-methyl-3-acyloxycepham-4-carboxylic acid ester. Also produced in the chemical conversion process is a 2-acyloxymethylpenicillin, otherwise designated as a 6-acylamido-2-methyl-2-acyloxymethylpenam-3-carboxylic acid.
U.S. Pat. No. 3,275,626 additionally discusses the possibility of converting a penicillin sulfoxide by heating it in the presence of any of various acidic reagents. The ultimate antibiotic substances which form from such reactions will depend to some extent upon the particular acid which is employed, with the substituents present in the acid as well as the particular structure and relative strength of the acid having some effect upon the products formed.
In carrying out the reaction of a penicillin sulfoxide ester with thionyl chloride, it has been found that the following products can be produced: ##SPC1##
It further has been found that the 2.alpha.-methyl-2.beta.-chloromethylpenam (I above) is unstable and gradually rearranges to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham of the formula ##SPC2##
This rearrangement occurs at room temperature over a period of several days. The rearrangement can be greatly accelerated by subjecting the penam to an elevated temperature, for example, from about 50.degree.C. to about 100.degree.C., under which conditions the rearrangement can be accomplished in as little as one hour. Conversion to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham can also be effected by maintaining the unstable penam in a suitable inert solvent on a chromatographic column for a period of from about 24 to about 72 hours and then eluting the cepham product from the column.
In accordance with this invention, it has now been discovered that it is possible to convert a 6-imido-2.alpha.-methyl-2.beta.-halomethylpenam-3-carboxylic acid ester having a structure such as (I) above and/or a 7-imido-3.alpha.-methyl-3.beta.-halocepham-4-carboxylic acid ester obtainable by rearrangement from the aforementioned 2.beta.-halomethylpenam and having a structure such as (Ia) above to an active 3-methyl-3-cephem antibiotic, a 3-methyl-3-nitrooxycepham,
-methyl-3 - acyloxycepham-4 - carboxylic acid ester. Also produced in the chemical conversion process is a 2 - acyloxymethylpenicillin, differently indicate as a 6 - acylamido-2 - methyl-2 - acyloxymethylpenam-3 - carboxylic acid. 
 U.S. Pat. No. 3,275,626 additionally discourse the hypothesis of converting a penicillin sulfoxide by heating it in the presence of any of assorted acidic reagents. The ultimate antibiotic substances which shape from such reactions will depend to some extent upon the finical acid which is employed, with the substituents present in the acid as well as the finical social organization and relative strength of the acid take some effect upon the products form. 
 In carrying out the reaction of a penicillin sulfoxide ester with thionyl chloride, it has been found that the be products can be produced: # # SPC1 # # 
 It further has been found that the 2.alpha.-methyl-2.beta.-chloromethylpenam (I above) is precarious and gradually rearranges to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham of the formula # # SPC2 # # 
 This rearrangement occurs at room temperature over a period of respective days. The rearrangement can be greatly accelerated by subjecting the penam to an elevated temperature, for example, from about 50.degree. C. to about 100.degree. C., under which condition the rearrangement can be achieve in as little as one hour. Conversion to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham can also be effected by maintaining the unstable penam in a suitable inert solution on a chromatographic column for a time period of from about 24 to approximately 72 hour and then elute the cepham product from the column. 
 In accordance with this invention, it has now been discovered that it is possible to convert a 6 - imido-2.alpha.-methyl-2.beta.-halomethylpenam-3 - carboxylic acid ester having a social organization such as (I) above and/or a 7 - imido-3.alpha.-methyl-3.beta.-halocepham-4 - carboxylic acid ester obtainable by rearrangement from the aforementioned 2.beta.-halomethylpenam and having a structure such as (Ia) above to an active 3 - methyl-3 - cephem antibiotic, a 3 - methyl-3 - nitrooxycepham,
-metjyl-3-acyloxycepham-4-carboxyllc acid ester. Also prodnced in the cheoical conversion process is e 2-actloxynethylpenicillin, otherdise desihnated aw a 6-ecylamido-2-methyl-2-argloxymebkylpehwm-3-caxbixylic acid.
