CA1189866A - Heterocyclic acetic acid derivatives and a process for the preparation thereof - Google Patents
Heterocyclic acetic acid derivatives and a process for the preparation thereofInfo
- Publication number
- CA1189866A CA1189866A CA000418740A CA418740A CA1189866A CA 1189866 A CA1189866 A CA 1189866A CA 000418740 A CA000418740 A CA 000418740A CA 418740 A CA418740 A CA 418740A CA 1189866 A CA1189866 A CA 1189866A
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- group
- compound
- iii
- defined above
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New compounds of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protect-ing group and X is a selectively removable esterifying group, are prepared in the way that a compound of the general formula (IV) (IV) wherein y1 and y2 are as defined above, is nitrated and then reduced, the resulting compound of the general for-mula (III), wherein (III) y1 and y2 are as defined above and A stands for nitro group and then for amino group, is converted into an ester of the general formula (II), wherein y1, y2 and X are as defined above, (II) and the aminophenyl protecting group of the resulting compound is split off.
The new compounds of ths general formula (I) can be applied primarily as intermediats in the synthesis of thienamycin or thieuamycin analogues.
New compounds of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protect-ing group and X is a selectively removable esterifying group, are prepared in the way that a compound of the general formula (IV) (IV) wherein y1 and y2 are as defined above, is nitrated and then reduced, the resulting compound of the general for-mula (III), wherein (III) y1 and y2 are as defined above and A stands for nitro group and then for amino group, is converted into an ester of the general formula (II), wherein y1, y2 and X are as defined above, (II) and the aminophenyl protecting group of the resulting compound is split off.
The new compounds of ths general formula (I) can be applied primarily as intermediats in the synthesis of thienamycin or thieuamycin analogues.
Description
~EW ~ YCI;[C ~ IC ~CID DERIV~IVES AND ~ :FROC:E; SS FO~
~E :E~EPARA~I ON ~
r~he invontion re:Lates to new h~terocyclic ~cetic acid d0rivatives of tihe g~ral îormula (I) yl y2 H H
H3~ - C ~aH2COC~
o~~ ~H ( I) where i~
yl and y2 form ~og~ther a remo~ble carbon;srl protecting group;
pr~f~rably a ketal group or a khioanalogue thereo~g and 10 ~ i~ a ~electively rsmo~T~ble est~ri~ying g:roup~ pre~Eerably an arylmet~yl or a diarylm3thyl group~
as woll as tc a process ~or the preparation thereo~O
~ he aze~Ghidineacetic acid derivatives o:~ the general îormula (I) as well as their precursors of the genaral ~o:rmulae (II) and (III) ~ wherein yl~ y~ and X are as de~ined above a~d A repr~sents nitro o.r amino group7 ~18~6
~E :E~EPARA~I ON ~
r~he invontion re:Lates to new h~terocyclic ~cetic acid d0rivatives of tihe g~ral îormula (I) yl y2 H H
H3~ - C ~aH2COC~
o~~ ~H ( I) where i~
yl and y2 form ~og~ther a remo~ble carbon;srl protecting group;
pr~f~rably a ketal group or a khioanalogue thereo~g and 10 ~ i~ a ~electively rsmo~T~ble est~ri~ying g:roup~ pre~Eerably an arylmet~yl or a diarylm3thyl group~
as woll as tc a process ~or the preparation thereo~O
~ he aze~Ghidineacetic acid derivatives o:~ the general îormula (I) as well as their precursors of the genaral ~o:rmulae (II) and (III) ~ wherein yl~ y~ and X are as de~ined above a~d A repr~sents nitro o.r amino group7 ~18~6
2 ~
~1 y2 13: C13:2COO}~
1 LY ~H2 O ~ ~ ~ LI) ~1 ~2 H H CH2C OOEI
H3C - a - oJ_~ (III) l I
\~
~re ~ew compounds alld can be u~ad primarily a~ i~bermodia~s in the ~ynthasis o:E thlena~yci~ or thienamycin analoguesO
~ hie~amycin, an antibio~ic of broad spsctrum of act1vityg was pr~parad first on microbiolo~ical way (U~ pa~nt ~pecificatio~ NoO 3j950,357) and later on b~ chemical sy~th~sis (Gsrman Oïfenle~ungsschrift NoO 2,751,597~.
Our aim was to provlde a new roube for th0 ~ynthesis of thienamycin and lts analogues3 wherein the azethidi~orle sk~leto~ and the ~c-hydro~yethyl side chain, or a side chai:n ~0 which can be converted easily into ~-~hydroxyethyl group, are ~oxmad simulkaneously ab the early sbage of th~ sy~thasi3 an~ the resulti~g key intermedia te is converted then into the desired end~productO
It has been found kha t whe~ a dialkyl (probectsd 25 amino,~-malonate îs acylabed with diketene a~d ~he rasulting acylated pxoduct is reac~ed with iodine and an alkali. metal alcoholatej a~ aze~hidinone compound of the gen~ral ~ormul~ -(IX~ 9 containing an ~-acetyl side chain~ is obtai~ed~ which caa be utilized a~ key intermediate in the s~nthesisO In 30 this ~orrL ula Z rapresent~ a Cl_5 alkyl group D
~ 3 ~
H3C ; à ~ (~3Z)2 0 ~ ~ (I~) ~ he intermediate 9 0~ the general ~ormula (I~ and their preparation ara described in detail in o~r previous Hun~arian pate~t No . 181,186 . The preparation o~ th~se intermedia~e~ is al~o described i~ th0 examples of th~ presant application.
It has also been obser~ed that9 prior to converting bha intermediate o~ the general ~ormula (IX) i~to thienamycln or an analogue ~hereo~g it is pre~erable to protect the keto .
group o~ the ~-C~acetyl side chain with a group~ particularly a ketal gxoup or a thioanalogue thereof, which c~ be removed at a later stage o~ the s~nthesi~0 ~thylsne glycol or 3 ~hio-analogue thereo~? ~uch as mercapto-ethanol~ can be applied particularly pre~rably to ~'orm th0 flthyle~eketal or hemi thioketal protecting group. ~he resulti~g compound o~ th~
gen~ral formula (VIII) 7 yl ~2 ~I3C ~"C ~= ICOOZ) 2 ~ ( VIII~
wherein yl and y2 ~orrn toge ther a group ~or the temporary protec~ion oî the carbonyl moiety~ pr~erably ethyleneketal .
~;roup or a thioanalogue thareoIj and Z i~ as deîi~ed abov3~, is r0ac~-ed then ~with an alkali motal halide in pyridine or 30 a ralatad solv0nt or in aqueou~ dimethyl sul~o~ide ~o obtain ,, ~.
~8~
a compou~d of the genqral formula ~VII)g yl y2 H
~ f 2 ~ ~90Z
H3C - ~ f_ ~r ~ (VII) ~, wherein z~ yl a~d y2 are as dsfined above~
I'he resulting compound of tha general formula (VII) is a mixtura o~ cis and trans isomersO The isomers can b9 separ~kad from each other by chromatography or on ~he basis o~ their different solubilitiesO The separated trans isomer of the general formula (VIIa) ~1 52 C OOZ
0 ~ (VIIa) can be convarted inko the trans carboxylic acid o~ the general formula (VI~
~1 ~2 H H
H3C w ~ _ ~ g~COOH
~ (VI) ' ~.' by 'nydrolysisG It is more preferabls~ howeverg to subjec~
the iso~eric mixt~re itself to hydroly,sis 9 sinca the reackion i3 sslective~ i.e~ only khe trans ester converts into the respective carboxylic acid~
Thc separated krans carboxylic aci.d of the general Xormula (~rL) is raacted firsk wikh an activator for the ~ 6~
carboxy group and then with diazomathanH, a~d the resulti~g compou~d of the general formula (V) ~ / ~ GOOH~
H3C - C ~ 2 O ~ ~ ~ (V) ll J
iB subj~cted to WolPf rearrangement in khs pr~s~ce o~ wa~er bo obtai~ a~ az~thidinoacetic acid of the gen9ral formula (IV~, yl y2 H H
H~a ~ CH ~ OOH
. Q~ ~ - (IV~
which ca~ be u~ed as starting substa~ce in ~he procass o~ tha i~ventionO In ~he compounds of the general ~ormulae (VI~ to (IV) yl a~d y2 have the same meaning as de~i~ed abov3~
~he n~w compou~ds of the general ~ormulae (~ to (IV) and their prepara~ion are de~cribed i~ detail in our co-pend-L~g pate~ appl~catisn No. 418,739. The preparation of these new compounds is also described in the examples of the present application.
