CA1191854A - Thienamycin derivatives - Google Patents
Thienamycin derivativesInfo
- Publication number
- CA1191854A CA1191854A CA000418743A CA418743A CA1191854A CA 1191854 A CA1191854 A CA 1191854A CA 000418743 A CA000418743 A CA 000418743A CA 418743 A CA418743 A CA 418743A CA 1191854 A CA1191854 A CA 1191854A
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
- C07D477/02—Preparation
- C07D477/04—Preparation by forming the ring or condensed ring systems
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Pharmacology & Pharmacy (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Bicyclic compounds of the general formula (I), (I) wherein y1 and y2 represent a removable carbonyl protecting group, and Q is a Cl-5 alkyl group or a substituted benzyl group, are prepared in such a way that a) a compound of the ganaral formula (V), (V) wherein y1 and y2 are as defined above and R' is a removable amido protecting group othar than phenyl group, is activated on the carboxy group and then reacted with a salt of a malonic acid hemiestar, wherein the alcohol component is a Cl-5 aliphatic alcohol or a substituted benzyl alcohol, the resulting compound of the general formula (IV), (IV) wherein R', Q, yl and y2 are as defined above; is reacted with a sulfonic azide in the presence of a tertiary amine, or b) a compound of the general formula (V) is activat-ed on its carboxy group and reactad then with a diazoacatic acid ester, thereafter the R' protecting group of a resulting compound of the general formula (III) (III) is removed, and the resulting compound of the general formula (II)
Bicyclic compounds of the general formula (I), (I) wherein y1 and y2 represent a removable carbonyl protecting group, and Q is a Cl-5 alkyl group or a substituted benzyl group, are prepared in such a way that a) a compound of the ganaral formula (V), (V) wherein y1 and y2 are as defined above and R' is a removable amido protecting group othar than phenyl group, is activated on the carboxy group and then reacted with a salt of a malonic acid hemiestar, wherein the alcohol component is a Cl-5 aliphatic alcohol or a substituted benzyl alcohol, the resulting compound of the general formula (IV), (IV) wherein R', Q, yl and y2 are as defined above; is reacted with a sulfonic azide in the presence of a tertiary amine, or b) a compound of the general formula (V) is activat-ed on its carboxy group and reactad then with a diazoacatic acid ester, thereafter the R' protecting group of a resulting compound of the general formula (III) (III) is removed, and the resulting compound of the general formula (II)
Description
The inve~tion xelates to a process for the prepara-tion of new bicyclic compounds of the general formula (I)~
E3C - C ~ ~. ~ ~0 . 0~ ~ ` COOQ (I) whersin yl and Y2 repreC,ent a rernovable carbonyl protecting group3 pre~erably a ketal group or a thioanalogue there-oE, and Q is a al 5 alk~l group or a substituted benzyl groupO
Some o:E the compounds having the general formula (I) areuseful inhibitors of ~-lactamase,others are valuable intermediates of the synthesis of thienamycin and ~hiena-mycin analoguesO
~h.ienamycin~ an antibiotic of broad spectrum o~
activity~ was prepared first or. microbiological way (US patent specificat;ion No~ 3,950,357) and later on by chemical synthesis (G~rman Offenlegungsschrift No~ 2~751~597)o Our aim was to provide a new route for the synthesis of thienam-ycin and its analogues~ wherein th~ azethldinone skeleton and the ~-hydroxyethyl side chain7 or a side chain which can be converted easily into ~-hydroxyethyl group9 are fo.rmed simultaneously at the early stage of the synthesis7 lo and the resu:Lting ~ey intermediate is converted than into ths desired end-product.
It has been :Eound that when a dialkyl (protected amino)-malonate is acylated with diketene and the resulti~g ac~lated prod!uct is reacted with iodi~e and an al~ali metal alcoholate 9 an azethidi.none compound of the general formula . (X)~ O
3 C ~ (COOZ)2 (X) R~
containing an ~-acetyl side chain, is obtained5 which ca~ be utilized a~ ~ey intermediate in the synthesisO
In the above formula R' represen~s a removabl~
amido protacti.ng group other than phenyl group, preferably a phenyl or benæyl group bearing one or more Cl 4 alkoxy substituents, and Z is a Cl_~ al~yl group.
~he intermediates o.~ the general formllla (X) and their preparation are described in detail in our previous Canadian pate~t applicaliion No. 393~595- The preparatio~ o~
~, thesa inter~ed'Lates is a:Lso described in the examples of the ~l9l~5~
pre~ent applical;ionO
It has also been obser~ed ~ha~ prior to convertin~
the in~ermediake o~ the general formula (X) i~to k~ie~a-m-ycin or an ana]ogue thereof~ it is preferclble to protect the keto ~roup o~ the ~C-acet;yl sid~ chain with a group~
particularly a '~etal group or a thioa~alogue thercof, which can be remov~d at a later s~age of the synthesis~ Ethyl0ne glycol or a thioanalogue thereof~ such as marcapko~etha~ol9 can be applied par~icular:Ly praferably to form th~3 et~yle~e-ketal or hemithioketal protscti~g group. '~he resul~ingcompou~d of the general formula (IX3 yl ~2 C - C ~ (cooz)2 0~ ~ \ (IX) wherain yL and y2 form togather a group for the temporary pro~ction o~ ~he carbonyl moiety, preferably ethyleneketal group or a thioanalogue thereof~ and R' and Z are as de~ined above9 is reacted then with an alkali metal halide in pyridi~e or a related soLvent or in aqueous dimethyl sul~o~ide ~o ob~ain a compound of the general formula (VIII~
yl y2 H H
H3C -\C-- ~ t - cooz ~ ~ (VIII~
\ ~' wherein R'~ z~ yl and y2 are as defined above.
~he resulting compound o~ the general formula ¦VIII) is a mi~ture of cis and trans isomersO ~he isomers can be separated from each other by chromatography or on the basis of their dif~e:rent solubilities. ~he separated trans isomer 3~
_, Ll ~_ of the g~neral ~ormula (VIIIa) yl y2 H H^ C00 H3C - C ~ 1- ~
0 ~ --N ~VIIIa) can be conv~r~ed into the ~rans carboxylic acid o~ the general formula (VII) yl y2 H COOH
H3C ~ C~
~ Rs (V~) by hydrolysic,, It is more pre~erable9 howaver~ to subjec~
the isomeric mixtur~ itself to hydrolysis1 sinc~ ~he reac~ion ' iS s910ctive~ iOeo only the ~rans ester converts into the respective carbo~ylic acid~
The separated ~rans carboxylic acid of ths general ~ormula ~VII) is reactod ~irst with an activator ~or the carboxy group and then with diazomethane, and th0 resulting compound of the general ~ormula (VI) yl y2 H H
COC~IN
H3C - C ~ 2 0 ~ ~ (VI) R~
is subjected to Wol~ rearrangement in the presGnce of wa~or ~o obtain an azethidi~oacetic acid of ths general ~ormula ~V) ~ / H CH COOH
H C - C ~ r 2 ol --~, . (V) R~
~0 which can ba applied as starting substanco in ths process of the inventionO
In the gsneral ~ormulae (VII3 9 ~VI) and (V) R'~ yl a~d y2 are as defined above~
Some o~ the new compounds of ~ha general formula (I~3 are described in our previous Hungaria~ patent NoO 180,608. ~he other co!mpounds o~ the general formula (IX) 7 as w~ll as the new compounds of the general formulae ~VIII) to (V) are described i~ detail in the examples of the present pa tent application .
~ha compounds of the general ~ormula (V) can b~
converted into the desired end-products of ~ho ge~eral ~ormula (I) by two alternative methods.
According to uhe one method a compound of the gen~ral formula (V) is reactad with a salt o~ a malonic acid hemi-ester, and the resulting compound of the general formula ~IV) 3 yl y2 H H
H3C - C ~ -~ CH2COCH2C0OQ
\ R' wher~in R'g Q, yl and y2 are as defined above, is treat~d wi~h a sulfonic azide in the presence of a tertiary amine to ob~ain a compound of the general formula (III~, yl ~2 H3C - C ---__9 H/ CH2COC~2CooQ
0 '~ ~ ~ (III) wherein R'7 Q, yl and Y' are as defined above ~he compound~
of the general formulae (IV) and (III) are new and are also embracsd by the scope of the present application~
' ~0 According to the other method a compound of th0 ge~eral f`oxmula IV) i'3 activ2ted on its carbo~y group ancl roacted then with a di.azoacetic acid as~er to obtain a compound of the generall formula (III)~
~he R~ protecting group of the resulting compou~d of the general formula (III) is then removed~ and the result~
ing compound o~` the gelneral formula ~II), ~1 ~2 H H
~I C ~C~ 17~ CH2C OCN2COOQ
0~ ~ H (.II) whsrein ~ yL and y2 ars as da~i~ed above9 is sub3ected to ring closure to obtai~. the desired compou~d o~ tha general formula (I)~
The compounds of thG general ~ormulae (I~ to (V) are racamic ~nixturesO
Based on the above, the invention relates to a process for t,he preparation of a compound o~ the general formula (I)~ wherein yl and y2 xeprssent a removable carbonyl protecting group, pre~arably a ketal group or a thioanalogue there-o~, and Q is a Cl_5 alkyl group or a substitutsd bsnzyl group, in such a way that a) a compound of ~hs general ~ormula (V)~ wherei~
yl and y2 are as definl3d above and R~ is a removable amido protecting group other than phenyl group~ pre~erably a phenyl or benzyl group bearin~ one or more Cl 4 alkoxy sub-stituents, i; activatecl on the carboxy group and the~ react-ed with a salt of a malom c acid hemiester, wherein the alcohol component is a Cl 5 aliphatic alcohol or a substitut ~;~'9~
~ 7 ~
ed benzyl alcohol~ the rec,ulking compound o~ the gene:ral ~ormula (IV) ~ wherai~ yl~ y~ R9 and Q are as de~ined above~
is r0acted wi~h a sulfonic. azide i.n the presence of a tertiar-~
amine~ thereaft~r protecting~ group R~ of th~ resulting com-pound of the general f'ormulla (III) is removed~ and t.he resulk-ing compound of ~he general formula (II) is subjected to ri~g closure pre~erab:l~ in the pr~sence of a rhodium salk, or a compound of the general formula (IV)g wherei~ yl7 Y j R' and Q are as defined above~ is reacted with a sulfonic azide in the p:resence o~ a tartiary amine 9 th~reafter proteGt-ing group R~ of l.he resulting compound o~ the general formula (III~ is removec~D and the resulting compound o~ thfl general ~ormula (II) is subjected ~o ring cl.osure preferably in the . presence of a rhodium salt; 9 or protectil~ group J.~ of a compound of the gsneral formula (III) 3 wherein R', Q, yl and y2 are as defin3d above9 .is removed~ and th~ resulting compound of the general formula (II) is subjected to ring closu.re preferably in the presencs . o~ a rhodium salt~ or a compound o~ the general formula (II~, wherein Q~
yl and y2 are as definecL above~ is subjected to ring closure pra~erably in the presenc:e of a rhodium salt3 or b) a compound of the general formula ~V), wharei.n R~, Q, yl and y2 arfl as defined above7 i5 activated on its caxbo~y .
~5 group and. raacted then with a diazoacetic acid ester~ protoct-ing group R' of the resulting compound of the general formula (III), wharein R', Q, yl and y2 are as de~ined above~ is re~
moved~ and the resulting compound of the general ~ormula (II~
wh~rei~ ~, yl and y2 are as de~ined above~ is subjected to ring closure preferably in the presence of a rhodium sal~
8~f~
aIld tl~ resl1lting compound of the general JEormula ( I) is s~paratsdD
According to Method A) OI the i~entiorl a compou~d of the genaral formula (V~ is activated first on its carbo~y 5 groupO Any activating agent compatible with the ~3-lactam ring can be utilized for this purpose9 o~E which carbo~yl diîmid~
aæole proved to be particularly praîerableO
The activat~d compound is reactl3d then wîth 2 salt oî a malonic; acid hemiester, preIerably with a salt oe et~l 10 malonat~ or (p-nitrobexlzyl) malonateO
The resulting compound oï tho general ~Eormula ~IV~
is treated then, in the presonce of a tertiary amin~" witih a sulfonic a2iide~ preI0rably tosyl azideg to ~Eorm a compou~d of the gene;~al formula (III)9 and then protactirg group R' 15 is removed Erom the rl3sulting~ compound.
Protiecting group R' can be removed by oxidativc m~thods9 Wh~3n a dimethoxybenzyl protecti~g group i5 to ba re-movad~ a pexoxydisulfate typa compound7 preferably potassium or sodium peroxydisu]fate (K2S20~ a2S208) ~ is applied as 20 oxidizing~ agent. The reaction is performed in the presence of water and an organic solventl, and the mixture is buf~ar~d o p~ 7 0 When a me thoxyphenyl protecting group is ~o be xe-moved, it is pre~erred to apply a cerium~IV) salt as oxidizing 25 agent in the presence of an acid. ~ solutio~ of ceric arrmonium ~itrate in dilute aqueous suLfuric acid p~ oved to be particularly appropriate for this purpose 0 Oxidation is per-formed in the pres~nce of an organic solvent 0 ïn the final step of the synthesis the resulting 30 compound o~ ~he general formula III) is subJected to ring 5~
_ g _ closure. ~his reaction is performed in an iner-t solvent under heating, in the presence of a rhodium salt, preferably dirhodium tetraacetate. ~he product is separated from -the reaction mig-ture preferably by evap-ora-tion.
According to Method B) of the inven-tion a compound of -I;he general formula (V) is activated ~irst on the carboxy group with an activa-tor compa-tible with the B-lactam ring. Activators which form acyl chlorides proved to be particularly preferabl,e.
~ he activated compound is reacted then with a diazoacetic acid ester, preferably with eth~l diazo~
acetateJ ~he resulting compound of the general formula (III) is converted then into the desired end-product of the general formula (I) as described above.
Of the compounds having the general ~ormula (I) those wherein Q stands for a substituted benzyl group can be converted into thienamycin or a -thienamycin analogue as ,illustrated on Scheme (A)~
- 10 ~
Scheme (.A) H C -~C~ _ ! ~
COOQ:
1. O-acylation
E3C - C ~ ~. ~ ~0 . 0~ ~ ` COOQ (I) whersin yl and Y2 repreC,ent a rernovable carbonyl protecting group3 pre~erably a ketal group or a thioanalogue there-oE, and Q is a al 5 alk~l group or a substituted benzyl groupO
Some o:E the compounds having the general formula (I) areuseful inhibitors of ~-lactamase,others are valuable intermediates of the synthesis of thienamycin and ~hiena-mycin analoguesO
~h.ienamycin~ an antibiotic of broad spectrum o~
activity~ was prepared first or. microbiological way (US patent specificat;ion No~ 3,950,357) and later on by chemical synthesis (G~rman Offenlegungsschrift No~ 2~751~597)o Our aim was to provide a new route for the synthesis of thienam-ycin and its analogues~ wherein th~ azethldinone skeleton and the ~-hydroxyethyl side chain7 or a side chain which can be converted easily into ~-hydroxyethyl group9 are fo.rmed simultaneously at the early stage of the synthesis7 lo and the resu:Lting ~ey intermediate is converted than into ths desired end-product.
It has been :Eound that when a dialkyl (protected amino)-malonate is acylated with diketene and the resulti~g ac~lated prod!uct is reacted with iodi~e and an al~ali metal alcoholate 9 an azethidi.none compound of the general formula . (X)~ O
3 C ~ (COOZ)2 (X) R~
containing an ~-acetyl side chain, is obtained5 which ca~ be utilized a~ ~ey intermediate in the synthesisO
In the above formula R' represen~s a removabl~
amido protacti.ng group other than phenyl group, preferably a phenyl or benæyl group bearing one or more Cl 4 alkoxy substituents, and Z is a Cl_~ al~yl group.
