CA1308109C - Intermediates for the preparation of monosulfactams - Google Patents
Intermediates for the preparation of monosulfactamsInfo
- Publication number
- CA1308109C CA1308109C CA000615882A CA615882A CA1308109C CA 1308109 C CA1308109 C CA 1308109C CA 000615882 A CA000615882 A CA 000615882A CA 615882 A CA615882 A CA 615882A CA 1308109 C CA1308109 C CA 1308109C
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- amino
- acid
- solution
- 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 - Lifetime
Links
Classifications
-
- 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
Abstract
ABSTRACT
This invention relates to compounds having the formula:
wherein A1 is a carboxyl protecting group, A2 is hyd-rogen or an amino protecting group, and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms, which are useful as intermediates in the preparation of monocyclic .beta.-lactam antibiotics of the formula:
This invention relates to compounds having the formula:
wherein A1 is a carboxyl protecting group, A2 is hyd-rogen or an amino protecting group, and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms, which are useful as intermediates in the preparation of monocyclic .beta.-lactam antibiotics of the formula:
Description
: . , .
Compounds having the formula I
/~N~C~ l C~I IR2 H2~ C
N-o-l - -0~ ~ N-o-So3H
~C\
and pharmaceutically acceptable salts thereof, have antibacterial activity. In formula I, and throughout the specification, the symbols are as defined below.
R1 and R2 are the same or different and 15 each is hydrogen or alkyl, or Rl and R2 together are -(CH2)n~ wherein n is 2, 3, 4, 5 or 6; and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms.
The term "alkyl", unless otherwise defined, refers to both straight and branched chain groups.
Those groups having 1 to 10 carbon atoms are preferred.
The compounds of thi~ invention form basic salts with inorganic and organic bases which are also within the scope of this invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts, and salts with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-gluccamine, hydrabamine and the like.
.
1308~09 The compounds of this invention are pictured as acids. They can also exist, however, as zwitterions (internal or inner salts), and these are also included within the language 5- "pharmaceutically acceptable salts~' and the scope of this invention.
The ~-lactams of formula I, and pharmaceutically acceptable salts thereof, have activity against gram-positive and sram-negative organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.q., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals, a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably bout 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contempla~ed for use with ~-lactams of thi~ invention. Such methods of administration include oral, intravenous, intramuscular and as a suppository.
The compounds of this invention can be prepared from a compound having the fo~mula H2N_O_I_C_O_ / \
wherein "Al" is a ca-~oxyl protecting group.
Carboxyl ~rotecting groups are well known in th-a-t, and are used to p~event involvQmAnt of 'he carboxyl group in su2sQsuAnt r-ac~ior.s. Ex~mplary srou?s usAd to prote-t ca-~oxyl g-ou?s ar~
d_scribed in Unit_d Sta._s pat-n~ ,~ 3, issued March 13, 1979. PrefArred grou~s are t-bu-.yl, diphenylmAthyl and phenylmQ'Jhyl. ~_moval of a carboxyl protecting group can be accom~lish-d using art-recognized procedures ~hat will va~y depending on the particular protecting group. For example, if the protecting group is t-butyl, it can be removed using trifluoroacetic a~cid, dichloro-methan~ and anisole, using trifluoroacetic acid and thioanisole, or using trimethylsilyliodide and an acid scavenger such as N-methyl-N-(trimethyl-silyl)trifluoroacetamide. If the prot-cting group i3 diphenylm-thyl, it can be removed using tri-fluoroacetic acid, dichloromethane and anisole. If the protecting group is phenylmethyl, it can be removed using trifluoroacetic acid and thioanisole, or trimethylsilyliodide and an acid scavenger such as N-methyl-N-(trimethylsilyl)trifluoroacetamide.
The compounds of formula II are novel, and as such, form an in~egral part of this invention.
Reaction of a compound of formula II with
Compounds having the formula I
/~N~C~ l C~I IR2 H2~ C
N-o-l - -0~ ~ N-o-So3H
~C\
and pharmaceutically acceptable salts thereof, have antibacterial activity. In formula I, and throughout the specification, the symbols are as defined below.
R1 and R2 are the same or different and 15 each is hydrogen or alkyl, or Rl and R2 together are -(CH2)n~ wherein n is 2, 3, 4, 5 or 6; and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms.
The term "alkyl", unless otherwise defined, refers to both straight and branched chain groups.
Those groups having 1 to 10 carbon atoms are preferred.
The compounds of thi~ invention form basic salts with inorganic and organic bases which are also within the scope of this invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts, and salts with organic bases such as dicyclohexylamine, benzathine, N-methyl-D-gluccamine, hydrabamine and the like.
.
1308~09 The compounds of this invention are pictured as acids. They can also exist, however, as zwitterions (internal or inner salts), and these are also included within the language 5- "pharmaceutically acceptable salts~' and the scope of this invention.
The ~-lactams of formula I, and pharmaceutically acceptable salts thereof, have activity against gram-positive and sram-negative organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.q., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals, a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably bout 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contempla~ed for use with ~-lactams of thi~ invention. Such methods of administration include oral, intravenous, intramuscular and as a suppository.
The compounds of this invention can be prepared from a compound having the fo~mula H2N_O_I_C_O_ / \
wherein "Al" is a ca-~oxyl protecting group.
Carboxyl ~rotecting groups are well known in th-a-t, and are used to p~event involvQmAnt of 'he carboxyl group in su2sQsuAnt r-ac~ior.s. Ex~mplary srou?s usAd to prote-t ca-~oxyl g-ou?s ar~
d_scribed in Unit_d Sta._s pat-n~ ,~ 3, issued March 13, 1979. PrefArred grou~s are t-bu-.yl, diphenylmAthyl and phenylmQ'Jhyl. ~_moval of a carboxyl protecting group can be accom~lish-d using art-recognized procedures ~hat will va~y depending on the particular protecting group. For example, if the protecting group is t-butyl, it can be removed using trifluoroacetic a~cid, dichloro-methan~ and anisole, using trifluoroacetic acid and thioanisole, or using trimethylsilyliodide and an acid scavenger such as N-methyl-N-(trimethyl-silyl)trifluoroacetamide. If the prot-cting group i3 diphenylm-thyl, it can be removed using tri-fluoroacetic acid, dichloromethane and anisole. If the protecting group is phenylmethyl, it can be removed using trifluoroacetic acid and thioanisole, or trimethylsilyliodide and an acid scavenger such as N-methyl-N-(trimethylsilyl)trifluoroacetamide.
The compounds of formula II are novel, and as such, form an in~egral part of this invention.
Reaction of a compound of formula II with
2-amino-~-thiazolylglyoxylic acid (or an amino p-otectAd de~ivativo thereof) yields a -om~ound having thA formula 13~)8~LO9 GC241 III S ll o H /~;NJ\ ll A2~ OH
Il 1l N-O-c-C-O-/ \R
wheroin A2 is hydrogen or an 2mino protec~ing srou~. Amino protecting groups a-e well known in the art, and are used to prev_nt involvement of the amino sroup in subsequent reactions. Exemplary 2mino protesting groups are aromatic acyl groups such as p-nitrobenzyl and p-tert-butylbenzoyl;
aliphatic acyl groups such as formyl, acetyl, l; propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroace.yl; est^rified carboxyl groups such as methoxyc2rbonyl, el_hoxy-ca_bonyl, t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycar~onyl, ~ -trichloroethoxy-carbonyl, benzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, diphenyl-methyloxycarbonyl, methoxymethyloxycarbonyl, acctylmethyloxycarbonyl, isobornyloxycarbonyl and phenyloxycarbonyl; methylene groups such as (h^xahydro-l~-azepin-1-yl)methylene; sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl;
and amino-protecting groups oth-r than acyl groups, such as trityl, 2-nitrophenylthio, di-or trialkylsilyl, benzyl and p-nitrobenzyl.
Thc carboxylic acid of formula III is a novel compound, and as such, forms an integral part of this invention.
~308~09 _5_ GC241 Coupling a carboxylic acid of formula III with a ~-lactam having the formula IV
A2N \ R~
S rH C~ R
~C N-O- S0 o ~-iQ~ o-~Qs?onding compound having -o~mula V
E ~ ~ c-c-~ c~ c," R
A2~ 0-S13~ . `
N-o-C-C-o-A1 /~\
The reaction proceeds most readily if ~he carboxylic acid is in an activated form. Activated forms of carboxylic acids are well known in the art and include acid halides, acid anhydrides (including mixed anhydrides), activated acid amides and activated acid esters. Deprotection of a compound of fo~mula V using art-rocognized procedures yields the corresponding product of formula I.
Alternatively, a compound of formula II
ca~ be reacted with a glyoxylic acid having the formula VI
s ~ C-~-N~ - CH l2 2 0,~ -0-503H
to yield the corrQsponding compound of formula V
which can be deprotQctQd to yield ~he cor~sponding pr~du_t of formula I.
AltQr~atively, ~h~ com?ounds of fo-mula I
5 _an bQ prQpared by dQpro~Qcting a _ompound of formula II using art-recognized procQdures, ylQlding the product having th~ formula ~2N-O-C-C-OH
~
Compounds of formula VII are novel and as such constitute an integral part of this inven'ion.
A compound of fo~mula VII can be reacted with a compound of fonmula VI to give a com?ound of formula I after optional deprotection.
The ~-lactams of formula IV can be p-e?ared by first coupling a compound having ~he formula VIII ~ I ~ R
l~ C - _R2 ~C-O~I , where.in A3 is an amino protecting group, preferably t-butoxycarbonyl or benzyloxycarbonyl, with an O-protect-d hydroxylamine having ~e formula wherein A4 is a protecting group such as benzyl, trityl or pi~aloyl, yielding the corresponding compound having the formula X A3-NX I~" ' ,CH - C R2 C- ~--O-A4 _7_ GC24 Th~ rQaction proce~ds in the pr~sQnce of a coupling agsnt (~ a., l-~th~1-3-(dimQthvlamino-propyl)^a-bodiimid~, dicycloh~yl_ar~odi~mld~ or dicvcloh~x~lca-bodiimid~ hydlo~:v~nzo'. L asol~).
R~c.ion of a compound of formula X ~-i_h pyridin~ (optionally substitut~d)-sulfur ,rioY.ide compl~x having _he formula ~T (~~~3)m ~ \\
~ ~ 503, w;~-~ein m is 0, 1, 2 or 3, yields _he co~responding compound having the fonmula XII ~ ~ (r~3)m l; A3~ Rl 1~ R2 ~ CN~-0-A4.
The sulfonation reaction can be run in an organic solvent (e.~., pyridine, mono-, di- or trimethyl-pyridine, dichloromethane, 1,2-dichloro-thane, acetonitrile, dimethylformamide or dioxane).
Cyclization of a compound of for~ula XII can be accomplished by treatment with a base, and yields the corresponding compound having he fo mula XIII
A3 N~ R2 \~ _l I I IR
~ C - _ N-O-A4 The base is preferably an inorganic bzse su_h 25 an al~ali m~al ca~bonate and the rcac.ion -an be run in a mix~ur- of water and an orsani^ solvent ......
1308~09 -` GC241 (e.a., ethyl acetate, methyl butyl keto~e, pyridine or mono-, di- or trimethylpyr1din~).
R~mo~-al of the A4 protecting group from a compound of formula XI I I ~ields th~ correspon~ing S compound having the formula XIV Al-NH l2 I ~ Cl I I Rl ~C N-O~
and can be accomplished using art-recognized technigues. For example, if R4 is benzyl, deprotection can be accomplished by catalytic hydroganation. If A4 is pivaloyl, deprotection can be ac~omplished by treatment with a base such as sodium sulfid~ or sodium hydroxide. If A4 is trityl, deprotoction can be accomplished by treatment with 80% agueous acetic acid.
A compound of fo-mula XIV can be tr~ated with a pyridine (optionally substituted)-sulfur trioxide complex of formula XI to yield the pyridinium salt of the corresponding compound having the formula XV A3 N~\ R2 R
~ C ~-0-5O3~ .
The reaction can be run in a solvent such as pyridine (optionally substituted), dichloromethane or 1,2-dichloroethane. Using conventional technigues (e.q., ion-exchange resins) the pyridinium salt formed above can be converted to other salts and the free acid.
Those compounds of formula IV wh~rQin A2 is hydrogen are obtained by deprotection of the corresponding compound of formula XV. The ~308~09 dQprot~ctlon proc~dur~ used will d~p~nd on the particular protectlng group. If, for e~:ampl~, th~
prot~ting group is t-butoxycarbonyl, Irlfluo-o-a_~tic acid can bs usQd to d~rot~ct th~ amino srou?. If ths prot~~_ing srou? is benzylo~:y-ca-bonyl, catalytic hydrog~nation can be us~d.
~ h~ ~-la~t~.s of fo~mula IV ~an ~lso b^
prepar-d using th^ me~no~olo~v d-s-rib~d in Unit~
Statos patent 4,337,197, issued June 29, 1962.
Using ~he a_ylation technioues dGs-ribsd in 'ke pa~-nt, ons can al~o pre-a-e com?ounds of ~o~mula VI.
~ hs amino acids of Lo-mula VIII are eitner known or 2rs readily obt2i~abls usi~g art--~~og~iz-d 1~ procadurss; see, for sxampls, J. Org. Chem.,- A~
3967(1979); J. Ora. Chsm., _, 2809(1981);
Z. Ch~m., 10, 393(1970); etrah~dron, 39, 2085(1983); Liebi~s Annalsn der Chsm., 763, 1(1972); Svnthesis, 216(1979); Bull. Chsm. Soc.
Ja~an, 39, 2287(1966). Tnose procedures include the reaction (an aldol condensation) of protect-d glycine (both amino and carboxyl groups are protected) with the appropriate ketone o (R1-C-R2), followed by removal of the carboxyl protecting group.
The compounds of formula II whsrein "A1" is ~-butyl and R3 and R4 are _ach hydrog-n can be preparQd by treating a compound having th- formula XVI ~O
~ ~ N-O-C-C-O-A
1308109 GC'~ 41 with hydra2ine or methylhydra~ine. The compound of formula XVI whe~ein Al ~s ~-butyl is }:nown;
see, ~or exam?le, ~elglan palent 866,r-2. ~y mGthods }-~own in thQ art, 'he _-bu~yl group can ~Q
~emoved 2nd repla-Qd wi_h an alternale p-o~Q-_~ng group such as diphenylmethyl or phenylmethyl.
A -ompound of formula II can be p-Qpared from a ketone or aldehydQ having the 03~ula XVII O
Reaction of a com?ound of formula XVII wiLh an a-haloaceta.e ester (e.~., e_hyl chloroac~tate) in the presenco of a s..on~ ~ase (e ~., potassium t-butoxide) and subsQ~uQnt hydrolysis of ~ne resulting glycidic eStQr (see J. or~.-Chem./
26:3176 (1961)) yields a salt of the corresponding compound having the fo~mula XVIII O
R3-~C~[-n-O~I
Alternatively, a compound of formula XVIII
can be prepared from a sal~ of a compound having the formula XIX R3-~=C~
by treatment with agueous hydrogen peroxide in the presence of catalytic sodium tungstate (see J. Orq. Chem., 50:1979 (1985)).
