74 (3H, s, OCH3), 4.26 (1H, m, CH3.CH.CH), 5.36 (1H, d, J=2.2Hz, CH.CH.S), 7.2-7.9 (4H, m, Ar) and 12.37 ppm (1H, br s, OH); 3R-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1enyl)-azetidin-2-one, starting form 3R-(1 R-t-butyldimethyl-silyloxyethyl)-4R-benzthiazolyldithio-1-(1-meth- oxy-carbonyl-2-methyl-1-prop-2-enyl)-azetidin-2-one; vmax (film) 3200, 1773, 1710, 1665 and 1620 cm-1; 5 (CDCl3) 0.20 (6H, s, SiMe2), 0.94 (9H, s, SiBut), 1.52 (3H, d, J=6Hz, CH3.CH), 2.17 (3H, br s, =C.CH3), 3.6-3.7 (4H, s+dd, OCH3 and CH.CH.CH), 4.4 (1H, m, CH3.CH.CH), 5.25 (1H, d, CH.CH.S) and 7.3-7.9 ppm (4H, m, Ar); 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one, starting from crude 3S-(1 R-hydroxyethyl )-4R-benzthiazolyldithio-1-(1-diphenyl methoxycarbonyl2-methyl-1-prop-2-enyl)-2-azetidin-2-one; vmax (CHCI3 film) 3400, 1770, 1730 and 1650 cm-1; 3S-01R-t-butyidimethylsilyloxyethyl)-4R-benzthiazolyl-dithio- 1-{1-dEphenylmethoxycarbonyl-2-hydroxy- 1prop- 1-enyl)-azetidin-2-one, starting from crude 3S(1 R-t-butyl-dimethylsilyloxyethyl)-4R-benzthiazolyidi- thio-1 -(1 -diphenylmethoxycarbonyl-2-methyl-1 -prop-2-enyl)- -azetidin-2-one;vmax (CHCI3 film) 3400, 1775, 1735, 1700 sh, 1655 and 1610 cm-1; 5 (CDCI3) 0.06 (6H, s, SiMe2), 0.82 (9H, s, But), 1.26 (3H, d, J=6Hz, CH3.CH), 2.08 (3H, s, =C.CH3), 3.33 (1H, dd, J=3 and 5.5Hz, CH.CH.CH), 4.18 (1H, m, CH3.CH.CH), 5.22 (1H, d, J=2Hz, CH.CH.S), 6.86 (1H, s, OCHPh2) and 7.2-7.9 ppm (14H, mAr);; and 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop i-enyl)-azeUdin-2-one; 5 (CDCl3) 1.50 (3H, d, J=6Hz, CH3.CH), 2.14 (3H, s, =C.CH3), 3.67 (1H, dd, J=2.2 and 5.5Hz, CH.CH.CH), 3.82 (3H, s, OCH3), 4.62 (2H, ABq, J=12Hz, separation of inner lines 2Hz, OCH2), 5.105.40 (2H, m, CH3.CH.CH and CH.CH.S), 7.20-8.00 (4H, m, Ar) and 12.40 ppm (1H, br s, OH); and in a likewise fashion, starting from the corresponding t-butyl and diphenylmethyl ester, 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-t-butoxycarbonyl-2-hydroxy-1-prop-1enyl)-azetidin-2-one; 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy 1-prop-1-enyl)-azetidin-2-one; and 3S-{1R-t-butyidimethylsilyloxyethylJ-4R-benzthiazolyl-dithio- 1-r1-t-butoxycarbonyl-2-hydroxy- i-prop- 1-enylazetidin-2-one.
Example 9 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)azetidin-2-one A solution of 130 mg (0.03 mmol) of 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbonyl- 2-hydroxy-1-prop-1-enyl)-azetidin-2-one, prepared as described in Example 8, in 8 ml of anhydrous dichloromethane was sequentially treated at -40 C with 0.043 ml (0.3 mmol) of triethylamine and 0.024 ml (0.31 mmol) of methane-sulphonyl chloride. The reaction was quenched after 5 minutes with cold 2% aqueous sodium bicarbonate solution. Removal of the solvent from the organic layer gave the crude title product (quantitative yield), which was used as such for the next step.
By following the same experimental procedure, there was obtained: 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy 1-prop- 1-enyl)-azetidin-2-one, starting from 3S-(1 R-t-butyl-dimethylsilyloxyethyl )-4R-benzthiazolyldithio-1 (1 -methoxycarbonyl-2-hydroxy-1 -prop-1 -enyl)-azetidin-2-one; an aliquot of this product was purified by flash chromatography (silica gel; ethyl acetate-cyclohexane as eluant) to afford the pure title compound as a 1:1 mixture of E and Z isomers; vmax (film) 1885, 1730, 1363 and 1165 cm-1; # (CDCl3) 0.05 and 0.10 (each 3H, s, SiMe2), 0.88 (9H, s, SiBu'), 1.29 (3H, d, J=6.5Hz, CH3.CH), 2.20 and 2.53 (3H, each s, =C.CH3), 3.18 and 3.29 (3H, each s, SO2CH3), 3.42 (1H, m, CH.CHCH), 3.71 and 3.78 (3H, each s, OCH3), 4.30 (1H, m, CH3.CH.CH), 5.59 and 5.64 (1H, each d, J=2Hz, CH.CH.S) and 7.12-7.96 ppm (4H, m, Ar).
When tetrahydrofuran was used instead of dichloromethane as a solvent, the formation of the undesired E isomer was almost suppressed, and the pure Z isomer thus collected; 5 (CDCl3) 0.05 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.29 (3H, d, J=6.5Hz, CH30H), 2.53 (3H, s, =C.CH3), 3.29 (3H, s, SO3CH3), 3.42 (1H, dd, J=2 and 5Hz, CH.CH.CH), 3.71 (3H, s, OCH3), 4.30 (1H, m, CH2. CH.CH), 5.59 (1H, d, J=2Hz, CH.CH.S) and 7.12-7.95 ppm (4H, m. Ar).
By following this last procedure (tetrahydroduran as a solvent in the mesylation step), there were obtained: 3R- I iR-t-b utyldim ethylsilyloxyethyl)-4R-benzthiazolyl-dithio- 1-[1-methoxycarbonyl-2-methylsulphonyloxy- 1-prop-1-(Z)-enyl]-azetidin-2-one, starting from 3R-( 1 R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio- 1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; vmax (CHCl3 film) 1775, 1735, 1365 and 1165 cm 5 (CDCl3) 0.18 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.42 (3H, d, J=6.5Hz, CH3.CH), 2.33 (3H, s, =C.CH3), 3.05 (3H, s, SO3CH3), 3.45 (3H, s,OCH3), 3.62 (1H, dd, CH.CH.CH), 4.3 (1H, m, CH3.CH.CH), 5.40 (1H, d, J=5Hz, CH.CH.S) and 7.15-7.85 ppm (4H, m, Ar); 3S-(1R-hydroxyethyl)-4R-benzthiazolyldithio-1-[1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop 1-(Z)-enyl]-azetidin-2-one, starting from 3S-(1 R-hydroxy-ethyl )-4R-benzthiazolyldith io-1 -(1 -di phenyl methoxy-carbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; may (film) 3400, 1775, 1730, 1365 and 1170 cm-1; 5 (CDCl3) 1.22 (3H, d, J=6.5Hz, CH3.CH), 2.43 (3H, s, =C.CH3), 3.13 (3H, s, SO3CH3), 3.35 (1H, dd, J=2.5 and 4Hz, CH.CH.CH), 4.1 (1H, m, CH3.CH.CH), 5.40 (1H, d, J=2.5Hz, CH.CH.S), 6.85 (1H, s, OCHPh2) and 7.1-7.9 ppm (14H, m, Ar);3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-[1-diphenylmethoxycarbonyl-2-(Z)-methylsulphonyl-oxy-1-prop-1-enyl]-azetidin-2-one, starting from 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; vmax (CHCl3 film) 1775, 1725, 1370 and 1175cm-1; 8 (CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.28 (3H, d, J=6Hz, CH3.CH), 2.5 (3H, s, =C.CH3), 3.25 (3H, s, SO3CH3), 3.35 (1H, dd, J=2.5 and 5Hz, CH.CH.CH), 4.20 (1H, m, CH3.CH.CH), 5.50 (1H, d, J=2.5Hz, CH.CH.S), 6.9 (1H, s, OCHPh3) and 7.1-7.9 ppm (14H, m, Ar); 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-[1-t-butoxycarbonyl-2-(Z)-methylsulphonyloxy-1-prop-1-enyl]-azetidin-2-one, starting from 3S-(1 R-t-butyldimethylsilyloxyethyl )-4R-benzthiazolyldithio-1-(1-butoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; v= (film) 1773, 1710, 1370 and 1165 cm-1; 5 (CDCl3) 0.06 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.25 (3H, d, J=6Hz, CH3.CH), 1.49 (9H, si, OBut), 2.45 (3H, s, =C.CH3), 3.25 (3H, s, SO3CH3), 3.35 (1H, dd, J=2.5 and 5Hz), 4.3 (1H, m, CH3.CH.CH), 5.60 (1H, d, J=2.5Hz, CH.CH.S) and 7.1-7.9 ppm (4H, m, Ar); and 3S-(1R-trichloroethoxycarbonyloxyethyl-4R-benzthiazolyl-dithio-1-[1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl]-azetidin-2-one, starting from 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2-one; vmax (CHCl3 film) 1780, 1755 sh, 1730, 1380, 1250 and 1167 cm-1; 5 (CDCI3) 1.48 (3H, d, J=6Hz, CH3.CH), 2.52 (3H, s, =C.CH3), 3.25 (3H, s, SO3CH3), 3.72 (4H, s+dd, OCH3 and CH.CH.CH), 4.68, (2H, s, OCH3), 5.2 (1H, m. Ch3.CK.CH), 5.47 (1H, d, J=2.5Hz, CH.CH.S) and 7.1-7.9 ppm (4H, m, Ar); and likewise, starting from the corresponding t-butyl and diphenylmethyl esters, there was obtained: 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-[1-t-butoxycarbonyl-2-methylsulphonyloxy- i-prop- 1(Z)-en ylj-azetidin-2-one; and 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyl-dithio-1-[1-diphenylmethoxycarbonyl-2-methylsulphonyloxy- i-prop- 1(Z)-en ylLazetidin -2-one.