In th~ next step of the sy~thesis the phsnyl protect i~g group o~ 'Ghe amido moiaty is removedO ~his i~ psrformed accordi-ng to ~h0 invention by an indirect m~thod9 ~o th~t the ph~yl group is nitral;ed ïir~t3 th0 ~i~roph~nyl group is conv~x~ed thsn inko aminophe~yl grollp by reduclGio~ and thl~3 latter protecting group is split o~ a~t~Yr e~3teri~ying the acetic acid ~3ide chainO ~o our be~3t knowledge llO method wa,Y kns~Jn c30 far for ~he removal of a pheny:L p:rotecting , ~61~98~
group ~rom the nitrogen atom of a ~-lactam ring; thare~ore these steps ot` the p~ocess accordi~g ~o ~he inventio~ aro rsgarded as a pion~er solution~
Bassd on the above9 the invantion relates to a 5 process f or the prepara tion o~ new compounds havi~g ~he ge~era 1 f ormula ( I) whorein yl and y2 form togethar a removable carbonyl protecting group~
pr~ferably a ketal group or a ~hioanal~gue thereo~
and X is a selec~ively .removable esteri~ying group9 prefarably an arylmethyl or a diarylmethyl group9 in w,~ich a.compound o~ the gensral .~ormula ~IV)s wherein yl and y2 are as definad abovs~ is nitrated and then rsduced~
the resulting compound of ~he general formula (III), wharei~
yl and Y~ are as de~ined above and A s~ands ~or ~itro group a~ ~hen for amino group9 is converted lnto an ~star of the general ~ormula (Il)~ wherein yl~ y2 and ~ are as defined above7 in a ~anner known per so, and ~he aminoph2n~1 pxotect~
ing group o~ the resulting compound o~ ~-he general ~ormula (II) is split of~, or a compound of the ge~ral ~ormula (III) 9 wherein yl and y2 are as do~lned above and ~ is amino group~ i5 co~vert-ed into an ester o~ the ge~sral ~ormula (XI3~ ~herein ylg y2and ~ are as de~insd above~ in a manner known p~r se 9 and the aminophe-~yl protecting group o~ th~ rssulting compound o~
the general ~ormu].a (II) is ~plit o~f~ or the aminophenyl protec~ing group o~ a co~pound o~
tha general formula ~ wherein yl~ y2 and X are as de~i-ned ~9~6 above~ is ~plit of:E~
~ h~ nsw compound~ oî th0 g0n~ral forrnulae IIII) ) (II) and (I); which ~re racflm~c mlxture~ can bs convert~d in~o t;hiena~yci~ o:r a thiena~ycin analogua eOgO as showrL in 5 Scheme (~) O In the formul~ giva:n in Schem0 (A~ Y~, ~ and 2 ~ra a ~ de~insd above 5 Q i9 a Cl 5 al~ roup or a ~uh~tituted be~zyl group~
Q9 i~ ~ al 5 alkyl group~ a ~ub~ti~ut~d be~zyl group9 4y~o~
ge~ ~tom or an alkali m~tal ion~ and 10 R~9 is a benzyl9 aminoet~rl or ~acylaminoethgl groupO
~1 y2 13: C13:2COO}~
1 LY ~H2 O ~ ~ ~ LI) ~1 ~2 H H CH2C OOEI
H3C - a - oJ_~ (III) l I
\~
~re ~ew compounds alld can be u~ad primarily a~ i~bermodia~s in the ~ynthasis o:E thlena~yci~ or thienamycin analoguesO
~ hie~amycin, an antibio~ic of broad spsctrum of act1vityg was pr~parad first on microbiolo~ical way (U~ pa~nt ~pecificatio~ NoO 3j950,357) and later on b~ chemical sy~th~sis (Gsrman Oïfenle~ungsschrift NoO 2,751,597~.
Our aim was to provlde a new roube for th0 ~ynthesis of thienamycin and lts analogues3 wherein the azethidi~orle sk~leto~ and the ~c-hydro~yethyl side chain, or a side chai:n ~0 which can be converted easily into ~-~hydroxyethyl group, are ~oxmad simulkaneously ab the early sbage of th~ sy~thasi3 an~ the resulti~g key intermedia te is converted then into the desired end~productO
It has been found kha t whe~ a dialkyl (probectsd 25 amino,~-malonate îs acylabed with diketene a~d ~he rasulting acylated pxoduct is reac~ed with iodine and an alkali. metal alcoholatej a~ aze~hidinone compound of the gen~ral ~ormul~ -(IX~ 9 containing an ~-acetyl side chain~ is obtai~ed~ which caa be utilized a~ key intermediate in the s~nthesisO In 30 this ~orrL ula Z rapresent~ a Cl_5 alkyl group D
~ 3 ~
H3C ; à ~ (~3Z)2 0 ~ ~ (I~) ~ he intermediate 9 0~ the general ~ormula (I~ and their preparation ara described in detail in o~r previous Hun~arian pate~t No . 181,186 . The preparation o~ th~se intermedia~e~ is al~o described i~ th0 examples of th~ presant application.
It has also been obser~ed that9 prior to converting bha intermediate o~ the general ~ormula (IX) i~to thienamycln or an analogue ~hereo~g it is pre~erable to protect the keto .
group o~ the ~-C~acetyl side chain with a group~ particularly a ketal gxoup or a thioanalogue thereof, which c~ be removed at a later stage o~ the s~nthesi~0 ~thylsne glycol or 3 ~hio-analogue thereo~? ~uch as mercapto-ethanol~ can be applied particularly pre~rably to ~'orm th0 flthyle~eketal or hemi thioketal protecting group. ~he resulti~g compound o~ th~
gen~ral formula (VIII) 7 yl ~2 ~I3C ~"C ~= ICOOZ) 2 ~ ( VIII~
wherein yl and y2 ~orrn toge ther a group ~or the temporary protec~ion oî the carbonyl moiety~ pr~erably ethyleneketal .
~;roup or a thioanalogue thareoIj and Z i~ as deîi~ed abov3~, is r0ac~-ed then ~with an alkali motal halide in pyridine or 30 a ralatad solv0nt or in aqueou~ dimethyl sul~o~ide ~o obtain ,, ~.
~8~
a compou~d of the genqral formula ~VII)g yl y2 H
~ f 2 ~ ~90Z
H3C - ~ f_ ~r ~ (VII) ~, wherein z~ yl a~d y2 are as dsfined above~
I'he resulting compound of tha general formula (VII) is a mixtura o~ cis and trans isomersO The isomers can b9 separ~kad from each other by chromatography or on ~he basis o~ their different solubilitiesO The separated trans isomer of the general formula (VIIa) ~1 52 C OOZ
0 ~ (VIIa) can be convarted inko the trans carboxylic acid o~ the general formula (VI~
~1 ~2 H H
H3C w ~ _ ~ g~COOH
~ (VI) ' ~.' by 'nydrolysisG It is more preferabls~ howeverg to subjec~
the iso~eric mixt~re itself to hydroly,sis 9 sinca the reackion i3 sslective~ i.e~ only khe trans ester converts into the respective carboxylic acid~
Thc separated krans carboxylic aci.d of the general Xormula (~rL) is raacted firsk wikh an activator for the ~ 6~
carboxy group and then with diazomathanH, a~d the resulti~g compou~d of the general formula (V) ~ / ~ GOOH~
H3C - C ~ 2 O ~ ~ ~ (V) ll J
iB subj~cted to WolPf rearrangement in khs pr~s~ce o~ wa~er bo obtai~ a~ az~thidinoacetic acid of the gen9ral formula (IV~, yl y2 H H
H~a ~ CH ~ OOH
. Q~ ~ - (IV~
which ca~ be u~ed as starting substa~ce in ~he procass o~ tha i~ventionO In ~he compounds of the general ~ormulae (VI~ to (IV) yl a~d y2 have the same meaning as de~i~ed abov3~
~he n~w compou~ds of the general ~ormulae (~ to (IV) and their prepara~ion are de~cribed i~ detail in our co-pend-L~g pate~ appl~catisn No. 418,739. The preparation of these new compounds is also described in the examples of the present application.