Trea ment of a com2ound of fo_mula XVIII wi h a reagent such as acetone oxime, benzaldehyde oxime, ~-methoxybenzaldehyde oxime or t-butyl N-hydroxy carbamate in the D-_sen-e of a base (e q., an alkali metal hydroxidQ) in a solvent (Q q., water, wa~e-/dioxanQ, water/dim-_nyl-sulfoxide, water/ethanol, ethanol, dimethyl--- 13081.09 GC241 formamide, or dimethylsulfo~:ide) yields a compound having the ro~mula XX ~
A5=N-O-~ -OH
wherein ~5 ls isopropylidenQ, ber.zylldQr.e or D-meth~xyjenzylidQnQ, or ".~,=N-" is t-buto~y-carDonylzmino. If A5 is isopropylidene, benzylidene, or ?-methoxyDenzvlidQns, conversion of a com?ound of -o-mula XX ~o a compound having an alterna_e prote-ting group ~e.g., A; is phthaloyl or th~ group "A5=N" is t-butoxycarbonylamino) can be a_hieved by removing ~he pro~e^_ing group with a mineral a^id in -.r.e presence of wa;er and replacing it with the alternate protecting group using art-re^ognized ~Q^hni~ues. If "A~=N-" is t-butoxycarbonylamino, conversion of a ^ompound of formula XX to a compound having an alternate protecting group can be achieved by removing the protecting group with trifluoroacetic acid and anisole and replacing it with the alternats protecting group using art-recognized techniquss.
Esterification of a compound of ~o~mula XX
~or a com~ound cor esponding thereto wi-~h a di~fcrent protecting group) with a carboxyl protecting group Al yields the corresponding compound having th~ formula XXI O~
R I R
A =N-O-C~-~-O-A
Dehydrz-ion of a compound of .~ormula ~I
using any one of a n D er of ar~-re~ogniz~d 13081~9 C~C2~1 techni~ues ~ri~lds the corresponding compound having Ih~ -ormula i~II R3_r_R4 A5=~j o ¦~ r G A
o For ex2mple, dehydration can be a_hiQv~d by trea5m~nt of a compound of ~ormula Y~I wi.h m^_hanesulIoryl chloride in .he ?-esenAe of ~wo c.
more equivalenLs of t~iethylamine. Alte-nativQly, trea'ment of a compound of fo-mula Y~.I wi_h me-L~anesulfonyl chloride in ~he presence of one eauivalent of triethylamine, isolation of ~he cor-~s?onding mesylate, and finally elimination by '~ea m2nt wi-~h an inorganic base (such as potasslum c2-bonate) in an orgaric solvent (sucn as dimethylformamide) yields a compound of formula XXII. Alterr.atively, compound Y~I can be converLed to a compound having formula Y~II usin~ a reagent such as thionyl chloride/pyridine, phosgene/pyridine, or die~hylaminosulfur trifluoride/pyridine.
Selective deprotection of a compound of formula XXII to yield the desired compound of formula II can be accom~lished using art-recogn~zQd techniguQs. Al~ernativQly, art-recognized deprotection techniaues can be used to convert a compound of formula XXII to the corresponding compound of formula VII.
In -h- above-described synthetic procedu-es for thQ preparation of a compound of formula II or III, a compound of formula XVIII wherein R4 is trans to the ca~boxyl moiety will ~esult in a -ompound of -ormula I wherQin R4 is ~i3 ~0 the ~a_boxyl moie~y.
~5 AlternativQly, a _ompound of ~ormu'a II or VII (wherein one of R3 and R4 is hydrogen and thQ
1;~08109 -13- GC~41 oth~r is 21}:yl of 1 to 3 carbon atoms) can b~
pr~par~d Irom an amino a~id havlng ~h~ formula ~;III o C~ G~I
/ \
Il 1l N-O-c-C-O-/ \R
wheroin A2 is hydrogen or an 2mino protec~ing srou~. Amino protecting groups a-e well known in the art, and are used to prev_nt involvement of the amino sroup in subsequent reactions. Exemplary 2mino protesting groups are aromatic acyl groups such as p-nitrobenzyl and p-tert-butylbenzoyl;
aliphatic acyl groups such as formyl, acetyl, l; propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroace.yl; est^rified carboxyl groups such as methoxyc2rbonyl, el_hoxy-ca_bonyl, t-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycar~onyl, ~ -trichloroethoxy-carbonyl, benzyloxycarbonyl, p-nitrobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, diphenyl-methyloxycarbonyl, methoxymethyloxycarbonyl, acctylmethyloxycarbonyl, isobornyloxycarbonyl and phenyloxycarbonyl; methylene groups such as (h^xahydro-l~-azepin-1-yl)methylene; sulfonyl groups such as 2-amino-2-carboxyethylsulfonyl;
and amino-protecting groups oth-r than acyl groups, such as trityl, 2-nitrophenylthio, di-or trialkylsilyl, benzyl and p-nitrobenzyl.
Thc carboxylic acid of formula III is a novel compound, and as such, forms an integral part of this invention.
~308~09 _5_ GC241 Coupling a carboxylic acid of formula III with a ~-lactam having the formula IV
A2N \ R~
S rH C~ R
~C N-O- S0 o ~-iQ~ o-~Qs?onding compound having -o~mula V
E ~ ~ c-c-~ c~ c," R
A2~ 0-S13~ . `
N-o-C-C-o-A1 /~\
The reaction proceeds most readily if ~he carboxylic acid is in an activated form. Activated forms of carboxylic acids are well known in the art and include acid halides, acid anhydrides (including mixed anhydrides), activated acid amides and activated acid esters. Deprotection of a compound of fo~mula V using art-rocognized procedures yields the corresponding product of formula I.
Alternatively, a compound of formula II
ca~ be reacted with a glyoxylic acid having the formula VI
s ~ C-~-N~ - CH l2 2 0,~ -0-503H
to yield the corrQsponding compound of formula V
which can be deprotQctQd to yield ~he cor~sponding pr~du_t of formula I.
AltQr~atively, ~h~ com?ounds of fo-mula I
5 _an bQ prQpared by dQpro~Qcting a _ompound of formula II using art-recognized procQdures, ylQlding the product having th~ formula ~2N-O-C-C-OH
~
Compounds of formula VII are novel and as such constitute an integral part of this inven'ion.
A compound of fo~mula VII can be reacted with a compound of fonmula VI to give a com?ound of formula I after optional deprotection.
The ~-lactams of formula IV can be p-e?ared by first coupling a compound having ~he formula VIII ~ I ~ R
l~ C - _R2 ~C-O~I , where.in A3 is an amino protecting group, preferably t-butoxycarbonyl or benzyloxycarbonyl, with an O-protect-d hydroxylamine having ~e formula wherein A4 is a protecting group such as benzyl, trityl or pi~aloyl, yielding the corresponding compound having the formula X A3-NX I~" ' ,CH - C R2 C- ~--O-A4 _7_ GC24 Th~ rQaction proce~ds in the pr~sQnce of a coupling agsnt (~ a., l-~th~1-3-(dimQthvlamino-propyl)^a-bodiimid~, dicycloh~yl_ar~odi~mld~ or dicvcloh~x~lca-bodiimid~ hydlo~:v~nzo'. L asol~).
R~c.ion of a compound of formula X ~-i_h pyridin~ (optionally substitut~d)-sulfur ,rioY.ide compl~x having _he formula ~T (~~~3)m ~ \\
~ ~ 503, w;~-~ein m is 0, 1, 2 or 3, yields _he co~responding compound having the fonmula XII ~ ~ (r~3)m l; A3~ Rl 1~ R2 ~ CN~-0-A4.
The sulfonation reaction can be run in an organic solvent (e.~., pyridine, mono-, di- or trimethyl-pyridine, dichloromethane, 1,2-dichloro-thane, acetonitrile, dimethylformamide or dioxane).
Cyclization of a compound of for~ula XII can be accomplished by treatment with a base, and yields the corresponding compound having he fo mula XIII
A3 N~ R2 \~ _l I I IR
~ C - _ N-O-A4 The base is preferably an inorganic bzse su_h 25 an al~ali m~al ca~bonate and the rcac.ion -an be run in a mix~ur- of water and an orsani^ solvent ......
1308~09 -` GC241 (e.a., ethyl acetate, methyl butyl keto~e, pyridine or mono-, di- or trimethylpyr1din~).
R~mo~-al of the A4 protecting group from a compound of formula XI I I ~ields th~ correspon~ing S compound having the formula XIV Al-NH l2 I ~ Cl I I Rl ~C N-O~
and can be accomplished using art-recognized technigues. For example, if R4 is benzyl, deprotection can be accomplished by catalytic hydroganation. If A4 is pivaloyl, deprotection can be ac~omplished by treatment with a base such as sodium sulfid~ or sodium hydroxide. If A4 is trityl, deprotoction can be accomplished by treatment with 80% agueous acetic acid.
A compound of fo-mula XIV can be tr~ated with a pyridine (optionally substituted)-sulfur trioxide complex of formula XI to yield the pyridinium salt of the corresponding compound having the formula XV A3 N~\ R2 R
~ C ~-0-5O3~ .
The reaction can be run in a solvent such as pyridine (optionally substituted), dichloromethane or 1,2-dichloroethane. Using conventional technigues (e.q., ion-exchange resins) the pyridinium salt formed above can be converted to other salts and the free acid.
Those compounds of formula IV wh~rQin A2 is hydrogen are obtained by deprotection of the corresponding compound of formula XV. The ~308~09 dQprot~ctlon proc~dur~ used will d~p~nd on the particular protectlng group. If, for e~:ampl~, th~
prot~ting group is t-butoxycarbonyl, Irlfluo-o-a_~tic acid can bs usQd to d~rot~ct th~ amino srou?. If ths prot~~_ing srou? is benzylo~:y-ca-bonyl, catalytic hydrog~nation can be us~d.
~ h~ ~-la~t~.s of fo~mula IV ~an ~lso b^
prepar-d using th^ me~no~olo~v d-s-rib~d in Unit~
Statos patent 4,337,197, issued June 29, 1962.
Using ~he a_ylation technioues dGs-ribsd in 'ke pa~-nt, ons can al~o pre-a-e com?ounds of ~o~mula VI.
~ hs amino acids of Lo-mula VIII are eitner known or 2rs readily obt2i~abls usi~g art--~~og~iz-d 1~ procadurss; see, for sxampls, J. Org. Chem.,- A~
3967(1979); J. Ora. Chsm., _, 2809(1981);
Z. Ch~m., 10, 393(1970); etrah~dron, 39, 2085(1983); Liebi~s Annalsn der Chsm., 763, 1(1972); Svnthesis, 216(1979); Bull. Chsm. Soc.
Ja~an, 39, 2287(1966). Tnose procedures include the reaction (an aldol condensation) of protect-d glycine (both amino and carboxyl groups are protected) with the appropriate ketone o (R1-C-R2), followed by removal of the carboxyl protecting group.
The compounds of formula II whsrein "A1" is ~-butyl and R3 and R4 are _ach hydrog-n can be preparQd by treating a compound having th- formula XVI ~O
~ ~ N-O-C-C-O-A
1308109 GC'~ 41 with hydra2ine or methylhydra~ine. The compound of formula XVI whe~ein Al ~s ~-butyl is }:nown;
see, ~or exam?le, ~elglan palent 866,r-2. ~y mGthods }-~own in thQ art, 'he _-bu~yl group can ~Q
~emoved 2nd repla-Qd wi_h an alternale p-o~Q-_~ng group such as diphenylmethyl or phenylmethyl.
A -ompound of formula II can be p-Qpared from a ketone or aldehydQ having the 03~ula XVII O
Reaction of a com?ound of formula XVII wiLh an a-haloaceta.e ester (e.~., e_hyl chloroac~tate) in the presenco of a s..on~ ~ase (e ~., potassium t-butoxide) and subsQ~uQnt hydrolysis of ~ne resulting glycidic eStQr (see J. or~.-Chem./
26:3176 (1961)) yields a salt of the corresponding compound having the fo~mula XVIII O
R3-~C~[-n-O~I
Alternatively, a compound of formula XVIII
can be prepared from a sal~ of a compound having the formula XIX R3-~=C~
by treatment with agueous hydrogen peroxide in the presence of catalytic sodium tungstate (see J. Orq. Chem., 50:1979 (1985)).
Trea ment of a com2ound of fo_mula XVIII wi h a reagent such as acetone oxime, benzaldehyde oxime, ~-methoxybenzaldehyde oxime or t-butyl N-hydroxy carbamate in the D-_sen-e of a base (e q., an alkali metal hydroxidQ) in a solvent (Q q., water, wa~e-/dioxanQ, water/dim-_nyl-sulfoxide, water/ethanol, ethanol, dimethyl--- 13081.09 GC241 formamide, or dimethylsulfo~:ide) yields a compound having the ro~mula XX ~
A5=N-O-~ -OH
wherein ~5 ls isopropylidenQ, ber.zylldQr.e or D-meth~xyjenzylidQnQ, or ".~,=N-" is t-buto~y-carDonylzmino. If A5 is isopropylidene, benzylidene, or ?-methoxyDenzvlidQns, conversion of a com?ound of -o-mula XX ~o a compound having an alterna_e prote-ting group ~e.g., A; is phthaloyl or th~ group "A5=N" is t-butoxycarbonylamino) can be a_hieved by removing ~he pro~e^_ing group with a mineral a^id in -.r.e presence of wa;er and replacing it with the alternate protecting group using art-re^ognized ~Q^hni~ues. If "A~=N-" is t-butoxycarbonylamino, conversion of a ^ompound of formula XX to a compound having an alternate protecting group can be achieved by removing the protecting group with trifluoroacetic acid and anisole and replacing it with the alternats protecting group using art-recognized techniquss.
Esterification of a compound of ~o~mula XX
~or a com~ound cor esponding thereto wi-~h a di~fcrent protecting group) with a carboxyl protecting group Al yields the corresponding compound having th~ formula XXI O~
R I R
A =N-O-C~-~-O-A
Dehydrz-ion of a compound of .~ormula ~I
using any one of a n D er of ar~-re~ogniz~d 13081~9 C~C2~1 techni~ues ~ri~lds the corresponding compound having Ih~ -ormula i~II R3_r_R4 A5=~j o ¦~ r G A
o For ex2mple, dehydration can be a_hiQv~d by trea5m~nt of a compound of ~ormula Y~I wi.h m^_hanesulIoryl chloride in .he ?-esenAe of ~wo c.
more equivalenLs of t~iethylamine. Alte-nativQly, trea'ment of a compound of fo-mula Y~.I wi_h me-L~anesulfonyl chloride in ~he presence of one eauivalent of triethylamine, isolation of ~he cor-~s?onding mesylate, and finally elimination by '~ea m2nt wi-~h an inorganic base (such as potasslum c2-bonate) in an orgaric solvent (sucn as dimethylformamide) yields a compound of formula XXII. Alterr.atively, compound Y~I can be converLed to a compound having formula Y~II usin~ a reagent such as thionyl chloride/pyridine, phosgene/pyridine, or die~hylaminosulfur trifluoride/pyridine.
