CA1071213A - Thiazoleneazetidinones from penicillin sulfoxides - Google Patents

Abstract

A B S T R A C T

There is provided a new group of thiazolene azetidinones such as methyl 3-anilino-4-thia-2,6-diazabicyclo-[3,2,0]hept-2-ene-7-one-6-isopropenyl(and propenyl)acetate, methyl 3-methylamino-4-thia-2,6-diazabicyclo [3.2.0]hept-2-ene-7-one-6-isopropenyl(and propenyl)acetate and methyl 3-phenoxy-4-thia-2,6-diazabicyclo [3,2,0]hept-2-ene-7-one-6-isopropenyl-(and propenyl)acetate. These compounds are useful intermedi-ates in the preparation of known cephalosporins or penicillins.

Description

1()71Z13 PRIOR ART
There is disclosed in the prior art certain thiazol-eneazetidinones 1 of the formula:
-N ~ S

R~' ~ `H j N

wherein R stands for benzyl or phenoxymethyl, R2 stands forhydrogen and Rl is a cleavable radical. The compounds since they are obtained from natural penicillin G or V can thus only yield corresponding cephems in any synthetic routes. These compounds thus provide a limited utility in the synthesis of cephalosporins and penicillins.

THE INVENTION
In accordance with the present invention there is provided a novel process for preparing thiazoleneazetidinones 1 of the general formula:

N ~ S

0~

N

COOR
wherein:
R stands for phenoxyloweralkyl, phenylthiolower-alkyl, benzyl, lower alkyl, phenyl, heteroaryl, heteroarylmethyl, ~-aminobenzyl and protected derivatives thereof, 4-amino-4-carboxy-1-butyl and protected derivatives thereof, R30-, R3S-, and R3R4N-1~7~Z~3 wher3e R is lower alkyl, phenyl, heteroaryl, or aryl-loweralkyl, R4 is hydrogen or radical R3, R is hydrogen or methoxy;
R is hydrogen, lower alkyl, loweralkoxymethyl, aryloxyme.thyl, 2,2,2-trichloroethyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl, or trimethyl-silyl.
Formula 1 is representative of the two isomers depicted by la and lb:
R R

~5 COOR COOR
la lb ~he novel process of the present invention comprises Cyclizing a penic~llin sulfoxide thioamide 2 of the formula:

10~7~213 RCNH ~ S~

H COOR
The cyclization is carried out by heating the penicillin sulfoxide thioamide 2, alone or optionally in the presence of catalysis such as monopyridinium dichloromethyl-phosphonate, or sulfur extraction compounds such as trimethyl phosphite. When the R substituent in the penicillin sulfoxide thioamide stands for R3R4N- the heating is carried out for a period of above five hours or less. When the value of R as defined previously is other than R3R4N- the heating is carried out for a period of at least twenty hours and for as long as forty-eight hours. In all cases the heating is carried out in a suitable inert solvent, for example, dioxane, toluene, xylene, and dichlorobenzene.
The thiazoleneazetidinones 1, are particularly useful intermediates in the preparation of cephalosporins and penicillins. For example, the thiazoleneazetidinones 1 react with sulfenyl chlorides to form unsym-azetidinone disulfides, _ (W.G.E. Underwood, Glaxo Labs Ltd., Ger. Offen. 2,303,889, 26 Jan. 1973), which upon reaction with iodine will form the 3-iodocephams, 4, as disclosed in copending Canadian appl.
Ser. No. 229,909 filed 23-06-75, which upon dehydroiodination will provide the corresponding 3-cephems, 5. Also, the thiazoleneazetidinones 1, react with iodine or better sulfenyl iodides in presence of moisture, to form the 3-iodocephams, 4 which are readily dehydroiodinated to the 3-cephems, 5 ~see Flowsheet 1).

~7~LZ~3 ISl R2 H ~
RcNH ~ Sy N ~

H COOR' -:
R

N ~ S

R ~ H , R3SClRCONH ~ S - S - R3 H ~ H20 > ~ N ~
COOR' 3 COOR' ~ ~ 2 ~ 2 RCONH ~ ~ I 4 ~N~<CH3 H COOR' Pyridine ~ /

RCONH ~ S ~
~ ~ CH3 COOR' ~71;213 Also within the scope of the present invention are those compounds where R stands for R 0~, R3S~, and R3R4N~
wherein R3 and R4 are as previously defined. The advantage of the new compounds where R stands for R 0,, R S~, and R3R4N- over the known compounds where R stan(l.~ for benzyl (0CH2-) or phenoxymethyl (00CH2-~ is that they are better suited to certain chemical reactions usually employed in the chemical modification of these compounds, Thus bromi~
nations employing N-bromosuccinimide would be expected to give a cleaner product with those compounds derived from 1 (R ~ R30-, R3S-, and R3R4N_ with R3 being phenyl and heteroaryl) whlle with compounds 1 (R = 0CH2, and 00CH2) bromination o~ the methylene group would be an added complication~

