CA1189865A - Heterocyclic acetic acid derivatives and a process for the preparation thereof - Google Patents
Heterocyclic acetic acid derivatives and a process for the preparation thereofInfo
- Publication number
- CA1189865A CA1189865A CA000418739A CA418739A CA1189865A CA 1189865 A CA1189865 A CA 1189865A CA 000418739 A CA000418739 A CA 000418739A CA 418739 A CA418739 A CA 418739A CA 1189865 A CA1189865 A CA 1189865A
- Authority
- CA
- Canada
- Prior art keywords
- trans
- dioxolan
- methyl
- oxo
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
New heterocyclic acetic acid compounds of the general formula (I), ( I) wherein y1 and y2 form together a removable carbonyl protecting group, and R is a removable amido protecting group, are prepared in the way that a compound of the general formula (III), ( III) wherein R, y1 and Y2 are as defined above, is activated on the carboxy group and then reacted with diazomethane, and the resulting compound of the general formula (II), ( II) wherein R, y1 and y2 are as defined above, is subjected to diazoketone rearrangement in the presence of water.
The new compounds according to the invention are valuable intermediates in the synthesis of thiena-mycin and thienamycin analogues.
New heterocyclic acetic acid compounds of the general formula (I), ( I) wherein y1 and y2 form together a removable carbonyl protecting group, and R is a removable amido protecting group, are prepared in the way that a compound of the general formula (III), ( III) wherein R, y1 and Y2 are as defined above, is activated on the carboxy group and then reacted with diazomethane, and the resulting compound of the general formula (II), ( II) wherein R, y1 and y2 are as defined above, is subjected to diazoketone rearrangement in the presence of water.
The new compounds according to the invention are valuable intermediates in the synthesis of thiena-mycin and thienamycin analogues.
Description
8~
~W ~n~'l~ROCYCI~tC ACE~Ia ~CID DERIVA~IV~`S A~D A :EROC:E~SS FO:R
P~`PARAr~ION ~HE~R:EOF
rrhe i~v~ntion rela ~es to new he terocyclic acetic acid dexivativos of tha gene:ral foxmula (I) y~ y2H :H
~ CEI COOH
H3C C _r 2 whexairL
yl arld y2 îorm together a removable carbonyl pro~ec~ ; group~
preIerably a ke tal group or a ~hioanalo~ e thereo~
and R is a remov3ble amido protecting ~;roup~ pre~erably a benzyl group bearing o~e or more Gi L~. alko~y ~ubstitue~ts or a phenyl group b~ari~g optionally one or more Cl ~, alko~y ~ub~ti~ue~ts The~e compound~ carl ba co~verted in'Go thierlan~yGi~
and relatad compoux~fl~ 6~ ;o a~ show~n on Scheme ~A~, ~661~-67 , sch9m~ (A) }-~2C003~
.
~CH2C~OH
ed (l~ ~ i sn ~ - CH2~0()H 2.esterif~cation _~
0~ I R ~ C~)O
malon~c ~cid ~ Nl I
semiester sal~ 2 ~o 0~
~s ~ ~2~0C~2~
v ~ - , ~-~ C~O~X
~ C) `R ~
c3 ~NH
3~slllfc nic acid ~
. ~ Qn . . azlde Hl t H ~ ~c~
N~C(~ L3 f n ~ m cllsrl iC a~i d O \~ . 5ellrlie5tel' 5alt O~NH
9c ~
c~c~
:~89~
- 2a -Scheme ~A~ contlnueJ
~3 H~G~2 ~NH
~h~ salt H
~N~C ICIQ
O- ~yl~ti~
mercaptan rm~
~3 - ~
D
~ 5 3 ~
In the formulae shown on Schema ~A) yl~ y2 and R ars as definad above 9 X is a selectively r~movable esterifyi~g group~
Q is a Cl 5 alkyl g~roup or a substituted benzyl group~
Q9 is a Cl 5 alkyl group9 a substi~uted benzyl group9 hydro-ge~ atom or an al~ali metal ion~ and R" is a benzyl, aminoe~hyl or .~-acyl~aminoebhyl group ~hienamyci~9 a~ antibiotic o~ broad spectrum o~
activity, wa~s prepared firs~ on microbiological way (US patsnk specification No~ 399509375) and later on by ch~mical syn~hesis (German Qffenlsgungsschrift NoO 2~751~597)~
Qur aim was to provide a new route for the synthesis o~ thianamyci~ and its analogues, wherain bhe azethidi~o~e skelston and the ~-hydroxyethyl side chain, or a sida chain which can be conver~ed easily into ~-hydroxy~hyl group~ are ~ormed simultaneously at the aarly stage of th~ sy~thesis, and the resulting key intermediate is conve.rted then i~o the desired end~produc~
It has been foun~ tb.a~ whe~ a dialkyl (protecbed a~ino~malo~ate is acylated with diketene and ~he resulbing acylated product i5 reactad wi~h iodine and an alk~li me~al alcoholate7 an azethldi~one compound. o~ the g~naral ~oxmula (VI)i 0 H3C - C ~ ~ (Cz)2 / ~ ~VI) 0 \ R
containing an ~-ace~yl side chain7 is ob~ain~da which can be u~ilized as key inte~mediata in the synthasi~O
In the above ~ormula -R has the same maaning as givan 30 abov~ and Z i9 a Cl_5 al~y~ g~oupO
_ L~ ~
The in~ermediates o~ the general formula (VI) and 'their preparation are dsscribed in detail in our Hu~garian patent ~o. 181,186. The preparation of these intermediat~s is also described in the examples of the present application.
It has also been observed that7 prior to converting the intermediate of the general formula ~VI) into thiena~
mycin or an analogue thereof~ i~ is prefera~le to protect the keto group of the ~-C-a~etyl side chain with a group9 particularly a ketal group or a thioanalogue th~reof, which can be removed at a later stags of the synShe~is~ Ethylene glycol or a thioanaloguo thereof, such as mercapto-ethanol, can be applied particularly preferably to ~orm the ethylene-~etal or hemithioketal pro~ecting groupO The resulting com 5 pound of the general,formula (V), l y2 H3C - C ~ (cooz)2 ~ _ ~ N (V) O ~R
20 wherein R, Z9 -~1 and y2 are as dofined above9 is raacted then with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxida to obtain a compou~d of the gen~ral formula (I~) 9 ~1 ~ H
25H3C - C -'- t ~ cooz ' 0 ~ N R (IY~
wherein R9 yl7 y2 and Z are as dafined above~
' 'llhe resul~ing oompound of the general formula (IV) is a ~ ture o~ cis and trans iso~ersO '~he isomers can ba ~eparated from each other by chromatography or on the basis of their different solubilities. The separated trans isomer of the genexal formula (IVa) y\l~ COO~ , ~ ¦IVa) , ca~ be converted into the trans carboxylic acid of the ~eneral ~ormula (III) yl y2 H H
H3C ~ r COOH
~ ~ (III) \ R
by hydrolysis~ It i8 ~ore preferable, however~ to subject ths isomeric mixture itself to hydrolysis, since the raac~ion is sslective, i.e. only the trans ester convert~ into the respective carboxylic acid.
Some of the compounds of the general formulae ~V~, (IV) and (IVa) are described in our previous Hungarian patent No. 180,608, whereas t.~e other representatives of these compounds and the compounds of the general formula (III) are de~cribed in our co-pending pa~ent application~ D The pra-parat~on of the compound~ of the general formulae ~VI) to (III) is also described in the examples of the present applica-~ion.
The separated trans carboxylic acid of the gsneral formula (III) is reacted first wi~h an activator for the carb-oxy group and then with diazomethana~ and the resulting com-pound of the general formula (II) 7 wherein R, yl and ~ are as defined above~
yl y2 X H
COC~2 ,L
i~ subjected to diazoketione exchange (Wolf~ rearraxlge~
ment) i~ the presance o~ water~ In bhis lat~Gex stap ~he desired products o:~ the gen~ral formula (I) a~e ob~ai~d"
The compnunds o.~ l;he general ~ormulac ~I) bo (VI~
ar~ racemic mix~uresO
Based on ~he abov6~ the inve~tion rela~os ~o a proc8 î or the prapara ~io~ oi a ~ew compound of ~he ge~ral ~ormula ( I) ~ wherein yl a~d y2 ~orm ~ogether a removable carbo~yl protecting group~
preIexably a ketal group or a ~hioanalogue thereo and R is a removable amido pro~ectiDg gro~lp~ prefarab~y a be~z~l group beaxing o~ or more C1_L~ alko~y substi~uen~ ox pb~nyl group bearing optio~ally on~ or more C~ ox~
~ub~tu~ J 0 ln 3uoh a w~y ~h3t a compou~d o~ the general ~ormula (III) 3 wherai~ R~
~1 and y2 are a~ defined above~ is ac~iv~ted o~ ~he carbox~
group and the~ reacted with diazoma~han~ wh~reaf~0r the rasultl~g compou~d o~ the genaral ~ormula ~ 3 wherei~ R~ Y~
and ~ are a9 defi~ed abova~ is ~ubjec~0d to diazoketo~a exchan~a in the presenca o~ ~a~er~ or a compou~d o~ the ge~eral ~ormula ~ wherein R~ Y~
and y2 ars a~ de~ined above~ is ~ubjec~ed to diazoketone exch~nye in th~ pr~sance o.~' water~
~O and the resul~ing produo~ o~ ~he general ~ormula (I~
8~86 is s0para tedD
'~he prepara~ion of the starting substances of the general forlllula (III) is described in detail in the exampl~sO
The azethidin~carbo~ylic acid of the general formula ~IlI) is activated fîrst o~ the carbo~y group~ Any activati~g agsnt compatible ~ith the ~lacta'm ring can be a,pplied for this purposa~ I~ is pre.ferred to activat~ ~he carboxy group as a mixed anhydride~ fo.r which purpose ethyl chloroformata pxovad ~o be a parti.cularly suitabla reactant~ ~he mi~d a~hydxide is formed in the presence of an acid binding agent, preferably a ~ertiary amine~ The sal~ of the tertiary amine which separates from the reaction mixturs can be removed aasily~
The activated form of the compound of formula (III) is reac~ed ~hen with diazomethane~ Diazomathane is prepa.red pre~
~erably from N~methyl-N-nitroso-urea and i.s added to the re-action mixtuxe pref0rably as an etheral solu~ion~ Whe~ the .ga~ evolution ceases; the excoss of diazomet'hane is d0compo~ed pre.~arably with acetic acid, and the rasulting compound o~
tha ~en~ral foxmula (II) is ssparated from the react~on m tureO I~ necessary~ this product can be purifi~d ~Og~ by co'lum~ chromatography~
Thereafter the resulting com~?ound o~ the general ~ormula (II~ is subjected ~o Wolff rearrangement, whereupon ~he ~~diazoketona side chai~ converts first in~o ketane by nitrogen slimina~ion~ and ~hen i~ reacts with wa~er to ~orm the dasired product of the genaral formu'La (I)~
Wolff rearrangement can be promoted with a cataly~
b~J ixradiati-~g the mixture with ultraviolet 'Light 3 by ther~al treakment~ and an~ combi,nation thereo~ Irradiation with ultra violet li~,ht -~ro~red to be pa:rticularl~J pre~erable~ I:rradi.ation ~ 8 -can be per~ormod e g. in a photor~actor, pre~arably under inert gas atmosphere, in the presenca of water and optionally a~
inert organic solventO
The resul~ing product can be separa~ed from the roacO
tion mixt~rs by evaporatioll and/or phase trans~er msthods~
and ca~ be puri~ied e~g~ by recrystallization, if nacessaI~O
The i~ven~ion is elucidated in detail by the aid of the ~ollowing non-limiting ~`xamples~
~r ~ ~ ~
A mi~ture of 2025 g (6 mmoles~ of tra~s-4~-tdiazoacetyl)-1-(2 9 L~dimethoxybenzyl)-3-(2-methyl 1,3-dioxolan~2~yl)-2~az~
ethidino~o~ 100 ml of paroxide-Lree tetrahydrofuran and 50 ml of water is irradiatod ~or about 4 hours with a high~pr~ssure mercury lamp ~EIPK 125~5 immersed into the reac~ion vessel mad~
o~ pyrex glass~ under argon atmosphere~ rl`he solution is evaporated in ~acuo to a final volume of 50 ml, and the con-centxate ls dilutod with water to 1~0 mlO 2~4 ml of a lO~o aqueous sodium hydroxid~ solution are added to the aqueous mixture~ and the alkaline mixture- is washed thrice with 20 ~1 o~ dichlorom~thane, each. ~hereafter the aqueous phaso is acidified to pH - 2 with concentrated aqueous hydrochloric acid. The acidic solution is extracted khrice with 20 ~1 o~
dichlorome~hane, each9 ~he ex~racts are combined~ dried over magnesium sulfate3 Yiltered, and the iiltrate is eva-poraked to dryness~ ~he rasidue is crystallized with ather~ 1~82 g ~83 %) of th~ aimed compound are obtained as a whiteg cx~y~talIine substance~ mOpO~ 124C (ether)0 IR (KBr): 3500-23009 ?9001 1730~ 1700 cm 1, ~ g _ Analysis:
calculated for C18H23N07 (365~37):
C0 59.17 ~0~ H: 6~34 %, N: ~.8~ %~
~ound: C: 59.22 (~0, H: 6.49 %, N: 4~07 %O
~he staxting substancs can b~ prepared as ~ollows:
a) A mix~ure of 10907 g (0~66 mola) of 2~dimethoxy~
banzaldehyde9 72 ml (0366 mole) of banzylamine and 660 ml of methanol is stirred at room temperature for 20 minute~3 where~
upon a claar solu~ion is obtained from the susp~nsion~ The solution is cooled with ice water9 and 1302 g (0O33 mole) of sodi.um borohydride are added to i~ in small portionsO
rrhe progress of the reaction is moni~orad by thi~
laysr chromato$raphy (Kieselgel G according to Stahl; develop~
ing solvsnt: a 9.1 mixture of benzene and ace~one)~ and at tha end of the reaction the mixture is e~aporated to dryne~
in vacuoO ~he residue is admixed with 300 ml of watar~ a~d the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml portions of eth0rO The ether~al solutions ars combined~ dxied ovax magnesium sulfata~ filtered, and then 112 ml (0066 mole3 o~ diathyl bromomalonat~ and 9~ ml (0.66 mole) of ~riethyl amine are added to the filtrate9 rrhe raac~ion mixture i.s stirred at room temparature for 2-3 days. rrhe separatad kri~
ethyl ammonium bromide is filtersd off and washed with etherO
'rhe mother liquor is evaporated, and the residue is re~
cr~stallized from 150 ml o~ ethanolO The resulting 210 g o~
crude product ~e recrystallized again from 400 ml of ethanol to obtain 197 g (72 'Y0) of diethyl ~-benzyl_~(2~4-dimethoxy-benzyl)-amino-malonate; m.p~: 62-6~C (ekhanol)O
IR (~3r)o 1750/1725 cm 1 9 d, ~O b) 61~7 g (00149 mole3 Or diethyl N-benzyl~N~(2~4~di 8~iS
m~thoxybe~zyl)~ami~o~malo~ate3 pr~pared as describad i~ point a) abov~ are hydrog~natad in 500 m.l o~ et~lanol under atmo sph~xic p.r~ssure in tho presenc~ of about 20 g o~ p~ dium~
o~charcoal ca~alystO The catalyst -ls ~ilt~red of~ a~d tha .~iltrato is ~vaporatsd~ ~701 ~ (97 %) of di~thyl ~2~4-dime~h~
o~ybenzylamino)-malonata aro obtainsdO ~ho product can b~
converted into i~s hydrochlor~.de by r~acting it wi~h hy~ro~
chloric ~cid~ The hydrochlorid~ malts at 122-124C a~r crys~allizatio~ ~rom ethyl acetate~
~nalysis:
calculatad for C16H2L~ClM06 (361082) C: 53011 %3 H~ 6~69 %9 Cl: 9~80 %, N: 3~B7 %a ~ound~ C: 52~51 %9 H: 6.77 %~ Cl: 10030 %9 ~ 4~09 %o IR (~ilm): ~250~ 2900, 2850, 1730~ 1720 cm 1, H ~ (CDC13? ~ = 1.3 (s~ 6H)~ 3~7~ (s~ 3H)~ 3082 (87 3H) L~-21 (q~ L~H)~ 6~20 (sg 2~I) D 6~L~6~6 ~m~ 2~) ~ 7~3-7055 (m~ lH)~ 797 (broad s) lH) ppm~
c) ~ mixtura o~ 3906 g (00122 mola) of diethyl l2 dimethoxybenzylamino)-r~ lona~e~ prepared as describ~d in poi~
2Q b) above; 80 ml o~ ~lacial ac,etic acid and 1203 g (11~2 ml~
00146 mole) of dikotene i5 boiled for 005 hour~ Glacial acetiG
acid is dis~illed of.~ in vacuo over watar b~h~ and the oily r6sidu~ is triturated wi~h 150 ml of watera Th~ re~ulting crgstalline substancc is di.ssolved in 60 ml of ~thyl acetat~
and pxecipitated with petrolaum ethorO 29,6 g ~60 ~ of di~
athyl N ~2~4 dimethoxybanzyl) 3-hydroxy~3~methy~ 5~0~0~2g2 pyrrolidine-dicarboxylate and/or its tautomor are obtai~d~
m O p.: 106~107C.