~he intermediates o.~ the general formllla (X) and their preparation are described in detail in our previous Canadian pate~t applicaliion No. 393~595- The preparatio~ o~
~, thesa inter~ed'Lates is a:Lso described in the examples of the ~l9l~5~
pre~ent applical;ionO
It has also been obser~ed ~ha~ prior to convertin~
the in~ermediake o~ the general formula (X) i~to k~ie~a-m-ycin or an ana]ogue thereof~ it is preferclble to protect the keto ~roup o~ the ~C-acet;yl sid~ chain with a group~
particularly a '~etal group or a thioa~alogue thercof, which can be remov~d at a later s~age of the synthesis~ Ethyl0ne glycol or a thioanalogue thereof~ such as marcapko~etha~ol9 can be applied par~icular:Ly praferably to form th~3 et~yle~e-ketal or hemithioketal protscti~g group. '~he resul~ingcompou~d of the general formula (IX3 yl ~2 C - C ~ (cooz)2 0~ ~ \ (IX) wherain yL and y2 form togather a group for the temporary pro~ction o~ ~he carbonyl moiety, preferably ethyleneketal group or a thioanalogue thereof~ and R' and Z are as de~ined above9 is reacted then with an alkali metal halide in pyridi~e or a related soLvent or in aqueous dimethyl sul~o~ide ~o ob~ain a compound of the general formula (VIII~
yl y2 H H
H3C -\C-- ~ t - cooz ~ ~ (VIII~
\ ~' wherein R'~ z~ yl and y2 are as defined above.
~he resulting compound o~ the general formula ¦VIII) is a mi~ture of cis and trans isomersO ~he isomers can be separated from each other by chromatography or on the basis of their dif~e:rent solubilities. ~he separated trans isomer 3~
_, Ll ~_ of the g~neral ~ormula (VIIIa) yl y2 H H^ C00 H3C - C ~ 1- ~
0 ~ --N ~VIIIa) can be conv~r~ed into the ~rans carboxylic acid o~ the general formula (VII) yl y2 H COOH
H3C ~ C~
~ Rs (V~) by hydrolysic,, It is more pre~erable9 howaver~ to subjec~
the isomeric mixtur~ itself to hydrolysis1 sinc~ ~he reac~ion ' iS s910ctive~ iOeo only the ~rans ester converts into the respective carbo~ylic acid~
The separated ~rans carboxylic acid of ths general ~ormula ~VII) is reactod ~irst with an activator ~or the carboxy group and then with diazomethane, and th0 resulting compound of the general ~ormula (VI) yl y2 H H
COC~IN
H3C - C ~ 2 0 ~ ~ (VI) R~
is subjected to Wol~ rearrangement in the presGnce of wa~or ~o obtain an azethidi~oacetic acid of ths general ~ormula ~V) ~ / H CH COOH
H C - C ~ r 2 ol --~, . (V) R~
~0 which can ba applied as starting substanco in ths process of the inventionO
In the gsneral ~ormulae (VII3 9 ~VI) and (V) R'~ yl a~d y2 are as defined above~
Some o~ the new compounds of ~ha general formula (I~3 are described in our previous Hungaria~ patent NoO 180,608. ~he other co!mpounds o~ the general formula (IX) 7 as w~ll as the new compounds of the general formulae ~VIII) to (V) are described i~ detail in the examples of the present pa tent application .
~ha compounds of the general ~ormula (V) can b~
converted into the desired end-products of ~ho ge~eral ~ormula (I) by two alternative methods.
According to uhe one method a compound of the gen~ral formula (V) is reactad with a salt o~ a malonic acid hemi-ester, and the resulting compound of the general formula ~IV) 3 yl y2 H H
H3C - C ~ -~ CH2COCH2C0OQ
\ R' wher~in R'g Q, yl and y2 are as defined above, is treat~d wi~h a sulfonic azide in the presence of a tertiary amine to ob~ain a compound of the general formula (III~, yl ~2 H3C - C ---__9 H/ CH2COC~2CooQ
0 '~ ~ ~ (III) wherein R'7 Q, yl and Y' are as defined above ~he compound~
of the general formulae (IV) and (III) are new and are also embracsd by the scope of the present application~
' ~0 According to the other method a compound of th0 ge~eral f`oxmula IV) i'3 activ2ted on its carbo~y group ancl roacted then with a di.azoacetic acid as~er to obtain a compound of the generall formula (III)~
~he R~ protecting group of the resulting compou~d of the general formula (III) is then removed~ and the result~
ing compound o~` the gelneral formula ~II), ~1 ~2 H H
~I C ~C~ 17~ CH2C OCN2COOQ
0~ ~ H (.II) whsrein ~ yL and y2 ars as da~i~ed above9 is sub3ected to ring closure to obtai~. the desired compou~d o~ tha general formula (I)~
The compounds of thG general ~ormulae (I~ to (V) are racamic ~nixturesO
Based on the above, the invention relates to a process for t,he preparation of a compound o~ the general formula (I)~ wherein yl and y2 xeprssent a removable carbonyl protecting group, pre~arably a ketal group or a thioanalogue there-o~, and Q is a Cl_5 alkyl group or a substitutsd bsnzyl group, in such a way that a) a compound of ~hs general ~ormula (V)~ wherei~
yl and y2 are as definl3d above and R~ is a removable amido protecting group other than phenyl group~ pre~erably a phenyl or benzyl group bearin~ one or more Cl 4 alkoxy sub-stituents, i; activatecl on the carboxy group and the~ react-ed with a salt of a malom c acid hemiester, wherein the alcohol component is a Cl 5 aliphatic alcohol or a substitut ~;~'9~
~ 7 ~
ed benzyl alcohol~ the rec,ulking compound o~ the gene:ral ~ormula (IV) ~ wherai~ yl~ y~ R9 and Q are as de~ined above~
is r0acted wi~h a sulfonic. azide i.n the presence of a tertiar-~
amine~ thereaft~r protecting~ group R~ of th~ resulting com-pound of the general f'ormulla (III) is removed~ and t.he resulk-ing compound of ~he general formula (II) is subjected to ri~g closure pre~erab:l~ in the pr~sence of a rhodium salk, or a compound of the general formula (IV)g wherei~ yl7 Y j R' and Q are as defined above~ is reacted with a sulfonic azide in the p:resence o~ a tartiary amine 9 th~reafter proteGt-ing group R~ of l.he resulting compound o~ the general formula (III~ is removec~D and the resulting compound o~ thfl general ~ormula (II) is subjected ~o ring cl.osure preferably in the . presence of a rhodium salt; 9 or protectil~ group J.~ of a compound of the gsneral formula (III) 3 wherein R', Q, yl and y2 are as defin3d above9 .is removed~ and th~ resulting compound of the general formula (II) is subjected to ring closu.re preferably in the presencs . o~ a rhodium salt~ or a compound o~ the general formula (II~, wherein Q~
yl and y2 are as definecL above~ is subjected to ring closure pra~erably in the presenc:e of a rhodium salt3 or b) a compound of the general formula ~V), wharei.n R~, Q, yl and y2 arfl as defined above7 i5 activated on its caxbo~y .
~5 group and. raacted then with a diazoacetic acid ester~ protoct-ing group R' of the resulting compound of the general formula (III), wharein R', Q, yl and y2 are as de~ined above~ is re~
moved~ and the resulting compound of the general ~ormula (II~
wh~rei~ ~, yl and y2 are as de~ined above~ is subjected to ring closure preferably in the presence of a rhodium sal~
8~f~
aIld tl~ resl1lting compound of the general JEormula ( I) is s~paratsdD
According to Method A) OI the i~entiorl a compou~d of the genaral formula (V~ is activated first on its carbo~y 5 groupO Any activating agent compatible with the ~3-lactam ring can be utilized for this purpose9 o~E which carbo~yl diîmid~
aæole proved to be particularly praîerableO
The activat~d compound is reactl3d then wîth 2 salt oî a malonic; acid hemiester, preIerably with a salt oe et~l 10 malonat~ or (p-nitrobexlzyl) malonateO
The resulting compound oï tho general ~Eormula ~IV~
is treated then, in the presonce of a tertiary amin~" witih a sulfonic a2iide~ preI0rably tosyl azideg to ~Eorm a compou~d of the gene;~al formula (III)9 and then protactirg group R' 15 is removed Erom the rl3sulting~ compound.
Protiecting group R' can be removed by oxidativc m~thods9 Wh~3n a dimethoxybenzyl protecti~g group i5 to ba re-movad~ a pexoxydisulfate typa compound7 preferably potassium or sodium peroxydisu]fate (K2S20~ a2S208) ~ is applied as 20 oxidizing~ agent. The reaction is performed in the presence of water and an organic solventl, and the mixture is buf~ar~d o p~ 7 0 When a me thoxyphenyl protecting group is ~o be xe-moved, it is pre~erred to apply a cerium~IV) salt as oxidizing 25 agent in the presence of an acid. ~ solutio~ of ceric arrmonium ~itrate in dilute aqueous suLfuric acid p~ oved to be particularly appropriate for this purpose 0 Oxidation is per-formed in the pres~nce of an organic solvent 0 ïn the final step of the synthesis the resulting 30 compound o~ ~he general formula III) is subJected to ring 5~
_ g _ closure. ~his reaction is performed in an iner-t solvent under heating, in the presence of a rhodium salt, preferably dirhodium tetraacetate. ~he product is separated from -the reaction mig-ture preferably by evap-ora-tion.
According to Method B) of the inven-tion a compound of -I;he general formula (V) is activated ~irst on the carboxy group with an activa-tor compa-tible with the B-lactam ring. Activators which form acyl chlorides proved to be particularly preferabl,e.
~ he activated compound is reacted then with a diazoacetic acid ester, preferably with eth~l diazo~
acetateJ ~he resulting compound of the general formula (III) is converted then into the desired end-product of the general formula (I) as described above.
Of the compounds having the general ~ormula (I) those wherein Q stands for a substituted benzyl group can be converted into thienamycin or a -thienamycin analogue as ,illustrated on Scheme (A)~
- 10 ~
Scheme (.A) H C -~C~ _ ! ~
COOQ:
1. O-acylation
2. -~ mercaptan
3. salt formation , yl y2 H3C - C ~ _ SR"
.... _ 0 COOQ' In the above formulae yl and y2 represen-t a removable carbon~l protecting group, Q is a Cl 5 alkyl or a substi-tuted benz~l group, Q' is a Cl 5 alkyl group, ; a substituted benzyl group~ hydrogen atom or an alkali me-tal ion, ana R" is a benzyl 5 aminoethyl or N acyl--aminoethyl group~
lhe compounds of the general formula (I) wherein Q is a Cl 5 alkyl group are pharmaceuticall~
active.
~he in~ention is elucidated in detail by the aid of the following non-limiting E~.amples.
ll -Example 1 Et~yl 6-(2-meth-yl-1,3-dioxolan-2~ 3,7--di_xo-l-azabic~clo[3.2.0]heptane~2-~carbox~late Dirhodium te-traacetate ~Rh2(0Ac)4.2~E~] is added in small por-tions to a boiling solution of 1.245 g (4.0 mmoles) of ethyl 2-diazo-4-~trans-3-(2--methyl-1~3~dioxolan 2-yl)~4-oxo-2~azethidinyl]~3-oxo~-~butanoate in 10 ml of benzene until the starting substance reacts comple-tely (this requires about 0003 g of the rhodium sal-t). The reaction mixture is filtered through a Celi-te pad, and the filtrate is evaporated. lhe residue crys-tallizes on s-tanding. 1.13 g (100 %) of the aimed compound are obtained, mOp.:
109 C.
IR (KBr)o 1750, 1735 cm 1.
lH ~MR: ~ = 1.30 (t, 3H, J = 7.4 Hz), 1.49 (s, 3H), 2041 (dd, lH~ Jgem = 19-5 Hz, Jvic 7 2.90 (dd, lH, Jgem = 19.5 Hz, Jvic 7 (d, lH, J = 2.4 Hz), 3.97 4.20 (m, 5H), 4.24 (~, 2H, J = 704 Hz), 4.63 (t, lH, J = o.6 Hz) ppm.
lhe starting substance can be prepared from a compound bearing a 2,4-dimethoxybenzyl protecting group as follows:
a) A mixture of 109.8 g (o.66 mole) of 2,4 -dimethoxybenzaldehyde, 72 ml (oO66 mole) of benzylamine and 660 ml of methanol is stirred at room temperature ~or 20 minutes, whereupon a clear solutLon is obtained ~rom - lla -the suspension. The solution is cooled wi-th ice water, and 13.2 g (0.33 mole) of sodium borohydride are added to it in small portionsc rrhe progress of -the reac-tion is moni-tored by thin layer chromatography (Kieselgel G according to Stahl; developing solvent: a ~:1 mixture of benzene and acetone), and at the end of the reaction -the mixture is evaporated -to dryness in vacuo. rrhe residue is admixed with 300 ml of water9 and the aqueous mixture is extracted with 500 ml 3 200 ml and 200 ml portions of ether. r~he ethereal solutions are combined, dried over magnesium sulfate, filtered, and then 112 ml (oO66 mole) of diethyl bromomalonate and 93 ml (0.66 mole) of triethyl amine are added -to the filtrate. rrhe reaction mixture is stirred at room temperature for 2-3 days. r~he separated trie-thyl ammonium bromide is filtered off and washed with ether. The mother liquor is evaporated, and -the residue is recrystallized from ]50 ml of ethanol. r~he resulting 210 g of crude product are recrystallized again from 400 ml of ethanol to obtain 197 g (72 %) of diethyl N~benzyl-N~(2,4~dimethoxybenzyl)-amino--malonate; mOpO: 62~63 C (ethanol).
IR (KBr): 1750/1725 cm 1, d.
b) 61.7 g (00149 mole) of diethyl M-benzyl--N-(2,4-dimethoxybenzyl)-amino-malona-te, prepared as described in point a) above, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of 5~
- llb -about 20 g of palladium~on-charcoal catalyst. ~he catalyst is filtered off and -the liltrate is evap-orated. 47.1 g (97 %) of diethyl ,~. ., ~2,4-dimsthoxybenzylamino)-malonate are obtain2dq ~he producti can be conv~rted into i.ts hydrochloride by reactirlg it with hydrochloric acid.} ~he hydrochlori.de meltis ati 122-124C atte.r recrystallizaliion from e thyl acetate n Analyc,is.
calculated :~~ 6H24C~-N6 ( ~i ) C: 53,11 %7 H 6~,6g %~ C:L~ 9 80 %, N- 3~87 %~
f o und - C~ 52 ~ 51 % ~ H 6 0 77 ~ 10 . 30 % 9 1~ 4 0 09 %
IR (f ilm): 3250 !1 29û0 g 28509 1730~ 1720 cm ln H ~aR (CDC13): ~= 1.3 (t9 6E) ~ 3078 (S9 3~I) 7 3082 (S9 3E~), 4 21 ~99 4H), 6.20 (~ 2H) 9 604-6~,6 (m, 2H) ~ 7~3-7s~55 (m, lH) ~ 707 (broad s, lH) ppm.
c) A mixture OI 3906 g (00122 mole~ OI diekhyl ~274-di methoxy~,enzy:l.ami~o~-malonatie~ p.repared as described in poinb b~ above, 80 ml o~ glacial acetic acid and 12 .3 g ( 11.2 ml~
0.146 mole) oî diketene is boiled for 0.5 hourO Glacial acebic acid is distiilled ofî in vacuo over water bath, and the oily re~idue is trituratad with 150 ml of watierO ~hs rasulting crysltalline ~ubstance is dissolved in 60 ml o~ ethyl acetiatis 21) and precipitated with petroleum ethsr~ 2906 g (60 %) of di-e thyl N ( 2, 4-dime thoxyb enzyl ) -3-hydroxy-3-me thyl-5~oxo~2 1 2 pyrrolidine-dicarboxylat~ and~or its tautomer are obtained;
m~p.: 106-107C1.