Example 10 3S-(1R-methylsulphonyloxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1prop- 1-enyl)-azetidin-2-one.
When in the reaction described in Example 9 the starting material was exposed to an excess (2 molar equivalents) of methanesulphonylchloride and triethylamine, the title product was obtained as a foam in quantitative yield as a mixture of E (20%) and Z (80%) isomers; vmax (film) 1780, 1730, 1360 and 1170 cm-1; 5 (CDCI3) 1.58 (3H, d, J=6Hz, CH3.CH), 2.22 and 2.56 (3H, each s, =C.CH3 of E and Z isomers), 3.00 (3H, s, CH3SO2 on the hydroxyethyl chain), 3.20 (1H, dd, J=2.2 and 4.5Hz, CH.CH.CH), 3.28 (3H, s, CH3SO2 on the crotonic appendage), 3.76 (3H, s, OCH3), 5.11 (1H, m, CH3.CH.CH), 5.52 (1H, d, J=2.2Hz, CH.CH.S) and 7.30-7.95 ppm (4H, m, Ar).
By following the same procedure, but using THF as a solvent, 3S-(1R-methylsulphonyloxyethyl)-4R- benzthiazolyl-dithio- 1-[1-diphenylmethoxycarbonyl-2-methylsulphonyloxy- i-prop- I-(Zl-en yl]-azetidin-2-one was prepared and displayed the following spectral data: may (film) 1777, 1728, 1360 and 1170 cm-1; 5 (CDCl3) 1.50 (3H, d, J=6Hz, CH3.CH), 2.52 (3H, s, =C.CH3), 2.9 (3H, s, CH3SO2 on the hydroxyethyl chain), 3.23 (3H, s, CH3SO2 on the crotonic appendage), 3.62 (1H, dd, J=2.5 and 5.5Hz, CH.CH.CH), 5.05 (1H, m, CH3.CH.CH), 5.45 (1H, d, J--2.5Hz, CH.CH.S), 6.95 (1H, s, OCHPh3) and 7.10-7.95 ppm (14H, m, Ar).
Example ii 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1-methoxycarbonyl-2-trifluoromethylsulphonyloxy- 1-prop- 1-enyl)-azetidin-2-one 300 mg of crude 3S-(1 R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1 -(1 -methoxycarbonyl-2-hy- droxy-1-prop-1-enyl)-azetidin-2-one in 5 ml of THF at -40OC was sequentially treated with 0.170 ml of triethylamine and 0.180 ml of trifluoromethanesulphonic anhydride. Work-up and chromatography gave the two separate geometrical isomers of the title product, as foams: E isomer: vmax (CHCIs) 1778, 1730, 1420, 1215 and 1135cm-1; 5 ( CDCl2)0.08 (6H,s, SiMe2), 0.86 (9H, s, SiBu'), 1.26 (3H, d, J=6Hz, CH3.CH), 2.05 (3H, s, =C.CH3), 3.46 (1H, dd, 2.2 and 4Hz, CH.CH.CH), 3.81 (3H, s, OCH3), 4.28 (1H, m, CH3.CH.CH), 5.76 (1H, d, J=2.2Hz, CH.CH.S) and 7.25-7.90 (4H, m, Ar); Z isomer (inter alia) 5 (CDCI3) 2.45 (3H, s, =C.CH3), 3.40 (1H, dd, J=2 and 4Hz, CH.CH.CH), 3.64 (3H, s, OCH3), 4.30 (1H, m, CH3.CH.CH) and 5.65 ppm (1H, d, J=2Hz, CH.CH.S).
Example 12 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 0.5 ml of triethylamine in 10 ml of dichloromethane was saturated at -50 C with hydrogen sulphide. After purging with nitrogen, 0.34 ml of this solution was added to a cold (-50 C) solution of 75 mg (0.121 mmol) of 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycar- bonyl-2-methyl-sulphonyloxy-1-prop-1-enyl)-azetidin-2-one. The mixture was allowed to warm up to room temperature and then washed with water, dried on anhydrous sodium sulphate and evaporated.Separation of the new compound from the formed 2-mercaptobenzthiazole and minor impurities was achieved by silica gel chromatography (ethyl acetate: cyclohexane as eluant), thus obtaining the title compound as white crystals (19 mg, 20%), mp 85-87 C, A maX (EtOH) 223 ( 4,773), 277 (6,335), and 326 (2,922) nm, vmax (CHCl3film) 1785 and 1730 cm-l; 3 (CDCl3) 0.08 (6H, s, SiMe2), 0.88 (9H, s, SiBut), 1.25 (3H, d, J=6Hz, CH3.CH), 2.22(3H, s, CH3), 3.07 (1H, dd, J=2.2 and 3.5Hz, CH.CH.CH), 3.8 (3H, s, OMe), 4.36 (1H, m.
CH3.CH.CH) and 4.62 ppm (1H, d, J=2.2Hz, CH.CH.S).
Found: C, 49.08; H, 6.96; N, 3.52; S, 15.16. C16H2,NO4SiS2 requires C, 49,32; H, 6.99; N, 3.60; S, 16.46% When, instead of hydrogen sulphide and triethylamine, a solution of NaHS(0.9 mol equiv) in DMF was used, and quenching (partition between water and ethyl acetate) followed within 1 minute at OOC, the isolated yield of the pure title product was raised to 40-45%.
When the above process was performed on the geometrical Z isomer of the starting material, the yield was further enhanced (up to 60-65%). On the contrary, the E isomer afforded only a very low amount of the title product.
By following the same experimental procedure, methyl (7R,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate was obtained starting from 3R-( 1 R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyl-dithio-1-(1 -methoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one; may (film) 1785 and 1725 cm-l; 3 (CD3COCD3) 0.03 and 0.05 (each 3H, s, SiMe2), 0.84 (9H, s, SiBut), 1.19 (3H, d, 6.5 Hz, CH3.CH), 2.08 (3H, s, CH3), 3.72 (3H, s, OCH3), 4.11 (1H, dd, J=5.5 and 8.0Hz, CH.CH.CH), 4.20 (1H, m, CH3.CK.CH) and 5.01 ppm (1H, d, J=5.5Hz, CH.CH.S).
Example 13 Methyl (75, 6R)-7-( iR-h ydroxyeth yl)-3-methyl-2-thiacephem-4-carb oxylate 145 mg (0.287 m mol) of crude 3S-(1R-hydroxyethyl)-4R-benzothiazolyldithio-1-(1-methoxycarbonyl-2- methyl-sulphonyloxy-1-prop-1-enyl)-azetidin-2-one, prepared as described in Example 9, was dissolved in 2 ml of anhydrous dimethylformamide and treated at +20 C with a freshly prepared solution of 16 mg (0.287 mmol) of NaHS in 1.6 ml of the same solvent. The mixture was stirred for 2 minutes and then partitioned between ethyl acetate and water.
After repeated washings with water, the solvent was removed leaving a residue which was purified by pressure chromatography on silica gel (ethyl acetate cyclohexane as eluant) to give the pure title product in 45% yield as a white powder; vma, (nujol) 3400, 1770 and 1720 cm-1; 3 (CDCl3) 1.37 (3H d J=7Hz CH3.CH); 2.22 (3H, s, CH3), 2.40 (1H, br s, OH), 3.12 (1H, dd, J=2.0 and 4.5Hz, CH.CH.CH), 3.86 (3H, s, OCH2), 4.35 (1H, m, CH3.CH.CH) and 4.65 ppm (1H, d, J=2.0Hz, CH.CH.S).