Analys~s:
calculat~d r~ C20H2.7~J8 (~ 9 3 ~1 -58967 %~ H: 60G~ %9 N: 33~2 %~
~ound~ C. 58079 %~ H~ Go~ %~ N. 303~ %0 IR (I~Br): 3~009 2950~ 2850~ 1730 (1740~ sh)~ 1710 cm ~ NMR (C~13): ~- lol (~ 3H) 9 1017 (~, 3H) 9 1~52 f s~v3H) 7 208 (~ Ool ~) 9 2065 (broad 93 2H) 3 3075 (s~ 6E)~
~8~4015 (m, 4H) 3 6~7 (bxoad s~ 2H) 9 6~25-6045 (m) ~ 74~7~25 ~m~ 3H) ppm~
d3 20o5 g (50 mmol~s~ o.~ th3 product pxapared as de~
scribsd in point c) abov~ ar~ suspo~dsd i~ 50 ml o~ dr~ ~hex~
a~d a solutio~ o~ 3045 g (150 mmol~s) o~' m~allic sodium i~
100 ml o~ dry othanol and a solution of 1207 g (50 mmolos) o~
iodins in 150 ml o~ dry ~her aro added simul~an00usl~ ~rom ~wo dropping ~u~nels~ to the vigorously stirrad su~pensio~
under cooling with ice water~ ~h~rea~ter 5 g o~' sodium hydxo~
sulfite3 dissolved in 200 ml of a saturatad a~u~ous sodium chloride solutio~9 are added to the stirred mixture. Th~ mix~
~ure is fillod i~to a separating funnel and 60 ml of water ar0 added to dissolve the ~oparated inorga~ic ~alks. ~he oxganlc pha3e is removod, dri~d over magr~esi.um ~ulfato1 .~ilter~d~ and ~0 the ~lltra~e ~3 evaporatedO '~he oily re~idue7 w~ighin~ 1805 g~
i~ cry~tallized from ~0 ml o~ 2-propanol3 10~9 g (5~ %) sf die~hyl 3-ac~tyl~ 29L~dim3~hoxyb~zyl~4~0~0~292~aze~hidIne~
~icarboxylate are obtain3d~ m.pD 84~85~ ~2~propa~01~3 A~aly~iso calcula~ed for C20H25N0~ (407041~:
c: 58~96 %9 H, 6~19 %9 N~ 3~ %9 ~ound: a: 58099 %9 E: 6~04 %~ N. 3057 %p lH NMR (GDC13): ~- 1012 (t, 3~) 9 1.21 ~t/ 3H)~ 2031 (~ 3H)~ 3~76 (s) 6H), 3.8~3.~ (rn~ 4H) 7 4~53 (d, lH) a 4~63 (d, l~f)~ 4069 (s~ lH)~ 6~3~60L~ (rn7 2H) * 7,07 (d~ lH) ppm~
~9~5 ~ 12 e~ 179 ml ~206 g9 1~452 molq~ o~ boro~ trifluor~de diath-gl e~herate axa added dropwis3 to a v1gorous~y stirrecl solu~-io~ o:E -179 g (00484 mole) of diethyl 3~ac~tyl~ 294~di~
me~hoxybenzyl)-4-oxo-292-azethidine~dicarbo~yLate a~d 107 ml ( 120 g~ 10936 moles) of ethylene glycol in 500 ml of dry di~
oxane undar cooliDg~ wi.~h ice wa terO '~h~ reaction mi~t~re i~
allowfld to stand at room t0mperature ~or ox~ day~ dllring l;his period th~ mixt~re is occasionally stirr~dO '~hsrea:Eter 415 g ( 10452 mole~ of Na2C03,10H2o are added ~lowly ~o the stirred mixtur3 und~r cooli~g with ~ce water3 and the mixtur0 is stirred for 15 mi~u~es~ '~hereaft~r 1 litre of e ther and 1 litre o~ water are added~ and th~
phases are separated from ear,h otherO The aqueous phas sha~e~ twice with 500 ml of diethyl ether; eachO ~he e~heral phase is dri~d over magnesium sulfate~ filtered~ and ~he filtrate is evaporated.u 33~9 g (0058 mol~) of sodium chlorid~S
170~ ml (0.968 mole) of water and ~20 ml o~ dimethyl sulfoxide are added to the residue, and tha mix~ure is ~tirred on a~
oîl bath at 180C. The progras~ of the rsaction i~ monitorad by thin layer chrom~to~raphy (adsorben~: ~leselgel G accordi~g to Stahl.; developing solv0nt~ a 6:4 mixture of ben~c~e a~d eth~l acetate)~ At ~he and of the reaction~ iOe~ a~ter about 15 hours, the mixture is pour~d into 1100 ml of saturatcd aqueous sodium chloride solutio~ and th~ resulting mixture i9 shakan with 1000 ml and then twice with 500 ml of diethyl ather~ eachO ~he etherea'solut`ions ara combinad9 dacolou~i~ed wi~h charcoal~ driad over magnesium sulfata 3 and tha filtrata is evapora ted to a final volume of cca, 200 mlO Thi~ con-cerltra~ed solution is coolod with ice water to obtain 59 g (35 %3 of trans -ethyl 1-(2 7 ll~dimethox;yb~næyl) - 3-~2~methyl~13 3-9~s dioxola~2~yl)~4-oxo-2~azethidine-carboxyla~e; mOp.~ 95C.
~) A mixture o~ 0~5 g ~102 mmoles~ of diethyl 3~ace~y1 1~2~4~di~lethoxybenzyl1~4-oxo-2,2~azethidine-dicarboxyl~e~
prepared as desc:Libed in point d) above, 3 ml of dry te~ra~
~y~ro~uran and 0053 g (306 mmole~) of mercapto~etha~ol is ~oiled :~or 4 hours, and then 10 ml of' water and 10 ml o~ chloroform are added to the reaction mixture. The organic pha~e is separatad) washed with a 5% aqueous sodium ~ydrocarbo~ak~ solu~
tion9 dried over magnesium sulfa~e, filtered9 and the pxoduct is separated ~rom the ~ rate by prepaxatî~e ~hin layer chroma~ography (adsorbent: Kieselgel 60 PF254~366, de~eloping solvellt: a 8:2 mix~ure o.~ toluene and ac~tono). 0.30 g (53 %) of diothyl 1-~2~4-dimethoxybenzyl)-3-(2 methyl~l73~oxathiolan~
~W ~n~'l~ROCYCI~tC ACE~Ia ~CID DERIVA~IV~`S A~D A :EROC:E~SS FO:R
P~`PARAr~ION ~HE~R:EOF
rrhe i~v~ntion rela ~es to new he terocyclic acetic acid dexivativos of tha gene:ral foxmula (I) y~ y2H :H
~ CEI COOH
H3C C _r 2 whexairL
yl arld y2 îorm together a removable carbonyl pro~ec~ ; group~
preIerably a ke tal group or a ~hioanalo~ e thereo~
and R is a remov3ble amido protecting ~;roup~ pre~erably a benzyl group bearing o~e or more Gi L~. alko~y ~ubstitue~ts or a phenyl group b~ari~g optionally one or more Cl ~, alko~y ~ub~ti~ue~ts The~e compound~ carl ba co~verted in'Go thierlan~yGi~
and relatad compoux~fl~ 6~ ;o a~ show~n on Scheme ~A~, ~661~-67 , sch9m~ (A) }-~2C003~
.
~CH2C~OH
ed (l~ ~ i sn ~ - CH2~0()H 2.esterif~cation _~
0~ I R ~ C~)O
malon~c ~cid ~ Nl I
semiester sal~ 2 ~o 0~
~s ~ ~2~0C~2~
v ~ - , ~-~ C~O~X
~ C) `R ~
c3 ~NH
3~slllfc nic acid ~
. ~ Qn . . azlde Hl t H ~ ~c~
N~C(~ L3 f n ~ m cllsrl iC a~i d O \~ . 5ellrlie5tel' 5alt O~NH
9c ~
c~c~
:~89~
- 2a -Scheme ~A~ contlnueJ
~3 H~G~2 ~NH
~h~ salt H
~N~C ICIQ
O- ~yl~ti~
mercaptan rm~
~3 - ~
D
~ 5 3 ~
In the formulae shown on Schema ~A) yl~ y2 and R ars as definad above 9 X is a selectively r~movable esterifyi~g group~
Q is a Cl 5 alkyl g~roup or a substituted benzyl group~
Q9 is a Cl 5 alkyl group9 a substi~uted benzyl group9 hydro-ge~ atom or an al~ali metal ion~ and R" is a benzyl, aminoe~hyl or .~-acyl~aminoebhyl group ~hienamyci~9 a~ antibiotic o~ broad spectrum o~
activity, wa~s prepared firs~ on microbiological way (US patsnk specification No~ 399509375) and later on by ch~mical syn~hesis (German Qffenlsgungsschrift NoO 2~751~597)~
Qur aim was to provide a new route for the synthesis o~ thianamyci~ and its analogues, wherain bhe azethidi~o~e skelston and the ~-hydroxyethyl side chain, or a sida chain which can be conver~ed easily into ~-hydroxy~hyl group~ are ~ormed simultaneously at the aarly stage of th~ sy~thesis, and the resulting key intermediate is conve.rted then i~o the desired end~produc~
It has been foun~ tb.a~ whe~ a dialkyl (protecbed a~ino~malo~ate is acylated with diketene and ~he resulbing acylated product i5 reactad wi~h iodine and an alk~li me~al alcoholate7 an azethldi~one compound. o~ the g~naral ~oxmula (VI)i 0 H3C - C ~ ~ (Cz)2 / ~ ~VI) 0 \ R
containing an ~-ace~yl side chain7 is ob~ain~da which can be u~ilized as key inte~mediata in the synthasi~O
In the above ~ormula -R has the same maaning as givan 30 abov~ and Z i9 a Cl_5 al~y~ g~oupO
_ L~ ~
The in~ermediates o~ the general formula (VI) and 'their preparation are dsscribed in detail in our Hu~garian patent ~o. 181,186. The preparation of these intermediat~s is also described in the examples of the present application.
It has also been observed that7 prior to converting the intermediate of the general formula ~VI) into thiena~
mycin or an analogue thereof~ i~ is prefera~le to protect the keto group of the ~-C-a~etyl side chain with a group9 particularly a ketal group or a thioanalogue th~reof, which can be removed at a later stags of the synShe~is~ Ethylene glycol or a thioanaloguo thereof, such as mercapto-ethanol, can be applied particularly preferably to ~orm the ethylene-~etal or hemithioketal pro~ecting groupO The resulting com 5 pound of the general,formula (V), l y2 H3C - C ~ (cooz)2 ~ _ ~ N (V) O ~R
20 wherein R, Z9 -~1 and y2 are as dofined above9 is raacted then with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxida to obtain a compou~d of the gen~ral formula (I~) 9 ~1 ~ H
25H3C - C -'- t ~ cooz ' 0 ~ N R (IY~
wherein R9 yl7 y2 and Z are as dafined above~
' 'llhe resul~ing oompound of the general formula (IV) is a ~ ture o~ cis and trans iso~ersO '~he isomers can ba ~eparated from each other by chromatography or on the basis of their different solubilities. The separated trans isomer of the genexal formula (IVa) y\l~ COO~ , ~ ¦IVa) , ca~ be converted into the trans carboxylic acid of the ~eneral ~ormula (III) yl y2 H H
H3C ~ r COOH
~ ~ (III) \ R
by hydrolysis~ It i8 ~ore preferable, however~ to subject ths isomeric mixture itself to hydrolysis, since the raac~ion is sslective, i.e. only the trans ester convert~ into the respective carboxylic acid.