The starting penicillln sul~oxlde thioamldes 2are themselves obtained in a number o~ ways, The penlcillin sul~oxide thioamides 2 where R stands ior R30-, R3S-, and R3R4N-, and R stands ~or H may be conveniently obtained by thioacylation o~ 6-aminopenicillanic acid sulfoxide with a thioacylating agent corresponding to the following formulae:

RCSCl, RCSYR3, CS2/.R X, R ~=C=S, CSC12/R R NH, wherein R
and R are as previously defined, Y is sulfur or oxygen and X is halogen. The thioacylation re'action is carried out in the manner known in the art. This procedure is il]u~.trated in Flowsheet 2. It is also possible to obtain the penicillin sul~oxide thioamides 2 wh~rein R stands i'or R30-, R3S- or R3R4N- by treating a 6-isothiocyanate o~ penicillanic acld sul~oxide wlth an alcohol ot the ~ormula R30H, a thlol o~

the ~orm~la R3SH, or a secondary amine oi the ~ormula R3R4NH.

1C~7~Z13 H 2 N T~ S~,<CC H 3 `COOR

s is l i RCCl or RCYR3 RN-CSS or R3R4NH/CSC12 Base/CS2/R3X/R ' Y
Route 1 Route 2 \ / Route 3 \ /

RCNH ~ 1 R3R4HcHH ~

`COOR `COOR

2 2 \ /

R35CNH ~ CH3 o N~kC H 3 `COOR

~O~lZ~3 Alternatively, the penicillin sulfoxide thioamides ~2 may be derived from Penicillin G, N or V sulfoxides in which case R is benzyl when starting from penicillin G, R is phenoxy-methyl when starting from Penicillin V and R is 4-amino-4-carboxy-l-butyl when starting from Penicillin N, in which case it is preferred to protect the amino group by acylation and the carboxy group by esterification. The preparation of the penicillin sulfoxide thioamides ~ may be schematically illus-trated by reference to Flowsheet ~.

.

` 1071Z13 R l -NH j~xCH3 ~IPC15 RC_~CH3 CO o R 7 ~2S

R C N ~S C H 3 N kCH3 C o OR 7 ~071213 More particularly, Penicillin G sulfoxide, Penicil-lin N sulfoxide or Penicillin V sulfoxide 7 is chlorinated with a suitable agent such as phosphorus pentachloride in the presence of a base such as dimethylaniline or pyridine. Other chlorinating agents such as phosgene can also be used. The chloroimine compound 8 is then readily transformed to its corresponding thioamide 2 by reaction with hydrogen sulfide in the presence of an acid catalyst such as hydrogen chloride or sulfuric acid or the like.
It should be appreciated that the thiazoleneazetidi-nones 1 of the present invention are useful intermediates for the preparation of cephalosporins. For example, on treatment with sulfenyl iodides they provide 3-iodocephams which can be converted to the cephem compounds, such as 7-ADCA (7-amino-desacetoxycephalosporanic acid) by methods known to the art.
EXAMPLES
The present invention will be more readily under-stood by referring to the following Examples which are given only to illustrate the invention rather than limit its scope.
EXAr~PLE 1 (R ~ 0OCH2_, R1 = CH3) .
Phosphorus pentachloride (26.4 g., 0.126 mole) was added in one lot to a stirred, cold (-70) solution of methyl penicillin V sulfoxide (45.0 g., 0.1185 mole) and dimethyl-aniline (36.3 g., 0.3 moles) in methylene chloride (600 ml), and the mixture stirred for 2 1/2 hrs. at -50 or lower. H2S
is then bubbled into the reaction mixture at -70 and after approximately 1/2 hr. the mixture becomes a clear yellow from a clear dark brown colour. The H2S is continued for 1 hr. at -50 and the mixture warmed to 0 by applying an ice bath.