Selective deprotection of a compound of formula XXII to yield the desired compound of formula II can be accom~lished using art-recogn~zQd techniguQs. Al~ernativQly, art-recognized deprotection techniaues can be used to convert a compound of formula XXII to the corresponding compound of formula VII.
In -h- above-described synthetic procedu-es for thQ preparation of a compound of formula II or III, a compound of formula XVIII wherein R4 is trans to the ca~boxyl moiety will ~esult in a -ompound of -ormula I wherQin R4 is ~i3 ~0 the ~a_boxyl moie~y.
~5 AlternativQly, a _ompound of ~ormu'a II or VII (wherein one of R3 and R4 is hydrogen and thQ
1;~08109 -13- GC~41 oth~r is 21}:yl of 1 to 3 carbon atoms) can b~
pr~par~d Irom an amino a~id havlng ~h~ formula ~;III o C~ G~I
/ \
3 4 Conva-aion of a compound of fo-mula ~III to _he ~o--~s?on~ing ben-yl e.h~r can b~ a-_om?lish~d using convantional methodology and yields a -ompound having the formula X~IV O
Na2-C~-C-OH
1~ ~C~O- C~2~ .
R^ac_ion of a com?ound of fo-mula XXIV wi h nitrous acid in the prasence of bromida ion yielcs 'he -orreaponding com~ound having ~ne formula ~XV O
Br-C~-C-O~
~C~O-C~
A compound of formula XXV can ba estarifie~
with, for exampla, a t-bu~yl group using conventional mathodology to yi~ld he corrasponding compound having the formula XXVI O
~_-C~-U-O-c(c~3)3 ~ R4 Raa--ion of a compound of o~mula ~ I wi-h ~-hydroxyphthalimlda in _ha prQsQn_Q of a asa 081(~9 ~C241 --1~--such as potasslum carbonate in dimeth~lformamide yields a com?ound having the formula ~XVII ll ~ / N-G-C-C-O-C(C:~3~3 Remov21 of -h- ben~yl protec_~g grou?s ~y hyo~ogenolysls followed by dehydra-ion yields a com?ound havlng .r^ formula XXVIII 1l ~ o-r-r-o-c(c~3)3 Using methods known in the art, the ~-butyl group of a com?ound of formula XXVIII ^an b^
repla~ed with an alternate pro'e-ting group such as diphenylm-thyl to yield a compound having the formula XXIX
~O ll ca-o-c~ )2 -~ R3 R4 Treatment of a compound of formula Y~IX
with hydrazine or methylhydrazine yields the corresponding com~ound of fo-mula II wherein Al is diphenylmethyl. Standard deprotection and protection technigues can be used to convert that compound to other compounds of fo-mulas II and VII.
Alternatively, a compound of formula Y~ I
can be converted ~o the corrasponding com?oun~.
having the fo~mula _15_ Gc24 Y~X 1' ~
(c~3)3C-o-C-NH-o-CH-C-O-C(CH3)3 /c-c-c~2~/~
R3 ~4 by treatment with t-butyl-N-hydroxycarbama'~
in the p-esence of a base su^h 25 sodi~m hydride in a solv~nt su_h 25 dim~'hylIO~mamide.
Removal of the benzyl protec_ing 5~ou? from a compound of formula YY~ by hyd~ogenolysls, and subsequent dehydration, yields a com?o~n~ having the formula YJKXI o o (c~3~3c_0_c_ ~ _0-~-e-~-c(c~3)3 .
/ \
Standard deprotection and protection technlques can be used to convert a compound of formula YY~I
to a compound of formula II which can optionally be readily converted to the corresponding compound of formula VII.
Using the above methodology, a compound having the geometry NR2_~ C-O~
~0~
R`3 -R4 will yield a compound having '~he geometry XXXIII
N~2-0-C-C-O~
~C~
Alte-nat~vely, a compound having ~he formula X~IV O
'ir--C-O~I
/ C\
-`3 ~4 wh~_oin cne of R3 a~d R4 is hyàr~gGn a~d ~h~ olh~r s alkvl of 1 _o 3 ca-bon atoms, can be conv~.t^d ~o a com~ound of fonmula XXVIII by melhodology ~alo~ous to that us~d in th~ p~ -2 .ion o, compounds of formula XVI and desc~i~ed in 3~1sian ?atent 866,422.
A compound kavin3 -he geOmQtry oî ~ormula XJKXIV wh~rQin R~ is ci, to th~ car~oxyl grou? wi'l ~ converted to a _om?ound of formula X~III
wherein R4 i~ cis to ~he carboxyl group.
'5 The compounds of formula I con-ain at l^ast one chiral center~ .e carbon atom (in the 3-?osition of th- ~-lactam nucleus) to whi-h the am no or acylamino s~bstituent is attach-d. This invention is directed to those ~-lactams which have been described above, wherein the stereo-_hemistry at the chiral center in the 3-position o~ the ~-lactam nucleus i~ the same as the configuration at .he carbon atom in the 6-position of naturally occurring penicillins (e.~., per.icillin G).
The compounds of formula I contain the group R3-~-R4 and can, if R3 and R4 are diffQrent, exist 2S 'he s~n or anti isomQr or as a mixturQ of isomers. All of these isomeric forms are within '~he scope of this invention.
The _ompouncs of fo~mula I have the imino su~s'ituQnt -C- and _an, thQrerorQ, QXist as ths N
svn or anti isomer or as a mi~:ture of isom~rs.
All of these isomeric forms are within ,he s_o?e of this invQn.ion. In general, however, _he s~
isome_ of a _om?ound of fo~mula I has ~he s~e~'~ât a^tivi.y.
Th~ ~ollowing ~xæm~l~ is a s?eciIic ~m~odiment of this inv~._ion.
1308~09 GC241 ExamDle_ 1 ( Z ) -~- [ [ [ 1- ( 2-.~mino-" -thlazolyl ) -~~ [ [4, ~ dime'h~
2-o~ (sulToo~:y)-3-azQtidinyl]amino~2-oY.oQ~h~li-~Gne1~11'.~ r.olo~:v1-~ o~enoic acid A) 2-[(1, a -Dioxo-æ'i-isoindol-2-yl)oxy]-2-pro?enoiC
_~id A solu~ion c- ~-[(1,3-~ioxo-2:--isoin~ol-2-yl)oxy]-2-p,~penoi- a^id, t-bu.yl ester (1.75 g, '0 5.7 mmole) in me-hyl^ne chloridQ (10 ml) an~
arisole (10 ml) was ~-ea_Qd with triIluo-oa_e'ic acid (5 ml). A-ter stirring overnight at room tempera.ure, _olueTQ W25 added and ~hQ r-action m_x~ure was con_Qn~-a_Qd ~n vacuo. The residuQ was 15 triturated tWiCQ wi n hexanQ to give 1.5 g ol 'ne title compound.
3) 2-[(1,3-Dioxo-~'--isoindol-2-yl)oxy]-2-pro?enoi_ acid, diDhenvlm~-hvl ~ster .
2-~(1,3-Dioxo-2~-isoindol-2-yl)oxy]-2-propenoic acid (1.;4 g, 4.8 mmole) was dissolved in 25 ml of ac-tonitrile and a solution of diphenyl-diazomethane (1.17 g, 5.94 mmole/50 ml acetoni-trile) was added dropwlse. Aft~r approximately 1.1 eguivalents of diphenyldiazome'~hane had been added, tlc showed no starting material remaining. The excess diph-nyldiazomethane was decomposed wi~h tne addition of a small amount of acetic acid. The -eaction solution was _oncentrated to a residuQ, dissolved in ethyl acetate, washed consecutively wi'~h lN sodium bicarbonate and brine, dried over anhydrous magnQsium sul~a'e and evaporated to a solid. ~ItQr __i'u_ation wi~h hexanQ, 1.9 g OI 'hQ
~itle compound ~'25 obt2inQd.
~5 .
i, :
1308~09 C~ 2-Amino-a-[[[1-(diphenylmethoxy)carbonyl]-ethenYl]oxYlimino]-4-thiazoleacetic acid To a solution of 2-[(1,3-dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid, diphenylmethyl ester (0.8 g, 2 mmole) in 50 ml of methylene chloride under argon at O~C was added hydrazine hydrate (100 mg, 2 mmole in 1 ml absolute ethanol~. The reaction mixture was slowly warmed from 0C to room temperature over a one hour period and then was stirred at room temperature for an additional two hours. The white precipitate was filtered off and the solution was diluted with diethyl ether and - filtered again. The volatiles were then removed from the filtrate to give 2-aminooxy-2-propenoic acid as a residue. The 2-aminooxy-2-propenoic - acid was then dissolved in ethanol (6 ml) and water (4 ml) and 2-aminothiazole-4-glyoxylic acid (0.31 g, 1.8 mmol) was added to the solution.
Aftor stirring at room temperature for 17 hours, tlc indicated that the reaction was incomplete.
Additional ethanol and water were added and a small amount of dimethylformamide was added to solubilize the reactants. After stirring for 72 hours, tlc showed no remaining 2-aminooxy-2-propenoic acid.
Evaporation yielded the crude title compound which wa~ chromatographed on an HP20 column eluting with an acetonitrile/water gradient (0 to 80%).
Fractions containing the product were concentrated to remove the acetonitrile. Filtration of the re6ulting agueous slurry gave the title compound as a precipitate. After drying ln vacuo overnight, 167 mg of the title compound was obtained.
~', ., .
1308~09 -~0--D) N-(~-~utylo~:~r~ 3n~1)-N2-(?h~n~lmetho~:y)-D, L-3-h~d~o~:~alinamidQ
-A solu_ion of ~4 ~a g (106.6 mmol) of N-_-~u_yl~:yca-~o~yl-D,L-3-hy~ro~y~-alins a~ 15.33 g (105.6 mmol) of hydroxybQn~otriazol~ mon~hy~~a~Q
in 500 ml of dry t~~-ahydrofuran was cool~d to -~0C and 22 ~ (106.6 mmol) of dicyclohexyl-c~-~od~ imidQ w2S adied. Th- m xture was sti__ed under nitrog_n for 1 hour at 0C. Subseouently, a solution of 13.13 g (106.6 mmol) of 0-benzyl-hydroxylamine in 2,0 ml of dry tetrahydrofuran was add-d over 15 minutes to the activated es~-r mix_urQ, ~r.~ the _esul~ant mixture W25 stir~Qd und-r nitrogen for 1 hour at 0C. The insol~ble r,a~erizl W25 ~_lte~-d away, and the filt-ate wzs evaporated to a foam ~n vacuo. The foam was ^xtracted with eLhyl a_etate and more ir.solu~le ma~Qrial was removed by 'iltration. The fil~_at^
W25 washed two times with 5% sodium bicarbonate solution. The organic phase was dried (sodium sulfate) and evaporated to a syrup, which was crystallized from 130 ml of isopropyl ether to givs 24.7 g of the title compound, melting point 76-78C.
E) N-(t-Butyloxyca-bonyl)-N2-(phenylmethoxy)-D,L-3-~sulfooxv~valinamide, ~vridinium salt Dry pyridin~ (8.08 ml, 0.10 mole) was pla^ed in a 500 ml round bottom flask and cooled to -10C
under nitrogQn. Trimethylsilyl chlorosulfonate (15.6 ml, 0.10 mole) wzs added dropwise (vigorous magnQtic sti_~ing) aftQr which _he very thi-k reaction mi~:_u~e (duQ _O produ-t prQ-ipita_ion) W25 stirred for 0.5 hou-s at 0C. Chlorot~ime~hyl-silane was remo~red ln racuo ~iQlding 15 g of ?Y-idi~G-sul~ur trios:id~ compl~x.
~ '-(t-~u_~lo~:yca~on~l)-N2-(phQn~lme~ho~ D,L-3-hydro~t~-alinamide ( lo. 92 g, ~0 mmol) ~as S dissolv-d in 200 ml of dry pyridin~, ~nd 9.&7 g (62.5 mmol) of pyridlne~sulfur trioxide complQx was adde~. mhe mix_ure ~-as sti__ed at 55C under ni.-ogen -^~r 2 hou-s. ~nother ?ortion (790 m3, 5 ~mol) of ?~--idin^-sul-ur trioxide complex -~as aaded and sti_~ing ~-as _ontinued ~or 1 hour longer. T;~e ~eac,ion mixture was stripped ~n va-uo to an oil. The oil was s_ripped from ac-ton~_-ile -~h-eo tlm^s ln vacuo to glve c~l~e title compo~nd as a Icam. The yield W25 assumed 15 to ~e ou2~-i Lative.
F ) ( ' ) -3 - ~ ( ~-3utylo~ycarbonyl)amino~-4,4-dimethyl-l-(Dhenvlm-~hoxv)-2-azetidinone The flask containing crud~ N-(t-bu.yloxy-carbonyl)-N2-(ph-nylm-thoxy)-D,L-3-(sulfooxy~-valinamide, pyridinium salt (ca. ;0 mmol) wasplaced in an ice bath and 400 ml of ethyl acetate, followed by a solution of 42.8 g (0.31 mole) of potassium carbonate in 90 ml of water, was added wi~h vigorous stirring. The resultant mixtu_e was 2; stirred vigorously under reflux for 2 hou_s under ni~rog~n. The reaction mixture was cooled .o room tempera_ure and the phases were s-parated. ~he agueou~ phase was x_racted with 2x200 ml of ethyl acetate and 211 organic phases wer- combined, dried (sodium sulfate) and evaporated in vacuo.
The oil was taken into 40~ ethyl acetate/hexane (125 ml) and filtQred rapidly through a 350 ml pad (10 cm) of ~allinkrodt Sili-hR CC-7 using 3-4 lite-s or 40% ethyl acs'a_~/hexane. Th- L-~ 1 _ra~ was evapo~a-ed ~5 ln va~uo to a solid (12.2 g). C-ystallization GC~41 ~rom 50 ml of iso?rop~l ether gave 7.15 g of _hQ
~i.le compouni, melting point llO~C.
3-[('-~ut~io~y~ onyl)2~ino]-l-h~d~o~J-
Na2-C~-C-OH
1~ ~C~O- C~2~ .
