CA1193272A - O-sulfated beta-lactam hydroxamic acids - Google Patents
O-sulfated beta-lactam hydroxamic acidsInfo
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- CA1193272A CA1193272A CA000461837A CA461837A CA1193272A CA 1193272 A CA1193272 A CA 1193272A CA 000461837 A CA000461837 A CA 000461837A CA 461837 A CA461837 A CA 461837A CA 1193272 A CA1193272 A CA 1193272A
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- beta
- lactam
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
ABSTRACT OF THE DISCLOSURE
.beta.-Lactams having the formula:
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl which are useful as intermediates in the preparation of corresponding .beta.-lactams of the formula:
.beta.-Lactams having the formula:
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl which are useful as intermediates in the preparation of corresponding .beta.-lactams of the formula:
Description
O-SULFATED 3-LACTAM HYDROX~MIC ACIDS
, This invention is directed to a novel family of B lactam anti~iotics, and to the use of such compounds as an~i~actexial agen~s.
It has ~een discovexed that the ~ lactam nucleus can ~e biologically activated ~y a sulfa~e (-O-SOe3M~ su~sti~uen~ attache~ ~o the nitroge~ atom in th.e nucleus.
~-Lactams having a sulfate su~stituent in ~he l-posi~ion and an acylamino substitu~nt in the 3-position exhibit activity against a range o~ yram-negative and gxam-positive ~ackeria.
The preferred mem~ers of the noYel family of ~lactam antibiotic~ of this invention are those encompassed ~y the formul.a _z R4 Rl-NH-I ~f R3 ~ O~S03M .
In addition to th~ abov~ described ~lactams ha~ing a sula~e substituen~ in the l~posi~io~
and an acyl~mino ~u~stituent in ~h~ 3~position, this invention also encompasses ~-lactams having a sulfate su~stituent .in the l~position and a~ amino (NH2~ s~s~i~uent,including protected a~ino, in the 3 position.
The preferred compounds of this type have the formula . Ia 12 R~
N~I2-C ~ C R3 0-S0~3M~
These compounds are intermediates useful f~r the preparation of corresponding 3-acylamin~
compounds.
As u~ed in formula~ I and Ia, and th~ough-out ~he ~peeiication, the symbols are as defined belowO
Rl i~ acyl; Ri ls hydrogen, a~ amino protecting group or acyl;
R2 is hydrogen or alkoxy of 1 to 4 carbons;
- R3 and R4 are the same or different and
, This invention is directed to a novel family of B lactam anti~iotics, and to the use of such compounds as an~i~actexial agen~s.
It has ~een discovexed that the ~ lactam nucleus can ~e biologically activated ~y a sulfa~e (-O-SOe3M~ su~sti~uen~ attache~ ~o the nitroge~ atom in th.e nucleus.
~-Lactams having a sulfate su~stituent in ~he l-posi~ion and an acylamino substitu~nt in the 3-position exhibit activity against a range o~ yram-negative and gxam-positive ~ackeria.
The preferred mem~ers of the noYel family of ~lactam antibiotic~ of this invention are those encompassed ~y the formul.a _z R4 Rl-NH-I ~f R3 ~ O~S03M .
In addition to th~ abov~ described ~lactams ha~ing a sula~e substituen~ in the l~posi~io~
and an acyl~mino ~u~stituent in ~h~ 3~position, this invention also encompasses ~-lactams having a sulfate su~stituent .in the l~position and a~ amino (NH2~ s~s~i~uent,including protected a~ino, in the 3 position.
The preferred compounds of this type have the formula . Ia 12 R~
N~I2-C ~ C R3 0-S0~3M~
These compounds are intermediates useful f~r the preparation of corresponding 3-acylamin~
compounds.
As u~ed in formula~ I and Ia, and th~ough-out ~he ~peeiication, the symbols are as defined belowO
Rl i~ acyl; Ri ls hydrogen, a~ amino protecting group or acyl;
R2 is hydrogen or alkoxy of 1 to 4 carbons;
- R3 and R4 are the same or different and
2~ each is hydrogen or alkyl; and M~ is hydrogen or a cationO
Lis~ed below are definitions of V~EioU5 terms us~d to descxibe the ~lactams o this in~en-tion. These deinitions apply to the te~ms as they are used throughou~ ~he spe~ifi-cation (unless they are o~hexwi~e lLmi~ed in specific instances~ either individually or as paxt of a larger group.
2~2 The terms "alkyl" and "alkox~" refer to both straight and branched chain groups. Those groups haviny l to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cyc]oalkenyl" refer to cycloalkyl and cycloalkenyl groups having 3,4,5,6, or 7 carbon atoms.
The term "alkenyl" refers to both` straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "protected carboxyl" refers to a carboxyl group which has been esteri~ied with a conventional ester protecting group. These groups are well known in the art; see, or example, United States patent 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydr~l and t-butyl esters.
The term "acyl" includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, of course, preferred, but this preference should no~ be viewed as a limitation of the scope of this inve~tion. Exemplary acyl groups are those acyl groups which have been used in ~he past to acylate ~-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and deriva-tives; see, for example, Cephalosporlns and Penicillins, edited by Flynn, Academic Press (1972)~ German Offenlegungsschrift 2,716,677 published October 10, 1978, Belgian patent 867,994, published December 11, 197 United States patent 4~152,432, issued _4_ ;
May 1, 1979, United States patent 3,971,778, issued July 27, 1976, United States patent 4,172,199, issued October 23, 1979, and British patent 1,348,894, published March 27, 1974.
S The following list of acyl groups is presented to further exempllfy the term "acyl"; it should not be regarded as limitiny that term~ Exemplary acyl groups are:
(a) Aliphatic groups having the formula wherein R5 is alkyl; cycloalkyl; alkoxy; alkenyl;
cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl su~stituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups.
(b) Carbocyclic aromatic groups having the formula R6~ (CH2 ) r~ C
6~ ~ R2 R~ ~ CH2-O-C- , ~ ~ 3 ~a~
. W ~f~ GC159 R6 ~O-CH -C -, R6~R~ 1, S-CH2-C- or j~; ~R 8 ~=~CH2-S -C- , wherein n is 0, 1, 2 or 3; R6, R7, and R~ each is independently hydrogen, halogen, hydroxyl, nitro, amlno, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Rg is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sul~oamino salt, azido, halogen, hydrazino, alkylhydrazlno, phenylhydrazino, or ~(alkylthio)thioxomethyl~thio.
Preferred carbocyclic aromakic acyl groups include those having the formula CH
CH `
.H2NH2 ~3~
o HO ~ CH-C- IRg is preferably Xg a carboxyl salt or sulfo sal t) and ~ CH-C- (.Rg is prererably 15a carboxyl salt or sulfo salt).
(c) Heteroaromatic yroups having the :f ormula o . . Il ~0- ( CH2 ) n~C~ ' ~CH-~-Rg .o Rlo O-CH~2 -C- , ..
Rlo-s-(:~H2-c- ~ or o O
R~.o~(;~C~ ~ -wherein n is 0, 1, 2 or 3; R9 is as def ined above; and Rlois a substituted or unsubstituted 5 ,6-or ~membered heterocyclic ring containing 301, 2, 3 or 4 (preferably 1 or 2) nitrogen, - oxygen and suLfur atoms. Exemplary .heterocyclic ~9 ~7 ~ GC159 rings are thienyL, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, morpllolinyl, pyrimidinyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoro-methyl, alkyl of 1 to ~ carbon atoms, or alkoxyof 1 to 4 carbon atoms~
Preferred heteroaromatic acyl groups include those groups o~ the above formulas wherein R1Ois 2-amino-4 thiazolyl, 2~amino--5-halo- ~
4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-thiad~azol-5-yl, 2-thienyl or 2-furanyl.
(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl)-carbonyl~amino]arylacetyl groups having the formula 1~ li , 11 ~
~ C~CH-NE~WC~N N~R12 R
., 11 h~
O O
wherein R~ is an aroma~ic group (includlng carbocyclic aromatics such as those of -the formula 6 ~ R8 ~5 and heteroaromatics as included within the definition of Rl~and ~ is alkyl, substituted alkyl (wherein ~he alkyl group is substi~uted with one or more halogen, cyano, nitro, amino or mercapto groups)~ arylmethyleneamino (i.e , -N=CH Rll wherein Rll is as defined above), arylcarbonylami~o O
(l.e., ~NI~-C-R11 wherein Rllis as defined ~bove) or alkylcarbcnylamino.
^` (iC~l~Y
Preferred [~14-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino~arylacetyl groups include those wherein R12 is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups having the formula O , .
~C-C=N-O-R13 Rll wherein ~llis as defined above and R13 is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-O
carbonyl (l.e., -~-NH-Rll wherein Rllis as defined above) or substituted alkyl (wherein t~e alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rl~, carboxyl (includin~ salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenyLmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, J hydroxy (phenyLme~hoxy)phosphinyl, or dialkoxy phosphinyl substituents).
Preferred (substituted oxyimino)aryl~
acetyl groups include those wherein Rl1is 2-amino-4-thlazolyl. Also preferred are those groups wherein R13 is methyl, ethyl, carboxy~
methyl, ox 2-carboxyisopropylO
(f) (Acylamino)arylacetyl ~roups having the formula O o -~ cH-N~c-~l4 R~
wherein Rllis as defined above and R14 is 932'72 GG 159 _g_ ~ (CH2 ) n~~ ~ amino, alkylamino, 5 (cyanoalkyl ) amino, amido, alkylamido, (cyanoalkyL ) -amido, -CH2-NH-J ~ ~ , -CEi~CH2-C-NH-CH3 , S02-N (CH2~c~2~0H) 2 ~ ~CH3 ~ .
OH
.
OH OH
~ ~N~ N ~ )l 20~ N ~ , or ~ ~ N ~ N~_JN~CE~ O
Pre~erred (acylamino)arylacetyl groups of the above formula include those groups wherein ~4 is amino, or amido. Also preferr~d are those groups wherein R11is phenyl or 2-thienyl.
(g ) [ [ [3~Substituted-2-oxo-1-imidazoli-dinyl ] carbonyl~ aminol arylacetyl groups having the formula o o Ol /C ~
-C-CH-N}~-C-N N-R15 RLl CH 2--CH 2 '~ GC159 wherein Rllis as defined above and R15 is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., -N=CH-~1wherein R11is as defined above), -C-R16 (wherein R16 is hydrogen, alk~l or halogen substituted alkyl), aromati.c group (as defined by R]1above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen,cyano, nitro, amino or mercapto groups).