1~7~Z13 The H2S addition is continued at 0C. for 1 1/2 hrs, after which the reaction mixture is poured into ice water (750 ml) and the resulting mixture stirred with aqueous sodium bi-carbonate (90 g. in 200 ml). The layers were separated and the organic layer extracted sequentially with water (300 ml), aqueous HC1 (3 molar, 2 x 300 ml) and salt water (300 ml).
The organic layer was dried (MgSO4), filtered and the filtrate concentrated to a yellow powder, 44.5 g., which was estimated to contain about 60~ of methyl 6-phenoxythioacetamido-penicillanate sulfoxide from its nmr spectrum.
The crude thioamide was purified by column chroma-tography over silica gel (Grace Davidson SMR7-1498 grade 951-MS, 450 g.) using chloroform as eluent and collecting about 50 ml fractions. The process was monitored by tlc of the fractions. Fractions 11 to 145 contained the thioamide and were combined and concentrated to give 26.6 g. of the thioamide which was washed with methanol to give 22.8 g. of pure thioamide. An analytical sample was obtained by re-crystallization from methanol as white crystals, m.p. 144-20 145.
Analysis: Calcd. C 51.51, H 5.05, N 7.07, S 16.16 Found C 51.55, H 5.03, N 7.08, S 15.83 The ir and nmr spectra were in agreement with the assigned structure. The nmr spectrum was quite characteristic and differed appreciably from the starting amide. The nmr (CDC13) spectrum had signals at ~1.23(s,3H), 1.73(s,3H), gem.
CH3; 3.85(s,3H), COOCH3; 4.73(s,1H), C3-H; 4.95(s,2H), -OCH2-;
5.20(d,1H, J=5cps), C5-H; 6.67 to 7.40(m,6H), C6H5 and C6-H;
9.78(d,lH), -CSN_-.
The methyl penicillin V sulfoxide was collected in later fractions.

1C~71213 (R = ~OCH2-, R1 = H) Anhydrous penicillin V sulfoxide ~1.098 g., 3 mmoles, prepared by drying penicillin V sulfoxide at 60C.
under vacuum over P2O5 to constant weight) and dimethylaniline (1.14 ml., 9 mmoles) were dissolved in dry methylene chloride (20 ml., dried by distillation over P2O5) and cooled to 0C.
Trimethylchlorosilane (0.418 ml., 3.3 mmoles) was added and the yellow solution stirred for 30 mins at 0C. The mixture was then cooled to -30 and PC15 (0.685 g., 3.3 mmoles) added.
The mixture was stirred for 3 hours at -35 to -25, by which time the mixture became a dark green colour. H2S was then passed through the stirred solution. On contact with H2S, the green colour was immediately discharged. After 30 mins the temperature of the reaction mixture was raised to 0 by placing it in an ice-bath and, after stirring a further 30 mins at this temperature, the H2S addition was discontinued and nitrogen was passed through the mixture which was diluted with methylene chloride. The mixture was extracted with satu-rated aqueous sodium bicarbonate (3 times, until the pH of the aqueous layer was 8). The alkaline solution was then extracted with ether (4 times) and then acidified to pH 2.0 with hydrochloric acid (3 normal). At this stage some of the compound precipitated. The mixture was extracted with ethyl acetate (3 times). The combined organic extracts were washed with water, dried over Na2SO4 and taken to dryness to give 0.73 g. of a yellow solid, whose thin layer chromatogram and ir and nmr spectra showed a mixture of the amide and thio-amide. The 6-phenoxythioacetamidopenicillanic acid sulfoxide was estimated to be present in about 70~ yield from the nmr spectrum. Purification of this thioamide can be effected by column chromatography, using silicic acid.

(R = ~O-, Rl = H) Aqueous potassium hydroxide (2 normal) was added slowly to an ice-cold stirred suspension of 6-APA sulfoxide ~23.2 g., 0.1 mole) in water (275 ml), until a pH of 8Ø The solution was diluted with THF (125 ml). The solution was stirred in the ice-bath and separate solutions of phenoxythio-carbamoyl chloride (17.2 g., 0.1 mole) in THF (50 ml.) and aqueous KOH (2 normal) added by two separate dropping funnels at such a rate as to maintain the pH constant at 8Ø The reaction mixture was stored in a refrigerator overnight and then extracted with ethyl acetate (2 x 250 ml.). The water layer was covered with ethyl acetate (150 ml.) in an ice-bath and the pH adjusted to 1.5 with hydrochloric acid (12 normal).
The layers were separated and the aqueous layer extracted with ethyl acetate (2 x 125 ml). The combined ethyl acetate layers were dried over MgSO4, concentrated and dried under vacuum to yield 34.3 g. (92%) of the crude 6-phenoxythiocarbamido-penicillanic acid sulfoxide as a yellow brown foam.
The product was further purified by stirring with ether (3 x 25 ml per gram of crude), filtering and discarding the insoluble yellow solid. The ether filtrate was treated with decolorizing charcoal, filtered and concentrated to a small volume. The white solid that separated (about 50%
recovery) had m.p. 153 - 156 (decomp), and nmr and ir spectra in agreement with the proposed structure.
Analysis: Calcd. C 48.91, H 4.34, N 7.60, S 17.39 Found C 48.63, H 4.68, N 7.41, S 17.30 1071Z~3 (R = ~O, Rl = CH3OCH2-) Chloromethylmethyl ether (2.66 g., 0.033 mole) was added slowly to an ice-cold stirred solution of 6-APA sulf-oxide (6.96 g., 0.03 mole) and triethylamine (6.66 g., 0.066 mole) in methylene chloride (50 ml) and the reaction mixture stirred in the ice-bath for 1/2 hr. Phenoxythiocarbonyl chloride (5.7 g., 0.033 mole) was then added slowly, when a mild exothermic reaction (the temp rising to 5) occurred.
The reaction mixture was stirred an additional hour, by which time the yellow solution containing a moderate amount of solid had become almost clear and black. The reaction mixture was washed with water (2 x 30 ml.), dried (MgSO4 with added de-colorizing carbon) filtered and concentrated to 11 g. (88.7%) of a brown foam. The solid was stirred with ethyl acetate (200 ml) for 1/2 hr and filtered and the solid washed with ethyl acetate. The combined filtrates on concentration gave 8.4 g. (67.7%) of methoxymethyl 6-phenoxythiocarbamido-penicillanate sulfoxide as a yellow foam whose ir and nmr spectra were in agreement with the assigned structure.
EXAMPLE S