R^ac_ion of a com?ound of fo-mula XXIV wi h nitrous acid in the prasence of bromida ion yielcs 'he -orreaponding com~ound having ~ne formula ~XV O
Br-C~-C-O~
~C~O-C~
A compound of formula XXV can ba estarifie~
with, for exampla, a t-bu~yl group using conventional mathodology to yi~ld he corrasponding compound having the formula XXVI O
~_-C~-U-O-c(c~3)3 ~ R4 Raa--ion of a compound of o~mula ~ I wi-h ~-hydroxyphthalimlda in _ha prQsQn_Q of a asa 081(~9 ~C241 --1~--such as potasslum carbonate in dimeth~lformamide yields a com?ound having the formula ~XVII ll ~ / N-G-C-C-O-C(C:~3~3 Remov21 of -h- ben~yl protec_~g grou?s ~y hyo~ogenolysls followed by dehydra-ion yields a com?ound havlng .r^ formula XXVIII 1l ~ o-r-r-o-c(c~3)3 Using methods known in the art, the ~-butyl group of a com?ound of formula XXVIII ^an b^
repla~ed with an alternate pro'e-ting group such as diphenylm-thyl to yield a compound having the formula XXIX
~O ll ca-o-c~ )2 -~ R3 R4 Treatment of a compound of formula Y~IX
with hydrazine or methylhydrazine yields the corresponding com~ound of fo-mula II wherein Al is diphenylmethyl. Standard deprotection and protection technigues can be used to convert that compound to other compounds of fo-mulas II and VII.
Alternatively, a compound of formula Y~ I
can be converted ~o the corrasponding com?oun~.
having the fo~mula _15_ Gc24 Y~X 1' ~
(c~3)3C-o-C-NH-o-CH-C-O-C(CH3)3 /c-c-c~2~/~
R3 ~4 by treatment with t-butyl-N-hydroxycarbama'~
in the p-esence of a base su^h 25 sodi~m hydride in a solv~nt su_h 25 dim~'hylIO~mamide.
Removal of the benzyl protec_ing 5~ou? from a compound of formula YY~ by hyd~ogenolysls, and subsequent dehydration, yields a com?o~n~ having the formula YJKXI o o (c~3~3c_0_c_ ~ _0-~-e-~-c(c~3)3 .
/ \
Standard deprotection and protection technlques can be used to convert a compound of formula YY~I
to a compound of formula II which can optionally be readily converted to the corresponding compound of formula VII.
Using the above methodology, a compound having the geometry NR2_~ C-O~
~0~
R`3 -R4 will yield a compound having '~he geometry XXXIII
N~2-0-C-C-O~
~C~
Alte-nat~vely, a compound having ~he formula X~IV O
'ir--C-O~I
/ C\
-`3 ~4 wh~_oin cne of R3 a~d R4 is hyàr~gGn a~d ~h~ olh~r s alkvl of 1 _o 3 ca-bon atoms, can be conv~.t^d ~o a com~ound of fonmula XXVIII by melhodology ~alo~ous to that us~d in th~ p~ -2 .ion o, compounds of formula XVI and desc~i~ed in 3~1sian ?atent 866,422.
A compound kavin3 -he geOmQtry oî ~ormula XJKXIV wh~rQin R~ is ci, to th~ car~oxyl grou? wi'l ~ converted to a _om?ound of formula X~III
wherein R4 i~ cis to ~he carboxyl group.
'5 The compounds of formula I con-ain at l^ast one chiral center~ .e carbon atom (in the 3-?osition of th- ~-lactam nucleus) to whi-h the am no or acylamino s~bstituent is attach-d. This invention is directed to those ~-lactams which have been described above, wherein the stereo-_hemistry at the chiral center in the 3-position o~ the ~-lactam nucleus i~ the same as the configuration at .he carbon atom in the 6-position of naturally occurring penicillins (e.~., per.icillin G).
The compounds of formula I contain the group R3-~-R4 and can, if R3 and R4 are diffQrent, exist 2S 'he s~n or anti isomQr or as a mixturQ of isomers. All of these isomeric forms are within '~he scope of this invention.
The _ompouncs of fo~mula I have the imino su~s'ituQnt -C- and _an, thQrerorQ, QXist as ths N
svn or anti isomer or as a mi~:ture of isom~rs.
All of these isomeric forms are within ,he s_o?e of this invQn.ion. In general, however, _he s~
isome_ of a _om?ound of fo~mula I has ~he s~e~'~ât a^tivi.y.
Th~ ~ollowing ~xæm~l~ is a s?eciIic ~m~odiment of this inv~._ion.
1308~09 GC241 ExamDle_ 1 ( Z ) -~- [ [ [ 1- ( 2-.~mino-" -thlazolyl ) -~~ [ [4, ~ dime'h~
2-o~ (sulToo~:y)-3-azQtidinyl]amino~2-oY.oQ~h~li-~Gne1~11'.~ r.olo~:v1-~ o~enoic acid A) 2-[(1, a -Dioxo-æ'i-isoindol-2-yl)oxy]-2-pro?enoiC
_~id A solu~ion c- ~-[(1,3-~ioxo-2:--isoin~ol-2-yl)oxy]-2-p,~penoi- a^id, t-bu.yl ester (1.75 g, '0 5.7 mmole) in me-hyl^ne chloridQ (10 ml) an~
arisole (10 ml) was ~-ea_Qd with triIluo-oa_e'ic acid (5 ml). A-ter stirring overnight at room tempera.ure, _olueTQ W25 added and ~hQ r-action m_x~ure was con_Qn~-a_Qd ~n vacuo. The residuQ was 15 triturated tWiCQ wi n hexanQ to give 1.5 g ol 'ne title compound.
3) 2-[(1,3-Dioxo-~'--isoindol-2-yl)oxy]-2-pro?enoi_ acid, diDhenvlm~-hvl ~ster .
2-~(1,3-Dioxo-2~-isoindol-2-yl)oxy]-2-propenoic acid (1.;4 g, 4.8 mmole) was dissolved in 25 ml of ac-tonitrile and a solution of diphenyl-diazomethane (1.17 g, 5.94 mmole/50 ml acetoni-trile) was added dropwlse. Aft~r approximately 1.1 eguivalents of diphenyldiazome'~hane had been added, tlc showed no starting material remaining. The excess diph-nyldiazomethane was decomposed wi~h tne addition of a small amount of acetic acid. The -eaction solution was _oncentrated to a residuQ, dissolved in ethyl acetate, washed consecutively wi'~h lN sodium bicarbonate and brine, dried over anhydrous magnQsium sul~a'e and evaporated to a solid. ~ItQr __i'u_ation wi~h hexanQ, 1.9 g OI 'hQ
~itle compound ~'25 obt2inQd.
~5 .
i, :
1308~09 C~ 2-Amino-a-[[[1-(diphenylmethoxy)carbonyl]-ethenYl]oxYlimino]-4-thiazoleacetic acid To a solution of 2-[(1,3-dioxo-2H-isoindol-2-yl)oxy]-2-propenoic acid, diphenylmethyl ester (0.8 g, 2 mmole) in 50 ml of methylene chloride under argon at O~C was added hydrazine hydrate (100 mg, 2 mmole in 1 ml absolute ethanol~. The reaction mixture was slowly warmed from 0C to room temperature over a one hour period and then was stirred at room temperature for an additional two hours. The white precipitate was filtered off and the solution was diluted with diethyl ether and - filtered again. The volatiles were then removed from the filtrate to give 2-aminooxy-2-propenoic acid as a residue. The 2-aminooxy-2-propenoic - acid was then dissolved in ethanol (6 ml) and water (4 ml) and 2-aminothiazole-4-glyoxylic acid (0.31 g, 1.8 mmol) was added to the solution.
Aftor stirring at room temperature for 17 hours, tlc indicated that the reaction was incomplete.
Additional ethanol and water were added and a small amount of dimethylformamide was added to solubilize the reactants. After stirring for 72 hours, tlc showed no remaining 2-aminooxy-2-propenoic acid.
Evaporation yielded the crude title compound which wa~ chromatographed on an HP20 column eluting with an acetonitrile/water gradient (0 to 80%).
Fractions containing the product were concentrated to remove the acetonitrile. Filtration of the re6ulting agueous slurry gave the title compound as a precipitate. After drying ln vacuo overnight, 167 mg of the title compound was obtained.
~', ., .
1308~09 -~0--D) N-(~-~utylo~:~r~ 3n~1)-N2-(?h~n~lmetho~:y)-D, L-3-h~d~o~:~alinamidQ
-A solu_ion of ~4 ~a g (106.6 mmol) of N-_-~u_yl~:yca-~o~yl-D,L-3-hy~ro~y~-alins a~ 15.33 g (105.6 mmol) of hydroxybQn~otriazol~ mon~hy~~a~Q
in 500 ml of dry t~~-ahydrofuran was cool~d to -~0C and 22 ~ (106.6 mmol) of dicyclohexyl-c~-~od~ imidQ w2S adied. Th- m xture was sti__ed under nitrog_n for 1 hour at 0C. Subseouently, a solution of 13.13 g (106.6 mmol) of 0-benzyl-hydroxylamine in 2,0 ml of dry tetrahydrofuran was add-d over 15 minutes to the activated es~-r mix_urQ, ~r.~ the _esul~ant mixture W25 stir~Qd und-r nitrogen for 1 hour at 0C. The insol~ble r,a~erizl W25 ~_lte~-d away, and the filt-ate wzs evaporated to a foam ~n vacuo. The foam was ^xtracted with eLhyl a_etate and more ir.solu~le ma~Qrial was removed by 'iltration. The fil~_at^
W25 washed two times with 5% sodium bicarbonate solution. The organic phase was dried (sodium sulfate) and evaporated to a syrup, which was crystallized from 130 ml of isopropyl ether to givs 24.7 g of the title compound, melting point 76-78C.
E) N-(t-Butyloxyca-bonyl)-N2-(phenylmethoxy)-D,L-3-~sulfooxv~valinamide, ~vridinium salt Dry pyridin~ (8.08 ml, 0.10 mole) was pla^ed in a 500 ml round bottom flask and cooled to -10C
under nitrogQn. Trimethylsilyl chlorosulfonate (15.6 ml, 0.10 mole) wzs added dropwise (vigorous magnQtic sti_~ing) aftQr which _he very thi-k reaction mi~:_u~e (duQ _O produ-t prQ-ipita_ion) W25 stirred for 0.5 hou-s at 0C. Chlorot~ime~hyl-silane was remo~red ln racuo ~iQlding 15 g of ?Y-idi~G-sul~ur trios:id~ compl~x.
~ '-(t-~u_~lo~:yca~on~l)-N2-(phQn~lme~ho~ D,L-3-hydro~t~-alinamide ( lo. 92 g, ~0 mmol) ~as S dissolv-d in 200 ml of dry pyridin~, ~nd 9.&7 g (62.5 mmol) of pyridlne~sulfur trioxide complQx was adde~. mhe mix_ure ~-as sti__ed at 55C under ni.-ogen -^~r 2 hou-s. ~nother ?ortion (790 m3, 5 ~mol) of ?~--idin^-sul-ur trioxide complex -~as aaded and sti_~ing ~-as _ontinued ~or 1 hour longer. T;~e ~eac,ion mixture was stripped ~n va-uo to an oil. The oil was s_ripped from ac-ton~_-ile -~h-eo tlm^s ln vacuo to glve c~l~e title compo~nd as a Icam. The yield W25 assumed 15 to ~e ou2~-i Lative.
F ) ( ' ) -3 - ~ ( ~-3utylo~ycarbonyl)amino~-4,4-dimethyl-l-(Dhenvlm-~hoxv)-2-azetidinone The flask containing crud~ N-(t-bu.yloxy-carbonyl)-N2-(ph-nylm-thoxy)-D,L-3-(sulfooxy~-valinamide, pyridinium salt (ca. ;0 mmol) wasplaced in an ice bath and 400 ml of ethyl acetate, followed by a solution of 42.8 g (0.31 mole) of potassium carbonate in 90 ml of water, was added wi~h vigorous stirring. The resultant mixtu_e was 2; stirred vigorously under reflux for 2 hou_s under ni~rog~n. The reaction mixture was cooled .o room tempera_ure and the phases were s-parated. ~he agueou~ phase was x_racted with 2x200 ml of ethyl acetate and 211 organic phases wer- combined, dried (sodium sulfate) and evaporated in vacuo.
The oil was taken into 40~ ethyl acetate/hexane (125 ml) and filtQred rapidly through a 350 ml pad (10 cm) of ~allinkrodt Sili-hR CC-7 using 3-4 lite-s or 40% ethyl acs'a_~/hexane. Th- L-~ 1 _ra~ was evapo~a-ed ~5 ln va~uo to a solid (12.2 g). C-ystallization GC~41 ~rom 50 ml of iso?rop~l ether gave 7.15 g of _hQ
~i.le compouni, melting point llO~C.
3-[('-~ut~io~y~ onyl)2~ino]-l-h~d~o~J-
4 ~-dim^_h~ asQtil1non~
(~)-3-[(.-~utyloxycarbonyl)amino]-4,~-~im__h.yl-l-(ph_nylm_thoY~y)-2-a__tidinon_ (8.07 g, ~5 r~ol) W25 hydrogena'Gd at a_mos?heric pressuro and zmbient temperature in 40 ml of methanol with 0.6 g of 10% palladium on cnarcoal as catalyst for hours. The reaction mix turG W2S filtGred ~nrough a pad of C~lit~ æ~d the filtrate ~-as -oncent-ated to yield 5.78 g of _he title compound zs a solid.
l;
~) (+)-3-[(t-Butyloxyca-bonyl)amino]-4, -dimethyl-2-oxo-1-azetidinvl'sul-ate, te'rabutvlàmmonium salt A solution of chlo~osulfonic a~i~ (12.27 g, 0.105 mole) in 210 ml'of dichloromethzne at -40C
under argon was treated with 20.5 g (0.26 mole) of pyridine dropwise over 10 minutes. The mixturA is stirred for 10 more minutes at 0C ~nd 10 minutes at 25C. A slurry of (~)-3-t(t-butyloxyca-bonyl)-amino]-l-hydroxy-4,4-dimethyl-2-azetidinone in 20 ml of dichloromethane was added a~d the mixturA
stirxed at 2~C for 3.5 hours. The nearly homogenous solution was then trAated with 250 ml of water and 17 g (0.05 mole) of 'e~ z~utylammonium hydrogen sulfate. mhe m~x'~u-e wzs mixed wAll an~
the orsanic layer separated and dried over sodium sulfate. Evaporation ln vacuo gave a oam, which wzs puri ied _ur'~her by di solu~ion in e_h~l a-e'_a'Q, ~emoving ir-ol~bles, zrd e~2por2_ion .o .he title compound zs a Loam/ 30 g.
_ ~
-- 1308109 GC~41 I) (~)-3-Amino-~,4-dim~th~Tl-~-o~:o-l-a~etidin~l sul-a_~
.
.i solution OI 30 g (0.05 mol~) of (_)-3-[(_-bu~-ylo~:y~a~bon~l)amino]-~, A -dim~thyl-2-o~o-1-az~ldinyl sul~a~ a~u'~l mmor.ium salt in 125 ml of dichlorom~hanQ an~ 10 ml of anisol~ at -5C un~Qr argon was tr~ated wi ~ 50 ml of '-i--'u~-Ga_~tic a_id d-o~-ise ove- 10 minut~s. L - ' ~r ati_ring for 2.; hours at -5 -o 0C, the mixture 10 ~-25 d~lut~d wi-h 50 ml o_ ~,h~l a^et_tQ and ~ l~e-Qd. The solid W25 w2shed wi_n dichloro-m~'~han~ and ~h~n with ~thyl a~etate and dA ~d ~n -v-a-uo to give 9.4 g of th~ _itlQ co~?ound aa a wr.it- granular solid.
