CA1189864A - Heterocyclic carboxylic acids and a process for the preparation thereof - Google Patents
Heterocyclic carboxylic acids and a process for the preparation thereofInfo
- Publication number
- CA1189864A CA1189864A CA000418738A CA418738A CA1189864A CA 1189864 A CA1189864 A CA 1189864A CA 000418738 A CA000418738 A CA 000418738A CA 418738 A CA418738 A CA 418738A CA 1189864 A CA1189864 A CA 1189864A
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- Prior art keywords
- general formula
- compound
- trans
- hydrolysed
- defined above
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Classifications
-
- 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
-
- 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
- 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
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New heterocyclic carbogylic acids of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protecting group and R is a removable amido protecting group, are prepared in such a way that a compound of the gen-eral formula (IV), ( IV) wherein Z is a C1-5 alkyl group and R is as defined above, is reacted with a compound capable for the tem-porary protection of the carbonyl group, the resulting compound of the general formula (III), (III) wherein R, Z, y1 and y2 are as defined above, is treated with an alkali metal halide, and the resulting compound of the general formula (II), (II) wherein Z, R, y1 and y2 are as defined above, is either hydrolysed selectively or separated into its isomers and the trans isomers is then hydrolysed.
The resulting compounds of the general formula (I) are valuable intermediates of the synthesis of thienamycin and thienamycin analogues.
New heterocyclic carbogylic acids of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protecting group and R is a removable amido protecting group, are prepared in such a way that a compound of the gen-eral formula (IV), ( IV) wherein Z is a C1-5 alkyl group and R is as defined above, is reacted with a compound capable for the tem-porary protection of the carbonyl group, the resulting compound of the general formula (III), (III) wherein R, Z, y1 and y2 are as defined above, is treated with an alkali metal halide, and the resulting compound of the general formula (II), (II) wherein Z, R, y1 and y2 are as defined above, is either hydrolysed selectively or separated into its isomers and the trans isomers is then hydrolysed.
The resulting compounds of the general formula (I) are valuable intermediates of the synthesis of thienamycin and thienamycin analogues.
Description
~9 ~
HETEROCYCLIC CARBOXX~IC ACIDS AND A PROCESS ~CR THE
PREPARA~ION TH~REOF
~ he i.nv~ntion relates to ~ew heterocyclic carboxylic acids of the general formula (I) 9 H3~ -~ ~ COOH
o R
whorain yl and y2 form together a removable carbonyl protscting group~
preferably a ketal group or a thioanalogua ~hereo~D
a~d R ~.s a :~e~ovable amido protacSing group, preferably a benzyl group beari~g one or more Cl ~ alkoxy subs~ituants or a phe~yl group bearing optionally one or more Gl 4 ~lko~y substituen~s~
These new compounds are valuable intermodia~es o~
khe sy~thesis of thienamycin and related compou~ds9 Thiena-~yci~ and its analogues can be prepared from ~he compounds according ko the invention e~gO as shown in Scheme (8)~
~t Y~ Schem~
g ~ ~ G~
CN~ ~f '`~
~COCt IN~ 2COOH
R ~ ~r~
1.9~l ight ~ b ~J C~ o~ . r~uc~
,~ X. st~
~ 0~ .
malonic ~id 11 semiester salt ~j~ I ~2 ~ ~ ~ ~ ~ ~1 1~ Q :~ ~J
,~C~0~ I ~/
I~
s ~N~ S)OX
; R
su~fonic Qeid d~
. ~
I
n~ e~
O ~ ~@mi~
s~
8~
~ 2a ~
ScSl~me ~A) continueJ
yll~ on~
t 5~ 0 9~36~
In the ~:'ormulae shown o~ Schome ~ yl~ ~ and R are a~ deflned ~bove 9 ~: is a ~electively r~movab:La esljari~ing g.roup~
Q, is a Cl 5 alkyl group or a subs~itu~ad berlzyl group~
5 ~ s a Gl 5 al~l group9, a sub~titutad benzyl ~sroupg ~d:ro~
gan atom or an alkali m~t;al io~9 and R'~ is a benzyl9 aminoathyl o* ~-acyl~minooth;yl grOUp9 ~ hi3namycirl, an antibio~ic o~ broad spactrum o~
activity9 wa~ prepar6d fir~ n micxobiological way (U~ pa~
spsci~icatio~ NoO 3~,95û~75~ and lator on by chsmical ~ynthe3is (German O~.~anlegu~$sschri~t NoO 2~751~597~o Our aim was to pro~idc a new rou~e ~or ~he ~ynthesis o~ thiena~ycin and its analogue~ wherei~ the az~bhid~no~e ~eleton and the ~-hydroxyethyl ~ide chain~ or a side chai~
15 which ca~ be converted e~sily into ~hydro~yethyl gX0Up9 are ~'o.rmsd simultaneously at th~ early stage o~ tb.e ~y~th~sis~ and the resulting key in~ermediate is convertod ths~ into the desired end~productO
It h~ been ~ou~d that when a dialkyl (protcckad amino)~malonate is ac~lated with di.ketene ~d the re~ulti~g ac,yla~ed produc~ i~ reacted wikh iodine and an alkali metal alcoholate~ an azethidinone compouna o~ ths g~neral ~ormula O
H3C ~ (G~OZ~2 ~ ~ R (I~) co~taining a~ ~_acetyl side chain3 ~s obtained~ which can ~e u~lizod a,~ k~y int~rmGdiate in the sy~the~i~O
In th~ above ~ormula R has ~he same maa~in~ a~
3 Ki~en a~ove and Z i~ a Cl 5 alk~l groupO
1189~364 Tho int~rmedia tes of t;he general. f'o.rmula (IV7 a:~d khair p:x:epara~ioll are des~,riba(l in detail in o~Lr provlou~ Xungar~ar patell~ appl.icati.oll No~ 2262/80., '~h~ pr~paratlorl of th~s9 int~rmediat~s is al~-~o de~cribcd ill the a~:ample~ o~ kh~ pr~s~
a ppli ca k i on, I~ ha s a l~o baen ob~orved tha k ~ prior t9 corLverting ~ e intermediato of the ga~eral ~ormula ~IV~ into khi.orl~mycin or an analogu0 therool:` 3 it i~ pre.~rabla to protect the koto g.roup of tlle oc~C~acetyl ~;ide chain with a group9 pa.rticularly 10 a keta:l group or a thioanalogu~ kh~reo~ which can b~ remov3d ~t a lakor stage o~ the synthe~is~ :EI;hyle~ glycol or a ~hio~
arlalogue th~reo~ uch as rnorcapto~ethar~ol, can be applied partLcula.rly pre:~erably ~o form ~h~ othyle~oL{otal or hemithio-l~atal protectirlg groupO Th~ r~sulting compourlcl oP tih~ gen~ral 15 formula ( III) ~
yl ~2 :H~;C ~ COOZ) 2 0~ i~ (:CII) ~ R
20 Wh~Jrein Rg z~ yl and y2 are a,~ defined abova,, i~ react~d the with an al.kali m~tal halide i~ pyridine or a related solvent or i~ aguaous dimethyl sul~o~ide to obtairl a ccmpolmd oî
~he gerloral formula (II) 9 yl y2 ~I H
~I3~ ~`C~--lL~ Z
0 ~
R
wh~reirl R7 yl~ ~2 and Z ar~ a~3 daPined ahov~O
~L'he :r ~sulliing compound o-f' th~ gerlera 1 :Eo.rmula ( II) is 30 a m-L~:'sur~ of' ci~3 and ~ran~ .isom~r~ Th~ i~30m~rs ca~ bo ~9 ~ 5 separated .fro~ each other by chromatography OI' on tha basi~
of their difCe.rent solubilities~ ~he separated txa~s isomer of the generel ~`oImula (IIa) ~1 ~2 EI H
H3G - C ~_ _ j COQZ
t IIa ) ~ R
can be co~verted into the trans carboxylic acid o~ the general ~ormula (I) by hydrolysisO It is more pre~arablag however, to subject the isomeric mixture itsel~ ~o hydrolysis, since the reaction is selective, i.eO only the tra~s ester converts into the respective carboxylic acidO
r~hs compounds of ths genexal formulae ~III)~ (II) and (IIa) wherein R is a dimethoxybenzyl group3 yl and ~2 form together an othyleneketal or hemithiokctal group and Z
is ethyl are described in our previous Hu~garian paten~
application NoO 2263/80, their preparatio~ iS9 however~ de~
scribed in the examples of the present applicatio~ as w011i r~he other compou~ds o~' the ge~eral formulae (III), (II) a~d (IIa) are newO ~he compou~ds of the general formulaa (I) ~o (IV) are racemic mixturesO
Based on the above~ the invention ralatas to a process for the preparation o.~ new heterocyclic carboxylic acids of the general formula tI), wherei~ ~
yl and y2 form together a removable carbo~yl pro~ecting group9 preferably a ketal group or a thioanslogue ~hereof~
and R is a re~ovable amido prote~ting grcup~ proI~3rably a bonz-gl g:roup bearing one or more Cl L. alkoxy substitua-nts or a phenyl ~;roup bea:rin~ optionally one or more C1_L~ all~oxy 8~i~
subs~ituents 9 :i ,r) 'jJIl :i. C 11 a compound of the general formula (IV~ 9 wherein Z î~
a Cl 5 alkyl. group and R is as de~ined abov03 i~ reac~ed wi~h a compound capable for the temporary pro~actlon of ~he carbo~yl group, preferably wi~h a ketal-~ormin~ agan~ or a thioanalogua thereof~ in ~he pres0nca o~ a compou~d which ~acilitates the xeac~ion~ ~he resul~ing compou~d o~ ~h~
gener~l ~ormula (III) ~ wherein Z~ R3 ~1 and y2 ara a~ daPined above, i~ reac~ed with a~ alkali metal halide i~ pyrldl~e or a .related solven~ or in aqueou~ dim~thyl ~ulfoxide~ and ~hq resulting compound o~` ~hs general .formula (II) ~ whexein Za R3 yl and y2 are as de~inad above and which i~ ~ mlx~ure of Ci3 a~d ~ran~ isomers, is .
a) hydroly~ed salec~ively3 or b) sapara~ed in~o it~ compo~en~s, and the ~ran~
i~omer o~ th0 gen~ral formula ¦IIa) i9 hydrolysed; or a compound oî the general :eo.rmula (III) ~ whera~l~
Z3 R~ ~1 a~d y2 are as do~in~d above~ ~s xoact~d with an alkall me ~al h~lide in pyridine or a rela tad ~olven~ ox irL
aqueous dimethyl sulfogida, and khe resul~ing compound o:e the ganeral ~oxmula (II) g wherain Z9 Rg yl and y2 are as de~
îinad above and which is a mixt;urs of ci~ a~d tran~ isomer~
i~
a) hydrolys~ sel~ctival;y9 or b) ~aparaked into it~ compo~ent~, a~d the t:ra~
isomer o~ the ganeral ~ormula ( IIa~ ~s hydroly~ed7 or a compound o~ the gen3ral ~'ormula (II~ g whe~ei;~
Z7 R7 ~1 and y2 are as de~ined above and whlch i~ a mixtu:re f' Ci.s and ~xans isoraex~7 i~
.~ 7 ~
a) hydrolysed selectivoly~ or b) separated into its compo~ent~,and the trans isomer of ~he general formula (IIa~ is hydrolysed~
whereafter the trans compound o~ th~ ganeral formula (I) is separa~ed ~rom the reaction mi~ur~
According to ~he process of the inventio~ a com~
pound of the general ~ormula ~IV) is convert~d fir~ into a compound o~ the ~eneral ~ormula (III)o It is praferred ~o app~
a ~otal-~orming compound or a thioanaloguQ ~hereo~ as raactan~
~or the temporary pro~action o~ th~ ke~o groupO The rcactio~
is performed pre~erably in the presence of a co~pound~ such a~ boron tri~luoride-diethyl e~hara~e or an arylsulfonic acid (aOgO p-toluenesul~onic acid or naphthalenesul~onic acid~
which ~acili~ates the conv~rsion.