Some of the compounds of the general formulae ~V~, (IV) and (IVa) are described in our previous Hungarian patent No. 180,608, whereas t.~e other representatives of these compounds and the compounds of the general formula (III) are de~cribed in our co-pending pa~ent application~ D The pra-parat~on of the compound~ of the general formulae ~VI) to (III) is also described in the examples of the present applica-~ion.
The separated trans carboxylic acid of the gsneral formula (III) is reacted first wi~h an activator for the carb-oxy group and then with diazomethana~ and the resulting com-pound of the general formula (II) 7 wherein R, yl and ~ are as defined above~
yl y2 X H
COC~2 ,L
i~ subjected to diazoketione exchange (Wolf~ rearraxlge~
ment) i~ the presance o~ water~ In bhis lat~Gex stap ~he desired products o:~ the gen~ral formula (I) a~e ob~ai~d"
The compnunds o.~ l;he general ~ormulac ~I) bo (VI~
ar~ racemic mix~uresO
Based on ~he abov6~ the inve~tion rela~os ~o a proc8 î or the prapara ~io~ oi a ~ew compound of ~he ge~ral ~ormula ( I) ~ wherein yl a~d y2 ~orm ~ogether a removable carbo~yl protecting group~
preIexably a ketal group or a ~hioanalogue thereo and R is a removable amido pro~ectiDg gro~lp~ prefarab~y a be~z~l group beaxing o~ or more C1_L~ alko~y substi~uen~ ox pb~nyl group bearing optio~ally on~ or more C~ ox~
~ub~tu~ J 0 ln 3uoh a w~y ~h3t a compou~d o~ the general ~ormula (III) 3 wherai~ R~
~1 and y2 are a~ defined above~ is ac~iv~ted o~ ~he carbox~
group and the~ reacted with diazoma~han~ wh~reaf~0r the rasultl~g compou~d o~ the genaral ~ormula ~ 3 wherei~ R~ Y~
and ~ are a9 defi~ed abova~ is ~ubjec~0d to diazoketo~a exchan~a in the presenca o~ ~a~er~ or a compou~d o~ the ge~eral ~ormula ~ wherein R~ Y~
and y2 ars a~ de~ined above~ is ~ubjec~ed to diazoketone exch~nye in th~ pr~sance o.~' water~
~O and the resul~ing produo~ o~ ~he general ~ormula (I~
8~86 is s0para tedD
'~he prepara~ion of the starting substances of the general forlllula (III) is described in detail in the exampl~sO
The azethidin~carbo~ylic acid of the general formula ~IlI) is activated fîrst o~ the carbo~y group~ Any activati~g agsnt compatible ~ith the ~lacta'm ring can be a,pplied for this purposa~ I~ is pre.ferred to activat~ ~he carboxy group as a mixed anhydride~ fo.r which purpose ethyl chloroformata pxovad ~o be a parti.cularly suitabla reactant~ ~he mi~d a~hydxide is formed in the presence of an acid binding agent, preferably a ~ertiary amine~ The sal~ of the tertiary amine which separates from the reaction mixturs can be removed aasily~
The activated form of the compound of formula (III) is reac~ed ~hen with diazomethane~ Diazomathane is prepa.red pre~
~erably from N~methyl-N-nitroso-urea and i.s added to the re-action mixtuxe pref0rably as an etheral solu~ion~ Whe~ the .ga~ evolution ceases; the excoss of diazomet'hane is d0compo~ed pre.~arably with acetic acid, and the rasulting compound o~
tha ~en~ral foxmula (II) is ssparated from the react~on m tureO I~ necessary~ this product can be purifi~d ~Og~ by co'lum~ chromatography~
Thereafter the resulting com~?ound o~ the general ~ormula (II~ is subjected ~o Wolff rearrangement, whereupon ~he ~~diazoketona side chai~ converts first in~o ketane by nitrogen slimina~ion~ and ~hen i~ reacts with wa~er to ~orm the dasired product of the genaral formu'La (I)~
Wolff rearrangement can be promoted with a cataly~
b~J ixradiati-~g the mixture with ultraviolet 'Light 3 by ther~al treakment~ and an~ combi,nation thereo~ Irradiation with ultra violet li~,ht -~ro~red to be pa:rticularl~J pre~erable~ I:rradi.ation ~ 8 -can be per~ormod e g. in a photor~actor, pre~arably under inert gas atmosphere, in the presenca of water and optionally a~
inert organic solventO
The resul~ing product can be separa~ed from the roacO
tion mixt~rs by evaporatioll and/or phase trans~er msthods~
and ca~ be puri~ied e~g~ by recrystallization, if nacessaI~O
The i~ven~ion is elucidated in detail by the aid of the ~ollowing non-limiting ~`xamples~
~r ~ ~ ~
A mi~ture of 2025 g (6 mmoles~ of tra~s-4~-tdiazoacetyl)-1-(2 9 L~dimethoxybenzyl)-3-(2-methyl 1,3-dioxolan~2~yl)-2~az~
ethidino~o~ 100 ml of paroxide-Lree tetrahydrofuran and 50 ml of water is irradiatod ~or about 4 hours with a high~pr~ssure mercury lamp ~EIPK 125~5 immersed into the reac~ion vessel mad~
o~ pyrex glass~ under argon atmosphere~ rl`he solution is evaporated in ~acuo to a final volume of 50 ml, and the con-centxate ls dilutod with water to 1~0 mlO 2~4 ml of a lO~o aqueous sodium hydroxid~ solution are added to the aqueous mixture~ and the alkaline mixture- is washed thrice with 20 ~1 o~ dichlorom~thane, each. ~hereafter the aqueous phaso is acidified to pH - 2 with concentrated aqueous hydrochloric acid. The acidic solution is extracted khrice with 20 ~1 o~
dichlorome~hane, each9 ~he ex~racts are combined~ dried over magnesium sulfate3 Yiltered, and the iiltrate is eva-poraked to dryness~ ~he rasidue is crystallized with ather~ 1~82 g ~83 %) of th~ aimed compound are obtained as a whiteg cx~y~talIine substance~ mOpO~ 124C (ether)0 IR (KBr): 3500-23009 ?9001 1730~ 1700 cm 1, ~ g _ Analysis:
calculated for C18H23N07 (365~37):
C0 59.17 ~0~ H: 6~34 %, N: ~.8~ %~
~ound: C: 59.22 (~0, H: 6.49 %, N: 4~07 %O
~he staxting substancs can b~ prepared as ~ollows:
a) A mix~ure of 10907 g (0~66 mola) of 2~dimethoxy~
banzaldehyde9 72 ml (0366 mole) of banzylamine and 660 ml of methanol is stirred at room temperature for 20 minute~3 where~
upon a claar solu~ion is obtained from the susp~nsion~ The solution is cooled with ice water9 and 1302 g (0O33 mole) of sodi.um borohydride are added to i~ in small portionsO
rrhe progress of the reaction is moni~orad by thi~
laysr chromato$raphy (Kieselgel G according to Stahl; develop~
ing solvsnt: a 9.1 mixture of benzene and ace~one)~ and at tha end of the reaction the mixture is e~aporated to dryne~
in vacuoO ~he residue is admixed with 300 ml of watar~ a~d the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml portions of eth0rO The ether~al solutions ars combined~ dxied ovax magnesium sulfata~ filtered, and then 112 ml (0066 mole3 o~ diathyl bromomalonat~ and 9~ ml (0.66 mole) of ~riethyl amine are added to the filtrate9 rrhe raac~ion mixture i.s stirred at room temparature for 2-3 days. rrhe separatad kri~
ethyl ammonium bromide is filtersd off and washed with etherO
'rhe mother liquor is evaporated, and the residue is re~
cr~stallized from 150 ml o~ ethanolO The resulting 210 g o~
crude product ~e recrystallized again from 400 ml of ethanol to obtain 197 g (72 'Y0) of diethyl ~-benzyl_~(2~4-dimethoxy-benzyl)-amino-malonate; m.p~: 62-6~C (ekhanol)O
IR (~3r)o 1750/1725 cm 1 9 d, ~O b) 61~7 g (00149 mole3 Or diethyl N-benzyl~N~(2~4~di 8~iS
m~thoxybe~zyl)~ami~o~malo~ate3 pr~pared as describad i~ point a) abov~ are hydrog~natad in 500 m.l o~ et~lanol under atmo sph~xic p.r~ssure in tho presenc~ of about 20 g o~ p~ dium~
o~charcoal ca~alystO The catalyst -ls ~ilt~red of~ a~d tha .~iltrato is ~vaporatsd~ ~701 ~ (97 %) of di~thyl ~2~4-dime~h~
o~ybenzylamino)-malonata aro obtainsdO ~ho product can b~
converted into i~s hydrochlor~.de by r~acting it wi~h hy~ro~
chloric ~cid~ The hydrochlorid~ malts at 122-124C a~r crys~allizatio~ ~rom ethyl acetate~
~nalysis:
calculatad for C16H2L~ClM06 (361082) C: 53011 %3 H~ 6~69 %9 Cl: 9~80 %, N: 3~B7 %a ~ound~ C: 52~51 %9 H: 6.77 %~ Cl: 10030 %9 ~ 4~09 %o IR (~ilm): ~250~ 2900, 2850, 1730~ 1720 cm 1, H ~ (CDC13? ~ = 1.3 (s~ 6H)~ 3~7~ (s~ 3H)~ 3082 (87 3H) L~-21 (q~ L~H)~ 6~20 (sg 2~I) D 6~L~6~6 ~m~ 2~) ~ 7~3-7055 (m~ lH)~ 797 (broad s) lH) ppm~
c) ~ mixtura o~ 3906 g (00122 mola) of diethyl l2 dimethoxybenzylamino)-r~ lona~e~ prepared as describ~d in poi~
2Q b) above; 80 ml o~ ~lacial ac,etic acid and 1203 g (11~2 ml~
00146 mole) of dikotene i5 boiled for 005 hour~ Glacial acetiG
acid is dis~illed of.~ in vacuo over watar b~h~ and the oily r6sidu~ is triturated wi~h 150 ml of watera Th~ re~ulting crgstalline substancc is di.ssolved in 60 ml of ~thyl acetat~
and pxecipitated with petrolaum ethorO 29,6 g ~60 ~ of di~
athyl N ~2~4 dimethoxybanzyl) 3-hydroxy~3~methy~ 5~0~0~2g2 pyrrolidine-dicarboxylate and/or its tautomor are obtai~d~
m O p.: 106~107C.
Analys~s:
calculat~d r~ C20H2.7~J8 (~ 9 3 ~1 -58967 %~ H: 60G~ %9 N: 33~2 %~
~ound~ C. 58079 %~ H~ Go~ %~ N. 303~ %0 IR (I~Br): 3~009 2950~ 2850~ 1730 (1740~ sh)~ 1710 cm ~ NMR (C~13): ~- lol (~ 3H) 9 1017 (~, 3H) 9 1~52 f s~v3H) 7 208 (~ Ool ~) 9 2065 (broad 93 2H) 3 3075 (s~ 6E)~
~8~4015 (m, 4H) 3 6~7 (bxoad s~ 2H) 9 6~25-6045 (m) ~ 74~7~25 ~m~ 3H) ppm~
d3 20o5 g (50 mmol~s~ o.~ th3 product pxapared as de~
scribsd in point c) abov~ ar~ suspo~dsd i~ 50 ml o~ dr~ ~hex~
a~d a solutio~ o~ 3045 g (150 mmol~s) o~' m~allic sodium i~
100 ml o~ dry othanol and a solution of 1207 g (50 mmolos) o~
iodins in 150 ml o~ dry ~her aro added simul~an00usl~ ~rom ~wo dropping ~u~nels~ to the vigorously stirrad su~pensio~
under cooling with ice water~ ~h~rea~ter 5 g o~' sodium hydxo~
sulfite3 dissolved in 200 ml of a saturatad a~u~ous sodium chloride solutio~9 are added to the stirred mixture. Th~ mix~
~ure is fillod i~to a separating funnel and 60 ml of water ar0 added to dissolve the ~oparated inorga~ic ~alks. ~he oxganlc pha3e is removod, dri~d over magr~esi.um ~ulfato1 .~ilter~d~ and ~0 the ~lltra~e ~3 evaporatedO '~he oily re~idue7 w~ighin~ 1805 g~
i~ cry~tallized from ~0 ml o~ 2-propanol3 10~9 g (5~ %) sf die~hyl 3-ac~tyl~ 29L~dim3~hoxyb~zyl~4~0~0~292~aze~hidIne~
~icarboxylate are obtain3d~ m.pD 84~85~ ~2~propa~01~3 A~aly~iso calcula~ed for C20H25N0~ (407041~:
c: 58~96 %9 H, 6~19 %9 N~ 3~ %9 ~ound: a: 58099 %9 E: 6~04 %~ N. 3057 %p lH NMR (GDC13): ~- 1012 (t, 3~) 9 1.21 ~t/ 3H)~ 2031 (~ 3H)~ 3~76 (s) 6H), 3.8~3.~ (rn~ 4H) 7 4~53 (d, lH) a 4~63 (d, l~f)~ 4069 (s~ lH)~ 6~3~60L~ (rn7 2H) * 7,07 (d~ lH) ppm~
~9~5 ~ 12 e~ 179 ml ~206 g9 1~452 molq~ o~ boro~ trifluor~de diath-gl e~herate axa added dropwis3 to a v1gorous~y stirrecl solu~-io~ o:E -179 g (00484 mole) of diethyl 3~ac~tyl~ 294~di~
me~hoxybenzyl)-4-oxo-292-azethidine~dicarbo~yLate a~d 107 ml ( 120 g~ 10936 moles) of ethylene glycol in 500 ml of dry di~
oxane undar cooliDg~ wi.~h ice wa terO '~h~ reaction mi~t~re i~
allowfld to stand at room t0mperature ~or ox~ day~ dllring l;his period th~ mixt~re is occasionally stirr~dO '~hsrea:Eter 415 g ( 10452 mole~ of Na2C03,10H2o are added ~lowly ~o the stirred mixtur3 und~r cooli~g with ~ce water3 and the mixtur0 is stirred for 15 mi~u~es~ '~hereaft~r 1 litre of e ther and 1 litre o~ water are added~ and th~
phases are separated from ear,h otherO The aqueous phas sha~e~ twice with 500 ml of diethyl ether; eachO ~he e~heral phase is dri~d over magnesium sulfate~ filtered~ and ~he filtrate is evaporated.u 33~9 g (0058 mol~) of sodium chlorid~S
170~ ml (0.968 mole) of water and ~20 ml o~ dimethyl sulfoxide are added to the residue, and tha mix~ure is ~tirred on a~
oîl bath at 180C. The progras~ of the rsaction i~ monitorad by thin layer chrom~to~raphy (adsorben~: ~leselgel G accordi~g to Stahl.; developing solv0nt~ a 6:4 mixture of ben~c~e a~d eth~l acetate)~ At ~he and of the reaction~ iOe~ a~ter about 15 hours, the mixture is pour~d into 1100 ml of saturatcd aqueous sodium chloride solutio~ and th~ resulting mixture i9 shakan with 1000 ml and then twice with 500 ml of diethyl ather~ eachO ~he etherea'solut`ions ara combinad9 dacolou~i~ed wi~h charcoal~ driad over magnesium sulfata 3 and tha filtrata is evapora ted to a final volume of cca, 200 mlO Thi~ con-cerltra~ed solution is coolod with ice water to obtain 59 g (35 %3 of trans -ethyl 1-(2 7 ll~dimethox;yb~næyl) - 3-~2~methyl~13 3-9~s dioxola~2~yl)~4-oxo-2~azethidine-carboxyla~e; mOp.~ 95C.