By following a similar experimental procedure, there were obtained: Diphenylmethyl (7S,6R)-7-(1R-hydroxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S-(1Rhydroxy-ethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1enyl)-azetidin-2-one; XmaX (EtOH) 281 (8= 5,900) and 326 (3,670) mm; may (KBr) 3550-3250, 3080, 3060, 3020, 2960, 2920, 2840, 1775, 1720, 1660 and 1490 cm-1; 3 (CDCl3) 1.36 (3H, d, J=6.5Hz, CH3.CH), 2.17 (3H, s, CH3), 3.12 (1H, dd, J=2.0 and 5Hz, CH.CH.CH), 4.36 (1H, m. CH3.CH.CH), 4.76 (1H, d, J=2.0Hz, CH.CH.S), 6.97 (1H, s, OCH2Ph) and 7.30 (10H, m, Ar);; Diphenylmethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-diphenylmethoxycarbonyl-2-methylsulphonyloxy-1-prop-1-enyl)-azetidin-2-one; 3 (CDCl3) 0.06 (6H, s, SiMe2); 0.83 (9H, s, SiBut); 1.27 (3H, d, J=6.5Hz, CH3.CH), 2.05 (3H, s, CH3), 3.08 (1H, dd, J=3.0 and 5.0Hz, CH.CH.CH), 4.32 (1H, m, CH3.CH.CH), 4.60 (1H, d, J=3.0Hz, CH.Cll.S), 7.02 (1H, s, OCHPh2) and 7.30 ppm (10H, s, Ar); t-Butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S (1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-t-butoxycarbonyl-2-methylsulphonyloxy-1prop-1-enyl)-azetidin-2-one; ajax (CHCI3) 278 (= 6,300 ) and 327 nm (E= 2,560); vmax (CHCI3 film) 1780 and 1720 cm-l; 3 (CDCl3) 0.12 (6H, s, SiMe2), 0.88 (9H,s, SiBut), 1.25 (3H, d, J=6Hz, CH3.CH), 1.52 (9H, s, OBut), 2.10 (3H, s, CH3), 3.02 (lH, dd, J=2.5 and 5Hz, CH.CH.CH), 4.28 (1H, m, CH3.CH.CH) and 4.53 ppm (1H, d, J=2.5Hz, CH.CH.S); Methyl (7S,6R)-7-(1R-methylsulphonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S (1 R-methyl-sulphonyloxyethyl )-4R-benzthiazolyldithio-1 -(1 -methoxy-carbonyl-2-methylsulphonyloxy-1- prop-1-enyl)-azetidin-2- -one; vmax 1780, 1725, 1360 and 1175 cm-1; 3 (CDCl3) 1.60 (3H, d, J=6.5Hz, CH3.CH), 2.25 (3H, s, CH3), 3.07 (3H, s, CH3SO2), 3.27 (1H, dd, J=2.2 and 5Hz, CH.CH.CH),3.83 (3H, s, OCH2), 4.70 (1H, d, J=2.2Hz, CH.CH.S) and 5.24 ppm (1H, m, CH3CH.CH) Diphenylmethyl (7S,6R)-7-(1R-methylsulphonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S-( 1 R-methylsu lphonyloxyethyl)-4R-benzthiazolyldithio-1 -(1 -diphenylmethoxycarbonyl-2-methylsul phonyloxy-1-prop-1-enyl)-azetidin-2-one; # max (CHCl3) 282 (#= 7,080) and 330 (3,966) nm; vmax (CHCl3 film) 1778, 1720, 1255 and 1170 cml; 5 (CDCl3) 1.53 (3H, d, J=6Hz, CH3.CH), 2.10 (3H, s, CH3), 2.71 (3H, s, CH3SO2), 3.22 (1H, dd, J=2.5 and 5.5 Hz, CH.CH.CH), 4.67 (1H, d, J=2.5 Hz, CH.CH.S), 5.05 (1H, m, CH3.CH.CH); 6.90 (1H, s, OCHPh3) and 7.25 (10H, s, Ar); Methyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from 3S-(1 R-trichloroethoxycarbonyloxyethyl)-4R-benzthiazolyidithio-1 -(1 -methoxycarbonyl-2-methylsulphony- loxy-1-prop-1-enyl)-azetidin-2-one; may (film) 1787, 1760 sh, 1725 and 1250 cm-1; 5 (CDCl3) 1.54 (3H, d, J=5.5Hz, CH3.CH), 2.23 (3H, s, CH3), 3.30 (1H, dd, J=2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OCH3), 4.68 (1H, d, J=2Hz, CH.CH.S), 4.78 (2H, s, OCH2) and 5.37 ppm (1H, m, CH3.CH.CH); and Diphenylmethyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate, starting from (3S)-(1 R-p-nitrobenzyloxycarbonyloxyethyl)-4R -benz-thiazolyldithio-1-( -(1 -diphenyl methoxy carbonyl-2-methyl-sulphonyloxy-1-prop-1-enyl)-azetidin-2-one; may 1787, 1745, 1720 sh cm-1; 5 (CDCl3) 1.53 (3H, d, CH3 CH), 2.17 (3H, s, CH3), 3.28 (1H, dd, J=2 and 6.5Hz, CH-CH-CH), 4.65 (1H, d, J=2Hz, CH.CH.S), 5.15 (2H, s, OCH2), 5.28 (1H, m, CH2.CH.CH), 6.97 (1H, s, OCHPh2), 7.2-7.5 (12H, m, Ar) and 8.17 ppm (2H, d, J=9Hz, Ar); and, likewise, there were obtained: t-butyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; diphenylmethyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate; trichloroethyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxy- ethyl)-3-methyl-2-thiacephem-4-carboxylate; trichloroethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; acetoxymethyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate; acetoxymethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; and acetoxymethyl (7S,6R)-7-(1R-trimethylsilyloxyethyl)-3-methyl-2-thiacephem-carboxylate.
Example 14 35-rl R-t-butyidimethylsilyloxyethyl)-4R-succinimidothio- 1-r1-methoxycarbonyl-2-methyl- i-prop-2-en yl)- azetidin-2-one A solution of 2.32 g of methyl 6&alpha;-(1R-t-butyldimethyl-silyloxyethyl)-penicillanate-1-oxide in 35 ml of dimethylacetamide was treated with 0.15 ml of acetic acid, purged with nitrogen, and heated for 3 1/2 hours at 105 C in the presence of 5 g of N-trimethylsilyl-succinimide. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and cold water.Fractionation of the material obtained from the organic layer (silica gel chromatography, ethyl acetate:cyclohexane) afforded the title product as a white foam, 1.2 g (43%); vmax (CHCI3 film) 1770, 1735, 1710 sh and 1680 cm-1; 5 (CDCl3) 0.08 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.32 (3H, d, J=6.5Hz, CH3.CH), 1.84 (3H, s, =C.CH3), 2.85 (4H, s, CO.CH2.CH2.CO), 3.29 (1H, dd, J=3 and 4.5Hz, CH.CH.CH), 3.73 (3H, s, OMe), 4.24 (1H, m, CH3.CH.CH), 4.66 (1H, s, N.CH.CO), 4.85 (1H, d, J=2.5Hz, CH.CH.S) and 5.00 ppm (2H, br s, CH2=C).
By following a similar experimental procedure, there were also obtained: 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-succinimidothio-1-(1-diphenylmethoxycarbonyl-2-methyl-1-prop-2enyl)-azetidin-2-one, and 35-r1R-t-butyldimethylsilyloxyethyl)-4R-phthalimidothio- 7-(l-diphenylmethoxycarbonyl-2-methyl- 1-prop-2enyl)-azetidin-2-one, both isolated as crude materials and used as such in the following steps.
Example 15 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phthalimidothio-1-[1-methoxycarbonyl-2-methylsulphonyloxy-1prop- i-(Z)-en ylJ-azetidin-2-one A solution of 100 mg of 3S-(1R-t-butyldimethylsilyloxy-ethyl)-4R-benzothiazolyldithio-1-[1-methoxycar- bonyl-2-methylsulphonyloxy-1-prop-1-(Z)-enyl]-azetidin-2-one in 9 ml of acetone was treated with 34 mg of silver nitrate, soon followed by an ethanolic slurry of 30 mg of potassium phthalimide.After 30 minutes stirring at room temperature, the precipitate was collected partitioned between water and ethyl acetate, and purified by short silica gel chromatography to afford the title product (55%); vmax (film) 1780, 1745 and 1725 cm ; 5 (CDCl3) 0.1 (6H, s, SiMe2), 0.89 (9H, s, But), 1.4 (3H, d, CH3.CH), 2.2 (3H, s, =C.CH3), 3.05 (3H, s, SO2.CH3), 3.4 (1H, m, CH.CH.CH), 3.6 (3H, s, OCH3), 4.2 (1H, m. CH3.CH.CH), 5.45 (1H, d, J=2Hz, CH.CH.SJ and 7.8 ppm (4H, m, Ar).
Example 16 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-succinimidothio-1-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)azetidin-2-one The title product was obtained by ozonolysis of 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-succinimidothio-1 -(1 -methoxycarbonyl-2-methyl-1 -prop-2-enyl)-azetidin-2-one in dichloromethane according to the procedure described in Example 8, and used as such for further reactions. A sample was characterized as its dimethylketal (MeOH/dry HCI): may 1770, 1730 and 1715 sh cm-1; 5 (CDCl3) 0.04 and 0.09 (each 3H, s, SiMe2), 0.90 (9H, s, SiBut), 1.31 (3H, d, J=5Hz, CH3.CH), 1.49 (3H, s, CH3), 2.84 (4H, s, COCH2.CH2CO), 3.21 and 3.26 (each 3H, s, ketal OCH3), 3.24 (1H, dd, J=2.5 and 5Hz), 3.73 (3H, s, ester OCH2), 4.20 (1H, m, CH3.CH.CH), 4.43 (1H, s, N.CH.CO) and 4.94 ppm (1H, d, J=2.5Hz).
Likewise, 3S-r1R-t-butyidimethylsilyloxwethyl)-4R-phthalimidothio-1-{1-diphenylmethoxycarbonyl-2-hy- droxy-1-prop-1-enyl)-azetidin-2-one was obtained starting from 3S-(1R-t-butyldimethylsilyloxyethyl)-4R. phthalimido-thio-1 -(1 -diphenyl methoxycarbonyl-2-methyl-1 -prop-2-enyl)-azetidin-2-one.
Example 17 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 400 mg of 3S-(1R-t-butyldimethylsilyloxy-ethyl)-4R-phthalimidothio-1-[1-methoxycarbonyl- 2-methyl-sulphonyloxy-1-prop-1-(Z)-enylj-azetidin-2-one in 4 ml of dimethylformamide was treated with 50 g of finely ground NaHS under vigorous stirring. As soon as the last reagent was dissolved, the reaction was quenched by partition between diethyl ether and water. Work-up gave the title compound, identical with the sample described in Example 12.