~he reaction is performed in a~ organic ~olventJ
such a,s benzeneD koluQn~1 dioxane, t~trah~dro~uran7 etcO3 a~
a tempsrature ~rom xoom t~mperatura to the boili~g point o~
th3 xeactiion mi~tura ., '~herea~ter a compound of tho ge~oral :formula (III3 ~0 i~ raactod with an alkali metal halida~ prefer~bly sodium or likhium chl.orids~ in the pras~nce o~ pyridi~s~ quinolins~ a homologue or a miæture ~heroo~, or - preîerably ~ -ln aquoous dimathyl sul~oxide to obtai~ a -compound oP kh3 gen~ral ~ormula 5II~. If dssirad~ this skap can also bo per~orm~d without 25 sopara ti~g the compound o~ the gensral formula (III~ ~rom kh~
raac,tion mix~ur~ where it was form~d~
~ he compounds of the goneral ~ormula ~II) are isomeric mixturesO '~ha trans compon0nt of the mixtura car~ ba . utiliz~cl for khe preparatio~ of thienamycin or thienamycln ~0 analogua ;s~
~8~8 ~ he isorneric mixture OL' the general ~ormula (IX) can be hydrolysed with an alkali~ whereupon th0 tra~s compound o~
the general formula (I~ i.s ~orm~d selectivelyO ~he alkaline hy~rolysing agent is us~d in a molar equivalent amount or in a raasonable excessO
If desired3 ths isomexic mixture o~ bhe genaral ~ormula (II) is separa~ed first into its components~ ~he individual isom~rs of the compou~ds wherein R is 2,4~dimsthoxyb0nzyl~ Z
i~ athyl and yl and y2 ~orm a 1~3-dio~ola~yl group can be ~aparated ~rom each other eOg~ by chromatog.raphy, u~ilizing Kieselgel 60 (~ = 00063-0~200 mm) as ad~orbenb and benzen~
with gradu~lly i~creasing acetons content (elu~ion is started with benza~e and then the aceton~ content i~ incr~ased up ~o a benzene:aceton~ ratio Q~ 9'13 a~ eluting agsnt~ The individual 15 isomsrs can also be sapara ted :Erom each other o~ the basis o~
their difïoren~ solubilitie s 7 since on~y the cis estQrs are soluble ir~ sther type ~olv~nbs9 such a~ diethyl ~thar~
~ her~a~ker the separa~3d trans isom0r of tho gonaral xormula (IIa) i~ hydrolysed bo ohtain th~ ~ran~ product o~
~0 tha genoral formula (I) .
~ hs l~ven~ion i~ elucida~sd in d~tail b~T khe aid o~
the f ollowing non-limi ~ing Example ~ ~, ~ ~_ 25 2~ 4-oxo-2~azethidin~ carboxYlic ~cid ~ .
~ solution of 5O21 g (00130 mol~) o~ sodltlm hydroxide in 60 ml o~ wa'G~r is add~d ~o a suspe~sion o~ 4io2 g ~0~109 molo) o~ tran~ethyl 1-(2,4~dimethoxy~enz~1)w3-(2~mekhyl~1~3-dioxol~n~2-yl)~oxo 2- azsthidine~carboxylate in 50 ml o:~
30 e~hanol under stirri~g a-ad cooling with iCfl wa~er~ and ~tirri~;
_ 9 _ is co~tinLIed uII~il a cl~ar solution is obtainsd ~abou~ 20 minutes~ 100 ml o:l water are added the~ to tha soluti.on~ and the mix~uI~e i5 sh~ken with 100 ml of etherO The aqueous phase is acidifi~d ~o p:H - 1 wi~h concerLtrated aqueous hydrochloric acid7 arld then shakon quickly with 100 ml a.nd twic~ with 50 ml o~ dichloromath~ne, each~ ~he dichloromethana solutions are combined? dri~d oveI~ magrlesium sul~ate, filteredg, and th~
~iltrat~ is a~rapo.ratedO ~he oily residue is cry,stallized Prom a mixture of toluene and p~trol~um ath~r to obtain 35 g ~92 %) ô:~ trans-1-(2~4-dimethoxybenzyl) -~3- (2-m~ ~hyl-l ~3~dioxolan~2-yl)~
4-oxo-2-azsthidine-carboxylic acid~ m.p.: 117~11aC (tolu~ne),.
Analysis:
calculated ~or C17H21N07 5351035):
C~ 58~ H: 6003 %~ N: 3099 %7 found: C: 58~,17 %, H: 6,30 %, N: 41~24 ~0 IR (:KBr): 3500-2500, 2900~ 1760~ 1720 cm 1~
H N~[R (CDC13): ~= 1.39 (s, 3H), 3,,50 (d~ lH7 J - 2~5 Hz) ~ 3.77 ( s" 3E) 9 3079 ~ s, 3H), 308~ (d9 lH, J = 2.,5 :F{z) ~ 3096 (~, 4H) ~ 4~21 ~ 4.,56 (d, 2E[7 ~B = 15 Hz~ ~ 6~44 (m, 2H) ~ 7~15
HETEROCYCLIC CARBOXX~IC ACIDS AND A PROCESS ~CR THE
PREPARA~ION TH~REOF
~ he i.nv~ntion relates to ~ew heterocyclic carboxylic acids of the general formula (I) 9 H3~ -~ ~ COOH
o R
whorain yl and y2 form together a removable carbonyl protscting group~
preferably a ketal group or a thioanalogua ~hereo~D
a~d R ~.s a :~e~ovable amido protacSing group, preferably a benzyl group beari~g one or more Cl ~ alkoxy subs~ituants or a phe~yl group bearing optionally one or more Gl 4 ~lko~y substituen~s~
These new compounds are valuable intermodia~es o~
khe sy~thesis of thienamycin and related compou~ds9 Thiena-~yci~ and its analogues can be prepared from ~he compounds according ko the invention e~gO as shown in Scheme (8)~
~t Y~ Schem~
g ~ ~ G~
CN~ ~f '`~
~COCt IN~ 2COOH
R ~ ~r~
1.9~l ight ~ b ~J C~ o~ . r~uc~
,~ X. st~
~ 0~ .
malonic ~id 11 semiester salt ~j~ I ~2 ~ ~ ~ ~ ~ ~1 1~ Q :~ ~J
,~C~0~ I ~/
I~
s ~N~ S)OX
; R
su~fonic Qeid d~
. ~
I
n~ e~
O ~ ~@mi~
s~
8~
~ 2a ~
ScSl~me ~A) continueJ
yll~ on~
t 5~ 0 9~36~
In the ~:'ormulae shown o~ Schome ~ yl~ ~ and R are a~ deflned ~bove 9 ~: is a ~electively r~movab:La esljari~ing g.roup~
Q, is a Cl 5 alkyl group or a subs~itu~ad berlzyl group~
5 ~ s a Gl 5 al~l group9, a sub~titutad benzyl ~sroupg ~d:ro~
gan atom or an alkali m~t;al io~9 and R'~ is a benzyl9 aminoathyl o* ~-acyl~minooth;yl grOUp9 ~ hi3namycirl, an antibio~ic o~ broad spactrum o~
activity9 wa~ prepar6d fir~ n micxobiological way (U~ pa~
spsci~icatio~ NoO 3~,95û~75~ and lator on by chsmical ~ynthe3is (German O~.~anlegu~$sschri~t NoO 2~751~597~o Our aim was to pro~idc a new rou~e ~or ~he ~ynthesis o~ thiena~ycin and its analogue~ wherei~ the az~bhid~no~e ~eleton and the ~-hydroxyethyl ~ide chain~ or a side chai~
15 which ca~ be converted e~sily into ~hydro~yethyl gX0Up9 are ~'o.rmsd simultaneously at th~ early stage o~ tb.e ~y~th~sis~ and the resulting key in~ermediate is convertod ths~ into the desired end~productO
It h~ been ~ou~d that when a dialkyl (protcckad amino)~malonate is ac~lated with di.ketene ~d the re~ulti~g ac,yla~ed produc~ i~ reacted wikh iodine and an alkali metal alcoholate~ an azethidinone compouna o~ ths g~neral ~ormula O
H3C ~ (G~OZ~2 ~ ~ R (I~) co~taining a~ ~_acetyl side chain3 ~s obtained~ which can ~e u~lizod a,~ k~y int~rmGdiate in the sy~the~i~O
In th~ above ~ormula R has ~he same maa~in~ a~
3 Ki~en a~ove and Z i~ a Cl 5 alk~l groupO
1189~364 Tho int~rmedia tes of t;he general. f'o.rmula (IV7 a:~d khair p:x:epara~ioll are des~,riba(l in detail in o~Lr provlou~ Xungar~ar patell~ appl.icati.oll No~ 2262/80., '~h~ pr~paratlorl of th~s9 int~rmediat~s is al~-~o de~cribcd ill the a~:ample~ o~ kh~ pr~s~
a ppli ca k i on, I~ ha s a l~o baen ob~orved tha k ~ prior t9 corLverting ~ e intermediato of the ga~eral ~ormula ~IV~ into khi.orl~mycin or an analogu0 therool:` 3 it i~ pre.~rabla to protect the koto g.roup of tlle oc~C~acetyl ~;ide chain with a group9 pa.rticularly 10 a keta:l group or a thioanalogu~ kh~reo~ which can b~ remov3d ~t a lakor stage o~ the synthe~is~ :EI;hyle~ glycol or a ~hio~
arlalogue th~reo~ uch as rnorcapto~ethar~ol, can be applied partLcula.rly pre:~erably ~o form ~h~ othyle~oL{otal or hemithio-l~atal protectirlg groupO Th~ r~sulting compourlcl oP tih~ gen~ral 15 formula ( III) ~
yl ~2 :H~;C ~ COOZ) 2 0~ i~ (:CII) ~ R
20 Wh~Jrein Rg z~ yl and y2 are a,~ defined abova,, i~ react~d the with an al.kali m~tal halide i~ pyridine or a related solvent or i~ aguaous dimethyl sul~o~ide to obtairl a ccmpolmd oî
~he gerloral formula (II) 9 yl y2 ~I H
~I3~ ~`C~--lL~ Z
0 ~
R
wh~reirl R7 yl~ ~2 and Z ar~ a~3 daPined ahov~O
~L'he :r ~sulliing compound o-f' th~ gerlera 1 :Eo.rmula ( II) is 30 a m-L~:'sur~ of' ci~3 and ~ran~ .isom~r~ Th~ i~30m~rs ca~ bo ~9 ~ 5 separated .fro~ each other by chromatography OI' on tha basi~
of their difCe.rent solubilities~ ~he separated txa~s isomer of the generel ~`oImula (IIa) ~1 ~2 EI H
H3G - C ~_ _ j COQZ
t IIa ) ~ R
can be co~verted into the trans carboxylic acid o~ the general ~ormula (I) by hydrolysisO It is more pre~arablag however, to subject the isomeric mixture itsel~ ~o hydrolysis, since the reaction is selective, i.eO only the tra~s ester converts into the respective carboxylic acidO
r~hs compounds of ths genexal formulae ~III)~ (II) and (IIa) wherein R is a dimethoxybenzyl group3 yl and ~2 form together an othyleneketal or hemithiokctal group and Z
is ethyl are described in our previous Hu~garian paten~
application NoO 2263/80, their preparatio~ iS9 however~ de~
scribed in the examples of the present applicatio~ as w011i r~he other compou~ds o~' the ge~eral formulae (III), (II) a~d (IIa) are newO ~he compou~ds of the general formulaa (I) ~o (IV) are racemic mixturesO
Based on the above~ the invention ralatas to a process for the preparation o.~ new heterocyclic carboxylic acids of the general formula tI), wherei~ ~
yl and y2 form together a removable carbo~yl pro~ecting group9 preferably a ketal group or a thioanslogue ~hereof~
and R is a re~ovable amido prote~ting grcup~ proI~3rably a bonz-gl g:roup bearing one or more Cl L. alkoxy substitua-nts or a phenyl ~;roup bea:rin~ optionally one or more C1_L~ all~oxy 8~i~
subs~ituents 9 :i ,r) 'jJIl :i. C 11 a compound of the general formula (IV~ 9 wherein Z î~
a Cl 5 alkyl. group and R is as de~ined abov03 i~ reac~ed wi~h a compound capable for the temporary pro~actlon of ~he carbo~yl group, preferably wi~h a ketal-~ormin~ agan~ or a thioanalogua thereof~ in ~he pres0nca o~ a compou~d which ~acilitates the xeac~ion~ ~he resul~ing compou~d o~ ~h~
gener~l ~ormula (III) ~ wherein Z~ R3 ~1 and y2 ara a~ daPined above, i~ reac~ed with a~ alkali metal halide i~ pyrldl~e or a .related solven~ or in aqueou~ dim~thyl ~ulfoxide~ and ~hq resulting compound o~` ~hs general .formula (II) ~ whexein Za R3 yl and y2 are as de~inad above and which i~ ~ mlx~ure of Ci3 a~d ~ran~ isomers, is .