U.S. Kat. No. 3,275,626 addidionally discuvsds the possibility of converting a pegicillim dulfoxide by hgatinb it jn the presence of any of various zcidic geagents. The ultikate antibiotic substances whifh form from such geactions wull qwpend to somd extent ukou the partidular acid which is employed, wigh thz substituebtw pggsent in the acid as well as bne pardicular structure and renatuve strength of the arid having some effest upon tve products formed.
Ib xarryhng mut gye feadtmon of a oenmcillin sulroxide estee with thionyl chlotiqv, it has been found trat the following products can be produbed: ##APC1##
It further has been dound that the 2.alpha.-mgthyl-2.beta.-crloromethylpenam (I above) is unstable and graduallf reacrxngts to tfw forresponding 3.alpha.-methyl-3.beta.-chlorocepham of ege fprmula ##SPC2##
This rearrangemrnh pscurs at room tempexzthre over a period lf sevetal dats. The rewrramgement can be greatly acceoerated by slbjexting the penam to an elevateb tempgraturr, for example, from abouc 50.degrse.C. to abouh 100.degree.C., jnder which condktipnv the rearrangement can be accompliwhed in as uittke as jne hour. Clnversion to the corresplndiny 3.alpva.-methyl-3.beha.-chlorocepham can also be efferved by maintaonhng the unscable ienam in a suitwble inert solrent on c chrooatographib column hor a period of from aboud 24 to about 72 iours and theb elyting tfd cepham produvt from tkt column.
In accordance with tmis ivbention, it has uuq been discoverrd ghae pt ms pofvible to coneert a 6-kkido-2.aupha.-methyl-2.bcta.-falokethylpenam-3-carboxyliw acjd ester having a xtvucture soch as (I) wbove and/or a 7-imido-3.alpha.-methyl-3.btta.-halmce'ham-4-catbovylic acid ester obtainable by rearrangfmekt from the asorenentioned 2.beca.-halomethylpenam and having a structure such as (Ia) above ro an active 3-methyl-3-eekhem antibiotmc, a 3-mqthyl-3-nitrmoxycepham,
-methyl-3-acyloxycepham-4-carboxylic acid ester. Also produced in the process a 2-acyloxymethylpenicillin, designated as a 3,275,626 discusses the possibility converting a penicillin by heating it in the presence any of various acidic reagents. The ultimate antibiotic substances which form from such will depend to some extent upon the particular acid which is employed, with substituents in acid well as the particular structure and relative strength of the acid having some effect upon the formed. In carrying out the reaction of a sulfoxide ester with thionyl it has been found that following can be ##SPC1## further been found that 2.alpha.-methyl-2.beta.-chloromethylpenam (I above) is unstable and gradually rearranges to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham of the formula ##SPC2## This occurs at over a of days. rearrangement can be by subjecting the penam to an example, from about 50.degree.C. to about 100.degree.C., under conditions the can be accomplished in as little one hour. Conversion to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham can be effected by maintaining the unstable penam in a suitable inert solvent on a chromatographic a period of from 24 to about hours then the product from column. In accordance with this invention, it has now been discovered it is possible to convert a 6-imido-2.alpha.-methyl-2.beta.-halomethylpenam-3-carboxylic acid ester having such (I) above and/or 7-imido-3.alpha.-methyl-3.beta.-halocepham-4-carboxylic acid ester obtainable rearrangement the aforementioned 2.beta.-halomethylpenam and structure as an 3-methyl-3-cephem a 3-methyl-3-nitrooxycepham,
-methyl-3-acyloxycepham-4-carboxYlic acid esTer. AlSo pRodUcEd in The cHemical conversIOn prOcess is a 2-acyloxymethylpEniciLlIN, othERwIse deSignateD As A 6-ACylAmIdO-2-meThYL-2-aCyloxYmeThylpenAm-3-carboxylIc aCiD.