Example 18 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate 0.8 g of 3S-(1 R-t-butyidimethylsilyloxyethyl )-4R-succinimidothio-1 -(1 -methoxycarbonyl-1 -prop-2-enyl)azetidin-2-one in dichloromethane was ozonized at -70 C until tic showed complete conversion. Excess ozone was purged with nitrogen and 1 ml of dimethylsulphide was added.After 1 hour at room temperature, any volatile material was removed in vacuo and the residue reacted in dichloromethane at -200C to 0 C with equimolar amounts of triethylamine and mesyl chloride until conversion of the enol into the mesylates was judged complete by talc. The mixture was concentrated in vacuo and partitioned between ethyl acetate and a cold, aqueous solution of sodium bicarbonate. The organic layer was evaporated to afford the crude mixture of E,Z mesylates which without purification was treated with NaHS in DMF according to the prcoedure described in Example 13. Purification of the resulting product by silica gel chromatography afforded the title compound, identical with the material obtained according to Example 12.
By a similar procedure, Diphenylmethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate was obtained, starting from 3S-( 1 R-t-butyldimethylsilyloxy-ethyl)-4R-phthalimidothio-1 -(1 -diphenylmethoxycar- bonyl-2-methyl-1 -prop-2-enyl)-azetidin-2-one, and showed the same spectral properties as the material previously described (Example 13).
Example 19 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacepyhem-4carboxylate 120 mg of 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-(1-methyl-5-tetrazolyldithio)-1-{1-methoxycarbonyl-2- [(1-methyl-5-tetrazolylthio)-methyl]-1-prop-2-enyl]-azetidin-2-one in dichloromethane was subjected to the reaction sequence reported in Examples 8, 9 and 17 (ozonolysis, mesylation, reaction with NaHS).The crude product was partitioned between ethyl acetate and aqueous sodium bicarbonate solution, thus removing the liberated mercaptotetrazole; the organic layer was washed several times with water, evaporated and the residue fractionated by silica gel chromatography to afford the title product, 17 mg (17%); Vma, (film) 1787, 1725, 1587, 1360 and 1250 cm-1; 5 (CDCl3) 0.10 (6H, s, SiMe2), 0.89 (9H, s, SiBut), 1.26 (3H, d, J=6Hz, CH3-CH), 3.15 (1H, dd, J=2.2 and 3.5Hz CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, NMe), 4.38 (1H, m, CH3.CH.CH), 4.46 (2H, ABq, J=14Hz, separation of inner lines 14Hz) and 4.68 ppm (1H, d, J=2.2Hz, CH.CH.S).
Example 20 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-(1-methoxycarbonyl-2-methyl-1-prop-2 enyl)-azetidin-2-one 2.6 6 g of 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-benzthiazolyldithio-1-(1-methoxycarbonyl-2-methyl-1- prop-2-enyl)-azetidin-2-one, prepared as described in Example 7, in 160 ml of acetone and 18 ml of water was treated under vigorous stirring with 0.98 g of silver nitrate, immediately followed by 0.79 g of sodium benzenesulphinate in 60 ml of water. After 1 hour at room temperature the white precipitate was filtered off, and the filtrate concentrated in vacuo and then partitioned between water and ethyl acetate.
Removal of the solvent from the organic layer left the title product as a yellowish powder (2.43 g, 98%), recrystallizable from cyciohexane (white leaflets, mp 105-106"C); ir (KBr) 3080, 3020, 2960, 2930, 2900, 2860, 1770, 1750, 1330 and 1145 cm-1; 5 (CDCl3) 0.05 (6H, s, SiMe2), 0.98 (12H, s+d, SiBut and CH3.CH), 1.84 (3H, s, =C.CH3), 3.22 (1H, dd, J=2 and 2.5Hz, CH.CH.CH), 3.75 (3H, s, OMe), 4.19 (1H, m, CH3.CH.CH), 4.58 (1H, s, N.CH.CO), 5.00 (2H, m, C=CH2), 5.37 (1H, d, J=2Hz, CH.CH.S), 7.60 and 7.96 ppm (3 and 2H, each m, Ar).
Found: C, 53.69; H, 6.99; N, 2.70; S, 12.42%, C23H35NO sSiS2 requires C, 53.77, H, 6.87; N, 2.74; S, 12.48%.
By following the same procedure, there were also obtained: 3S-rlR-t-butyidimethylsílyloxyethyl)-4R-phenylsulphonyl-thio- 1-{1-t-butoxyearbonyl-2-methyl- 1-prop-2- en yl)-azetidin-2-one; 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-(1-diphenylmethoxycarbonyl-2-methyl-1 prop-2-en yl)-azetidin-2-one; 3S-(iR-trichloroethoxycarbonyloxyethyl)-4R-phenyl-sulphon ylthio- 1-01-methoxycarbonyl-2-methyl- i-prop- 2-en yl)-azetidin-2-one; 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-phenylsulphonyl-thio-1-(1-trichloroethoxycarbonyl-2-methyl-1 prop-2-enyl)-azetidin-2-one.
Example 21 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-[1-methoxycarbonyl-2-methylsulphony loxy- i-prop- 1-gZJ-enyll-azetidin-2-one Procedure A 1 g of 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenyl-sulphonylthio-1-(1-methoxycarbonyl-2-methyl-1 prop-2-enyl)-azetidin-2-one, prepared as described in Example 20, in dry dichloromethane was ozonized at -70 C. After purging with nitrogen, 3.5 ml of dimethylsulphide was added and the mixture was stirred for 3 hours at room tmeperature. After removal of any volatile material in vacuo, the residue was parti tioned between ethyl acetate and water.Evaporation of the solvent left the intermediate 3S-(1R-t-butyldi methylsilyloxyethyl)-4R-phenylsulphonylthio-1-(1-methoxycarbonyl-2-hydroxy-1-prop-1-enyl)-azetidin-2 one; vmax 3450, 1778, 1658 and 1620 cm-1; # (CDCl3) 0.08 (6H, SiMe2, 0.90 (9H, s, SiBut), 1.13 (3H, d, J=6Hz, CH3.CH), 1.90 (3H, s, =C.CH3), 3.12 (1H, dd, J=2.5 and 4Hz, CH.CH.CH), 3.72 (3H, s, OMe), 4.2 (1H, m, CH3.CH.CH), 5.52 (1H, d, J=2.5Hz, CH.CH.S), 7.4-8.0 (5H, m, Ar) and 13 ppm (1H, s, OH).
This material was mesylated with 0.272 ml of triethylamine and 0.151 ml of mesyl chloride in 10 ml of dry THF according to the procedure of Example 10, thus obtaining the title product as a foam, 550 mg after silica gel chromatography; ir (film) 1780, 1730, 1640, 1370 and 1145 cm-1; # (CDCl3) 0.05 (6H, s, SiMe2), 0.80 (9H, s, SiBut), 0.97 (3H, d, J=6Hz, CH.CH), 2.50 (3H, s, =C.CH3), 3.15 (4H, m, SO2CH3 and CH.CH.CH), 3.76 (3H, s, OCH3), 4.13 (1H, m, CH3.CH.CH), 5.7 (1H, d, J=2.8Hz, CH.CH.S) and 7.6-8.0 ppm (5H, m, Ar).
Procedure B 100 mg of 3S-(1R-t-b7utyldimethylsilyloxyethyl)-4R-benz-thiazolyldithio-1-[1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl]-azetidin-2-one in 9 ml of acetone and 1 ml of water was sequentially treated under stirring with 34.3 mg of silver nitrate and 26.6 mg of sodium benzene-sulphinate in 4 ml of water. After 15 minutes at room temperature the precipitated silver benzthiazole-mercaptide was re moved by filtration and the solution partitioned between dichloromethane and water. Removal of the solvent left the title product as a syrup (quantitive yield), having the same spectral properties as the sample from procedure A.
According to the same methodology, there were obtained: 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-[1-t-butoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl]-azetidin-2-one; and 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-phenyl-sulphonylthio-1-[1-trichloroethoxycarbonyl-2-methylsulphonyloxy-1-prop-1(Z)-enyl]-azetidin-2-one.
Example 22 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate 3S-(1R-t-butyldimethylsilyloxyethyl)-4R-phenylsulphonyl-thio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1-prop-1Z-enyl)-azetidin-2-one was allowed to react with NaHS in DMF following the procedure described in Example 13 thereby obtaining the title product, identical with the material previously described. This preparation allows for a simpler purification of the product, since the by-product, sodium benzenesulphinate, is soluble in water and does not need chromatographic separation or fractional crystallization to be removed (unlike, e.g. mercapto-benzthiazole).
According to the same methodologies, there were obtained: t-Butyl (7S,6T)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate; and Trichloroethyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate.
Example 23 3S-(1R-trichloroethoxycarbonyloxyethyl)-4R-acetyldithio-1-(1-methoxycarbonyl-2-methylsulphonyloxy-1prop-1Z-enyl-azetidin-2-one A solution of 340 mg of 3S-(1R-trich loroethoxycarbonyloxy-ethyl)-4R- benzth iazolyldithio-1 -(1 -methoxy- carbonyl-2-methylsulphonyloxy-1-prop-1Z-enyl)-azetidin-2-one in 5 ml of THF was treated with 0,043 ml of thioacetic acid.Five minutes later the mixture was evaporated and the crude reaction product freed from 2-mercaptobenzthiazole by chromatography to obtain the pure title compound as a colourless syrup, 280 mg(96%); vmax (film) 1775, 1760 sh, 1730 br cm-1; 3 (CDCl3) 1.50 (3H, d, CH3.CH), 2.48 (3H, s, =C.CH3), 2.62 (3H, s, COCH3), 3.29 (3H, s, SO2CH3), 3.44 (1H, dd, CH.CH.CH), 3.83 (3H, s, OMe), 4.77 (2H, ABq, J=11.5Hz, separation of inner lines 2Hz), 5.24 (1H, d, CH.CH.S) and 5.25 (1H, m, CH3.CH. CH).
