2&α-ALKOXYMETHYL CEPHALOSPORINS: REACTIONS OF exo-2-METHYLENE CEPHALOSPORIN SULFONES WITH ALCOHOLS

Article abstract of DOI:10.1135/cccc19942282

A series of 2α-alkoxymethyl cephem sulfones were prepared by nucleophilic addition of a variety of alcohols to exo-2-methylene cephem sulfones.The 2α-alkoxymethyl group was introduced with the aim of improving the inhibitory activity against human leukocy

Full text of DOI:10.1135/cccc19942282

2282
Cummings et al.:
2α-ALKOXYMETHYL CEPHALOSPORINS: REACTIONS
OF exo-2-METHYLENE CEPHALOSPORIN SULFONES WITH ALCOHOLS
Maxwell D. CUMMINGS, David P. CZAJKOWSKI, John BRUNSTEIN,
Narender A. V. REDDY, Oludotun A. PHILLIPS, Charles FIAKPUI,
Paul SPEVAK, Ronald G. MICETICH and Samarendra N. MAITI*
SynPhar Laboratories Inc.,
Taiho Alberta Centre, #2, 4290-91A Street, Edmonton, Alberta, Canada T6E 5V2
Received December 14, 1993
Accepted July 22, 1994
A series of 2α-alkoxymethyl cephem sulfones were prepared by nucleophilic addition of a variety of
alcohols to exo-2-methylene cephem sulfones. The 2α-alkoxymethyl group was introduced with the
aim of improving the inhibitory activity against human leukocyte elastase (HLE) over the unsub-
stituted compounds. However, against HLE the in vitro activity was still inferior to that shown by the
C-2 unsubstituted cephem sulfones.
In recent years much attention has focused on the chemical modification of the C-2,
C-3, C-4 and C-7 position of the cephalosporin moiety with the aim of obtaining potent
elastase inhibitors1–4. Some of these inhibitors also show in vivo activity such as I and
II which prevent lung damage in hamsters treated intratracheally with human leukocyte
elastase1,5 (HLE).
Our effort in this area has produced a series of 2-spirocyclopropyl cephem sulfones
(III) with the derivatization of the carboxylic function at the C-4 position of the cephem
nucleus as esters6, amides7, and ketones8 and were found to exhibit potent inhibitory
activity against HLE. It is further evidenced from the subsequent literatures9 that the
introduction of a substituent at C-2 position of the cephem skeleton will generally in-
crease inhibitory activity against HLE; examples of such inhibitors include 2α- and
2β-CH3, 2α-OCH3, and 2α-CH2SPh. Alpegiani et al.2,3 further reported a series of C-2
substituted cephem-4-ketones (IV) as potent elastase inhibitors. On these grounds, a
research programme devoted to the synthesis and evaluation of new C-2 substituted
cephem sulfones was undertaken in our laboratory. We wish to report here the synthesis
of 2α-alkoxymethyl cephem sulfones V.
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2α-Alkoxymethyl Cephalosporins
2283
In 1971, Wright et al.10 reported that refluxing of cephalosporin sulfoxide esters in a
mixture of 2-methyl-2-propanol and methylene chloride with aqueous formaldehyde
under Mannich conditions gave a single product, exo-2-methylene sulfoxide. In an at-
tempt to introduce a double bond at C-2 position of the cephem sulfone VI under such
conditions we found that the cephem sulfone VIa, gave exo-2-methylene cephem sul-
fone VIIIa as the major product, along with a minor product Va (Scheme 1). This inter-
esting observation prompted us to investigate the reaction in detail. Suprisingly, when
methylene chloride was replaced with dioxane, no alkoxymethyl cephem derivative Va
was observed.
The intermediate VIIa under the reaction conditions can undergo nucleophilic dis-
placement by 2-methyl-2-propanol or the product VIIIa can undergo nucleophilic addi-
tion at the exocyclic double bond to form the 2α-alkoxymethyl cephem sulfone Va.