In th~ next step of the sy~thesis the phsnyl protect i~g group o~ 'Ghe amido moiaty is removedO ~his i~ psrformed accordi-ng to ~h0 invention by an indirect m~thod9 ~o th~t the ph~yl group is nitral;ed ïir~t3 th0 ~i~roph~nyl group is conv~x~ed thsn inko aminophe~yl grollp by reduclGio~ and thl~3 latter protecting group is split o~ a~t~Yr e~3teri~ying the acetic acid ~3ide chainO ~o our be~3t knowledge llO method wa,Y kns~Jn c30 far for ~he removal of a pheny:L p:rotecting , ~61~98~
group ~rom the nitrogen atom of a ~-lactam ring; thare~ore these steps ot` the p~ocess accordi~g ~o ~he inventio~ aro rsgarded as a pion~er solution~
Bassd on the above9 the invantion relates to a 5 process f or the prepara tion o~ new compounds havi~g ~he ge~era 1 f ormula ( I) whorein yl and y2 form togethar a removable carbonyl protecting group~
pr~ferably a ketal group or a ~hioanal~gue thereo~
and X is a selec~ively .removable esteri~ying group9 prefarably an arylmethyl or a diarylmethyl group9 in w,~ich a.compound o~ the gensral .~ormula ~IV)s wherein yl and y2 are as definad abovs~ is nitrated and then rsduced~
the resulting compound of ~he general formula (III), wharei~
yl and Y~ are as de~ined above and A s~ands ~or ~itro group a~ ~hen for amino group9 is converted lnto an ~star of the general ~ormula (Il)~ wherein yl~ y2 and ~ are as defined above7 in a ~anner known per so, and ~he aminoph2n~1 pxotect~
ing group o~ the resulting compound o~ ~-he general ~ormula (II) is split of~, or a compound of the ge~ral ~ormula (III) 9 wherein yl and y2 are as do~lned above and ~ is amino group~ i5 co~vert-ed into an ester o~ the ge~sral ~ormula (XI3~ ~herein ylg y2and ~ are as de~insd above~ in a manner known p~r se 9 and the aminophe-~yl protecting group o~ th~ rssulting compound o~
the general ~ormu].a (II) is ~plit o~f~ or the aminophenyl protec~ing group o~ a co~pound o~
tha general formula ~ wherein yl~ y2 and X are as de~i-ned ~9~6 above~ is ~plit of:E~
~ h~ nsw compound~ oî th0 g0n~ral forrnulae IIII) ) (II) and (I); which ~re racflm~c mlxture~ can bs convert~d in~o t;hiena~yci~ o:r a thiena~ycin analogua eOgO as showrL in 5 Scheme (~) O In the formul~ giva:n in Schem0 (A~ Y~, ~ and 2 ~ra a ~ de~insd above 5 Q i9 a Cl 5 al~ roup or a ~uh~tituted be~zyl group~
Q9 i~ ~ al 5 alkyl group~ a ~ub~ti~ut~d be~zyl group9 4y~o~
ge~ ~tom or an alkali m~tal ion~ and 10 R~9 is a benzyl9 aminoet~rl or ~acylaminoethgl groupO
3~
yl y~ H ,~1 CH~COCH
~'C/~ ?COO x ~r h~l O ~ ~ J~l malonlc acid semiester sal~
,- ~ /
~cH2coc~ 2cout~ f -l2 ~ulfon~ c azide ~ 2 ~,~ Nl-l t, ~Rh salt ~~
~1 1 - N C00(2 O acylation mercaptan sal~; f o rm2~ ion , H
r~--~\ SR '~
'~L~ I ~
,~ N-- ~ COO~;
- 9 ~ i6 Tha co~lpound.s of the gener.31 L'orrnula (IV) 7 beari~g a phanyl protecbinOr g.roup of the amido nitrogen atom~ are nitrated firs~O It is prefarred to apply a mixturo o~ n:itric aci~ and acetic anhydridr3 as nitrating mixture~ rrhe reaction is per~ormed at a ternperature o~ about 0C, preferably a~
10C to ~5C. hcetyl nitrate, which ~orms upon the i.nterac-tion o~ nitric acid and acetic acid and is soluble in the axcess of acetic acid, serves as ni.trating agent in this re-action~
The resulting corr3pound o~' the general formula (III)~
wherain A is nitro group~ is then reduced pre~erably by catalytic hyd~ogen.-3tionO rrhereaf'ter the amino derivative o~
the general formula (III) is separated frorn the reaction mi~-ture or9 more preferably, esterified directly in the reac-tion mixture where it was for~ed to obtain a compound of the general ~ormula (II)"
It is preferred to ap~ly phenyl diazomethane or di-phenyl dia~orn~thane as esteril'ying agent to introduce the selectively :rernovable esteri~`~ing g~roup X into the mol.eculaO
'~hereaf'ter thb ami.dopherlyl prot,ecting group o~ tho interrnediate of the gene:ral ~ormula (II) is removedO Oxidiz-ing agents, such as a mixture oL' a ceric salt and a mineral acid or7 more preferabl~9 chrornium o~ide in glacial acetic acid7 can be applied for this purposeO The resulting product ~ the general for~nula (I) is separated then from the reac~
tion mi~tureO
The invention is elucidated in detail by the aid of the l'ollo~ing non limiting hxample~
oxo~2~ e-0045 g (1 mrnoLe3 o~ benzhydryl trans~ (2-amino~
phenyl)-3-(2-me~hyl~1,3-dioxolan-2-yl)-4-oxo~2~azethidiny ~ -acetate is dissolved in 2 ml of glacial acetic acid9 and a solution of 002 g ~2 mmolas) o:E chromium trioxide in 2 ml o~
glacial ac~tic acid and 0~2 ml of water is added dropwis~ to the above solution at xoom temparaturoO ~he mixt~Lre is stirred ~t room temperature ~or 3 hours, therea~ter poured into 10 ml of ethyl acstate and washed with a 5% aqueous sodium hydro~
carbonate solution until neutral. The organic phase is driad ovor mzgnesium sulfata, ~iltered~ and the filtrate is evapora~=
ed in vacuoO ~he rasidue is puri~i~d by preparative thîn layer chromatography (adsorbent: Kiasolgel 60 P~
developing solvent: a 7 3 mixture of benzene and acetone)~
0009 g (30 %) Of the aimed compound is obtain~d, m~pr 129-130C ~a tha~ol)0 l~I NMR (CDC13): ~= 1039 (s~ 3~I); 2~63 (dd~ 2H7 J -~0~ Hz) and 2.89 (dd, 2H9 J = 9~1 Hz), 3~97 (m~ 5H) 3 6~12 (~9 lH) t 7028 (s~ lOH) ppm~
'~he starting substance is prepared as follows:
a ) A mix ture of 38 g ( 0 1,152 mole ) of dia th-yl anilino malonat~ ~Ro 131ank. Ber~ ~1, 1815 ( 189817, 3~ ml of glacial acfltiC acid 0nd 1503 g (1309 ml~ OD1~32 mole~ of diketen.e i~
boiled for 005 hour. Glacial acetic acid is evapora ted in vacuo on a water bath, and the oily esidue is crystallized by triturating it vwith ether~ 36~5 g (72 Y0~ of diethyl (N phenyl~
3-h~Jdrox~y~3~me thyl-5-oxo-2 ,2-pyrrolidine~dicarbox-,ylate ~ a-rld/or it~3 tautorner are obtained7 m.pO~ 98-99C (ethyl acetate and petroleum ether~0 ~ nalysis:
calcllla ted :~or C17H21N06 (335235):
C: 60.88 %, FL: 6031 ~0, N: 4.18 5'0;
found: Co 60083~9 H: 6.15 '~, N. 4~43 %0 IR (KBr) 3 3350, 2950, 1760, 1750 (d), 1700 cm~l lH NMR (CDC13): ~= 1002 ( tg 3H) 7 1~3 ( ti~ 3~ ïo6 (s, 3H) 9 2~8 (s,, 3H) 9 306 (broad s, lH)~ 4~4~4~45 (ml 4H) 3 7,2 (s, 5H) pp~0 b) 50 g (0.149 mol~) of die~hyl (N-phenyl-3-hydroxy-3~methyl-5-oxo-2,2-pyrrolidine dicarboxylata) 9 prepared as d~scribsd in point a) above, are added to a solution of 10.2 g (0c447 mole) of metallic sodium in t~50 ml of dry ethanol9 thereafter a solution of` 37~9 g ~00149 mole3 o~ iodine in 200 ml o~ dry ether is added under vigorous stirring. When thc raaction is over, 805 ml (8.9 g, 00149 mol~) of glacial acctic acid, 200 ml o:E water and 100 m~ o~ ether are added ko the mixtureg the o:rganic phase is separated, and the aqueou~
phase i.s extIacted w-lth 100 ml of ether. ~he eth~r~al pha~es are combined7 dried ov~r magnesium ~u:l~ate, ~iltered~ and the filt:rate is evaporated. ~he olly residue is crystallized from 50 ml of` 2-propanol to obtain 31 g ~62 ~0) of die~hyl (3-acetyl~
1 phenyl-4~oxo-2,2-aæethidine-dicarboxylate3, mlp.: 55-56(, (2-propanol).