a) hydroly~ed salec~ively3 or b) sapara~ed in~o it~ compo~en~s, and the ~ran~
i~omer o~ th0 gen~ral formula ¦IIa) i9 hydrolysed; or a compound oî the general :eo.rmula (III) ~ whera~l~
Z3 R~ ~1 a~d y2 are as do~in~d above~ ~s xoact~d with an alkall me ~al h~lide in pyridine or a rela tad ~olven~ ox irL
aqueous dimethyl sulfogida, and khe resul~ing compound o:e the ganeral ~oxmula (II) g wherain Z9 Rg yl and y2 are as de~
îinad above and which is a mixt;urs of ci~ a~d tran~ isomer~
i~
a) hydrolys~ sel~ctival;y9 or b) ~aparaked into it~ compo~ent~, a~d the t:ra~
isomer o~ the ganeral ~ormula ( IIa~ ~s hydroly~ed7 or a compound o~ the gen3ral ~'ormula (II~ g whe~ei;~
Z7 R7 ~1 and y2 are as de~ined above and whlch i~ a mixtu:re f' Ci.s and ~xans isoraex~7 i~
.~ 7 ~
a) hydrolysed selectivoly~ or b) separated into its compo~ent~,and the trans isomer of ~he general formula (IIa~ is hydrolysed~
whereafter the trans compound o~ th~ ganeral formula (I) is separa~ed ~rom the reaction mi~ur~
According to ~he process of the inventio~ a com~
pound of the general ~ormula ~IV) is convert~d fir~ into a compound o~ the ~eneral ~ormula (III)o It is praferred ~o app~
a ~otal-~orming compound or a thioanaloguQ ~hereo~ as raactan~
~or the temporary pro~action o~ th~ ke~o groupO The rcactio~
is performed pre~erably in the presence of a co~pound~ such a~ boron tri~luoride-diethyl e~hara~e or an arylsulfonic acid (aOgO p-toluenesul~onic acid or naphthalenesul~onic acid~
which ~acili~ates the conv~rsion.
~he reaction is performed in a~ organic ~olventJ
such a,s benzeneD koluQn~1 dioxane, t~trah~dro~uran7 etcO3 a~
a tempsrature ~rom xoom t~mperatura to the boili~g point o~
th3 xeactiion mi~tura ., '~herea~ter a compound of tho ge~oral :formula (III3 ~0 i~ raactod with an alkali metal halida~ prefer~bly sodium or likhium chl.orids~ in the pras~nce o~ pyridi~s~ quinolins~ a homologue or a miæture ~heroo~, or - preîerably ~ -ln aquoous dimathyl sul~oxide to obtai~ a -compound oP kh3 gen~ral ~ormula 5II~. If dssirad~ this skap can also bo per~orm~d without 25 sopara ti~g the compound o~ the gensral formula (III~ ~rom kh~
raac,tion mix~ur~ where it was form~d~
~ he compounds of the goneral ~ormula ~II) are isomeric mixturesO '~ha trans compon0nt of the mixtura car~ ba . utiliz~cl for khe preparatio~ of thienamycin or thienamycln ~0 analogua ;s~
~8~8 ~ he isorneric mixture OL' the general ~ormula (IX) can be hydrolysed with an alkali~ whereupon th0 tra~s compound o~
the general formula (I~ i.s ~orm~d selectivelyO ~he alkaline hy~rolysing agent is us~d in a molar equivalent amount or in a raasonable excessO
If desired3 ths isomexic mixture o~ bhe genaral ~ormula (II) is separa~ed first into its components~ ~he individual isom~rs of the compou~ds wherein R is 2,4~dimsthoxyb0nzyl~ Z
i~ athyl and yl and y2 ~orm a 1~3-dio~ola~yl group can be ~aparated ~rom each other eOg~ by chromatog.raphy, u~ilizing Kieselgel 60 (~ = 00063-0~200 mm) as ad~orbenb and benzen~
with gradu~lly i~creasing acetons content (elu~ion is started with benza~e and then the aceton~ content i~ incr~ased up ~o a benzene:aceton~ ratio Q~ 9'13 a~ eluting agsnt~ The individual 15 isomsrs can also be sapara ted :Erom each other o~ the basis o~
their difïoren~ solubilitie s 7 since on~y the cis estQrs are soluble ir~ sther type ~olv~nbs9 such a~ diethyl ~thar~
~ her~a~ker the separa~3d trans isom0r of tho gonaral xormula (IIa) i~ hydrolysed bo ohtain th~ ~ran~ product o~
~0 tha genoral formula (I) .
~ hs l~ven~ion i~ elucida~sd in d~tail b~T khe aid o~
the f ollowing non-limi ~ing Example ~ ~, ~ ~_ 25 2~ 4-oxo-2~azethidin~ carboxYlic ~cid ~ .
~ solution of 5O21 g (00130 mol~) o~ sodltlm hydroxide in 60 ml o~ wa'G~r is add~d ~o a suspe~sion o~ 4io2 g ~0~109 molo) o~ tran~ethyl 1-(2,4~dimethoxy~enz~1)w3-(2~mekhyl~1~3-dioxol~n~2-yl)~oxo 2- azsthidine~carboxylate in 50 ml o:~
30 e~hanol under stirri~g a-ad cooling with iCfl wa~er~ and ~tirri~;
_ 9 _ is co~tinLIed uII~il a cl~ar solution is obtainsd ~abou~ 20 minutes~ 100 ml o:l water are added the~ to tha soluti.on~ and the mix~uI~e i5 sh~ken with 100 ml of etherO The aqueous phase is acidifi~d ~o p:H - 1 wi~h concerLtrated aqueous hydrochloric acid7 arld then shakon quickly with 100 ml a.nd twic~ with 50 ml o~ dichloromath~ne, each~ ~he dichloromethana solutions are combined? dri~d oveI~ magrlesium sul~ate, filteredg, and th~
~iltrat~ is a~rapo.ratedO ~he oily residue is cry,stallized Prom a mixture of toluene and p~trol~um ath~r to obtain 35 g ~92 %) ô:~ trans-1-(2~4-dimethoxybenzyl) -~3- (2-m~ ~hyl-l ~3~dioxolan~2-yl)~
4-oxo-2-azsthidine-carboxylic acid~ m.p.: 117~11aC (tolu~ne),.
Analysis:
calculated ~or C17H21N07 5351035):
C~ 58~ H: 6003 %~ N: 3099 %7 found: C: 58~,17 %, H: 6,30 %, N: 41~24 ~0 IR (:KBr): 3500-2500, 2900~ 1760~ 1720 cm 1~
H N~[R (CDC13): ~= 1.39 (s, 3H), 3,,50 (d~ lH7 J - 2~5 Hz) ~ 3.77 ( s" 3E) 9 3079 ~ s, 3H), 308~ (d9 lH, J = 2.,5 :F{z) ~ 3096 (~, 4H) ~ 4~21 ~ 4.,56 (d, 2E[7 ~B = 15 Hz~ ~ 6~44 (m, 2H) ~ 7~15
2() (d~ lH~ J = 10 Hz) 7 7~58 (broad s~ lH) ppm.
r~h~ starting substa~ce is pr~pared as ~ollow~o a) A mixture o~ lO9~R g (0"66 mol0) o.~ 2~4~dime~ho~y-benzald0hyda ~ 72 ml ~0~66 mols~ o~ benzylami~ and 660 ml of methanol is stirred ak room temp~ratllre for 20 mixLutos7 whare~
25 upon a clear solutlon is obtai~d ~rom th~ suspanaion.. ~h~
solution is coolad wikh ica wakora and 130~ g ~0~,~3 mole3 oî
sodium boro~rdride are added to it in sma 11 port~onsD
r~he progress o~ the reaction is monitor~d by thin lay~r chromatoc,raphy (Kieselgal G according to .Stahl9 daveïop~
~0 irl~ sc)lven~: a 9.1 mi~ ure o~ benzena anc3. ac0tor~ and at 9B~
the e~d o ~he reactLon the mix~ure is evaporated to dryne~s in vacuo~ The residue is admixed with 300 ml of wa~er~ and the aqueous mixture i~ ex~racted with 500 ml J ?0~ ml and 200 ml portions of e~her. The ethe~l solutions axa combined7 driad over magnesium sulfate, ~iltared~ and then 112 ml (0066 mole) of diathyl bromomalona~e and 93 ml (0066 mole) o~ txiet~yl amine are added to the filtrate~ The reactio~ mixture i~
~tirred at room temperature for ~r-3 days~ The separated tri.~
ethyl ammonium bromide -1~ filtered o~ and wa~hed with ethe.rO
The mo~har Liquor is evapora~ed9 and the residue is r0cry~tall~
ized from 150 ml of ethanol. The re~ulting 210 g o~ crude product are recrystallized again ~rom 400 ml o~ e~ha~ol ~o ob~
tain 197 g (72 ~) of diethyl N-benzyl~N;~2~4-dime~ho~ybenzyl~
amino-malonate~ m~p.: 6~63C (ethanol).
IR tKBr): 1750/1725 cm 1, b) 6107 g (0.149 mole) o~ diethyl N--benzyl~N-(2~4~di~-methoxybenzyl) am-lno-malonateg prepared as desGrib0d in poin~
a) cbove, ar~ hydrogenated in 500 ml of ethanol undar atmo~
~phexic pressure ifl the presance of abouk 20 g o~ a palladium on-charcoal catalys~. ~he catalyst is ~iltered o~f ~nd tho filtrate is evaporatedO 4701 g ~97 %~ o~ diethyl (2,4~dim~th o~ybenzylamino)-malo~ate are obtainedO ~he product c3n be convertod into its hydrochloridc by ~cacting it wi~h ~ydro~
chloric acid~ ~he hydrochloride melts at 122-124C aîter re-crystallization ~rom ethyl acctato.
Analysis~
calculated îor C16H24ClN06 (3610~32) C- 53011 %~ H: 6.,69 %~ Gl. 9~D80 %~ N~ 3~,87 %~
~ourld: C 5Zo51 %~ H: 6077 7~ Cl: 10c~30 %3 N: 4'40~;3 %o
r~h~ starting substa~ce is pr~pared as ~ollow~o a) A mixture o~ lO9~R g (0"66 mol0) o.~ 2~4~dime~ho~y-benzald0hyda ~ 72 ml ~0~66 mols~ o~ benzylami~ and 660 ml of methanol is stirred ak room temp~ratllre for 20 mixLutos7 whare~
25 upon a clear solutlon is obtai~d ~rom th~ suspanaion.. ~h~
solution is coolad wikh ica wakora and 130~ g ~0~,~3 mole3 oî
sodium boro~rdride are added to it in sma 11 port~onsD
r~he progress o~ the reaction is monitor~d by thin lay~r chromatoc,raphy (Kieselgal G according to .Stahl9 daveïop~
~0 irl~ sc)lven~: a 9.1 mi~ ure o~ benzena anc3. ac0tor~ and at 9B~
the e~d o ~he reactLon the mix~ure is evaporated to dryne~s in vacuo~ The residue is admixed with 300 ml of wa~er~ and the aqueous mixture i~ ex~racted with 500 ml J ?0~ ml and 200 ml portions of e~her. The ethe~l solutions axa combined7 driad over magnesium sulfate, ~iltared~ and then 112 ml (0066 mole) of diathyl bromomalona~e and 93 ml (0066 mole) o~ txiet~yl amine are added to the filtrate~ The reactio~ mixture i~
~tirred at room temperature for ~r-3 days~ The separated tri.~
ethyl ammonium bromide -1~ filtered o~ and wa~hed with ethe.rO
The mo~har Liquor is evapora~ed9 and the residue is r0cry~tall~
ized from 150 ml of ethanol. The re~ulting 210 g o~ crude product are recrystallized again ~rom 400 ml o~ e~ha~ol ~o ob~
tain 197 g (72 ~) of diethyl N-benzyl~N;~2~4-dime~ho~ybenzyl~
amino-malonate~ m~p.: 6~63C (ethanol).