This is readily proven by the fact that the exo-2-methylene cephem sulfones VIII can be
converted to V by further reaction with a variety of alcohols like methanol, ethanol,
2-propanol and 2-methyl-2-propanol at ambient to refluxing temperatures using
methylene chloride as a solvent. The isolated products V were not a mixture of C-2
epimers, but they were single compounds (2α-isomer) in each case. The stereoselectiv-
ity of additions to the exocyclic double bond has been described elsewhere9. The nature
of the ester protecting group R4 affected the ease of the addition. With electron with-
drawing trichloroethyl group, the addition was much faster but with electron donating
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2284
Cummings et al.:
tert-butyl esters no addition was observed even with methanol. As would be expected
both from steric and nucleophilic effects consideration, methanol was found to add
rapidly and a nearly complete conversion to product Vd was obtained. 2-Propanol
added more slowly than did ethanol, while the 2-methyl-2-propanol was found to be
almost unreactive under a variety of conditions, with the best result being approxi-
mately 40% product after 24 h at reflux in the presence of three equivalents of dimethy-
lammonium chloride. Use of Lewis acids like AlCl3 and TiCl4 accelerated the rate of
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2α-Alkoxymethyl Cephalosporins
2285
addition; however, they failed to drive the reaction to completion. Other Lewis acids
like ZnCl2 and SnCl4 led to extensive decomposition.
Introduction of the 2α-alkoxymethyl group in the cephem skeleton did not improve
the inhibitory activity against human leukocyte elastase. The compound Vb had only
39% inhibition at 750 nM while its parent compound VIb had an IC50 value of 480 nM
against HLE.
EXPERIMENTAL
Melting points were determined on a Thomas Hoover capillary melting point apparatus and are un-
corrected. NMR spectra (δ, ppm; J, Hz) were recorded with Bruker AC-200E (200 MHz) spec-
trometer in CDCl3 and are reported relative to TMS as an internal standard.
Benzhydryl 7α-Bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide7 (VIa)
To an ice-cooled mixture of 7β-amino-3-methyl-3-cephem-4-carboxylic acid (10.0 g, 0.047 mol),
ethanol (270 ml), water (83 ml) and HBr (48%, 56.7 ml) was added NaNO2 (4.67 g, 0.67 mol) in
small portions over 25 min and the mixture was stirred at ice-temperature for 2.5 h. Ethanol was
removed under reduced pressure and the residual mass was diluted with methylene chloride, washed
with water. The aqueous washings were saturated with brine and re-extracted with methylene
chloride. The combined organic layer was washed with brine, dried (Na2SO4) and concentrated to
give 9.8 g (75%) of 7α-bromo-3-methyl-3-cephem-4-carboxylic acid which was directly used for the
next step.
To a stirred solution of the crude acid (9.8 g, 0.035 mol) in dry methylene chloride (50 ml) was
added dropwise a solution of diphenyldiazomethane (8.21 g, 0.043 mol) dissolved in methylene
chloride (50 ml). The mixture was stirred at room temperature for 3 h, washed with 10% NaHCO3
solution, water, brine, and dried (Na2SO4). Concentration under reduced pressure gave a brown foam
(11.9 g, 76%) which was purified over a silica gel column. Elution of the column with a mixture of
hexane–ethyl acetate (85 : 15) gave 8.0 g (51%) of pure benzhydryl 7α-bromo-3-methyl-3-cephem-
4-carboxylate. This compound (8.0 g, 0.018 mol) was dissolved in methylene chloride (35 ml), per-
acetic acid (12.3 g, 0.162 mol) was added slowly and the mixture was stirred at room temperature for
72 h, then washed successively with water, 10% NaHCO3 solution and water. After drying (Na2SO4)
and concentration, the product was purified over a silica gel column using methylene chloride as
1
eluant. The title compound was obtained as a pale yellow foam (3.35 g, 40%). H NMR spectrum:
2.10 s, 3 H (CH3); 3.80 brs, 2 H (H-2); 4.80 brs, 1 H (H-6); 5.25 brs, 1 H (H-7); 6.95 s, 1 H
(CHPh2); 7.2 – 7.6 m, 10 H (arom.)
Benzhydryl 7α-Bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide7 (VIIIa)
To a stirred solution of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (VIa,
2.80 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylammonium chloride (1.44 g,
0.0176 mol), formaldehyde (37% aqueous solution, 0.61 g, 0.02 mol) and 2-methyl-2-propanol (100
ml), the mixture was heated to reflux for 3 h. Solvent was removed under reduced pressure and the
residue was dissolved in methylene chloride, washed with water, dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified over a silica gel column. Elution of the column
with a mixture of hexane–ethyl acetate (75 : 25) gave 2.00 g (69%) of pure product as a white foam.