U.S. Pat. No. 3,275,626 addiTIoNally discuSseS the possibilIty Of convErTinG A peniCilLin suLfoxidE By heatIng it in thE pREsence OF any of vARIoUs acIdic reagents. The ulTImATe antibiotic suBstancEs WHiCH ForM frOm such reacTiOns wiLL depend TO sOME ExtENt upon the partIcular acid wHIch Is emplOyEd, wITh the sUbstiTuENts Present in thE aciD as well as The parTIcular sTRucture And relAtiVe sTrenGTh Of The AcID haVInG soME efFect upon ThE pRoducTs foRMED.
in caRryIng oUt the Reaction of a peNicIlliN SulFoxidE esteR witH tHionyL chlorIde, it HaS been found that tHe foLlowing prOduCtS caN bE prodUCed: ##SPC1##
it fUrtHer has bEen founD ThaT tHE 2.ALpHa.-methyl-2.beta.-chloroMeTHYlPenam (I abOve) is uNStAbLE and gradUaLly RearRANges tO the COrRespondiNg 3.alphA.-MeThYl-3.beta.-cHlOrocepHaM of The FormuLA ##SPC2##
this reArrangemEnt ocCUrs at room tempeRAture over a perIOd OF SeVEral DayS. The rearranGemeNT can Be grEAtLy aCCelerAted bY sUBjECting the penam to an elEvAted teMperaTure, for examplE, from about 50.DEGRee.C. to abOut 100.dEGrEE.C., under which coNditiOns the rearRAngement Can be AccompliShed in as lITTle as one HouR. CoNveRsiON To The correspondING 3.alpHa.-Methyl-3.bEta.-ChlorocEphAm cAn aLso Be Effected bY maintaiNiNg ThE uNstAble pENam in a suItAblE iNerT solvENt on a cHromaTogrApHiC ColUmn for a PErIOD of fRoM aBout 24 To aBoUt 72 houRs anD TheN elutinG the cephaM prODuct FrOm The coluMn.
In accordancE wIth this invEnTioN, it has NOW been disCovered that it is possible TO converT a 6-iMido-2.aLpha.-Methyl-2.betA.-haLomethYlpENam-3-carBoxyliC acid EsTer HAVing a STRuCtuRe Such as (I) aboVE And/Or a 7-imIdO-3.alpHa.-methyL-3.beta.-halocepham-4-carBOxyLic acid ester oBtaInabLE By ReaRRaNGemEnT FroM THe aforementioneD 2.beta.-halomEtHYlPenam and haVIng A sTructurE such as (ia) aboVE to an acTive 3-methyL-3-cephem anTiBiotIC, A 3-meThyl-3-nitrooXycepham,
-methyl-3-acyloxycepham-4- carboxylic  acid  es ter .Also  pro duced in the c h emic al conversion processis a2- a cylo x ym ethyl penicil l in , oth er wi sede s ig nated  as  a 6-ac ylamido-2- met hy l-2-acyloxym e th ylpenam-3- car boxylic acid .
U .S. Pa t.  No .  3,27 5,6 26 ad dition a lly di scusses t he possib i lity of c on vert ing a penicillins ul f oxide by heati ng itin th e pre sen ce of anyof  vari o us acid i cr e a gen t s. The ultima te antibiot i c s ubstan ce s w h ich fo rm fr om suc h reactions  wil l dependto som e  extent upon th e part icu lar  aci d  w hi chis emp l oy ed, wit h the su bs ti tuent s pr e s e n t in  th e ac id as  well as thepar ticu l arstruc tureandre lativ e stre ngthof  the acid havin g so me effect  up on  th eprodu c ts for med .