IR tKBr): 1750/1725 cm 1, b) 6107 g (0.149 mole) o~ diethyl N--benzyl~N-(2~4~di~-methoxybenzyl) am-lno-malonateg prepared as desGrib0d in poin~
a) cbove, ar~ hydrogenated in 500 ml of ethanol undar atmo~
~phexic pressure ifl the presance of abouk 20 g o~ a palladium on-charcoal catalys~. ~he catalyst is ~iltered o~f ~nd tho filtrate is evaporatedO 4701 g ~97 %~ o~ diethyl (2,4~dim~th o~ybenzylamino)-malo~ate are obtainedO ~he product c3n be convertod into its hydrochloridc by ~cacting it wi~h ~ydro~
chloric acid~ ~he hydrochloride melts at 122-124C aîter re-crystallization ~rom ethyl acctato.
Analysis~
calculated îor C16H24ClN06 (3610~32) C- 53011 %~ H: 6.,69 %~ Gl. 9~D80 %~ N~ 3~,87 %~
~ourld: C 5Zo51 %~ H: 6077 7~ Cl: 10c~30 %3 N: 4'40~;3 %o
3~ IR (l~ilrrl). 32~0~ 29(X) ~ 2850~ 1730l 1720 crr~
9~
H NI~R (C~C13)- ~ = 103 (S9 6H)~ 3.78 (s~ 3H)~ 3.82 (S3 3H), 4~21 (q~ 4H)~ 60~0 (~ 2H), 6~4-6.6 (m~ 2H) ~ 703~7.55 ~m, lH~g 70r7 (broad s~ lH) ppm.
c) ~ mixture o~ 3906 g (00122 mols~ of diethyl (2,4 dim~thoxybenæylamino)~malonate9 preparod a~ d~scribed in poi~t b) above7 80 ml o~ glacial acetic acid and 12.3 g (1102 ml~
00146 mole) of dike~e i.s boiled ~or 0~5 hour~ Glacial acetiG
acid i~ distilled of~ in vacuo over a wat~r ba~h, and the oily r~iduH i5 ~riturated with 150 ml o~` water~ '~he resulting crystalli~ substancs is dissolv~d in 60 ml o.~ athyl ace~ate and precipitat0d with petroleum 0thsr~ 2936 g (60 %) o.~ di-ethyl N-~2,4-dimethoxybenzyl)-3-hydroxy~3~methyl~5~oxo-2~2 pyrrolidine~dicarboxylat~ and/or it~ tautome.r are obtaLned~
m.p.: 106 107~CD
A~alysi~:
calculatod ~or C20H2r~08 (409.43).
C: 58.67 %, H- 6.65 %, N: 3J42 ~;
found: a: 58.79 %~ H: 6~33 %~ N: 3034 %~
IR ~KBr): 3400~ 29509 2850~ 1730 (1740 ~h) 3 1710 cm 2~ lH NMR (cDal~3 ~ 3H)~ 1.17 (~ 3H)~ 1/52 ~s9~H)~ 208 (~ 0,1 H), 2065 ~broad s~ 2~) 9 3~75 ( 9 ~ 6H) 9 308~4015 (m~ 4H~ 6~7 (broad S7 2H~, 6025-6045 (m) ~ 700~70~5 ~m, 3H~ ppm~
d~ 2005 g ~50 mmoles) of' the product propar~d a~
described in point c3 above ar3 su~p~decl in 50 ml o~ c~ry othor~ and a ~olution sf 3~45 g (150 ~mol~s~ o~ m~tallic ~odium i~ 100 ml of dry atha-nol and a 901u~io~ 0~ 12~7 g (50 mmole~
0X i.odi~o in 150 ml of clry ~ther ara added simultarl~ollsly~
~rom two clroppîng Xun-aels7 to the vlgorously stirred ~uspansio~
~mdar cool~n~ with ice waterl ~herea~ter 5 g of ~odi.um hyc~o~
~9 ~6 ~ L2 -sulfite~ di~olved in 200 ml of a saturated aqu00us sodium chloride 501ution9 ara ~dded to ths stirr~d mixtureO '~he mix~
~ure is filled into a scparating funnel, and 60 ml of water are added to dissolve the separa~d inorganic saltsO ~ha organ~
ic pha~e is r~mov~d, dri~d over magn~ium sul~ate9 filtered~
and the fil~rate is ~vaporated~ ~he oily r~siduo 9 w0ighing 18.5 g7 is crystallized from 30 ml of 2~propanol~ 1OD9 g (54 %) of dieth-yl 3d cetyl~ (2~4 dimethoxybenzyl)~4-oxo-2,2~azeth;;
idino-dicarboxylate are ob~ained; mOpo 84~85C (2-propanol)~
Analysis:
calculated for C20E25N8 (4070 a 58~96 %, ~I: 6.19 %9 ~ 3~ L~ %3 ~ound: C: 58~99 %~ H- 6~04 %9 N: 3~57 %0 1~ NMR (C~C13): ~ = 1;12 (t9 3H) ? 1021 (~; 3H) 9 2;31 .
(S9 3H), 3.76 (59 6H)~ 3.8-3~4 (m, 4~I) 9 4153 (d9 lH) 9 4~63 (d~ lH) ~ 4069 (S7 lH) 9 6.3-604 (m, 2H) ~ 7~07 (d9 lH) ppm7 e~ 179 ml (206 g, 10452 moles) of boron trifluorida-diethyl 0therate are added dropwise to a vigorously stirred ~olution of 179 g ~OoL~4 mole) of di0thyl 3-acetyl-1~(2~ di-~0 me~hoxyb~nY,yl)~4-o~o-2~2-azethidine-dicarbox~Jlate and 107 ml (120 g7 10936 moles3 of othylene glycol in 500 ml of dry di~
oxans under cooling with ice waterO ~he reaction mixture i~
allowad to stand at room temFerature for one day~ during this period tho mixtura is occasionally stirredO Ther~after 415 g (1.452 molss) of Na~C03~ lGH20 are added slowly to the stirred mixture und~r cooling with ice water~ and tha mixture is stixred for 15 minut9sO ~h~rsafter 1 litre of ether a~d 1 litre of water are added7 and ths phasa~ are ~oparatsd from each otherO ~h~ aqu~ous phase is ~haken tw~ce with 500 ml of diethyl ~thor7 eachO ~he ethereal phase is dried ovar magnesium sul~ate 9 filtered9 and the filtratc is ev~poratedO 33~9 g (0058 mola) of sodium chloride9 170L~ ml (0~9~8 mole) of water and 220 ml of dimethyl sul~oxida are added to the residue9 and the mixture is stirred on an oil bath at 180C. The prog;ress of the reaction is monitored by thin layer chromatography ~adsorben~. Kieselgel G according to Stahl, developing solv~n~: a 6:4 mi~tur~ o~ benzene a~d ethyl acetat~)~ At the end of ~he reaction~ i.e. a~ter about 15 hours, the mixture is poured into 1100 ml o~ saturated aqueous sodium chloride soluti.onp and the resulting mixture is shal{en with 1000 ml and then twîce with 500 mL o~ diethyl ether? each. The ether~ solutions are combined~ d~colourized with charcoal, dried over magnesium sul~ats~ and the ~iltrate is evaporated to a ~inal volume o~ ccaO 200 ml. This co~centrat~
ed solution is cooled with ice water to obtain 59 g (35 %) o~
trans-ethyl 1-(2,~dimethoxyb~zyl)-3-(2-methyl~1~3~dio~olan~
2-yl)-4-oxo-2~azethidine carbo~ylata; m~p~: 95C~
~ A m-ixt~re of 005 g (1~2 mmoles~ o~ diethyl ~acetyl~
1~(2,4~dimothoxybHnz~yl)-4~oxo-2,2-azethidine-dicarho:x~ylato~
prepared as described in point d~ above~ 3 ml of dry totra~
hydro~an and 005~ g (3~6 mmoles~ o~ mercapto~thanol is boiled ~or 4 hours~ and then 10 ml o~ water and 10 ml of chloro~
form are add~d to the reaction mixtureD ~he organic phase is separatsd7 washed wi~h a 5~0 a~ueous sodium hydrocarbo~ate solution, dried over ma~nesium sul~ate9 ~il'G~red7 and the pxoduct is separated from the ~iltrate by preparative thin layer chromatography (adsorbsnt: ~ieselgel 60 PF25~669 devcloping solvent: a ~:2 mixture of toluene and acetone)c 0~30 g (53 %3 of diethyl 1-(2,4~dimethoxybenzyl~-3-¦2~methyl~
3(~ 1~3-oxathiolan~2~-~l)JI~oxo~2~2~azethidine~dicarboxylate are obtained~
lH N~ ~CD~13)o ~ ~ 0~8-1~55 ~m, 6H~ 72 ~ 1~77 ~da 3H) 9 2~9-3~4 (m, 2H~ 3~75 (s, 6H), 4~0~5.0 (m, 9H)g 6~4 (m~
2E) ~ 7O1 ~d~ lH) ppmO
~ 2 tr = o-2-a~,L~h~2==~8a~ 118_~9 11 g (000245 mola) o~ diothyl ~(2 methyl lg~di~
o~ola~-2~yl)~1~(L~metho~yphenyl3-~oxo~2~2-aza~hidi~e dicarb-oxyla~e are dissolved in 2Q ml of.` dimethyl sul~oxide 9 1~72 g (000295 mol~) o~ sodium chloride and 009 ml (00049 mola) o~
water are addod~ and the mixture is s~irred at 175C u~til a complet~ reaction is obtained~ 'rhe progress o~ tha reactio~ is monitored b-~ thin layer chromatograp~y ladsorbent: Eieselgel G according to Stahl.7 developing solvent: a 6:4 mixture of benzene and ethyl acetate)~
'~he mixture i5 cooled~ poured inko 150 ml o~ a satur~
a~ed aqueous sodium chloride solution~ a~d extracted thr-lc~
with 50 ml o~ diothyl ether, each~ 'rhe organic phas~s are com~
bined~ dried over mag~esium sulf.'ate; ~iltered, and the ~iltrate i~ evaporat~dO ~'he resulting oily .residue3 weighi~g 6 g~ is dis,solved in 25 ml o~ 96% ethanol9 and a solution of 0.72 g (00018 mola) o~ sodium hydroxide in 10 ~1 o~ w~ter is added to the alcoholic mi~ture under cooling wi~h icc water~ The mixture is stirred for 075 hour~ ~h~n diluted with 50 ml o~
water and washed twice with 25 ml o~ dichloromatha~e, ~ach~
~he aquaous pha~e is acidified to pH = 1 with concentratqd aqueous hydrochloric acid~ and then extracted thrice with ~5 ml of dichloromethane~ each. The or~anic phases are combi.ned., ~ried over ~agnesium sul~ate~ ~ilt~red3 and th~ .~ilk.ra~e is ~ 15 evaporated~ ~he oily residu~ is crystallized wi~h benze~
9~
H NI~R (C~C13)- ~ = 103 (S9 6H)~ 3.78 (s~ 3H)~ 3.82 (S3 3H), 4~21 (q~ 4H)~ 60~0 (~ 2H), 6~4-6.6 (m~ 2H) ~ 703~7.55 ~m, lH~g 70r7 (broad s~ lH) ppm.
c) ~ mixture o~ 3906 g (00122 mols~ of diethyl (2,4 dim~thoxybenæylamino)~malonate9 preparod a~ d~scribed in poi~t b) above7 80 ml o~ glacial acetic acid and 12.3 g (1102 ml~
00146 mole) of dike~e i.s boiled ~or 0~5 hour~ Glacial acetiG
acid i~ distilled of~ in vacuo over a wat~r ba~h, and the oily r~iduH i5 ~riturated with 150 ml o~` water~ '~he resulting crystalli~ substancs is dissolv~d in 60 ml o.~ athyl ace~ate and precipitat0d with petroleum 0thsr~ 2936 g (60 %) o.~ di-ethyl N-~2,4-dimethoxybenzyl)-3-hydroxy~3~methyl~5~oxo-2~2 pyrrolidine~dicarboxylat~ and/or it~ tautome.r are obtaLned~
m.p.: 106 107~CD
A~alysi~:
calculatod ~or C20H2r~08 (409.43).