~na lysis:
calculated for C20H27N08 (409.43~:
C 58~67 %~ H 6~65 %~ N: 342 %"
fou~d: C: 58.79 %, H: 6 33 %~ N: 3,34 %0 I;R (KBr): 3400, 2950, 2850g 1730 (1740~ sh); 1710 cm 1.
lH NMR (CDC13): ~= 1.1 (t, 3H) ~ 1.17 (t, 3H) ~ 1052 .
(s,1~3H), 2~8 1~ 0.1 H), 2065 (broad s, 2H) 9 3075 (s; 6H), s~
308~4015 ~m, 4H)~ 6~7 (broad S9 2H), 6~25-6045 ~m) t 700~7025 (m, ~H) ppmO
d) 20.,5 g (50 mmoles~ of the product prepared as described in point c) above ara susperLded in 50 ml o:E dry ether~ and a soluZ;ion of 304-5 g (150 mmoles~ o~ me~allic sodiurn in 100 ml o~ dry ethanol atld a solution o:~ 12.7 g (50 mmole~3 of iodirL~3 in 150 ml o~ dry ether are acLded simul-taneously, from two dropping îu~els, ~o the vigorousïy stirred suspe~Lsion uncler cooling with ica watierO ThereaItier 5 g of sodium h~ydrosulîite, dissolved in 200 ml of a saturated aqueou~
sodium chloricLe solutiion~ are added to the stirrqd mixtureO
The mix'Gura is îilled into a separating :Eu~n~l~ and 60 ml o~
wat;ar are added lio dissolve ~he separated inorgarLic salts ~he orgarLic phase is removed, dried over magnesium sulfate?
filtiered7 and the ~iltrat;e is evaporated~ ~he oily rasidue, weighing 1805 g~ is crystalliæed from 30 ml o~ 2-propanoll, 10l9 g (5L~7o) oî diathyl 3-ace~yl-1-(2,4-dimethoxybenzyl)
.... _ 0 COOQ' In the above formulae yl and y2 represen-t a removable carbon~l protecting group, Q is a Cl 5 alkyl or a substi-tuted benz~l group, Q' is a Cl 5 alkyl group, ; a substituted benzyl group~ hydrogen atom or an alkali me-tal ion, ana R" is a benzyl 5 aminoethyl or N acyl--aminoethyl group~
lhe compounds of the general formula (I) wherein Q is a Cl 5 alkyl group are pharmaceuticall~
active.
~he in~ention is elucidated in detail by the aid of the following non-limiting E~.amples.
ll -Example 1 Et~yl 6-(2-meth-yl-1,3-dioxolan-2~ 3,7--di_xo-l-azabic~clo[3.2.0]heptane~2-~carbox~late Dirhodium te-traacetate ~Rh2(0Ac)4.2~E~] is added in small por-tions to a boiling solution of 1.245 g (4.0 mmoles) of ethyl 2-diazo-4-~trans-3-(2--methyl-1~3~dioxolan 2-yl)~4-oxo-2~azethidinyl]~3-oxo~-~butanoate in 10 ml of benzene until the starting substance reacts comple-tely (this requires about 0003 g of the rhodium sal-t). The reaction mixture is filtered through a Celi-te pad, and the filtrate is evaporated. lhe residue crys-tallizes on s-tanding. 1.13 g (100 %) of the aimed compound are obtained, mOp.:
109 C.
IR (KBr)o 1750, 1735 cm 1.
lH ~MR: ~ = 1.30 (t, 3H, J = 7.4 Hz), 1.49 (s, 3H), 2041 (dd, lH~ Jgem = 19-5 Hz, Jvic 7 2.90 (dd, lH, Jgem = 19.5 Hz, Jvic 7 (d, lH, J = 2.4 Hz), 3.97 4.20 (m, 5H), 4.24 (~, 2H, J = 704 Hz), 4.63 (t, lH, J = o.6 Hz) ppm.
lhe starting substance can be prepared from a compound bearing a 2,4-dimethoxybenzyl protecting group as follows:
a) A mixture of 109.8 g (o.66 mole) of 2,4 -dimethoxybenzaldehyde, 72 ml (oO66 mole) of benzylamine and 660 ml of methanol is stirred at room temperature ~or 20 minutes, whereupon a clear solutLon is obtained ~rom - lla -the suspension. The solution is cooled wi-th ice water, and 13.2 g (0.33 mole) of sodium borohydride are added to it in small portionsc rrhe progress of -the reac-tion is moni-tored by thin layer chromatography (Kieselgel G according to Stahl; developing solvent: a ~:1 mixture of benzene and acetone), and at the end of the reaction -the mixture is evaporated -to dryness in vacuo. rrhe residue is admixed with 300 ml of water9 and the aqueous mixture is extracted with 500 ml 3 200 ml and 200 ml portions of ether. r~he ethereal solutions are combined, dried over magnesium sulfate, filtered, and then 112 ml (oO66 mole) of diethyl bromomalonate and 93 ml (0.66 mole) of triethyl amine are added -to the filtrate. rrhe reaction mixture is stirred at room temperature for 2-3 days. r~he separated trie-thyl ammonium bromide is filtered off and washed with ether. The mother liquor is evaporated, and -the residue is recrystallized from ]50 ml of ethanol. r~he resulting 210 g of crude product are recrystallized again from 400 ml of ethanol to obtain 197 g (72 %) of diethyl N~benzyl-N~(2,4~dimethoxybenzyl)-amino--malonate; mOpO: 62~63 C (ethanol).
IR (KBr): 1750/1725 cm 1, d.
b) 61.7 g (00149 mole) of diethyl M-benzyl--N-(2,4-dimethoxybenzyl)-amino-malona-te, prepared as described in point a) above, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of 5~
- llb -about 20 g of palladium~on-charcoal catalyst. ~he catalyst is filtered off and -the liltrate is evap-orated. 47.1 g (97 %) of diethyl ,~. ., ~2,4-dimsthoxybenzylamino)-malonate are obtain2dq ~he producti can be conv~rted into i.ts hydrochloride by reactirlg it with hydrochloric acid.} ~he hydrochlori.de meltis ati 122-124C atte.r recrystallizaliion from e thyl acetate n Analyc,is.
calculated :~~ 6H24C~-N6 ( ~i ) C: 53,11 %7 H 6~,6g %~ C:L~ 9 80 %, N- 3~87 %~
f o und - C~ 52 ~ 51 % ~ H 6 0 77 ~ 10 . 30 % 9 1~ 4 0 09 %
IR (f ilm): 3250 !1 29û0 g 28509 1730~ 1720 cm ln H ~aR (CDC13): ~= 1.3 (t9 6E) ~ 3078 (S9 3~I) 7 3082 (S9 3E~), 4 21 ~99 4H), 6.20 (~ 2H) 9 604-6~,6 (m, 2H) ~ 7~3-7s~55 (m, lH) ~ 707 (broad s, lH) ppm.
c) A mixture OI 3906 g (00122 mole~ OI diekhyl ~274-di methoxy~,enzy:l.ami~o~-malonatie~ p.repared as described in poinb b~ above, 80 ml o~ glacial acetic acid and 12 .3 g ( 11.2 ml~
0.146 mole) oî diketene is boiled for 0.5 hourO Glacial acebic acid is distiilled ofî in vacuo over water bath, and the oily re~idue is trituratad with 150 ml of watierO ~hs rasulting crysltalline ~ubstance is dissolved in 60 ml o~ ethyl acetiatis 21) and precipitated with petroleum ethsr~ 2906 g (60 %) of di-e thyl N ( 2, 4-dime thoxyb enzyl ) -3-hydroxy-3-me thyl-5~oxo~2 1 2 pyrrolidine-dicarboxylat~ and~or its tautomer are obtained;
m~p.: 106-107C1.
~na lysis:
calculated for C20H27N08 (409.43~:
C 58~67 %~ H 6~65 %~ N: 342 %"
fou~d: C: 58.79 %, H: 6 33 %~ N: 3,34 %0 I;R (KBr): 3400, 2950, 2850g 1730 (1740~ sh); 1710 cm 1.
lH NMR (CDC13): ~= 1.1 (t, 3H) ~ 1.17 (t, 3H) ~ 1052 .
(s,1~3H), 2~8 1~ 0.1 H), 2065 (broad s, 2H) 9 3075 (s; 6H), s~
308~4015 ~m, 4H)~ 6~7 (broad S9 2H), 6~25-6045 ~m) t 700~7025 (m, ~H) ppmO
d) 20.,5 g (50 mmoles~ of the product prepared as described in point c) above ara susperLded in 50 ml o:E dry ether~ and a soluZ;ion of 304-5 g (150 mmoles~ o~ me~allic sodiurn in 100 ml o~ dry ethanol atld a solution o:~ 12.7 g (50 mmole~3 of iodirL~3 in 150 ml o~ dry ether are acLded simul-taneously, from two dropping îu~els, ~o the vigorousïy stirred suspe~Lsion uncler cooling with ica watierO ThereaItier 5 g of sodium h~ydrosulîite, dissolved in 200 ml of a saturated aqueou~
sodium chloricLe solutiion~ are added to the stirrqd mixtureO
The mix'Gura is îilled into a separating :Eu~n~l~ and 60 ml o~
wat;ar are added lio dissolve ~he separated inorgarLic salts ~he orgarLic phase is removed, dried over magnesium sulfate?
filtiered7 and the ~iltrat;e is evaporated~ ~he oily rasidue, weighing 1805 g~ is crystalliæed from 30 ml o~ 2-propanoll, 10l9 g (5L~7o) oî diathyl 3-ace~yl-1-(2,4-dimethoxybenzyl)
4-oxo-2,2~azet;idine-dicarboxylate ara obtiained; m.pO 84-85C
(2-propanol~0 Analysis:
calculated ~or C20H25~08 (407.41)-~
C 53 96 %, H: 6.19 %, N~ 3.L~ %~
Iound: C: 58.99 %, H: 6004 %, N: 3057 %.
lH NMR (CDC13): o~= 1.12 ~ti9 ~H)~ 1.21 ~t;, 3H)~ 2.31 (s, 3H), 3076 (s, 6H)~ ~o8 3.4 (m, 4H), 4,53 (d, lH)~ 4.63 (d~ lH), 4 69 (s, lH), 6.3-6,4 (m, 2H) ~ 7.07 (d7 lH) ppm.
e) 1.79 ml (206 g, 10452 moles) of boron tri~luoride-diethyl etheratie are added dropwise to a vigorously stirred solution of 179 g (00484 mole) oE diethyl 3-acetyl-1~(2,4-di~
methoxybonzyl)-4 oxo 2~2-azethidine-dicarboxylaiie and 107 ml - 14 ~
(120 gg 1,936 moles) of ethylene glycol in 500 ml of dry dioxane under cooling with ice water~ ~he reaction mixture is allowed to stand at room temperature for one day, during this period -the mixture is occasional-ly stirred. ~hereafter ~15 g (1~452 moles) of ~a2C03.10H20are added slowly to the stirred mixture under cooling wi-th ice water, and the mixture is stirred for 15 minutes. Thereafter 1 litre of ether and 1 litre of water are added, and the phases are separated from each other. The aqueous phase is shaLcen twice with 500 ml of diethyl ether, each. The ethereal phase is dried over magnesium sulfate, filtered, and the filtra~e is evapora-l;ed 33~9 g (0.58 mole) of sodium chloride, 17.4 ml (0.968 mole) of water and 220 ml of dime-thyl sulfoxicle are added to the residue, and the mixture is stirred on an oil bath at 180 C. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; developing solvent: a 6:~ mixture of benzene and ethyl acetate).
~t the end of the reaction, i.eu after about 15 hoursg the mixture is poured on-to 1100 ml of saturated aqueous sodium c~loride solution, and the resulting mixture is shaken wlth 1000 ml and -then twice with 500 ml of di-ethyl ether, each. The ethereal solutions are combined, decolourized with charcoal, dried over magnesium sul-fate, and the fil-trate is evaporated to a final volume of cca. 200 mlO This concentrated solution is cooled with ice water to obtain 59 g (35 %) of trans-ethyl S~
- l~a~
1-(2,4-dimethoxybenzyl)-3-(2-methyl 1,3-dioxolan-2-yl)-~4 oxo-2-azethidine-carboxylate; m.p.: 95 C.
f) A mixture of 0.5 g (1.2 mmoles) of di-ethyl 3~acety:1-1-(2,4-dimethoxybenzyl)-4-oxo-2,2~
-azethidine-dicarboxylate, prepared as descri.bed in point d) above, 3 ml of dry te-tra-" 15 ~
hvvdroIuran and 0 53 g (31O6 mmoles) of mercapto~etklarLol isboiled fox 4 hours, and then 10 ml of watar and 10 ml o~
chloroform are added ko ~he reaction mixture. The organic phasa is separated~ washt~d with ~% aqueous sodium hydrocarbon-
(2-propanol~0 Analysis:
calculated ~or C20H25~08 (407.41)-~
C 53 96 %, H: 6.19 %, N~ 3.L~ %~
Iound: C: 58.99 %, H: 6004 %, N: 3057 %.
lH NMR (CDC13): o~= 1.12 ~ti9 ~H)~ 1.21 ~t;, 3H)~ 2.31 (s, 3H), 3076 (s, 6H)~ ~o8 3.4 (m, 4H), 4,53 (d, lH)~ 4.63 (d~ lH), 4 69 (s, lH), 6.3-6,4 (m, 2H) ~ 7.07 (d7 lH) ppm.
e) 1.79 ml (206 g, 10452 moles) of boron tri~luoride-diethyl etheratie are added dropwise to a vigorously stirred solution of 179 g (00484 mole) oE diethyl 3-acetyl-1~(2,4-di~
methoxybonzyl)-4 oxo 2~2-azethidine-dicarboxylaiie and 107 ml - 14 ~
(120 gg 1,936 moles) of ethylene glycol in 500 ml of dry dioxane under cooling with ice water~ ~he reaction mixture is allowed to stand at room temperature for one day, during this period -the mixture is occasional-ly stirred. ~hereafter ~15 g (1~452 moles) of ~a2C03.10H20are added slowly to the stirred mixture under cooling wi-th ice water, and the mixture is stirred for 15 minutes. Thereafter 1 litre of ether and 1 litre of water are added, and the phases are separated from each other. The aqueous phase is shaLcen twice with 500 ml of diethyl ether, each. The ethereal phase is dried over magnesium sulfate, filtered, and the filtra~e is evapora-l;ed 33~9 g (0.58 mole) of sodium chloride, 17.4 ml (0.968 mole) of water and 220 ml of dime-thyl sulfoxicle are added to the residue, and the mixture is stirred on an oil bath at 180 C. The progress of the reaction is monitored by thin layer chromatography (adsorbent: Kieselgel G according to Stahl; developing solvent: a 6:~ mixture of benzene and ethyl acetate).