~) A mixture o~ 0~5 g ~102 mmoles~ of diethyl 3~ace~y1 1~2~4~di~lethoxybenzyl1~4-oxo-2,2~azethidine-dicarboxyl~e~
prepared as desc:Libed in point d) above, 3 ml of dry te~ra~
~y~ro~uran and 0053 g (306 mmole~) of mercapto~etha~ol is ~oiled :~or 4 hours, and then 10 ml of' water and 10 ml o~ chloroform are added to the reaction mixture. The organic pha~e is separatad) washed with a 5% aqueous sodium ~ydrocarbo~ak~ solu~
tion9 dried over magnesium sulfa~e, filtered9 and the pxoduct is separated ~rom the ~ rate by prepaxatî~e ~hin layer chroma~ography (adsorbent: Kieselgel 60 PF254~366, de~eloping solvellt: a 8:2 mix~ure o.~ toluene and ac~tono). 0.30 g (53 %) of diothyl 1-~2~4-dimethoxybenzyl)-3-(2 methyl~l73~oxathiolan~
2~yl)~4-oxo-292-az6~hidine-dicarboxylate are obtain~dO
lX NMR (CDC13): G~ = 0 8~1055 (m~ 6H) 9 1072 ~ 1.77 (d9 3H); 209-304 ~m~ 2H); 3~75 (s~ 6H), 400-500 (m, 9E)~ 6~4 (m9 2H) ~ 701 (d, lH) ppm~
g) h solution of' 5421 g (0.130 mole) o~ sodi.um hydx~
oxide in 60 ~1 of water is added to a suspension of 4102 g (OolO9 mole) o~ tran~s~ethyl 1~(2~4~dimethoxyb~nzyl~-3~(2~m~thyl~
1~3-dioxolan 2-yl)-r4-oxo~2-azethidine-carboxylate 9 prapared as described in poin~ e) above, i~ 50 ml o~ ethanol u~der stirring and coolir~ with ice water3 and stirring is con~
tinued until a clear solution is obtained (about 20 ~inut~)0 100 ml of wa~er are add~d then to the solution; and the mix~
ture i5 shakerl with 100 ml of etherO ~he aqusous phase is acidi~ied ko pH = 1 with concentrated a~ueous hydrochloric acid9 and then shaken quickl~ wi~h 100 ml and twice with 50 ml 0~ diChloro~De~hane 9 each. ~'he dichloromethane solutions are ~0 co~sl'Dine~, dried over magnesium .sulfate; filtex~d7 and the -- l L~ 9 ~, 5i filtrate is evaporated3 Thfl oily residue is cr~y3tallizec1 from a mixture of toluene and petroleum ether to obtai~ 35 g (92 %) of trans~ 2~4~dimetho.xybenzyl)-3 (2-methyl-1 3 3-dioxolan~2 yl)~L~oxo~2 azethidirle-carbo~ylic acid~ mOpo 117-118C
(t~luene)0 Analy~is:
c~lculated for C17H21N07 (351~35) C ~ 58 oll %~ H 6 ~03 %~ N~ 3 ~99 %;
fou~d: C: 58017 %9 H: 6~30 %~ N- 4n24 %~
IR ~I~Br3: 3500-2500~ 29009 17609 1720 cm`l~
lH NMR (CDCl~)o ~ = 1039 (Sg 3H)~ 3O50 (d, lHg a = 2~5 Ez), 3~77 (s~ 3H), 3079 ~s~ 3H) ~ 3~86 (d, lI-I~ J = 205 Hz) 7 3a96 (m, 4H) ~ 4,21 * 4~56 (d~ 2H~ JAB= 15 Hz) 9 6044 (m~ 2H) ~ 7015 (d~ lH~ J = 10 ~z)~ 7~58 (broad s, lH) ppm~
h~ 7~ ml (52~5 mmoles) of triethyl'amine are added to a solutio~ of 17~6 g (50 mmoles) of ~rans-1-(2,L~di.methoxy-benzyl) 3~2 methyl;l93-dioxolan-2-yl)-4 oxo~2~azethidine-carb~
oxylic acid9 prepared as described in poi~t g) above, i~
150 ml of d~'t~tra~ydrofuran, and then 500 ml (52~5 m~oles) 2~ of ethyl chloroformate ar3 added to tha mixture undqr cooli~g with ice~ The mixture is cooled to -15C, sti.rred at this temperature f'or 20 minutes, and the separated triethyl amine salt is f'il~ered off at the same temperature under axgon atmo~
sphareO A solution of 150 mmolss o~ diazomethan6 in 230 ml of cold diethyl ~t'nor is addad ~o the ~iltrateO ~he mixtuxe i5 stirr~d9 al'lowed to warm to room t~mperaturo~ a~d a~ter 2 hours o~ stirring i~ is evapoxated to drynessO ~'he bro~ thick residue is disso].ved in 20 ml o~ ~anzene, and khe produck is separated by column chromatography (adsorbent: 150 g o~ Kiesal-~0 gel 60, ~ = 0006~0~200 ~, eluting agent: a 7~2 mixture o~
~39~5 5 ~
benxene and ac0t;0ne)0 12~0 g (64 %) of trans~(diazoac~tyl3~~ 4 dimethoxybenzyl)~3-(2-methyl 193-dioxola~-2~yl)~2~az~
ekhidinone are o~tainedO
Ana ly5i 5:
5calculated for C18H;~lN306 (375037): C: 57~59 %, H~ 5064 %~
~ound: C 57078 ~ H. 5~9 %3 IR (KBr): 29009 ~1103 1760 cm 1, Exam~
10 ~aL=~oxo-2-a z~cid
lX NMR (CDC13): G~ = 0 8~1055 (m~ 6H) 9 1072 ~ 1.77 (d9 3H); 209-304 ~m~ 2H); 3~75 (s~ 6H), 400-500 (m, 9E)~ 6~4 (m9 2H) ~ 701 (d, lH) ppm~
g) h solution of' 5421 g (0.130 mole) o~ sodi.um hydx~
oxide in 60 ~1 of water is added to a suspension of 4102 g (OolO9 mole) o~ tran~s~ethyl 1~(2~4~dimethoxyb~nzyl~-3~(2~m~thyl~
1~3-dioxolan 2-yl)-r4-oxo~2-azethidine-carboxylate 9 prapared as described in poin~ e) above, i~ 50 ml o~ ethanol u~der stirring and coolir~ with ice water3 and stirring is con~
tinued until a clear solution is obtained (about 20 ~inut~)0 100 ml of wa~er are add~d then to the solution; and the mix~
ture i5 shakerl with 100 ml of etherO ~he aqusous phase is acidi~ied ko pH = 1 with concentrated a~ueous hydrochloric acid9 and then shaken quickl~ wi~h 100 ml and twice with 50 ml 0~ diChloro~De~hane 9 each. ~'he dichloromethane solutions are ~0 co~sl'Dine~, dried over magnesium .sulfate; filtex~d7 and the -- l L~ 9 ~, 5i filtrate is evaporated3 Thfl oily residue is cr~y3tallizec1 from a mixture of toluene and petroleum ether to obtai~ 35 g (92 %) of trans~ 2~4~dimetho.xybenzyl)-3 (2-methyl-1 3 3-dioxolan~2 yl)~L~oxo~2 azethidirle-carbo~ylic acid~ mOpo 117-118C
(t~luene)0 Analy~is:
c~lculated for C17H21N07 (351~35) C ~ 58 oll %~ H 6 ~03 %~ N~ 3 ~99 %;
fou~d: C: 58017 %9 H: 6~30 %~ N- 4n24 %~
IR ~I~Br3: 3500-2500~ 29009 17609 1720 cm`l~
lH NMR (CDCl~)o ~ = 1039 (Sg 3H)~ 3O50 (d, lHg a = 2~5 Ez), 3~77 (s~ 3H), 3079 ~s~ 3H) ~ 3~86 (d, lI-I~ J = 205 Hz) 7 3a96 (m, 4H) ~ 4,21 * 4~56 (d~ 2H~ JAB= 15 Hz) 9 6044 (m~ 2H) ~ 7015 (d~ lH~ J = 10 ~z)~ 7~58 (broad s, lH) ppm~
h~ 7~ ml (52~5 mmoles) of triethyl'amine are added to a solutio~ of 17~6 g (50 mmoles) of ~rans-1-(2,L~di.methoxy-benzyl) 3~2 methyl;l93-dioxolan-2-yl)-4 oxo~2~azethidine-carb~
oxylic acid9 prepared as described in poi~t g) above, i~
150 ml of d~'t~tra~ydrofuran, and then 500 ml (52~5 m~oles) 2~ of ethyl chloroformate ar3 added to tha mixture undqr cooli~g with ice~ The mixture is cooled to -15C, sti.rred at this temperature f'or 20 minutes, and the separated triethyl amine salt is f'il~ered off at the same temperature under axgon atmo~
sphareO A solution of 150 mmolss o~ diazomethan6 in 230 ml of cold diethyl ~t'nor is addad ~o the ~iltrateO ~he mixtuxe i5 stirr~d9 al'lowed to warm to room t~mperaturo~ a~d a~ter 2 hours o~ stirring i~ is evapoxated to drynessO ~'he bro~ thick residue is disso].ved in 20 ml o~ ~anzene, and khe produck is separated by column chromatography (adsorbent: 150 g o~ Kiesal-~0 gel 60, ~ = 0006~0~200 ~, eluting agent: a 7~2 mixture o~
~39~5 5 ~
benxene and ac0t;0ne)0 12~0 g (64 %) of trans~(diazoac~tyl3~~ 4 dimethoxybenzyl)~3-(2-methyl 193-dioxola~-2~yl)~2~az~
ekhidinone are o~tainedO
Ana ly5i 5:
5calculated for C18H;~lN306 (375037): C: 57~59 %, H~ 5064 %~
~ound: C 57078 ~ H. 5~9 %3 IR (KBr): 29009 ~1103 1760 cm 1, Exam~
10 ~aL=~oxo-2-a z~cid
3 . 3 g ( 0~ 01 mole) o~ trans-~(diazoacetyl)~3~(2-m~thyl~
193~dioxolan-2-yl3-1~(4-methoxyphenyl)-2~azethid~none are di~-solved in a mixturo o~ 50 ml o~ wator and 100 ml Or tetr~
hydro~uranO ~he mixtura is irradiated with a high pxe~sur0 mercury lamp in a photoreactor under nitrogan atmosphare a~
room temperat~e~ and the progrsss of' ~he reacbion is monitoraa by thin layer chromatography (adsorbent- Kieselgel G according ~o Stahl~ dev~lopi~g solvent: a 7:1 mixture o~ benzene and acetorlo)" When kh~ reaction is ove:r~ t~trahyaxof`uran is 20 distill~d o~f in vacuo, I;he residue is rendcred alka~ nc with 20% aclueous ~30dium hydroxide solution, and ~h~ ~olutio~ is washod twice wi~h 15 ml of dichlorom~tharle ~ oachO ~hc aqueous ph3~e is acidiîied ~o pH 1 2 with conc~ntrat~d aqlleous hydro-chloxic acid and ~he~ extracted thrice with 20 ml of dichloro~
25 me thane ~ oach~ ~he orgarlic phasas a~e combins~ driod over magnesium sulfate3 îilteroda and th~ îiltrat~ is ~vaporal.0dO
106 g (50 %) o~ the eimed compound are obtai~ed3 Ana lys is:
calculated ~or C16H19N06 ~321~33 C: 59080 %, H: 5b96 %, N: ~36 %~
found- C: 59060 %~ H: 5076 %~ N: 4v08 ~0 IR (film): 3500-2500~ 1760-1700 cm ~0 ~'he starting substance can be prepared as ~ollows~
a) A mixture of 24-o6 g tl~ mole~ o:E 4- methoxyanilino and 23"9 g (17 ml, 0.1 mole~ of diethyl bromomalonate is stirred at room temperature for 2 days,, The resul~i~g mass i5 triturated with 100 ~nl o.f` diethyl ether9 the separated L~meth~
oxy-anisidin~ hydrobromide is filtered off and wash0d with a small amoun~ of die~hyl e~herO The mothar li~uor is ~vapoxat~
0d and the r6sidue is crystallized from diluta acetic ~lcido 1302 g (47 ~o) of diethyl (4-mc~hoxyf~nilino)-malonate ar~ ob~
tained~ mOpO: 64~65C (ethanol).
Analysis:
calculatod for C14H19~5 (281-31 15C: 59077 %) lI: 6.~1 %7 ~: 4~,99 %~
~ound- C: 59099 %, H: 61~97 %~ N: 5025 %"
Bx): 3300, 17757 1725 cm lo LH NDqR (CDC13): ~- 1.23 (t~ 6H, J = 7-2 H~z~ 9 3-~7 (s, 3II), 402 (c, /~H~ J = '7~.2 Hz)~ 4O62 (s~ lH~, 401_L~o5 (broad s, lH~ 6055 (2H) ~ 6073 t2H9 AA'BB9~ J = 9 Hz) ppmO
b) A mixture of' 1102 g (0004 mol~ of dieth~l (L~meth~
o~yani:lino)-malonate~ prepared as described in point a) abo~r03 15 ml of glacial acetic acid and 4 g (3.7 ml~ 0~,048 mol~) o~
diketena is boiled for 0~5 hour~ The solution is evaporatad 25 ~n ~acuo, the oily residue is tril~urated wit;h diethyl other3 and the solid is Liltered of:~. 10~5 ~ (72 %) OI diathyl 1~(4~methoxyphen~ hydroxy~3~methyl-5~oxow2,2-pyrrolidine~
dicarboxyla ta and/or it~ tautomar are obtain~d, m"p,,~
1~6~137C (~thyl aceta~o~.