Preferred [[3-substituted-2-oxo-1-imidazoli-dinyl]carbonyl]aminolarylace-tyl groups of the above formula include those wherein Rllis phenyl or 2-thienyl. Also preferred are those groups wherein Rl's is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-fur~lmethyleneaminoO
The term "cation", as used throughout the specification, refers to any positively charged atom or group o atoms. The "-O-S03M " ~u~stituent ~0 on the nitrogen atom of the B-lactams of this invention encompasse~ all sulfat~ salts.
Pharmaceutically acceptable salts are, of course, preferred, although other salts are also useful in purifying the ~roducts of this invention or as intenne~iates for the preparation of pharmaceutically acceptable salts. The cationic portion of the sulfonic acid salts of this inve~tion can be obtained from either organic or inorganic bases. Such cationic portion includes, but is not limited to, the following ions: ammonium; substituted ammonium, such as alkylammonium (~ , tetra n butylammonium, referred to herelnafter as tetrabutylammonium);
alkali metal, such as lithium, sodium and potassi~m;
alkaline earth metal, such as calcium and magnesium;
pyridinium; dicyclohexylammonium; hydrabaminium;
benzathinium; N-methyl~D~glucaminium.
As set forth in formula I, and in the definitions following formula I, M can be hydrcgen e~ially ~en the Rl group contams a basic function. Such compounds are often re~erred ~o in the art as "inner salts" by virtue of a positive and negative charge in the molecule.
Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases water of hydration may be formed. This invention co~-templates stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes suh as lyophiliaation~
~ -Lactams having a sulfate substituent in ~he l-position and an amino or acylamino substituent in the 3-position contain at least one chiral center - the carbon atom (in the
Lis~ed below are definitions of V~EioU5 terms us~d to descxibe the ~lactams o this in~en-tion. These deinitions apply to the te~ms as they are used throughou~ ~he spe~ifi-cation (unless they are o~hexwi~e lLmi~ed in specific instances~ either individually or as paxt of a larger group.
2~2 The terms "alkyl" and "alkox~" refer to both straight and branched chain groups. Those groups haviny l to 10 carbon atoms are preferred.
The terms "cycloalkyl" and "cyc]oalkenyl" refer to cycloalkyl and cycloalkenyl groups having 3,4,5,6, or 7 carbon atoms.
The term "alkenyl" refers to both` straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "protected carboxyl" refers to a carboxyl group which has been esteri~ied with a conventional ester protecting group. These groups are well known in the art; see, or example, United States patent 4,144,333, issued March 13, 1979. The preferred protected carboxyl groups are benzyl, benzhydr~l and t-butyl esters.
The term "acyl" includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are, of course, preferred, but this preference should no~ be viewed as a limitation of the scope of this inve~tion. Exemplary acyl groups are those acyl groups which have been used in ~he past to acylate ~-lactam antibiotics including 6-aminopenicillanic acid and derivatives and 7-aminocephalosporanic acid and deriva-tives; see, for example, Cephalosporlns and Penicillins, edited by Flynn, Academic Press (1972)~ German Offenlegungsschrift 2,716,677 published October 10, 1978, Belgian patent 867,994, published December 11, 197 United States patent 4~152,432, issued _4_ ;
May 1, 1979, United States patent 3,971,778, issued July 27, 1976, United States patent 4,172,199, issued October 23, 1979, and British patent 1,348,894, published March 27, 1974.
S The following list of acyl groups is presented to further exempllfy the term "acyl"; it should not be regarded as limitiny that term~ Exemplary acyl groups are:
(a) Aliphatic groups having the formula wherein R5 is alkyl; cycloalkyl; alkoxy; alkenyl;
cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl su~stituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio, or cyanomethylthio groups.
(b) Carbocyclic aromatic groups having the formula R6~ (CH2 ) r~ C
6~ ~ R2 R~ ~ CH2-O-C- , ~ ~ 3 ~a~
. W ~f~ GC159 R6 ~O-CH -C -, R6~R~ 1, S-CH2-C- or j~; ~R 8 ~=~CH2-S -C- , wherein n is 0, 1, 2 or 3; R6, R7, and R~ each is independently hydrogen, halogen, hydroxyl, nitro, amlno, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms or aminomethyl; and Rg is amino, hydroxyl, a carboxyl salt, protected carboxyl, formyloxy, a sulfo salt, a sul~oamino salt, azido, halogen, hydrazino, alkylhydrazlno, phenylhydrazino, or ~(alkylthio)thioxomethyl~thio.
Preferred carbocyclic aromakic acyl groups include those having the formula CH
CH `
.H2NH2 ~3~
o HO ~ CH-C- IRg is preferably Xg a carboxyl salt or sulfo sal t) and ~ CH-C- (.Rg is prererably 15a carboxyl salt or sulfo salt).
(c) Heteroaromatic yroups having the :f ormula o . . Il ~0- ( CH2 ) n~C~ ' ~CH-~-Rg .o Rlo O-CH~2 -C- , ..
Rlo-s-(:~H2-c- ~ or o O
R~.o~(;~C~ ~ -wherein n is 0, 1, 2 or 3; R9 is as def ined above; and Rlois a substituted or unsubstituted 5 ,6-or ~membered heterocyclic ring containing 301, 2, 3 or 4 (preferably 1 or 2) nitrogen, - oxygen and suLfur atoms. Exemplary .heterocyclic ~9 ~7 ~ GC159 rings are thienyL, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, morpllolinyl, pyrimidinyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoro-methyl, alkyl of 1 to ~ carbon atoms, or alkoxyof 1 to 4 carbon atoms~
Preferred heteroaromatic acyl groups include those groups o~ the above formulas wherein R1Ois 2-amino-4 thiazolyl, 2~amino--5-halo- ~
4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2,4-thiad~azol-5-yl, 2-thienyl or 2-furanyl.
(d) [[(4-Substituted-2,3-dioxo-1-piperazinyl)-carbonyl~amino]arylacetyl groups having the formula 1~ li , 11 ~
~ C~CH-NE~WC~N N~R12 R
., 11 h~
O O
wherein R~ is an aroma~ic group (includlng carbocyclic aromatics such as those of -the formula 6 ~ R8 ~5 and heteroaromatics as included within the definition of Rl~and ~ is alkyl, substituted alkyl (wherein ~he alkyl group is substi~uted with one or more halogen, cyano, nitro, amino or mercapto groups)~ arylmethyleneamino (i.e , -N=CH Rll wherein Rll is as defined above), arylcarbonylami~o O
(l.e., ~NI~-C-R11 wherein Rllis as defined ~bove) or alkylcarbcnylamino.
^` (iC~l~Y
Preferred [~14-substituted-2,3-dioxo-1-piperazinyl)carbonyl]amino~arylacetyl groups include those wherein R12 is ethyl, phenylmethylene-amino or 2-furylmethyleneamino.
(e) (Substituted oxyimino)arylacetyl groups having the formula O , .
~C-C=N-O-R13 Rll wherein ~llis as defined above and R13 is hydrogen, alkyl, cycloalkyl, alkylaminocarbonyl, arylamino-O
carbonyl (l.e., -~-NH-Rll wherein Rllis as defined above) or substituted alkyl (wherein t~e alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic group (as defined by Rl~, carboxyl (includin~ salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenyLmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, J hydroxy (phenyLme~hoxy)phosphinyl, or dialkoxy phosphinyl substituents).
Preferred (substituted oxyimino)aryl~
acetyl groups include those wherein Rl1is 2-amino-4-thlazolyl. Also preferred are those groups wherein R13 is methyl, ethyl, carboxy~
methyl, ox 2-carboxyisopropylO
(f) (Acylamino)arylacetyl ~roups having the formula O o -~ cH-N~c-~l4 R~
wherein Rllis as defined above and R14 is 932'72 GG 159 _g_ ~ (CH2 ) n~~ ~ amino, alkylamino, 5 (cyanoalkyl ) amino, amido, alkylamido, (cyanoalkyL ) -amido, -CH2-NH-J ~ ~ , -CEi~CH2-C-NH-CH3 , S02-N (CH2~c~2~0H) 2 ~ ~CH3 ~ .
OH
.
OH OH
~ ~N~ N ~ )l 20~ N ~ , or ~ ~ N ~ N~_JN~CE~ O
Pre~erred (acylamino)arylacetyl groups of the above formula include those groups wherein ~4 is amino, or amido. Also preferr~d are those groups wherein R11is phenyl or 2-thienyl.
(g ) [ [ [3~Substituted-2-oxo-1-imidazoli-dinyl ] carbonyl~ aminol arylacetyl groups having the formula o o Ol /C ~
-C-CH-N}~-C-N N-R15 RLl CH 2--CH 2 '~ GC159 wherein Rllis as defined above and R15 is hydrogen, alkylsulfonyl, arylmethyleneamino (i.e., -N=CH-~1wherein R11is as defined above), -C-R16 (wherein R16 is hydrogen, alk~l or halogen substituted alkyl), aromati.c group (as defined by R]1above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen,cyano, nitro, amino or mercapto groups).
Preferred [[3-substituted-2-oxo-1-imidazoli-dinyl]carbonyl]aminolarylace-tyl groups of the above formula include those wherein Rllis phenyl or 2-thienyl. Also preferred are those groups wherein Rl's is hydrogen, methylsulfonyl, phenyl-methyleneamino or 2-fur~lmethyleneaminoO
The term "cation", as used throughout the specification, refers to any positively charged atom or group o atoms. The "-O-S03M " ~u~stituent ~0 on the nitrogen atom of the B-lactams of this invention encompasse~ all sulfat~ salts.
Pharmaceutically acceptable salts are, of course, preferred, although other salts are also useful in purifying the ~roducts of this invention or as intenne~iates for the preparation of pharmaceutically acceptable salts. The cationic portion of the sulfonic acid salts of this inve~tion can be obtained from either organic or inorganic bases. Such cationic portion includes, but is not limited to, the following ions: ammonium; substituted ammonium, such as alkylammonium (~ , tetra n butylammonium, referred to herelnafter as tetrabutylammonium);
alkali metal, such as lithium, sodium and potassi~m;
alkaline earth metal, such as calcium and magnesium;
pyridinium; dicyclohexylammonium; hydrabaminium;
benzathinium; N-methyl~D~glucaminium.