Example 24 Methyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 140 mg of 3S-(1R-trichloroethoxycarbonyloxy-ethyl)-4R-acetyldithio-1-(1-methoxycarbonyl2-methyl-sulphonyloxy-1-prop-1Z-enyl)-azetidin-2-one, prepared as described in Example 23, in 10 ml of THF was treated at 0 C with a solution of 65 mg of tetrabutylammonium hydrogen sulphide in the same solvent.
Work-up and chromatography afforded the title product: #max (EtOH) 280 (e4,974) and 327 nm (2,262); may (film) 1787, 1769 sh, 1725 cm-1; # (CDCl3) 1.54 (3H, d, CH3.CH), 2.23 (3H, s, CH3), 3.30 (1H, dd, 2 and 7.5Hz, CH.CH.CH), 3.84 (3H, s, OMe), 4.68 (1H, d, CH.CH.S), 4.78 (2H, s, OCH2CCI3) and 5.37 ppm (1H, m, CH3 CH.CH), followed by some recovered starting material.
Example 25 Methyl (75, 6R)-7-( iR-t-butyldimeth ylsilyloxyeth yl)-3-brom omethyl-2-thiacephem-4-carb oxylate 0.52 g of methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate, 0.95 ml of propylene oxide, 0.52 g of N-bromosuccinimide and 0.05 g of azobisisobutyronitrile in 40 ml of carbon tetra-chloride were refluxed for six hours. The reaction mixture was cooled to room temperature and filtered.The filtrate was evaporated in vacuo and the residue was purified by silica gel column eluting with ethyl acetate: hexane mixtures, thus obtaining the title product as a yellowish oil (80%); AmaX (CHCl3) 282 and 336 nm; vmax (CHCl2 film) 1785, 1730 cm-1; # (CDCI3) 0.10 (6H, s, SiMe2), 0.89 (9H, s, SiBut), 1.28 (3H, d, CH3.CH.OSi), 3.23 (1H, dd, J=2.0 and 3.5Hz, CH.CH.CH), 3.87 (3H, s, OCH3), 4.65 (2H, center ABq, s.i.l. 4Hz, J=11.5Hz, CH2Br), 4.30 (1H, m, CH3.CH.CH) and 4.76 ppm (1H, d, J=2.0Hz, CH.CH.S).
Found C, 41.1; H, 5.64; N, 3.01; S, 13.55; Br, 17.20; C16H26BrNO4SiS2 requires C, 41.02; H, 5.59; N, 2.99; S, 13.69; Br, 17.06.
By following a similar procedure, there were obtained: t-butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; #max (CDCl2) 283 and 332 nm; vmax (film) 1787 and 1720 cm-1; 3 (CDCl3) 0.9 (6H, s, SiMe2), 0.9 (9H, SiBut), 1.28 (3H, d, CH3.CH), 1.55 (9H, s, OBu'), 3.18 (1H, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.35 (3H, m, CH2Br and CH3.CH.CH) and 4.71 ppm (1H, d, J=2.5Hz, CH.CH.S); p-nitrobenzyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; # (CDCl3) 1.45 (3H, d, CH3.CH), 3.43 (1H, dd, J=2.5 and 6Hz, CH.CH.CH), 4.45 (2H, ABq, J=12Hz, CH2Br), 4.80 (1H, d, J=2.5Hz, CH.CH.S), 5.2, 5.5 (5H, m, two OCH2Ar and CH3.CH.CH); 7.47 and 7.60 (each 2H, d, J=8.5Hz, Ar), and 8.20 ppm (4H, d, J=8.5Hz, Ar); diphenylmethyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; 3 (CDCl3) 1.45 (3H, d, CH3.CH), 3.32 (1H, dd, J=3 and 6Hz, CH.CH.CH), 4.18 (2H, ABq, J=11Hz, CH2Br), 4.70 (1H, d, J=3Hz, CH.CH.S), 5.20 (2H, s, OCH2Ar), 5.30 (1H, m, CH3.CH.CH), 6.97 (1H, s, OCHPh3), 7.10-7.40 (10H, br s, Ar), 7.45 and 8.15 ppm (each 2H, d, J=9Hz, Ar); diphenylmethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; vmax (film) 1790 and 1730 cm-1; 3 (CDCl3) 0.05 (6H, s, SiMe2, 0.8 (9H, s, SiBut), 1.22 (3H, d, J=6.5Hz, CH3.CH), 3.10 (1H, dd, J=2.7 and 4.5Hz, CH.CH.CH), 4.05 (2H, s, CH2Br), 4.2 (1H, m, CH3.CH.CH), 4.63 (1H, d, J=2.7Hz, CH.CH.S), 6.92 (1H, s, OCHPh2), and 7.05-7.40 ppm (10H, mAr): #max (CHCl3) 283 (E 7,867) and 336 nm (e=3,533); trichloroethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxylate; and trichloroethyl (7S,6R)-7-(1R-trichloroethoxycarbonyloxy-ethyl-3-bromomethyl-2-thiacephem-4-carboxylate.
Example 26 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4carboxylate A THF solution of crude methyl (7S,6R)-7-(1 R-t-butyl-dimethylsilyloxyethyl)-3-bromomethyl-2-thiace- phem-4-carboxylate was kept overnight in the presence of sodium 1-methyl-tetrazole-5-mercaptide bihydrate (3 mol equiv). Work-up and chromatography afforded the title product as an oil in 85% yield; #max (EtOH) 281 and 333 nm; vmax (film) 1790 and 1725 cm-1; 3 (CDCl3) 0.10 (6H, s, SiMe2), 0.89 (9H, s, But), 1.26 (3H, d, CH3.CH), 3.15 (1H, dd, J=2.2 and 3.5Hz, CH.CH.CH), 3.88 (3H, s, OMe), 3.92 (3H, s, N.CH3), 4.38 (1H, m, CH3.CH.CH), 4.46 (2H, ABq, sep. of inner lines 14Hz, J=14Hz) and 4.68 ppm (1H, d, CH.CH.S, J=2.2Hz).
By following a similar procedure, there were obtained: t-butyl(7S,6R)-7-butyldimethylsilyloxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylate, starting from t-butyl (7S,6R)-7-(1R-t- butyldimethylsilyloxyethyl-3-bromomethyl-2-thiacephem-4carboxylate; and diphenylmethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-{(8-aminotetrazolo[1,5-b]pyridazin-6-ylthio)methyl}-2-thiacephem-4-carboxylate Example 27 (5aR,6S)-6-(1R-t-butyldimethylsilyloxyethyl)-5a,6-dihydro-3H,7H-azeto[2,1-c]furo[3,4-e]1,2,4-dithiazine-1,7dione Procedure A): A solution of 15 mg of methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem- 4-carboxylate in 2 ml of DMSO and 1.5 ml of water was stirred with 50 mg of cuprous oxide at 50 C for 2 1/2 hours. The reaction mixture was partitioned between water and ethyl acetate. Evaporation and chromatography of the organic extracts afforded the title product as a white powder; vmax (CHCl3 film) 18001760 br cm-1; 3 (CDCI3) 0.06 (3H, s, SiCH3), 0.11 (3H, s, SiCK2), 0.90 (9H, s, But), 1.33 (3H, d, CH3.CH), 3.33 1H, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.44 (1H, m, CH3CH.CH), 4.62 (1H, d, J=2.5Hz, CH.CH.S) and 4.98 pm (2H, s, CK3O).
Procedure B): 250 mg of the 2-bromomethyl precursor in 35 ml of acetone:water (2:1 by volume) was stirred for 15 minutes at 0 C with 153 mg of silver perchlorate. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was evaporated off to leave a residue. Silica gel chromatography afforded the title product, identical with the sample described above under A).
Example 28 t-Butyl (7S, 6R)- 7- ( iR-t-b utyldimeth ylsllyloxyeth yl)-3-hydroxym eth yl-2-thiacephem-4-carb oxylate 300 mg of t-Butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxy- late in 10 ml of a 2:1 by volume acetone:water mixture was stirred for 15 minutes at 0 C with 150 mg of silver perchlorate.Removal of the solvent, followed by water:ethyl partition and work-up of the organic layer, gave 250 mg (96%) of the title product; #max (CHCl3) 281 and 335 nm; may (film) 3450, 1785 and 1712 cm-1; 5 (CDCl3) 0.1(6H, s, SiMe2), 0.86 (9H, s, SiBut), 1.25 (3H, d, CH3CH), 1.50 (9H, s, OBu'), 3.13 (1H, dd, J=2.5 and 4.5Hz, CH.CH.CH), 4.25 (centre of ABq, J=13Hz, CH2OH), 4.37 (1H, m, CH3.CH.CH) and 4.60 ppm (1H, d, J=2.5Hz, CH.CH.S).