Analysis:
calculated for C17HlgM06. C: 61025 %~ H: 5~75 ~, M: 4.20 %~
C. 61~38 %, H: 5 89 %9 N: 4-o24 %o IR (KBr). 1770, 1740 3 1720 cm lo lH NME~ (CDC13) ~ ~= 1.12 (t, 6H)~ 203 ~37 3H~ 3 4~25 (q3 ~H) 7 L~ 75 (s, lH.); 700~716 (m, 5H) ppmO
~ 33~
-- 12 ~
c) 2~5 g' (000~5 molo~ of diethyl 3~acet~1~ phenyl~
yl y~ H ,~1 CH~COCH
~'C/~ ?COO x ~r h~l O ~ ~ J~l malonlc acid semiester sal~
,- ~ /
~cH2coc~ 2cout~ f -l2 ~ulfon~ c azide ~ 2 ~,~ Nl-l t, ~Rh salt ~~
~1 1 - N C00(2 O acylation mercaptan sal~; f o rm2~ ion , H
r~--~\ SR '~
'~L~ I ~
,~ N-- ~ COO~;
- 9 ~ i6 Tha co~lpound.s of the gener.31 L'orrnula (IV) 7 beari~g a phanyl protecbinOr g.roup of the amido nitrogen atom~ are nitrated firs~O It is prefarred to apply a mixturo o~ n:itric aci~ and acetic anhydridr3 as nitrating mixture~ rrhe reaction is per~ormed at a ternperature o~ about 0C, preferably a~
10C to ~5C. hcetyl nitrate, which ~orms upon the i.nterac-tion o~ nitric acid and acetic acid and is soluble in the axcess of acetic acid, serves as ni.trating agent in this re-action~
The resulting corr3pound o~' the general formula (III)~
wherain A is nitro group~ is then reduced pre~erably by catalytic hyd~ogen.-3tionO rrhereaf'ter the amino derivative o~
the general formula (III) is separated frorn the reaction mi~-ture or9 more preferably, esterified directly in the reac-tion mixture where it was for~ed to obtain a compound of the general ~ormula (II)"
It is preferred to ap~ly phenyl diazomethane or di-phenyl dia~orn~thane as esteril'ying agent to introduce the selectively :rernovable esteri~`~ing g~roup X into the mol.eculaO
'~hereaf'ter thb ami.dopherlyl prot,ecting group o~ tho interrnediate of the gene:ral ~ormula (II) is removedO Oxidiz-ing agents, such as a mixture oL' a ceric salt and a mineral acid or7 more preferabl~9 chrornium o~ide in glacial acetic acid7 can be applied for this purposeO The resulting product ~ the general for~nula (I) is separated then from the reac~
tion mi~tureO
The invention is elucidated in detail by the aid of the l'ollo~ing non limiting hxample~
oxo~2~ e-0045 g (1 mrnoLe3 o~ benzhydryl trans~ (2-amino~
phenyl)-3-(2-me~hyl~1,3-dioxolan-2-yl)-4-oxo~2~azethidiny ~ -acetate is dissolved in 2 ml of glacial acetic acid9 and a solution of 002 g ~2 mmolas) o:E chromium trioxide in 2 ml o~
glacial ac~tic acid and 0~2 ml of water is added dropwis~ to the above solution at xoom temparaturoO ~he mixt~Lre is stirred ~t room temperature ~or 3 hours, therea~ter poured into 10 ml of ethyl acstate and washed with a 5% aqueous sodium hydro~
carbonate solution until neutral. The organic phase is driad ovor mzgnesium sulfata, ~iltered~ and the filtrate is evapora~=
ed in vacuoO ~he rasidue is puri~i~d by preparative thîn layer chromatography (adsorbent: Kiasolgel 60 P~
developing solvent: a 7 3 mixture of benzene and acetone)~
0009 g (30 %) Of the aimed compound is obtain~d, m~pr 129-130C ~a tha~ol)0 l~I NMR (CDC13): ~= 1039 (s~ 3~I); 2~63 (dd~ 2H7 J -~0~ Hz) and 2.89 (dd, 2H9 J = 9~1 Hz), 3~97 (m~ 5H) 3 6~12 (~9 lH) t 7028 (s~ lOH) ppm~
'~he starting substance is prepared as follows:
a ) A mix ture of 38 g ( 0 1,152 mole ) of dia th-yl anilino malonat~ ~Ro 131ank. Ber~ ~1, 1815 ( 189817, 3~ ml of glacial acfltiC acid 0nd 1503 g (1309 ml~ OD1~32 mole~ of diketen.e i~
boiled for 005 hour. Glacial acetic acid is evapora ted in vacuo on a water bath, and the oily esidue is crystallized by triturating it vwith ether~ 36~5 g (72 Y0~ of diethyl (N phenyl~
3-h~Jdrox~y~3~me thyl-5-oxo-2 ,2-pyrrolidine~dicarbox-,ylate ~ a-rld/or it~3 tautorner are obtained7 m.pO~ 98-99C (ethyl acetate and petroleum ether~0 ~ nalysis:
calcllla ted :~or C17H21N06 (335235):
C: 60.88 %, FL: 6031 ~0, N: 4.18 5'0;
found: Co 60083~9 H: 6.15 '~, N. 4~43 %0 IR (KBr) 3 3350, 2950, 1760, 1750 (d), 1700 cm~l lH NMR (CDC13): ~= 1002 ( tg 3H) 7 1~3 ( ti~ 3~ ïo6 (s, 3H) 9 2~8 (s,, 3H) 9 306 (broad s, lH)~ 4~4~4~45 (ml 4H) 3 7,2 (s, 5H) pp~0 b) 50 g (0.149 mol~) of die~hyl (N-phenyl-3-hydroxy-3~methyl-5-oxo-2,2-pyrrolidine dicarboxylata) 9 prepared as d~scribsd in point a) above, are added to a solution of 10.2 g (0c447 mole) of metallic sodium in t~50 ml of dry ethanol9 thereafter a solution of` 37~9 g ~00149 mole3 o~ iodine in 200 ml o~ dry ether is added under vigorous stirring. When thc raaction is over, 805 ml (8.9 g, 00149 mol~) of glacial acctic acid, 200 ml o:E water and 100 m~ o~ ether are added ko the mixtureg the o:rganic phase is separated, and the aqueou~
phase i.s extIacted w-lth 100 ml of ether. ~he eth~r~al pha~es are combined7 dried ov~r magnesium ~u:l~ate, ~iltered~ and the filt:rate is evaporated. ~he olly residue is crystallized from 50 ml of` 2-propanol to obtain 31 g ~62 ~0) of die~hyl (3-acetyl~
1 phenyl-4~oxo-2,2-aæethidine-dicarboxylate3, mlp.: 55-56(, (2-propanol).