C: 58.67 %, H- 6.65 %, N: 3J42 ~;
found: a: 58.79 %~ H: 6~33 %~ N: 3034 %~
IR ~KBr): 3400~ 29509 2850~ 1730 (1740 ~h) 3 1710 cm 2~ lH NMR (cDal~3 ~ 3H)~ 1.17 (~ 3H)~ 1/52 ~s9~H)~ 208 (~ 0,1 H), 2065 ~broad s~ 2~) 9 3~75 ( 9 ~ 6H) 9 308~4015 (m~ 4H~ 6~7 (broad S7 2H~, 6025-6045 (m) ~ 700~70~5 ~m, 3H~ ppm~
d~ 2005 g ~50 mmoles) of' the product propar~d a~
described in point c3 above ar3 su~p~decl in 50 ml o~ c~ry othor~ and a ~olution sf 3~45 g (150 ~mol~s~ o~ m~tallic ~odium i~ 100 ml of dry atha-nol and a 901u~io~ 0~ 12~7 g (50 mmole~
0X i.odi~o in 150 ml of clry ~ther ara added simultarl~ollsly~
~rom two clroppîng Xun-aels7 to the vlgorously stirred ~uspansio~
~mdar cool~n~ with ice waterl ~herea~ter 5 g of ~odi.um hyc~o~
~9 ~6 ~ L2 -sulfite~ di~olved in 200 ml of a saturated aqu00us sodium chloride 501ution9 ara ~dded to ths stirr~d mixtureO '~he mix~
~ure is filled into a scparating funnel, and 60 ml of water are added to dissolve the separa~d inorganic saltsO ~ha organ~
ic pha~e is r~mov~d, dri~d over magn~ium sul~ate9 filtered~
and the fil~rate is ~vaporated~ ~he oily r~siduo 9 w0ighing 18.5 g7 is crystallized from 30 ml of 2~propanol~ 1OD9 g (54 %) of dieth-yl 3d cetyl~ (2~4 dimethoxybenzyl)~4-oxo-2,2~azeth;;
idino-dicarboxylate are ob~ained; mOpo 84~85C (2-propanol)~
Analysis:
calculated for C20E25N8 (4070 a 58~96 %, ~I: 6.19 %9 ~ 3~ L~ %3 ~ound: C: 58~99 %~ H- 6~04 %9 N: 3~57 %0 1~ NMR (C~C13): ~ = 1;12 (t9 3H) ? 1021 (~; 3H) 9 2;31 .
(S9 3H), 3.76 (59 6H)~ 3.8-3~4 (m, 4~I) 9 4153 (d9 lH) 9 4~63 (d~ lH) ~ 4069 (S7 lH) 9 6.3-604 (m, 2H) ~ 7~07 (d9 lH) ppm7 e~ 179 ml (206 g, 10452 moles) of boron trifluorida-diethyl 0therate are added dropwise to a vigorously stirred ~olution of 179 g ~OoL~4 mole) of di0thyl 3-acetyl-1~(2~ di-~0 me~hoxyb~nY,yl)~4-o~o-2~2-azethidine-dicarbox~Jlate and 107 ml (120 g7 10936 moles3 of othylene glycol in 500 ml of dry di~
oxans under cooling with ice waterO ~he reaction mixture i~
allowad to stand at room temFerature for one day~ during this period tho mixtura is occasionally stirredO Ther~after 415 g (1.452 molss) of Na~C03~ lGH20 are added slowly to the stirred mixture und~r cooling with ice water~ and tha mixture is stixred for 15 minut9sO ~h~rsafter 1 litre of ether a~d 1 litre of water are added7 and ths phasa~ are ~oparatsd from each otherO ~h~ aqu~ous phase is ~haken tw~ce with 500 ml of diethyl ~thor7 eachO ~he ethereal phase is dried ovar magnesium sul~ate 9 filtered9 and the filtratc is ev~poratedO 33~9 g (0058 mola) of sodium chloride9 170L~ ml (0~9~8 mole) of water and 220 ml of dimethyl sul~oxida are added to the residue9 and the mixture is stirred on an oil bath at 180C. The prog;ress of the reaction is monitored by thin layer chromatography ~adsorben~. Kieselgel G according to Stahl, developing solv~n~: a 6:4 mi~tur~ o~ benzene a~d ethyl acetat~)~ At the end of ~he reaction~ i.e. a~ter about 15 hours, the mixture is poured into 1100 ml o~ saturated aqueous sodium chloride soluti.onp and the resulting mixture is shal{en with 1000 ml and then twîce with 500 mL o~ diethyl ether? each. The ether~ solutions are combined~ d~colourized with charcoal, dried over magnesium sul~ats~ and the ~iltrate is evaporated to a ~inal volume o~ ccaO 200 ml. This co~centrat~
ed solution is cooled with ice water to obtain 59 g (35 %) o~
trans-ethyl 1-(2,~dimethoxyb~zyl)-3-(2-methyl~1~3~dio~olan~
2-yl)-4-oxo-2~azethidine carbo~ylata; m~p~: 95C~
~ A m-ixt~re of 005 g (1~2 mmoles~ o~ diethyl ~acetyl~
1~(2,4~dimothoxybHnz~yl)-4~oxo-2,2-azethidine-dicarho:x~ylato~
prepared as described in point d~ above~ 3 ml of dry totra~
hydro~an and 005~ g (3~6 mmoles~ o~ mercapto~thanol is boiled ~or 4 hours~ and then 10 ml o~ water and 10 ml of chloro~
form are add~d to the reaction mixtureD ~he organic phase is separatsd7 washed wi~h a 5~0 a~ueous sodium hydrocarbo~ate solution, dried over ma~nesium sul~ate9 ~il'G~red7 and the pxoduct is separated from the ~iltrate by preparative thin layer chromatography (adsorbsnt: ~ieselgel 60 PF25~669 devcloping solvent: a ~:2 mixture of toluene and acetone)c 0~30 g (53 %3 of diethyl 1-(2,4~dimethoxybenzyl~-3-¦2~methyl~
3(~ 1~3-oxathiolan~2~-~l)JI~oxo~2~2~azethidine~dicarboxylate are obtained~
lH N~ ~CD~13)o ~ ~ 0~8-1~55 ~m, 6H~ 72 ~ 1~77 ~da 3H) 9 2~9-3~4 (m, 2H~ 3~75 (s, 6H), 4~0~5.0 (m, 9H)g 6~4 (m~
2E) ~ 7O1 ~d~ lH) ppmO
~ 2 tr = o-2-a~,L~h~2==~8a~ 118_~9 11 g (000245 mola) o~ diothyl ~(2 methyl lg~di~
o~ola~-2~yl)~1~(L~metho~yphenyl3-~oxo~2~2-aza~hidi~e dicarb-oxyla~e are dissolved in 2Q ml of.` dimethyl sul~oxide 9 1~72 g (000295 mol~) o~ sodium chloride and 009 ml (00049 mola) o~
water are addod~ and the mixture is s~irred at 175C u~til a complet~ reaction is obtained~ 'rhe progress o~ tha reactio~ is monitored b-~ thin layer chromatograp~y ladsorbent: Eieselgel G according to Stahl.7 developing solvent: a 6:4 mixture of benzene and ethyl acetate)~
'~he mixture i5 cooled~ poured inko 150 ml o~ a satur~
a~ed aqueous sodium chloride solution~ a~d extracted thr-lc~
with 50 ml o~ diothyl ether, each~ 'rhe organic phas~s are com~
bined~ dried over mag~esium sulf.'ate; ~iltered, and the ~iltrate i~ evaporat~dO ~'he resulting oily .residue3 weighi~g 6 g~ is dis,solved in 25 ml o~ 96% ethanol9 and a solution of 0.72 g (00018 mola) o~ sodium hydroxide in 10 ~1 o~ w~ter is added to the alcoholic mi~ture under cooling wi~h icc water~ The mixture is stirred for 075 hour~ ~h~n diluted with 50 ml o~
water and washed twice with 25 ml o~ dichloromatha~e, ~ach~
~he aquaous pha~e is acidified to pH = 1 with concentratqd aqueous hydrochloric acid~ and then extracted thrice with ~5 ml of dichloromethane~ each. The or~anic phases are combi.ned., ~ried over ~agnesium sul~ate~ ~ilt~red3 and th~ .~ilk.ra~e is ~ 15 evaporated~ ~he oily residu~ is crystallized wi~h benze~
4 g (54 %3 of' ~he ai~ed compound are obtained. Mop~
132 ~b~nzene).
Analysis:
calculated ~or C15H17N6, (307r3 ) C 58063 %7 H: 5~57 ~V7 N: 4~56 %1 îou~d: S~ 586,40 %~ H: 5 J80 %~ N, 4s~66 ~Oo IR tKBx). 34QO-27007 1750 ~broad3 cm l.
lH NDI[R (CDC13~: S= 1.5 ~s~ 3H~ 9 3;7 ~d~ J = ~45 :Hz~ 9 3076 (~3~ 3H~ ~ 4.0 (m, L~:H) ~ 4,,38 (d~ lH9 J = 205 Hæ) 3 6~82 (2EI~
~ 7026 (2.H9 AA~BB', J = 905 Hz)9 902 ~S9 lH) ppmO
~he startin~ substance is prepared as ~`ollow~:
a) ~ mixburo of` 2446 g (002 mole) of ~ me~ho~ya~iline and 23~9 g 117 ml~ Ool mole) o~ die~hy]. bromomalonate i~
stirred ab room ~emperature for 2 daysO ~he resulbing mass is triburated wibh 100 ml of diethyl ~ther, the separa~sd 4-~m0th oxy-anisidine hydrobromide is ~iltsre.d off and washed wibh a ~mall amoun~ o~ diethyl e~h~rO The mobh0r liquor i~ avapora~
ed and the residue is crystall-lzed ~rom dilute acetic acidO
1302 g (4? %~ ~ die~hyl (4~me~hoxyanilino)~malorlab0 a.re ob~
bain0d~ m~pl.: 6L~ 65G ( sthanol) 0 ~na ly~i s -calculated for C14Hl9M05 (281031):
C. 59977 %9 Hs 6081 %; ~0 4~99 %~
~ound: C: 59099 %~ H. 6097 ~, ~. 5025 %0 IR (EBr): 3300~ 1775 7 1725 cm 1.
~H ~ ~CDCl3)~ S - 1.23 ~tg 6H~ J - 7.2 Hz) ~ 3067 (s, 3H)~ 402 ~q~ 4Ht J ~ 7D2 Hz~ ~ 4062 ~s~ lH) 9 4~1~4~5 (b~oad s, lH) 7 6055 (2H) ~ 6~73 (2H~ AA9B~ J ~ 9 Hz3 ppm~
b3 ~ mix~ure o~ 1102 g (0~04 molo3 o~ diothyl ~4~meth-o~anilino-malonato~ prcpared as describod in point ~) abovo.~
-- 16 ~
15 ml of glacial acet-ic acid a~d 4 ~; (307 ml~ 00048 mole3 o:~
diket~rle is boileà for 0~,5 hour. ~he 501iltiOrL iS evaporatied in ~acuo ~ lihe oily re sidue is tritura ted witih di~ tihyl e tihsr~
an~. ~he solid is i:'lltiered off~ 1005 g (72 %) o:~ diethyl l~
132 ~b~nzene).
Analysis:
calculated ~or C15H17N6, (307r3 ) C 58063 %7 H: 5~57 ~V7 N: 4~56 %1 îou~d: S~ 586,40 %~ H: 5 J80 %~ N, 4s~66 ~Oo IR tKBx). 34QO-27007 1750 ~broad3 cm l.
lH NDI[R (CDC13~: S= 1.5 ~s~ 3H~ 9 3;7 ~d~ J = ~45 :Hz~ 9 3076 (~3~ 3H~ ~ 4.0 (m, L~:H) ~ 4,,38 (d~ lH9 J = 205 Hæ) 3 6~82 (2EI~
~ 7026 (2.H9 AA~BB', J = 905 Hz)9 902 ~S9 lH) ppmO
~he startin~ substance is prepared as ~`ollow~:
a) ~ mixburo of` 2446 g (002 mole) of ~ me~ho~ya~iline and 23~9 g 117 ml~ Ool mole) o~ die~hy]. bromomalonate i~
stirred ab room ~emperature for 2 daysO ~he resulbing mass is triburated wibh 100 ml of diethyl ~ther, the separa~sd 4-~m0th oxy-anisidine hydrobromide is ~iltsre.d off and washed wibh a ~mall amoun~ o~ diethyl e~h~rO The mobh0r liquor i~ avapora~
ed and the residue is crystall-lzed ~rom dilute acetic acidO
1302 g (4? %~ ~ die~hyl (4~me~hoxyanilino)~malorlab0 a.re ob~
bain0d~ m~pl.: 6L~ 65G ( sthanol) 0 ~na ly~i s -calculated for C14Hl9M05 (281031):
C. 59977 %9 Hs 6081 %; ~0 4~99 %~
~ound: C: 59099 %~ H. 6097 ~, ~. 5025 %0 IR (EBr): 3300~ 1775 7 1725 cm 1.