As set forth in formula I, and in the definitions following formula I, M can be hydrcgen e~ially ~en the Rl group contams a basic function. Such compounds are often re~erred ~o in the art as "inner salts" by virtue of a positive and negative charge in the molecule.
Some of the compounds of this invention may be crystallized or recrystallized from solvents containing water. In these cases water of hydration may be formed. This invention co~-templates stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes suh as lyophiliaation~
~ -Lactams having a sulfate substituent in ~he l-position and an amino or acylamino substituent in the 3-position contain at least one chiral center - the carbon atom (in the
3~position of the B-lactam nucleus) to which the amino or acylamino substituent is attached.
This invention is directed to those ~lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the ~-lactam nuclues is the same as the configuration at the carbon atom in the 6-position o naturally occurring penicillins (~ ~, penicillin G) and as th2 con~iyuration at the carbon atom in the 77position o na~urally ~32~ ~Cl59 occurring cephamycins (e.g., cephamycin C).
With respeet to the preferred ~-lactams of formulas I and Ia, the structural formulas have been drawn to show the stereochemistry at the chiral center in the 3-posi~ion. Because of the nomenclature convention,those compounds o formulas I and Ia wherein R2 is hydrogen have the S-eonfiguration and those compounds of formulas I and Ia wherein R2 is alkoxy have the R configuration.
Also included within the scope of this invention are raeemic mixtures which contain the above-deseribed ~-laetams.
~,~
0~ GC159 13~
~ -Lactams having a sul~ate (-O-SO3M ) substituent in the l-position and an acylamino substituent in the 3-position have activity against a range o~ gram-n gative and gram~positive organisms. The sulfate substi~uent is essential -to the activity o~ the compounds of this invention.
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 domestica~ed animals (e.g., dogs, cats, cows, horses, and the like) ~nd humans.
For aombating bactexlal 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 about 14 mg/kg/day to about lO0 mg/kg/day. All modes of adminis-tration which have been used in the past to deliver penicillins and cPphalosporins to the site of the in~ection are also contemplated for use with the novel family o~ Bolactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.
.
~93~ GC159 The B-lactams of thls invention can be prepared from the corresponding hydroxamic acid having the formula II
R2 _4 Rl-NH I l R3 ~C - N-OH.
A compound of formula II can be O-sulfated by reacting the precursor compound with a complex of pyridine and sulfur tr1oxidec The reaction can be run in an organiC solvent ~ preferably pyridineO~ This reaction yields a compound of fo~mula I wherein M~ is pyrldinium ion~ Instead of using a pre-formed complex of pyridine ~nd sulur trioxide, the complex can be formed in situ, e g., using chlorosulfonyltrimethylsilyl . ~ .
ester and pyridine as reagents. Alternatively, a complex of dLmethylformamide sulfur txioxide or 2,6-lutidine-Sulfurtrioxide can be used.
using conventional techniques (~ , ion-exchange resins, crystallization, or ion pair extraction) the pyridinium salt formed by the above procedure can be converted to other salts.
These techniques are also useful for converting the products of formula I or any of the inter~
mediates described herein to other salts.
~9~ GC159 Compounds of formula II can be prepared from an amino acid having the formula III tH~R4 NH2-lH C R3 ~C - OH .
The amino group is first protected with a classical protecting group (~ , t-butoxycarbonyl, benzyloxy-carbonyl, o nitrophenylsulfenyl, etc.), yieldinga compound having the formula XV OH R
~ ` 4 A~NH CH - ~ ;R3 ' ,l - OH.
.In oxmula IV, and throughout the specification, t~e symbol "A" refers to a nitrogen protecting group.
The carboxyl group o a protected amino acid of ormula IV is then reacted with an amine salt having the formula Y-O-NH3Cl, In formula V, and throughout the specification, the symbol "Y" refers to benzyl or pivaloyl. The reaction proceeds in the presence of a coupling agent such as l ethyl~3~3-dimethylaminopropyl)carbodiimide 30 or dicyclohex~lcarbodiimide, and yields a compou~d having the formula ~ 3~7æ GC159 VI
OH
A-NH-f~I - C - R3 ~,C - NH-O-Y.
O
The hydroxyl group o a compound of formula VI
is converted to a leaving group, using, for example, a classical reagent such as methane sulfonyl chloride (methanesulfonyl is referred to hereinater as "Ms").
The fully protected compound having the formula VII OMs , A~NH CH - C`- ~
~C - NH`O-Y
is cyclized by treatment with base, e.~., potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditionsj and yields a compound having the formula VIXI . R4 A-NH~fH I ~3 C - N O~Y .
Alternatively, cyclization of a compound of formula VI can be accomplished wit~out irst co~verting th~ hydroxyl group to a leaving groupO
. ~932 ~ 2 GC159 ~17-Treatment of a compound o~ formula VI with triphenylphosphlne and d ethylazodicarboxylate, yields a compound of formula VIII.
Both of the methods disclosed above for ring closure of a compound of formula VI re~ult in the inversion of the stereochemistry of the R3 and R4 substituents.
Deprotection of the 3-amino substituent of a compound of formula VIII can be accomplished using art-recognized techniques. If, for example, the protecting group is t-butoxycarbonyl, trifluoroacetlc acid can be used to deprotec~
the amino group. If the protecting group is benzyloxycarbonyl catalytic (_ ~, palladiu~ on 15 charcoaL) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, ~toluenesulonlc acid can be u~ed in combination with ~thiocresol. The dep~otected compound has the ~ormula 2~
IX _4 NH~-CH - C ~ R3 ~C - N-O-Y .
Well known acylation techniques can be used to convert a compound having the formula IX
to a compound having the formula Rl-NH f ~ I R3 C - N-O-Y .
27:~
GClS9 Exemplary techniques include reaction wlth a carboxylic acid (Rl-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions wi-th a carboxylic acid procee~ most readily in the presence of a carbodiimide such as dicyclohexylcarbodiLmide and a substance capable o~ forming a reactive intermediate 1n situ such as N hydroxybenzotriazole or 4-dlmethyl-aminopyridine. In those instances wherein the acyl group (Rl) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect these functional groups, then carry out the acylation reaction, and inally deprotect the resulting productO
Conversion of a compound of ormula X
to the corresponding compound having a 3 alkoxy substituent can be accomplished by first halogenating the amide nitrogen to obtain a compound having the formula ~0 Rl-N-~IH I R3 ~C - N~O-~ ~
Reagents and procedures for N chlorinating amides are known in the art. Exemplary reagents axe tert.~butyl hypochlorite, sodium hypochlorite, and chlorine. The reaction can be run in an organic solvent (~ , a lower alkanol such as methanol) or in a two phase solvent system (~ water/me~lylene chloride) in the presence of a ~ase such as sodiu~
borate decahydrate. The reaction is preerably run at a reduced temperature.
Reaction of a compound of formula XI
with an alkoxylating agent, e , an alkali metal alkoxide, yields a compound (in combination with its enantiomer) having the formula XII
0-alkyl R4 R -NH~C ~ C-R
The reaction can be run in an organic solvent, e.q., a polar organic solvent such as tetxa-hydrouran, at a reduced temperature.where Rl functions as an amino protecting group, it can be removed by con~entional pro~edure~ to give the amino derivative.
Alternatively, a compound of formula X
can be converted to a compound o formula XII
using a single step proceduxe. The alkoxylatiny agent can first be mixed with a compound of 2G formula X and the N-chlorinatlng rea~ent then added to the reaction mixture.
Reduction of a compound of formula X
or XII to yield the corresponding compound of formula II, iue., Rl-NH-C - C-R
O~C N~OH
can be accomplished by catalytic hydrogenation ox, if Y is pivaloyl, by treatment with a base such as sodium sulfide or sodium hydroxide.
Alternatively, ~ benzyloxycarbonyl-~aminoxy-D-alanine, methyl ester hydrochloride, or other compounds having the "NH-0~" grouping, 2~2 .
can be used in place of an amine salt o formula V
in the above described synthesis.
An alternative synthesi~ for the compounds of this invention wherein R2 is hydrogen comprises preparation o~ a compound of formula VIII followed by deprotection o the l-hydroxy group of that co~pound to yield a compound having the formula -A-MH-CH - C-R
0~C N-O~ .
Deprotection can be accomplished using art~recognized procedures, ~ ~, if Y is pivaloyl, treatment with hydrogen peroxide and a base or treatment with sodium sulfide, or ifY i5 benzyl, by hydrogenolysis.
. Sulfation of a compound of formula IX or XII
using the above-described procedures (lOe., reaction of the precursor compound with a compLex of pyridine and sulfur trioxide, dime~hylformamide and sulfur trioxide or 2,6.lutidine and sulfur trioxide) yields a compound having the formula XIII l2 R~
A-NH-f - C R
C - N-O-S03M~.
O~
Removal of the protecting group "A" from a compound of ~ormula XIII yields a ~ey ~9~
~21-intermediate having the formula XIV l2 _4 NH -C -C - R
~C N-O~S03M
The technique used for removal of the pxotecting group will depend on the particular protectin~
group. For example, i~ A is ~enzyloxycarbonyl, catalytic hydrogenation can be used.
Acylation of an intermediate of formula XIV
using any of the ~echniques described above yields a corresponding product of formula I~
The following examples are specific embodiments of this invention.
.
~9 327 ~ GC159 Example 1 (3S-trans)~4-Methyl-2-oxo-3-[(phenylacetyl)amino]-l-azetidin 1 sulate, ~vridine salt _ _ Y- ' A) N~(Phen lacet l)-L-threonine L-Threonine (3S.7 g) is dissolved in lN
sodium hydroxide (1 liter) and chilled to 5 to -10C. To the cold, mechanically stirred solution is added dropwise phenylacetyl chloride (46.3 g). The reaction mixture is stir.red ~or about 16 hours as the temperature rises to 26C.
The mixture is washed with ether, acidified to pH 2 wi~h hydrochloric acid, and extracted wi~h e~hyl acetate (two times). The combined extracts.
axe dried over sodium sulate and concentrated under reduced pressure until crystalline solids form. Ether is added to the mixture and the c~ystals are collected (34.8 g); melting point 161~163C.