Analysis:
calculated for C17HlgM06. C: 61025 %~ H: 5~75 ~, M: 4.20 %~
C. 61~38 %, H: 5 89 %9 N: 4-o24 %o IR (KBr). 1770, 1740 3 1720 cm lo lH NME~ (CDC13) ~ ~= 1.12 (t, 6H)~ 203 ~37 3H~ 3 4~25 (q3 ~H) 7 L~ 75 (s, lH.); 700~716 (m, 5H) ppmO
~ 33~
-- 12 ~
c) 2~5 g' (000~5 molo~ of diethyl 3~acet~1~ phenyl~
4 oxo-2,2-azethidine-dicarbnxylate, preparod as d~scribed in step b) above 9 are dissolved in a mixtura of 90 ml o.~ d.ry di-oxane and 2]. g (180~ ml9 0~34 mole) of dr~ eth~lsne glycol~
and 3605 g (31~5 ml9 00255 mole) o~ boron trifluoride-diekhyl etherate complc~ are added dropwisa to the solutio~ u~dor vigorous stLrring and cooling wi~h ico waterO lha solution is stirred ~or additional 2 hours at room tamperature and thon neutralized with saturated aqueous sodium carbonate solutionO
r~he neutral solutio~l is diluted with 100 ml of wator and then extracted thrice ~ith 50 ml of diethyl et.her9 eachO ~h~
organic phases are combined, dried ovor magnesium su~ako~
.~iltered9 arld the ~iltrate is e~aporated in ~acuoO r~he oily residue is crystallized by triturating it with etharO 2805 g (9 %`3 ~ diethyl 1-phen~1-3-(2-methyl~ 3 dioxolan-~yl)-4-oxo-2,2-azethidine-dicarboxylate are obtained3 m.p.: 59~61C
(petrol)~
Analysi~:
19 23 7 7 %~ ol ~ %~ N: 3.71 %~
found~C: 60074 %, H: 6021 %9 M 3~79 %~
IR (I~r): 1770, 17L~ cm 1~
H Nl~ (C~C13)~ (t~ 3H7 J = 7.2 H 1.24 (t~ 3H, J = 702 Hz) 9 1051 (s, 3H), 3~92 (m9 4H); 4.3 (m9 5H) 9 7~2 (m, 5H) ppm~
A mlxture of 28~5 g (00075 mole) of diethyl l-phenyl-3- ( 2-r~e thyl-].,3~-dioxolan~2-yl)-4~oxo-292-azethidine-dicarb~
oxylate, pxepared as described in point c) above; 4L~ ml of di~
methyl sul:ro~ide~ 5.6 g (041 mole) of ,sodiurn chlorida and 3.05 r l (0~17 rnole) of water is stirred at 175C until the re~
30 acti,on pro~,ee¢l.c.O ~rhe ~¢~ oc~:L~es5 oL' th¢J~ reaction is rnon.itored by a8~i ~ 13 ~
thirl layer chromatograph;~ (adso:rbent~ Ki~selgel G according tio Stahlg clevelopi~ olvent: a 6-4 mixture of b~nzene a~d ethyl acetate)0 rI`he sol~ltion is poured in~o Z00 ml o:~ a sa turated aqueous sodium chlorid~ soluti.on and oxtracted thrice with 150 ml of di~tihyl ether9 eachO The oxganic phas~s are col~in~d, driod nver magrlesium sulîatie~ ~iltiex~d~ and tiho flltratie is ~vaporatedO rl'he r~3sulti.ng 160~ g o.t' oily r~si.due a:re dissolved in 100 ml of ethanol; and a solution of 2c,15 g (0~,054 mole) o~ sodium h~droxide in 30 ml of wat~r is added to it under stirring over an ice watier bath. After 0~,5 hour of stirring the mLxtur~ is dilutsd with 150 ml OI water and extracted thrice with 20 ml o:~ dîathyl otihar, eachO Th0 aqueous phase is aci.difi~d tio pH = 1 with concantxatad aqueous hydrochloric acid and ~xtractad tiherl thrice with 50 ml of di chloromethan~, each~, The organic phases are combin~d~ dri~d over magnesium sulfatis, ~ilterad~ and ths filtratie i~ ~Tapora~
. edO r~he oily :residu~3 is crystallizad from benzenr3 ko obtain 12 g ( 56 %~ of l;ran~ phengl~ -(2 mr3thyl-:L,3-dio}~olarl-2-yl)~
~oxo~2~azethidine~carboxylic acid9 m~,p,, . 165C (b~nzene~ O
Ana 1~rSiS:
Ca1CU1at~d fr C1~15N5 ~277-~7) C. 60364 %~ H: 5045 %~ N~ 5005 ~OUnd: C- 60~64 %~ H: 5O72 ~ N: 4099 %~
IR t KBr): 3500~2700 9 1770 ~ 1730 Cm 10 H ~MR (CDC13) ~ ~= 105` ( Sg 3~) ~ 3O69 (d~ 1H~ J = 3 EIZ~ 3 400 (m~ 4H)~ 4,42 (1H~ d9 J ~ 3 HZ)~ 703 (m~ 5~I)7 7055 (SD ~H) ppm 0 o) 13.8 g (0.05 mola) of trar~ pher~ 3~2~meth;~
lg3~dirJxolan-2 ~yl)-4-oxo~2~az~thidin3 carbo~ylic acid~ prcparaa as d~crib~d in poin.t d~ abov~3 7 are dis301v~d in 100 ml o~' - lL~ --dIy tetrallydr(~ura~, and 5055 g (7~7 ml) 00055 mole3 of ethyl chlorofor~late are added to the solution at ~15CO After 20 minutes of sti:rrin~, the ~epa.rated salt is filtared off under nitIogen atmosphere~ and an e~heral ~olution of 2256 g
and 3605 g (31~5 ml9 00255 mole) o~ boron trifluoride-diekhyl etherate complc~ are added dropwisa to the solutio~ u~dor vigorous stLrring and cooling wi~h ico waterO lha solution is stirred ~or additional 2 hours at room tamperature and thon neutralized with saturated aqueous sodium carbonate solutionO
r~he neutral solutio~l is diluted with 100 ml of wator and then extracted thrice ~ith 50 ml of diethyl et.her9 eachO ~h~
organic phases are combined, dried ovor magnesium su~ako~
.~iltered9 arld the ~iltrate is e~aporated in ~acuoO r~he oily residue is crystallized by triturating it with etharO 2805 g (9 %`3 ~ diethyl 1-phen~1-3-(2-methyl~ 3 dioxolan-~yl)-4-oxo-2,2-azethidine-dicarboxylate are obtained3 m.p.: 59~61C
(petrol)~
Analysi~:
19 23 7 7 %~ ol ~ %~ N: 3.71 %~
found~C: 60074 %, H: 6021 %9 M 3~79 %~
IR (I~r): 1770, 17L~ cm 1~
H Nl~ (C~C13)~ (t~ 3H7 J = 7.2 H 1.24 (t~ 3H, J = 702 Hz) 9 1051 (s, 3H), 3~92 (m9 4H); 4.3 (m9 5H) 9 7~2 (m, 5H) ppm~
A mlxture of 28~5 g (00075 mole) of diethyl l-phenyl-3- ( 2-r~e thyl-].,3~-dioxolan~2-yl)-4~oxo-292-azethidine-dicarb~
oxylate, pxepared as described in point c) above; 4L~ ml of di~
methyl sul:ro~ide~ 5.6 g (041 mole) of ,sodiurn chlorida and 3.05 r l (0~17 rnole) of water is stirred at 175C until the re~
30 acti,on pro~,ee¢l.c.O ~rhe ~¢~ oc~:L~es5 oL' th¢J~ reaction is rnon.itored by a8~i ~ 13 ~
thirl layer chromatograph;~ (adso:rbent~ Ki~selgel G according tio Stahlg clevelopi~ olvent: a 6-4 mixture of b~nzene a~d ethyl acetate)0 rI`he sol~ltion is poured in~o Z00 ml o:~ a sa turated aqueous sodium chlorid~ soluti.on and oxtracted thrice with 150 ml of di~tihyl ether9 eachO The oxganic phas~s are col~in~d, driod nver magrlesium sulîatie~ ~iltiex~d~ and tiho flltratie is ~vaporatedO rl'he r~3sulti.ng 160~ g o.t' oily r~si.due a:re dissolved in 100 ml of ethanol; and a solution of 2c,15 g (0~,054 mole) o~ sodium h~droxide in 30 ml of wat~r is added to it under stirring over an ice watier bath. After 0~,5 hour of stirring the mLxtur~ is dilutsd with 150 ml OI water and extracted thrice with 20 ml o:~ dîathyl otihar, eachO Th0 aqueous phase is aci.difi~d tio pH = 1 with concantxatad aqueous hydrochloric acid and ~xtractad tiherl thrice with 50 ml of di chloromethan~, each~, The organic phases are combin~d~ dri~d over magnesium sulfatis, ~ilterad~ and ths filtratie i~ ~Tapora~