~H ~ ~CDCl3)~ S - 1.23 ~tg 6H~ J - 7.2 Hz) ~ 3067 (s, 3H)~ 402 ~q~ 4Ht J ~ 7D2 Hz~ ~ 4062 ~s~ lH) 9 4~1~4~5 (b~oad s, lH) 7 6055 (2H) ~ 6~73 (2H~ AA9B~ J ~ 9 Hz3 ppm~
b3 ~ mix~ure o~ 1102 g (0~04 molo3 o~ diothyl ~4~meth-o~anilino-malonato~ prcpared as describod in point ~) abovo.~
-- 16 ~
15 ml of glacial acet-ic acid a~d 4 ~; (307 ml~ 00048 mole3 o:~
diket~rle is boileà for 0~,5 hour. ~he 501iltiOrL iS evaporatied in ~acuo ~ lihe oily re sidue is tritura ted witih di~ tihyl e tihsr~
an~. ~he solid is i:'lltiered off~ 1005 g (72 %) o:~ diethyl l~
5 me thoxyph~nyl) ~3-hyclroxy-3-~me thylN5 ~oxo-2 ~ 2-pyrrolidin~ ~di~
c~rbo~late and/or its tautomer are obtiainad9 mOp. 136~137~C
~thyl acetiatie)0 Ana lysis 0 calculati8d for C1~3H23N7 (365038) lû C: 59~.17 %, H~ 6.39 %, N: 3O8~ %;
:~ound: C: 58c,9& ~/09 E~: 6090 %, No 400LI~ %~
IR (K:3r): 3600~3000, 17609 17409 1685 cm la lH NMR ( CD~ 13 ) 0 ~ 0 7 ( t 7 3H ~ J = 7 ~ 2 Hz ~ r9 1 t3 2 8 (t, 3H~ J = 7~2 Hz) ~ 1~,58 ~s, 3H) ~ 2076 ~s, 2H) ~ 3~64 (S9 l~
3,,76 ~sl 3H) ~ 4.1 (q, 2H, J = 7.2 Hz) 5, 4027 (q~ 2H9 J = 7~2 H~) 9 607 (2H) ~ 7~,0 (2H, AA'BB' ? J = 9 Hz~ ppmO
c) 9ol g (O.025 mo1~) o:f di a thyl 1~ methoæyph~n;y~
3-hydroxy~-me thyl-5- oxo~2, 2~-p,yrrol idine -di c arboxyla tie ~ pr~
parHd as describ~d in pointi b) above, a.re susponded in 50 of d:ry distihyl ethex7 and a solutiorl of 1072 g of m~tiallic sodium in 30 r~ of dry stihanol and a solution o~ 6~35 g (0~025 mole) of iodine in 50 ml o~ dr-y diethyl sther are simul~
taneously dropped in~o Ghe suspension under vigorous stirri~g and cooling wi~h iceO ~hereafter the mixtur~ is poured into 100 ml of a saturated aqueous sodium chloridq solutiona and 2 g of sodium h~Jdrosulfite and 2 ml o~ glac-lal acetic acid are add~dO Th0 ether~ e is separated~ and the aqueous phase is extract3d thrice with 50 ml of die~hyl eth~r, eaGh~
'l'he ethe~ phases are combined~ dried over magnosium sulfat~
~0 ~ilt~red3 arld ~he liltrate is evapo~ated~ The oily resi.dua is t;ritllrated with 2~propanol ~o obtain 602 ~; (68 %~ of crystalline dietl~l 3~ac~tyl~ 4--mathox~ph~nyl3~oxo~2~2 a~e~hidiIle~dicarboxylat~9 mOpO 70~71C ~e~hanol)~, Ana lysis:
calculated for C18H21:~07 (36303~):
C 59050 %, H: 5 ,82 %7 N: 3085 %~
:Eou~d: C~ 59~,04 %3 E: 5084 %7 N: 4008 %0 IR ( I~3r): 1760 , 1735 9 1720 cm 1 o ~I .NN~ (CDC13?: cr = 1020 ( t, 3H9 J = 702 Hz) ~ 1022 (t, 3~I, J -- 7~,2 EIz~ g 2033 (s, 3:H), 307 (s, 3II) 3 4017 (cl~ 2E~
J ^- 792 Hz)~ 4019 (q9 2H, J = 702 Hz)~ L~7 (s~ lH)" 607 (2H~
7.31 (2H, AA9~ 133 ~ J = 9 Xz) ppm~, d) 6 ~, (0~,0165 mole) o~ diethyl 3-acetyl~ ~m~ox;y phenyl)-~oxo-2~2-azathidine-dicarboxyl~3ts; praparecl as de~
15 scribed in point c) a bove ~ aro dissolved în 20 ml o~ clry di~
oxane and ~1 g (3075 ml) 0.066 mole) of ethylene gl~colO 701 g (6~,3 ml) 0.05 mole) of boron trifluoride~diath;yl athera~o complox aro added dropwiso ko khe stirr~d solukion undor ic~
sooling? and khe reaction mixkure is s~irrod for additional 20 2 ho~s at room temperature~ ~he sollltion is xendersd alkaline with saturat~d aqueous sodium hydrocarbo~at~ solution; ~hers-=
aft~r 100 ml of waker ara added, and th~ mix~ur~ i~ e~tract~d t~rice with 50 ml of di~kh~yl e~her9 aachO Tha organic pha~e~
ara combi~d~ dried over magzlHsium ~ulfatq~ fil~ered~ and ~he 25 ~ill;rate -ls ~vaporated~ The oily residue is tritura~d with diethyl ether to obtai~ 5 g (89 %) o~ cr~s~alline di~th~l 3-(2~methyl~1~3-dio~olan-2 yl)-1 ~4-mc tho~syphe~;yl?w~oxo~2~2 a~sethidin~ dicarboxyl.ate 9 mOpo~ 82-83G (ethanol) O
IR (KJ3r): 1740 cm 1 (~road) 3 H ~ R (C~Dal3) ~ ~ = 1.,17 ~ ~3 3H~ J = 7,2 IIz) 9 1026 ~ 8986~
(~9 3~ J = 7~2 Hz~s 105 (s~ 3E) ,5 307 (s, ~H), 309 ~mD 4~ D
4.2 (m, 5H)~ 6~67 (2H) ~ 7034 (2H7 ~A7BB9, J = 9 ~Iz~ ppmO
Analysis.
calculatod fo.r C20H25N08 (407043):
C: 58096 %~ H: 6~18 %, ~: 34~ %~
fou~d: Co 58070 %, E: 5068 %, ~- 3~63 %~
E~a~3~_~
~ ~h ~ .
A mixture oP 28.5 g ~00075 mole) oP dis~hyl l~phen~l~
3-(2 me~hyl~l~3~dioxolan-2-yl3-4~oxo-2,2-azethidina dicarb~
oxyl~te, 44 ml of dimethyl sulfo~id~9 506 g (0.1 mol0) of sndium chloride and 3005 ml (0017 mole) oP water is ~ti~red a~ 175C until th~ r0action proceeds. The progr~s of tha raac-~io~ is monitor0d by khi~ layer chromatography G~dsorban~:
Kieselgel G accordi~g to Stahl~ developing solve~: a 60~ mi~-kurs of benæene and ethyl acstate)0 The solukion is pour~d in ~o 200 ml of a saturatfld aqueous sodium chlorid~ solutio-Q and e~tracked khrLce wikh 150 ml oP dieth~l ether~ each~ The organic phas~ ara cornbin~d, dri~d over ma~ne~ium ~ul~a~3~
~ilbered, and ~he filtrat~ is ~vapora~dO I'he r~ulti~g 16.4 g of oily r0sidue are dissolvad in 100 ml o~ ethanoll and a ~olution of 2015 g ~00054 mols) of sodium hydro~ido in 30 ml o~ water is addod to it under stirri~g over a~ ice water bath.
A~t~r 005 hour o~ stirring the mixture is diluted with 150 ml o~ water and e~raGtad thrica wi~h 20 ml o~ di~thyl eth~lr~
~achO ~he aqueous phas~ is acidified ~o pH = 1 with concen~rat;
3d aqueous hydrochloric acid and extracted thon thrica with 50 ml of dichloroma~hane~ eachO ~he organic pha~es are com-bined, ~;ied over magn~ium sul.~e, fiL~sredl and the ~ ra~0 8~'~
_ ~.9 is ~vaporat~3dO The oily residue is cr~ystall~ d ~rom berlzen~
to obtair:l 12 g (56 %~ of ~ha aimod compound~ m.p~0 165C
(~enz~ne ) 0 Ana lysis:
c lculated ~or C14H15~05 (277027)-C~ 60064 %~ H: 5045 %~ ~ 5~,05 %9 found~ C: 60064 %9 H: 5072 (~/o9 N: 4099 %0 IR (KBr): 3500-2700~ 17707 1730 cm~li, lH NMR (CDC13) 0 ~ 5 (s~ 3H? ~ 3~69 (~ lHs J - 3 Hz) g4"0 (m, 4H) ~ 4042 (d, lH, J = 3 Hz) ~, 7.3 (m~ 5H) 5 7055 ~sS, lH) ppmO
Tho starting sub~tance is proparQd a~ ~ollow~-a ) A mix ture oP 38 g ( O o 152 mole 3 of di~ th;yl anilino~.
malollate ~0 :Blank. Ber~ ~1, 1815 (1898~7; 38 ml o:e glacial ac~tic acid and 15~ g (1309 ml~ 00182 mol~) o~ diketon~ is boiled for 005 ho~r~, Glacial acetic acid i~ evaporated in vacuo ove.r a water bath9 and the oily ra~idue i9 cry~tallized by ~riturating it wi~h ethorO 36"5 g (72 %) of dL~thy~ phanyl~
3-h;ydroxy-~3~mo thyl-5--oxo~ 2, 2-pyrrolidine~dicarbox-,yla ~e~
a~d/or ik~ ~automor are obtai~(3da mOpo 98~99C (ath~l ac~a~e and pe troleum e the~
Ana ly~is:
c~lculated for C17H2LN06 (33535) C 60~88 ~o9 H~ 6.31 %9 N: 4918 %9 found: a: 60083 %) H: 6015 %, ~: 4~43 %a IR (KBr): 3350;, 29503, 1760~ 1750 ~d) ~ 1700 cm lo H N~R (CDC13) ~ c~ = 1002 (t7 3H) a 103 (t9 3H~ g 1-~Is~ 3H) 7 2~8 (sa ~H) ? 31~6 (broad S7 lH) ~ ~ 4~45 5m~ 4H) ~ 7~2 (~3a 5H) ppmO
b) 50 g (0~ 9 mola) of di~th-~l (N~phenyl~3~hydro~
~ ~9 3~methyl-5~oxo-2~2-pyrrolidins-dicarboxyla~ pr~pa.r~d a~
described in point a) abov~, are added to a solut~on o~ 10~2 tO~I~7 mole~ o~ m~allic ~odium in 250 ml of dry othanol~
thflr~after a solutio~ o~ 37~9 g (00149 mols) o~ iodine in 5 200 ml of dry e ther is addod under vigorous s tir.ring . When the r~action is ov~r~ 8D5 ml ~809 g9 0011~9 mol~j o~ glaclal acet~
ic acid~ 200 ml of water and 100 ml o~ athsr ara added to the mixture~ th3 or~anic phase is saparatod, and tha aqu~ou~ phsse i3 o~{tractod with 100 ml of stherO ~he et~r~al phas~ ara com~
bined, driad over magnesium suLfa~e~ filter~d, a~d the ~lltratc is svflporatedO Th~ oily rssidue is cryskallized ~rom 50 ml of 2~propanol to obtai~ 31 ~ (62 %) o~ di~thyl (3-ac~tyl~
l-phar~ L~oxo~2,2 a~,athidin~dicarboxylata) 9 m;p;, 55~56C
t2~propa~ol)c Analysis:
calculated ~ox Cl ~19~6a C 61-25 ~; H 5075 %~ ~o 4,20 %~
found: C: 61.38 %9 Ho 50~9 %t ~ ~Z~ %~
I~ (KBr): 1770~ 17~0~ 1720 cm 1.