3~ IR ~KBr3~ 3600-3C00~ 176(), 1740~ :L685 cm 1.
Anal~sis.
calculated f 017 Cl~H23~07 (365~38):
C 59~17 %, H: 60~9 %, N. 3~83 %7 found. C0 5~3098 %~ H: 6090 v~? N: L~oO4 ~0O
lH N~ (C~Cl~ 0? (t, ~Hg J = 7~2 Hz)~ 1028 (~
3H9 J = 702 Hz~9 1~58 (S9 3H)~ 2~76 (s~ 2H)7 306~ (S9 l~I)9 3~76 [S9 3H), 401 (q~ 2~9 J = 7~2 H~)~ 4~27 (q~ 2H7 J = 702 Hz~ 9 607 ~2H~ ~ 7~0 (2H, AA9~B9) J = 9 Hz) ppm~
c) 901 g (0.025 mole) of diethyl 1-(4~mathox~phsnyl)-~
3~hydro.xy~-mathyl-5-oxo-272~pyrrolidi.ne-dicaxbo.~-,ylat~ pr0-pared as described in point b) aboveS are suspended .in 50 ml of dry diethyl ether) and a solution of 1.72 g of metallic sodium in 30 ml o~ dry etha~ol and a solution of 6335 g (03025 molo) of iodine in 50 ml of dry diethyl ekher ar~ simul-tan00usly dropped inko the suspension under vigorous stirring and cooli~g with ice~ rrhereafte.r the mix~ure is poured into 100 ml o~' a sa~u.rated aqueous sod-ium chloride solution~ and 2 g o~ sodium hydrosul~ite and 2 ml of glacial acetic acid are addedO rrhH ethexeal phase is separa~ed, and ~he aqueous phasa is e~xtracked khrice with 50 ml of diethyl ether9 each3 r~h~
~there~ phases ara combined, drisd over magnesium sul~at~
filtared7 and ~he ~ilkrate is evaporat~dJ The oily residu~
i~ txi~urated with 2-propanol to obtain 6~2 g ~68 %~ o~
crys~alli~e die~hyl 3-ace~yl~ methoxyphenyl)-4 oxo 2~2 azethidina dicarboxylate; m~pO- 70-71~ (e~hanol)~
Analysis:
calculated ~or C18H21~07 (363.38):
C: 59050 %, H- 5~82 %, N: 3085 %~
~ourld~ C~ 59004 %, H: 5084 %, N- 4.08 %.
IR (KBr): 17607 17~5 7 1720 cm 1, 891~S
8 _ H NMR (CDC13)~ ~= 1.20 ~t, 3Hg J - 7~2 Hz3~ 1022 (~ 3H~ J - 702 Hz)~ 2.~3 (59 3H)~ 3~7 ~9 3H) 9 4017 (q~ 2H~
J = 7.2 Hz)~ 4~19 ~q9 2H3 J = 702 Hz), 407 (~ lH)g 6~7 ~2.
7~1 (2H9 AA'~B' 3 J = 9 EIz) ppm, d) 6 g ~000155 mole) o~ diethyl 3-acetyl~ (4wm~ho~y~
ph~3~1)-L~o~o-~g2-aæet:~hidin~3-dicarbo~ylal:i~J 9 pr~par~d ~
de~cribed i~ poi~t c~ abovs~ are dissolved in 20 ml o~ d~y di~
o~ane and 4~1 g (3075 ml, 01066 mole) o.~ ethyl~ne glyCO~-D
701 g ~6~3 ml~ 0~05 mole) o~ boron trifluoride--diathyl ether2te complex are added dropwise to the stirred solu~ion under iC3 coolingg and the rsaction mi~ture is stirred fo.r addi~.onal 2 hours at room temper~ureO The solution is rendered alkaline with saturat~d aqueous sodium hydrocarbonate solution~ thsre~
af~er 100 ml o~ water are added~ and the mixture is axtracked thrice with 50 ml oî die thyl e ther, each i Th~ organic phases ~re combined3 dried over magnesium sulfate9 f'ilterod., ~nd ~h~
. ~iltra~e is ~vapora~ed~ Tho oily rasidue is triturated wi~
die thyl o thar to ob tairl 6 g ( 89 %) o:E cxys ta llinc die l;h~T1 3- (2~m~thyl~1 j3~di.o}~olar:l-2~ (L~me~ho~ph~ ? ~4~oxo~2~2~
aze~hidin~Ddicarbo~yla~e; m.p.~ 82~83~C (ethanol~0 lysis:
, . calcula~ad ~or C20H25N0~3 (L~07043)-C: 58396 %j H: 6.18 %9 No 3044 %"
~ound: C: 58~70 %9 H: 5~68 ~9 N~ 3363 %0 IR (KBr): 1740 cm 1 (broad) H NMR ~CDC~33 ~= 1.17 ~'l;7 3~I~ J -- 7-~ Hz) ~ 6 (~ 3H3 J = 702 Hz), 105 ~s~ 3H) 9 307 (~ 3H) 9 3~9 ~m, 4H~
~92 ~m7 5H) ~ 6~67 (2H) ~ 7034 (2Ha, AA9~:B9 7 J ~ 9 Hz) ppmO
~)~11 g (0~0245 mole~ o.f di~thyl 3~(2~m~1;hyl~133~di~-oxolan-2-;7l)~l-(4-me~hox,~pher1yl)-4~oxo~2~2-azethidin~dicarb~
1365~
oxylate~ pr~pared as dflscri~ed in point d) ~bova~ aro dis~
solved in 20 ml of dimethyl su~ oxide 9 1D72 g ~0~0295 mole~
o~ sodium chloride and 0.9 ml ~0~049 mole) o~ water are added~
a~d the mix~ure is stirred at 175C ~mtil a complete reaction i~ obtaîned~ r~he progrsss of the reaction i.5 monitored by thin layar chromabography (adsorb~nt: Kicselga:l G according to Stahl~ dev~lopi.~g solvent: a 6 4 mixtura of b~n~fl~e and ethyl acetate)0 ~he mixturo is cooled~ poured into 150 ml of a ~at~ra~
ed a~ueous sodium chloride solution, a~d oxtractod thrice with 50 ml o~ diethyl cthqr, each~ ~he orgallic phases a.rfl comhi.ned~
dried over maOrnesium sulfate, filtered, and the filtra~e i9 evaporated. The resulting oily residue 9 wsi.ghi~g 6 g9 iS dis~
solvad in 25 ml of 96% ethanol~ and a so;lutio~ of 0072 g (0~018 mole) o~ sodium hydroxide in 10 ml o~ water is added to bhc alcoholic mix~ure u~der cooii~l~ with ice water~ ~he mi~ture is stirred fox 005 hour, then dilutod with 50 ml of water and ~ashed twice with 25 ml o~ dlchloromethane 9 sach~ The aquoous ~ ~phase is acidi.~ied bo pH = 1 with concentrated aquaous hydro~
chlorlc acid, and then sxtract~d thricfl with 25 ml o~ dichloro m~tha~o, each. The organic phases are combined7 ~xiad over magnesium sul~ate~ fil~ered, and ths fi.ltrate is avaporatsd~
The oily residue is crys~allized with benzene. 4 g (54 %~ o~
trans;-3~(2-methyl-1,3-dio~olan~2~yl)~1-(L~methox~phanyl)~L~oxo~
2-azsthidine~carbo~ylic acid axe obtained~
Analysis~
calculat9d ~or C15H17~ 6 ~3 7~3 C 5~o6~ %~ ~ 5~57 %, N: L~56 %~
foun~l: C: 58~L~o %~ H: 5080 %~ N: L~o66 ~o IR (~3r)0 3400-2700~ 1750 (broad~ cm lo s _ 20 ~
1H N~R ~C'DC13). ~ = 105 (S7 3H) 9 3~7 td9 lHq J - 2~5 Hz)~ 3~76 (s~ ~H), 400 (m, 4H) 9 4038 (d, lH~ J = 2~5 Hz)~ 6082 (2~ ~ 7~26 (2H, A~'BB', J = 9 Hz) 7 902 (s, lH) ppmO
f) 1011 g (1056 ml~ 0~011 mole? o~ dry triethyl ami~ are addad to a solution o.f 3 g (O.Gl mole) o~ a compou~d prepared a~ dascribed in point e3 abovc ln 20 ml o~ dry tetra-hydro~uranO ~he solution is coolsd to ~15C 7 and 1.2 g ~1.06 m19 0JO11 mols) of eth.yl chloroformate are added dropwis~ to t~a s~irred solution~ er 20 min~tes of stirring the separak~
ad ~al~ is f~ltared o~f ~mder nitrogen atmospher~ 9 and a solu ~io~ o~ 408 g (0.025 moie) o~ diazomethane in diethyl. ether i9 added to ~he ~iltrate at room temperature. A~ter 2 hours o~ s~irring the excess o~ diazomethane is.decomposed with acetic acid~ and the solution is evaporated in vacuoe ~he oily residue slowly crystallizes. 3 g (90 %~ o~ trans-4~(diazo~
acekyl~-3-(2-methyl-1,3 dioxolan-2-yl)~1_(4~metho~yphenyl)~
2-azethidinone are obtai~ed7 m~pO: 95-96C (berlzene and ekher3J
IR. (KBr)- 2209; 1760~ 1640 cm 1.
H NMR (CDC13) ~ = 1.50 (s~ 3H)~ 3~51 (d, 1~{, J
~0 2l6 Hz)5 3075 (~7 3~I), 4.05 (m, ~H)7 4.31 (d~ lH9 J = 2~6 Hæ)~
5.47.(~, lH)~ 6085 ~2H) ~ 7~30 (2H9 AA'BBa~ J = 9 Hz) ppmO
Exam~
~ran~ by~ !y~ol~
~xo-2~a~thid~,7 ~ L~.~a .
308 g (000126 mole) of krans~4~(dia~oacotyl) 1-phonyl-3~(2 methyl-1,3-dioxolan-2 yl~-2-azethidinone are dis~
solvad in a mixture o~ 100 ml of totrahydro~uran and 50 ml o~
wat~r7 and the solution is irradiated with a high -pr~ssure mercury lamp in a pho~oreac~or a~ room temp~rature under nitro~
3 Kon atmo~pher~0 The progre~,~ o~ the reacti.on is monitor3d by 3~
thin layer ~ o.:~ato~raphy (adsorbent: Kies~l~rel G accoxding to Stanl, developini; solvent: a 7:1 mixture of benzene and ace-torle)~ At the end of the reaction tetrahydro~uran is evaporat-ed in vacuo, ~he L~esidue is rendered al~aline ~ith a 20 aqueous socli.um ~ydroxide solution, and the alkaline solutio~
is washed thrice with 15 ml of dichloromethane, aach~ ~he aqueous phase is acidi.fied to pH = 1-2 with conce~trated aqueous hydrochloric acid and then ext~ac~sd thrice wi~h 20 ml o~ d.ichlororl~ethane, each. '~he organic phases are combined~
dried ovex magnesium sul~ate 9 filtered9 and the filtxate is e~aporateclO The ()i.l~ r~sidu~ i~ triturated with skher to ob-kai~ 1~8 g (50 ~0) of crystalline ~krans~l-pher~tl-3-(2~methyl-1~3-dioxolan~-yl)-4~oxo~2-azethidiny ~ -acetic ~cid~ mDp.
128-129C (ethanol,~
Analysis:
calculated fox C15H17N05 (291029):
C: 62000 ~ H: 5.88 %, N: 4082 ~ound: C: 61075 '~, H: 5 86 ~0, N: 5.08 IR (KI~.r): 1760~ 17L~ cm 1 lFf NIlE2 (C~Cl~ = loLl8 ( S9 3~f), 2065 (dd~ lH~
Jgem = 15 Hz~ J~ic= 8 Hz) ~ 301~ (dd~ lfI~ Jgem = 15 Hz9 Jvic = 8 Xz), 30~7 (d, lH, J = 205 Hz), ~98 (m9 L~H3, L~oL~ ~m, lH), 7.3 (m, ~H) a 9~33 (broad s 3 lH) ppm.
~he starting substance can be prepared as follows, a) h rnixture of 38 g (0~.152 mole) of diethyl ~nilino malonate ~. Blank: BerO ,~19 1815 (1898~77 38 ml of glacial acetic acid and 15~3 g~ (13.9 mlg 0"182 mole) of diketene is boiled ~or 0.5 hourO ~lacial acetic acid i~; evaporated in vacuo over a t;Jal~er bath, and the oil~y residue is crystallized by ~0 tritllr~3ting it; with ethex 0 3605 ~, (72 '70) of diethyl (N~phenyl-8~i5 ~ 22 ~
3~hydroxy~3~me thyl-~oxo-2,2~pyrroliclir3e-dicarb~a~ylate) and~or :i.ts tautomer are obtained3 mOpo 98~99 (~ (ethyl acetate and pe troleum etihcr~ ~.