B) N2~Phenylacet l)-N-( henvlmethox )~-threoninamide N-(Ph2~ylacetyl)-L-threonine (9.5 g) is suspended in water (approximakely 50 ml), and a solution of O~benzylhydroxylamine hydrochloride (7.04 g) in water (50 ml) is added. The pH of the stirred mixture is adjusted ~o 4.2 with lN
potassium hydroxide~ and a solution o~ 8.43 g o 1-ethyl-3-(3-dimethylaminopropyl)carbodilmide hydrochloride in water (50 ml~ is added. The p~
is maintained at 4 . 2 with lN hydrochloric acid .
~ ~ ~ GC15~ -After thirty minutes an oily precipitate is present in the reaction vessel. The product is partitioned ~etween ethyl acetate and brine, and the organic layer is then dried over sodium sul~ate and concentrated to a solid (.8.7 g).
`C) (3S-trans)-4-Methyl-3-(phenylacetyl)-l-_ To a cold (.0C~ solution of N (phenylacet~11-N-(phenylmethoxy)-L-threoninamide (7.5 g) in dry tetrahydrofuran (200 ml) is added diethyl-azodicarboxylate (4.2 g) followed ~y triphenyl-phosphine (6.34 g). The reaction mixture is stirred for about 16 hours at 26C under nitrogen.
The solven~ is then removed, and ~he residue chromatographed on silica gel (ether~hexane) to afford the title compound (200 g) white solids.
R~crystallization from chloroform/hexane affords a purified sample, ~elting point 97099C.
D) (3S trans)~l-Hydroxy4~methyl 3~(phenylacetyl)-amino]-2-azetidinone A solution of (3S-trans)~4-me~hyl 3 (phenyl-__ acetyL) l-(phenylmethoxyJ-2-azetidinone (0.5 g) in ethanol (15 mL) containing O . 250 of lO~
palladium on charcoal is hydrogenated at 26 C
for one hour. The reaction mixture is ~iltered, the catalyst washed with ethanol, and the combined filtrates evaporated to an oily residue. Ether (approxLmately lO ml) is added and the resulting ~9 ~7 ~ GC153 solids are hardened and collected yielding 0.34 gof the title compound, melting point 118 135 C, dec.
AnalO Calc'~. for C12Hl4M203:
C, 61.52, H, 6.02; N, 11.96 Found:
C, 61.06; H, 6.03; N, 1]..80 Ej (3S trans)-4 Methyl-2-oxo-3-[(phenylacetyl)~
__ amino~ azetidin~l sul~ate, ~yridine salt To a solution of (3S-trans)-l-hydroxy-4 methyl-3-~(phenylacetyl)amino]-2-azetidinone (0.225 g) in dry pyridine (9 ml) is added molecular sieves 4A (1 ml) followed by pyridine-sulfur txioxidP complex ~0.61 g)0 The rPaction mixture is stirred under nitrogen or five hour5 .
at 26C, f~lterad and concentrated under reduced pxessure. Purification on HP~20 resin (water/
acetone) affords 0013 y of ~he produot as a hygroscopic solid.
Anal. Calc'd. for C H gN30 SH20:
C, 49.62; H, 5014; N, 10c21; S, 7~79 Found:
C, 50.37; H, 5007, N, 10~32, S, 7.73 7~
Example 2 [3S-[3~(R*)4Bl]-3-[[~(4-Ethyl-2,3-di.oxo-l-~iperazlnyl) , carbonyl]amino]pherlylacetyl]amino~-4-methyl-2-oxo-l-azetidinyl sulfate, pyridine aalt (1:1) A) 2-Nitrophenylthio-L-threonine L~threonine (11.9 g) is added to dioxane (125 ml) and ZN sodium hydroxide (50 ml). To the vigorously stirred solution, o-nitrophenyl-sulfenyl chloride (20.9 g) is added in ten equalportions over ifteen minutes, while 2N sodium hydroxide ( 60 ml) is slowly added dropwise. -After five more minutes the reaction mixture is diluted with water (400 ml) and acidified to pH 2.5 wi~h .
10% potassium hisulate. The organic layer is immediately ex~racted with ethyl acetate (three 200 ml portions), and the combined extracts are dried over sodium sulfate, and then concentrated to an oil. The product crystallizes on scratching (20.0 g). Rec~ystallization of 17 g from acetone/hexane affords g.5 g o crystals, melting point 145-148C which are stor~d in a freezer and used promptl~.
B) MZ-[(2-NitroPhenYl)thio] N~(phenylmethoxY) ~5 ~
L-threoninamide .
2-Ni~rophenylthio-Lrthreonine (39.0 g) and O-benzylhydroxylamine hydrochloride (22.92 g) are suspended .in water (500 ml) and with VigOEOuS
stirring the pH is adjusted to 4 . 2 with lN sodium hydroxide. ~ solution of l~ethyl-3~(3-dimethyl -26- .
aminopropyl)carbodiimide hydrochloride in water (100 ml) is added portionwise, while the pH is controlled at 4.2 with addition of 10~ potassium bisulfate. The addition lasts five minutes, and stirring and pH control is continued ~or an additional thirty minutes, whereupon a heavy granular precipitate is present. The reaction mixture is extracted with ethyl acetate (foux 300 ml portions) and the com~ined extracts are dried over sodium sulfate and concentrated to an oil (approximately 50 g).
Chromatography on SilicAR CC-7 (2 kg/
methylene chloride~50% methylene chloride/ethyl-acetat~) affords the product as a foam tl9.5 g).
A portion is crystallized and recrystallized from acetone/hexane to provide an analytical sample, melting point 130-133~C.
C) (3S-trans)-4-Methyl-3-~L(2 nitrophenyl~thio~-To a cold solution (0C) of N -[(2-nitro~
phenyl)thio]-N-~phenylmethoxy)-L~hreoninamide ~9.4 g) in pyridine (34 ml) is added methane~
sulfonyl chloride (8.58 g). After two hours at 0C the mixture is poured into ice water (100 ml) and extracted with ethyl acetate (five ~G0 ml portions). The extracts are washed with ice cold 10~ po-tassium bisulfate (four 100 ml portions), dried over sodium sulfate, and concentrated under reduced pressure without heat, yielding 9.6 g of a residue.
A solution of the residue in acetone (125 ml), is added dropwise over thirty-five minutes to a refluxing mixture o~ anhydrous potassium carbonate (10 g) and acetone (approximately 600 ml). Ater 2.5 hours the mixture is cooled to 26C, ~iltered, and evaporated ~o a foam.
Chromatography on SilicAR CC-7 (methylene chloride/
hexane 9:1~methylene chloride)- affords the product as a clear oil (2.15 g). Crystallization and recrystallization from chloroform/hexane produces an analytical sample, melting point.
97 laOC.
D) (3S trans) 3-Amino-4 methyl-l (phenylmethoxy)~
Z azetidinone,toluenesulfonate . . , . . _ To a stirred solution of (3S-trans)~4-methyl~3-L[(2-nitrophenyl~thio~amino]-1-(phenyl-methoxy)-2-azetidinQne (1.07 g) in methylene chloride (20 ml) is added ~-tolusnesulfonic acid (0.57 g) and ~thiocresol (0.74 g). The reaction mixture i5 stirred under nitrogen for tw~ hours, whereupon the solvents are removed in acuo, and the residue is triturated with ether (four 25 ml portions), to afford 0.9 g of the title compound.
~93272 GC15~
E) (3S-trans)-3-[[[l(4-Ethy1-2,3-dioxo-1 _ i erazinvl)carbonYl]aminolphenylacetyl]amino~-4-~ ~ ,, ., ~
methy~-l-(E~nYlmethoxyL__-azetidinone A suspension of ~-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]benzeneacetic acid (0.879 g) hydroxybenzotriazole (0.42 g), and dicyclohexylcarbodiimide (0.56 g), in dimethyl-formamide (15 ml) is stirred at 26 C ~or one hour, at which point a solution of (3S-trans)-3-amino-4-methyl-l~(phenylmethoxy)-2-azetidinone, toluenesulfonate (0.95 g) and diisopropylethyl-amine (0.44 ml) in dimethylformamide (5 ml) is addedO The reaction mixture is stirred at room t~mperature for about 16 hours, then poured i~to water (lOO~ml) and extracted with ethyl acetate (thLee 100 ml portions). The combined organic ~extracks are washed with wa~er (three 100 ml portions) and aqueous sodium bicarbonate solution (one 100 ml portion), then dried over sodium 2Q sulfate and concentrated und~r reduced pressure to a semi~solid residue. Liquid chromatography (ethyl acetate) affords the desired product as a foam ~0.599 g). Recrystallization from chloroorm/isopropyl ether ,yields the title compound, melting point 100~105C.
~ 3%7~ GC159 F) (3S-trans)-3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]phenyla etyl~amino]-l-hydroxy-4-methyl-2-azetidinone (3S-trans)-3-[~[~(4~ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino~-4-methyl l-(phenylmethoxy)-2~azetidinone (0.270 g~ is dissolved in ethanol (25 ml) and hydroyenated over 10 palladium on charcoal catalyst (130 mg) ~or two hours. The reaction mixture is filtered and concentrated to a solid (0.220 g)~
G) ~3s~[3u(R*)~4B]~3-[I[~(4-Et-hyl-2~3-di m 15 salt (1~
To a solution of (3S trans)-3~[[[[(4~ethyl=
2,3 dioxo~l piperazinyl)carbonyl~aminoi l~hydroxy~
This invention is directed to those ~lactams which have been described above, wherein the stereochemistry at the chiral center in the 3-position of the ~-lactam nuclues is the same as the configuration at the carbon atom in the 6-position o naturally occurring penicillins (~ ~, penicillin G) and as th2 con~iyuration at the carbon atom in the 77position o na~urally ~32~ ~Cl59 occurring cephamycins (e.g., cephamycin C).
With respeet to the preferred ~-lactams of formulas I and Ia, the structural formulas have been drawn to show the stereochemistry at the chiral center in the 3-posi~ion. Because of the nomenclature convention,those compounds o formulas I and Ia wherein R2 is hydrogen have the S-eonfiguration and those compounds of formulas I and Ia wherein R2 is alkoxy have the R configuration.
Also included within the scope of this invention are raeemic mixtures which contain the above-deseribed ~-laetams.
~,~
0~ GC159 13~
~ -Lactams having a sul~ate (-O-SO3M ) substituent in the l-position and an acylamino substituent in the 3-position have activity against a range o~ gram-n gative and gram~positive organisms. The sulfate substi~uent is essential -to the activity o~ the compounds of this invention.