lH M~ (CDC1~3. d _ 1.12 (t9 6H~ 2v3 (sg ~H)~ ~25 (q, L~H), 1~o75 (s, lE); 7~0-706 (my 5H) ppm~
c) 28~5 g (OgO85 mole~ of diathyl 3~ace~J~ ;ph~n L~oxo-2,2~azethidine-dicarboxyla~eg prepaIed as describsd -i~
stap b) above~ are dissolvad in a mixture o~ 90 ml of dry di~
oxane and Zl g (1808 ml, 0~34 mol~) o~ dry ethyla~e glycol~
.
and ~6.5 g (~105 ml7 0.255 mole~ of boron trifluorid~-di~h~l etharate complqx are add~d dropwis~ ko tha solution u~der vigorous stirring and cooling with ic~ wa~r. ~h~ 501utio~ iS
~tirrod for additional 2 hours at room tampsrak~r~ a~d then neukralized with saturated aqueous sodium carbo~ate solutionO
~0 rrhr.~ neu~ral ~olution is dilut~d with 100 ml of wak~r and th~n ~ 8~3 8~
extract~d thrice with 50 ml of dieth~l ether, ~achO '~hc organic phases a.re combin~d9 dri~d over magn~sium sulfa~
filt~red, and th~ L`iltrate is evaporated in vacuo~ ~he oily r~sidue is cry~allized by triturati~g it with etherO 28~5 g (90 %~ of dlethyl l~phenyl-3-(2-m~ thyl-l,3-dioxolan-2~yl)~
4-oxo~2~2~a~thidin~dicarboxylat~ are obtain~d; mOpO0 59~61C
ben;zcne ~ O
~nalysis:
calculated ~or ClgH2~.N07: C: 60~47 ~0, H- 6.14 %, No 3071 ~9 found: C: 60074 ~0, H: 6021 %~ N: 3079 %O
IR ( ~Br): 1770 ~ 1740 cm lo H NMR (CDC13)~ 18 (t? 3H~ J = 7~2 ~Iz~ 1024 (t3 3H9 J = 7.2 Hz)~ 1.51 (s, 3H)~ 3~92 (m, 4H), 403 ~m~ 5H~
702 (~9 5H) pp~,
c~rbo~late and/or its tautomer are obtiainad9 mOp. 136~137~C
~thyl acetiatie)0 Ana lysis 0 calculati8d for C1~3H23N7 (365038) lû C: 59~.17 %, H~ 6.39 %, N: 3O8~ %;
:~ound: C: 58c,9& ~/09 E~: 6090 %, No 400LI~ %~
IR (K:3r): 3600~3000, 17609 17409 1685 cm la lH NMR ( CD~ 13 ) 0 ~ 0 7 ( t 7 3H ~ J = 7 ~ 2 Hz ~ r9 1 t3 2 8 (t, 3H~ J = 7~2 Hz) ~ 1~,58 ~s, 3H) ~ 2076 ~s, 2H) ~ 3~64 (S9 l~
3,,76 ~sl 3H) ~ 4.1 (q, 2H, J = 7.2 Hz) 5, 4027 (q~ 2H9 J = 7~2 H~) 9 607 (2H) ~ 7~,0 (2H, AA'BB' ? J = 9 Hz~ ppmO
c) 9ol g (O.025 mo1~) o:f di a thyl 1~ methoæyph~n;y~
3-hydroxy~-me thyl-5- oxo~2, 2~-p,yrrol idine -di c arboxyla tie ~ pr~
parHd as describ~d in pointi b) above, a.re susponded in 50 of d:ry distihyl ethex7 and a solutiorl of 1072 g of m~tiallic sodium in 30 r~ of dry stihanol and a solution o~ 6~35 g (0~025 mole) of iodine in 50 ml o~ dr-y diethyl sther are simul~
taneously dropped in~o Ghe suspension under vigorous stirri~g and cooling wi~h iceO ~hereafter the mixtur~ is poured into 100 ml of a saturated aqueous sodium chloridq solutiona and 2 g of sodium h~Jdrosulfite and 2 ml o~ glac-lal acetic acid are add~dO Th0 ether~ e is separated~ and the aqueous phase is extract3d thrice with 50 ml of die~hyl eth~r, eaGh~
'l'he ethe~ phases are combined~ dried over magnosium sulfat~
~0 ~ilt~red3 arld ~he liltrate is evapo~ated~ The oily resi.dua is t;ritllrated with 2~propanol ~o obtain 602 ~; (68 %~ of crystalline dietl~l 3~ac~tyl~ 4--mathox~ph~nyl3~oxo~2~2 a~e~hidiIle~dicarboxylat~9 mOpO 70~71C ~e~hanol)~, Ana lysis:
calculated for C18H21:~07 (36303~):
C 59050 %, H: 5 ,82 %7 N: 3085 %~
:Eou~d: C~ 59~,04 %3 E: 5084 %7 N: 4008 %0 IR ( I~3r): 1760 , 1735 9 1720 cm 1 o ~I .NN~ (CDC13?: cr = 1020 ( t, 3H9 J = 702 Hz) ~ 1022 (t, 3~I, J -- 7~,2 EIz~ g 2033 (s, 3:H), 307 (s, 3II) 3 4017 (cl~ 2E~
J ^- 792 Hz)~ 4019 (q9 2H, J = 702 Hz)~ L~7 (s~ lH)" 607 (2H~
7.31 (2H, AA9~ 133 ~ J = 9 Xz) ppm~, d) 6 ~, (0~,0165 mole) o~ diethyl 3-acetyl~ ~m~ox;y phenyl)-~oxo-2~2-azathidine-dicarboxyl~3ts; praparecl as de~
15 scribed in point c) a bove ~ aro dissolved în 20 ml o~ clry di~
oxane and ~1 g (3075 ml) 0.066 mole) of ethylene gl~colO 701 g (6~,3 ml) 0.05 mole) of boron trifluoride~diath;yl athera~o complox aro added dropwiso ko khe stirr~d solukion undor ic~
sooling? and khe reaction mixkure is s~irrod for additional 20 2 ho~s at room temperature~ ~he sollltion is xendersd alkaline with saturat~d aqueous sodium hydrocarbo~at~ solution; ~hers-=
aft~r 100 ml of waker ara added, and th~ mix~ur~ i~ e~tract~d t~rice with 50 ml of di~kh~yl e~her9 aachO Tha organic pha~e~
ara combi~d~ dried over magzlHsium ~ulfatq~ fil~ered~ and ~he 25 ~ill;rate -ls ~vaporated~ The oily residue is tritura~d with diethyl ether to obtai~ 5 g (89 %) o~ cr~s~alline di~th~l 3-(2~methyl~1~3-dio~olan-2 yl)-1 ~4-mc tho~syphe~;yl?w~oxo~2~2 a~sethidin~ dicarboxyl.ate 9 mOpo~ 82-83G (ethanol) O
IR (KJ3r): 1740 cm 1 (~road) 3 H ~ R (C~Dal3) ~ ~ = 1.,17 ~ ~3 3H~ J = 7,2 IIz) 9 1026 ~ 8986~
(~9 3~ J = 7~2 Hz~s 105 (s~ 3E) ,5 307 (s, ~H), 309 ~mD 4~ D
4.2 (m, 5H)~ 6~67 (2H) ~ 7034 (2H7 ~A7BB9, J = 9 ~Iz~ ppmO
Analysis.
calculatod fo.r C20H25N08 (407043):
C: 58096 %~ H: 6~18 %, ~: 34~ %~
fou~d: Co 58070 %, E: 5068 %, ~- 3~63 %~
E~a~3~_~
~ ~h ~ .
A mixture oP 28.5 g ~00075 mole) oP dis~hyl l~phen~l~
3-(2 me~hyl~l~3~dioxolan-2-yl3-4~oxo-2,2-azethidina dicarb~
oxyl~te, 44 ml of dimethyl sulfo~id~9 506 g (0.1 mol0) of sndium chloride and 3005 ml (0017 mole) oP water is ~ti~red a~ 175C until th~ r0action proceeds. The progr~s of tha raac-~io~ is monitor0d by khi~ layer chromatography G~dsorban~:
Kieselgel G accordi~g to Stahl~ developing solve~: a 60~ mi~-kurs of benæene and ethyl acstate)0 The solukion is pour~d in ~o 200 ml of a saturatfld aqueous sodium chlorid~ solutio-Q and e~tracked khrLce wikh 150 ml oP dieth~l ether~ each~ The organic phas~ ara cornbin~d, dri~d over ma~ne~ium ~ul~a~3~
~ilbered, and ~he filtrat~ is ~vapora~dO I'he r~ulti~g 16.4 g of oily r0sidue are dissolvad in 100 ml o~ ethanoll and a ~olution of 2015 g ~00054 mols) of sodium hydro~ido in 30 ml o~ water is addod to it under stirri~g over a~ ice water bath.
A~t~r 005 hour o~ stirring the mixture is diluted with 150 ml o~ water and e~raGtad thrica wi~h 20 ml o~ di~thyl eth~lr~
~achO ~he aqueous phas~ is acidified ~o pH = 1 with concen~rat;
3d aqueous hydrochloric acid and extracted thon thrica with 50 ml of dichloroma~hane~ eachO ~he organic pha~es are com-bined, ~;ied over magn~ium sul.~e, fiL~sredl and the ~ ra~0 8~'~
_ ~.9 is ~vaporat~3dO The oily residue is cr~ystall~ d ~rom berlzen~
to obtair:l 12 g (56 %~ of ~ha aimod compound~ m.p~0 165C
(~enz~ne ) 0 Ana lysis:
c lculated ~or C14H15~05 (277027)-C~ 60064 %~ H: 5045 %~ ~ 5~,05 %9 found~ C: 60064 %9 H: 5072 (~/o9 N: 4099 %0 IR (KBr): 3500-2700~ 17707 1730 cm~li, lH NMR (CDC13) 0 ~ 5 (s~ 3H? ~ 3~69 (~ lHs J - 3 Hz) g4"0 (m, 4H) ~ 4042 (d, lH, J = 3 Hz) ~, 7.3 (m~ 5H) 5 7055 ~sS, lH) ppmO
Tho starting sub~tance is proparQd a~ ~ollow~-a ) A mix ture oP 38 g ( O o 152 mole 3 of di~ th;yl anilino~.
malollate ~0 :Blank. Ber~ ~1, 1815 (1898~7; 38 ml o:e glacial ac~tic acid and 15~ g (1309 ml~ 00182 mol~) o~ diketon~ is boiled for 005 ho~r~, Glacial acetic acid i~ evaporated in vacuo ove.r a water bath9 and the oily ra~idue i9 cry~tallized by ~riturating it wi~h ethorO 36"5 g (72 %) of dL~thy~ phanyl~
3-h;ydroxy-~3~mo thyl-5--oxo~ 2, 2-pyrrolidine~dicarbox-,yla ~e~
a~d/or ik~ ~automor are obtai~(3da mOpo 98~99C (ath~l ac~a~e and pe troleum e the~
Ana ly~is:
c~lculated for C17H2LN06 (33535) C 60~88 ~o9 H~ 6.31 %9 N: 4918 %9 found: a: 60083 %) H: 6015 %, ~: 4~43 %a IR (KBr): 3350;, 29503, 1760~ 1750 ~d) ~ 1700 cm lo H N~R (CDC13) ~ c~ = 1002 (t7 3H) a 103 (t9 3H~ g 1-~Is~ 3H) 7 2~8 (sa ~H) ? 31~6 (broad S7 lH) ~ ~ 4~45 5m~ 4H) ~ 7~2 (~3a 5H) ppmO
b) 50 g (0~ 9 mola) of di~th-~l (N~phenyl~3~hydro~
~ ~9 3~methyl-5~oxo-2~2-pyrrolidins-dicarboxyla~ pr~pa.r~d a~
described in point a) abov~, are added to a solut~on o~ 10~2 tO~I~7 mole~ o~ m~allic ~odium in 250 ml of dry othanol~
thflr~after a solutio~ o~ 37~9 g (00149 mols) o~ iodine in 5 200 ml of dry e ther is addod under vigorous s tir.ring . When the r~action is ov~r~ 8D5 ml ~809 g9 0011~9 mol~j o~ glaclal acet~
ic acid~ 200 ml of water and 100 ml o~ athsr ara added to the mixture~ th3 or~anic phase is saparatod, and tha aqu~ou~ phsse i3 o~{tractod with 100 ml of stherO ~he et~r~al phas~ ara com~
bined, driad over magnesium suLfa~e~ filter~d, a~d the ~lltratc is svflporatedO Th~ oily rssidue is cryskallized ~rom 50 ml of 2~propanol to obtai~ 31 ~ (62 %) o~ di~thyl (3-ac~tyl~
l-phar~ L~oxo~2,2 a~,athidin~dicarboxylata) 9 m;p;, 55~56C
t2~propa~ol)c Analysis:
calculated ~ox Cl ~19~6a C 61-25 ~; H 5075 %~ ~o 4,20 %~
found: C: 61.38 %9 Ho 50~9 %t ~ ~Z~ %~
I~ (KBr): 1770~ 17~0~ 1720 cm 1.