~t the end of the reaction, i.eu after about 15 hoursg the mixture is poured on-to 1100 ml of saturated aqueous sodium c~loride solution, and the resulting mixture is shaken wlth 1000 ml and -then twice with 500 ml of di-ethyl ether, each. The ethereal solutions are combined, decolourized with charcoal, dried over magnesium sul-fate, and the fil-trate is evaporated to a final volume of cca. 200 mlO This concentrated solution is cooled with ice water to obtain 59 g (35 %) of trans-ethyl S~
- l~a~
1-(2,4-dimethoxybenzyl)-3-(2-methyl 1,3-dioxolan-2-yl)-~4 oxo-2-azethidine-carboxylate; m.p.: 95 C.
f) A mixture of 0.5 g (1.2 mmoles) of di-ethyl 3~acety:1-1-(2,4-dimethoxybenzyl)-4-oxo-2,2~
-azethidine-dicarboxylate, prepared as descri.bed in point d) above, 3 ml of dry te-tra-" 15 ~
hvvdroIuran and 0 53 g (31O6 mmoles) of mercapto~etklarLol isboiled fox 4 hours, and then 10 ml of watar and 10 ml o~
chloroform are added ko ~he reaction mixture. The organic phasa is separated~ washt~d with ~% aqueous sodium hydrocarbon-
5 ate solution~ dried o~er magnssium sul.~ate~ :~iltered,, and kheproduct is separated from the ~ilt.rate by preparative thin layer chromatograph~ (adsorbent Kieselgel 60 ~`254-~-36~,~
daveloping so]!vent: a 8~2 mi~ture oî toluene and acstone~.
0030 g (53 ~o) o~ diethyl 1-~2~4-dimethoxybenzyl) 3~(2-methyl~
1~3~oxathio~an-2-yl~-4-oxo-2 ,2~azethidine-dlcarboxylate is obtai~ed H NMlR ~CDC13). ~- 008-1.55 (m~ 6H); 1.72 ~ 1 77 (d~
~H)7 2~9-304 ~m, 2H)7 3975 (s~ 6H)) 440~500 tm, 9H)~ 60L~ (m, 2H) -~ 7 o l ( d, lH) ppm..
g) A solution of 5.21 g (0.130 mole) oî sodium h~dr-oxide in 60 ~1 oî water is added to a suspension o~ 4102 g ~ 0 0109 mo le ) o~ trans- e thyl 1- ( 2 7 L~-dime thoxyb enz~ ( 2-me thyl~
1 ,3-dioxolan-2-yl) -4-oxo-2-azethidine-carboxyla te 5 prepared as described ln point e) abova9 in 50 ml o~ ethanol under 20 stirring and cooling with ice waker, and stirring is con~inued until a clear solution is obtained (about 20 minul;a~) O 100 ml o:e l,vater are adcled therl to the solution, a~d khe mi}~ture is shak~n with 100 ml of ether. ~he aqueous phase is acidiîied to pH = 1 with concentrated aqueous hydrochloric acid, and ~h~n shaken quickly with 100 ml and twice with 50 ml of di-chloromathane, each~ ~he dichlorom~thana solu~ions are combined~
dried ovar magnesium sul~ate~ filtsred, and the filtrato is evaporatedD ~ho oily residuo is crystallized from a mixture oî toluene and petroleum ether to obtain 35 g (l92 ~0) o~ tran~-~0 1-(2,~-dimetho~ybenzyl)~3-(2-methyl-1,3-dioxola~2~yl~ 4Doxo~
., - 16 ~
2-azethidine-carboxylic acid; m.pO: 117~118 C
(toluene).
Analysis:
calculate~ fcr C17H21N7 (351-35) 5C: 5~.11 %, H: 6003 %, M: 3.99 %;
:Eound: ~: 58.17 %, H: 6.30 %, M: 4.24 %.
IR (K~r): 3500~2500, 2900, 1760, 1720 cm lH-M~R (CDC13): ~ = 1039 (s, 3H), 3.50 (d, lH, J = 2.5 Hz), 3.77 (s, 3H)9 3.79 (s, 3H), 3.86 (d, lH, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JA~ =
= 15 Hz), 6044 (m, 2H) + 7015 (d, lH, J = 10 Hz), 7O5~ (broad s, lH) ppm.
h) 7.3 ml (52.5 mmoles) of triethyl amine are added -to a solution of 17.6 g (50 mmoles) of trans--1-(2,~-dimethoxybenzyl)-3-(2-me-thyl~1,3-dioxolan-2-yl)~
~~-oxo-2 azethidine-carboxylic acid, prepared as described in point g~ above, in 150 ml of dry tetrahydrofuran, and then 5.0 ml (52.5 mmoles) of ethyl chloroformate are added to the mixture under cooling with ice. ~he mixture is cooled to -15 C, stirred at this tempera-ture for 20 minutes, and the separated triethyl amine salt is fil-tered off at the same -temperature under argon atmosphere. A solution of 150 mmoles of diazomethane in 230 ml of cold diethyl ether is added to the fil-trateO
~he mixture is stirred, allowed to warm to room tempera-ture, and after 2 hours of stirring it is evaporated to dryness. r~he brown, thick residue is dissolved in 20 ml of benzene, and the product is separated by column .~, 5~
~ 17 ~
chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063~-0.200 mm, eluting agent: a 7:2 mixture of benzene and acetone)O 1200 g (64 %) of trans~4~-(diazo-acetyl)-1-(2,4~dimethoxybenzyl)~3-(2-methyl-1,3-dioxolan-5 ~2-yl)-2-azethidinone are obtained.
IR (K13r): 2900 ~ 2110 ~ 1760 cm lo Analysis:
calculated Eor C18H21~36 (375 3 found: ~: 57~78 %~ H: 5.39 %.
i) A mixture of 2.25 g (6 mmoles) of trans-4--(diazoace-tyl)~l (2,4-dimethoxybenzyl)-3-(2-me-thyl-1,3--dioxolan~2-yl)-2-azethidirLone, prepared as described in point h) above, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water is irradia-ted for about 4 hours with 15 a high-pressure mercury lamp (HPK 125) ~ immersed into the reaction vessel made oE pyrex glass 7 under argon atmosphere~ ~he solution is evaporated in vacuo to a final volume of 50 ml, and the concentrate is diluted with water -to 130 ml. 2 ~ 4 ml of a 10 % aqueous sodium 20 hydroxide solution are added to the aqueous mixture, and the alkaline mixture is washed thrice with 20 ml of di-chloromethane, each. Thereafter the aqueous phase is acidified -to pH = 2 with concentrated aqueous hydro-chloric acid. ~he acidic solution is extracted thrice 25 with 20 ml oE dichloromethane, each, the extracts are combi-ned, dried over magnesium sulfate, filtered, and the filtrate is evaporated to dryness. ~he residue is crystallized with ether. 1~82 g (83 %) of [trans-l-17a ~(2,4-dimethoxybenzyl)-3-(2-methyl-1~3-dioxolan-2-yl)~
4-oxo-2-azethidinyl]-ace-tic acid are obtained; m.p.:
124 ~ (ether).
Analysis:
f 18II23N7 (365.37) C: 59.17 %, H: 6.34 %, M: 3.83 %;
found: C: 59~22 %, H: 6.49 %, N: 4~07 %O
I:R (K~r): 3500-2300, 2900, 1730, 1700 cm 1 j) o.364 g (2.2 mmoles) of 98 % carbonyl diimidazole is added to a solution of 07730 g (2 mmoles) of ~trans-l-:L8 ~2~4-dimethoxybenz-yl)-3-(2-methyl-lg3~dioxolan-2 ~1) 4--oxo~
2 azathidi-nyl7~acetic acid~ prepare(l as described in point i) aboveg, in 10 ml OI dry tetrahydro~uran~ and the mixture is ~tirrsd fo.r 20 minuts~30 00~15 g (202 mmoles) oï mag~esium 5 athyl malona~ is added to the solution9 and ~tirring is con~
tinued for 2 hoursO ~he reaction mixture is evaporatedg tha residus is sh~ken with 40 ml o:E dichlorometha~e and 40 ml o:E
a ûo5 n aqueolls h;ydrochloric acid7 and the two phases ars sspara~ed from each other, ~rhe aqu~ous phase is extractsd with 10 20 ml of dichloromethan~O The organic phasss are combirled, washed twice ~Jith 10 ml of a ~% aqusous sodium carbonate solu-tion~ each~ dried over n~g~esium sul~ata, liltared7 a~d the ~iltrate is ~vaporatedO 0.41 g (47 %) of ethyl ~rans~ 2 dimethox;Ybenzyl)-3-(2-methyl-173-dioxolan-2-yl)-4-o~o-2~az-15 othidi~y_7-3- oxo-bu~arloate is obtainedO
IR (filn): 1750l 1740, 1720 cm 1~, lH NMR (GDC13): ~ = 1.26 (t9 3H?~ 1.39 (s~ 3H~" 2 2-303 (m, 5H)~ 3..65-4.45 (m, 14H)9 6~25~6e~6 and 7~05-7025 (m7 3H~ ppm.
k3 0~,6~3 ml (5~0 mmoles) o~ triethyl amine and Q.986 g (500 mmoles) o~ tosyl azi.de are added to a solutio~ o.~ 20177 g (500 mmo~es) oi~ ethyl trans~ (2~4-dimethoxyben~byl~-3-(2-mathyl-1,3-dio~olan-2-yl)-~oxo-2-azcthidiny~ 3-o~o~butanoa~e, prepared as d~scribed in point j) above, in 15 ~1 o~ dry 25 acc~oIlitrila undor ice cooling. ~he solution is stirred for 3 hours and during this period it is a llowed to warm to room temperature. The solu~ion is evaporated to dryness, and the resîdu~ is processed b~y columrl chromatography (adsorben~:
Kieselgel 60, ,0 = 0.063-0..200 mm, eluting agent: a 1~3 mi~{ture of ~enzene and acetone). 1.~1 g (61 ~3 of ethyl 2 diazo-4 trans-~ ~(2~4-dimethox~benzyl~-3 (2~methyl-1~3~dioxolan~2-yl)-4-oxo-2-azethidirLy ~ ~3-oxo-butanoate are obtairl~d~
1~ 5~4 g (20 mmoles~ o~ potassium peroxydis~ ate (K2S208)~ 702 ~ (L~ mm.oles) of disodium hydrophosphate mono~
hyclrate (Na2HPO~ I?0~ and 18 ml of water are added to a solu-tion of 2~340 g (500 mmoles~ of e~hyl 2~diazo~4~ra~s~ (2~4-dimethoxybe~zyl)-3-(2-methyl-1~3-dio.yol.an-2-yl)~4 oxo-2-az-~3thidi~yl7~3 oxo-butanoate, prepared as described i~ point k) above~ in 30 ml of acetonitrila~ and the mixture is boil~3d for 10 hours. Th~3 reaction mixture i9 cooled, fil~ered~ and the t~.~Jo phases of the filtrata are separated from each other. The aqueous phase is extracted thrice with 10 ml of ethyl acetat6 9 oachO ~he org~anic phases are combi~ed~ dried over mag~osium sulfate, .~iltered, and the fil~rate is evaporated. ~he residue 15 is processed by column chromatography (adsorbent: Kiesalg~l 60, 0 = 00063-00200 mm, ~31utirlg agent: a 7:3 mixture o~ benzene .and aceton~) to obtain 0~56 g (36 %) o~ ethyl 2-diazo-4-trans~
-(2-methyl 1,3-dioxolan-2-yl)-4~oxo~2-azethidinyl7-3-oxo-butanoateO
IR (~ilm): 3280, 2160, 1760, 17209 1640 cm 1.
m3 ~he product obtained in point k3 above can also be prepared according to Method B) of the i~vention as follows:
One drop of dimethyl ~ormamide and 0037 ml (500 mmolas~
of thionyl chloride are added to a stirxed solution of 10830 g (500 mmoles) o~ ~trans-1-(294~dimethoxybenzyl)~3 (2-m~thyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidiny ~ -acetic acid, prepared as de~cribed in point i) above~ in 10 ml o~ dichloro-methane under ice cooling. ~hereafter 107 ml of ethyl diazo-acetate are added to th.e mixture~ and the mixt~re is stirred at room tempera~ure ~or 24 hoursO ~he dark solution is 5~
~ 20 ~
e~aporated, and the residue is processed by column chroma-tography (adsorbent: Kieselgel 609 ~ = 00063-0.200 mm, eluting agen~t: a 7:2 mixture of benzene and acetone) to obtain 0.17 g (7.3 %) of ethyl 2-diazo~4--trans-[1~(2,4~dime-thoxybenzyl) 3~(2-methyl~1,3--dioxolan~2-yl)-4-oxo-2-azethidinyl]~3-oxo-bu-tanoate.
IR (film): 2160, 1750, 17209 1640 cm lo ~he starting substance of Example 1 can also be prepared from a compound wherein R' is 4-methoxy-phenyl group as follows:
A) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) o~ diethyl bromomalona-te is stirred at room temperature for 2 days.
~he resulting mass is triturated with 100 ml of diethyl ether, the separated 4-methoxy-anisidine hydrobromide is filtered off and washed with a small amount of di-ethyl ether. ~he mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13.2 g (47 %) of diethyl (4-methoxyanilino)~malonate are ob-tained; m.pO: 64-65 C (e-thanol) ~ nalysis:
calculated for C14HlgN05 (281.31):
C 59.77 %, H: 6.81 %, N: 4O99 %;
found: C 59a99 %~ H: 6.97 %, N: 5~25 %.
I~ (KBr): 3300, 1775, 1725 cm 1, lH-NMR (CDC13): ~ = 1023 (t~ 6Hg J = 7.2 Hz)g 3.67 (S9 3H), 402 (q, 4H, J = 7~2 Hz), 4.62 (s, lH)g 4.1-4.5 ~broad s, lH), 6.55 (2H) + 6.73 (2H, AA'BB', t5'~
~ 21 J = 9 Hz) ppm~
B) A mixture of 1102 g (0O04 mole) of di-ethyl (4-~e-thoxyanilino)-malonate, prepared as described in point A) above, 15 ml of glacial ace-tic acid and 4 g (3.7 ml, 0.048 mo]e) o~ diketene is boiled for 0.5 hour.
The solution is evaporated in vacuo, the oily residue is -triturated with diethyl ether, and the solid is filtered off. 10.5 g (72 %) of diethyl 1-(4-methoxy-phenyl)-3~hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or its tautomer are obtained; m~p.:
136-137 ~ (ethyl acetate)O
Analysis:
a ~ated for C18H23N7 (365.38):
C: 59.17 %, H: 6.39 %, N: 3.83 %3 15found: C: 58098 ~0, H: 6.90 %, N: 4.04 %.