'S
J) (-)-tZ)-2-~r[1-(2-Amino-4-thiazolyl)-2-~[4, -dime'hyl-2-oxo-1-(sulfooxy)-3-az~tidlnyl]amino]-2-oxo~'~hyliden-]amino]oxy]-2-propenoic acid, di~h-nvlm-thvl est-r To a solution of 2-amino-a-[[[1-(diphQnyl-methoxy)carbonyl]ethenyl]oxy]imino]-4-thiazol e-acetic acid(167 mg, 0.4 mmole) and triethylaminQ
(56 ~1, 1.0 eguivalents) under argon at -30C was add-d diphenyl chloro~hospha~- (107 mg, 0.4 mmolQ).
2a The reaction mixture was stirred at -30C for one hour to form the mixed a~hydride. (+)-3-Amino-4,~-dime~hyl-2-oxo-1-azetidinyl sulfate (126 mg, 0.6 mmole) was dissolved in dime'~hylformamid- at 0C and this solution and '_ie'hylaminQ (71 ~1, 0.8a equival~nts) were simultan-ously addQd to the mixed anhydrids solution at -30C. ThQ reaction mixtur~ was stirr-d for one-half hour at -30C and _hQn slowly wa~mQd to 0C ovQr a onQ nour ?~_iod.
~hQ ~Qac~ion mix-u-Q W2S ~on~Qn_-at~d ~n ~-a^uo, taken u? in a~etonQ/watQr and adjus_Qd to ?:~ 6.5 ~308~09 with lN potassium bicarbonate. A Dowex AG50 (K ) column was run eluting with 30% acetone/water. The appropriate fractions were combined and con-centrated and the residual aqueous solution was applied to an HP20 column. The column was eluted with water and then with an acetone/water gradient (0-100%). The appropriate fractions were combined and lyophilized to give the title compound which was all used in the next step.
K) (+)-(Z)-2-[[[1-(2-Amino-4-thiazolyl)-2-[[4,4-dimethyl-2-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethvlidene]aminoloxy~-2-propenoic acid To the flask containing (i)-(Z)-2-[[[1-(2-amino-4-thiazolyl)-2-[[4,4-dimethyl-2-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-propenoic acid, diphenylmethyl ester was added methylene chloride (10 ml) and anisole (lO ml).
After cooling to -5C, trifluoroacetic acid (8 ml) wa~ added and the reaction mixture was stirred at
(~)-3-[(.-~utyloxycarbonyl)amino]-4,~-~im__h.yl-l-(ph_nylm_thoY~y)-2-a__tidinon_ (8.07 g, ~5 r~ol) W25 hydrogena'Gd at a_mos?heric pressuro and zmbient temperature in 40 ml of methanol with 0.6 g of 10% palladium on cnarcoal as catalyst for hours. The reaction mix turG W2S filtGred ~nrough a pad of C~lit~ æ~d the filtrate ~-as -oncent-ated to yield 5.78 g of _he title compound zs a solid.
l;
~) (+)-3-[(t-Butyloxyca-bonyl)amino]-4, -dimethyl-2-oxo-1-azetidinvl'sul-ate, te'rabutvlàmmonium salt A solution of chlo~osulfonic a~i~ (12.27 g, 0.105 mole) in 210 ml'of dichloromethzne at -40C
under argon was treated with 20.5 g (0.26 mole) of pyridine dropwise over 10 minutes. The mixturA is stirred for 10 more minutes at 0C ~nd 10 minutes at 25C. A slurry of (~)-3-t(t-butyloxyca-bonyl)-amino]-l-hydroxy-4,4-dimethyl-2-azetidinone in 20 ml of dichloromethane was added a~d the mixturA
stirxed at 2~C for 3.5 hours. The nearly homogenous solution was then trAated with 250 ml of water and 17 g (0.05 mole) of 'e~ z~utylammonium hydrogen sulfate. mhe m~x'~u-e wzs mixed wAll an~
the orsanic layer separated and dried over sodium sulfate. Evaporation ln vacuo gave a oam, which wzs puri ied _ur'~her by di solu~ion in e_h~l a-e'_a'Q, ~emoving ir-ol~bles, zrd e~2por2_ion .o .he title compound zs a Loam/ 30 g.
_ ~
-- 1308109 GC~41 I) (~)-3-Amino-~,4-dim~th~Tl-~-o~:o-l-a~etidin~l sul-a_~
.
.i solution OI 30 g (0.05 mol~) of (_)-3-[(_-bu~-ylo~:y~a~bon~l)amino]-~, A -dim~thyl-2-o~o-1-az~ldinyl sul~a~ a~u'~l mmor.ium salt in 125 ml of dichlorom~hanQ an~ 10 ml of anisol~ at -5C un~Qr argon was tr~ated wi ~ 50 ml of '-i--'u~-Ga_~tic a_id d-o~-ise ove- 10 minut~s. L - ' ~r ati_ring for 2.; hours at -5 -o 0C, the mixture 10 ~-25 d~lut~d wi-h 50 ml o_ ~,h~l a^et_tQ and ~ l~e-Qd. The solid W25 w2shed wi_n dichloro-m~'~han~ and ~h~n with ~thyl a~etate and dA ~d ~n -v-a-uo to give 9.4 g of th~ _itlQ co~?ound aa a wr.it- granular solid.
'S
J) (-)-tZ)-2-~r[1-(2-Amino-4-thiazolyl)-2-~[4, -dime'hyl-2-oxo-1-(sulfooxy)-3-az~tidlnyl]amino]-2-oxo~'~hyliden-]amino]oxy]-2-propenoic acid, di~h-nvlm-thvl est-r To a solution of 2-amino-a-[[[1-(diphQnyl-methoxy)carbonyl]ethenyl]oxy]imino]-4-thiazol e-acetic acid(167 mg, 0.4 mmole) and triethylaminQ
(56 ~1, 1.0 eguivalents) under argon at -30C was add-d diphenyl chloro~hospha~- (107 mg, 0.4 mmolQ).
2a The reaction mixture was stirred at -30C for one hour to form the mixed a~hydride. (+)-3-Amino-4,~-dime~hyl-2-oxo-1-azetidinyl sulfate (126 mg, 0.6 mmole) was dissolved in dime'~hylformamid- at 0C and this solution and '_ie'hylaminQ (71 ~1, 0.8a equival~nts) were simultan-ously addQd to the mixed anhydrids solution at -30C. ThQ reaction mixtur~ was stirr-d for one-half hour at -30C and _hQn slowly wa~mQd to 0C ovQr a onQ nour ?~_iod.
~hQ ~Qac~ion mix-u-Q W2S ~on~Qn_-at~d ~n ~-a^uo, taken u? in a~etonQ/watQr and adjus_Qd to ?:~ 6.5 ~308~09 with lN potassium bicarbonate. A Dowex AG50 (K ) column was run eluting with 30% acetone/water. The appropriate fractions were combined and con-centrated and the residual aqueous solution was applied to an HP20 column. The column was eluted with water and then with an acetone/water gradient (0-100%). The appropriate fractions were combined and lyophilized to give the title compound which was all used in the next step.
K) (+)-(Z)-2-[[[1-(2-Amino-4-thiazolyl)-2-[[4,4-dimethyl-2-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethvlidene]aminoloxy~-2-propenoic acid To the flask containing (i)-(Z)-2-[[[1-(2-amino-4-thiazolyl)-2-[[4,4-dimethyl-2-oxo-1-(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-propenoic acid, diphenylmethyl ester was added methylene chloride (10 ml) and anisole (lO ml).
After cooling to -5C, trifluoroacetic acid (8 ml) wa~ added and the reaction mixture was stirred at
-5 to O~C under argon for 45 minutes. Toluene was added, and the reaction mixture was evaporated to a re~iduo. Water and hexane were added to the re~idue and the layers were separated. The aqueous layer was adjusted to pH 2.5 with 10% potassium bicarbonate. An HP20 column was run eluting first with water and then an acetone/water gradient. The appropriate fractions were combined and lyophilized to give the title compound as a white solid.
lH-NMR (1:1 D20/CD3C~ 1.57 (B, 3H); 1.75 (s, 3H); 5.09 (B, lH); 5.75 (d, J = 2.3 Hz, lH); 5.86 (d, J2.3Hz, lH); 7.42 (B, lH).
*Trade-mark 1~08~09 ~ GC241 Exam~le 2 [3S(Z)]-~-[[[1-(2-Amino-4-thia~olyl)-~-[[4,4-dimG_hyl-2-oxo-1-(sul~ooxy)-3-a~Qticinvl~amino3-7 -o~:o~thvlid~n~l2minoloxv~ rc~e~oi_ a-ld_ .i) 2-[(l,3-Dioxo-2:~-isoindol-2-yl)oxy]-2-p~o?~noic a-id A solu-ion of 2-~(1,3-dioxo-2~-isoindol-2-yl)-o~.y3-2-pro?enoic acid, t-butyl ester (49.9 g, '0 0.'73 mole) n methyl-ne _hloride (300 ml) and ~risole ~1~0 ml) was t_ea.ed wi,n tri~luo-oa~etic acid (300 ml). A ter s~irring overnight at room -empe-a'u-e, 800 ml o- d~y toluene ~-~s added and tne .eaction mixture ~-2s con~ent-ated ~'n ~-acuo.
'5 ~he -~sidue ~zs -ritura_^d ~wi_e wi.h h~x ne to give 39.6 g of the title compound.
3) 2-~(1,3-Dioxo-2~-isoindol-2-yl)o~y]-2-p~opg~oic acid, diDhenvlme-,hvl es~er 2-~(1,3-Dioxo-2~-isoindol-2-yl)oxy]-2-propenoic acid (39.6 g, 0.17 mole) was dissolved in 800 ml of ac~tonitrile and a solution of diphenyldiazo-me~hane'(43.4 g, 0.224 mol-/1000 ml acetonitrile) was added d~opwise ov^r 3 hou~s at 0C. Th-~eaction solution was evaporated 'o a solid whi_h was triturated with hexane. The resulting solid was dlssoived in dichloromethane and filtered 'h.-ough a pad of silica gal (~ieselg~l 60).
.~ddi'ion of hexane produced 47.7 g of ~he ti'le compound.
C) 2-.~mino-a-[~[1-(diph~nylmethoxy)-a~bonvl]-G'_henvlloxvlimino~ hizzolsa-a~ ld To a solu'ion of 2-[(1,3-dioxo-~:-'-lqoin~ol-2-yl)oxy]-2-propenoic acid, diphenylmethyl es~er (6.07 ~, 15.2 mmolQ) in 375 ml of mQ~hyl~nQ
chloridQ llndGr ar~on at 0C w~s a~d hydra- nQ
h; r~_~ (0.76 g, 15.2 ~mol~) in ~ ml a~solu~Q
~_hznol. A t~r on~ hour al O~c, _~Q mi~:tu~~ s 5 e~-apo-a_ed to dryness at +10C and tri~u~a_Qd ~
ethyl ether. ~iltration and concentra_ion of =`~.Q
filtrates ~avQ 2-aminooxy-2-propenoic a~id, diphenylme-~hyl ester 2S a residue. m:~is s~m?ou~
was then treated at 20C with a solution of 2-amino-a--hiazoleglyoxylic acid (2.61 g, 15.2 mmole) in dime hylformamide (50 ml), follGw-d by ; ml of water. The reaction was stir_ed at 20C
for 20 hours, and was ~hQn chilled 2nd diluled wi~h 250 ml of water. S'irring of ,he resul'ir.g ~um ~S gavQ a granular solid which was fil'Qred, washed with water, and ~hen azeotro~d with a~etonitri 1Q
'o dry~ess. The dry solid was slu--ied with 100 ml of ace.orit~lle, filtered, and firlally washed sequentially wi'Jh acetonitrile, ethyl ether, and hexane. Drying in air gave 1.97 g of th~ title compound.
D) N-(~-3utyloxycarbonyl)-L-3-hydro~yvaline, a-m~thvlb-r.z~lamin- salt A solution of N-~-butyloxy~arbonyl-D,L-3-hydroxyvaline (7.02 g, 30 mmole) in 250 ml of ~hyl ether was treated with 3.63 g (30 mmol~s) of S-(-)-a-m-'hyl b~r~ylamine. A.ter 8 hours, '~e -esulting solid was filtered. m~ hr-~ recryst211i~a-tions from acetonitrile gave 5.80 g of the ti' compound, m-lting point 146-147C, ~a~D = ~4 5 (C = 2.0, m~thanol).
~ ~ ~L3081.09 GC 'al ~) N-(t-3u~1ox ~r a~~on~rl)-L-3 -h~rdrox~ zl i ~Q
A m~xtur~ of 804.5 g (0.577 mole) of 1~
~u,ylo~:vo2~~on.~1)-L-3-hyd~oxy~-~linQ, ~-mg_h~l-' ~Q ~ _1 '_ I Q _h~l Z~Q _2 ~Q (3~) and a solution o~ 130 ~ of ?o_zssium ~ aUl~~a~Q 2~ 0 of sodium chlo-idQ in lL of wa_Qr was shakQn, thQ
'aye_s s-?~_a'ed and _ne o~ganl_ ?hase washQd w~th -~a_er and ~-iQd ov_r magnQsium sul a.e. concer.-_ration of the organic solution and trituration with 800 ml of hexane gave 136 g of the title -om?ound, mQlting point 120-121C, ~]D = +7.81.
r ) ~ -3utyloxy_ a-bonyl)-N ?-(?h Qnylm~hoxy)-L-3-hvdroxv-v 2_ inamid~
~ol'owing _hQ p-o-Qdur~ of ~xample 1, pa. t D, but substi-,uting N-(t-butyloxycarbonyl)-L-3-hydroxy~-2linQ 'or ~ -butyloxycarbonyl)-D,L-3-hydroxyv21in~ yield~d .hs titl~ compound.