1H NMR spectrum: 2.10 s, 3 H (CH3); 4.93 d, 1 H, J (6,7) = 1.5 (H-6); 5.33 d, 1 H, J (6,7) = 1.5
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2286
Cummings et al.:
(H-7); 6.20 d, 1 H, J = 2.0 (=CH2); 6.70 d, 1 H, J = 2.0 (=CH2); 6.98 s, 1 H (CHPh2); 7.30 – 7.45 m,
10 H (arom.)
The above reaction conditions always give the Va as a minor product. In another experiment, 3.75 g
(0.0079 mol) of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (VIa) was dis-
solved in dioxane (35 ml); dimethylammonium chloride (1.925 g, 0.024 mol), formaldehyde (37%
aqueous solution, 0.830 g, 0.028 mol) and 2-methyl-2-propanol (8.5 ml) were added. The mixture
was heated at 70 °C for 2 h. Solvent was removed under reduced pressure. The residue was taken in
methylene chloride, washed successively with water, brine, dried (Na2SO4) and concentrated to give
pure benzhydryl 7α-bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (VIIIa) in
98% yield (3.8 g) as a white solid.
Benzhydryl 7α-Bromo-2α-(1,1-dimethylethoxy)methyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (Va)
To a solution of benzhydryl 7α-bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide
(VIIIa, 300 mg, 0.614 mmol) in methylene chloride (1.5 ml) were added dimethylammonium chloride
(150 mg, 1.84 mmol) and 2-methyl-2-propanol (10.7 ml). The mixture was heated to reflux for 24 h.
Solvent was removed under reduced pressure and the residue was taken in methylene chloride,
washed with water, brine and dried (Na2SO4). After concentration, the product was purified by prepa-
1
rative TLC. The title compound Va was obtained as a pale yellow foam (0.104 g, 30%). For H NMR
spectrum, see Table I.
Benzhydryl 7α-Bromo-2α-methoxymethyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (Vd)
To a solution of benzhydryl 7α-bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide
(VIIIa, 1.0 g, 2.05 mmol) in methylene chloride (24 ml) was added methanol (24 ml) followed by a
catalytic amount of AlCl3 (4 mg). The reaction mixture was stirred at room temperature for 6 h. The
1
progress of the reaction was monitored by TLC. After 6 h of stirring, H NMR analysis of the reac-
tion mixture indicates that about 90% of the product has been formed. Extended period of stirring
and further addition of AlCl3 did not improve the yield. After usual work up the title compound Vd
was obtained as an off-white foam (698 mg) which was crystallized twice (benzene–hexane) to give
1
an analytically pure sample (72 mg). For H NMR spectrum, see Table I. The compound (Vd) could
not be purified by silica gel column chromatography; it has a tendency to convert back to 2-exo-
methylene cephem sulfone (VIIIa).
Benzhydryl 7α-Bromo-2α-ethoxymethyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (Ve)
A solution of benzhydryl 7α-bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide
(VIIIa, 0.174 g, 0.36 mmol) in a mixture of methylene chloride (5 ml) and anhydrous ethanol (5 ml)
was refluxed for 12 h. Solvent was removed under reduced pressure and the residue was taken in
methylene chloride, washed successively with water, brine, dried (Na2SO4) and concentrated to give
a gummy mass (0.161 g, 85%) which was rapidly purified over a silica gel column (elution with
hexane–ethyl acetate, 3 : 2). The title compound Ve was obtained as a pale yellow foam (100 mg,
53%). On a longer exposure to silica gel column the compound Ve converts back to VIIIa. For 1H NMR
spectrum, see Table I.
Benzhydryl 7α-Bromo-2α-(1-methylethoxy)methyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (Vf)
To a solution of benzhydryl 7α-bromo-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide
(VIIIa, 0.5 g, 1.02 mmol) in a mixture of methylene chloride (12 ml) and 2-propanol (12 ml) was
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2α-Alkoxymethyl Cephalosporins
2287
added AlCl3 (14 mg) and the mixture was stirred at room temperature for 6 h. An additional amount
of AlCl3 (14 mg) was added and the mixture was heated to reflux for 8 h. After usual work up the
product was obtained as a white foam (314 mg) which was purified by column chromatography over
a silica gel column. 1H NMR spectrum (see Table I) of this product indicates that it is about 95%
pure. The product is contaminated with the starting 2-exo-methylene compound VIIIa. Attempted
purification by crystallization or by preparative TLC was not successful.