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 domestica~ed animals (e.g., dogs, cats, cows, horses, and the like) ~nd humans.
For aombating bactexlal 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 about 14 mg/kg/day to about lO0 mg/kg/day. All modes of adminis-tration which have been used in the past to deliver penicillins and cPphalosporins to the site of the in~ection are also contemplated for use with the novel family o~ Bolactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.
.
~93~ GC159 The B-lactams of thls invention can be prepared from the corresponding hydroxamic acid having the formula II
R2 _4 Rl-NH I l R3 ~C - N-OH.
A compound of formula II can be O-sulfated by reacting the precursor compound with a complex of pyridine and sulfur tr1oxidec The reaction can be run in an organiC solvent ~ preferably pyridineO~ This reaction yields a compound of fo~mula I wherein M~ is pyrldinium ion~ Instead of using a pre-formed complex of pyridine ~nd sulur trioxide, the complex can be formed in situ, e g., using chlorosulfonyltrimethylsilyl . ~ .
ester and pyridine as reagents. Alternatively, a complex of dLmethylformamide sulfur txioxide or 2,6-lutidine-Sulfurtrioxide can be used.
using conventional techniques (~ , ion-exchange resins, crystallization, or ion pair extraction) the pyridinium salt formed by the above procedure can be converted to other salts.
These techniques are also useful for converting the products of formula I or any of the inter~
mediates described herein to other salts.
~9~ GC159 Compounds of formula II can be prepared from an amino acid having the formula III tH~R4 NH2-lH C R3 ~C - OH .
The amino group is first protected with a classical protecting group (~ , t-butoxycarbonyl, benzyloxy-carbonyl, o nitrophenylsulfenyl, etc.), yieldinga compound having the formula XV OH R
~ ` 4 A~NH CH - ~ ;R3 ' ,l - OH.
.In oxmula IV, and throughout the specification, t~e symbol "A" refers to a nitrogen protecting group.
The carboxyl group o a protected amino acid of ormula IV is then reacted with an amine salt having the formula Y-O-NH3Cl, In formula V, and throughout the specification, the symbol "Y" refers to benzyl or pivaloyl. The reaction proceeds in the presence of a coupling agent such as l ethyl~3~3-dimethylaminopropyl)carbodiimide 30 or dicyclohex~lcarbodiimide, and yields a compou~d having the formula ~ 3~7æ GC159 VI
OH
A-NH-f~I - C - R3 ~,C - NH-O-Y.
O
The hydroxyl group o a compound of formula VI
is converted to a leaving group, using, for example, a classical reagent such as methane sulfonyl chloride (methanesulfonyl is referred to hereinater as "Ms").
The fully protected compound having the formula VII OMs , A~NH CH - C`- ~
~C - NH`O-Y
is cyclized by treatment with base, e.~., potassium carbonate. The reaction is preferably carried out in an organic solvent such as acetone, under reflux conditionsj and yields a compound having the formula VIXI . R4 A-NH~fH I ~3 C - N O~Y .
Alternatively, cyclization of a compound of formula VI can be accomplished wit~out irst co~verting th~ hydroxyl group to a leaving groupO
. ~932 ~ 2 GC159 ~17-Treatment of a compound o~ formula VI with triphenylphosphlne and d ethylazodicarboxylate, yields a compound of formula VIII.
Both of the methods disclosed above for ring closure of a compound of formula VI re~ult in the inversion of the stereochemistry of the R3 and R4 substituents.
Deprotection of the 3-amino substituent of a compound of formula VIII can be accomplished using art-recognized techniques. If, for example, the protecting group is t-butoxycarbonyl, trifluoroacetlc acid can be used to deprotec~
the amino group. If the protecting group is benzyloxycarbonyl catalytic (_ ~, palladiu~ on 15 charcoaL) hydrogenation can be used. If the protecting group is o-nitrophenylsulfenyl, ~toluenesulonlc acid can be u~ed in combination with ~thiocresol. The dep~otected compound has the ~ormula 2~
IX _4 NH~-CH - C ~ R3 ~C - N-O-Y .
Well known acylation techniques can be used to convert a compound having the formula IX
to a compound having the formula Rl-NH f ~ I R3 C - N-O-Y .
27:~
GClS9 Exemplary techniques include reaction wlth a carboxylic acid (Rl-OH) or corresponding carboxylic acid halide or carboxylic acid anhydride. The reactions wi-th a carboxylic acid procee~ most readily in the presence of a carbodiimide such as dicyclohexylcarbodiLmide and a substance capable o~ forming a reactive intermediate 1n situ such as N hydroxybenzotriazole or 4-dlmethyl-aminopyridine. In those instances wherein the acyl group (Rl) contains reactive functionality (such as amino or carboxyl groups) it may be necessary to first protect these functional groups, then carry out the acylation reaction, and inally deprotect the resulting productO
Conversion of a compound of ormula X
to the corresponding compound having a 3 alkoxy substituent can be accomplished by first halogenating the amide nitrogen to obtain a compound having the formula ~0 Rl-N-~IH I R3 ~C - N~O-~ ~
Reagents and procedures for N chlorinating amides are known in the art. Exemplary reagents axe tert.~butyl hypochlorite, sodium hypochlorite, and chlorine. The reaction can be run in an organic solvent (~ , a lower alkanol such as methanol) or in a two phase solvent system (~ water/me~lylene chloride) in the presence of a ~ase such as sodiu~
borate decahydrate. The reaction is preerably run at a reduced temperature.
Reaction of a compound of formula XI
with an alkoxylating agent, e , an alkali metal alkoxide, yields a compound (in combination with its enantiomer) having the formula XII
0-alkyl R4 R -NH~C ~ C-R
The reaction can be run in an organic solvent, e.q., a polar organic solvent such as tetxa-hydrouran, at a reduced temperature.where Rl functions as an amino protecting group, it can be removed by con~entional pro~edure~ to give the amino derivative.
Alternatively, a compound of formula X
can be converted to a compound o formula XII
using a single step proceduxe. The alkoxylatiny agent can first be mixed with a compound of 2G formula X and the N-chlorinatlng rea~ent then added to the reaction mixture.
Reduction of a compound of formula X
or XII to yield the corresponding compound of formula II, iue., Rl-NH-C - C-R
O~C N~OH
can be accomplished by catalytic hydrogenation ox, if Y is pivaloyl, by treatment with a base such as sodium sulfide or sodium hydroxide.
Alternatively, ~ benzyloxycarbonyl-~aminoxy-D-alanine, methyl ester hydrochloride, or other compounds having the "NH-0~" grouping, 2~2 .
can be used in place of an amine salt o formula V
in the above described synthesis.
An alternative synthesi~ for the compounds of this invention wherein R2 is hydrogen comprises preparation o~ a compound of formula VIII followed by deprotection o the l-hydroxy group of that co~pound to yield a compound having the formula -A-MH-CH - C-R
0~C N-O~ .
Deprotection can be accomplished using art~recognized procedures, ~ ~, if Y is pivaloyl, treatment with hydrogen peroxide and a base or treatment with sodium sulfide, or ifY i5 benzyl, by hydrogenolysis.
. Sulfation of a compound of formula IX or XII
using the above-described procedures (lOe., reaction of the precursor compound with a compLex of pyridine and sulfur trioxide, dime~hylformamide and sulfur trioxide or 2,6.lutidine and sulfur trioxide) yields a compound having the formula XIII l2 R~
A-NH-f - C R
C - N-O-S03M~.
O~
Removal of the protecting group "A" from a compound of ~ormula XIII yields a ~ey ~9~
~21-intermediate having the formula XIV l2 _4 NH -C -C - R
~C N-O~S03M
The technique used for removal of the pxotecting group will depend on the particular protectin~
group. For example, i~ A is ~enzyloxycarbonyl, catalytic hydrogenation can be used.
Acylation of an intermediate of formula XIV
using any of the ~echniques described above yields a corresponding product of formula I~
The following examples are specific embodiments of this invention.
.
~9 327 ~ GC159 Example 1 (3S-trans)~4-Methyl-2-oxo-3-[(phenylacetyl)amino]-l-azetidin 1 sulate, ~vridine salt _ _ Y- ' A) N~(Phen lacet l)-L-threonine L-Threonine (3S.7 g) is dissolved in lN
sodium hydroxide (1 liter) and chilled to 5 to -10C. To the cold, mechanically stirred solution is added dropwise phenylacetyl chloride (46.3 g). The reaction mixture is stir.red ~or about 16 hours as the temperature rises to 26C.
The mixture is washed with ether, acidified to pH 2 wi~h hydrochloric acid, and extracted wi~h e~hyl acetate (two times). The combined extracts.
axe dried over sodium sulate and concentrated under reduced pressure until crystalline solids form. Ether is added to the mixture and the c~ystals are collected (34.8 g); melting point 161~163C.
B) N2~Phenylacet l)-N-( henvlmethox )~-threoninamide N-(Ph2~ylacetyl)-L-threonine (9.5 g) is suspended in water (approximakely 50 ml), and a solution of O~benzylhydroxylamine hydrochloride (7.04 g) in water (50 ml) is added. The pH of the stirred mixture is adjusted ~o 4.2 with lN
potassium hydroxide~ and a solution o~ 8.43 g o 1-ethyl-3-(3-dimethylaminopropyl)carbodilmide hydrochloride in water (50 ml~ is added. The p~
is maintained at 4 . 2 with lN hydrochloric acid .
~ ~ ~ GC15~ -After thirty minutes an oily precipitate is present in the reaction vessel. The product is partitioned ~etween ethyl acetate and brine, and the organic layer is then dried over sodium sul~ate and concentrated to a solid (.8.7 g).
`C) (3S-trans)-4-Methyl-3-(phenylacetyl)-l-_ To a cold (.0C~ solution of N (phenylacet~11-N-(phenylmethoxy)-L-threoninamide (7.5 g) in dry tetrahydrofuran (200 ml) is added diethyl-azodicarboxylate (4.2 g) followed ~y triphenyl-phosphine (6.34 g). The reaction mixture is stirred for about 16 hours at 26C under nitrogen.
The solven~ is then removed, and ~he residue chromatographed on silica gel (ether~hexane) to afford the title compound (200 g) white solids.
R~crystallization from chloroform/hexane affords a purified sample, ~elting point 97099C.