lH M~ (CDC1~3. d _ 1.12 (t9 6H~ 2v3 (sg ~H)~ ~25 (q, L~H), 1~o75 (s, lE); 7~0-706 (my 5H) ppm~
c) 28~5 g (OgO85 mole~ of diathyl 3~ace~J~ ;ph~n L~oxo-2,2~azethidine-dicarboxyla~eg prepaIed as describsd -i~
stap b) above~ are dissolvad in a mixture o~ 90 ml of dry di~
oxane and Zl g (1808 ml, 0~34 mol~) o~ dry ethyla~e glycol~
.
and ~6.5 g (~105 ml7 0.255 mole~ of boron trifluorid~-di~h~l etharate complqx are add~d dropwis~ ko tha solution u~der vigorous stirring and cooling with ic~ wa~r. ~h~ 501utio~ iS
~tirrod for additional 2 hours at room tampsrak~r~ a~d then neukralized with saturated aqueous sodium carbo~ate solutionO
~0 rrhr.~ neu~ral ~olution is dilut~d with 100 ml of wak~r and th~n ~ 8~3 8~
extract~d thrice with 50 ml of dieth~l ether, ~achO '~hc organic phases a.re combin~d9 dri~d over magn~sium sulfa~
filt~red, and th~ L`iltrate is evaporated in vacuo~ ~he oily r~sidue is cry~allized by triturati~g it with etherO 28~5 g (90 %~ of dlethyl l~phenyl-3-(2-m~ thyl-l,3-dioxolan-2~yl)~
4-oxo~2~2~a~thidin~dicarboxylat~ are obtain~d; mOpO0 59~61C
ben;zcne ~ O
~nalysis:
calculated ~or ClgH2~.N07: C: 60~47 ~0, H- 6.14 %, No 3071 ~9 found: C: 60074 ~0, H: 6021 %~ N: 3079 %O
IR ( ~Br): 1770 ~ 1740 cm lo H NMR (CDC13)~ 18 (t? 3H~ J = 7~2 ~Iz~ 1024 (t3 3H9 J = 7.2 Hz)~ 1.51 (s, 3H)~ 3~92 (m, 4H), 403 ~m~ 5H~
702 (~9 5H) pp~,
Claims (12)
1. A process for the preparation of a new hetero-cyclic carboxylic acid of the general formula (I), (I) wherein Y1 and Y2 form together a removable carbonyl protecting group, and R is a removable amido protecting group, characterized in that a compound of the general formula (IV), (IV) wherein Z is a C1-5 alkyl group and R is as defined above, is reacted with a compound capable for the temporary protection of the carbonyl group, in the presence of a compound which facilitates the reaction, the resulting compound of the general formula (III), (III) wherein Z, R, y1 and y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), (II) wherein Z, R, y1 and y2 are as defined above and which is a mixture of cis and trans isomers, is a) hydrolysed selectively, or b) separated into its components, and the trans isomer of the general formula (IIa) (IIa) is hydrolysed; or a compound of the general formula (III), wherein Z, R, y1 and y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), wherein Z, R, y1 and Y are as defined above and which is a mixture of cis and trans isomers, is a) hydrolysed selectively, or b) separated into its components, and the trans isomer of the general formula (IIa) is hydrolysed, or a compound of the general formula (II), wherein Z, R, y1 and y2 are as defined above and which is a mixture of cis and trans isomers, is a) hydrolysed selectively, or b) separated into its components and the trans isomer of the general formula (IIa) is hydrolysed, whereafter the trans compound of the general formula (I) is separated from the reaction mixture.
2. A process for the preparation of a new hetero-cyclic carboxylic acid of the general formula (I), (I) wherein Y and Y form together a ketal group or a thioanalogue thereof, and R is a benzyl group bearing one or more C1-4 alkoxy substituents or a phenyl group bearing optionally one or more C1-4 alkoxy substituents, characterized in that a compound of the general formula (IV), (IV) wherein Z is a C1-5 alkyl group and R is as defined above, is reacted with a ketal-forming agent or a thioanalogue thereof, in the presence of a compound which facilitates the reaction, the resulting compound of the general formula (III), ( III ) wherein Z, R, y1 and y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), ( I I ) wherein Z, R, y1 and y2 are as defined above and which is a mixture of cis and trans i.somers, is a) hydrolysed selectively, or b) separated into its components, and the trans isomer of the general formula (IIa) (IIa) is hydrolysed; or a compound of the general formula (III), wherein Z, R, y1 and Y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), wherein Z, R, Y and Y are as defined above and which is a mixture of cis and trans isomers, is a) hydrolysed selectively, or b) separated into its components, and the trans isomer of the general formula (IIa) is hydrolysed, or a compound of the general formula (II), wherein Z, R, Y and Y are as defined above and which is a mixture of cis and trans isomers, is a) hydrolysed selectively, or b) separated into its components and the trans isomer of the general formula (IIa) is hydrolysed, whereafter the trans compound of the general formula (I) is separated from the reaction mixture.
3. A process as claimed in claim 1 or claim 2, characterized in that hydrolysis is performed in the presence of a molar equivalent of an alkali, calculated for the compound of the general formula (II) or (IIa), or the alkali is applied in a reasonable excess.
4. A process as claimed in claim 1 or claim 2, characterized in that the trans isomer of the general formula (IIa) is separated from the cis isomer by dissolving it in an ether type solvent.
5. A process as claimed in claim 1 for the preparation of trans-1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, characterized in that ethyl 1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate or the trans isomer thereof is hydrolysed.
6. A process as claimed in claim 1 for the preparation of trans-1-(4-methoxyphenyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, characterized in that ethyl 1-(4-methoxyphenyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate is hydrolysed.
7. A process as claimed in claim 1 for the preparation of trans-1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, characterised in that ethyl 1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate is hydrolysedO
8. A compound of the general formula 1 I ), ( I ) wherein y1 and y2 form together a removable carbonyl protecting group, and R is a removable amido protecting group, whenever prepared by the process of claim 1 or its obvious chemical equivalents.
9. A compound of the general formula (I)), ( I ) whereln y1 and y2 form together a ketal group or a thio-analogue thereof, and R is a benzyl group bearing one or more C1-4 alkoxy substituents or a phenyl group bearing optionally one or more C1-4 alkoxy substituents, whenever prepared by the process of claim 2 or its obvious chemical equivalents.
10. Trans-1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, whenever prepared by the process of claim 5 or its obvious chemical equivalents.
11. Trans-1-(4-methoxyphenyl)-3-(2-methyl-1,3-di-oxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, whenever prepared by the process of claim 6 or its obvious chemical equivalents.
12. Trans-1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid, whenever prepared by the process of claim 7 or its obvious chemical equi-valents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU4011/81 | 1981-12-30 | ||
| HU814011A HU184494B (en) | 1981-12-30 | 1981-12-30 | Process for producing new azetidinone-caraoxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1189864A true CA1189864A (en) | 1985-07-02 |
Family
ID=10966500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418738A Expired CA1189864A (en) | 1981-12-30 | 1982-12-30 | Heterocyclic carboxylic acids and a process for the preparation thereof |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS58118565A (en) |
| AT (1) | AT378769B (en) |
| AU (1) | AU556905B2 (en) |
| BE (1) | BE895493A (en) |
| CA (1) | CA1189864A (en) |
| CH (1) | CH655927A5 (en) |
| DE (1) | DE3248671A1 (en) |
| ES (1) | ES8504119A1 (en) |
| FI (1) | FI824515L (en) |
| FR (1) | FR2518997B1 (en) |
| GB (1) | GB2112392B (en) |
| GR (1) | GR78430B (en) |
| HU (1) | HU184494B (en) |
| IT (1) | IT1210967B (en) |
| LU (1) | LU84566A1 (en) |
| NL (1) | NL8205069A (en) |
| PL (1) | PL137738B1 (en) |
| SE (1) | SE453082B (en) |
| ZA (1) | ZA829592B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55111463A (en) * | 1979-02-21 | 1980-08-28 | Sankyo Co Ltd | Beta-lactam compound and its preparation |
| ATE15039T1 (en) * | 1979-04-27 | 1985-09-15 | Merck & Co Inc | PROCESS FOR THE PREPARATION OF 3-(1-HYDROXYAETHYL)-AZETIDINONES. |
| JPS56142259A (en) * | 1980-03-11 | 1981-11-06 | Sankyo Co Ltd | Beta-lactam compound and its preparation |
-
1981
- 1981-12-30 HU HU814011A patent/HU184494B/en not_active IP Right Cessation
-
1982
- 1982-12-10 AT AT0450682A patent/AT378769B/en not_active IP Right Cessation
- 1982-12-24 JP JP57235005A patent/JPS58118565A/en active Pending
- 1982-12-28 BE BE1/10680A patent/BE895493A/en not_active IP Right Cessation
- 1982-12-29 FR FR8221977A patent/FR2518997B1/en not_active Expired
- 1982-12-29 SE SE8207474A patent/SE453082B/en not_active IP Right Cessation
- 1982-12-29 CH CH7603/82A patent/CH655927A5/en not_active IP Right Cessation
- 1982-12-29 LU LU84566A patent/LU84566A1/en unknown
- 1982-12-30 IT IT8225059A patent/IT1210967B/en active
- 1982-12-30 CA CA000418738A patent/CA1189864A/en not_active Expired
- 1982-12-30 PL PL1982239884A patent/PL137738B1/en unknown
- 1982-12-30 GB GB08236916A patent/GB2112392B/en not_active Expired
- 1982-12-30 ES ES518719A patent/ES8504119A1/en not_active Expired
- 1982-12-30 FI FI824515A patent/FI824515L/en not_active Application Discontinuation
- 1982-12-30 GR GR70185A patent/GR78430B/el unknown
- 1982-12-30 DE DE19823248671 patent/DE3248671A1/en not_active Withdrawn
- 1982-12-30 AU AU91967/82A patent/AU556905B2/en not_active Ceased
- 1982-12-30 NL NL8205069A patent/NL8205069A/en not_active Application Discontinuation
- 1982-12-30 ZA ZA829592A patent/ZA829592B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IT1210967B (en) | 1989-09-29 |
| AT378769B (en) | 1985-09-25 |
| BE895493A (en) | 1983-06-28 |
| PL137738B1 (en) | 1986-07-31 |
| CH655927A5 (en) | 1986-05-30 |
| ES518719A0 (en) | 1985-04-16 |
| SE8207474L (en) | 1983-07-01 |
| SE8207474D0 (en) | 1982-12-29 |
| DE3248671A1 (en) | 1983-07-07 |
| IT8225059A0 (en) | 1982-12-30 |
| SE453082B (en) | 1988-01-11 |
| AU9196782A (en) | 1983-07-07 |
| HU184494B (en) | 1984-08-28 |
| NL8205069A (en) | 1983-07-18 |
| AU556905B2 (en) | 1986-11-27 |
| FR2518997A1 (en) | 1983-07-01 |
| GB2112392B (en) | 1985-08-14 |
| GR78430B (en) | 1984-09-27 |
| GB2112392A (en) | 1983-07-20 |
| PL239884A1 (en) | 1984-01-02 |
| FI824515A0 (en) | 1982-12-30 |
| LU84566A1 (en) | 1984-10-22 |
| FI824515L (en) | 1983-07-01 |
| ATA450682A (en) | 1985-02-15 |
| ES8504119A1 (en) | 1985-04-16 |
| JPS58118565A (en) | 1983-07-14 |
| FR2518997B1 (en) | 1985-09-06 |
| ZA829592B (en) | 1983-10-26 |
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