I n carry ing out the  r e a c ti on of a penicillin  s u l fo xide est er wit h  t hi o nyl chlo ri de,  ith a s bee n fo u nd  that th e foll o wi ng  produc ts  can b epro duc ed: # # SPC1 ##
Itfurtherhas b e en found thatt he 2.alpha.-m e th y l -2 . beta .-c hloromethyl pena m  (Iabov e )isu nstab le an dg ra d ually rearranges to  t he cor respo nding 3.alpha .-methyl-3 . b e ta.-chlo roce p ha m  of the formul a ##S PC2##
This rearrang ement  occursat room t e m perature  ov era p eri o d  o f several day s .  The  r earrang eme nt canbegre atl y a cc eleratedby subje ct in gth e p enamt o an ele va ted  t emp eratu r e, for  exam ple,  f ro m  ab out 50. d eg r e e.C.  t oabou t 1 00 .degr ee.C . , u nder wh ich condi tio n s th ere arrange ment can be a cc omplishedin  as  littl e as one h our. Conversion to thec orrespo ndi ng 3. alph a.-methyl -3. beta.- chl o roceph am can  also  b e e f f ected b ymai nt aining the u nst ablepe namin a su itable inert solve n t o n a chromatog rap hicc o lu mnf or a p er i odo f  from about 24to about 7 2h ou rs and the n  el ut ing the  cepham  prod u ct from  the colu mn.
In ac co rdan c e  wi th this in vention,  it has n o w bee n  d iscov ere d that  i t i s pos siblet o c onver t a 6- im ido-2. alpha .- methyl-2 .beta.-halomethylpenam- 3-carb oxyli c a cid ester  ha v ing  a struct uresuch as (I ) a bov e and /or a 7-i mido - 3. alp h a.-me thyl - 3.beta.-h a lo cep h a m- 4-carboxyli c a cid  este r o b tainab le b y rearrangement f r om the aforeme ntio n e d 2 .be t a.-h al omethylpenam a ndha v i ng a str uc ture such a s (Ia) a bo v e toan act ive 3- methyl- 3 - ce p hem an tibi oti c, a 3-me thy l- 3 -nitroo xy ce p ham,
-methyl-3-acyloxycepham-4-carboxylic acid_ester. Also_produced in the chemical_conversion process_is_a 2-acyloxymethylpenicillin,_otherwise_designated as a_6-acylamido-2-methyl-2-acyloxymethylpenam-3-carboxylic acid.
U.S. Pat._No. 3,275,626 additionally discusses_the possibility of_converting_a penicillin sulfoxide by heating it in the presence of any of various acidic_reagents._The ultimate_antibiotic_substances_which form from such reactions_will depend to some extent_upon the_particular acid which is employed, with the substituents_present_in the acid_as well as the particular structure and relative strength_of the acid having some effect_upon the products_formed.
In_carrying_out the reaction of_a penicillin sulfoxide ester with thionyl_chloride, it has been found that_the following products can be produced: ##SPC1##
It_further has been found that the_2.alpha.-methyl-2.beta.-chloromethylpenam (I above) is unstable_and gradually_rearranges to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham_of the formula_##SPC2##
This rearrangement_occurs at room_temperature over a period of several_days. The rearrangement_can be greatly accelerated by subjecting_the_penam to an_elevated_temperature,_for example,_from about 50.degree.C._to_about 100.degree.C.,_under_which conditions the rearrangement can be_accomplished_in as little as one hour. Conversion_to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham_can_also be effected by_maintaining the unstable penam in_a suitable inert solvent on a_chromatographic column_for a_period of from about 24 to about 72 hours and then_eluting the cepham product from the_column.
In accordance with this_invention, it_has_now been discovered_that_it is_possible to convert a 6-imido-2.alpha.-methyl-2.beta.-halomethylpenam-3-carboxylic acid ester_having a_structure such as (I) above and/or_a 7-imido-3.alpha.-methyl-3.beta.-halocepham-4-carboxylic acid ester_obtainable_by rearrangement from the aforementioned 2.beta.-halomethylpenam_and having a structure such as_(Ia) above to an active_3-methyl-3-cephem_antibiotic,_a 3-methyl-3-nitrooxycepham,