D) (3S trans)~l-Hydroxy4~methyl 3~(phenylacetyl)-amino]-2-azetidinone A solution of (3S-trans)~4-me~hyl 3 (phenyl-__ acetyL) l-(phenylmethoxyJ-2-azetidinone (0.5 g) in ethanol (15 mL) containing O . 250 of lO~
palladium on charcoal is hydrogenated at 26 C
for one hour. The reaction mixture is ~iltered, the catalyst washed with ethanol, and the combined filtrates evaporated to an oily residue. Ether (approxLmately lO ml) is added and the resulting ~9 ~7 ~ GC153 solids are hardened and collected yielding 0.34 gof the title compound, melting point 118 135 C, dec.
AnalO Calc'~. for C12Hl4M203:
C, 61.52, H, 6.02; N, 11.96 Found:
C, 61.06; H, 6.03; N, 1]..80 Ej (3S trans)-4 Methyl-2-oxo-3-[(phenylacetyl)~
__ amino~ azetidin~l sul~ate, ~yridine salt To a solution of (3S-trans)-l-hydroxy-4 methyl-3-~(phenylacetyl)amino]-2-azetidinone (0.225 g) in dry pyridine (9 ml) is added molecular sieves 4A (1 ml) followed by pyridine-sulfur txioxidP complex ~0.61 g)0 The rPaction mixture is stirred under nitrogen or five hour5 .
at 26C, f~lterad and concentrated under reduced pxessure. Purification on HP~20 resin (water/
acetone) affords 0013 y of ~he produot as a hygroscopic solid.
Anal. Calc'd. for C H gN30 SH20:
C, 49.62; H, 5014; N, 10c21; S, 7~79 Found:
C, 50.37; H, 5007, N, 10~32, S, 7.73 7~
Example 2 [3S-[3~(R*)4Bl]-3-[[~(4-Ethyl-2,3-di.oxo-l-~iperazlnyl) , carbonyl]amino]pherlylacetyl]amino~-4-methyl-2-oxo-l-azetidinyl sulfate, pyridine aalt (1:1) A) 2-Nitrophenylthio-L-threonine L~threonine (11.9 g) is added to dioxane (125 ml) and ZN sodium hydroxide (50 ml). To the vigorously stirred solution, o-nitrophenyl-sulfenyl chloride (20.9 g) is added in ten equalportions over ifteen minutes, while 2N sodium hydroxide ( 60 ml) is slowly added dropwise. -After five more minutes the reaction mixture is diluted with water (400 ml) and acidified to pH 2.5 wi~h .
10% potassium hisulate. The organic layer is immediately ex~racted with ethyl acetate (three 200 ml portions), and the combined extracts are dried over sodium sulfate, and then concentrated to an oil. The product crystallizes on scratching (20.0 g). Rec~ystallization of 17 g from acetone/hexane affords g.5 g o crystals, melting point 145-148C which are stor~d in a freezer and used promptl~.
B) MZ-[(2-NitroPhenYl)thio] N~(phenylmethoxY) ~5 ~
L-threoninamide .
2-Ni~rophenylthio-Lrthreonine (39.0 g) and O-benzylhydroxylamine hydrochloride (22.92 g) are suspended .in water (500 ml) and with VigOEOuS
stirring the pH is adjusted to 4 . 2 with lN sodium hydroxide. ~ solution of l~ethyl-3~(3-dimethyl -26- .
aminopropyl)carbodiimide hydrochloride in water (100 ml) is added portionwise, while the pH is controlled at 4.2 with addition of 10~ potassium bisulfate. The addition lasts five minutes, and stirring and pH control is continued ~or an additional thirty minutes, whereupon a heavy granular precipitate is present. The reaction mixture is extracted with ethyl acetate (foux 300 ml portions) and the com~ined extracts are dried over sodium sulfate and concentrated to an oil (approximately 50 g).
Chromatography on SilicAR CC-7 (2 kg/
methylene chloride~50% methylene chloride/ethyl-acetat~) affords the product as a foam tl9.5 g).
A portion is crystallized and recrystallized from acetone/hexane to provide an analytical sample, melting point 130-133~C.
C) (3S-trans)-4-Methyl-3-~L(2 nitrophenyl~thio~-To a cold solution (0C) of N -[(2-nitro~
phenyl)thio]-N-~phenylmethoxy)-L~hreoninamide ~9.4 g) in pyridine (34 ml) is added methane~
sulfonyl chloride (8.58 g). After two hours at 0C the mixture is poured into ice water (100 ml) and extracted with ethyl acetate (five ~G0 ml portions). The extracts are washed with ice cold 10~ po-tassium bisulfate (four 100 ml portions), dried over sodium sulfate, and concentrated under reduced pressure without heat, yielding 9.6 g of a residue.
A solution of the residue in acetone (125 ml), is added dropwise over thirty-five minutes to a refluxing mixture o~ anhydrous potassium carbonate (10 g) and acetone (approximately 600 ml). Ater 2.5 hours the mixture is cooled to 26C, ~iltered, and evaporated ~o a foam.
Chromatography on SilicAR CC-7 (methylene chloride/
hexane 9:1~methylene chloride)- affords the product as a clear oil (2.15 g). Crystallization and recrystallization from chloroform/hexane produces an analytical sample, melting point.
97 laOC.
D) (3S trans) 3-Amino-4 methyl-l (phenylmethoxy)~
Z azetidinone,toluenesulfonate . . , . . _ To a stirred solution of (3S-trans)~4-methyl~3-L[(2-nitrophenyl~thio~amino]-1-(phenyl-methoxy)-2-azetidinQne (1.07 g) in methylene chloride (20 ml) is added ~-tolusnesulfonic acid (0.57 g) and ~thiocresol (0.74 g). The reaction mixture i5 stirred under nitrogen for tw~ hours, whereupon the solvents are removed in acuo, and the residue is triturated with ether (four 25 ml portions), to afford 0.9 g of the title compound.
~93272 GC15~
E) (3S-trans)-3-[[[l(4-Ethy1-2,3-dioxo-1 _ i erazinvl)carbonYl]aminolphenylacetyl]amino~-4-~ ~ ,, ., ~
methy~-l-(E~nYlmethoxyL__-azetidinone A suspension of ~-[[(4-ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]benzeneacetic acid (0.879 g) hydroxybenzotriazole (0.42 g), and dicyclohexylcarbodiimide (0.56 g), in dimethyl-formamide (15 ml) is stirred at 26 C ~or one hour, at which point a solution of (3S-trans)-3-amino-4-methyl-l~(phenylmethoxy)-2-azetidinone, toluenesulfonate (0.95 g) and diisopropylethyl-amine (0.44 ml) in dimethylformamide (5 ml) is addedO The reaction mixture is stirred at room t~mperature for about 16 hours, then poured i~to water (lOO~ml) and extracted with ethyl acetate (thLee 100 ml portions). The combined organic ~extracks are washed with wa~er (three 100 ml portions) and aqueous sodium bicarbonate solution (one 100 ml portion), then dried over sodium 2Q sulfate and concentrated und~r reduced pressure to a semi~solid residue. Liquid chromatography (ethyl acetate) affords the desired product as a foam ~0.599 g). Recrystallization from chloroorm/isopropyl ether ,yields the title compound, melting point 100~105C.
~ 3%7~ GC159 F) (3S-trans)-3-[[[[(4-Ethyl-2,3-dioxo-1-piperazinyl)-carbonyl]amino]phenyla etyl~amino]-l-hydroxy-4-methyl-2-azetidinone (3S-trans)-3-[~[~(4~ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino]phenylacetyl]amino~-4-methyl l-(phenylmethoxy)-2~azetidinone (0.270 g~ is dissolved in ethanol (25 ml) and hydroyenated over 10 palladium on charcoal catalyst (130 mg) ~or two hours. The reaction mixture is filtered and concentrated to a solid (0.220 g)~
G) ~3s~[3u(R*)~4B]~3-[I[~(4-Et-hyl-2~3-di m 15 salt (1~
To a solution of (3S trans)-3~[[[[(4~ethyl=
2,3 dioxo~l piperazinyl)carbonyl~aminoi l~hydroxy~
4.methyl-2~azetidinone (0.220 g) in pyridine (7 ml) is added 4A molecular sieves (approximately 1 ml) and pyridine-sulfur trioxide complex (O.33 g). After stirring under nitrogen at 26C for 4.5 hours, the xeaction mixture i5 filtered and concentrated to an oil. Chroma-tography on HP 20 AG resin (water/acetone) followed by lyophilization of the appropriate fractions afrords the desired product as a powder (0.080 g).
Anal. Calc d. f ~19 23 5 9 5 5 Z
C, 47O05; H, 5.26; N, 13.72 Found:
C, 46.36; H, 4.74; N~ 13O42 Example 3 [3S(Z)}3-[~(2-Amino-4-thiazolyl)(methoxyimino)-acetyl~aminoJ-2~oxo-1-azetidinyl sulfate, po-tassium salt s A) -[(Phenylmethyl?oxy]-~-aminoxy-~-alanine methyl ester hydrochloride Hydrogen chloride gas is bubbled into ice cold methanol (200 ml) for twenty minutes.
lo ~-L (phenylmethyl)oxy]-D-cycloserine (5.0 g) is added, and the cloudy solution is stirred at 26C for twelve hours. The reaction mixture is iltered and concentrated into a semisolid residue which upon titration with ether (two 200 ml por~ions) gives 4.6 g o solid, melting point 110 112C.
[A more quantitative alternative procedure c~mprises preparation of ca. lN methanolic hydrogen chloride solution by adding 7.1 ml acetyl chloride dropwise to 100 ml of chilled, stirred, me~hanol. After thirty minutes, a f ~phenylmethyl)oxy]cycloserine (5.0 g) is added, the mixture is evaporated after l2 hours, and the residue is triturated wlth ether. The resulting cxystalline mass is collected by filtration and dried ln vacuo yielding 5~7 g of t~e title compound.]