Ana lysis:
ca lc u la te d I or ~17H21N6 (335 ~P 35):
C. 60088 %, H: 6031 %" N- 4~18 %D
.Eound~ ~: 60083 (~, H: 6015 %1 N- 4~43 IR (K13r): 33~0~ 29501 17609 1750 (d~ 9 1700 cm ~
lH NA~ (aDc~= 1.02 ( k9 3H) 3 1.3 (t; 3 3E) 3 106 (s5, 3H) 92,.8 ~,s~ 3II) q 3.~6 (broad s, lH) ~ 4-4045 (m? 4H) 9 702 ( s~ 5H) ppm.
b) 50 g (00149 mole) o:f diethy;l. ~N-phe~yl-3~hydrox~
3-m~thyl-5~oxo-2 j2~pyrrolidine-dicarbo.~{yla te) ~ prepared as des~rib0d in point a~ above 3 are added to a solutio~ of ï0e,2 g (00447 mole) of metallic sodium in 250 ml oE dry e~ha~ol3 ther0aïter a solution of 37ç9 g ~00149 mole) of iodine in 200 ml of dry ether is added under vigorous s~i:rri~g~0 When the reac~
tiorl is over~ 805 ml (8.9 g7 0~,149 molo),~o~ glacial acetic acid, 200 ml of: water and 100 ml o:E e ther are added to the mixture, tha organic phase is separated~ and ~he aqueou~ pha~e is extracted with 100 ml o~ e~her~ ~he c~ crc~ phases are com~
bined, dried over magnesium sulfate, ~iltorsd9 and tho filtrate is evaporatedO '~he oily residue is crys~alliz~d from 50 ml o~
2-propa~ol to obtai~ 31 g (62 ~0) of diethyl (3-acetyl~l-phe~yl=
193~dioxolan-2-yl3-1~(4-methoxyphenyl)-2~azethid~none are di~-solved in a mixturo o~ 50 ml o~ wator and 100 ml Or tetr~
hydro~uranO ~he mixtura is irradiated with a high pxe~sur0 mercury lamp in a photoreactor under nitrogan atmosphare a~
room temperat~e~ and the progrsss of' ~he reacbion is monitoraa by thin layer chromatography (adsorbent- Kieselgel G according ~o Stahl~ dev~lopi~g solvent: a 7:1 mixture o~ benzene and acetorlo)" When kh~ reaction is ove:r~ t~trahyaxof`uran is 20 distill~d o~f in vacuo, I;he residue is rendcred alka~ nc with 20% aclueous ~30dium hydroxide solution, and ~h~ ~olutio~ is washod twice wi~h 15 ml of dichlorom~tharle ~ oachO ~hc aqueous ph3~e is acidiîied ~o pH 1 2 with conc~ntrat~d aqlleous hydro-chloxic acid and ~he~ extracted thrice with 20 ml of dichloro~
25 me thane ~ oach~ ~he orgarlic phasas a~e combins~ driod over magnesium sulfate3 îilteroda and th~ îiltrat~ is ~vaporal.0dO
106 g (50 %) o~ the eimed compound are obtai~ed3 Ana lys is:
calculated ~or C16H19N06 ~321~33 C: 59080 %, H: 5b96 %, N: ~36 %~
found- C: 59060 %~ H: 5076 %~ N: 4v08 ~0 IR (film): 3500-2500~ 1760-1700 cm ~0 ~'he starting substance can be prepared as ~ollows~
a) A mixture of 24-o6 g tl~ mole~ o:E 4- methoxyanilino and 23"9 g (17 ml, 0.1 mole~ of diethyl bromomalonate is stirred at room temperature for 2 days,, The resul~i~g mass i5 triturated with 100 ~nl o.f` diethyl ether9 the separated L~meth~
oxy-anisidin~ hydrobromide is filtered off and wash0d with a small amoun~ of die~hyl e~herO The mothar li~uor is ~vapoxat~
0d and the r6sidue is crystallized from diluta acetic ~lcido 1302 g (47 ~o) of diethyl (4-mc~hoxyf~nilino)-malonate ar~ ob~
tained~ mOpO: 64~65C (ethanol).
Analysis:
calculatod for C14H19~5 (281-31 15C: 59077 %) lI: 6.~1 %7 ~: 4~,99 %~
~ound- C: 59099 %, H: 61~97 %~ N: 5025 %"
Bx): 3300, 17757 1725 cm lo LH NDqR (CDC13): ~- 1.23 (t~ 6H, J = 7-2 H~z~ 9 3-~7 (s, 3II), 402 (c, /~H~ J = '7~.2 Hz)~ 4O62 (s~ lH~, 401_L~o5 (broad s, lH~ 6055 (2H) ~ 6073 t2H9 AA'BB9~ J = 9 Hz) ppmO
b) A mixture of' 1102 g (0004 mol~ of dieth~l (L~meth~
o~yani:lino)-malonate~ prepared as described in point a) abo~r03 15 ml of glacial acetic acid and 4 g (3.7 ml~ 0~,048 mol~) o~
diketena is boiled for 0~5 hour~ The solution is evaporatad 25 ~n ~acuo, the oily residue is tril~urated wit;h diethyl other3 and the solid is Liltered of:~. 10~5 ~ (72 %) OI diathyl 1~(4~methoxyphen~ hydroxy~3~methyl-5~oxow2,2-pyrrolidine~
dicarboxyla ta and/or it~ tautomar are obtain~d, m"p,,~
1~6~137C (~thyl aceta~o~.
3~ IR ~KBr3~ 3600-3C00~ 176(), 1740~ :L685 cm 1.
Anal~sis.
calculated f 017 Cl~H23~07 (365~38):
C 59~17 %, H: 60~9 %, N. 3~83 %7 found. C0 5~3098 %~ H: 6090 v~? N: L~oO4 ~0O
lH N~ (C~Cl~ 0? (t, ~Hg J = 7~2 Hz)~ 1028 (~
3H9 J = 702 Hz~9 1~58 (S9 3H)~ 2~76 (s~ 2H)7 306~ (S9 l~I)9 3~76 [S9 3H), 401 (q~ 2~9 J = 7~2 H~)~ 4~27 (q~ 2H7 J = 702 Hz~ 9 607 ~2H~ ~ 7~0 (2H, AA9~B9) J = 9 Hz) ppm~
c) 901 g (0.025 mole) of diethyl 1-(4~mathox~phsnyl)-~
3~hydro.xy~-mathyl-5-oxo-272~pyrrolidi.ne-dicaxbo.~-,ylat~ pr0-pared as described in point b) aboveS are suspended .in 50 ml of dry diethyl ether) and a solution of 1.72 g of metallic sodium in 30 ml o~ dry etha~ol and a solution of 6335 g (03025 molo) of iodine in 50 ml of dry diethyl ekher ar~ simul-tan00usly dropped inko the suspension under vigorous stirring and cooli~g with ice~ rrhereafte.r the mix~ure is poured into 100 ml o~' a sa~u.rated aqueous sod-ium chloride solution~ and 2 g o~ sodium hydrosul~ite and 2 ml of glacial acetic acid are addedO rrhH ethexeal phase is separa~ed, and ~he aqueous phasa is e~xtracked khrice with 50 ml of diethyl ether9 each3 r~h~
~there~ phases ara combined, drisd over magnesium sul~at~
filtared7 and ~he ~ilkrate is evaporat~dJ The oily residu~
i~ txi~urated with 2-propanol to obtain 6~2 g ~68 %~ o~
crys~alli~e die~hyl 3-ace~yl~ methoxyphenyl)-4 oxo 2~2 azethidina dicarboxylate; m~pO- 70-71~ (e~hanol)~
Analysis:
calculated ~or C18H21~07 (363.38):
C: 59050 %, H- 5~82 %, N: 3085 %~
~ourld~ C~ 59004 %, H: 5084 %, N- 4.08 %.
IR (KBr): 17607 17~5 7 1720 cm 1, 891~S
8 _ H NMR (CDC13)~ ~= 1.20 ~t, 3Hg J - 7~2 Hz3~ 1022 (~ 3H~ J - 702 Hz)~ 2.~3 (59 3H)~ 3~7 ~9 3H) 9 4017 (q~ 2H~
J = 7.2 Hz)~ 4~19 ~q9 2H3 J = 702 Hz), 407 (~ lH)g 6~7 ~2.
7~1 (2H9 AA'~B' 3 J = 9 EIz) ppm, d) 6 g ~000155 mole) o~ diethyl 3-acetyl~ (4wm~ho~y~
ph~3~1)-L~o~o-~g2-aæet:~hidin~3-dicarbo~ylal:i~J 9 pr~par~d ~
de~cribed i~ poi~t c~ abovs~ are dissolved in 20 ml o~ d~y di~
o~ane and 4~1 g (3075 ml, 01066 mole) o.~ ethyl~ne glyCO~-D
701 g ~6~3 ml~ 0~05 mole) o~ boron trifluoride--diathyl ether2te complex are added dropwise to the stirred solu~ion under iC3 coolingg and the rsaction mi~ture is stirred fo.r addi~.onal 2 hours at room temper~ureO The solution is rendered alkaline with saturat~d aqueous sodium hydrocarbonate solution~ thsre~
af~er 100 ml o~ water are added~ and the mixture is axtracked thrice with 50 ml oî die thyl e ther, each i Th~ organic phases ~re combined3 dried over magnesium sulfate9 f'ilterod., ~nd ~h~
. ~iltra~e is ~vapora~ed~ Tho oily rasidue is triturated wi~
die thyl o thar to ob tairl 6 g ( 89 %) o:E cxys ta llinc die l;h~T1 3- (2~m~thyl~1 j3~di.o}~olar:l-2~ (L~me~ho~ph~ ? ~4~oxo~2~2~
aze~hidin~Ddicarbo~yla~e; m.p.~ 82~83~C (ethanol~0 lysis:
, . calcula~ad ~or C20H25N0~3 (L~07043)-C: 58396 %j H: 6.18 %9 No 3044 %"
~ound: C: 58~70 %9 H: 5~68 ~9 N~ 3363 %0 IR (KBr): 1740 cm 1 (broad) H NMR ~CDC~33 ~= 1.17 ~'l;7 3~I~ J -- 7-~ Hz) ~ 6 (~ 3H3 J = 702 Hz), 105 ~s~ 3H) 9 307 (~ 3H) 9 3~9 ~m, 4H~
~92 ~m7 5H) ~ 6~67 (2H) ~ 7034 (2Ha, AA9~:B9 7 J ~ 9 Hz) ppmO
~)~11 g (0~0245 mole~ o.f di~thyl 3~(2~m~1;hyl~133~di~-oxolan-2-;7l)~l-(4-me~hox,~pher1yl)-4~oxo~2~2-azethidin~dicarb~
1365~
oxylate~ pr~pared as dflscri~ed in point d) ~bova~ aro dis~
solved in 20 ml of dimethyl su~ oxide 9 1D72 g ~0~0295 mole~
o~ sodium chloride and 0.9 ml ~0~049 mole) o~ water are added~
a~d the mix~ure is stirred at 175C ~mtil a complete reaction i~ obtaîned~ r~he progrsss of the reaction i.5 monitored by thin layar chromabography (adsorb~nt: Kicselga:l G according to Stahl~ dev~lopi.~g solvent: a 6 4 mixtura of b~n~fl~e and ethyl acetate)0 ~he mixturo is cooled~ poured into 150 ml of a ~at~ra~
ed a~ueous sodium chloride solution, a~d oxtractod thrice with 50 ml o~ diethyl cthqr, each~ ~he orgallic phases a.rfl comhi.ned~
dried over maOrnesium sulfate, filtered, and the filtra~e i9 evaporated. The resulting oily residue 9 wsi.ghi~g 6 g9 iS dis~
solvad in 25 ml of 96% ethanol~ and a so;lutio~ of 0072 g (0~018 mole) o~ sodium hydroxide in 10 ml o~ water is added to bhc alcoholic mix~ure u~der cooii~l~ with ice water~ ~he mi~ture is stirred fox 005 hour, then dilutod with 50 ml of water and ~ashed twice with 25 ml o~ dlchloromethane 9 sach~ The aquoous ~ ~phase is acidi.~ied bo pH = 1 with concentrated aquaous hydro~
chlorlc acid, and then sxtract~d thricfl with 25 ml o~ dichloro m~tha~o, each. The organic phases are combined7 ~xiad over magnesium sul~ate~ fil~ered, and ths fi.ltrate is avaporatsd~
The oily residue is crys~allized with benzene. 4 g (54 %~ o~
trans;-3~(2-methyl-1,3-dio~olan~2~yl)~1-(L~methox~phanyl)~L~oxo~
2-azsthidine~carbo~ylic acid axe obtained~
Analysis~
calculat9d ~or C15H17~ 6 ~3 7~3 C 5~o6~ %~ ~ 5~57 %, N: L~56 %~
foun~l: C: 58~L~o %~ H: 5080 %~ N: L~o66 ~o IR (~3r)0 3400-2700~ 1750 (broad~ cm lo s _ 20 ~
1H N~R ~C'DC13). ~ = 105 (S7 3H) 9 3~7 td9 lHq J - 2~5 Hz)~ 3~76 (s~ ~H), 400 (m, 4H) 9 4038 (d, lH~ J = 2~5 Hz)~ 6082 (2~ ~ 7~26 (2H, A~'BB', J = 9 Hz) 7 902 (s, lH) ppmO
f) 1011 g (1056 ml~ 0~011 mole? o~ dry triethyl ami~ are addad to a solution o.f 3 g (O.Gl mole) o~ a compou~d prepared a~ dascribed in point e3 abovc ln 20 ml o~ dry tetra-hydro~uranO ~he solution is coolsd to ~15C 7 and 1.2 g ~1.06 m19 0JO11 mols) of eth.yl chloroformate are added dropwis~ to t~a s~irred solution~ er 20 min~tes of stirring the separak~
ad ~al~ is f~ltared o~f ~mder nitrogen atmospher~ 9 and a solu ~io~ o~ 408 g (0.025 moie) o~ diazomethane in diethyl. ether i9 added to ~he ~iltrate at room temperature. A~ter 2 hours o~ s~irring the excess o~ diazomethane is.decomposed with acetic acid~ and the solution is evaporated in vacuoe ~he oily residue slowly crystallizes. 3 g (90 %~ o~ trans-4~(diazo~
acekyl~-3-(2-methyl-1,3 dioxolan-2-yl)~1_(4~metho~yphenyl)~
2-azethidinone are obtai~ed7 m~pO: 95-96C (berlzene and ekher3J
IR. (KBr)- 2209; 1760~ 1640 cm 1.
H NMR (CDC13) ~ = 1.50 (s~ 3H)~ 3~51 (d, 1~{, J
~0 2l6 Hz)5 3075 (~7 3~I), 4.05 (m, ~H)7 4.31 (d~ lH9 J = 2~6 Hæ)~
5.47.(~, lH)~ 6085 ~2H) ~ 7~30 (2H9 AA'BBa~ J = 9 Hz) ppmO
Exam~
~ran~ by~ !y~ol~
~xo-2~a~thid~,7 ~ L~.~a .