Benzhydryl 7α-Methoxy-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-dioxide7 (VIb)
To 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (27.2 g, 99.9 mmol) was added water
(500 ml) and sodium bicarbonate (9.3 g, 111 mmol); the pH of the mixture was adjusted to 6.5 with
10% NaOH solution, NaN3 (13.1 g, 201 mmol) and acetone (350 ml) were added. The mixture was
heated at 60 °C for 6 h and left stirring overnight at room temperature. Acetone was removed under
reduced pressure and the mixture was cooled in an ice-bath, acidified with concentrated HCl to pH 3.5;
the precipitated solid was filtered off, dried over P2O5 to give 14.3 g (56%) of 7β-amino-3-azido-
methyl-3-cephem-4-carboxylic acid which was used for the next step.
To a suspension of this compound (20.7 g, 81 mmol) in a mixture of methylene chloride (250 ml)
and dimethyl sulfoxide (250 ml) was added dropwise a solution of diphenyldiazomethane (17.53 g,
90 mmol) in methylene chloride (150 ml). The mixture was stirred at room temperature for 68 h,
filtered and the filtrate was concentrated under reduced pressure. The residue was taken into ethyl
acetate (250 ml) and washed successively with 10% NaHCO3 solution, water, brine, dried (Na2SO4)
and concentrated under reduced pressure to give a residue which was purified over a silica gel col-
umn (elution with methylene chloride–ethyl acetate, 1 : 1). The product was obtained as a mixture of
∆2- and ∆3-isomers (18.4 g, 54%).
To a stirred solution of the isomeric mixture (16 g, 38 mmol) in ethyl acetate (500 ml) at 0 °C
was added sodium tungstate dihydrate (1.254 g, 3.8 mmol) and hydrogen peroxide (30% solution,
17.5 ml). After stirring at 0 °C for 15 min, the mixture was stirred at room temperature for 2 h when
another portion of hydrogen peroxide (4.4 ml) was added and the resulting mixture was stirred over-
night. The mixture was cooled in an ice-bath and sodium bisulfite solution (13 g in 100 ml of water)
was added dropwise and the mixture was stirred for 10 min, Na2CO3 solution (4 g in 80 ml of water)
was added to the above mixture and stirred for 10 min. The organic layer was separated out and the
aqueous layer was re-extracted with two portions of ethyl acetate. The combined organic extracts
were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. To the residue
hexane was added and the mixture was stirred with ice-cooling. The precipitated solid was collected
by filtration to give 12.2 g (71%) of pure benzhydryl 7β-amino-3-azidomethyl-3-cephem-4-carboxylate-
1
1,1-dioxide. H NMR spectrum: 2.35 brs, 2 H (NH2); 3.70 and 4.01 q, 2 H, J = 18.0 (H-2); 4.25 brs,
2 H (CH2N3); 4.80 d, 1 H, J = 5.0 (H-6); 4.95 d, 1 H, J = 5.0 (H-7); 7.05 s, 1 H (CHPh2); 7.40 – 7.65 m,
10 H (arom.).
To an ice-cooled stirred solution of benzhydryl 7β-amino-3-azidomethyl-3-cephem-4-carboxylate-
1,1-dioxide (1.1 g, 2.43 mmol) in methylene chloride (15 ml) was added an ice-cold solution of
NaNO2 (184 mg, 2.67 mmol) in water (9 ml); 1.75 M H2SO4 (1.1 ml) was added dropwise at such a
rate that the temperature was below 0 °C. The mixture was stirred at 0 °C for 1 h; the methylene
chloride layer was separated out and the aqueous layer was re-extracted with methylene chloride
(2 × 20 ml). The combined organic layer was washed with water, brine, dried (Na2SO4) and filtered.