(R ~ CH S and Rl CH3) and 6-METHYLDITHIOCARBAMIDO-PENICIL~ANIC ACID SULFOXIDE 2 (R = CH3S, Rl = H) Carbon disulfide (3.35 g., 0.044 mole) was added to an ice-cold stirred solution of 6-APA sulfoxide (9.28 g., 0.04 mole), and triethylamine (8.5 g., 0.084 mole) in dry DMF
(25 ml). After 1/2 hour stirring in the ice-bath, methyl iodide (12.4 g., 0.088 mole) was added, the mixture stirred an additional hour in the ice-bath and then stirred at ambient temperature overnight (16 hours). The solution was poured, ~71Z13 with vigorous stirring into excess water when a sticky solid separated. The solid was taken up in chloroform, the organic layer washed with water (3 x 50 ml); dried over MgSO4 with decolorizing carbon, filtered, and the filtrate concentrated to a brown foam 8.6 g., (62%). The nmr and ir spectra indi-cated that the desired compounds were present in the product.
A tlc using ether as the developing solvent and iodine for visualizing the components, inaicated the presence of at least four components.
The crude product (5.0 g.) was purified by chroma-tography on silicic acid (250 g.) using ether as eluant and collecting fractions (10 ml.). White crystals appeared in many of the fractions 48 - 82, which all showed the same component to be present by tlc. These crystals, from the nmr spectrum were a mixture of the methyl 6-methyldithiocarbamido-penicillanate sulfoxide (2) and 6-methyldithiocarbamido-penicillanic acid sulfoxide (2) in a ratio of about 2:1.
These fractions were combined and concentrated to give 2.7 g.
of a brown foam whose nmr spectrum indicated a mixture of the methyl ester and the acid in the ratio of about 1:1. A
partial separation could be effected with ether.
The methyl ester was obtained pure by treating a solution of the mixture in chloroform with aqueous sodium bicarbonate, drying the organic layer and concentrating, whereby the methyl ester was obtained as a white foam, m.p.
138 - 142. The ir and nmr spectra were in agreement with the assigned structure and the C,H values were within 0.4% of the calculated values.
Analysis: Calcd. C 39.28, H 4.76 Found C 39.06, H 5.09 A high resolution mass spectral analysis of this 10712~3 compound gave a mass of 336.0268 for the parent ion. Calcu- -An attempt to recover the acid from the bicarbonate layer was not successful.

SULFOXIDE 2 (R = CH3OCH2S and Rl = CH3OCH2-) Carbon disulfide (1.7 g., 0.022 moles) was added to an ice-cold, stirred solution of 6-APA sulfoxide (4.65 g., 10 0.02 mole) and triethylamine (4.9 g., 0.048 mole) in methylene chloride (65 ml), and the mixture stirred 1/2 hour in the ice-bath and 1 hour at room temperature. The mixture was cooled in an ice-bath and chloromethylmethyl ether (3.5 g., 0.044 mole) added dropwise over 1/2 hour. The reaction mixture was stirred an additional hour in the ice-bath, then at room temperature for 1 hour, finally cooled and washed rapidly with ice-water (3 x 20 ml). The organic layer was dried (MgSO4) and concentrated to 6.1 g. of the methoxymethyl 6-methoxy-methyldithiocarbamidopenicillanate sulfoxide as a sticky yellow solid. The ir and nmr spectrum of this compound were in agreement with the assigned structure. The compound under-went rapid hydrolysis with water and became quite sticky on exposure to the air.