IR (KBr): 3600-3000, 1760, 1740, 1685 cm 1.
lI-I-NMR (CDC13): ~ = 1007 (t, 3H, J = 7~2 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1~58 (s, 3H), 2.76 (s, 2H), 3.64 (s, lH), 3.76 (s, 3H), 4.1 (q, 2H, J = 702 Hz), 4.27 (q, 2H, J = 7~2 Hz), 607 (2H) -~ 7.0 ~2H, AA'BB'~
J = 9 Hz) ppm~
G') 9.1 g ~0.025 mole) of diethyl 1-(4-methoxy-phenyl)-3-hydroxy-3-methyl-5-oxo-292-pyrrolidine-di-carboxylate, preparecl as described in point B) above, are suspended in 50 ml oI dry diethyl ether, and a solution of 1072 g o~ metallic sodium i-n 30 ml of dry ethanol and a solution of ~O35 g (00025 mole) of iodine in 50 ml of dry diethyl ether are simultaneously dropped ~, s~
- 21a -into the suspension under vigorous stirring and cooling with ice. ~hereaf-ter the mixture is poured into ]00 ml of a saturated aqueous sodium chloride solution, and 2 g of sodium hydrosulfite and 2 ml of glacial acetic acid are added. The etheral phase is separated~ and the aqueous phase is extracted thrice wLth 50 ml of diethyl ether, each ~he e-theral phases are combinedg dried over magnesium sulfate, fi]-tered, and the filtrate is evapor-ated. ~he oily residue is triturated with 2 propanol to obtain 6.2 g (68 %) of cxystalline cLiethy~ 3-acetyl-1 (4 methoxyphenyl~-4-oxo~2 9 2-azq~hidine-dicarboxylate; m~p.: 70~71C (sthanol~D
A~alysis:
calculated ~or C18H21N07 ~363038):
C: 59~50 %, H: 5082 %, N: 3~85 %3 fou~d: C: 59004 %1 H: 5.84 %, N: 4~08 %~
IR (KBr).: 1760; ~l735 3 1720 cm 1.
lH NMR (CDC13): ~= 1020 (t, 3H, J = 7.2 Hz) 9 1.22 (t, 3H, J = 702 Hz)~ 2~33 (s~ ~H); 3~7 (s, 3H)9 4017 ~q, 2H~
J = 7~2 Hz), 4.19 (q, 2H, J - 702 Hz) 7 4O7 ~s~ lH)~ 6~7 (2H) 7031 (2X, AA~B~'? J ~ 9 Ez) ppmO
D~ 6 g (0.0165 mole) o~ diethyl 3-ac~tyl-1-(L~metihoxy-phenyl)~4-oxo-2,2-azethidine-dicarboxylate~ pr~par~d as dcscribad in point C) abo.ve, are dissolv~d in 20 ml o~ dry dioxane and 4.1 g (3 75 ml., 00066 mole~ o~ ethylena glycol~
7~1 g (6.3 ml, 0O05 mole) o~ boro~ trifluoride-diethyl etherate complex are added dropwise to the stirred solutio~ undar ice cooling, and the reaction mixture is stirred ~or additio~al 2 hours a~ roo.m temperatuxeO ~he solution is rendered alkalinQ
with saturated aqueous sodium hydrocarbonate ~olution, there~
a~t;er 100 ml of water are added, and the mixture is ~xt;racbed thrice with 50 ml o~ diethyl ether, each. ~he organic phases ara co~bi~ed, dried over magnesium sulfate~ ~iltered, and t~e ~iltrate is evaporatQd, ~he oily residue is triturated with diethyl ether to obtain 6 g (89 %) of crystalline diethyl 3 ~2~metihyl 1J3-dioxolan~2-yl)-1~(4 methoxyphenyl?-4~oxo-2~2-az~thidine-dicarboxylate; m~p.: 82-83C (stihanol~0 Analysi.s:
calculated for (~20H25~o8 (~7 3) C: 58096 ~ X: 6018 %, N: 3O44 ~;
5~
~ound: C: 58070 ~a, H 5068 %; N- 3063 ~, IR (K~r~7 1749 cm 1 (broad) lH NMR ~CDC13)~ ~ = 1017 (~ 3H~ J = 702 ~z); 1- 6 (t, 3H9 J = 702 Hz)~ 105 I'S) ~h) 9 307 ~s, 3H) ~ 3.9 ~mg ~
402 (m3 5H) ~ 6,.67 (2H) ~ ,703~ t2H, AA9~ , J - 9 Hz) ppmO
:E~) 11 g (0i,0245 mole) o~ die~hyl 3~(2-meth~yl 15,3~L~
oxolan~2~yl)~1~(4~methoxyE,he~,lyl) ~4~0xo-27~-azethidine-dicarb~
oxylate are clissolved in 20 m~ o.~ dimethyl sul.~oxide~ 1~72 g (000295 mol~) of sodium chloride and 0~9 ml (00049 mole3 o~E
wat0r ara added9 and t;he mixture ls sti.rred a~ 175C until a comple tq reactio~l is obtai:nsd. The progress o~ the reac~io~
is monitoxed by thi~ layer chromatography (adsorbent: Kiesel~
gel G according to Stahl; devqloping solvent: a 6~4 mixturs . o~ be~zene and sthyl acetat;e)0 The mixt uxe is cooled, poured into 150 ml oî a saturated aqueous sodium chloride solution~ and extracted . thrice with 50 ml of diethyl ether~ eachO Tne organic phases are combined~ dxied over magnesium sulfate, ~iltered~ and ~he filtrate i~ evaporated. The resulti~g oily residue, waighing
daveloping so]!vent: a 8~2 mi~ture oî toluene and acstone~.
0030 g (53 ~o) o~ diethyl 1-~2~4-dimethoxybenzyl) 3~(2-methyl~
1~3~oxathio~an-2-yl~-4-oxo-2 ,2~azethidine-dlcarboxylate is obtai~ed H NMlR ~CDC13). ~- 008-1.55 (m~ 6H); 1.72 ~ 1 77 (d~
~H)7 2~9-304 ~m, 2H)7 3975 (s~ 6H)) 440~500 tm, 9H)~ 60L~ (m, 2H) -~ 7 o l ( d, lH) ppm..
g) A solution of 5.21 g (0.130 mole) oî sodium h~dr-oxide in 60 ~1 oî water is added to a suspension o~ 4102 g ~ 0 0109 mo le ) o~ trans- e thyl 1- ( 2 7 L~-dime thoxyb enz~ ( 2-me thyl~
1 ,3-dioxolan-2-yl) -4-oxo-2-azethidine-carboxyla te 5 prepared as described ln point e) abova9 in 50 ml o~ ethanol under 20 stirring and cooling with ice waker, and stirring is con~inued until a clear solution is obtained (about 20 minul;a~) O 100 ml o:e l,vater are adcled therl to the solution, a~d khe mi}~ture is shak~n with 100 ml of ether. ~he aqueous phase is acidiîied to pH = 1 with concentrated aqueous hydrochloric acid, and ~h~n shaken quickly with 100 ml and twice with 50 ml of di-chloromathane, each~ ~he dichlorom~thana solu~ions are combined~
dried ovar magnesium sul~ate~ filtsred, and the filtrato is evaporatedD ~ho oily residuo is crystallized from a mixture oî toluene and petroleum ether to obtain 35 g (l92 ~0) o~ tran~-~0 1-(2,~-dimetho~ybenzyl)~3-(2-methyl-1,3-dioxola~2~yl~ 4Doxo~
., - 16 ~
2-azethidine-carboxylic acid; m.pO: 117~118 C
(toluene).
Analysis:
calculate~ fcr C17H21N7 (351-35) 5C: 5~.11 %, H: 6003 %, M: 3.99 %;
:Eound: ~: 58.17 %, H: 6.30 %, M: 4.24 %.
IR (K~r): 3500~2500, 2900, 1760, 1720 cm lH-M~R (CDC13): ~ = 1039 (s, 3H), 3.50 (d, lH, J = 2.5 Hz), 3.77 (s, 3H)9 3.79 (s, 3H), 3.86 (d, lH, J = 2.5 Hz), 3.96 (m, 4H), 4.21 + 4.56 (d, 2H, JA~ =
= 15 Hz), 6044 (m, 2H) + 7015 (d, lH, J = 10 Hz), 7O5~ (broad s, lH) ppm.
h) 7.3 ml (52.5 mmoles) of triethyl amine are added -to a solution of 17.6 g (50 mmoles) of trans--1-(2,~-dimethoxybenzyl)-3-(2-me-thyl~1,3-dioxolan-2-yl)~
~~-oxo-2 azethidine-carboxylic acid, prepared as described in point g~ above, in 150 ml of dry tetrahydrofuran, and then 5.0 ml (52.5 mmoles) of ethyl chloroformate are added to the mixture under cooling with ice. ~he mixture is cooled to -15 C, stirred at this tempera-ture for 20 minutes, and the separated triethyl amine salt is fil-tered off at the same -temperature under argon atmosphere. A solution of 150 mmoles of diazomethane in 230 ml of cold diethyl ether is added to the fil-trateO
~he mixture is stirred, allowed to warm to room tempera-ture, and after 2 hours of stirring it is evaporated to dryness. r~he brown, thick residue is dissolved in 20 ml of benzene, and the product is separated by column .~, 5~
~ 17 ~
chromatography (adsorbent: 150 g of Kieselgel 60, 0 = 0.063~-0.200 mm, eluting agent: a 7:2 mixture of benzene and acetone)O 1200 g (64 %) of trans~4~-(diazo-acetyl)-1-(2,4~dimethoxybenzyl)~3-(2-methyl-1,3-dioxolan-5 ~2-yl)-2-azethidinone are obtained.
IR (K13r): 2900 ~ 2110 ~ 1760 cm lo Analysis:
calculated Eor C18H21~36 (375 3 found: ~: 57~78 %~ H: 5.39 %.
i) A mixture of 2.25 g (6 mmoles) of trans-4--(diazoace-tyl)~l (2,4-dimethoxybenzyl)-3-(2-me-thyl-1,3--dioxolan~2-yl)-2-azethidirLone, prepared as described in point h) above, 100 ml of peroxide-free tetrahydrofuran and 50 ml of water is irradia-ted for about 4 hours with 15 a high-pressure mercury lamp (HPK 125) ~ immersed into the reaction vessel made oE pyrex glass 7 under argon atmosphere~ ~he solution is evaporated in vacuo to a final volume of 50 ml, and the concentrate is diluted with water -to 130 ml. 2 ~ 4 ml of a 10 % aqueous sodium 20 hydroxide solution are added to the aqueous mixture, and the alkaline mixture is washed thrice with 20 ml of di-chloromethane, each. Thereafter the aqueous phase is acidified -to pH = 2 with concentrated aqueous hydro-chloric acid. ~he acidic solution is extracted thrice 25 with 20 ml oE dichloromethane, each, the extracts are combi-ned, dried over magnesium sulfate, filtered, and the filtrate is evaporated to dryness. ~he residue is crystallized with ether. 1~82 g (83 %) of [trans-l-17a ~(2,4-dimethoxybenzyl)-3-(2-methyl-1~3-dioxolan-2-yl)~
4-oxo-2-azethidinyl]-ace-tic acid are obtained; m.p.:
124 ~ (ether).
Analysis:
f 18II23N7 (365.37) C: 59.17 %, H: 6.34 %, M: 3.83 %;
found: C: 59~22 %, H: 6.49 %, N: 4~07 %O
I:R (K~r): 3500-2300, 2900, 1730, 1700 cm 1 j) o.364 g (2.2 mmoles) of 98 % carbonyl diimidazole is added to a solution of 07730 g (2 mmoles) of ~trans-l-:L8 ~2~4-dimethoxybenz-yl)-3-(2-methyl-lg3~dioxolan-2 ~1) 4--oxo~
2 azathidi-nyl7~acetic acid~ prepare(l as described in point i) aboveg, in 10 ml OI dry tetrahydro~uran~ and the mixture is ~tirrsd fo.r 20 minuts~30 00~15 g (202 mmoles) oï mag~esium 5 athyl malona~ is added to the solution9 and ~tirring is con~
tinued for 2 hoursO ~he reaction mixture is evaporatedg tha residus is sh~ken with 40 ml o:E dichlorometha~e and 40 ml o:E
a ûo5 n aqueolls h;ydrochloric acid7 and the two phases ars sspara~ed from each other, ~rhe aqu~ous phase is extractsd with 10 20 ml of dichloromethan~O The organic phasss are combirled, washed twice ~Jith 10 ml of a ~% aqusous sodium carbonate solu-tion~ each~ dried over n~g~esium sul~ata, liltared7 a~d the ~iltrate is ~vaporatedO 0.41 g (47 %) of ethyl ~rans~ 2 dimethox;Ybenzyl)-3-(2-methyl-173-dioxolan-2-yl)-4-o~o-2~az-15 othidi~y_7-3- oxo-bu~arloate is obtainedO
IR (filn): 1750l 1740, 1720 cm 1~, lH NMR (GDC13): ~ = 1.26 (t9 3H?~ 1.39 (s~ 3H~" 2 2-303 (m, 5H)~ 3..65-4.45 (m, 14H)9 6~25~6e~6 and 7~05-7025 (m7 3H~ ppm.
k3 0~,6~3 ml (5~0 mmoles) o~ triethyl amine and Q.986 g (500 mmoles) o~ tosyl azi.de are added to a solutio~ o.~ 20177 g (500 mmo~es) oi~ ethyl trans~ (2~4-dimethoxyben~byl~-3-(2-mathyl-1,3-dio~olan-2-yl)-~oxo-2-azcthidiny~ 3-o~o~butanoa~e, prepared as d~scribed in point j) above, in 15 ~1 o~ dry 25 acc~oIlitrila undor ice cooling. ~he solution is stirred for 3 hours and during this period it is a llowed to warm to room temperature. The solu~ion is evaporated to dryness, and the resîdu~ is processed b~y columrl chromatography (adsorben~:
Kieselgel 60, ,0 = 0.063-0..200 mm, eluting agent: a 1~3 mi~{ture of ~enzene and acetone). 1.~1 g (61 ~3 of ethyl 2 diazo-4 trans-~ ~(2~4-dimethox~benzyl~-3 (2~methyl-1~3~dioxolan~2-yl)-4-oxo-2-azethidirLy ~ ~3-oxo-butanoate are obtairl~d~
1~ 5~4 g (20 mmoles~ o~ potassium peroxydis~ ate (K2S208)~ 702 ~ (L~ mm.oles) of disodium hydrophosphate mono~
hyclrate (Na2HPO~ I?0~ and 18 ml of water are added to a solu-tion of 2~340 g (500 mmoles~ of e~hyl 2~diazo~4~ra~s~ (2~4-dimethoxybe~zyl)-3-(2-methyl-1~3-dio.yol.an-2-yl)~4 oxo-2-az-~3thidi~yl7~3 oxo-butanoate, prepared as described i~ point k) above~ in 30 ml of acetonitrila~ and the mixture is boil~3d for 10 hours. Th~3 reaction mixture i9 cooled, fil~ered~ and the t~.~Jo phases of the filtrata are separated from each other. The aqueous phase is extracted thrice with 10 ml of ethyl acetat6 9 oachO ~he org~anic phases are combi~ed~ dried over mag~osium sulfate, .~iltered, and the fil~rate is evaporated. ~he residue 15 is processed by column chromatography (adsorbent: Kiesalg~l 60, 0 = 00063-00200 mm, ~31utirlg agent: a 7:3 mixture o~ benzene .and aceton~) to obtain 0~56 g (36 %) o~ ethyl 2-diazo-4-trans~
-(2-methyl 1,3-dioxolan-2-yl)-4~oxo~2-azethidinyl7-3-oxo-butanoateO
IR (~ilm): 3280, 2160, 1760, 17209 1640 cm 1.
m3 ~he product obtained in point k3 above can also be prepared according to Method B) of the i~vention as follows:
One drop of dimethyl ~ormamide and 0037 ml (500 mmolas~
of thionyl chloride are added to a stirxed solution of 10830 g (500 mmoles) o~ ~trans-1-(294~dimethoxybenzyl)~3 (2-m~thyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidiny ~ -acetic acid, prepared as de~cribed in point i) above~ in 10 ml o~ dichloro-methane under ice cooling. ~hereafter 107 ml of ethyl diazo-acetate are added to th.e mixture~ and the mixt~re is stirred at room tempera~ure ~or 24 hoursO ~he dark solution is 5~
~ 20 ~
e~aporated, and the residue is processed by column chroma-tography (adsorbent: Kieselgel 609 ~ = 00063-0.200 mm, eluting agen~t: a 7:2 mixture of benzene and acetone) to obtain 0.17 g (7.3 %) of ethyl 2-diazo~4--trans-[1~(2,4~dime-thoxybenzyl) 3~(2-methyl~1,3--dioxolan~2-yl)-4-oxo-2-azethidinyl]~3-oxo-bu-tanoate.
IR (film): 2160, 1750, 17209 1640 cm lo ~he starting substance of Example 1 can also be prepared from a compound wherein R' is 4-methoxy-phenyl group as follows:
A) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) o~ diethyl bromomalona-te is stirred at room temperature for 2 days.