To the filtrate, methanol (25 ml) was added and while stirring at room temperature, rhodium acetate
dimer (12 mg) was added in one portion. After stirring at room temperature for 1 h, the reaction
mixture was filtered through Celite and solvent was removed under reduced pressure. The residue
was purified over a silica gel column (elution with hexane–ethyl acetate, 3 : 2) to give pure benz-
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2288
Cummings et al.:
hydryl 7α-methoxy-3-azidomethyl-3-cephem-4-carboxylate-1,1-dioxide (370 mg, 33%). 1H NMR
spectrum: 3.56 s, 3 H (OCH3); 3.71 and 3.99 q, 2 H, J = 18.0 (H-2); 4.02 and 4.18 q, 2 H, J = 14.0
(CH2N3); 4.70 d, 1 H, J (6,7) = 1.5 (H-6); 5.19 d, 1 H, J (6,7) = 1.5 (H-7); 6.97 s, 1 H (CHPh2);
7.31 – 7.46 m, 10 H (arom.).
A solution of benzhydryl 7α-methoxy-3-azidomethyl-3-cephem-4-carboxylate-1,1-dioxide (3.1 g,
6.62 mmol) in ethylene glycol dimethyl ether (60 ml) was transferred to a steel bomb and cooled to
−78 °C; the reaction vessel was flushed with nitrogen for 15 min; 14.0 g of acetylene was taken in
the steel bomb and the reaction mixture was heated at 90 °C overnight. The steel bomb was cooled
in an ice-bath and the excess acetylene was slowly allowed to evaporate at room temperature. The
solvent was removed under reduced pressure. The crude product was purified over a silica gel col-
umn (elution with hexane–ethyl acetate, 1 : 1) to give a foam (1.9 g, 58%). Ether was added to the
1
foam and the precipitated solid was collected by filtration. H NMR spectrum: 3.55 s, 3 H (OCH3);
3.65 and 3.97 q, 2 H, J = 18.0 (H-2); 4.74 s, 1 H, (H-6); 5.16 s, 3 H (CH2-triazole + H-7); 7.10 s, 1 H
(CHPh2); 7.30 – 7.43 m, 10 H (arom.); 7.51 s, 1 H, and 7.67 s, 1 H (triazole).
Benzhydryl 7α-Methoxy-2-exo-methylene-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-
1,1-dioxide7 (VIIIb)
To a solution of benzhydryl 7α-methoxy-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-di-
oxide (VIb, 1.8 g, 3.85 mmol) in methylene chloride (30 ml) and 2-methyl-2-propanol (70 ml) was
added dimethylammonium chloride (940 mg, 11.54 mmol) and formaldehyde solution (37%, 410 mg,
13.5 mmol). The mixture was heated at 80 °C for 1.5 h and the solvent was removed. The residue
was taken in methylene chloride, washed with water, brine, dried (Na2SO4) and concentrated. The
residue was purified over a silica gel column (elution with hexane–ethyl acetate, 1 : 2) to give pure
benzhydryl 7α-methoxy-2-exo-methylene-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-di-
oxide (VIIIb, 910 mg, 49%). 1H NMR spectrum: 3.57 s, 3 H (OCH3); 4.87 d, 1 H, J (6,7) = 2.0
(H-6); 5.01 and 5.47 q, 2 H, J = 15.0 (CH2-triazole); 5.29 d, 1 H, J (6,7) = 2.0 (H-7); 6.55 d, 1 H,
J = 2.6 (=CH2); 6.64 d, 1 H, J = 2.6 (=CH2); 7.06 s, 1 H (CHPh2); 7.30 – 7.37 m, 10 H (arom.); 7.51 s,
1 H, and 7.58 s, 1 H (triazole). Benzhydryl 7α-methoxy-2α-(1,1-dimethylethoxy)methyl-3-methyl-3-
cephem-4-carboxylate-1,1-dioxide (Vb) was isolated as a minor component (12%) from this experi-
1
ment. For H NMR spectrum see Table I.
p-Methoxybenzyl 7α-Methoxy-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-dioxide7 (VIc)
A solution of p-methoxybenzyl-7β-amino-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-di-
oxide7 (800 mg, 1.85 mmol) in dry ethyl acetate was cooled to 10 °C under nitrogen. Isopropyl nitrite
(0.247 g, 2.8 mmol) was added to the above solution followed by 3 drops of trifluoroacetic acid. The
reaction mixture was further stirred at 10 °C for 1 h and cooled to −5 °C. Rhodium octanoate dimer
(18 mg) was dissolved in a mixture of ethyl acetate (10 ml) and anhydrous methanol (2 ml) and the
mixture was stirred under nitrogen at 0 °C. After stirring for 30 min, 5 drops of triethylamine was
added (the color changes from light green to purple) and the solution was further cooled to −5 °C.