. edO r~he oily :residu~3 is crystallizad from benzenr3 ko obtain 12 g ( 56 %~ of l;ran~ phengl~ -(2 mr3thyl-:L,3-dio}~olarl-2-yl)~
~oxo~2~azethidine~carboxylic acid9 m~,p,, . 165C (b~nzene~ O
Ana 1~rSiS:
Ca1CU1at~d fr C1~15N5 ~277-~7) C. 60364 %~ H: 5045 %~ N~ 5005 ~OUnd: C- 60~64 %~ H: 5O72 ~ N: 4099 %~
IR t KBr): 3500~2700 9 1770 ~ 1730 Cm 10 H ~MR (CDC13) ~ ~= 105` ( Sg 3~) ~ 3O69 (d~ 1H~ J = 3 EIZ~ 3 400 (m~ 4H)~ 4,42 (1H~ d9 J ~ 3 HZ)~ 703 (m~ 5~I)7 7055 (SD ~H) ppm 0 o) 13.8 g (0.05 mola) of trar~ pher~ 3~2~meth;~
lg3~dirJxolan-2 ~yl)-4-oxo~2~az~thidin3 carbo~ylic acid~ prcparaa as d~crib~d in poin.t d~ abov~3 7 are dis301v~d in 100 ml o~' - lL~ --dIy tetrallydr(~ura~, and 5055 g (7~7 ml) 00055 mole3 of ethyl chlorofor~late are added to the solution at ~15CO After 20 minutes of sti:rrin~, the ~epa.rated salt is filtared off under nitIogen atmosphere~ and an e~heral ~olution of 2256 g
5 (OD15 mole) of di.a~,omethane is added to the filtrate under stirringO When the ~as evolution ceases,the excess o~ diazo~
methan~ is decomposed with glacial acetic acid9 and the solu-~ion is evaporated~ ~he oi.ly residue is triturat0d with ether to obtain 11~5 g (77 %) of crystalline tra ns-4- ( diazoacet~
l-phenyl-3-(2-methyl-193~dioxolan~2~yl)-azethîdinone9 m~p.0 96--97C (benzene and ethex)0 IR (KBr): 2150, 17609 1635 cm~10 H N~ CDC13)~ 50 (S~ 3E) 9 305 (d, LH~ J = 2~6.
Hz) 9 3.50 (m, ~H)~ 4Q34 (d, llI~ J = 206 Hz), 5~45 (s; IH~ 9 7025 (m~ 5H) ppm.
e) 308 g (000126 mole) of trans-4-(diazoace~yl)-1~
. phenyl-3~(2-methyl-1,3~dioxolan~2-y`L~ azethidinone; prepared as doscribed in point e) above, are dissol.ved in a mjxture O:e 100 ml of te~rah-gdrofuran and 50 ml o e water9 and the solu-tion is irradiated with a high pressure mercury lamp in aphotoreactor at room temperature under nitrogen atmospher~
~he progress of' the reaction is monitored by thin laysr chro~
matoOraphy (adsorbent: Kieselgel G accordi~g to Stahll de~
veloping solvent: a 7.1 mixture of benzene and acetone)0 ~t the end ot' the reaction tetrah~drofuran is evaporated in vacuo, the residue is rendered alkaline with a 20% aqueous sodiu~ hydroxide solution~ and the alkaline solution is washed th.rice with 15 ml of' dichloro~ethane~ eachO ~'he aqueous phase is acidified to p~f - 1~2 with concentrated aqueous ~0 h~dr:ochlori~, acid and then e~tracted. thrice with 20 ml of di~
15 ~
chloromethane~ eachO The organic phases are combin0d, driad ~ver magnesium sul~a~e~ ~iltered, and tha ~iltrate is eva-poxa~-ed~ The oily rssidue is triturated with ether to obtain 1~8 g ~50 %) o~ cry~talline ~ xa~s~l~phe~yl-3-(2-me~hyl~193-dioxola~-2-yl~4~oxo~2-azathidi~y ~ ~acetic acid7 m~pO 128 129C
ethanol)0 A~al~sis~
~alculat9d ~or C15~17~5 (291029~-C: 62000 %, ~- 5~88 %1 ~- L~84 %;
~`ound: C: 61,75 %~ H: 5086 ~09 N: 5~08 ~0.
IR (KBr): 1760, 1740 cm~l~
lH ~MR (CDC13). S - 1~48 (sg 3H)9 2.65 (dd~ lH9 Jgem =
15 HZ9 Jvic= 8 Hz) ~ 3.12 (dd, lH, Jg~m = 15 HZ9 Jvic ~ 8 ~Z)r 3047 (d, lH~ J = 205 Hz)~ 3098 (m, ~H) ? 4~4 (m~ lH) 9 703 ( m7 5H), 9.33 (broad s, lH) ppmO
g) 0081 ml o~ concentratcd nitric acid (~ = 1.5) i~
addad dropwise, under co~stant stirri~g and cooling with iC9, to 3 ml of ace~ic anhydride so that th0 ~emperature o~ the mixturs do~s not ris~ above ~5CI. ~he rasulting nitrating mix~
~C) ~ure i~ added dropwi9e, a~ -5C, to a stir.red solution o~
209 ~ (0"01 mole) of ~rans-l-ph0n;srl 3 (2-methyl~1,3-dio~o-la~==
2~ oxo~-azethidi~ acetic acida preparsd as d~scrib~d in point ~) abev0~ in 20 ml of dry dichlorom~thane. ~It;er one hour of stirri-2g ~he solution is pouxed onko ice watex, and the phases ara separated ~rom each other. r~he aqueous phase is extracted ~wice w~th 25 ml o~ dichloromethana;, aach., r~he organic phases ara comhine~a dried over mag~e~ium sulfata7 ~iltared9 and ~he ~iltr~te is evaporated i~ vacuo~
r~he oil-y residue i~ triturated with ether to obtai~ 1095 g (58 %) of cry~talline ~ ra~s-3-(Z mathyl-la3~dloxolan~2~
~ 16 ~
1~ ( 2~ni~ rophenyl ) -4-ox o-2- az e ~hidiny~7~a c e ti c acid 3 m ~ p ,3 o 175~176$~C t ethanol) O
Analy~;is:
calcula~d for C15~16~27 (3~ 3 C ~ 5~o57 %1 H: 40 ~9 %, No 8~3~ %9 ~ourld~ C: 53.31 %~ Ho 4 ~68 %3 ~0 8021 %q~
IR (K:3r)~ 3600-29009 174()~ 1540~ 13LO cm~
h) 00336 g (1 mmo:l.a) o~ rans 3-(2~methgl~ 1~3Mdi.
oxolan-2~yl)~1-(2~ni~rophen~ ~oxo~2-azet~idiny;~7-ac0tic acid~ prepared as desc:ribecl in poinli g) aboveg i~ clissolved in 15 ml o~ m~hanol~ arld ~ha solution is h~yclro~sena ted und3.r atmospheric pressure in ~he presence o:E 0005 g of a palladium~
o~-c,harcoal ca~alystO ~he cataly~t is fil~er0d of'f~ ancl the filtrate is evapora ted,, Ths oily residue is dis~olved i~ 10 n~
~ dichlorome~hane9 0017 g (1 mmole~ of diphe~;yl diazom~thaxle is added, atld the mixtu.re is s~irred ~or 24 hours, ~heraa~ter ~he mixture is evaporated to obtain 004 g (90 %~ of' benz~
~;ydryl trans~(2-aminophellyl)-3-(2-me~hyl~ dioxolan-2~yl)-4--oa~o-2~aze thidiny~7~aceta ~e ,, IR (K~3r): 1740, 1720 cm~~0 Mass spec~rum: m/z = 472 (M~
methan~ is decomposed with glacial acetic acid9 and the solu-~ion is evaporated~ ~he oi.ly residue is triturat0d with ether to obtain 11~5 g (77 %) of crystalline tra ns-4- ( diazoacet~
l-phenyl-3-(2-methyl-193~dioxolan~2~yl)-azethîdinone9 m~p.0 96--97C (benzene and ethex)0 IR (KBr): 2150, 17609 1635 cm~10 H N~ CDC13)~ 50 (S~ 3E) 9 305 (d, LH~ J = 2~6.