G) (3S)-3-~(t-~utyloxycarbonyl)zmino]-4,4-dim-thvl-l-l~h-nvlmethoxY)-2-azstidinone A solution of 2-methylpyridine (296 ml, 3.0 mole) in methyl isobutyl ketone (2700 ml) under argon at -78C was treated dropwise with 2; chlorosulIonic acid (80 ml, 1.2 mole) ov~r 30 minutes. A''sr the addition, th~ mixture was brought to 25C over 30 minut~s and h~ld thsre anoth~r 30 minu-ss. To this slurry wzs add~d N-(.-bu'_yloxyca~jonyl)-N2-(ph-nylmo'Jhoxy)-L-3-hy~-oxy-valinamide (~38.4 g, 1.0 mole) and stirring continued for two hours. To this mix'~ure was addsd m~_hyl isobu-yl k~_ons (800 ml), K2B4O7-4 ~2 (1222 g, 4.0 molss), and W2 _5_ ( 2700 ml), an _h~
m xturQ was hsa~d _o 70C. Whil~ hsa_ing, ~N
~5 po_zssium hy~-oxid~ (1000 ml, 2 mols) wzs addsd d-opwi-s to -_h_ mix_ur~ ovsr 5 minut~s and ths -- 130810~
mixturQ ~-as hQat~d for another 55 mlnu' es. The layQrS wGre SQ?a-a' e~ ~nd the aquQous ?hZsG ~2s Qxtrac~Qd ~7i_h ~Q0 ~l of mQ_hyl is~bu_~l }G_~ne.
mhG COIllbiIlQd o_yari^ layQ-S we-e ChillQd _0 0C, ~ashQd wi.h 3L oI cold 20o ?ot2ssium ~isul--a~Q~ lL
of iCe water, ~nd a solution of 50 g of so~ium bicarbon te and lO0 g of socium chloridQ in lL of wa-er. The ors~nic lay~r ~-as d-iGd o-~Gr so-ium sul-at~ and con_entrat-d ~n vacuo. The -e~ldue 0 W2S crystallized f_om 1.75 L of isop-o?yl ~her ~o yield 161 g of the title compound, mel~ln~ ~o nt 121-122C, []D = + 21.06 (C = 2.55, r~2Cl2).
~) (35)-3-~(t-3utyloxycarbonyl)amino]-1-r.yd-oxy-'5 4,4-dime'hvl-2-aze'i~ino A solution of 14.77 g (0.0451 mole) of (~s)-3-[(t-butyloxycarbonyl)amino]~4,4-dimethyl-1-(phenylme~hoxy)-2-azetidinone in 15 ml of G_hanol and 85 ml of ethyl acetate ~-as hydrog-nated over 0.75 g of a% palladium-on-carbon catalyst for 1.5 hours at 1 atmosphere. The reaction mixture was filtered and concentrated to give a white solid.
Recrystallization from e_hyl acetate save 8.B2 g of the title compound, m-lting point 148-la9C, ~a]D = +31~ (C = 1, e,hyl acetate).
I) (3S)-3-[(t-3utyloxyca-bonyl)amino]-4,4-dimethyl-2-oxo-l-azetidinyl sul~ate, to_ra~u.yl-ammonium salt Following ~he procedure of Exam~le 1, but substituting (3S)-3-[(t-butyloxycarbonyl)amino]-1-hydroxy-4,4-dime'hyl-2-2zetidinon~ for ( )-3-[('-bu~yloxy-a_Donyl)amlno]-1-nycroxy-4,4-dime'hyl-2-~zQ-idinon- yielded tA- ti le com?ound as a foam.
08~09 - GC~41 _~9_ J) (~S)-~-~mino-.,a-dim~hyl-~-oxo-1-a-~tidinyl sul_at~
-ollo~l~,g _hQ ?~o_Gdu-Q of ~~zm?l~ a_t I, but subs~i~u_ing (~S)-3-[( -~u~ y^a-bo~yl)-~mino~ dimQ=h~ -oxo-' -azG~idin~ l sul.a~Q, .~_ræbu.ylammonium salt ror (i)-3 [(t-bu.yloxy-_a~onyl) zmino] -4, -dim~hyl-2-oxo-1-a~etidinyl sulfa~s, tQt-abutylammonium sal. yiQl~Qd _he ~
compound. Recrystalli-ation of a small sample from ethanol/water gave the li~le c~mpound as a c,ystallin~ solid, melting point 1&0-1C2 (d), [~]D = 74.8 (C = 1, H20).
K) ~3S(Z)]-2-[[[1-(2-.r~mino-~- hi2zolyl)-2-[ [4,C_ dim-~*.yl-2-oxo-1-(sul-ooxy)-3-~zGtidinyl]amin~-2-oxoethylidene]amino]oxy]-2-propenoic acid, di~h^rvlm~_hvl estor, t~abutvlammonium salt To a solution of 2-amino-a-[[[1-(di?heryl-methoxy)~æ bonyl]QthQnyl~oxy]imino]-4-thiazolG-acetic acid (1.423 g, 3.36 mmole) and triethyl-amine (0.404 g, 3.88 mmole) under argon at -30C
was added diphenyl chlorophosphate (0.902 g, 3.36 mmol-). The reaction mixturs was stirrQd at -30C ~or on~ hour to form the mixed anhydride.
~5)-3-Amino-4,~-dimethyl-2-oxo-1-azetidinyl sulfat~ (0.706 g, 3.36 mmole) was dissolvsd in 4 ml of dime~hylformamide at 0C and this solution and tri~'_hylamine (O.gO4 g, 3.88 mmole) w~s simul_aneously added to ~hQ mix~d anhyarids solution at -30C. The r~action mixture was slowly warmed to 0C over a one hour period. The -eaction mi~:'u-e was treat~d wi'h tri~hylamir.e (0.338 g, 3.35 mmole) and .:~an -on_~n'-a'~d ~n va-uo. The resiiu~ was t-eated wi~h wa~r ~o yield a gum which was se?a-ated ~-om _h~ a~uaous ~ l3~o8~9 GC241 la~Qr and washQd ~i_h more wzter. mhe gum was dissolved in 100 ml of me~hvlGnQ chlo-ide an~
sha};Qn wi_h 2 solution of tetrabutvlamm~nium h-~rogen sulratQ (1.14 g, 3.36 mm~lQ) 'n 30 ~l o--water. ~;aQ orgar.i_ ?hasQ ~2s se?a-a_Q~ and washe~
~hree -imes ~ h water, dried over sodium sul-atG
and e~a~orated to a foam. This ozm was dis~olvQd in 30 ml of mGthylenQ _hl~-ide an~ dilu-~d -~120 ml with ethyl acetate. The title compoun~
-rystallized zs 1.73 g of a wh~e solid, meltin~
?oint 170-172C.
L) [35(Z)]-2-[[[1-(2-Amino-_-~hiazolyl)-2-[~A,4-dime hyl-2-oxo-1-(sulfooxy)-3-aze_idir.yl]&mino]-2-oxoe_hvlidQnelamlnolo~vl-~-?-o?Qnoic a-id A solution of [35(Z)]-2-[[[1-(2-amino- -~hiazolyl)-2-[[4,4-dim~'_hyl-2-oxo-1-(sul~ooxy)-3-zzetidinyl]amino~-2-oxoe hyliiQne]ar.lno]oxy~-2-prop~noic acid, diph~nylmethyl estcr~ tetrabu,yl-ammonium salt (2.17 g, 2.54 mmole) in methylene chloride (24 ml) and anisole (1 ml) at -12C was treated with trifluoroacetic a~id (8 ml) and the reaction mixtu_e was stirred at -10C under argon for 1 hour. ~he mixture was tr-at~d dropwise wi_h 2~ 60 ml of ethyl a-et-~_- znd ',he ~~maining slurry stirred for 20 minu'es and 'hen ~iltered and washed with e-~hyl ac~tate and he~an-. After d ying in air, ~hQ solid wzs slurried wi'~h 50 ml of water at 20C an~ crystals .ormed within a _ew minutes. After c;ys'allization, the solution was filtered and the solid washed wi'h water and dried ~'n va-uo to give 0.9 g of 'he title sompound, m-lting point l G-170, a~^.
r~:~m~ 3 (Z)-~ [ [l~ r.ino-A-thia~olyl)- -o~:o-'`-[ [2-o~o-l-(sul~oo~:y)-l-a..2s~iro[3.3]he?.-3-yl]ami;lo]-~ ;r l i 2 ~ ~. '~ r l--~--~--0 2 ~ ~10 i C 2 _ i d -3uto~ycarbonyl)-a-(1-hydroxy~v~lobu_yl)-_l~_in~, ~^n-~l es_~r _ _ _ .~ solu,ion o- ~iiso?ro~ylamine (9.7 ml, 70 mmoles) in 150 ml of dry tet~ahydrofuran at lo -AOOC under argon ~-as tr~ated wi~h 39 ml (64.5 mmoles) of 1.71N n-butylllthium in he~an_ an~ the pale yellow solution stirred at - 0C ,or 20 mi~ul~s. ThG solution was cooled to -73C, znd a solution of 7.gS g (30 mmoles) of N-(~-butoxy-lS -a-bonyl) glycine, benzyl ~ster in 30 ml of d y tetrahydroruran W2s dripped in o~er S minu'es, resulting in a dark yellow solution, and, aIter 20 minu~e3, a slight ~urbidi~y. A,ter 0.5 hou-s, a solution of 2.~2 g (2.0 ml, 34.5 mmoles) of cyclo-butanone in 30 ml of tetrahydrofuran was added.
Th- resulting yellow turbid mixture was stirred at -78C for 15 minutes, then placed in a 0C ice ~a'~h for 2 hour-~. At an internal temperature of -25C (1 hour), ,h~ solution becam- clear, and a~
-13C turned dark purple. It was sti~~-d at 0C
for 0.; hours, then treated with 3.96 g (66 mmoles) of glacial acetic acid in 15 ml of tetrahydrofur2n, siving a turbid, light yellow mix'.u_e. Thi3 W2S poured into S00 ml of cold water and extracted twice with ethyl acetate. The -xtracts were washed with 2% potassium bisulfate, 5% sodium bi_a-bonate, and brine, d-ied (sodium sulfato) and e~-a?o-a_ed to a ~:ni~k oil. ~h-o~,a'o-graphy on 800 ml o_ LPS-1 in hexan~:e_hyl a^etate 1~08109 (2:1) and combination of the pro~uct rra~tions (R-= ~9) ga~e 7 8 ~ of ?~odu~t ~s an oil.
-3al_oxvca-~onvl)-~-(1-h~__c~v-v-lc~u~
a'~_ ne ~ u~oxycarbonyl)-~ hydroxycvclobu~yl)-glycine, ber.-yl es er (7.8 g, 23.3 mmoles) W'a hydrogenated at 1 z-mos?here over l.0 g o~ ~C~
palladium on charcoal in 150 ml of a~solu'Q
ethanol for 4 hours at 25~C. The ~_- lys- was filterQd and the solve~t e~apo~a~e~ in v_-uo.
Benzene ~-as added and e~-aporated -wice, .o ~ive 5.0 g of product 25 a hard -0?~.
C) ~'-(3en~yloxy)-N2-('-~u_o~y~a-bonyl)-~-(l-hvdroxv~v^lobutvl)~lvcinamide N-(t-Butoxyca~bonyl)-a-(1-hydroxycyclo~u-yl)-glyc-ne (5.0 g, 20.4 mmOlQS) W25 ~issolved in 150 ml of dry te,rahydrofuran under argon.
- 20 ~ydroxybenzotriazole hydrate (3.12 g, 20.4 mmole) was added, and the mixture was chilled to 0C, and then treated with 4.20 g (20.4 mmoles) of dicyclohexylcarbodilmide. Aft~r 1.75 hours at 0C, a solution o~ 0-b~nzylhydroxylamin~ in 15 ml of t~trahydro~u~zn W23 ad~d, and the mixtur~
stirr-d at 0-25C for 17 hours. The te rahydro-fura~ mixturn wzs '~hen chilled to -10C for 20 minut~s znd .h~ resul~ing solids ~ilte~ed znd wzshQd wi-~h d y ~-ræhyd_o~uran. ~h~ ~il--a-e W23 e~aporated and th- residu~ takQn u~ in ethyl acetate and wzshQd auickly with 2% potzssium bisul'a'e, b-inQ, -% sodium bica~bor.a-~, and brine, th~n d-iQd (so~ium sulfatQ) and ~V2~0- 'e~
'o a fGam. ~-i-u~z~ion wi-h isopropyl Q~hsr ~e ~30B109 GC241 4 . 69 g of produ~t as a whitQ solid, mQlt~ng ?o~nt o5-97c .
~) '-(3-r._ylo~:~)- 3 - [ ( _-~u ~^~:y_~ _~o~l)am~
o~: 3 - 1 - z ~ as~i~or3.3lhQ~tan~
~ '-53QnzyloY.y)-N2-(t-buto~:yca~bonyl)-~hy~-cxy_y-lobutyl)glycinamid~ (3.50 g, 10 mmol~) in ~0~ ml of cry tetran~dro u_an ât 0C u~iQr argon was treatQd with 2.4 ml (15 mmole) of diethyl-azodi~z-boxyla' a~ th~n with a solution of .riphenyl-hos~hine (5.2 g, 20 mmole) ln ~0 ml of ~_^trahydro-uran over 10 minutes, and the mixtur^ s_irred a~
0C Tor one hour. The y~llow color p~-si,'ed so an ad itional 0.52 g (2 mmole) of triph^r.yl-' '5 phJsp~ ^.a ~-as added. Af-er 15 minutes, ^-v-apo~a'_ion ln ~-a~uo gave an oil. Tritu~ation with 100 ml of hexane:e'~hyl acetate (2:1) gave a whi~e solid whi_h w2s filtered. Chromatogra~ny of he ,iltrate on 800 ml of L~S-1 gave product fractior.s [Rf=0.8 in hexane:ethyl acetate (1:1)] contaminated with a close-running impurity which was removed by trituration with isopropyl ether, gi~ing the product as a white solid, 1.07 g, melting point 155-157C.
2;
E) 3-~(t-Butoxycarbonyl)amino~-2-oxo-~-(sulfooxy)-1-az2s~iro r 3.3lhe~t2ne, monosodium salt 1-(genzyloxy)-3-[(t-butoxyca-bonyl)2mino~-2-oxo-'-azaspiro~3.3]hep'ane (1.07 g, 3.22 mmoles) was hydrogenated at 1 atmosph-re in 30 ml of absolute ethanol over 0.4 g of 10% palladium on ~ha~~021 for 3 hours at 2~C. The catalyst wzs -il-e~-d and 'he solvent ~emovQ~ :n va~uo at 10~C 'o give a solid. This was _aken U? in '9 ml 3; of dry ?yridine and '~~a~ed with 1. 4 g (9 mmoles) of pyridine-sulfur trioxide at 25c under argon.
After 4 hours, the volatiles were removed in vacuo, the residue taken up in water, and the pH
(5.40) adjusted to 6.45 with dilute sodium bicarbonate. Passing through a 40 ml Dowex AG50 (K+) column in water eluted the product within 300 ml. Lyophilization gave a white solid, which was chromatographed on HP-20, first in water, then with a gradient increase of acetone (20%). Product fractions were lyophilized to give 0.75 g of product as a white powder.
F) 3-Amino-2-oxo-1-(sulfooxy)-l-azaspiro[3.3]he~tane 3-[(t-Butoxycarbonyl)amino]-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, monosodium salt (0.3 g, 0.87 mmole) was slurried in 2.5 ml of dry dichloro-methane and 1.0 ml of anisole at -10C under ar~on, and then treated with 4.0 ml of trifluoroacetic acid. After 0.5 hour, a solid had formed. After 1.5 hours, 4 ml of dry toluene was added, and the mixture evaporated ln vacuo to give a solid, 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, which was triturated twice with hexane and dried ln vacuo at 25C for 1 hour.