(R = CH3S, Rl = CH3OCH2-) Chloromethylmethyl ether (2.5 g., 0.03 mole) was added to an ice-cold, stirred solution of 6-APA sulfoxide (6.9 g., 0.03 mole), and triethylamine (9.1 g., 0.09 mole) in methylene chloride, and the reaction mixture stirred for an additional 1/2 hour in the ice-bath. A mixture of carbon disulfide (2.4 g., 0.03 mole) and methyl iodide (8.6 g., 0.06 1(~712~3 mole) in methylene chloride (20 ml.) was added slowly to the cold (10C) stirred reaction mixture, which was then stirred an additional 2 hours at ambient temperature. The mixture was stirred with water. (It was necessary to add an excess of ethyl acetate to break the emulsion). The separated organic layer was washed with water (2 times), dried over MgSO4 with decolorizing carbon, filtered through celite, and the filtrate concentrated to a light yellow foam weighing 3.7 g. (34~) which was the methoxymethyl 6-methyldithiocarbamidopenicil-lanate sulfoxide.

SULFOXIDE 2 (R = CH3NH, Rl = (C2H5~3NH) Methylisothiocyanate (4.1 g., 0.055 mole) was added to an ice-cold, stirred solution of 6-APA sulfoxide (11.6 g., 0.05 mole), and triethylamine (11.1 g., 0.11 mole) in methyl-ene chloride. The reaction mixture was stirred an additional hour in the ice-bath, then for 2 hours at ambient temperature, then treated with decolorizing charcoal, filtered through celite and taken to dryness. The resulting yellow foam was triturated with ether, filtered, washed with ether and dried at the pump to provide 19.7 g. (97%) of a flesh-colored powder which was the triethylammonium 6-methylaminothiocarbamido-penicillanate sulfoxide. The ir and nmr spectra of the product were in agreement with the assigned structure.
The triethylammonium salts were converted to esters, such as the methyl esters, before the thermolysis to the 1,2,4-dithiaaz-3-enes. It is also possible to convert them to the trimethyl~ilyl esters prior to thermolysis.

~071Z13 SULFOXIDE 2 (R = ~NH, Rl = (C2H5)3NH) Triethylammonium 6-phenylaminothiocarbamidopenicil-lanate sulfoxide was made in the same way as in Example 8, by the action of phenylisothiocyanate on 6-APA sulfoxide in the --presence of triethylamine. The compound was obtained as a pale yellow powder, m.p. 145 - 148 (decomp) in 100% yield.
The ir and nmr spectra were in agreement with the assigned structure.
The triethylammonium salts were converted to esters, such as the methyl esters, before the thermolysis reactions.
It is also possible to convert them to the trimethylsilyl esters prior to thermolysis.

METHYL 3-ANILINO-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb (R = ~NH, Rl = CH3, R2 = H) AND
METHYL 3-ANILINO-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-PROPENYLACETATE, la (R = ~NH, Rl = CH3, R2 . H) BY
THERMOLYSIS OF PENICILLIN SULFOXIDE THIOAMIDE, 2 A solution of methyl 6-anilinothioamidopenicillanate sulfoxide (7.1 g., 10.8 mmoles) in dioxane ~350 ml) was heated with stirring under reflux for 4.5 hrs, and the reaction mixture then concentrated. The residue, a yellow-brown friable foam (6.6 g.) was chromatographed over Mallinckrodt SilicAr~ cc-7 (250 g., 200-325 mesh) using benzene:ethyl acetate (4:1) as eluant. Fractions (100 ml) were collected and the process monitored by thin layer chromatography of the fractions.
Fractions 5 and 6 contained the isomer lb (0.6 g.);
ir spectrum (CHC13); 1770, 1740, 1630, and 1600 cm 1; nmr spectrum (CDC13): ~8.0 to 6.9(m), 5.98(d, J = 4.5Hz, lH), 5.78(d, J . 4.5Hz, lH), 5.13(br s,lH), 5.00(br s,lH), 4.92 1~71Z13 (s, lH), 3.78(s, 3H), 1.87(s, 3H).
C H N S
16 17 3 3 5.17 12.68 9.67 Found: 57.13 5.13 12.25 10.53 Fractions 7 to 13 (2.0 g.) contained a mixture of la and lb as was evident from the nmr spectrum. A solution of this mixture (0.4 g., 1.1 mmole - containing about 65% of lb and 35% of la) in methylene chloride (8 ml) containing tri-ethylamine (0.16 g., 1.6 mmole) was left at ambient tempera-ture overnight. Concentration to dryness gave the ~ isomer la: ir spectrum (CHC13); 3400, 1770, 1720, 1640, and 1600 cm ; nmr spectrum (CDC13): ~8.0 to 7.0(m), 5.88(ABq, J = 4Hz, 2H), 3.80(s, 3H), 2.25(s, 3H), 1.93(s, 3H).