Example 29 t-Butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-(N-trichloroacetylcarbamoyloxymethyl)-2-thiacephem4-carboxylate 250 mg of t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxy-ethyl)-3-hydroxymethyl-2-thiacephem-4-carboxy- late in 2.5 ml of ethanol-free dichloromethane was treated at -40 C with 0.080 ml of trichloroacetyl-isocyanate. The mixture was allowed to rise to room temperature and then sequentially washed with 2% aqueous sodium bicarbonate solution and brine.Evaporation of the solvent from the organic layer gave the title product in quantitative yield; AmaX (EtOH) 275 and 329 nm; vmax 1795 and 1725 br cm-1; 5 (CD3CN), 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.3 (3H, d, CH3.CH), 1.5 (9H, s, OBut), 3.40 (1H, dd, J=3 and 4Hz, CH.CH.CH), 4.35 (1H, m, CH3.CH.CH), 4.80 (1H, d, J=3Hz, CH.CH.S) and 5.0 ppm (centre of ABq, CH2OCO).
Example 30 t-Butyl (75, 6R)- 7- ( iR-t-b utyldimeth ylsilyloxyethyl)-3-carbam o yloxym eth yl-2-thiacephem-4-carb oxyla te A methanolic solution of t-butyl (7S,6R)-7-(1R-t-butyl-dimethylsilyloxyethyl)-3-(N-trichloroacetylcarba- moyloxy-methyl)-2-thiacephem-4-carboxylate, prepared as described in Example 29, was stirred with silica gel for 20 hours.The slurry was then charged onto a silica gel column and the product eluted with ethyl acetate; 3 (CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBut), 1.35 (3H, d, CH3.CH), 1.60 (9H, s, OBu'), 3.1 (1H, dd, CH.CH.CH), 4.3(1K, m, CH3.CH.CH) 4.75(1K, d, J=3Hz, CH.CH.S) and 5.0 ppm (centre of ABq, OCH3CO).
Example 31 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-nitrooxymethyl-2-thiacephem-4-carboxylate A solution of 200 mg of methyl (7S,6R)-7-(1R-t-butyl-dimethylsilyloxyethyl)-3-bromomethyl-2-thiace- phem-4-carboxylate in 20 ml of acetone was stirred for 20 minutes in the presence of 100 mg of silver nitrate.The filtered reaction mixture was fractionated by silica gel chromatography to obtain the title product, 120 mg; #max (CHCl3) 280 and 337 nm; vmax (film) 1790, 1730, 1640 and 1280 cm-1; 5 (CDCl3) 0.08 (6H, s, SiMe2), 0.87 (9H, s, SiBut), 1.38 (3H, d, CH3CH), 3.18 (1H, dd, J=2.5 and 5.5Hz, CH.CH.CH), 3.85 (3H, s, OMe), 4.38 (1H, m, CH3.CH.CH), 4.73 (1H, d, J=2.5Hz, CH.CH.S) and 5.36 ppm (2H, ABq, J=13.5Hz, s.i.l.
29.5Hz, CH2ONO2); further elution then afforded some of the lactone described in Example 27.
Example 32 Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-formyloxymethyl-2-thiacephem-4-carboxylate 200 mg of methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-bromomethyl-2-thiacephem-4-carboxy- late in dichloromethane was treated at daily intervals with tetrabutylammonium formate (3 x 600 mg).
After 3 days at 5 C. tic showed 80% conversion in the product (ethyl acetate:light petroleum 1:2 by volume). Elution through a short silica gel column gave the title material; 5 (CDCl3) 0.1 (6H, s, SiMe2), 0.9 (9H, s, SiBu'), 1.35 (3H, d, CH3.CH), 3.20 (1H, dd, 2.5 and 7Hz, CH.CH.CH), 3.9 (3H, s, OMe), 4.5 (1H, m, CH3.CH.CH), 4.74 (1H, d, 2.5Hz, CH.CH.S) and 5.13 ppm (centre of ABq, CH2O).
In a similar way, starting from the corresponding t-butyl and diphenylmethyl esters, there were obtained: t-butyl (75, 6R)-7-( 1R-t-butyldim ethylsilyloxyethyl-3-formyloxymethyl-2-thiacephem-4-carboxylate; and diphenylmethyl (7S,6R)-7(1R-t-butyldimethylsilyloxyethyl)-3-formyloxymethyl-2-thiacephem-4-carboxylate and, in a likewise fashion, the corresponding acetates were obtained: methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate; t-butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate; diphenylmethyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate; and trichloroethyl (7S,6Rj-7-l IRlrichoroeth oxycarb on ylaxy-eth yll-3-acetoxymeth yl-2-thiacephem-4-carb oxy- late.
Example 33 Methyl (7S,6R)-7-(1R-hydroxyethyl)-3-methyl-2-thiacephem-4-carboxylate 0.75 g of methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate was added to a solution of 2.03 g of tetrabutylammonium fluoride trihydrate in 1.23 ml of acetic acid and 10 ml of THF. Work-up after 20 hours gave the title compound (virtually quantitative yield), showing the spectral properties described for the sample obtained in Example 13.
By similar experimental procedures, there were obtained: Methyl (7S,6R)-7-(1R-hydroxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate, starting from methyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl )-3-bromomethyl-2-thiacephem-4-carboxylate; v= (film) 1775, 1730 cm-1; 8 (CDCl3) 1.35 (3H, d, CH3.CH), 3.38 (1H, dd, CH.CH.CH), 3.60 (1H, br, s, OH), 3.97 (3H, s, OMe), 4.33 (1H, m, CH3.CH.CH), 4.46 (2H, centre of ABq, J=11Hz, sep. of inner lines 4Hz, CH2Br) and 4.88 ppm (1H, d, J=2.2Hz, CH.CH.S);; Methyl (7S,6R)-7-(1R-hydroxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylate, starting from methyl (7S,6R)-7-(1R-t-butyldimethyl-silyloxyethyl)-3-[(1-methyl-5-tetrazolythio)-methyl]-2- thiacephem-4-carboxylate; v, (KBr) 1765 and 1707 cm-1; 3 (CD3COCD3), 1.30 (3H, d, CH3.CH), 3.39 (1H, dd, CH.CH.CH), 3.79 (3H, s, NCK3), 3.97 (3H, s, OCH3), 4.0 (1H, m, CH3.CH.CH), 4.38 (2H, centre of ABq, J=16Hz, separation of inner lines 13Hz, CH2.S), 4.77 (1H, d, J=2.2Hz, CH.CH.S) and 5.0 ppm (1H, br s, OH);; and, analogously, the corresponding t-butyl, diphenyl-methyl and trichloroethyl esters were also prepared.
Example 34 (7S,6R)-7-(1R-methylsulphonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylic acid Diphenyl methyl (7S,6R)-7-(1 R-methylsulphonyloxyethyl )-3-methyl-2-thiacephem-4-carboxylate was dissolved in cold trifluoroacetic acid (0 C, neat). After 15 minutes stirring at the same temperature, carbon tetrachloride was added and the solution thoroughly evaporated under vacuum without external heating.
The residue was triturated in carbon tetrachloride and collected, thus obtaining the title product; AmaX (CHCl3) 281 and 326 nm;vmax (CHCl3) 3000-2300, 2970, 2930, 2850, 1775, 1710, 1530 and 1170 cm-1; 3 (CD3COCD3) 1.58 (3H, d, CH3.CH), 2.23 (3H, s, Me), 3.16 (3H, s, SO2Me), 3.66 (1H, dd, J=2 and 6Hz, CH.CH.CH), 4.85 (1H, d, J=2Hz, CH.CH.S) and 5.30 ppm (1H, m, CH3.CH.CH).
The same material was obtained by trifluoroacetic acid hydrolysis of the corresponding t-butyl ester, but prolonging the reaction time to about 1 hour.
Similarly hydrolyses of the t-butyl or diphenylmethyl precursors gave the following products: (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylic acid; {7S,6R)-7-rlR-hydroxyethyl)-3-methyl-2-thiacephem-4carboxylic acid; (7S,6R)-7-(1R-hydroxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylic acid; (7S,6R)-7-(1R-hydroxyethyl)-3-carbamoyloxymethyl-2-thiacephem-4-carboxylic acid; and (7S,6R)-7-(1R-hydroxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylic acid.
Example 35 p-Nitrobenzyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate A solution of 200 mg of diphenylmethyl (7S,6R)-7-(1 R-p-nitrobenzyloxycarbonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate in 25 ml of dichloromethane was treated for 30 min at 0 C with 0.4 ml of trifluoroacetic acid. Evaporation under vacuum in the cold left the crude 2-thiacephem-4-carboxylic acid, which was dissolved in 10 ml of acetonitrile:dimethylformamide (2:1 by voiume) and treated with 0.050 ml of triethylamine and 100 mg of p-nitrobenzyl bromide. After 1 hour at 25 C, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution.The organic layer, dried over anhydrous magnesium sulphate, was concentrated and the residue passed through a short silica column (ethyl acetate: light petrol as eluants) to afford the pure title product, 150 mg (79%); 3 (CDCI2) 1.45 (3H, d, CH3. CH) 3.43 (1H, dd, J=2.5 and 6Hz, CH-CH-CH), 4.45 (2H, ABq, J=12 Hz, CH2Br), 4.80 (1H, d, J=2.5 Hz, CH-CH-S), 5.2-5.5 (5H, m), 7.47 and 7.60 (each 2H, d, Ar) and 8.20 ppm (4H, d, Ar).