~i93~ GCl59 B) N -[[(Phenylmethyl~oxy]carbonyl]-N-[2-[[[(phenyl-methyl)oxy]carbonyl]amino]-3~methoxy-3-oxopropoxy]-L-serinamide To a suspension of N-[[(phenylmethyl]oxy]-carbonyl]-L~serine (3.46 g) in water (15 ml), is added an aqueous (lS ml) solution o a- r (phenylmethyl)oxy] ~-aminoxy-D-alanine methyl ester hydrochloride (4.49 g). The mixture is vigorously stirred (air stirrer), while adjusting to pH 4.2 with lN potassium hydroxide. A
solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide in water (10 ml) is added portionwise over five minutes, while the pH is maintained at 40 ~ by addition of lN hyd~ochloric acid~
After stirring or an additional twenty minutes, the reaction mixture is saturated with sodium chloride and extracted with ethyl acetate (five . t~mes). The combined ethyl acetate extxacts are dried over sodium sulfate and concentrated under reduced pressure to a V15COU5 oil (508 g~
c~ ) ~.v~ ~ _~D~-amino]~2-azetidinone To a cold (0 5C) solution of N ~[(phenyl-methyl)oxy]carbonyl]-N-[2-[[~(phenylmethyl)oxy~-carbonyl]amino]-3-methoxy-3-oxopropoxy~-L-serinamide (6008 g) in distilled tetrahydro~uran (lO0 ml) is added triphenylphosphine (3.6 g) followed by diethylazodicarboxylate (2.15 ml, 2~38 g). The reaction mixture is allowed to stir for twelve ~9327~ GC159 hours under nitrogen, whereupon 7.0 ml of1,8-diazabicyclo E5.4 .O.]undecan-7-ene is added.
After 30 minutes, tetrahydrofuran is removed by evaporation and the resulting residue is partitioned
Anal. Calc d. f ~19 23 5 9 5 5 Z
C, 47O05; H, 5.26; N, 13.72 Found:
C, 46.36; H, 4.74; N~ 13O42 Example 3 [3S(Z)}3-[~(2-Amino-4-thiazolyl)(methoxyimino)-acetyl~aminoJ-2~oxo-1-azetidinyl sulfate, po-tassium salt s A) -[(Phenylmethyl?oxy]-~-aminoxy-~-alanine methyl ester hydrochloride Hydrogen chloride gas is bubbled into ice cold methanol (200 ml) for twenty minutes.
lo ~-L (phenylmethyl)oxy]-D-cycloserine (5.0 g) is added, and the cloudy solution is stirred at 26C for twelve hours. The reaction mixture is iltered and concentrated into a semisolid residue which upon titration with ether (two 200 ml por~ions) gives 4.6 g o solid, melting point 110 112C.
[A more quantitative alternative procedure c~mprises preparation of ca. lN methanolic hydrogen chloride solution by adding 7.1 ml acetyl chloride dropwise to 100 ml of chilled, stirred, me~hanol. After thirty minutes, a f ~phenylmethyl)oxy]cycloserine (5.0 g) is added, the mixture is evaporated after l2 hours, and the residue is triturated wlth ether. The resulting cxystalline mass is collected by filtration and dried ln vacuo yielding 5~7 g of t~e title compound.]
~i93~ GCl59 B) N -[[(Phenylmethyl~oxy]carbonyl]-N-[2-[[[(phenyl-methyl)oxy]carbonyl]amino]-3~methoxy-3-oxopropoxy]-L-serinamide To a suspension of N-[[(phenylmethyl]oxy]-carbonyl]-L~serine (3.46 g) in water (15 ml), is added an aqueous (lS ml) solution o a- r (phenylmethyl)oxy] ~-aminoxy-D-alanine methyl ester hydrochloride (4.49 g). The mixture is vigorously stirred (air stirrer), while adjusting to pH 4.2 with lN potassium hydroxide. A
solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide in water (10 ml) is added portionwise over five minutes, while the pH is maintained at 40 ~ by addition of lN hyd~ochloric acid~
After stirring or an additional twenty minutes, the reaction mixture is saturated with sodium chloride and extracted with ethyl acetate (five . t~mes). The combined ethyl acetate extxacts are dried over sodium sulfate and concentrated under reduced pressure to a V15COU5 oil (508 g~
c~ ) ~.v~ ~ _~D~-amino]~2-azetidinone To a cold (0 5C) solution of N ~[(phenyl-methyl)oxy]carbonyl]-N-[2-[[~(phenylmethyl)oxy~-carbonyl]amino]-3-methoxy-3-oxopropoxy~-L-serinamide (6008 g) in distilled tetrahydro~uran (lO0 ml) is added triphenylphosphine (3.6 g) followed by diethylazodicarboxylate (2.15 ml, 2~38 g). The reaction mixture is allowed to stir for twelve ~9327~ GC159 hours under nitrogen, whereupon 7.0 ml of1,8-diazabicyclo E5.4 .O.]undecan-7-ene is added.
After 30 minutes, tetrahydrofuran is removed by evaporation and the resulting residue is partitioned
5 between ethyl acetate and saturated sodium bicarbonate. The aqueous layer is washed once with ethyl acetate, then adjusted to pH 2 with saturated potassium bisulfate, and extracted with ethyl acetate (five times). The combined extracts are dried and concentrated to a crystalline solid (1.8 g). A portion is recrystallized ~xom acetone/hexane (two times) to give an analytiGal sample, melting point 12~131Co D) ~
To a solution of (3S)-l~hydroxy 3-[[[(phenyl-' methyl)oxy]carbonyl~amino~azetidinone (lol g) in dry pyridine (45 ml) containing 4A molecular sieves (caO 1 ml) is added pyridine-sulfur trioxide complex (1.48 g~. After stirring for two.hours at 26C, under nitrogen, the pyrldine is removed under reduced pressure, and the residue is partitioned between pH 403 buffer (O.S M monobasic potassium phosphate, 50 ml) and ethyl acetate (50 ml). The aqueous layer is washed once more with ethyl acetate (50 ml), then treated with tetrabutyl ammonium hydrogen sulfate (1.57 g), and extracted with methylene . ~93~ GC159 chloride (three 50 ml portions)O The combined organic extracts are dried over sodium sulfate and concentrated to a viscous oil (1.81 y).
The material is puxified on SilicAR CC-4 using methylene chloride/methanol (1% to 8%) as eluant to afford 0.71 g of oil.
E) [3S(Z)]-3-~[(2-Amino-4-thiazolyl)_(methoxyimino)-acetyl]amino]-2-oxo-1-azetidin~l sulfate, potassium 1 0 5_ A solution of (3S)-3-[[[(phenylmethyl)oxy]-carbonyl]amino]-2-oxo-1-azetidinyl sulfate, tetrabutyLammonium salt (0.70 g) in dimethyl-formamide i5 hydrogenated for 6.5 hours using 10% palladium on charcoal catalyst (0.35 g)~
After filtration to remove catalyst, (Z) 2 amino-a (methoxyimino) 4 thiazoleacetic acid. (0.251 g) dicyclohexylcarbodiimide, followed by hydroxy~
benzotriazole (0.191 g) are added to the mixture and it was stirred for about 16 hours at 26C.
The rPaction mixture is concentrated under high vacuum (40C), diLuted with acetone (25 ml), and.then filtered. The solids are washéd with a small amount of acetone and the combined filtrate is treated with a solution of potassium perfluorobutane sulonate (0O425 g) in aceto~e (2 ml). Precipitation occurs at once. Ether (20 ml) is added and the precipitated solids are collected by filtration (0.250 g). Purification by HP~20AG chromatography using water-acetone ~93272 GC159 (0-5~) as eluant gives the product as a powder after lyophilization (O.Q45 g).
Anal. Calc'd. for CgHloN5S207K:
C, 26.79; H, 2.50; N, 17.36; S, 1~.89; K, 9.69 Found: C, 2g.63; H, 3.. 16; N, 16.95; S, 17.69; K, 1.78 The product is a mixture of tlle potassium salt and zwitte.rion, and displays appropriate IR and NMR spectra.
Exam~le 4 (S) 2-Oxo~3-[( hen lacetvl)amino]-l~azetidinyL
P _ Y ~ ~
sulfate, pyridine salt A) N -(Phenylacetyl)-N-[(~e~lmethyl)~y]-L~
serinamide ~ .
N-Phenylacetyl L-serine (808 g), l-hydroxy-.
benzotriaz~le hydrate (6.03 g) and o-benzyl~
hydroxylamine (4.84 g) are dissolved in tetra hydrofuran (450 ml) and chilled to 0C. A solution of dicyclohexylcarbodiimide (8~1 g), in tetra~
hydrofuran (50 ml) is added over a 0c5 hour period. The reaction is allowed to warm to 26 C
and stir for about 16 hours. The mixture is filtere~, and the iltrate concentrated under reduced pressure to a se~i-solid residué. The addition of ethyl acetate (50 ml) causes crystal-lization. The solids are collected and dried(6.9 g, melting point 150-151C).
The filtrate is washed with sodium bicarbonate, water, potassium bisulfate, and water (~wice~, and then dried over sodium sulfate and concentrated 30 until a second crop o crystals is obtained (2.6 g), melting point 131 135C.
~ 3~
B) (S?-3-~(Phenylacetyl)amino]-l-[(phenylmethyl)-ox~]-2-azetidinone To a cold solution (0C) of N~-(phenylacetyL)-N-[(phenylmethyl)oxy]-L-serinamide (6.88 g) in di.stilled tetrahydrofuran (300 ml), under nitrogen, is added triphenylphosphine (11.~0 g) followed by diethylazodicarboxylate (6,60 ml).
The solution is allowed to warm to 26C and stirred for twelve hours. After removal of solvent under reduced pressure the resulting residue is applied to a silica gel column (eluant ether/
hex~ne-~ether). Combination of fractions gives two batches; 1O3 g (pure) and 2~5 g (ca. 60% pure) (total yield ca~ 20 2 g)O The pure material is recrystallized from ethyl acetate/hexane to give solids; melting point 130-131C.
, Cl (S) l-Hydroxy-3-~(phenylacetyl)amino~-2-azetidino_ To an ethanolic (100 ml) solution o (S)-3-[(phenylacetyl)amino~ [(phenylmethyl) oxy~-2-azetidinone (0.8 g, contaminated with triphenylphosphine) is added 10~ palladi~n :
on charcoal catalyst (0.4 g) and the mixture is hydrogenated under ca. 1 atom pressure for one hour~ The reaction mixture is iltered through prewashed Celite and concentrated under reduced pressure to an oily residue. The product is partitioned between 50% sodium bicarbonate solution and et~yl acetateO The * Trade Mark aqueous layer is acidified with potassium bisulfate and extracted with ethyl acetate (three 50 ml portions). The combined extracts are dried over sodium sulfate and concentrated to a crystalline solid (ca. 200 mg~. Recrystalli2ation from met~anol/chloroorm a~fords an analytical sample, melting point 145-146C dec.