308 g (000126 mole) of krans~4~(dia~oacotyl) 1-phonyl-3~(2 methyl-1,3-dioxolan-2 yl~-2-azethidinone are dis~
solvad in a mixture o~ 100 ml of totrahydro~uran and 50 ml o~
wat~r7 and the solution is irradiated with a high -pr~ssure mercury lamp in a pho~oreac~or a~ room temp~rature under nitro~
3 Kon atmo~pher~0 The progre~,~ o~ the reacti.on is monitor3d by 3~
thin layer ~ o.:~ato~raphy (adsorbent: Kies~l~rel G accoxding to Stanl, developini; solvent: a 7:1 mixture of benzene and ace-torle)~ At the end of the reaction tetrahydro~uran is evaporat-ed in vacuo, ~he L~esidue is rendered al~aline ~ith a 20 aqueous socli.um ~ydroxide solution, and the alkaline solutio~
is washed thrice with 15 ml of dichloromethane, aach~ ~he aqueous phase is acidi.fied to pH = 1-2 with conce~trated aqueous hydrochloric acid and then ext~ac~sd thrice wi~h 20 ml o~ d.ichlororl~ethane, each. '~he organic phases are combined~
dried ovex magnesium sul~ate 9 filtered9 and the filtxate is e~aporateclO The ()i.l~ r~sidu~ i~ triturated with skher to ob-kai~ 1~8 g (50 ~0) of crystalline ~krans~l-pher~tl-3-(2~methyl-1~3-dioxolan~-yl)-4~oxo~2-azethidiny ~ -acetic ~cid~ mDp.
128-129C (ethanol,~
Analysis:
calculated fox C15H17N05 (291029):
C: 62000 ~ H: 5.88 %, N: 4082 ~ound: C: 61075 '~, H: 5 86 ~0, N: 5.08 IR (KI~.r): 1760~ 17L~ cm 1 lFf NIlE2 (C~Cl~ = loLl8 ( S9 3~f), 2065 (dd~ lH~
Jgem = 15 Hz~ J~ic= 8 Hz) ~ 301~ (dd~ lfI~ Jgem = 15 Hz9 Jvic = 8 Xz), 30~7 (d, lH, J = 205 Hz), ~98 (m9 L~H3, L~oL~ ~m, lH), 7.3 (m, ~H) a 9~33 (broad s 3 lH) ppm.
~he starting substance can be prepared as follows, a) h rnixture of 38 g (0~.152 mole) of diethyl ~nilino malonate ~. Blank: BerO ,~19 1815 (1898~77 38 ml of glacial acetic acid and 15~3 g~ (13.9 mlg 0"182 mole) of diketene is boiled ~or 0.5 hourO ~lacial acetic acid i~; evaporated in vacuo over a t;Jal~er bath, and the oil~y residue is crystallized by ~0 tritllr~3ting it; with ethex 0 3605 ~, (72 '70) of diethyl (N~phenyl-8~i5 ~ 22 ~
3~hydroxy~3~me thyl-~oxo-2,2~pyrroliclir3e-dicarb~a~ylate) and~or :i.ts tautomer are obtained3 mOpo 98~99 (~ (ethyl acetate and pe troleum etihcr~ ~.
Ana lysis:
ca lc u la te d I or ~17H21N6 (335 ~P 35):
C. 60088 %, H: 6031 %" N- 4~18 %D
.Eound~ ~: 60083 (~, H: 6015 %1 N- 4~43 IR (K13r): 33~0~ 29501 17609 1750 (d~ 9 1700 cm ~
lH NA~ (aDc~= 1.02 ( k9 3H) 3 1.3 (t; 3 3E) 3 106 (s5, 3H) 92,.8 ~,s~ 3II) q 3.~6 (broad s, lH) ~ 4-4045 (m? 4H) 9 702 ( s~ 5H) ppm.
b) 50 g (00149 mole) o:f diethy;l. ~N-phe~yl-3~hydrox~
3-m~thyl-5~oxo-2 j2~pyrrolidine-dicarbo.~{yla te) ~ prepared as des~rib0d in point a~ above 3 are added to a solutio~ of ï0e,2 g (00447 mole) of metallic sodium in 250 ml oE dry e~ha~ol3 ther0aïter a solution of 37ç9 g ~00149 mole) of iodine in 200 ml of dry ether is added under vigorous s~i:rri~g~0 When the reac~
tiorl is over~ 805 ml (8.9 g7 0~,149 molo),~o~ glacial acetic acid, 200 ml of: water and 100 ml o:E e ther are added to the mixture, tha organic phase is separated~ and ~he aqueou~ pha~e is extracted with 100 ml o~ e~her~ ~he c~ crc~ phases are com~
bined, dried over magnesium sulfate, ~iltorsd9 and tho filtrate is evaporatedO '~he oily residue is crys~alliz~d from 50 ml o~
2-propa~ol to obtai~ 31 g (62 ~0) of diethyl (3-acetyl~l-phe~yl=
4-oxo-232~azethidi~e-dicarbox-ylate~ mOp~ 55-56~C (2-propanol~;
Anal~sis:
calculated for C17HlgN06: C~ 61025 %~ H, 5075 %~ N 4020 %~
fou~d: C, 61O38 %; H~ 5089 ~07 N: 432~ %o IR (K~r): 17707 17L~0~ 1720 cm~
~-H I~rlJ~ (CDCl~): ~= 1.12 (t, 6H~ 9 203 (s, 3H)~ 4j25 ~ ~3 -(q? 4~ L~o75 ~s, lH), 70V--7~6 Im~ 5H) ppmO
c) 28~5 g (0~085 mole~ of diethyl ~-acetyl_l-phenyl~
4-oxo-292~azetihidine-dicarboxylate 9 prepared as described i~
poi~t d) above, are dissolved in a mixture o.~ 90 ml of ~ry dioxa~e and 21 g (18.8 ml9 0~34 mole) of dry othyl~ne glycol3 a~d 369~ g (3105 ml, 00255 mole) of boro~ tri~luoride ~ di~
o~hyl et~erate complex are added d~opwise to the solutio~
undeI vigorous stirring and cooli~g with ice water~ The solu_ ~ion is stirr~d for additional 2 hours at room tamperature and then neutralized with saturated aqueous ~odium carbona~e solutio~. qlh~ neutral solution i~ dilutod wîth 100 ml o~ wat2r a~d then extract~d thrice with 50 ml o~ diethyl ether, 3achO
~he organic phas~s a.re combined, dried over magnasium sul~ato 9 ~ erad~ and ~lla filtrate is evaporated in vacuo~ q~hs oily residue is crystallized by triturating it with ether~ 2805 g ~90 %) of diethyl 1-phenyl~3~(2-mo~hyl-1,3-dio~olan-2~yl)-4-oxo~2~2~azethidi~e~dicarbo~yla$e are o~tained~ m~pO: 59-61~C
(petrol)0 Analy~
caleulat~d :for Cl9H23N070 C: 60n47 %~ ~I 6014 %~ N: 3017 %~
.f~ou-nd: ~ C: 60~74 %, H: 642~1 %~ N. ~079 :IR (E~r). 1770" 1740 cm~l. -H ~ (CDC13): ~= 1.18 (ti~ 3EI~ J = 7.2 Ez) 7 1024 (tg 3H,.i = 7.2 Hz) 9 1051 ~s~ 3H), 3~92 (m,, 4H)~ 4~,3 ~m, 5H)~
~5 702 (m,5H) ppm.
d) A mixtiure of 28~5 g (0.075 mole) of diethyl 1-phe~yl~
( 2-me thyl-l a ~-diox olan-2-yl) ~oxo-2 ~ 2-a ~ e tihidi~e-dicarb~
ox~ylate~ p:repared as described in point c) abova) 44 ml of dimetihyl sulfoxid~t 5~6 g (Ool mol~) of sodium chloride and ~i405 ml ~0017 mole) o~ watier is stirred at 175C u~til the ~ 2~ -reaction proceeds~ The progress Q~ the r~action is moni~or~a by ~hin layer chromatography (adsorbent: Kieselg~l G according ~o Stahl; d.eveloping solvent- a 6:4 mixtura o~ benzene and ~thyl ace~ate)O Th~ solution is poured into 200 ml of a sa-turated aqueous sodium chloride solution and e~tracted thricewi~h 150 ml of diethyl ether9 eachO The organic phases are ~ombined, dried over ma~nesium sulfate, ~iltered~ and the ~iltrate is evaporated. ~he resulting 16~4 g of oily rasidue are dissolved in 100 ml of ethanol, and a solu~ion o~ 2~15 g (0O054 mole) of sodium hydroxide in 30 ml o~ water is added ~o it under stirring over an ice bathO A~ter 0.5 hour o~
stirrin~ the mixture is diluted with 150 ml of water and e~tracted thrice with 20 ml o~ dieth~l ether9 each. The aqueous phase is acidi~ied to pH = 1 with concentrated aqueous hydrochloric acid and extracted then thrice with 50 ml of di-chloromethane, each. The orga~ic phas~s are combined, dried .over magnesium sul~ate9 filt~red~ and the ~ilt.ra~e i5 ~vapora~-ed. '~he oily residue is crystalli7.ed ~rcm behze~e to obtain 12 g (56 %) o~ trans-l~phenyl-3~(2-m~thyl-1~3~dioxolan~2-yl~
L~oxo 2~aæethidine carbo~ylic acid; mOp~ 165C (be~zene~O
Analysis:
calculated ~or ClL~H15N05 (277027) Cu 60.64 %, H: ~945 %~ ~: 55 %?
~ound: C: 60~64 %, H' 5972 %9 N: 4.99 ~o J-H ~R (CDC13): ~ = 1.5 (s, 3H); 3~69 (d, lH9 J = 3 Hæ), ~-~0O (m, 4H)~ 4942 (d~ lH~ J = 3 Hz); 703 (m, 5H)~ 7O55 ( s, lH) ppm., e) 13u8 g (0005 mols~ o:E trans-l-phen~lw3-(2~mathyl~
1,3-dioxolan-2~yl~-4~oxo~2-aze~hidi~o carboxylic acid~ pre~
pared as de3cribed in point d3 above, are di~solv~3d in 100 m:L
~8~ 5 -- 25 _ o~ dry tQ~rahydrofura~9 and 5.55 g 57~7 mla 09055 mole~ of ethyl chloro~ormate aro added to ~h~ solutio~ at ~15Co A~er 20 minut~s o~ stirring the separated salt is fil~ered o~f . under nitrogen atmospher~ and an othe~al solution o~ 2206 g ~0015 mols) of diazomothane is added ~o th~ filtrat~ u~der stirri~g. When the gas svolution ceases,th~ e~co~ o~ dlazo~
methane is decompo~ad with glacial acot~c acid9 and. the solutio~
is avaporatod~ ~he oil-~ rssidue is triturat~d with ether to ob~
tain 11~5 g (77 %) of cry~tallin~ trans-4~(diazoacotyl)-1 phe~yl-3~(2-methyl-1,3-dioxolan-2~yl)-azethidinon~; m.pO:
96-97C (bsnzene and ether)~
- IR (KBr): 2150 3 1760 9 .1635 cm 1.
lH NMR (CDCl~ = 1.50 (S? 3~ 3.5 (da i~9 J = ~06 Hz)~ 3050 (m~ 4H)~ 4~34 (d~ lE9 J = 206 Hz)~ 5045 td7 lH) 7~25 ~m, 5H) ppmO
Anal~sis:
calculated for C17HlgN06: C~ 61025 %~ H, 5075 %~ N 4020 %~
fou~d: C, 61O38 %; H~ 5089 ~07 N: 432~ %o IR (K~r): 17707 17L~0~ 1720 cm~
~-H I~rlJ~ (CDCl~): ~= 1.12 (t, 6H~ 9 203 (s, 3H)~ 4j25 ~ ~3 -(q? 4~ L~o75 ~s, lH), 70V--7~6 Im~ 5H) ppmO
c) 28~5 g (0~085 mole~ of diethyl ~-acetyl_l-phenyl~
4-oxo-292~azetihidine-dicarboxylate 9 prepared as described i~
poi~t d) above, are dissolved in a mixture o.~ 90 ml of ~ry dioxa~e and 21 g (18.8 ml9 0~34 mole) of dry othyl~ne glycol3 a~d 369~ g (3105 ml, 00255 mole) of boro~ tri~luoride ~ di~
o~hyl et~erate complex are added d~opwise to the solutio~
undeI vigorous stirring and cooli~g with ice water~ The solu_ ~ion is stirr~d for additional 2 hours at room tamperature and then neutralized with saturated aqueous ~odium carbona~e solutio~. qlh~ neutral solution i~ dilutod wîth 100 ml o~ wat2r a~d then extract~d thrice with 50 ml o~ diethyl ether, 3achO
~he organic phas~s a.re combined, dried over magnasium sul~ato 9 ~ erad~ and ~lla filtrate is evaporated in vacuo~ q~hs oily residue is crystallized by triturating it with ether~ 2805 g ~90 %) of diethyl 1-phenyl~3~(2-mo~hyl-1,3-dio~olan-2~yl)-4-oxo~2~2~azethidi~e~dicarbo~yla$e are o~tained~ m~pO: 59-61~C
(petrol)0 Analy~
caleulat~d :for Cl9H23N070 C: 60n47 %~ ~I 6014 %~ N: 3017 %~
.f~ou-nd: ~ C: 60~74 %, H: 642~1 %~ N. ~079 :IR (E~r). 1770" 1740 cm~l. -H ~ (CDC13): ~= 1.18 (ti~ 3EI~ J = 7.2 Ez) 7 1024 (tg 3H,.i = 7.2 Hz) 9 1051 ~s~ 3H), 3~92 (m,, 4H)~ 4~,3 ~m, 5H)~
~5 702 (m,5H) ppm.
d) A mixtiure of 28~5 g (0.075 mole) of diethyl 1-phe~yl~
( 2-me thyl-l a ~-diox olan-2-yl) ~oxo-2 ~ 2-a ~ e tihidi~e-dicarb~
ox~ylate~ p:repared as described in point c) abova) 44 ml of dimetihyl sulfoxid~t 5~6 g (Ool mol~) of sodium chloride and ~i405 ml ~0017 mole) o~ watier is stirred at 175C u~til the ~ 2~ -reaction proceeds~ The progress Q~ the r~action is moni~or~a by ~hin layer chromatography (adsorbent: Kieselg~l G according ~o Stahl; d.eveloping solvent- a 6:4 mixtura o~ benzene and ~thyl ace~ate)O Th~ solution is poured into 200 ml of a sa-turated aqueous sodium chloride solution and e~tracted thricewi~h 150 ml of diethyl ether9 eachO The organic phases are ~ombined, dried over ma~nesium sulfate, ~iltered~ and the ~iltrate is evaporated. ~he resulting 16~4 g of oily rasidue are dissolved in 100 ml of ethanol, and a solu~ion o~ 2~15 g (0O054 mole) of sodium hydroxide in 30 ml o~ water is added ~o it under stirring over an ice bathO A~ter 0.5 hour o~
stirrin~ the mixture is diluted with 150 ml of water and e~tracted thrice with 20 ml o~ dieth~l ether9 each. The aqueous phase is acidi~ied to pH = 1 with concentrated aqueous hydrochloric acid and extracted then thrice with 50 ml of di-chloromethane, each. The orga~ic phas~s are combined, dried .over magnesium sul~ate9 filt~red~ and the ~ilt.ra~e i5 ~vapora~-ed. '~he oily residue is crystalli7.ed ~rcm behze~e to obtain 12 g (56 %) o~ trans-l~phenyl-3~(2-m~thyl-1~3~dioxolan~2-yl~
L~oxo 2~aæethidine carbo~ylic acid; mOp~ 165C (be~zene~O
Analysis:
calculated ~or ClL~H15N05 (277027) Cu 60.64 %, H: ~945 %~ ~: 55 %?