Hz) 9 3.50 (m, ~H)~ 4Q34 (d, llI~ J = 206 Hz), 5~45 (s; IH~ 9 7025 (m~ 5H) ppm.
e) 308 g (000126 mole) of trans-4-(diazoace~yl)-1~
. phenyl-3~(2-methyl-1,3~dioxolan~2-y`L~ azethidinone; prepared as doscribed in point e) above, are dissol.ved in a mjxture O:e 100 ml of te~rah-gdrofuran and 50 ml o e water9 and the solu-tion is irradiated with a high pressure mercury lamp in aphotoreactor at room temperature under nitrogen atmospher~
~he progress of' the reaction is monitored by thin laysr chro~
matoOraphy (adsorbent: Kieselgel G accordi~g to Stahll de~
veloping solvent: a 7.1 mixture of benzene and acetone)0 ~t the end ot' the reaction tetrah~drofuran is evaporated in vacuo, the residue is rendered alkaline with a 20% aqueous sodiu~ hydroxide solution~ and the alkaline solution is washed th.rice with 15 ml of' dichloro~ethane~ eachO ~'he aqueous phase is acidified to p~f - 1~2 with concentrated aqueous ~0 h~dr:ochlori~, acid and then e~tracted. thrice with 20 ml of di~
15 ~
chloromethane~ eachO The organic phases are combin0d, driad ~ver magnesium sul~a~e~ ~iltered, and tha ~iltrate is eva-poxa~-ed~ The oily rssidue is triturated with ether to obtain 1~8 g ~50 %) o~ cry~talline ~ xa~s~l~phe~yl-3-(2-me~hyl~193-dioxola~-2-yl~4~oxo~2-azathidi~y ~ ~acetic acid7 m~pO 128 129C
ethanol)0 A~al~sis~
~alculat9d ~or C15~17~5 (291029~-C: 62000 %, ~- 5~88 %1 ~- L~84 %;
~`ound: C: 61,75 %~ H: 5086 ~09 N: 5~08 ~0.
IR (KBr): 1760, 1740 cm~l~
lH ~MR (CDC13). S - 1~48 (sg 3H)9 2.65 (dd~ lH9 Jgem =
15 HZ9 Jvic= 8 Hz) ~ 3.12 (dd, lH, Jg~m = 15 HZ9 Jvic ~ 8 ~Z)r 3047 (d, lH~ J = 205 Hz)~ 3098 (m, ~H) ? 4~4 (m~ lH) 9 703 ( m7 5H), 9.33 (broad s, lH) ppmO
g) 0081 ml o~ concentratcd nitric acid (~ = 1.5) i~
addad dropwise, under co~stant stirri~g and cooling with iC9, to 3 ml of ace~ic anhydride so that th0 ~emperature o~ the mixturs do~s not ris~ above ~5CI. ~he rasulting nitrating mix~
~C) ~ure i~ added dropwi9e, a~ -5C, to a stir.red solution o~
209 ~ (0"01 mole) of ~rans-l-ph0n;srl 3 (2-methyl~1,3-dio~o-la~==
2~ oxo~-azethidi~ acetic acida preparsd as d~scrib~d in point ~) abev0~ in 20 ml of dry dichlorom~thane. ~It;er one hour of stirri-2g ~he solution is pouxed onko ice watex, and the phases ara separated ~rom each other. r~he aqueous phase is extracted ~wice w~th 25 ml o~ dichloromethana;, aach., r~he organic phases ara comhine~a dried over mag~e~ium sulfata7 ~iltared9 and ~he ~iltr~te is evaporated i~ vacuo~
r~he oil-y residue i~ triturated with ether to obtai~ 1095 g (58 %) of cry~talline ~ ra~s-3-(Z mathyl-la3~dloxolan~2~
~ 16 ~
1~ ( 2~ni~ rophenyl ) -4-ox o-2- az e ~hidiny~7~a c e ti c acid 3 m ~ p ,3 o 175~176$~C t ethanol) O
Analy~;is:
calcula~d for C15~16~27 (3~ 3 C ~ 5~o57 %1 H: 40 ~9 %, No 8~3~ %9 ~ourld~ C: 53.31 %~ Ho 4 ~68 %3 ~0 8021 %q~
IR (K:3r)~ 3600-29009 174()~ 1540~ 13LO cm~
h) 00336 g (1 mmo:l.a) o~ rans 3-(2~methgl~ 1~3Mdi.
oxolan-2~yl)~1-(2~ni~rophen~ ~oxo~2-azet~idiny;~7-ac0tic acid~ prepared as desc:ribecl in poinli g) aboveg i~ clissolved in 15 ml o~ m~hanol~ arld ~ha solution is h~yclro~sena ted und3.r atmospheric pressure in ~he presence o:E 0005 g of a palladium~
o~-c,harcoal ca~alystO ~he cataly~t is fil~er0d of'f~ ancl the filtrate is evapora ted,, Ths oily residue is dis~olved i~ 10 n~
~ dichlorome~hane9 0017 g (1 mmole~ of diphe~;yl diazom~thaxle is added, atld the mixtu.re is s~irred ~or 24 hours, ~heraa~ter ~he mixture is evaporated to obtain 004 g (90 %~ of' benz~
~;ydryl trans~(2-aminophellyl)-3-(2-me~hyl~ dioxolan-2~yl)-4--oa~o-2~aze thidiny~7~aceta ~e ,, IR (K~3r): 1740, 1720 cm~~0 Mass spec~rum: m/z = 472 (M~
Claims (11)
1. A process for the preparation of a new com-pound of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protecting group, and X is a selectively removable esterifying group, characterized in that a compound of the general formula (IV), (IV) wherein and y2 are as defined above, is nitrated and then reduced, the resulting compound of the general formula (III), (III) wherein y1 and y2 are as defined above and A stands for nitro group and then for amino group, is converted into an ester of the general formula (II), (II) wherein y1-y2 and X are as defined above, and the aminophenyl protecting group of the resulting compound of the general formula (II) is split off, or a compound of the general formula (III), wherein y1 and y2 are as defined above and A is an amino group, is converted into an ester of the general formula (II), wherein Y1, Y2 and X are as defined above, and the aminophenyl protecting group of the resulting compound of the general formula (II) is split off, or the aminophenyl protecting group of a com-pound of the general formula (II), wherein y1, y2 and X are as defined above, is split off.
2. A process as claimed in claim 1, character-ized in that a compound of the general formula (IV) is nitrated with a mixture of nitric acid and acetic anhydride.
3. A process as claimed in claim 1, character-ized in that a compound of the general formula (III) wherein A is nitro group is reduced by catalytic hydrogenation.
4. A process as claimed in claim 1, character-ized in that a compound of the general formula (III) wherein A is amino group is esterified with an aryl or diaryl diazomethane.
5. A process as claimed in claim 1, character-ized in that the aminophenyl protecting group is split off with an appropriate oxidizing agent.
6. A process as claimed in claim 1 or 5, characterized in that the aminophenyl protecting group is split off with chromium trioxide in glacial ace-tic acid.
7. A process as claimed in claim 1, character-ized in that in the intermediates compounds of general formulae (II), (III) and (IV), as well as in the final compound of formula (I), y1 and y2 form together a ketal group or a thioanalogue thereof, and X is an arylmethyl or a diarylmethyl group.