Example 36 (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-4-diphenyl-methoxycarbonyl-3-(pyridinium-methyl)-2-thiacephem bromide A solution of 310 mg of diphenylmethyl (7S,6R)-7-(1R-t-butyidimethylsilyloxyethyl)-3-bromomethyl-2- thiacephem-4-carboxylate in 15 ml of dry acetone was treated with 0.4 ml of pyridine. After 20 hours at room temperature the solvent was distilled off and the residue purified by silica gel chromatography. The product-containing fractions (eluted with dichloromethane:acetic acid: methanol 70:15;15 by volume) were collected and freed from the solvents to leave the title compound as a syrup; vm,x (CHCI3 film) 1790, 1715 cm-1; 3 (CDCl3) (inter alia) 1.32 (3H, d, J=6.5 Hz), 3.33 (1H, dd), 4.45 (1H, m), 5.0 (1H, d, J 2 Hz) and 7.11 ppm (1H, s); #max (CHC13) 283 and 337 nm (=4,060). In a likewise manner, and starting from p-nitrobenzyl (7S,6R)-7-(1 R-p-nitrobenzyloxycarbonyloxyethyl)-3-bromomethyl-2-thiacephem-4-car boxylate, there was obtained:: (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxyethyl)-4-p-nitrobenzyloxycarbonyl-3-(pyridinium-methyl)-2-thiacephem bromide Example 37 (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-4-carboxy-3-(pyridinium-methyl)-2-thiacephem trifluoroacetate A solution of (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-4-diphenylmethoxycarbonyl-3-(pyridiniummethyl)-thiacephem bromide, prepared as described in Example 36, in 10 ml of dichloromethane was treated with 2 ml of trifluoroacetic acid at 0 C for 15 minutes. After evaporation in vacuo, the residue was taken up in a small amount of chloroform.Diethyl ether was added under stirring and then decanted off, to leave the crude title product; vmax (CHCI3 film) 3420,1785, 1715 and 1635 br cm-1; 3 (CDCl3) (inter aiia) 1.30 (3H, d, J=6.5 Hz), 3.23 (1H, dd), 4.38 (1H, m) and 4.76 ppm (1H, d); Xx (CKCl3) 262 and 334 nm.
Example 38 (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxyethyl)-4-p-nitrobenzyloxycarbonyl-3-(3-carbamoylpyridiniummethyl)-2-thiacephem bromide.
A solution of 460 mg of p-nitrobenzyl (7S,6R)-7-(1R-p-nitobenzyloxycarbonyloxyethyl)-3-bromomethyl2-thiacephem-4-carboxylate in 5 ml of DMF was stirred overnight in the dark in the presence of 200 mg of nicotinamide. Most of the solvent was distilled off and the residue was taken up in 150 ml of tetrahydrofuran. This solution was washed with a solution of sodium chloride in 0.1 N hydrochloric acid (2 x 50 ml) and with brine (2 x 50 ml), dried on anhydrous sodium sulphate and evaporated to dryness. The residue was charged to the top of a column packed with silanised silica gel (Merck, Art. 7719). Excess nicotinamide and impurities were eluted with ethyl acetate, and the product was then collected by eluting with ethyl acetate:acetic acid (9:1 by volume). Evaporation in vacuo left the title product; vmax (CKCl3) 1800 1725, 1695 cm-; 3 (Deuteroacetone; 200 MHz) 1.67 (3H, d, J=6.4 Hz, CH3-CH), 4.14 (1H, dd, J=2.5 and 4.7 Hz, CH-CH-CH), 5.30 (1H, d, J=2.5 Hz, CH-CH-S), 5.4-5.7 (7H, m, 2xCH2OAr, CH2N+, and CH3-CH- CH), 7.7-8.4 !8H, mAr), and 8.0, 8.7, 9.5 and 9.7 ppm (each 1H, br s, pyridinium). Analogously, by using isonicotinamide instead of nicotinamide, there was obtained: (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyloxyethyl)-4-p-nitrobenzyloxycarbonyl-3-(4-carbamoylpyridiniummethyl)-2-thiacephem bromide.

Claims (73)

1. A process for the preparation of a 2-thiacephem derivative of the general formula Ila
wherein R, represents a hydrogen atom or an organic group and R3 represents a hydrogen atom or a carboxy protecting group from an azetidinone derivative of the general formula IV
wherein R, and R3 are as defined in this claim and Z represents (i) a group of the formula SR7 wherein R7 represents an alkyl group having from 1 to 8 carbon atoms, a phenyl or tolyl group, or a heterocyclic group, (ii) a group of the formula SCOR8 wherein R8 represents an optionally substituted lower alkyl group, (iii) a group of the formula
wherein Rs and R10 independently represent lower alkyl or aryl groups, or together with the dicarboxyamino group form a heterocyclic ring, or (iv) a group of the formula
wherein R,1 represents an optionally substituted lower alkyl or aryl group, the process comprising ozonolysing the carbon-carbon double bond, converting the hydroxy group in the resultant azetidinone to a halogen atom or an alkane sulphonyloxy group or an arene sulphonyloxy group and cyclising the resultant azetidinone by reaction with a sulphide or hydrosuiphide in the presence of a base.
2. Methyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
3. Methyl (7R,6R)-7-( 1 R-t-butyldimethylsilyloxyethyl)-3-methyl-24hiacephem-4-carboxylate prepared according to claim 1.
4. Diphenyl methyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxy-ethyl )-3-methyi-2-thiacephem-4-carboxylate prepared according to claim 1.
5. t-Butyl (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
6. Trichloroethyl (7S,6R)-7-( 1 R-t-butyldimethylsilyloxy-ethyl )-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
7. Acetoxymethyl (7S,6R)-7-( 1 R-t-butyldimethylsilyloxy-ethyl )-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
8. (7S,6R)-7-(1R-t-butyldimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylic acid prepared according to claim 1.
9. Methyl (7S,6R)-7-(1R-hydroxyethyl)-3-methyl-2- -thiacephem-4-carboxylate prepared according to claim 1.
10. Diphenylmethyl (7S,6R)-7-(1 R-hydroxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
11. (7S,6R)-7-( 1 R-hydroxyethyl)-3-methyl-2-thiacephem-4-carboxylic acid prepared according to claim 1.
12. Methyl (7S,6R)-7-(1R-methylsulphonyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
13. Diphenylmethyl (7S,6R)-7-(1 R-methylsuiphonyloxy-ethyl )-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
14. (7S,6R)-7-(1 R-methylsulphonyloxyethyl)-3-methyl-2-thiacephem-4carboxylic acid prepared according to claim 1.
15. Methyl (7S,6R)-7-(1 R-trichloroethoxycarbonyloxy-ethyl )-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
16. t-Butyl (7S,6R)-7-(1 R-trichloroethoxycarbonyloxy-ethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
17. Diphenyl methyl (7S,6R)-7-(1 R-trichloroethoxy-carbonyloxyethyl )-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
18. Trichloroethyl (7S,6R)-7-(1 R-trichloroethoxy-carbonyloxyethyl )-3-methyl-2-thiacephem-4-carboxy- late prepared according to claim 1.
19. Acetoxymethyl (7S,6R)-7-(1 R-trichloroethoxycarbonyl-oxyethyl)-3-methyl-2-thiacephem-4-carboxy- late prepared according to claim 1.
20. Acetoxymethyl (7S,6R)-7-(1R-trimethylsilyloxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
21. Diphenylmethyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyl-oxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
22. p-Nitrobenzyl (7S,6R)-7-(1R-p-nitrobenzyloxycarbonyl-oxyethyl)-3-methyl-2-thiacephem-4-carboxylate prepared according to claim 1.
23. A process for the preparation of a 2-thiacephem derivative of the general formula llb
wherein R1 and R2 are as defined in claim 1 and Hal represents a halogen atom, the process being according to claim 1 and further comprising halogenating the methyl group either of the azetidinone IV prior to the steps of claim 1 or of the 2-thiacephem after the steps of claim 1, the halogenation of the 2 thiacephem being effected by reaction with a halogenating agent in an inert organic solvent at a temperature of from 20"C to 130"C in the presence of a radical initiator and an acid scavenger.
24. A process according to claim 23 in which the halogenation of the 2-thiacephem is effected by reaction with N-bromosuccinimide or N-chlorosuccinimide.
25. A process according to claim 23 or claim 24 in which the radical initiator present during the halogenation of the 2-thiacephem is azobisisobutyronitrile or benzoyl peroxide.
26. A process according to any of claims 23 to 25 in which the acid scavenger present during the halogenation of the 2-thiacephem is an epoxide, an alkaline earth oxide or a molecular sieve.
27. A process according to any of claims 23 to 26 in which the inert organic solvent in which the halogenation of the 2-thiacephem is effected is benzene, carbon tetrachloride or ethyl formate.
28. Methyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27.
29. Diphenylmethyl (7S,6R)-7-(1 R-t-butyldimethylsilyl-oxyethyl)-3-bromomethyl-2-thiacephem-4-car- boxylate prepared according to any of claims 23 to 27.
30. Trichloroethyl (7S,6R)-7-(1 R-t-butyldimethylsilyl-oxyethyl)-3-bromomethyl-2-thiacephem-4-carboxy- late prepared according to any of claims 23 to 27.
31. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27.
32. Trichloroethyl (7S,6R)-7-(1 R-trichloroethoxycarbonyl-oxyethyl)-3-bromomethyl-2-thiacephem-4-car- boxylate prepared according to any of claims 23 to 27.
33. Diphenylmethyl (7S,6R)-7-(1 R-p-nitrobenzyloxy-carbonyloxyethyl)-3-bromomethyl-2-thiacephem-4- carboxylate prepared according to any of claims 23 to 27.