~ound: C: 60~64 %, H' 5972 %9 N: 4.99 ~o J-H ~R (CDC13): ~ = 1.5 (s, 3H); 3~69 (d, lH9 J = 3 Hæ), ~-~0O (m, 4H)~ 4942 (d~ lH~ J = 3 Hz); 703 (m, 5H)~ 7O55 ( s, lH) ppm., e) 13u8 g (0005 mols~ o:E trans-l-phen~lw3-(2~mathyl~
1,3-dioxolan-2~yl~-4~oxo~2-aze~hidi~o carboxylic acid~ pre~
pared as de3cribed in point d3 above, are di~solv~3d in 100 m:L
~8~ 5 -- 25 _ o~ dry tQ~rahydrofura~9 and 5.55 g 57~7 mla 09055 mole~ of ethyl chloro~ormate aro added to ~h~ solutio~ at ~15Co A~er 20 minut~s o~ stirring the separated salt is fil~ered o~f . under nitrogen atmospher~ and an othe~al solution o~ 2206 g ~0015 mols) of diazomothane is added ~o th~ filtrat~ u~der stirri~g. When the gas svolution ceases,th~ e~co~ o~ dlazo~
methane is decompo~ad with glacial acot~c acid9 and. the solutio~
is avaporatod~ ~he oil-~ rssidue is triturat~d with ether to ob~
tain 11~5 g (77 %) of cry~tallin~ trans-4~(diazoacotyl)-1 phe~yl-3~(2-methyl-1,3-dioxolan-2~yl)-azethidinon~; m.pO:
96-97C (bsnzene and ether)~
- IR (KBr): 2150 3 1760 9 .1635 cm 1.
lH NMR (CDCl~ = 1.50 (S? 3~ 3.5 (da i~9 J = ~06 Hz)~ 3050 (m~ 4H)~ 4~34 (d~ lE9 J = 206 Hz)~ 5045 td7 lH) 7~25 ~m, 5H) ppmO
Claims (12)
1. A process for the preparation of a new com-pound of the general formula (I), (I) wherein y1 and y2 form together a removable carbonyl protecting group, and R is a removable amido protecting group, characterized in that a compound of the general formula (III), (III) wherein R, y1 and y2 are as defined above, is activated on the carboxy group and then reacted with diazomethane, whereafter the resulting compound of the general formula (II), (II) wherein R, y1 and y2 are as defined above, is subjected to diazoketone exchange in the presence of water, or a compound of the general formula (II), wherein R, y1 and y2 are as defined above, is subjected to diazoketone exchange in the presence of water, and the resulting product of the general formula (I) is separated.
2. A process as claimed in claim 1, characterized in that the carboxy group of the compound of the general formula (III) is activated with ethyl chloroformate.
3. A process as claimed in claim 1, characterized in that the diazoketone exchange is performed under irradiation with ultraviolet light.
4. A process as claimed in claim 1, wherein in the intermediate compounds of general formula (II) and (III) as well as in the final compound of formula (I), y1 and y2 form together a ketal group or a thioanalogue thereof, and R is a benzyl group bearing one or more C1-4 alkoxy substituents or a phenyl group bearing optionally one or more C1-4 alkoxy substituents.
5. A process as claimed in claim 1 for the preparation of [trans-1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl] -acetic acid, characterized in that trans-1-(2,4-dime-thoxyberlzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-azethidine-carboxylic acid is activated on the carboxy group and reacted then with diazomethane, and the resulting trans-4-(diazoacetyl)-1-(2,4-dimethoxy-benzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-2-azethidinone is subjected to diazoketone exchange in the presence of water.
6. A process as claimed in claim 1 for the preparation of [trans-3-(2-methyl-1,3-dioxolan-2-yl)-1-(4-methoxyphenyl)-4-oxo-2-azethidinyl] -acetic acid, characterized in that trans-3-(2-methyl-1,3-dioxolan-2-y1)-1-(4-methoxyphenyl)-4-oxo-azethidine-carboxylic acid is activated at the carboxy group and reacted then with diazomethane, and the resulting trans-(4-diazo-acetyl)-3-(2-methyl-1,3-dioxolan-2-yl)-1-(4-methoxy-phenyl)-2-azethidinone is subjected to diazoketone exchange in the presence of water.
7. A process as claimed in claim 1 for the preparation of [trans-1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl] -acetic acid, characterized in that trans-1-phenyl-3-(2-methyl-1,3-dioxolan 2-yl)-4-oxo-2-azethidine-carboxylic acid is activated on the carboxy group and reacted then with diazomethane, and the resulting trans-4-(diazoacetyl)-1-phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-2-azethidinone is subjected to diazoketone exchange in the presence of water.
28 A compound of the general formula (I), (I) wherein y1 and Y form together a removable carbonyl protecting group, and R is a removable amido protecting group, whenever prepared by the process of claims 1, 2 or 3 or its obvious chemical equivalents.
9. A compound of the general formula (I), (I) wherein y1 and Y2 and R are as defined in claim 4, whenever prepared by the process of claim 4 or it's obvious chemical equivalents.
10. [trans-1-(2,4-Dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl] -acetic acid, whenever prepared by the process of claim 5 or its obvious chemical equivalents.
11. [trans-3-(2-Methyl-1,3-dioxolan-2-yl)-1-(4-methoxyphenyl)-4-oxo-2-azethidinyl] -acetic acid, whenever prepared by the process of claim 6 or its obvious chemical equivalents.
12. [trans-1-Phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2-azethidinyl] -acetic acid, whenever prepared by the process of claim 7 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU814012A HU184495B (en) | 1981-12-30 | 1981-12-30 | Process for preparing new azetidinone-acetic acids |
| HU4012/81 | 1981-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1189865A true CA1189865A (en) | 1985-07-02 |
Family
ID=10966505
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000418739A Expired CA1189865A (en) | 1981-12-30 | 1982-12-30 | Heterocyclic acetic acid derivatives and a process for the preparation thereof |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS58118566A (en) |
| AT (1) | AT379147B (en) |
| AU (1) | AU554739B2 (en) |
| BE (1) | BE895489A (en) |
| CA (1) | CA1189865A (en) |
| CH (1) | CH655926A5 (en) |
| DE (1) | DE3248672A1 (en) |
| ES (1) | ES518720A0 (en) |
| FI (1) | FI824516L (en) |
| FR (1) | FR2518998B1 (en) |
| GB (1) | GB2112393B (en) |
| GR (1) | GR78428B (en) |
| HU (1) | HU184495B (en) |
| IT (1) | IT1210968B (en) |
| LU (1) | LU84568A1 (en) |
| NL (1) | NL8205064A (en) |
| PL (1) | PL137593B1 (en) |
| SE (1) | SE453083B (en) |
| ZA (1) | ZA829593B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU190404B (en) * | 1982-07-30 | 1986-09-29 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for preparing amino-lactone-carboxylic acid |
| HU187424B (en) * | 1982-11-05 | 1986-01-28 | Richter Gedeon Vegyeszeti Gyar Rt,Hu | Process for preparing new azetidinyl-acetic acids |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT71553B (en) * | 1979-07-23 | 1981-12-14 | Merck & Co Inc | Process for the preparation of thienamycin and intermediates |
| JPS57167964A (en) * | 1981-04-09 | 1982-10-16 | Toyama Chem Co Ltd | Preparation of (4r)-3-substituted-4-(substituted or unsubstituted carboxymethyl)-2-azetidinone derivative |
| JPS57176982A (en) * | 1981-04-24 | 1982-10-30 | Shionogi & Co Ltd | Dioxolanylazetidinone compound, its preparation and use |
-
1981
- 1981-12-30 HU HU814012A patent/HU184495B/en not_active IP Right Cessation
-
1982
- 1982-12-10 AT AT0450782A patent/AT379147B/en not_active IP Right Cessation
- 1982-12-24 JP JP57235006A patent/JPS58118566A/en active Pending
- 1982-12-28 BE BE1/10676A patent/BE895489A/en not_active IP Right Cessation
- 1982-12-29 FR FR8221978A patent/FR2518998B1/en not_active Expired
- 1982-12-29 SE SE8207475A patent/SE453083B/en not_active IP Right Cessation
- 1982-12-29 LU LU84568A patent/LU84568A1/en unknown
- 1982-12-29 CH CH7602/82A patent/CH655926A5/en not_active IP Right Cessation
- 1982-12-30 IT IT8225060A patent/IT1210968B/en active
- 1982-12-30 NL NL8205064A patent/NL8205064A/en not_active Application Discontinuation
- 1982-12-30 PL PL1982239885A patent/PL137593B1/en unknown
- 1982-12-30 DE DE19823248672 patent/DE3248672A1/en not_active Withdrawn
- 1982-12-30 ES ES518720A patent/ES518720A0/en active Granted
- 1982-12-30 AU AU91968/82A patent/AU554739B2/en not_active Ceased
- 1982-12-30 GB GB08236917A patent/GB2112393B/en not_active Expired
- 1982-12-30 ZA ZA829593A patent/ZA829593B/en unknown
- 1982-12-30 GR GR70183A patent/GR78428B/el unknown
- 1982-12-30 CA CA000418739A patent/CA1189865A/en not_active Expired
- 1982-12-30 FI FI824516A patent/FI824516L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI824516A0 (en) | 1982-12-30 |
| SE8207475L (en) | 1983-07-01 |
| GB2112393B (en) | 1985-08-14 |
| PL137593B1 (en) | 1986-06-30 |
| LU84568A1 (en) | 1984-10-22 |
| ES8405761A1 (en) | 1984-06-16 |
| FR2518998A1 (en) | 1983-07-01 |
| IT1210968B (en) | 1989-09-29 |
| NL8205064A (en) | 1983-07-18 |
| HU184495B (en) | 1984-08-28 |
| CH655926A5 (en) | 1986-05-30 |
| JPS58118566A (en) | 1983-07-14 |
| SE8207475D0 (en) | 1982-12-29 |
| GR78428B (en) | 1984-09-27 |
| SE453083B (en) | 1988-01-11 |
| AT379147B (en) | 1985-11-25 |
| AU554739B2 (en) | 1986-09-04 |
| BE895489A (en) | 1983-06-28 |
| FI824516L (en) | 1983-07-01 |
| FR2518998B1 (en) | 1986-02-28 |
| PL239885A1 (en) | 1984-01-02 |
| AU9196882A (en) | 1983-07-07 |
| DE3248672A1 (en) | 1983-07-07 |
| ES518720A0 (en) | 1984-06-16 |
| IT8225060A0 (en) | 1982-12-30 |
| ATA450782A (en) | 1985-04-15 |
| ZA829593B (en) | 1983-10-26 |
| GB2112393A (en) | 1983-07-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU648345B2 (en) | New substituted azetidinones as anti-inflammatory and antidegenerative agents | |
| US4939248A (en) | Optically active azetidinones | |
| EP0234484A1 (en) | Novel azetidinone derivatives | |
| CA1189865A (en) | Heterocyclic acetic acid derivatives and a process for the preparation thereof | |
| CA2036516A1 (en) | Optically active 8-methoxyouinolonecarboxylic acid derivatives, their preparative processes and their intermediates | |
| US6143885A (en) | Preparation of beta-methyl carbapenem intermediates | |
| CA1134349A (en) | Penam 1,1-dioxides as beta-lactamase inhibitors | |
| US4731455A (en) | Process for the preparation of gamma-butyrolactams | |
| Kashima et al. | Synthesis of optically active β‐lactams by the reaction of 2‐acyl‐3‐phenyl‐l‐menthopyrazoles with C N compounds | |
| CA1199644A (en) | Process for the preparation of heterocyclic acetic acid derivatives | |
| CA1327045C (en) | Azetidinone derivative and process for preparing the same | |
| CA1189864A (en) | Heterocyclic carboxylic acids and a process for the preparation thereof | |
| EP0589626B1 (en) | Preparation of beta-methyl carbapenem intermediates | |
| Fitremann et al. | New C2 symmetric bis-aziridines efficient synthesis of (2S, 5S)-1, 6-Di (p-toluenesulfonyloxy)-2, 5-hexanediol, and (2S, 3E, 5S)-1, 6-Di (p-toluenesulfonyloxy)-2, 5-hexenediol | |
| CA1190931A (en) | Thienamycin intermediates | |
| CA1191854A (en) | Thienamycin derivatives | |
| CA1189866A (en) | Heterocyclic acetic acid derivatives and a process for the preparation thereof | |
| EP0739885A1 (en) | Process for producing 3-isoxazolecarboxylic acid | |
| CA1192202A (en) | Thienamycin analogues | |
| CA1110252A (en) | MONOCYCLIC .beta.-LACTAMS AS INTERMEDIATES FOR THE PRODUCTION OF 0-2-ISOCEPHEM ANTIBACTERIAL AGENTS | |
| JPS60185778A (en) | Beta-lactam | |
| JP3269867B2 (en) | Method for producing 4-substituted azetidinone derivative | |
| 구양모 et al. | Synthesis of 3-Acety1-2-azetidinones by [2+ 2] Cycloaddition of Diketene and Imines | |
| US4541955A (en) | Azetidinone-4-carboxylate containing a protected 3-acetyl group and process for their preparation | |
| JPH08119935A (en) | Production of 2-pyrrolidinone derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEC | Expiry (correction) | ||
| MKEX | Expiry |