~he resulting mass is triturated with 100 ml of diethyl ether, the separated 4-methoxy-anisidine hydrobromide is filtered off and washed with a small amount of di-ethyl ether. ~he mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13.2 g (47 %) of diethyl (4-methoxyanilino)~malonate are ob-tained; m.pO: 64-65 C (e-thanol) ~ nalysis:
calculated for C14HlgN05 (281.31):
C 59.77 %, H: 6.81 %, N: 4O99 %;
found: C 59a99 %~ H: 6.97 %, N: 5~25 %.
I~ (KBr): 3300, 1775, 1725 cm 1, lH-NMR (CDC13): ~ = 1023 (t~ 6Hg J = 7.2 Hz)g 3.67 (S9 3H), 402 (q, 4H, J = 7~2 Hz), 4.62 (s, lH)g 4.1-4.5 ~broad s, lH), 6.55 (2H) + 6.73 (2H, AA'BB', t5'~
~ 21 J = 9 Hz) ppm~
B) A mixture of 1102 g (0O04 mole) of di-ethyl (4-~e-thoxyanilino)-malonate, prepared as described in point A) above, 15 ml of glacial ace-tic acid and 4 g (3.7 ml, 0.048 mo]e) o~ diketene is boiled for 0.5 hour.
The solution is evaporated in vacuo, the oily residue is -triturated with diethyl ether, and the solid is filtered off. 10.5 g (72 %) of diethyl 1-(4-methoxy-phenyl)-3~hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or its tautomer are obtained; m~p.:
136-137 ~ (ethyl acetate)O
Analysis:
a ~ated for C18H23N7 (365.38):
C: 59.17 %, H: 6.39 %, N: 3.83 %3 15found: C: 58098 ~0, H: 6.90 %, N: 4.04 %.
IR (KBr): 3600-3000, 1760, 1740, 1685 cm 1.
lI-I-NMR (CDC13): ~ = 1007 (t, 3H, J = 7~2 Hz), 1.28 (t, 3H, J = 7.2 Hz), 1~58 (s, 3H), 2.76 (s, 2H), 3.64 (s, lH), 3.76 (s, 3H), 4.1 (q, 2H, J = 702 Hz), 4.27 (q, 2H, J = 7~2 Hz), 607 (2H) -~ 7.0 ~2H, AA'BB'~
J = 9 Hz) ppm~
G') 9.1 g ~0.025 mole) of diethyl 1-(4-methoxy-phenyl)-3-hydroxy-3-methyl-5-oxo-292-pyrrolidine-di-carboxylate, preparecl as described in point B) above, are suspended in 50 ml oI dry diethyl ether, and a solution of 1072 g o~ metallic sodium i-n 30 ml of dry ethanol and a solution of ~O35 g (00025 mole) of iodine in 50 ml of dry diethyl ether are simultaneously dropped ~, s~
- 21a -into the suspension under vigorous stirring and cooling with ice. ~hereaf-ter the mixture is poured into ]00 ml of a saturated aqueous sodium chloride solution, and 2 g of sodium hydrosulfite and 2 ml of glacial acetic acid are added. The etheral phase is separated~ and the aqueous phase is extracted thrice wLth 50 ml of diethyl ether, each ~he e-theral phases are combinedg dried over magnesium sulfate, fi]-tered, and the filtrate is evapor-ated. ~he oily residue is triturated with 2 propanol to obtain 6.2 g (68 %) of cxystalline cLiethy~ 3-acetyl-1 (4 methoxyphenyl~-4-oxo~2 9 2-azq~hidine-dicarboxylate; m~p.: 70~71C (sthanol~D
A~alysis:
calculated ~or C18H21N07 ~363038):
C: 59~50 %, H: 5082 %, N: 3~85 %3 fou~d: C: 59004 %1 H: 5.84 %, N: 4~08 %~
IR (KBr).: 1760; ~l735 3 1720 cm 1.
lH NMR (CDC13): ~= 1020 (t, 3H, J = 7.2 Hz) 9 1.22 (t, 3H, J = 702 Hz)~ 2~33 (s~ ~H); 3~7 (s, 3H)9 4017 ~q, 2H~
J = 7~2 Hz), 4.19 (q, 2H, J - 702 Hz) 7 4O7 ~s~ lH)~ 6~7 (2H) 7031 (2X, AA~B~'? J ~ 9 Ez) ppmO
D~ 6 g (0.0165 mole) o~ diethyl 3-ac~tyl-1-(L~metihoxy-phenyl)~4-oxo-2,2-azethidine-dicarboxylate~ pr~par~d as dcscribad in point C) abo.ve, are dissolv~d in 20 ml o~ dry dioxane and 4.1 g (3 75 ml., 00066 mole~ o~ ethylena glycol~
7~1 g (6.3 ml, 0O05 mole) o~ boro~ trifluoride-diethyl etherate complex are added dropwise to the stirred solutio~ undar ice cooling, and the reaction mixture is stirred ~or additio~al 2 hours a~ roo.m temperatuxeO ~he solution is rendered alkalinQ
with saturated aqueous sodium hydrocarbonate ~olution, there~
a~t;er 100 ml of water are added, and the mixture is ~xt;racbed thrice with 50 ml o~ diethyl ether, each. ~he organic phases ara co~bi~ed, dried over magnesium sulfate~ ~iltered, and t~e ~iltrate is evaporatQd, ~he oily residue is triturated with diethyl ether to obtain 6 g (89 %) of crystalline diethyl 3 ~2~metihyl 1J3-dioxolan~2-yl)-1~(4 methoxyphenyl?-4~oxo-2~2-az~thidine-dicarboxylate; m~p.: 82-83C (stihanol~0 Analysi.s:
calculated for (~20H25~o8 (~7 3) C: 58096 ~ X: 6018 %, N: 3O44 ~;
5~
~ound: C: 58070 ~a, H 5068 %; N- 3063 ~, IR (K~r~7 1749 cm 1 (broad) lH NMR ~CDC13)~ ~ = 1017 (~ 3H~ J = 702 ~z); 1- 6 (t, 3H9 J = 702 Hz)~ 105 I'S) ~h) 9 307 ~s, 3H) ~ 3.9 ~mg ~
402 (m3 5H) ~ 6,.67 (2H) ~ ,703~ t2H, AA9~ , J - 9 Hz) ppmO
:E~) 11 g (0i,0245 mole) o~ die~hyl 3~(2-meth~yl 15,3~L~
oxolan~2~yl)~1~(4~methoxyE,he~,lyl) ~4~0xo-27~-azethidine-dicarb~
oxylate are clissolved in 20 m~ o.~ dimethyl sul.~oxide~ 1~72 g (000295 mol~) of sodium chloride and 0~9 ml (00049 mole3 o~E
wat0r ara added9 and t;he mixture ls sti.rred a~ 175C until a comple tq reactio~l is obtai:nsd. The progress o~ the reac~io~
is monitoxed by thi~ layer chromatography (adsorbent: Kiesel~
gel G according to Stahl; devqloping solvent: a 6~4 mixturs . o~ be~zene and sthyl acetat;e)0 The mixt uxe is cooled, poured into 150 ml oî a saturated aqueous sodium chloride solution~ and extracted . thrice with 50 ml of diethyl ether~ eachO Tne organic phases are combined~ dxied over magnesium sulfate, ~iltered~ and ~he filtrate i~ evaporated. The resulti~g oily residue, waighing
6 g7 iS dissolved in 25 ml of 96~o ethanol, and a solutlon of 0072 g (00018 mole) of sodium hydroxide in 10 ml of water is added to the alcoholic mixture under cooling with ice waSer.
~he mixtur~ lS stirred for 0~5 hour, Sh~n dilu~ed with 50 ml of wa~er and washed twice w:ith 25 ml of dichloromethane~ each.
The aqueous pha~e is acidifi.ed to pH = 1 with concen~raSed aqueous hydrochloric acid9 ancl thsn extrac~ed Shrice with 25 ml of diohloromethane, each. r~he organic phases are combined9 dried over magnesium sulfateg filtered~ and the filtrate is evaporatedi ~he oily xesidue is crystallized with benzeneO
4 g (54 ~) of Sra~,-3-(2 methyl~ dioxola~-2-yl)-1-(4-meth-L~35~
oxyphenyl)-4-oxo~2~aze-thidine carboxylic acid are ob-tained.
Analysis:
calculated for Cll~Hl7N06 (307.32):
5C: 58063 %, H: 5.57 %, N: 4.56 %;
:Eound: C: 58O40 %, H: 5080 %, N: 4.66 %.
IR (KBr): 3400-2700, 1750 (broad) cm 1.
lH N~ (CDC13): ~ = 1.5 (s, 3H), 3.7 (d, lH;
J = 2.5 Hz), 3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, lH, J = 2.5 Hz), 6082 (2H) + 7.26 (2H, AA'BB', J = 9.5 Hz), 9.2 (s, lH) ppmO
~ ) l.l:L g (1.56 ml, OoOll mole) o~' dry tri~
ethyl ami'ne are added to a solution of 3 g (0~01 mole) of a compound prepared as described in point E) above in 20 ml of dry tetrahydrof'uran. ~he solution is cooled to -15 C, and 1.2 g (1.06 ml, OoOll mole) of ethyl chloroformate are added dropwise -to the stirred solution.
After 20 minutes of stirring the separated salt is fil~
tered off' under ni-trogen atmosphere, and a solution of 4.8 g (00025 mole) of diazomethane in diethyl ether is added to the filtrate at room temperature. Af-ter 2 hours of stirring the excess of diazomethane is decomposed with acetic acid, and the solution is evaporated in vacuo~ ~he oily residue slowly crystallizes. 3 g (90 %) of trans--4 (diazoacetyl)~3~(2-methyl~1,3-dioxolan-2-yl)~1-(4~
-methoxyphenyl)-2-azethidinone are obtainedj mOpO:
95-96 C (benzene and ether)O
IR (K~3r): 2200 7 1760, 1640 cm lo - 24a -lH NMR (CDC13): ~ = 1.50 (s, 3H), 3.51 (d, lH, J = 2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, lH, J = 2.6 Hz), 504r7 (s, lH), 6.85 (2H) -~ 7030 (2H, AA'BB', J = 9 Hz) ppmO
G) 3.3 g (0.01 mole) of trans-4-(diazoacetyl)~
-3~(2-methyl~1,3-dioxolan-2-yl)-1-(4~methoxyphenyl)-2--azethidinone, prepared as described in point ~) above, are dissol~ed in a s~
- 25 ~
- mi~ture o~ 50 ml of' watar ancl 100 ml of ~etrahy~rofuxa~ Tha mi~ture is irradiated with a high pressure marcury lamp in a photoxaactor at room temp6ratiure under nitrogan a~mosphara~
and tha progress of the raactiion is monitored by ~hin layer chromatography (adsorbent: Eie~elgel G accardi~ ~o Stahl~
deVfllOping 901vent: a 7:1 mix~uxe o.~ ba~ze~e a~d acatona)~
When the raac~ion is over~ te~rahydrofura~ is distilled o~.~ in vacuo 3 the residua is rand0red alkaline with a 20~o aqueous sodium hydroxide solution~ a1~d the solution is washad twica wi~h 15 ml o~ dichloromothana 9 sach~ The aqueous phasa is acidi~
~iad to pH 1~2 with. concantrated aqueous hydrochloric acid and ~han ~xtractad thrice with 20 ml o~ dichloromethane~ each~
~ha organic phases are combined5 dried over magn~sium sulfa~a D
~iltered, and the ~iltra~a i~3 evaporatadJ 1,,6 g ~50 %) o~
~rans-3 ( 2-me thyl- l ~ 3-di oxo :Larl~2-yl) ~ 4-me thoxyphen;yl) 4 oxo-2-azethidinyl7~acetic ac:id are obtainedO
Analysis:
calculated Por C16E[19N06 ~32;Lo33) C: 59~80 ~;, H: 5096 %, N: 4036 %~
~ound: C: 59~60 ~1 H: 5~76 %, N: 4008 %0 IR (film~: 3500-250(), 1760-1700 cm 1.
H) On22 g (1036 mmo]Les~ OI carbonyl diimidazola iæ
addad to a solutio~. o~ 00~ g ~172LI' mmolos) o:E /trans 3~(2-meth~l-1,3-dioxolan-2-yl)-1 ~4 msthoxyphenyl)-L~oxo~2-az =
25 ethidinyl7-acotic acid~ prepared as dasc.ribed in point G) above9 in 15 ml o~ dry tetrahydro~uran~ and the mixture is stirred at room ~emperature ~or about on~ hourO When the gas evolu-tion caases, 0~196 g (1.36 mmolss) o~ magnesium ethyl ma:Lonate is addsd to the mixturs, and stirring is coLLtinued for one 30 hour. ~he solution is evaporated, th~ residue is dissolved -- 26 ~
in 50 ml of di chlo:romethan~, a~d th~ solukioz:l is wash~d with 25 ml OI a 2rl aqueous hydrochloric acid solutio~. The aqueou~
phas~ is extract~d. with 25 ml o.~ d.ichloromethaneO ~he oxgallic phases a.re combined, washed t~vice with 20 ml o~ a 5~0 aqueous sodium hydrocarbo~ate solution~ each~ dried Gver magne~ium sulfate, ~ilt~red~ and tlle ~iltrat~ is evaporated~ 0~3 g (62 %) o~ ~thyl tran,s-4~ (2-methyl~1~3 dio~olan~2 yl)~l (4~methoxy~
phe~yl)~4~o~o~2 azethidi~y~-3-oxo-bu~anoate is obtainoa.
Analysis:
lC calc!llatad ~'or C20H25N07 (391.42~:
C: 61037 %9 H: 6.,L1~ %9 ~i~ 345~3 ~709 fou~d: CO 61020 %, H: 6~59 %9 N: 3072 %O
IR (îilm): 1750 cm 1 o I) 0c,5 g ( 1044 mmoles) of' e~hyl trans~ 2_mot:hyl-1, 3 -dioxolan~2~yl) 1- ( 4-me thoxyphe r~yl) -4-oxo~2-a ze thidinyl7-3 oxo--buta~oa te, prepared as described i~ point X~ above 9 is . dissolved in 6 ml o~ dry acstonitril0D a~d 0028 g (1044 mmoles~
o~ to,syl azide and 0O2 ml (1~44 mmoles~ of dry triethyl amine are added to the st-lrred solution u~dsr cooling with iC9 or waterO The progress o~ the reaction is monitored by thin layer chromatography (adsor~ent: Kieselgel G according to ~ahl, deve,loping $olvent: a 7:3 mi~ture of benzene and ace-kone). A~ter 2 hours of stirring at room temperature the mix-tura is evaporated, the residue is dissolved in 40 ml o~ di~
chloromethane, and the solution i5 washed acid~fxee with 10 ml of a 40~0 aqueous potassium hydroxide solution a~d then with 10 ml of waterO The organic phase is dried over magnesium sul~ake~ ~iltered, and ~he filtrate is evaporatedO ~he oily residue is puri~ied by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254~3669 developing solve~t: a ~ ~37~ ~f~
~he mixtur~ lS stirred for 0~5 hour, Sh~n dilu~ed with 50 ml of wa~er and washed twice w:ith 25 ml of dichloromethane~ each.
The aqueous pha~e is acidifi.ed to pH = 1 with concen~raSed aqueous hydrochloric acid9 ancl thsn extrac~ed Shrice with 25 ml of diohloromethane, each. r~he organic phases are combined9 dried over magnesium sulfateg filtered~ and the filtrate is evaporatedi ~he oily xesidue is crystallized with benzeneO
4 g (54 ~) of Sra~,-3-(2 methyl~ dioxola~-2-yl)-1-(4-meth-L~35~
oxyphenyl)-4-oxo~2~aze-thidine carboxylic acid are ob-tained.
Analysis:
calculated for Cll~Hl7N06 (307.32):
5C: 58063 %, H: 5.57 %, N: 4.56 %;
:Eound: C: 58O40 %, H: 5080 %, N: 4.66 %.