34. p-Nitrobenzyl (7S,6R)-7-(1 R-p-nitrobenzyloxy-carbonyloxyethyl)-3-bromomethyl-2-thiacephem-4carboxylate prepared according to any of claims 23 to 27.
35. Methyl (7S,6R)-7-(1 R-hydroxyethyl)-3-bromomethyl-2-thiacephem-4-carboxylate prepared according to any of claims 23 to 27.
36. A process for the preparation of a 2-thiacephem derivative of the general formula II
wherein R and R3 are as defined in claim 1 and Y represents an organic group, the process being according to any of claims 23 to 27 and further comprising converting the halomethyl group introduced by the halogenation into a methyl group substituted by the desired organic group, the conversion being effected at any point after the halogenation.
37. A process according to claim 36 in which the conversion is effected on the 3-halomethyl-2-thiacephem derivative.
38. Methyl (7S,6R)-7-(1 R-t-butyidimethylsilyloxyethyl)-3-nitrooxymethyl-2-thiacephem-4-ca rboxylate prepared according to claim 36 or claim 37.
39. A process according to claim 37 in which Y represents a hydroxy group and the conversion is effected by reacting the 3-halomethyl-2-thiacephem derivative with a salt of a strong inorganic acid and hydrolyzing the resultant labile ester of the inorganic acid.
40. A process according to claim 39 in which the salt is silver nitrate, silver perchlorate or sodium nitrate.
41. A process according to claim 39 or claim 40 in which the reaction is carried out in an acetone:water mixture at 0 C for 15 minutes, and the subsequent hydrolysis is carried out in the same reaction medium.
42. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl )-3-hydroxymethyl-2-thiacephem-4-carboxylate prepared according to any of claims 39 to 41.
43. A process according to claim 39 in which Y represents an unsubstituted or N-alkyl or N-acyl substituted carbamoyloxy group and the conversion is carried out according to any of claims 39 to 41 followed by reacting the 3-hydroxymethyl-2-thiacephem derivative with an alkyl isocyanate or an acyl isocyanate and, if desired, deprotecting the carbamoyloxy group.
44. A process according to claim 43 in which the reaction of the 3-hydroxymethyl-2-thiacephem with the isocyanate is carried out in dichloromethane at -40 C.
45. A process according to claim 43 or claim 44 in which the deprotection is carried out by stirring with silica gel in methanol for 20 hours.
46. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl) -3-( N-trichloroacetylcarbamoyloxymethyl )-2-thi- acephem-4-carboxylate prepared according to any of claims 43 to 45.
47. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl)-3-carbamoyloxymethyl-2-thiacephem-4-carboxy- late prepared according to any of claims 43 to 45.
48. (7S,6R)-7-(1 R-hydroxyethyl)-3-carbamoyloxymethyl-2-thiacephem-4-carboxylic acid prepared according to any of claims 43 to 45.
49. A process according to claim 37 in which Y represents an acyloxy group and the conversion is effected by reacting the 3-halomethyl-2-thiacephem with a carboxylic acid salt.
50. A process according to claim 49 in which the reaction is carried out in dichloromethane at 50C with addition of the salt portionwise in three days.
51. Methyl (7S,6R)-7-(1 T-butyl 1 R-t-butyidimethylsiloxyethyl)-3-formyloxymethyl-2-thiacephem-4-carboxylate prepared according to claim 49 or claim 50.
52. t-Butyl (7S,6R)-7-(1R-t-butyidimethylsiloxyethyl)-3-formyloxymethyl-2-thiacephem-4-carboxylate prepared according to claim 49 or claim 50.
53. Diphenylmethyl (7S,6R)-7-(1R-t-butyidimethylsiloxy-ethyi)-3-formyloxymethyl-2-thiacephem-4-car- boxylate prepared according to claim 49 or claim 50.
54. Methyl (7S,6R)-7-(f R-t-butyldimethylsiloxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylate prepared according to claim 49 or claim 50.
55. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsiloxyethyl )-3-acetoxymethyl-2-thiacephem-4-carboxylate prepared according to claim 49 or claim 50.
56. Diphenylmethyl (7S,6R)-7-(1R-t-butyidimethylsiloxy-ethyl)-3-acetoxymethyl-2-thiacephem-4-carbox- ylate prepared according to claim 49 or claim 50.
57. Trich loroethyl (7S,6R)-7-(1 R-trichloroethoxycarbonyl-oxyethyl )-3-acetoxymethyl-2-thiacephem-4- carboxylate prepared according to claim 49 or claim 50.
58. (7S,6R)-7-(1 R-hydroxyethyl)-3-acetoxymethyl-2-thiacephem-4-carboxylic acid prepared according to claim 49 or 50.
59. A process according to claim 37 in which Y represents a -S-Het group wherein Het denotes a saturated or unsaturated hetrocyclic ring containing at least one oxygen, sulphur and/or nitrogen heteroatom, and is preferably: A) a pentatomic or hexatomic heteromonocyclic ring, containing at least one double bond and at least one oxygen, sulphur and/or nitrogen heteroatom, such as a thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, triazinyl group, unsubstituted or substituted by one or more a') alkoxy groups having from 1 to 6 carbon atoms, aliphatic acyl groups having from 2 to 6 carbon atoms, hydroxy group and/or halogen atoms; b') alkyl groups having from 1 to 6 carbon atoms, unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms;; c') alkenyl groups having from 2 to 6 carbon atoms unsubstituted or substituted by one or more hydroxy groups and/or halogen atoms; d') groups of the general formula -S-R3 wherein R3 represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms; or groups of the general formula -S-CH2-COOR4 wherein R4 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a carboxy-protecting group; e') groups of the general formula -(CH2)m-COOR4 or -CK=CK-COOR4 or -(CH2)m-(n) -CN or -(CH2)m-CONH2 or -(CH2)m-SO3H wherein m is zero, 1, 2 or 3 and R4 is as defined above; f') groups of the general formula
wherein m is as defined above, and each of R5 and R6, which may be the same or different, represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aliphatic acyl group or when one of R5 and R6 is hydrogen, the other may be also an amino protecting group; and B) a heterobicyclic ring, containing at least two double bonds wherein each of the condensed heteromonocylcic rings, being the same or different, is a pentatomic or hexatomic heteromonocyclic ring containing at least one oxygen, sulphur or nitrogen heteroatom, said heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from a'), b'), c'), e') and f') as defined above, the process conversion being effected by the 3-halomethyl-2-thiacephem derivative in an organic solvent with a compound of the formula HS-Het in the presence of a base or with a preformed sodium salt of the compound HS-Het.
60. A process according to claim 59 in which the organic solvent is tetrohydrofuran, acetone, acetonitrite or dimethylformamide.
61. A process according to claim 59 or claim 60 in which the reaction is carried out overnight at room temperature.
62. A process according to any of claims 59 to 61 in which the base is triethylamine.
63. Methyl (7S,6R)-7-(1 R-t-butyldimethylsiloxyethyl)-3-[( 1 -methyl-5-tetrazolylthio)-methyl]-24hiace- phem-4-carboxylate prepared according to any of claim 59 to 62.
64. t-Butyl (7S,6R)-7-(1 R-t-butyldimethylsiloxyethyl)-3-[(1 -methyl-5-tetrazolylthio)-methyl]-24hiace- phem-4-carboxylate prepared according to any of claim 59 to 62.
65. Diphenylmethyl (7S,6R)-7-(1 R-t-butyidimethylsiloxy-ethyl)-34(8-aminotetrazol [1 ,5-bjpyridazin-6- ylthio)-methyl}-2-thiacephem-4-carboxylate prepared according to any of claim 59 to 62.
66. (7S,6R)-7-(1R-hydroxyethyl)-3-[(1-methyl-5-tetrazolylthio)-methyl]-2-thiacephem-4-carboxylic acid prepared according to any of claim 59 to 62.
67. Methyl (7S,6R)-7-(1 R-hydroxyethyl)-3-[(1 -methyl-S- -tetrazolylthio)-methyl]-2-thiacephem-4-carboxylic acid prepared according to any of claim 59 to 62.
68. A process according to claim 37 in which Y represents a 1-pyridinium group, unsubstituted or substituted in the meta or para position with a carbamoyl group, and the conversion is effected by reacting the 3-halomethyl-2-thiacephem derivative with pyridine, nicotinamide or isonicotinamide.
69. (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl)-4-diphenylmethoxycarbonyl-3-(pyridinium-methyl)-2-thi- acephem bromide prepared according to claim 68.
70. (7S,6R)-7-( 1 R-p-nitrobenzyloxycarbonyloxyethyl)-4-(p-nitrobenzyloxycarbonyl)-3-(pyridinium- methyl)-2-thiacephem bromide prepared according to claim 68.
71. (7S,6R)-7-(1 R-p-nitrobenzyloxycarbonyloxyethyl)-4-(p-nitrobenzyloxycarbonyl)-3-(3-carbamoylpyri- dinium-methyl)-2-thiacephem bromide prepared according to claim 68.
72. (7S,6R)-7-(1 R-p-nitrobenzyloxyca rbonyl oxyothyl )-4-(p-n itrobenzyloxycarbonyl )-3-(4-carbamoyl pyri- dinium-methyl)-2-thiacephem bromide prepared according to claim 68.
73. (7S,6R)-7-(1 R-t-butyldimethylsilyloxyethyl)-4-carboxy-3-(pyridinium-methyl)-2-thiacephem trifluoroacetate prepared according to claim 68.
GB08528360A 1982-12-08 1985-11-18 Preparation of 2-thiacephems Expired GB2166441B (en)

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