8. A process as claimed in claim 1 for the preparation of benzhydryl [trans-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl]-acetate, character-ized in that [trans-1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl ]-acetic acid is nitrated and then reduced, the resulting [trans-3-(2-methyl-1,3-dioxolan-2-yl)-1-(2-aminophenyl)-4-oxo-2-azethidinyl]-acetic acid is reacted with diphenyl diazomethane, and the aminophenyl protecting group of the resulting benzhydryl trans- [1-(2-aminophenyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl ]-acetate is split off.
9. A compound of the general formula (I), (I) wherein y1 and y2 form together a removable carhonyl protecting group, and X is a selectively removable esterifying group, whenever prepared by a process according to claims 1, 2 or 3 or its obvious chemical equivalents.
10. A compound of the general formula (I), (I) wherein y1 and y2 form together a ketal group or a thioanalogue thereof, and X is an arylmethyl or a diarylmethyl group, whenever prepared by a process according to claim 7, or its obvious chemical equivalents.
11. Benzhydryl trans- [3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl ]-acetate, whenever prepared by a process according to claim 8, or its obvious chemi-cal equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU814013A HU184496B (en) | 1981-12-30 | 1981-12-30 | Process for producing new azetidinon-acetic acid derivatives |
| HU4013/81 | 1981-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1189866A true CA1189866A (en) | 1985-07-02 |
Family
ID=10966510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418740A Expired CA1189866A (en) | 1981-12-30 | 1982-12-30 | Heterocyclic acetic acid derivatives and a process for the preparation thereof |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS58118564A (en) |
| AT (1) | AT378770B (en) |
| AU (1) | AU555597B2 (en) |
| BE (1) | BE895487A (en) |
| CA (1) | CA1189866A (en) |
| CH (1) | CH656123A5 (en) |
| DE (1) | DE3248673A1 (en) |
| ES (1) | ES8405762A1 (en) |
| FI (1) | FI824519L (en) |
| FR (1) | FR2518996B1 (en) |
| GB (1) | GB2114125B (en) |
| GR (1) | GR77071B (en) |
| HU (1) | HU184496B (en) |
| IT (1) | IT1210969B (en) |
| LU (1) | LU84565A1 (en) |
| NL (1) | NL8205068A (en) |
| PL (1) | PL137594B1 (en) |
| SE (1) | SE453084B (en) |
| ZA (1) | ZA829594B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT71553B (en) * | 1979-07-23 | 1981-12-14 | Merck & Co Inc | Process for the preparation of thienamycin and intermediates |
| JPS57167964A (en) * | 1981-04-09 | 1982-10-16 | Toyama Chem Co Ltd | Preparation of (4r)-3-substituted-4-(substituted or unsubstituted carboxymethyl)-2-azetidinone derivative |
| JPS57176982A (en) * | 1981-04-24 | 1982-10-30 | Shionogi & Co Ltd | Dioxolanylazetidinone compound, its preparation and use |
-
1981
- 1981-12-30 HU HU814013A patent/HU184496B/en not_active IP Right Cessation
-
1982
- 1982-12-14 AT AT0453282A patent/AT378770B/en not_active IP Right Cessation
- 1982-12-27 JP JP57234852A patent/JPS58118564A/en active Pending
- 1982-12-28 BE BE1/10674A patent/BE895487A/en not_active IP Right Cessation
- 1982-12-29 CH CH7606/82A patent/CH656123A5/en not_active IP Right Cessation
- 1982-12-29 LU LU84565A patent/LU84565A1/en unknown
- 1982-12-29 FR FR8221974A patent/FR2518996B1/en not_active Expired
- 1982-12-29 SE SE8207476A patent/SE453084B/en not_active IP Right Cessation
- 1982-12-30 GB GB08236915A patent/GB2114125B/en not_active Expired
- 1982-12-30 PL PL1982239886A patent/PL137594B1/en unknown
- 1982-12-30 AU AU91969/82A patent/AU555597B2/en not_active Ceased
- 1982-12-30 IT IT8225061A patent/IT1210969B/en active
- 1982-12-30 GR GR70188A patent/GR77071B/el unknown
- 1982-12-30 NL NL8205068A patent/NL8205068A/en not_active Application Discontinuation
- 1982-12-30 ZA ZA829594A patent/ZA829594B/en unknown
- 1982-12-30 FI FI824519A patent/FI824519L/en not_active Application Discontinuation
- 1982-12-30 DE DE19823248673 patent/DE3248673A1/en not_active Withdrawn
- 1982-12-30 ES ES518721A patent/ES8405762A1/en not_active Expired
- 1982-12-30 CA CA000418740A patent/CA1189866A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IT8225061A0 (en) | 1982-12-30 |
| GB2114125B (en) | 1985-09-25 |
| PL137594B1 (en) | 1986-06-30 |
| GR77071B (en) | 1984-09-05 |
| ES518721A0 (en) | 1984-06-16 |
| FI824519L (en) | 1983-07-01 |
| SE453084B (en) | 1988-01-11 |
| LU84565A1 (en) | 1984-10-22 |
| FI824519A0 (en) | 1982-12-30 |
| JPS58118564A (en) | 1983-07-14 |
| SE8207476L (en) | 1983-07-01 |
| NL8205068A (en) | 1983-07-18 |
| FR2518996A1 (en) | 1983-07-01 |
| AT378770B (en) | 1985-09-25 |
| CH656123A5 (en) | 1986-06-13 |
| ATA453282A (en) | 1985-02-15 |
| HU184496B (en) | 1984-08-28 |
| SE8207476D0 (en) | 1982-12-29 |
| PL239886A1 (en) | 1984-01-02 |
| ZA829594B (en) | 1983-10-26 |
| AU9196982A (en) | 1983-07-07 |
| IT1210969B (en) | 1989-09-29 |
| AU555597B2 (en) | 1986-10-02 |
| GB2114125A (en) | 1983-08-17 |
| BE895487A (en) | 1983-06-28 |
| FR2518996B1 (en) | 1986-02-28 |
| ES8405762A1 (en) | 1984-06-16 |
| DE3248673A1 (en) | 1983-07-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5306817A (en) | Process for the stereospecific synthesis of azetidinones | |
| US5561227A (en) | Process for the stereospecific synthesis of azetidinones | |
| HU201931B (en) | Process for producing 1-carba-(1-dethia)-3-cefem-4-carboxylic acid derivatives | |
| JPH04134077A (en) | Isoxazole compound | |
| JPH02218663A (en) | New proline derivative | |
| Oppolzer et al. | An Efficient Enantioselective Synthesis of (—)‐Serricorole | |
| CA1189866A (en) | Heterocyclic acetic acid derivatives and a process for the preparation thereof | |
| Katritzky et al. | A short asymmetric synthesis of 2, 5-disubstituted pyrrolidines | |
| Belanger et al. | The design and synthesis of nonpeptide compounds as mimics of a conformation of methionine-enkephaline | |
| US4588819A (en) | Process and intermediates for preparing trans-4-substituted-s-prolines | |
| US5696271A (en) | Process for the preparation of 3-isoxazolecarboxylic acid | |
| JPH08169878A (en) | Production of optically active pyrrolidine having high enantiomer purity | |
| CA1191854A (en) | Thienamycin derivatives | |
| WO1996036603A1 (en) | Improved process for producing 4-hydroxy-2-pyrrolidone | |
| CA2007732A1 (en) | Cyclohexaneacetamide derivatives | |
| Barco et al. | 1, 4-Diketones via isoxazole intermediates | |
| CA1189865A (en) | Heterocyclic acetic acid derivatives and a process for the preparation thereof | |
| CA1189864A (en) | Heterocyclic carboxylic acids and a process for the preparation thereof | |
| WO1998032736A1 (en) | Process for producing benzylsuccinic acid derivatives | |
| US5015653A (en) | [(5-oxo)-2-pyrrolidinyl)methyl]cyclohexaneacetamides, compositions and use | |
| JPH069553A (en) | Preparation of 1-(2s-methyl-3-mercaptopropionyl)- pyrrolidine-2s-carboxylic acid | |
| JP3740783B2 (en) | Process for producing 4- (2-alkenyl) -2,5-oxazolidinediones | |
| JPH0320392B2 (en) | ||
| JP3013760B2 (en) | Method for producing 4-hydroxy-2-pyrrolidone | |
| JPS58118588A (en) | Novel bicyclic compound and manufacture |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEC | Expiry (correction) | ||
| MKEX | Expiry |