IR (KBr): 3400-2700, 1750 (broad) cm 1.
lH N~ (CDC13): ~ = 1.5 (s, 3H), 3.7 (d, lH;
J = 2.5 Hz), 3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, lH, J = 2.5 Hz), 6082 (2H) + 7.26 (2H, AA'BB', J = 9.5 Hz), 9.2 (s, lH) ppmO
~ ) l.l:L g (1.56 ml, OoOll mole) o~' dry tri~
ethyl ami'ne are added to a solution of 3 g (0~01 mole) of a compound prepared as described in point E) above in 20 ml of dry tetrahydrof'uran. ~he solution is cooled to -15 C, and 1.2 g (1.06 ml, OoOll mole) of ethyl chloroformate are added dropwise -to the stirred solution.
After 20 minutes of stirring the separated salt is fil~
tered off' under ni-trogen atmosphere, and a solution of 4.8 g (00025 mole) of diazomethane in diethyl ether is added to the filtrate at room temperature. Af-ter 2 hours of stirring the excess of diazomethane is decomposed with acetic acid, and the solution is evaporated in vacuo~ ~he oily residue slowly crystallizes. 3 g (90 %) of trans--4 (diazoacetyl)~3~(2-methyl~1,3-dioxolan-2-yl)~1-(4~
-methoxyphenyl)-2-azethidinone are obtainedj mOpO:
95-96 C (benzene and ether)O
IR (K~3r): 2200 7 1760, 1640 cm lo - 24a -lH NMR (CDC13): ~ = 1.50 (s, 3H), 3.51 (d, lH, J = 2.6 Hz), 3.75 (s, 3H), 4.05 (m, 4H), 4.31 (d, lH, J = 2.6 Hz), 504r7 (s, lH), 6.85 (2H) -~ 7030 (2H, AA'BB', J = 9 Hz) ppmO
G) 3.3 g (0.01 mole) of trans-4-(diazoacetyl)~
-3~(2-methyl~1,3-dioxolan-2-yl)-1-(4~methoxyphenyl)-2--azethidinone, prepared as described in point ~) above, are dissol~ed in a s~
- 25 ~
- mi~ture o~ 50 ml of' watar ancl 100 ml of ~etrahy~rofuxa~ Tha mi~ture is irradiated with a high pressure marcury lamp in a photoxaactor at room temp6ratiure under nitrogan a~mosphara~
and tha progress of the raactiion is monitored by ~hin layer chromatography (adsorbent: Eie~elgel G accardi~ ~o Stahl~
deVfllOping 901vent: a 7:1 mix~uxe o.~ ba~ze~e a~d acatona)~
When the raac~ion is over~ te~rahydrofura~ is distilled o~.~ in vacuo 3 the residua is rand0red alkaline with a 20~o aqueous sodium hydroxide solution~ a1~d the solution is washad twica wi~h 15 ml o~ dichloromothana 9 sach~ The aqueous phasa is acidi~
~iad to pH 1~2 with. concantrated aqueous hydrochloric acid and ~han ~xtractad thrice with 20 ml o~ dichloromethane~ each~
~ha organic phases are combined5 dried over magn~sium sulfa~a D
~iltered, and the ~iltra~a i~3 evaporatadJ 1,,6 g ~50 %) o~
~rans-3 ( 2-me thyl- l ~ 3-di oxo :Larl~2-yl) ~ 4-me thoxyphen;yl) 4 oxo-2-azethidinyl7~acetic ac:id are obtainedO
Analysis:
calculated Por C16E[19N06 ~32;Lo33) C: 59~80 ~;, H: 5096 %, N: 4036 %~
~ound: C: 59~60 ~1 H: 5~76 %, N: 4008 %0 IR (film~: 3500-250(), 1760-1700 cm 1.
H) On22 g (1036 mmo]Les~ OI carbonyl diimidazola iæ
addad to a solutio~. o~ 00~ g ~172LI' mmolos) o:E /trans 3~(2-meth~l-1,3-dioxolan-2-yl)-1 ~4 msthoxyphenyl)-L~oxo~2-az =
25 ethidinyl7-acotic acid~ prepared as dasc.ribed in point G) above9 in 15 ml o~ dry tetrahydro~uran~ and the mixture is stirred at room ~emperature ~or about on~ hourO When the gas evolu-tion caases, 0~196 g (1.36 mmolss) o~ magnesium ethyl ma:Lonate is addsd to the mixturs, and stirring is coLLtinued for one 30 hour. ~he solution is evaporated, th~ residue is dissolved -- 26 ~
in 50 ml of di chlo:romethan~, a~d th~ solukioz:l is wash~d with 25 ml OI a 2rl aqueous hydrochloric acid solutio~. The aqueou~
phas~ is extract~d. with 25 ml o.~ d.ichloromethaneO ~he oxgallic phases a.re combined, washed t~vice with 20 ml o~ a 5~0 aqueous sodium hydrocarbo~ate solution~ each~ dried Gver magne~ium sulfate, ~ilt~red~ and tlle ~iltrat~ is evaporated~ 0~3 g (62 %) o~ ~thyl tran,s-4~ (2-methyl~1~3 dio~olan~2 yl)~l (4~methoxy~
phe~yl)~4~o~o~2 azethidi~y~-3-oxo-bu~anoate is obtainoa.
Analysis:
lC calc!llatad ~'or C20H25N07 (391.42~:
C: 61037 %9 H: 6.,L1~ %9 ~i~ 345~3 ~709 fou~d: CO 61020 %, H: 6~59 %9 N: 3072 %O
IR (îilm): 1750 cm 1 o I) 0c,5 g ( 1044 mmoles) of' e~hyl trans~ 2_mot:hyl-1, 3 -dioxolan~2~yl) 1- ( 4-me thoxyphe r~yl) -4-oxo~2-a ze thidinyl7-3 oxo--buta~oa te, prepared as described i~ point X~ above 9 is . dissolved in 6 ml o~ dry acstonitril0D a~d 0028 g (1044 mmoles~
o~ to,syl azide and 0O2 ml (1~44 mmoles~ of dry triethyl amine are added to the st-lrred solution u~dsr cooling with iC9 or waterO The progress o~ the reaction is monitored by thin layer chromatography (adsor~ent: Kieselgel G according to ~ahl, deve,loping $olvent: a 7:3 mi~ture of benzene and ace-kone). A~ter 2 hours of stirring at room temperature the mix-tura is evaporated, the residue is dissolved in 40 ml o~ di~
chloromethane, and the solution i5 washed acid~fxee with 10 ml of a 40~0 aqueous potassium hydroxide solution a~d then with 10 ml of waterO The organic phase is dried over magnesium sul~ake~ ~iltered, and ~he filtrate is evaporatedO ~he oily residue is puri~ied by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254~3669 developing solve~t: a ~ ~37~ ~f~
7:3 mixture of benzene and acetone) to obtain 002~ g (36 %) of e~hyl 2-diazo-L~trans~ (2~methyl-1,3-dioxola~2 yl~ l-( m~thoxyphenyl)-L~oxo-2~azethidiny ~ ~3-oxo-butanoate; mOp~o 131-132C (ether~0 Analysis:
calculated for C20H~N307 (417041)~
C: 57l~5 c,~, H: 5.55 %s N~ I0~07 %9 found: C: 57056 %9 H: 5o80 %~ N: 10008 ~
IR (KBr): 2200.1 1740, 1710~ 16L~0 cm~l.
J) 0045 g (00106 mole) of ethyl 2~diazoltrans 4~/3 (2-methyl~1,3-dioxolan-2-yl)-1-(L~methoxyphe~yl)~4~oxo_2-az_ ethidinyl7-3 oxo butanoate, prepared as describsd in point I~
above, .is dissolved in 405 ml of acetone~ and a sol~tion o~
1.500 g (207 mmoles) o:~ ceric ammonium ~i~rate in L~o5 ml of a 5% aqueous sul~uric acid is added dropwise under stirringO
Th~ reaction mixture is stirrod then for 5 minutes, thsraa~ter .kha yellow solution is neutralized with a 5% aqueous sodium hydrocarbona~e solution and extractsd thrice with 10 ml o~
ethyl acotate, each~ '.rhe organic phases are combined, dried over magnesium sul~ate~ filtersd, and the filtrate is evaporat-ed. Tho oil~ residue is purified as describsd in point I) above to obtain OolO g ~27 %) of ~thyl 2-diazo-tra~s-4- ~-(2-methyl-193-dioxoian-2-yl~-L~-oxo~2-azethidi~yl7-3~oxo-butanoateO
The IR spectrum o~ the produc~ is identical with that of ths co~pou~d prepared according ~o point 1)~
~`xample 2 ~ oben~ ~ ~met~
d-1oxo-l~azabi~clo~3~2 07he~a~ne-2-~carbox~late 0.050 g of dirhodium tetraacstate ~ h~(OAc)L~.2T ~
is addsd in several portions to a stirred and boiled suspension 5'~
o.~ 1~673 g (4i,() mmole5) of (p-nitrobenz~l) txans-2-diazo~4 ~_(2~me~ dioxolan-2 yl)-4-o~o-2-aza~hidi~ 3-oxo=
butanoata in 45 ml of dry be~zerle~, A:eter 10 hours o~ boilîrg the ~tarting substa~ce reacts complete lyO The mixture i~
5 coolad" the separated sub~tance is dissolv~d ill dichloro~
methane, and the solution is ~iltered through a Calite pad1 '~he fil~rate is ev~3pora$ed in vacuo, the residue i8 suspend~d ~ ether~ and khe sllspensio~ is ~iltered~. 1032 g ~84~6 %3 o:E
the ~imed oompound are obtai~ed; m.pO 167C
~Ll) IR ~KBr3: 1760, 1735 cm~l.
~I NMR~ ,4~ (S; ~H) I 2;47 (dd, lH~ Jg9m = 19 Hz~
Jvi.c = 8 H~), 2092 (dd9 lHD Jgem = 19 Hz~ Jvic = 3 Hz) 9 3046 ~d9 lH9 J - 2"4 Hz), ~oO~4~2 (m, 5H~, 4.75 (s~ l~I) ,, 5~,30 (dg 2H~ ~A3 = 14 Hz),, 7053 and 8.23 (d, 4H, JAE3 = 9 Hz) ppm.
~he s~arting substanc~ can be prepared as :f~ollows:
a~ A mix~ o~ 2~92 g (8.0 mmoles) oî ~trans-1-(2,4-dime thoxyb ~ n%yl) -3- ( 2-me ~hyl-l, 3-dloxola n-2 yl) -L~ oxo-2 a ~-ethidi~y~ aoetic aaid, prepared 3S described in point i) o~
:Example 1~ 1045 g ( 8 .8 mmole s) o~ 98% carbonyl di imida zole and 30 ml of dry telirahydrofuran is stirred at roorn tempera~
tùre for 30 minutes, tharea~t~r 2~,20 g (808 mmoles) of magnesium (p-nitrobenzyl)-malo~ate are added to the mixtureJ
and stiirrinO is co~tinu~d a~ room temperature for 2 hours~
The mixture i9 evaporated to clryness in vacuo 9 the reæidue is shaken with a mlxture of 150 ~ of dichlorometh~n~ and 150 ml of a 005 n aqueous h;ydrochloric acid,, and th~ phasos are ~eparated ~rom each other. The aqueous phase is extracted with 50 ml OI dichlo:come~haneO The organic phases ar~ combined9 washed twic~ with 25 ml of a 3% aqueous sodium hydrocarbonate ~olution9 each~ driad over magnesium sulfate, ~iltered,, and tj~
- 29 ~
the ~iltra~e is evaporat~d~ 3~L~ g (78 %3 o~ ~p~nitrobenzyl) tra~s~4~ 2,4-dimethoxybenzyl3-3-(2~methyl~113 dicxolan-2~yl)~
4-oxo~2-azethidin-yl7-3 oxo-butanoate are obtained.
IR ~ilm): 1740~ 1730, 1710 cm 1 o b) 0069 ml (500 mmoles) o~ ~rieth~l amine and 0099 g (5.0 mmoles) of tosyl azide are added to a stirred solub~o~
o~ 2071 g (500 ~lolesl o~ (p nitrobenzyl) trans~4~ t2~'~di-methoxybanzyl~-3-(2 methyl-1,3-dioxolan~2~yl)-4-oxo-2~azeth-idiny ~ 3-oxo-butanoate, prepared as described in psint a) abov~ 15 ml of dry acstonitrile under ice coolingO Tha solution is stirred f'or 3 hours~ during this period it i~
allowed to warm to room temperatur0~ Therea~ter the mixture i~ evaporated to dryness9 and the residue is processed by column chromatography (adsor'bent: Kieselgel 60, 0 = 0~063-00200 mm, ~lutir~ agen~. a 702 mixture of benzene and ace~one30 207 g (80 %) o~ (p-rlitrobenzyl) 2-diazo-L~trans-1-~2,4-di-methoxybenzyl)-3-~2-~methyl-1.,3-dioxolan-2~ 1?-L~oxo-2-az-ethidiny ~ 3-oxo-bu~;anoa~e are obtained; m.p~: 45-46C
(acetons)~ ~
IR (KBr): 2200~ 1750, 1730~ 1650 cm 1.
c3 ~ mixture o~ 2984 g (5.0 mmoles) of (p-nitrobenz~l) 2-diazo-4-~tra~s-1~(2,4-dimethoxybe~zyl);3 (2-methyl-1~3 di;-- o~olan;2-yl)-4 oxo--2-azethidiny~ -3-oxo~butanoate, prapared as described in poii.nt b) above~ 504 g (20 mmolss3 o~ potassium pero~ydi~ul~ate (~,S208), 7~2 g (40 mmoles) o~ disodium hydrophosphate monohydrate (~a2HP040H20), 30 ml of acetonitril~
a~d 18 ml of water is boiled and stirred for about 10 hoursO
~he reaction mixture is cooled, filtered, and ~he phas~s o~
the filtrate are separa~ed ~rom each other. ~he aq~eous phase is extracted thrice with 10 ml o~ ethyl acetate9 each.
. . .
~he or~anic phases ar~ combin~d9 dri~d ove.r magn~sium sulIata~
îilt6rod9 ar~d tha filtra te is evaporated,. ~he r~idus i5 procossed by colu~L~ chromatograph;y (adsorbent: Kiaselgel 60,, 0 = 00063-0.200 mm:, ~lu~ing agent: a 7~2 mixturo of be~z~no and ac2tone) to ob~ain 0~67 g (32 %) o~ (p-nitrob~nzyl) 2-di-a z o ~ trans-3- ( 2-ma thy l-l ~3-dioxolan-2-yl)-4-oxo 2-az a t hidin-y~ 3-oxo-bu~arloate; m~,p,: 1.63-164C ~thar) O
IR (EBr): 33209 21603 1750, 1710, 1630 cm 1, lH NMR: d-= 1.41 (s~ 3H) " 2.98 (dd) and 3.~ (dd9 2H, J = 10 Hz and 4 Hz) ~ 3018 (d, lH) J = 2J4 Hz); 3083-4.15 ~m, 5H~, 5~.36 (s~ 2H), 6~0 (s, lH) 9 7.54 (d) and 8.26 Id9 4H, AE?
J = 9 Hz ) ppm.
calculated for C20H~N307 (417041)~
C: 57l~5 c,~, H: 5.55 %s N~ I0~07 %9 found: C: 57056 %9 H: 5o80 %~ N: 10008 ~
IR (KBr): 2200.1 1740, 1710~ 16L~0 cm~l.