G) (+)-(Z)-~1-(2-Amino-4-thiazolyl)-2-oxo-2-[[2-oxo-1-(sulfooxy)-1-azaspiro[3.3]hept-3-yl]amino]-ethylidene]amino]oxy]-2-propenoic acid, diphenyl-methYl ester, tetrabutYlammonium salt Following the procedure of Example 2, part K, but substituting 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane for (3S)-3-amino-4,4-dimethyl-2-oxo-1-azetidinyl sulfate, yielded the title compound.
GC2~1 --'~ 5--(Z)-[[[1~ ino-~-thi~olyl)-'~-o~:o-2-[[''-oxo-1-(sulfooxy)-l-a,2s?iro[3 3]hQpt-3-~ ami~o]-e_h~lidQnQl2minolox~ ro~Qroi_ a_id .
~ -ing ~hQ p~O_Q~U-~ of -~?l~ _t L, but su~s_i_u__ng (+)-(Z)-[[[1-(2-2minc-~-~niazolyl)-2-oxo-2-[[2-oxo-1-(sulfooxy)-1-azas~iro-[3 3]hept-3-yl]amino]ethyli~ene~amino]oxy]-2-_-opQnoic a^id, diphenylme_hyl ester, .e~rabu~yl-ammonium salt for [35(Z)]-2-[[[1-(2-amino-4-_hiazolyl)-2-[~4,4-dimethyl-2-oxo-1-(sulfooxy~-3-azetidinyl]amino]-2-oxoQfhylidQne]amino]oxy]-2-?ropenoic acid, diphenylme-hyl ester, tetra-bu ylammonium salt and chroma.os-aphing ha preclpi ate from ~he ethyl a~etate dilu.ion on ~-20 rasin instead of re~rystallizing -rom water, yielded tho title compound, melting point 170-200C, dec ~: ;.... .... .
lH-NMR (1:1 D20/CD3C~ 1.57 (B, 3H); 1.75 (s, 3H); 5.09 (B, lH); 5.75 (d, J = 2.3 Hz, lH); 5.86 (d, J2.3Hz, lH); 7.42 (B, lH).
*Trade-mark 1~08~09 ~ GC241 Exam~le 2 [3S(Z)]-~-[[[1-(2-Amino-4-thia~olyl)-~-[[4,4-dimG_hyl-2-oxo-1-(sul~ooxy)-3-a~Qticinvl~amino3-7 -o~:o~thvlid~n~l2minoloxv~ rc~e~oi_ a-ld_ .i) 2-[(l,3-Dioxo-2:~-isoindol-2-yl)oxy]-2-p~o?~noic a-id A solu-ion of 2-~(1,3-dioxo-2~-isoindol-2-yl)-o~.y3-2-pro?enoic acid, t-butyl ester (49.9 g, '0 0.'73 mole) n methyl-ne _hloride (300 ml) and ~risole ~1~0 ml) was t_ea.ed wi,n tri~luo-oa~etic acid (300 ml). A ter s~irring overnight at room -empe-a'u-e, 800 ml o- d~y toluene ~-~s added and tne .eaction mixture ~-2s con~ent-ated ~'n ~-acuo.
'5 ~he -~sidue ~zs -ritura_^d ~wi_e wi.h h~x ne to give 39.6 g of the title compound.
3) 2-~(1,3-Dioxo-2~-isoindol-2-yl)o~y]-2-p~opg~oic acid, diDhenvlme-,hvl es~er 2-~(1,3-Dioxo-2~-isoindol-2-yl)oxy]-2-propenoic acid (39.6 g, 0.17 mole) was dissolved in 800 ml of ac~tonitrile and a solution of diphenyldiazo-me~hane'(43.4 g, 0.224 mol-/1000 ml acetonitrile) was added d~opwise ov^r 3 hou~s at 0C. Th-~eaction solution was evaporated 'o a solid whi_h was triturated with hexane. The resulting solid was dlssoived in dichloromethane and filtered 'h.-ough a pad of silica gal (~ieselg~l 60).
.~ddi'ion of hexane produced 47.7 g of ~he ti'le compound.
C) 2-.~mino-a-[~[1-(diph~nylmethoxy)-a~bonvl]-G'_henvlloxvlimino~ hizzolsa-a~ ld To a solu'ion of 2-[(1,3-dioxo-~:-'-lqoin~ol-2-yl)oxy]-2-propenoic acid, diphenylmethyl es~er (6.07 ~, 15.2 mmolQ) in 375 ml of mQ~hyl~nQ
chloridQ llndGr ar~on at 0C w~s a~d hydra- nQ
h; r~_~ (0.76 g, 15.2 ~mol~) in ~ ml a~solu~Q
~_hznol. A t~r on~ hour al O~c, _~Q mi~:tu~~ s 5 e~-apo-a_ed to dryness at +10C and tri~u~a_Qd ~
ethyl ether. ~iltration and concentra_ion of =`~.Q
filtrates ~avQ 2-aminooxy-2-propenoic a~id, diphenylme-~hyl ester 2S a residue. m:~is s~m?ou~
was then treated at 20C with a solution of 2-amino-a--hiazoleglyoxylic acid (2.61 g, 15.2 mmole) in dime hylformamide (50 ml), follGw-d by ; ml of water. The reaction was stir_ed at 20C
for 20 hours, and was ~hQn chilled 2nd diluled wi~h 250 ml of water. S'irring of ,he resul'ir.g ~um ~S gavQ a granular solid which was fil'Qred, washed with water, and ~hen azeotro~d with a~etonitri 1Q
'o dry~ess. The dry solid was slu--ied with 100 ml of ace.orit~lle, filtered, and firlally washed sequentially wi'Jh acetonitrile, ethyl ether, and hexane. Drying in air gave 1.97 g of th~ title compound.
D) N-(~-3utyloxycarbonyl)-L-3-hydro~yvaline, a-m~thvlb-r.z~lamin- salt A solution of N-~-butyloxy~arbonyl-D,L-3-hydroxyvaline (7.02 g, 30 mmole) in 250 ml of ~hyl ether was treated with 3.63 g (30 mmol~s) of S-(-)-a-m-'hyl b~r~ylamine. A.ter 8 hours, '~e -esulting solid was filtered. m~ hr-~ recryst211i~a-tions from acetonitrile gave 5.80 g of the ti' compound, m-lting point 146-147C, ~a~D = ~4 5 (C = 2.0, m~thanol).
~ ~ ~L3081.09 GC 'al ~) N-(t-3u~1ox ~r a~~on~rl)-L-3 -h~rdrox~ zl i ~Q
A m~xtur~ of 804.5 g (0.577 mole) of 1~
~u,ylo~:vo2~~on.~1)-L-3-hyd~oxy~-~linQ, ~-mg_h~l-' ~Q ~ _1 '_ I Q _h~l Z~Q _2 ~Q (3~) and a solution o~ 130 ~ of ?o_zssium ~ aUl~~a~Q 2~ 0 of sodium chlo-idQ in lL of wa_Qr was shakQn, thQ
'aye_s s-?~_a'ed and _ne o~ganl_ ?hase washQd w~th -~a_er and ~-iQd ov_r magnQsium sul a.e. concer.-_ration of the organic solution and trituration with 800 ml of hexane gave 136 g of the title -om?ound, mQlting point 120-121C, ~]D = +7.81.
r ) ~ -3utyloxy_ a-bonyl)-N ?-(?h Qnylm~hoxy)-L-3-hvdroxv-v 2_ inamid~
~ol'owing _hQ p-o-Qdur~ of ~xample 1, pa. t D, but substi-,uting N-(t-butyloxycarbonyl)-L-3-hydroxy~-2linQ 'or ~ -butyloxycarbonyl)-D,L-3-hydroxyv21in~ yield~d .hs titl~ compound.
G) (3S)-3-~(t-~utyloxycarbonyl)zmino]-4,4-dim-thvl-l-l~h-nvlmethoxY)-2-azstidinone A solution of 2-methylpyridine (296 ml, 3.0 mole) in methyl isobutyl ketone (2700 ml) under argon at -78C was treated dropwise with 2; chlorosulIonic acid (80 ml, 1.2 mole) ov~r 30 minutes. A''sr the addition, th~ mixture was brought to 25C over 30 minut~s and h~ld thsre anoth~r 30 minu-ss. To this slurry wzs add~d N-(.-bu'_yloxyca~jonyl)-N2-(ph-nylmo'Jhoxy)-L-3-hy~-oxy-valinamide (~38.4 g, 1.0 mole) and stirring continued for two hours. To this mix'~ure was addsd m~_hyl isobu-yl k~_ons (800 ml), K2B4O7-4 ~2 (1222 g, 4.0 molss), and W2 _5_ ( 2700 ml), an _h~
m xturQ was hsa~d _o 70C. Whil~ hsa_ing, ~N
~5 po_zssium hy~-oxid~ (1000 ml, 2 mols) wzs addsd d-opwi-s to -_h_ mix_ur~ ovsr 5 minut~s and ths -- 130810~
mixturQ ~-as hQat~d for another 55 mlnu' es. The layQrS wGre SQ?a-a' e~ ~nd the aquQous ?hZsG ~2s Qxtrac~Qd ~7i_h ~Q0 ~l of mQ_hyl is~bu_~l }G_~ne.
mhG COIllbiIlQd o_yari^ layQ-S we-e ChillQd _0 0C, ~ashQd wi.h 3L oI cold 20o ?ot2ssium ~isul--a~Q~ lL
of iCe water, ~nd a solution of 50 g of so~ium bicarbon te and lO0 g of socium chloridQ in lL of wa-er. The ors~nic lay~r ~-as d-iGd o-~Gr so-ium sul-at~ and con_entrat-d ~n vacuo. The -e~ldue 0 W2S crystallized f_om 1.75 L of isop-o?yl ~her ~o yield 161 g of the title compound, mel~ln~ ~o nt 121-122C, []D = + 21.06 (C = 2.55, r~2Cl2).
~) (35)-3-~(t-3utyloxycarbonyl)amino]-1-r.yd-oxy-'5 4,4-dime'hvl-2-aze'i~ino A solution of 14.77 g (0.0451 mole) of (~s)-3-[(t-butyloxycarbonyl)amino]~4,4-dimethyl-1-(phenylme~hoxy)-2-azetidinone in 15 ml of G_hanol and 85 ml of ethyl acetate ~-as hydrog-nated over 0.75 g of a% palladium-on-carbon catalyst for 1.5 hours at 1 atmosphere. The reaction mixture was filtered and concentrated to give a white solid.
Recrystallization from e_hyl acetate save 8.B2 g of the title compound, m-lting point 148-la9C, ~a]D = +31~ (C = 1, e,hyl acetate).
I) (3S)-3-[(t-3utyloxyca-bonyl)amino]-4,4-dimethyl-2-oxo-l-azetidinyl sul~ate, to_ra~u.yl-ammonium salt Following ~he procedure of Exam~le 1, but substituting (3S)-3-[(t-butyloxycarbonyl)amino]-1-hydroxy-4,4-dime'hyl-2-2zetidinon~ for ( )-3-[('-bu~yloxy-a_Donyl)amlno]-1-nycroxy-4,4-dime'hyl-2-~zQ-idinon- yielded tA- ti le com?ound as a foam.
08~09 - GC~41 _~9_ J) (~S)-~-~mino-.,a-dim~hyl-~-oxo-1-a-~tidinyl sul_at~
-ollo~l~,g _hQ ?~o_Gdu-Q of ~~zm?l~ a_t I, but subs~i~u_ing (~S)-3-[( -~u~ y^a-bo~yl)-~mino~ dimQ=h~ -oxo-' -azG~idin~ l sul.a~Q, .~_ræbu.ylammonium salt ror (i)-3 [(t-bu.yloxy-_a~onyl) zmino] -4, -dim~hyl-2-oxo-1-a~etidinyl sulfa~s, tQt-abutylammonium sal. yiQl~Qd _he ~
compound. Recrystalli-ation of a small sample from ethanol/water gave the li~le c~mpound as a c,ystallin~ solid, melting point 1&0-1C2 (d), [~]D = 74.8 (C = 1, H20).
K) ~3S(Z)]-2-[[[1-(2-.r~mino-~- hi2zolyl)-2-[ [4,C_ dim-~*.yl-2-oxo-1-(sul-ooxy)-3-~zGtidinyl]amin~-2-oxoethylidene]amino]oxy]-2-propenoic acid, di~h^rvlm~_hvl estor, t~abutvlammonium salt To a solution of 2-amino-a-[[[1-(di?heryl-methoxy)~æ bonyl]QthQnyl~oxy]imino]-4-thiazolG-acetic acid (1.423 g, 3.36 mmole) and triethyl-amine (0.404 g, 3.88 mmole) under argon at -30C
was added diphenyl chlorophosphate (0.902 g, 3.36 mmol-). The reaction mixturs was stirrQd at -30C ~or on~ hour to form the mixed anhydride.
~5)-3-Amino-4,~-dimethyl-2-oxo-1-azetidinyl sulfat~ (0.706 g, 3.36 mmole) was dissolvsd in 4 ml of dime~hylformamide at 0C and this solution and tri~'_hylamine (O.gO4 g, 3.88 mmole) w~s simul_aneously added to ~hQ mix~d anhyarids solution at -30C. The r~action mixture was slowly warmed to 0C over a one hour period. The -eaction mi~:'u-e was treat~d wi'h tri~hylamir.e (0.338 g, 3.35 mmole) and .:~an -on_~n'-a'~d ~n va-uo. The resiiu~ was t-eated wi~h wa~r ~o yield a gum which was se?a-ated ~-om _h~ a~uaous ~ l3~o8~9 GC241 la~Qr and washQd ~i_h more wzter. mhe gum was dissolved in 100 ml of me~hvlGnQ chlo-ide an~
sha};Qn wi_h 2 solution of tetrabutvlamm~nium h-~rogen sulratQ (1.14 g, 3.36 mm~lQ) 'n 30 ~l o--water. ~;aQ orgar.i_ ?hasQ ~2s se?a-a_Q~ and washe~
~hree -imes ~ h water, dried over sodium sul-atG
and e~a~orated to a foam. This ozm was dis~olvQd in 30 ml of mGthylenQ _hl~-ide an~ dilu-~d -~120 ml with ethyl acetate. The title compoun~
-rystallized zs 1.73 g of a wh~e solid, meltin~
?oint 170-172C.