METHYL 3-METHYLAMINO-4-THIA-2,5-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb (R = CH3NH, Rl = CH3, R2 = H) AND METHYL 3-METHYLAMINO-4-THIA-2,6-DIAZABICYCLO ~ ,2, ~HEPT-2-ENE-7-ONE-6-PROPENYLACETATE, la (R = CH3NH, Rl = CH3, R2 = H) BY THERMOLYSIS OF PENICILLIN SULFOXIDE THIOAMIDES, _ A solution of methyl 6-methylaminothioamide penicil-lanate sulfoxide (2.5 g.) in dioxane (250 ml) was heated under reflux for 4 hrs and the reaction mixture then concentrated.
l'he residue, a yellow-brown friable foam (2.3 g.) was chro-matographed over Mallinckrodt SilicAr cc-7 (100 g., 200 - 325 mesh) using a mixture of benzene and ethyl acetate (4:1) as eluant. Fractions (7 ml) were collected and the process monitored by thin layer chromatography of the fractions.
Fractions 126 - 160 contained the ~y isomer, lb (0.11 g): ir spectrum (CHC13): 3500, 1770, 1750, and 1630 30 cm ; nmr spectrum (CDC13): ~6.03(d, J = 4Hz, lH), 5.73 (d, J = 4Hz, lH), 5.20(br s, lH), 5.03(s, lH), 4.92(s, lH),

3.83(s, 3H), 3.02(s, 3H), 1.93(s, 3H).

1~71Z~L3 Fractions 161 - 190 (0. 31 g) contained a mixture of compounds lb and la.
Fractions 191 - 239 (0.32 g) contained mainly la; ir spectrum: (CHC13): 3500, 1770, 1720, and 1630 cm ; nmr spectrum (CDC13): ~6.00(S, J = 4HZ, lH), 5.83(s, ~ = 4Hz, lH), 3.88(s, 3H), 3.50(s, 3H), 2.32(s, 3H), 1.98(s, 3H).
A solution of lb (lO0 mg., 0.33 mole) in methylene chloride (2 ml) containing triethylamine (48 mg., 0. 48 mole) was allowed to stand overnight. Concentration gave the title compound, with ir and nmr spectra identical to those described above.

METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb, (R = ~OCH2, R1 = CH3, R = H) FROM METHYL PENICILLIN V THIOAMIDE SULE'OXIDE, 2 A mixture of methyl penicillin V thioamide sulf-oxide, 2 (250 mg., 0.63 mmoles) and monopyridinium dichloro-methylphosphonate (~25 mg., catalytic amount) in toluene (125 ml) was heated with stirring under reflux for 3 1/2 hrs in an oil bath maintained at 120C. The reaction mixture was then taken to dryness when a brown foam resulted. The nmr spectrum (CDC13) of this sample was the same as that from an authentic sample of lb made by the action of trimethyl-phosphite on methyl penicillin V sulfoxide.
_AMPLE 13 METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb, FROM METHYL PENICILLIN V
THIOAMIDE SULFOXIDE, _ USING TRIMETHYL PHOSPHITE
A solution of methyl penicillin V thioamide sulf-oxide, 2, (150 mg., 0.38 mmoles) and trimethylphosphite (70 mg., 0.57 mmoles) in dioxane, was heated with stirring under reflux at 120C for 3 1/2 hrs. The nmr spectrum of the product indicated the formation of lb, and also the formation of the corresponding thiazole by cleavage of the Nl-C4 bond of the azetidinone ring of _.

METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb, BY THERMOLYSIS OF METHYL
PENICILLIN V THIOAMIDE SULFOXIDE, 2, IN THE PRESENCE OF METHYL
PENICILLIN V SULFOXIDE
When a solution of methyl penicillin V thioamide sulfoxide, 2, containing about 14% of methyl penicillin V
sulfoxide was thermolysed for 3 1/2 hrs, the nmr spectrum of the residue from the reaction mixture showed the presence of _~

FROM METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO ~,2, ~-HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb (R = ~OCH2, R = CH3, R = H) A mixture of methyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo ~,2, ~hept-2-ene-7-one-6-isopropenylacetate, lb, and iodine (1 molar equivalent) were stirred at ambient temperature for 16 hrs while moist air was bubbled through.
The dark brown residue after concentration was taken up in chloroform, washed with aqueous sodium thiosulfate (twice~, then water (twice) and dried over magnesium sulfate. The nmr spectrum of the residue from the filtrate showed the presence of about 25~ of the 3-iodocepham compound. The presence of this compound was confirmed by thin layer chromatography.
Heating the 3-iodocepham for 1 hr in benzene con-taining pyridine gave an about 75% yield of methyl 7-phenoxy-acetamido-3-methylceph-3-ene-4-carboxylate.