J) 0045 g (00106 mole) of ethyl 2~diazoltrans 4~/3 (2-methyl~1,3-dioxolan-2-yl)-1-(L~methoxyphe~yl)~4~oxo_2-az_ ethidinyl7-3 oxo butanoate, prepared as describsd in point I~
above, .is dissolved in 405 ml of acetone~ and a sol~tion o~
1.500 g (207 mmoles) o:~ ceric ammonium ~i~rate in L~o5 ml of a 5% aqueous sul~uric acid is added dropwise under stirringO
Th~ reaction mixture is stirrod then for 5 minutes, thsraa~ter .kha yellow solution is neutralized with a 5% aqueous sodium hydrocarbona~e solution and extractsd thrice with 10 ml o~
ethyl acotate, each~ '.rhe organic phases are combined, dried over magnesium sul~ate~ filtersd, and the filtrate is evaporat-ed. Tho oil~ residue is purified as describsd in point I) above to obtain OolO g ~27 %) of ~thyl 2-diazo-tra~s-4- ~-(2-methyl-193-dioxoian-2-yl~-L~-oxo~2-azethidi~yl7-3~oxo-butanoateO
The IR spectrum o~ the produc~ is identical with that of ths co~pou~d prepared according ~o point 1)~
~`xample 2 ~ oben~ ~ ~met~
d-1oxo-l~azabi~clo~3~2 07he~a~ne-2-~carbox~late 0.050 g of dirhodium tetraacstate ~ h~(OAc)L~.2T ~
is addsd in several portions to a stirred and boiled suspension 5'~
o.~ 1~673 g (4i,() mmole5) of (p-nitrobenz~l) txans-2-diazo~4 ~_(2~me~ dioxolan-2 yl)-4-o~o-2-aza~hidi~ 3-oxo=
butanoata in 45 ml of dry be~zerle~, A:eter 10 hours o~ boilîrg the ~tarting substa~ce reacts complete lyO The mixture i~
5 coolad" the separated sub~tance is dissolv~d ill dichloro~
methane, and the solution is ~iltered through a Calite pad1 '~he fil~rate is ev~3pora$ed in vacuo, the residue i8 suspend~d ~ ether~ and khe sllspensio~ is ~iltered~. 1032 g ~84~6 %3 o:E
the ~imed oompound are obtai~ed; m.pO 167C
~Ll) IR ~KBr3: 1760, 1735 cm~l.
~I NMR~ ,4~ (S; ~H) I 2;47 (dd, lH~ Jg9m = 19 Hz~
Jvi.c = 8 H~), 2092 (dd9 lHD Jgem = 19 Hz~ Jvic = 3 Hz) 9 3046 ~d9 lH9 J - 2"4 Hz), ~oO~4~2 (m, 5H~, 4.75 (s~ l~I) ,, 5~,30 (dg 2H~ ~A3 = 14 Hz),, 7053 and 8.23 (d, 4H, JAE3 = 9 Hz) ppm.
~he s~arting substanc~ can be prepared as :f~ollows:
a~ A mix~ o~ 2~92 g (8.0 mmoles) oî ~trans-1-(2,4-dime thoxyb ~ n%yl) -3- ( 2-me ~hyl-l, 3-dloxola n-2 yl) -L~ oxo-2 a ~-ethidi~y~ aoetic aaid, prepared 3S described in point i) o~
:Example 1~ 1045 g ( 8 .8 mmole s) o~ 98% carbonyl di imida zole and 30 ml of dry telirahydrofuran is stirred at roorn tempera~
tùre for 30 minutes, tharea~t~r 2~,20 g (808 mmoles) of magnesium (p-nitrobenzyl)-malo~ate are added to the mixtureJ
and stiirrinO is co~tinu~d a~ room temperature for 2 hours~
The mixture i9 evaporated to clryness in vacuo 9 the reæidue is shaken with a mlxture of 150 ~ of dichlorometh~n~ and 150 ml of a 005 n aqueous h;ydrochloric acid,, and th~ phasos are ~eparated ~rom each other. The aqueous phase is extracted with 50 ml OI dichlo:come~haneO The organic phases ar~ combined9 washed twic~ with 25 ml of a 3% aqueous sodium hydrocarbonate ~olution9 each~ driad over magnesium sulfate, ~iltered,, and tj~
- 29 ~
the ~iltra~e is evaporat~d~ 3~L~ g (78 %3 o~ ~p~nitrobenzyl) tra~s~4~ 2,4-dimethoxybenzyl3-3-(2~methyl~113 dicxolan-2~yl)~
4-oxo~2-azethidin-yl7-3 oxo-butanoate are obtained.
IR ~ilm): 1740~ 1730, 1710 cm 1 o b) 0069 ml (500 mmoles) o~ ~rieth~l amine and 0099 g (5.0 mmoles) of tosyl azide are added to a stirred solub~o~
o~ 2071 g (500 ~lolesl o~ (p nitrobenzyl) trans~4~ t2~'~di-methoxybanzyl~-3-(2 methyl-1,3-dioxolan~2~yl)-4-oxo-2~azeth-idiny ~ 3-oxo-butanoate, prepared as described in psint a) abov~ 15 ml of dry acstonitrile under ice coolingO Tha solution is stirred f'or 3 hours~ during this period it i~
allowed to warm to room temperatur0~ Therea~ter the mixture i~ evaporated to dryness9 and the residue is processed by column chromatography (adsor'bent: Kieselgel 60, 0 = 0~063-00200 mm, ~lutir~ agen~. a 702 mixture of benzene and ace~one30 207 g (80 %) o~ (p-rlitrobenzyl) 2-diazo-L~trans-1-~2,4-di-methoxybenzyl)-3-~2-~methyl-1.,3-dioxolan-2~ 1?-L~oxo-2-az-ethidiny ~ 3-oxo-bu~;anoa~e are obtained; m.p~: 45-46C
(acetons)~ ~
IR (KBr): 2200~ 1750, 1730~ 1650 cm 1.
c3 ~ mixture o~ 2984 g (5.0 mmoles) of (p-nitrobenz~l) 2-diazo-4-~tra~s-1~(2,4-dimethoxybe~zyl);3 (2-methyl-1~3 di;-- o~olan;2-yl)-4 oxo--2-azethidiny~ -3-oxo~butanoate, prapared as described in poii.nt b) above~ 504 g (20 mmolss3 o~ potassium pero~ydi~ul~ate (~,S208), 7~2 g (40 mmoles) o~ disodium hydrophosphate monohydrate (~a2HP040H20), 30 ml of acetonitril~
a~d 18 ml of water is boiled and stirred for about 10 hoursO
~he reaction mixture is cooled, filtered, and ~he phas~s o~
the filtrate are separa~ed ~rom each other. ~he aq~eous phase is extracted thrice with 10 ml o~ ethyl acetate9 each.
. . .
~he or~anic phases ar~ combin~d9 dri~d ove.r magn~sium sulIata~
îilt6rod9 ar~d tha filtra te is evaporated,. ~he r~idus i5 procossed by colu~L~ chromatograph;y (adsorbent: Kiaselgel 60,, 0 = 00063-0.200 mm:, ~lu~ing agent: a 7~2 mixturo of be~z~no and ac2tone) to ob~ain 0~67 g (32 %) o~ (p-nitrob~nzyl) 2-di-a z o ~ trans-3- ( 2-ma thy l-l ~3-dioxolan-2-yl)-4-oxo 2-az a t hidin-y~ 3-oxo-bu~arloate; m~,p,: 1.63-164C ~thar) O
IR (EBr): 33209 21603 1750, 1710, 1630 cm 1, lH NMR: d-= 1.41 (s~ 3H) " 2.98 (dd) and 3.~ (dd9 2H, J = 10 Hz and 4 Hz) ~ 3018 (d, lH) J = 2J4 Hz); 3083-4.15 ~m, 5H~, 5~.36 (s~ 2H), 6~0 (s, lH) 9 7.54 (d) and 8.26 Id9 4H, AE?
J = 9 Hz ) ppm.
Claims (9)
1. A process for the preparation of a compound of the general formula (I), (I) wherein yl and y2 represent a ketal or thioketal group, and Q is a Cl-5 alkyl group or a nitro-substituted benzyl group, characterized in that a) a compound of the general formula (V), (V) wherein yl and y2 are as defined above and R' is a phenyl or benzyl group bearing one or more Cl-4 alkoxy substituents, is activated on the carboxy group and then reacted with a salt of a malonic acid hemiester, wherein the alcohol component is a Cl-5 aliphatic alcohol or a nitro-substituted benzyl alcohol, the resulting compound of the general formula (IV), (IV) wherein Y1, Y2, R' and Q are as defined above, is reac-ted with a sulfonic azide in the presence of a tri-(C1-4 alkyl) amine, thereafter the phenyl of benzyl group bearing one or more C1-4 alkoxy substituents R' of the resulting compound of the general formula (III), (III) wherein Y1, Y2, R' and Q are as defined above, is re-moved, and the resulting compound of the general formula (II), (II) wherein Q, Y1 and Y2 are as defined above, is subjected to ring closure in the presence of a rhodium salt, or a compound of the general formula (IV), wherein yl, y2, R' and Q are as defined above, is reacted with a sulfonic azide in the presence of a tri-(Cl-4 alkyl) amine, thereafter the phenyl or benzyl group bearing one or more Cl-4 alkoxy substituents R' of the resulting compound of the general formula (III), wherein R', Q, yl and y2 are as defined above, is removed, and the resulting compound of the general formula (II), wherein Q, yl and y2 are as defined aboveJ is subjected to ring closure in the presence of a rhodium salt, or the phenyl or benzyl group bearing one or more Cl-4 substituents of a compound of the general formula (III), wherein R', Q, yl and y2 are as defined above, is removed, and the resulting compound of the general formula (II), wherein Q, yl and y2 are as defined above, is subjected to ring closure in the presence of a rhodium salt, or a compound of the general formula (II), wherein Q, yl and y2 are as defined above, is subjected to ring closure in the presence of a rhodium salt, or b) a compound of t:he general formula (V), wherein R', Q, yl and y2 are as defined above, is activated on its carboxy group and reacted then with a diazoacetic acid ester, the phenyl or benzyl group bearing one or more Cl-4 alkoxy substituents R' of the resulting com-pound of the general formula (III), wherein R', Q, Y1 and Y2 are as defined above, is removed, and the re-sulting compound of the general formula (II), wherein Q, Y1 and Y2 are as defined above, is subjected to ring closure in the presence of a rhodium salt, and the resulting end-product of the general formula (I) is separated.
2. A process as claimed in claim 1, characterized in that magnesium ethyl malonate or magnesium (p-nitroben-zyl) malonate is applied as a salt of a malonic acid hemiester.
3. A process as claimed in claim 1, characterized in that ethyl diazoacetate is applied as a diazoacetic acid ester.
4. A process as claimed in claim 1, characterized in that tosyl azide is applied as sulfonic azide.
5. A process as claimed in claim 1, characterized in that dirhodium tetraacetate is applied as rhodium salt.
6. A process as claimed in claim 1, characterized in that when R' is 2,4-dimethoxybenzyl it is removed with a peroxydisulfate type compound, whereas when R' is 4-methoxyphenyl it is removed with a ceric salt in the presence of an acid.
7. A compound of the general formula (I) as defined in claim 1, wherein Y1, Y2 and Q are as defined in claim 1, whenever prepared by the process of any one of claims 1 to 3, or its obvious chemical equivalents.
8. A compound of the general formula (I) as defined in claim 1, wherein Y1, Y2 and Q are as defined in claim 1, whenever prepared by the process of any one of claims 4 and 5, or its obvious chemical equivalents.
9. A compound of the general formula (I) as defined in claim 1, wherein Y1, Y2 and Q are as defined in claim 1, whenever prepared by the process of claim 6, or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU4016/81 | 1981-12-30 | ||
| HU814016A HU185492B (en) | 1981-12-30 | 1981-12-30 | Process for producing new azetidinyl-butanoates |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1191854A true CA1191854A (en) | 1985-08-13 |
Family
ID=10966525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418743A Expired CA1191854A (en) | 1981-12-30 | 1982-12-30 | Thienamycin derivatives |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS58118589A (en) |
| AT (1) | AT376218B (en) |
| AU (1) | AU9197282A (en) |
| BE (1) | BE895491A (en) |
| CA (1) | CA1191854A (en) |
| DE (1) | DE3248677A1 (en) |
| ES (1) | ES8406481A1 (en) |
| FI (1) | FI824521L (en) |
| FR (1) | FR2519003A1 (en) |
| GB (1) | GB2114123B (en) |
| GR (1) | GR77072B (en) |
| HU (1) | HU185492B (en) |
| IT (1) | IT1218332B (en) |
| LU (1) | LU84570A1 (en) |
| NL (1) | NL8205066A (en) |
| PL (1) | PL239883A1 (en) |
| SE (1) | SE8207479L (en) |
| ZA (1) | ZA829599B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4536334A (en) * | 1979-06-28 | 1985-08-20 | Sumitomo Chemical Company, Limited | Preparation of β-lactam derivatives |
| IE52147B1 (en) * | 1980-03-27 | 1987-07-08 | Merck & Co Inc | 4-(3-carboxy-2-oxopropyl)-azetidin-2-ones and process for their preparation |
-
1981
- 1981-12-30 HU HU814016A patent/HU185492B/en not_active IP Right Cessation
-
1982
- 1982-12-14 AT AT0453582A patent/AT376218B/en not_active IP Right Cessation
- 1982-12-28 BE BE1/10678A patent/BE895491A/en not_active IP Right Cessation
- 1982-12-28 JP JP57235160A patent/JPS58118589A/en active Pending
- 1982-12-29 FR FR8221979A patent/FR2519003A1/en active Pending
- 1982-12-29 SE SE8207479A patent/SE8207479L/en not_active Application Discontinuation
- 1982-12-29 LU LU84570A patent/LU84570A1/en unknown
- 1982-12-30 IT IT25064/82A patent/IT1218332B/en active
- 1982-12-30 GR GR70189A patent/GR77072B/el unknown
- 1982-12-30 ES ES518724A patent/ES8406481A1/en not_active Expired
- 1982-12-30 FI FI824521A patent/FI824521L/en not_active Application Discontinuation
- 1982-12-30 AU AU91972/82A patent/AU9197282A/en not_active Abandoned
- 1982-12-30 DE DE19823248677 patent/DE3248677A1/en not_active Withdrawn
- 1982-12-30 PL PL23988382A patent/PL239883A1/en unknown
- 1982-12-30 CA CA000418743A patent/CA1191854A/en not_active Expired
- 1982-12-30 GB GB08236913A patent/GB2114123B/en not_active Expired
- 1982-12-30 NL NL8205066A patent/NL8205066A/en not_active Application Discontinuation
- 1982-12-30 ZA ZA829599A patent/ZA829599B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE895491A (en) | 1983-06-28 |
| LU84570A1 (en) | 1984-10-22 |
| AT376218B (en) | 1984-10-25 |
| FI824521A0 (en) | 1982-12-30 |
| IT1218332B (en) | 1990-04-12 |
| GB2114123B (en) | 1985-10-02 |
| SE8207479D0 (en) | 1982-12-29 |
| NL8205066A (en) | 1983-07-18 |
| HU185492B (en) | 1985-02-28 |
| ZA829599B (en) | 1983-10-26 |
| FR2519003A1 (en) | 1983-07-01 |
| FI824521L (en) | 1983-07-01 |
| GB2114123A (en) | 1983-08-17 |
| IT8225064A0 (en) | 1982-12-30 |
| ATA453582A (en) | 1984-03-15 |
| AU9197282A (en) | 1983-07-07 |
| PL239883A1 (en) | 1984-01-02 |
| ES518724A0 (en) | 1984-07-16 |
| DE3248677A1 (en) | 1983-07-07 |
| ES8406481A1 (en) | 1984-07-16 |
| GR77072B (en) | 1984-09-05 |
| JPS58118589A (en) | 1983-07-14 |
| SE8207479L (en) | 1983-07-01 |
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