L) [35(Z)]-2-[[[1-(2-Amino-_-~hiazolyl)-2-[~A,4-dime hyl-2-oxo-1-(sulfooxy)-3-aze_idir.yl]&mino]-2-oxoe_hvlidQnelamlnolo~vl-~-?-o?Qnoic a-id A solution of [35(Z)]-2-[[[1-(2-amino- -~hiazolyl)-2-[[4,4-dim~'_hyl-2-oxo-1-(sul~ooxy)-3-zzetidinyl]amino~-2-oxoe hyliiQne]ar.lno]oxy~-2-prop~noic acid, diph~nylmethyl estcr~ tetrabu,yl-ammonium salt (2.17 g, 2.54 mmole) in methylene chloride (24 ml) and anisole (1 ml) at -12C was treated with trifluoroacetic a~id (8 ml) and the reaction mixtu_e was stirred at -10C under argon for 1 hour. ~he mixture was tr-at~d dropwise wi_h 2~ 60 ml of ethyl a-et-~_- znd ',he ~~maining slurry stirred for 20 minu'es and 'hen ~iltered and washed with e-~hyl ac~tate and he~an-. After d ying in air, ~hQ solid wzs slurried wi'~h 50 ml of water at 20C an~ crystals .ormed within a _ew minutes. After c;ys'allization, the solution was filtered and the solid washed wi'h water and dried ~'n va-uo to give 0.9 g of 'he title sompound, m-lting point l G-170, a~^.
r~:~m~ 3 (Z)-~ [ [l~ r.ino-A-thia~olyl)- -o~:o-'`-[ [2-o~o-l-(sul~oo~:y)-l-a..2s~iro[3.3]he?.-3-yl]ami;lo]-~ ;r l i 2 ~ ~. '~ r l--~--~--0 2 ~ ~10 i C 2 _ i d -3uto~ycarbonyl)-a-(1-hydroxy~v~lobu_yl)-_l~_in~, ~^n-~l es_~r _ _ _ .~ solu,ion o- ~iiso?ro~ylamine (9.7 ml, 70 mmoles) in 150 ml of dry tet~ahydrofuran at lo -AOOC under argon ~-as tr~ated wi~h 39 ml (64.5 mmoles) of 1.71N n-butylllthium in he~an_ an~ the pale yellow solution stirred at - 0C ,or 20 mi~ul~s. ThG solution was cooled to -73C, znd a solution of 7.gS g (30 mmoles) of N-(~-butoxy-lS -a-bonyl) glycine, benzyl ~ster in 30 ml of d y tetrahydroruran W2s dripped in o~er S minu'es, resulting in a dark yellow solution, and, aIter 20 minu~e3, a slight ~urbidi~y. A,ter 0.5 hou-s, a solution of 2.~2 g (2.0 ml, 34.5 mmoles) of cyclo-butanone in 30 ml of tetrahydrofuran was added.
Th- resulting yellow turbid mixture was stirred at -78C for 15 minutes, then placed in a 0C ice ~a'~h for 2 hour-~. At an internal temperature of -25C (1 hour), ,h~ solution becam- clear, and a~
-13C turned dark purple. It was sti~~-d at 0C
for 0.; hours, then treated with 3.96 g (66 mmoles) of glacial acetic acid in 15 ml of tetrahydrofur2n, siving a turbid, light yellow mix'.u_e. Thi3 W2S poured into S00 ml of cold water and extracted twice with ethyl acetate. The -xtracts were washed with 2% potassium bisulfate, 5% sodium bi_a-bonate, and brine, d-ied (sodium sulfato) and e~-a?o-a_ed to a ~:ni~k oil. ~h-o~,a'o-graphy on 800 ml o_ LPS-1 in hexan~:e_hyl a^etate 1~08109 (2:1) and combination of the pro~uct rra~tions (R-= ~9) ga~e 7 8 ~ of ?~odu~t ~s an oil.
-3al_oxvca-~onvl)-~-(1-h~__c~v-v-lc~u~
a'~_ ne ~ u~oxycarbonyl)-~ hydroxycvclobu~yl)-glycine, ber.-yl es er (7.8 g, 23.3 mmoles) W'a hydrogenated at 1 z-mos?here over l.0 g o~ ~C~
palladium on charcoal in 150 ml of a~solu'Q
ethanol for 4 hours at 25~C. The ~_- lys- was filterQd and the solve~t e~apo~a~e~ in v_-uo.
Benzene ~-as added and e~-aporated -wice, .o ~ive 5.0 g of product 25 a hard -0?~.
C) ~'-(3en~yloxy)-N2-('-~u_o~y~a-bonyl)-~-(l-hvdroxv~v^lobutvl)~lvcinamide N-(t-Butoxyca~bonyl)-a-(1-hydroxycyclo~u-yl)-glyc-ne (5.0 g, 20.4 mmOlQS) W25 ~issolved in 150 ml of dry te,rahydrofuran under argon.
- 20 ~ydroxybenzotriazole hydrate (3.12 g, 20.4 mmole) was added, and the mixture was chilled to 0C, and then treated with 4.20 g (20.4 mmoles) of dicyclohexylcarbodilmide. Aft~r 1.75 hours at 0C, a solution o~ 0-b~nzylhydroxylamin~ in 15 ml of t~trahydro~u~zn W23 ad~d, and the mixtur~
stirr-d at 0-25C for 17 hours. The te rahydro-fura~ mixturn wzs '~hen chilled to -10C for 20 minut~s znd .h~ resul~ing solids ~ilte~ed znd wzshQd wi-~h d y ~-ræhyd_o~uran. ~h~ ~il--a-e W23 e~aporated and th- residu~ takQn u~ in ethyl acetate and wzshQd auickly with 2% potzssium bisul'a'e, b-inQ, -% sodium bica~bor.a-~, and brine, th~n d-iQd (so~ium sulfatQ) and ~V2~0- 'e~
'o a fGam. ~-i-u~z~ion wi-h isopropyl Q~hsr ~e ~30B109 GC241 4 . 69 g of produ~t as a whitQ solid, mQlt~ng ?o~nt o5-97c .
~) '-(3-r._ylo~:~)- 3 - [ ( _-~u ~^~:y_~ _~o~l)am~
o~: 3 - 1 - z ~ as~i~or3.3lhQ~tan~
~ '-53QnzyloY.y)-N2-(t-buto~:yca~bonyl)-~hy~-cxy_y-lobutyl)glycinamid~ (3.50 g, 10 mmol~) in ~0~ ml of cry tetran~dro u_an ât 0C u~iQr argon was treatQd with 2.4 ml (15 mmole) of diethyl-azodi~z-boxyla' a~ th~n with a solution of .riphenyl-hos~hine (5.2 g, 20 mmole) ln ~0 ml of ~_^trahydro-uran over 10 minutes, and the mixtur^ s_irred a~
0C Tor one hour. The y~llow color p~-si,'ed so an ad itional 0.52 g (2 mmole) of triph^r.yl-' '5 phJsp~ ^.a ~-as added. Af-er 15 minutes, ^-v-apo~a'_ion ln ~-a~uo gave an oil. Tritu~ation with 100 ml of hexane:e'~hyl acetate (2:1) gave a whi~e solid whi_h w2s filtered. Chromatogra~ny of he ,iltrate on 800 ml of L~S-1 gave product fractior.s [Rf=0.8 in hexane:ethyl acetate (1:1)] contaminated with a close-running impurity which was removed by trituration with isopropyl ether, gi~ing the product as a white solid, 1.07 g, melting point 155-157C.
2;
E) 3-~(t-Butoxycarbonyl)amino~-2-oxo-~-(sulfooxy)-1-az2s~iro r 3.3lhe~t2ne, monosodium salt 1-(genzyloxy)-3-[(t-butoxyca-bonyl)2mino~-2-oxo-'-azaspiro~3.3]hep'ane (1.07 g, 3.22 mmoles) was hydrogenated at 1 atmosph-re in 30 ml of absolute ethanol over 0.4 g of 10% palladium on ~ha~~021 for 3 hours at 2~C. The catalyst wzs -il-e~-d and 'he solvent ~emovQ~ :n va~uo at 10~C 'o give a solid. This was _aken U? in '9 ml 3; of dry ?yridine and '~~a~ed with 1. 4 g (9 mmoles) of pyridine-sulfur trioxide at 25c under argon.
After 4 hours, the volatiles were removed in vacuo, the residue taken up in water, and the pH
(5.40) adjusted to 6.45 with dilute sodium bicarbonate. Passing through a 40 ml Dowex AG50 (K+) column in water eluted the product within 300 ml. Lyophilization gave a white solid, which was chromatographed on HP-20, first in water, then with a gradient increase of acetone (20%). Product fractions were lyophilized to give 0.75 g of product as a white powder.
F) 3-Amino-2-oxo-1-(sulfooxy)-l-azaspiro[3.3]he~tane 3-[(t-Butoxycarbonyl)amino]-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, monosodium salt (0.3 g, 0.87 mmole) was slurried in 2.5 ml of dry dichloro-methane and 1.0 ml of anisole at -10C under ar~on, and then treated with 4.0 ml of trifluoroacetic acid. After 0.5 hour, a solid had formed. After 1.5 hours, 4 ml of dry toluene was added, and the mixture evaporated ln vacuo to give a solid, 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane, which was triturated twice with hexane and dried ln vacuo at 25C for 1 hour.
G) (+)-(Z)-~1-(2-Amino-4-thiazolyl)-2-oxo-2-[[2-oxo-1-(sulfooxy)-1-azaspiro[3.3]hept-3-yl]amino]-ethylidene]amino]oxy]-2-propenoic acid, diphenyl-methYl ester, tetrabutYlammonium salt Following the procedure of Example 2, part K, but substituting 3-amino-2-oxo-1-(sulfooxy)-1-azaspiro[3.3]heptane for (3S)-3-amino-4,4-dimethyl-2-oxo-1-azetidinyl sulfate, yielded the title compound.
GC2~1 --'~ 5--(Z)-[[[1~ ino-~-thi~olyl)-'~-o~:o-2-[[''-oxo-1-(sulfooxy)-l-a,2s?iro[3 3]hQpt-3-~ ami~o]-e_h~lidQnQl2minolox~ ro~Qroi_ a_id .
~ -ing ~hQ p~O_Q~U-~ of -~?l~ _t L, but su~s_i_u__ng (+)-(Z)-[[[1-(2-2minc-~-~niazolyl)-2-oxo-2-[[2-oxo-1-(sulfooxy)-1-azas~iro-[3 3]hept-3-yl]amino]ethyli~ene~amino]oxy]-2-_-opQnoic a^id, diphenylme_hyl ester, .e~rabu~yl-ammonium salt for [35(Z)]-2-[[[1-(2-amino-4-_hiazolyl)-2-[~4,4-dimethyl-2-oxo-1-(sulfooxy~-3-azetidinyl]amino]-2-oxoQfhylidQne]amino]oxy]-2-?ropenoic acid, diphenylme-hyl ester, tetra-bu ylammonium salt and chroma.os-aphing ha preclpi ate from ~he ethyl a~etate dilu.ion on ~-20 rasin instead of re~rystallizing -rom water, yielded tho title compound, melting point 170-200C, dec ~: ;.... .... .
Claims
1. A compound having the formula:
wherein A1 is a carboxyl protecting group, A2 is hyd-rogen or an amino protecting group, and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms.
wherein A1 is a carboxyl protecting group, A2 is hyd-rogen or an amino protecting group, and R3 and R4 are the same or different and each is hydrogen or alkyl of 1 to 3 carbon atoms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000615882A CA1308109C (en) | 1986-01-06 | 1990-10-05 | Intermediates for the preparation of monosulfactams |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US816,475 | 1986-01-06 | ||
| US06/816,475 US4684722A (en) | 1986-01-06 | 1986-01-06 | Monosulfactams |
| CA000524775A CA1308107C (en) | 1986-01-06 | 1986-12-08 | Monosulfactams |
| CA000615882A CA1308109C (en) | 1986-01-06 | 1990-10-05 | Intermediates for the preparation of monosulfactams |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524775A Division CA1308107C (en) | 1986-01-06 | 1986-12-08 | Monosulfactams |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1308109C true CA1308109C (en) | 1992-09-29 |
Family
ID=25671171
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615882A Expired - Lifetime CA1308109C (en) | 1986-01-06 | 1990-10-05 | Intermediates for the preparation of monosulfactams |
| CA000615883A Expired - Fee Related CA1327813C (en) | 1986-01-06 | 1990-10-05 | Monosulfactams |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000615883A Expired - Fee Related CA1327813C (en) | 1986-01-06 | 1990-10-05 | Monosulfactams |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1308109C (en) |
-
1990
- 1990-10-05 CA CA000615882A patent/CA1308109C/en not_active Expired - Lifetime
- 1990-10-05 CA CA000615883A patent/CA1327813C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA1327813C (en) | 1994-03-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5306817A (en) | Process for the stereospecific synthesis of azetidinones | |
| EP0371004A1 (en) | [(1-Alkoxy-1-methyl)-ethoxy]-amines, their preparation and their use for the preparation of 3-acylamino-1-hydroxy-2-azetidinones | |
| US5561227A (en) | Process for the stereospecific synthesis of azetidinones | |
| WO1998009949A1 (en) | Novel acetamide derivatives and protease inhibitors | |
| EP0073061A2 (en) | Optically uniform beta-lactams, their preparation and use in the preparation of antimicrobial beta-lactams, and starting compounds for use in their preparation | |
| EP0096296A2 (en) | 1-Sulfo-2-oxoazetidine derivatives | |
| US5288758A (en) | New urea derivatives, their preparation and their application in therapy | |
| EP0229012B1 (en) | Monosulfactams | |
| CA2036516A1 (en) | Optically active 8-methoxyouinolonecarboxylic acid derivatives, their preparative processes and their intermediates | |
| CA1114821A (en) | Substituted thio-substituted benzoylpropionyl-l- prolines | |
| CA1308109C (en) | Intermediates for the preparation of monosulfactams | |
| CA1283924C (en) | (3s)-3-amino-2-oxo-4,4-dimethyl-1-azetidinylsulfate | |
| GB2137203A (en) | Improvements in or relating to a process for producing b-lactam compounds | |
| FR2581062A1 (en) | O-SULFATE HYDROXAMIC B-LACTAM ACIDS WITH THERAPEUTIC ACTION | |
| JPS6023363A (en) | N-(substituted methyl)-azetidin-2-ones | |
| CA1296343C (en) | [(2,2,2-trichloroethoxy)methoxy)]amine | |
| US4694083A (en) | Certain carbamate ester derivatives forming salts with pyridinium or picolinium cations which are useful as intermediates | |
| KR900002673B1 (en) | Intermediate derivation for monosulfactams and their preparation | |
| KR900004398B1 (en) | Mediate for preparation monosulfactams | |
| CA1338539C (en) | 1-sulfo-2-oxoazetidine derivatives and their production | |
| KR900000738B1 (en) | (3s(z)-2(1-2-amino-4thiazolylyl)-2-(2,2-dimethyl-4 oxo-1(sulfooxy)-3-azetidinyl) amino) oxy) acetic acid and intermediate | |
| US4812564A (en) | Process for preparing 4,4-dialkyl-2-azetidinones utilizing a pyridine (or substituted pyridine) sulfur trioxide complex | |
| KR900001171B1 (en) | (3s)-3-amino-2-oxo-4,4-dimethyl-1-azetidinyl sulfate compound and salts thereof and the preparing process of it | |
| EP0187500A1 (en) | Monobactams | |
| JPS58164573A (en) | Manufacture of 1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-3-indole acetoxyacetic acids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20011001 |