The above two solutions were mixed together at −5 °C and stirred for 2 h. The reaction mixture
was diluted with 50 ml of ethyl acetate, made acidic with glacial acetic acid, washed successively
with cold water, brine, dried (Na2SO4) and concentrated to give a dark brown foam which was puri-
fied on a silica gel column (elution with hexane–ethyl acetate, 1 : 1) to give pure p-methoxybenzyl-
7α-methoxy-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-1,1-dioxide (VIc, 140 mg, 20%).
1H NMR spectrum: 3.54 s, 3 H (OCH3); 3.65 and 3.93 q, 2 H, J = 18.0 (H-2); 3.82 s, 3 H (OCH3);
4.70 d, 1 H, J (6,7) = 1.1 (H-6); 5.08 – 5.40 m, 5 H (CH2-triazole + CH2-benzylic + H-7); 6.91 d, 2 H
(arom.); 7.37 d, 2 H (arom.); 7.73 s, 2 H (triazole).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2α-Alkoxymethyl Cephalosporins
2289
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2290
Cummings et al.:
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2α-Alkoxymethyl Cephalosporins
2291
p-Methoxybenzyl 7α-Methoxy-2-exo-methylene-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-
1,1-dioxide7 (VIIIc)
To a solution of p-methoxybenzyl 7α-methoxy-3-[(1,2,3-triazolyl)methyl]-3-cephem-4-carboxylate-
1,1-dioxide (VIc, 1.27 g, 2.8 mmol) in dry methylene chloride (8 ml) were added dimethylammonium
chloride (0.692 g), formaldehyde solution (0.804 ml) and 2-methyl-2-propanol (35 ml). The mixture
was heated to reflux for 2 h and solvent was removed under reduced pressure. The residue was dis-
solved in methylene chloride, washed successively with water, brine, dried (Na2SO4) and evaporated
to give a sticky mass which was purified over a silica gel column (elution with hexane–ethyl acetate,
1 : 1). Fast moving component was the minor product, p-methoxybenzyl 7α-methoxy-2α-(1,1-di-
methylethoxy)methyl-3-methyl-3-cephem-4-carboxylate-1, 1-dioxide (Vc, 210 mg, 16%). 1H NMR
1
spectrum see in the Table I. Further elution of the column gave compound VIIIc. H NMR spectrum:
3.57 s, 3 H (OCH3); 3.81 s, 3 H (OCH3); 4.81 d, 1 H, J (6,7) = 1.5 (H-6); 5.17 – 5.54 m, 5 H
(CH2-triazole + CH2-benzylic + H-7); 6.56 d, 1 H, J = 2.6 (=CH2); 6.63 d, 1 H, J = 2.6 (=CH2); 6.90 d,
2 H (arom.); 7.35 d, 2 H (arom.); 7.66 s, 1 H (triazole); 7.76 s, 1 H (triazole).
2,2,2-Trichloroethyl 7α-Methoxy-3-methyl-3-cephem-4-carboxylate-1,1-dioxide7 (VIg)
2,2,2-Trichloroethyl-7α-methoxy-3-methyl-3-cephem-4-carboxylate7 (8.7 g, 24.12 mmol) was dis-
solved in 100 ml of methylene chloride, peracetic acid (51.6 ml) was added dropwise and stirred at
room temperature for 18 h. The mixture was washed successively with water, 10% NaHCO3 solution,
brine, dried (Na2SO4) and concentrated to give a sticky mass. To the sticky mass a mixture of ether–
hexane (1 : 1) was added with ice-cooling. The precipitated solid was collected by filtration (9.33 g,
1
98%). H NMR spectrum: 2.17 s, 3 H (CH3); 3.57 s, 3 H (OCH3); 4.13 brd, 2 H (H-2); 4.93 s, 1 H
and 5.20 s, 1 H (CH2CCl3); 5.15 brd, 1 H (H-6); 5.96 brd, 1 H (H-7).
2,2,2-Trichloroethyl 7α-Methoxy-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide7
(VIIIg)
A mixture of 2,2,2-trichloroethyl 7α-methoxy-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (VIg,
2.0 g, 5.1 mmol), dimethylammonium chloride (1.24 g, 15.28 mmol), 2-methyl-2-propanol (24 ml),
methylene chloride (5 ml) and formaldehyde (1.43 ml, 37% w/v in water) was heated to reflux for 1.5 h.
Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride,
washed successively with water, brine, dried (Na2SO4) and concentrated to give pure 2,2,2-trichloro-
ethyl 7α-methoxy-2-exo-methylene-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (VIIIg, 1.78 g,
86%) as a white solid. 1H NMR spectrum: 2.20 s, 3 H (CH3); 3.60 s, 3 H (OCH3); 4.80 d, 1 H, J = 14.0
and 5.20 d, 1 H (CH2CCl3); 4.90 brs, 1 H (H-6); 5.30 brs, 1 H (H-7); 6.23 brd, 1 H (=CH2); 6.75 brd,
1 H (=CH2).
2,2,2-Trichloroethyl 7α-Methoxy-2α-methoxymethyl-3-methyl-3-cephem-4-carboxylate-1,1-dioxide
(Vg)
To a stirred solution of 2,2,2-trichloroethyl 7α-methoxy-2-exo-methylene-3-methyl-3-cephem-4-carb-
oxylate-1,1-dioxide (VIIIg, 300 mg, 0.74 mmol) in methylene chloride (5 ml) was added methanol (7 ml)
and the mixture was refluxed at 50 °C for 5 h. Solvent was removed under reduced pressure and the
residue was taken in methylene chloride, washed successively with water, brine, dried (Na2SO4) and
concentrated to give a white foam (228 mg) which was rapidly purified over a silica gel column.
1H NMR (see Table I) of this product (Vg) indicates that it is 95% pure. The product is mixed with
the starting 2-exo-methylene cephem sulfone (VIIIg). Attempted purification by crystallization or by
preparative TLC was not successful.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2292
Cummings et al.:
REFERENCES
1. Finke P. E., Shah S. K., Ashe B. M., Ball R. G., Blacklock T. J., Bonney R. J., Brause K. A.,
Chandler G. O., Cotton M., Davies P., Dellea P. S., Dorn C. P. jr., Fletcher D. S., O’Grady L.
A., Hagmann W. K., Hand K. M., Knight W. B., Maycock A. L., Mumford R. A., Osinga D. G.,
Sohar P., Thompson K. R., Weston H., Doherty J. B.: J. Med. Chem. 35, 3731 (1992); and
references therein.
2. Alpegiani M., Bissolino P., Perrone E., Cassinelli G., Franceschi G.: Tetrahedron Lett. 32, 6207
(1991).
3. Alpegiani M., Bissolino P., Borghi D., Corigli R., Nero S. D., Perrone E., Razzano G., Rizzo V.:
Biomed. Chem. Lett. 2, 1127 (1992).
4. Alpegiani M., Baici A., Bissolino P., Carminati P., Cassinelli G., Nero S. D., Franceschi G.,
Orezzi P., Perrone E., Rizzo V., Sacchi N.: Eur. J. Med. Chem. 27, 875 (1992).
5. Bonney R. J., Ashe B., Maycock A., Dellea P., Hand K., Osinga D., Fletcher D., Mumford R.,
Davies P., Frankenfield D., Nolan T., Schaeffer L., Hagmann W., Finke P., Shah S., Dorn C.,
Doherty J. B.: J. Cell. Biochem. 39, 47 (1989).
6. Maiti S. N., Czajkowski D., Spevak P., Adachi K., Micetich R. G. (SynPhar Labs Inc.): U.S.
5, 264, 430 (1993).
7. Maiti S. N., Czajkowski D., Spevak P., Adachi K., Micetich R. G. (SynPhar Labs Inc.): U.S.
5, 264, 429 (1993).
8. Maiti S. N., Reddy N. A. V., Czajkowski D., Spevak P., Fiakpui C., Micetich R. G. (SynPhar
Labs Inc.): U.S. 5, 258, 377 (1993).
9. Hagmann W., O’Grady L., Ashe B. M., Dahlgren M. E., Weston H., Maycock A. L., Knight W.
B., Doherty J. B.: Eur. J. Med. Chem. 24, 599 (1989).
10. Kaiser G. V, Ashbrook C. W., Goodson T., Wright I. G., Heyningen E. M.: J. Med. Chem. 14,
426 (1971).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)