~071Z13 METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE,

4 ~R = ~OCH2, R = H, R = CH3) FROM METHYL 3-PHENOXYMETHYL-4-THIA-2,6-DIAZABICYCLO ~,2, ~HEPT-2-ENE-7-ONE-6-ISOPROPENYLACE-TATE, 1 (R = ~OCH2, R2 = H, Rl = CH3) USING SULFENYL IODIDES-IODINE-WATER
2-Mercaptobenzothiazole (70.2 mg., 0.42 mmoles) and iodine (213 mg., 0.84 mmoles) were added to a stirred solution of methyl 3~phenoxymethyl-4~thia-2,6-diazabicyclo ~,2, ~hept-2-ene-7-one-6-isopropenylacetate (100 mgs., 0.28 mmoles) in methylene chloride (15 ml), and the mixture stirred at ambient temperature for 15 mins. Water (15 mls) was then added and the mixture stirred overnight at room temperature. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. The nmr spectrum of the residue showed the presence of about 80~ of the 3-iodocepham.
In a similar manner using the thio-compounds such as thioacetamide, thioacetanilide, thiourea, N,N'-dimethylthio-urea, N,N'-diphenylthiourea, t-butyl mercaptan, isopropyl-mercaptan, thiophenol, p-chlorothiophenol, ethyl 2-mercapto-acetate, 2-mercaptobenzooxazole, 2-mercaptobenzimidazole, 2-mercaptothiazolene, triphenylmethylmercaptan, benzylmercaptan, dimethyl disulfide, dibenzyldisulfide, di-t-butyldisulfide, di-p-tolyldisulfide, thioacetic acid and thiobenzoic acid and the following compounds;
trichloroethyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo ~,2, ~-hept-2-ene-7-one-6-isopropenylacetate, ~-nitrobenzyl 3-phenoxymethyl-4-thia-2,6-diazabicyclo ~,2, ~-hept-2-ene-7-one-6-isopropenylacetate, trichloroethyl 3-benzyl-4-thia-2,6-diazabicyclo ~,2, ~hept-2-ene-7-one-6-isopropenylacetate, ~07~Z13 _-nitrobenzyl 3-benzyl-4-thia-2,6-diazabicyclo ~,2, ~hept-2-ene-7-one-6-isopropenylacetate, and trichloroethyl l-methoxy-3-phenoxymethyl-4-thia-2,6-diaza-bicyclo ~,2, ~hept-2-ene-7-one-6-isopropenylacetate, it is possible to obtain;
trichloroethyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate, p-nitrobenzyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate, trichloroethyl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate, _-nitrobenzyl 7-phenylacetamido-3-methyl-3-iodocepham-4-carboxylate, and trichloroethyl 7-methoxy-7-phenoxyacetamido-3-methyl-3-iodo-cepham-4-carboxylate.

METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE, 4, (R = ~OCH2-, R2 = H, R = CH3), USING PYRIDINE IN BENZENE

A solution of methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate and pyridine in benzene was heated under reflux, in an oil-bath maintained at 90. Periodically aliquots of the reaction mixture were removed and the progress of the reaction followed by analyzing the nmr spectrum of the residue. The 3-iodocepham in the mixture is characterized by the C4-H singlet at ~4.9, the C6-H doublet at ~5.38 and the C2-CH2 quartet at ~2.95; the ceph-3-em is characterized by its C6-H doublet at ~5.05 and its C2-CH2 doublet at ~3.35. Any ceph-2-em produced is easily detected by its C3-CH3 singlet at ~1.92 and its C2-H signal at ~6.1. In all our experiments using pyridine as the base there were no detectable amounts of the ceph-2-em lsomer produced. The following table summarizes the results of experiments in which the relative amount of pyridine was varied.

Dehydroiodination of 3-Iodocepham using Pyridine in Benzene No. Mole Ratio of Pyridine Time of Reflux Yield of Ceph-3-em(~) 1. 2.5 equivalents 0.5 hr 45 2. 2.5 " 1.0 hr 60 3. 2.5 " 1.5 hr 67 -4. 5 equivalents 0.5 hr 50 10 5. 5 " 1.0 hr 66 6. 5 " 1.5 hr 80 7. 5 " 3.0 hr ~100 8. 10 equivalents 0.5 hr 60 9. 10 " 1.0 hr ~100 10. 10 " 1.5 hr 100 There was no detectable trace of any ceph-2-em isomer in any of these experiments.

METHYL 7-PHENOXYACETAMIDO-3-METHYL-3-IODOCEPHAM-4-CARBOXYLATE, 4 (R = ~OCH2-, R2 = H, Rl = CH3J USING PYRIDINE ALONE
Methyl 7-phenoxyacetamido-3-methyl-3-iodocepham-4-carboxylate (100 mg) was dissolved in pyridine d5 (0.5 ml) and the reaction monitored by running an nmr spectrum on the sample periodically. After about 15 mins at ambient tempera-ture there was about 50~ conversion to the ceph-3-em, and after 2 hrs the reaction was complete. The nmr spectrum did not change after a 24-hour period and again no detectable amount of the ceph-2-em isomer was observed.

~071213 METHYL 3-PHENOXY-4-THIA-2,6-DIAZABICYCLO(3,2,0)HEPT-2-ENE-7-ONE-6-ISOPROPENYLACETATE, lb, BY THERMOLYSIS OF METHYL 6-PHENOXYTHIOCARBAMIDOPENICILLANATE SULFOXIDE IN THE PRESENCE
OF TRIMETHYLPHOSPHITE
A mixture of methyl 6-phenoxythiocarbamidopenicil-lanate sulfoxide (made by the action of diazomethane on the acid of Example 3) with trimethylphosphite (1 equivalent) in toluene was heated under reflux for 6 hrs. The reaction mixture was washed well with water, the organic layer dried (over MgSO4) and concentrated under reduced pressure. The nmr spectrum of the residue showed the presence of about 50% of methyl 3-phenoxy-4-thia-2,6-diazabicyclo(3,2,0)hept-2-ene-7-one-6-isopropenylacetate.

Claims (10)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. The process for preparing a compound of the formula:

wherein:
R stands for phenylamino or loweralkylamino;
R1 stands for loweralkyl; and R2 stands for hydrogen, which comprises heating alone or optionally in the presence of a catalyst or a sulfur extraction compound, a penicillin sulfoxide thioamide of the formula:

wherein R and R1 are as previously defined, said heating step being carried out for a period of less than about five hours.

2. The process of Claim 1, wherein methyl 6-anilino-thioamidopenicillanate sulfoxide is heated for a period of about 4 hours to form a mixture of methyl 3-anilino-4-thia-2,6-diazabicyclo [3,2,0]hept-2-ene-7-one-6-isopropenylacetate and methyl 3-anilino-4-thia-2,6-diazabicyclo [3,2.0]hept-2-ene-7-one-6-propenylacetate.

3. The process of Claim 2, wherein the mixture obtained is treated with an organic base to yield the methyl 3-anilino-4-thia-2,6-diazabicyclo [3,2,0,]hept-2-ene-7-one-6-propenylacetate.

4. The process of Claim 1, wherein methyl 6-methyl-aminothioamidopenicillanate sulfoxide is heated for a period of about 4 hours to form a mixture of methyl 3-methylamino-4-thia-2,5-diazabicyclo [3,2,0,]hept-2-ene-7-one-6-isopropenyl-acetate and methyl 3-methylamino-4-thia-2,6-diazabicyclo-[3,2,0]hept-2-ene-7-one-6-propenylacetate.

5. The process of Claim 4, wherein the mixture obtained is treated with an organic base to form the methyl 3-methylamino-4-thia-2,5-diazabicyclo [3,2,0.]hept-2-ene-7-one-6-propenylacetate.

6. The compounds of the formula:

which is representative of the two isomers depicted by 1a and 1b:

1a 1b wherein:
R stands for phenylamino or loweralkylamino;
R1 stands for loweralkyl; and R2 stands for hydrogen, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.

7. The methyl 3-anilino-4-thia-2,6-diazabicyclo-[3,2,0]hept-2-ene-7-one-6-isopropenyl(and propenyl)acetate, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.

8. The methyl 3-methylamino-4-thia-2,6-diazabicyclo-[3,2,0,]hept-2-ene-7-one-6-isopropenyl(and propenyl)acetate, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

9. The methyl 3-anilino-4-thia-2,6-diazabicyclo-[3,2,0,]hept-2-ene-7-one-6-propenylacetate, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

10. The methyl 3-methylamino-4-thia-2,5-diazabicyclo-[3,2,0]hept-2-ene-7-one-6-propenylacetate, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.