D~ (S)-2-Oxo-3-~(phenylacetyl)amino]-1-azet _inyl sulfate, ~Yridine salt 1 0 ~
(S)-l-Hydroxy-3-[(phenylacetyl)amino]-2-azetidinone (0 ol50 g) is dissol~ed in dry pyridine Clo ml) containing 4A molecular sieves. Pyridine 5ul~ur trioxide complex (0O216 g) is added and lS the solution is stirred under nitrogen for two houxs. After concentration under reduced p~essure, and vacuum drying, the product i5 purified on HP~20AG (25 ml). Elution with water and then 5% acetone/water, followed by lyophilization f the desired fractions affords the product (0.110 g) a~ a hygxoscopic powder;
~]D6= ~5.9 (c=0.645, water) Anal. Calc'd. for C16H17N3O6 2 C,. 4~.15; H, 4.74; N, 10~71; S, 8.34 Found:
C, 49.47; H, 4.67; N, 10~81; S, 8.25 .
~ `~ GC159 Example 5(S)-2-Oxo-3-[~ henylacetyl)amino]-l-azetidin~l sulfate, potassium salt -(S)-2-Oxo-3-[(phenylacetyl)amino]-1-azetidinyl sulfate, pyridine salt (1.5 g; see example 4) is dissolved in water and applied to a column containing 150 ml Dowex 50-X2K resin. Elution with 1500 ml double distilled water gives fi~e 300 ml fractions which are lyophilized. Fraction 1 contains 1.33 g of the title compound.
Anal. Calc d- for Cll 11 2 6 2 C, 36.15; H, 3.86; N, 7.66; S~ 8.77; K,- 10.70 Found:
C~ 36014; H, 3.15; N, 7020; S, 9.81; K~ 14.01 Exam~le 6 (S)-2-Oxo-3-[(phenylacetyl)amino]-l-azetidinyl sulate, tetrabutylammonium salt _ (S)-2-Oxo--3-[(phenylacetyl)amino~ aæetidinyl sulfate, potassium salt ~93 mg, see exam~le S) i5 dissolved in water (5 ml) and tetrabutylal~nonium hydrogen sulfate (102 mg) is added. The solution is $haken for a few m,inutes, saturated with sodi~m chloride and extracted with methylene chloride (four times). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure to an oil (112 mg).
~nalO Calc d- for Cll~llN26SCl6H36N
C, 59085; H, 8.74; N, 7.75, S, 5091 Found:
C, 60025; M, 9.40; N, 7.13; S/ 5.51 * Trade Mark GCl59 Example 7(S)-2-Oxo-3-[(2-thienylacetyl)amino]-1-azetidinyl sulfate, potassi~m salt A solution of (3g)-3~ (phenylme~hyl)oxy]-carbonyl]amino]-2-oxo-1 azetidinyl sul~ate, tetrabutylammonium salt (l.O g; see example 3a) in dimethylformamide (.20 ml) containing lO~
palladium on charcoal. (0.5 g) is hydrogenated or six hours at 26C. The mixture is filtered to remove catalyst~ Hydroxybenzotriazole (0.261 g) is added, followed by thiopheneacetic acid (0.243 g) and finally dicyclohexylcarbodiimide DCC (0.352 g). The reaction mixture i5 stirred at 26C or about 16 hours, and then Goncentrated at 4QC un~er high vacuum. The residue is diluted with acetone (lO ml) and the resulting precipitate is filtered and washed with acetone (2 ml).
To the acetone filtrate is added potassium perfluorobutane sulfonate (0.867 g) in acetone (2 ml). T~e solution is treated with ether (approximately lO ml) and the precipitate is filtered and dried in hiyh vacuwm. Chromatography on EP ~O resin (water~5~ acetone/water) affords the product after lyophilization as a solid (51 mg). This material contains approximately 50% potassium perfluo.robutane sulfonate.
Anal. Calc'd. Eor CgH906N2S2K:
C, 31038; H, 2.63; N, 8.14; S, 18.62; K, 1~o55 Foundo C, 22.58; H, 1.30; N, 4~17; S, 14.63; K, 8G62 39~
In an attempt t.o further purify this material, the substance is dissolved in a small amount of acetone and ether is added. The precipitate is collected, dissolved i,n water and lyophilized.
The filtrate is e~aporated, dissolved in water and lyophilized. The precipitate yives 13 mg of 60% pure product and the filtrate yields 16 my of 44% pure product.
lG Example 8 (3S-trans~-3~[(-2,~imethoxybenzoyl)amino~-4-methvl 2~oxo l-a-zetidinvl sulfate, Pyridine (1:1~ salt A) (3S trans)-3r-[-(2,6 Dimethoxybenzoyl)amino~-4~
_ ____ methyl-l-t~henylmethyl)oxv~-2 azetidinone ' ' To a cold (~10C) solution of (3S~trans)-3-amino-4-methyl~l (phenylmethoxy)~2-azetidinone, toluenesulfonate (0O95 g; see example 2D) in methylene-chloride (50 ml) is added 2,6~d.imethoxy~
benzoyl chloride (0.60 g) and 4~dimethylamino pyridine (0.61 g). The reaction is stirred under nitro~en and allowed to rise to 26C over ~ive hours. The reaction mixture is concentrated to an oil and partitioned between ethyl aceta~e and aqueous hydrogen sulfate solution. The organic layer is washed with aqueous sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to a foam (0.848 g).
GC15~ -B) (3S-trans)-3- L ( 2, 6-Dimethoxybenzoyl)amino]--l-hydroxy-4-methyl-2 azetidinone To a stirred solution of (3S-trans)-3-[(2,6-dLmethoxybenzoyl)aminoJ-4-methyl-1-[(phenylmethyl)oxyj-2-azetidinone ~0.848 g) in absolute ethanol (20 ml) under nltrogen is added 1,4-cyclohexadiene (8 ml) and ~reshly prepar~d palladium black (approximately 0.85 g). After one hour the reaction mixture is filtered and evapoxated to a solid (0.605 g).
C) (3S-trans )!-3- [ ( 2,6-Dimethoxybenzoyl)amino]-4~
met~l 2 oxo-l-azetidinYl sulfate vridine (1 1) salt ~ P~
To a solution of (3S-trans)-3 [(2,6~dimethoxy-, .
benzoyl)amino]~l-hydroxy-4-methyl-2 azetidinon~
(0.6~ g) in dry pyridine ~20 ml) under nitrogen is added 4A molecular sieves (approximately 3 ml) a~d pyridine-sulfur trioxide complex (1.35 g)O
After three hours the reaction mixture is flltered Z0 and the filtrate concentrated and applied to an ~P-20AG resin column (acetone/water)O The desired fractions are lyophilized to afford the title compound (0.19~ g) as a powder.
Anal. Calc d- for 18 21 3 8 C, 48.21; H, 4.94; N, 9.37; S, 7.15 Found:
C, 48.23; H, 4.94; N~ 9.37; S, 7~10 Examples 9-69 .
Following ~he procedure of example 3, but substituting the carboxylic acid lis-ted in column I for (Z)-2-amino a ~ (methoxyimino)-4-thiazole-acetic acid, yields the potassium salt of the compound 1isted in column II.
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To a solution of (3S)-l~hydroxy 3-[[[(phenyl-' methyl)oxy]carbonyl~amino~azetidinone (lol g) in dry pyridine (45 ml) containing 4A molecular sieves (caO 1 ml) is added pyridine-sulfur trioxide complex (1.48 g~. After stirring for two.hours at 26C, under nitrogen, the pyrldine is removed under reduced pressure, and the residue is partitioned between pH 403 buffer (O.S M monobasic potassium phosphate, 50 ml) and ethyl acetate (50 ml). The aqueous layer is washed once more with ethyl acetate (50 ml), then treated with tetrabutyl ammonium hydrogen sulfate (1.57 g), and extracted with methylene . ~93~ GC159 chloride (three 50 ml portions)O The combined organic extracts are dried over sodium sulfate and concentrated to a viscous oil (1.81 y).
The material is puxified on SilicAR CC-4 using methylene chloride/methanol (1% to 8%) as eluant to afford 0.71 g of oil.
E) [3S(Z)]-3-~[(2-Amino-4-thiazolyl)_(methoxyimino)-acetyl]amino]-2-oxo-1-azetidin~l sulfate, potassium 1 0 5_ A solution of (3S)-3-[[[(phenylmethyl)oxy]-carbonyl]amino]-2-oxo-1-azetidinyl sulfate, tetrabutyLammonium salt (0.70 g) in dimethyl-formamide i5 hydrogenated for 6.5 hours using 10% palladium on charcoal catalyst (0.35 g)~
After filtration to remove catalyst, (Z) 2 amino-a (methoxyimino) 4 thiazoleacetic acid. (0.251 g) dicyclohexylcarbodiimide, followed by hydroxy~
benzotriazole (0.191 g) are added to the mixture and it was stirred for about 16 hours at 26C.
The rPaction mixture is concentrated under high vacuum (40C), diLuted with acetone (25 ml), and.then filtered. The solids are washéd with a small amount of acetone and the combined filtrate is treated with a solution of potassium perfluorobutane sulonate (0O425 g) in aceto~e (2 ml). Precipitation occurs at once. Ether (20 ml) is added and the precipitated solids are collected by filtration (0.250 g). Purification by HP~20AG chromatography using water-acetone ~93272 GC159 (0-5~) as eluant gives the product as a powder after lyophilization (O.Q45 g).
Anal. Calc'd. for CgHloN5S207K:
C, 26.79; H, 2.50; N, 17.36; S, 1~.89; K, 9.69 Found: C, 2g.63; H, 3.. 16; N, 16.95; S, 17.69; K, 1.78 The product is a mixture of tlle potassium salt and zwitte.rion, and displays appropriate IR and NMR spectra.
Exam~le 4 (S) 2-Oxo~3-[( hen lacetvl)amino]-l~azetidinyL
P _ Y ~ ~
sulfate, pyridine salt A) N -(Phenylacetyl)-N-[(~e~lmethyl)~y]-L~
serinamide ~ .
N-Phenylacetyl L-serine (808 g), l-hydroxy-.
benzotriaz~le hydrate (6.03 g) and o-benzyl~
hydroxylamine (4.84 g) are dissolved in tetra hydrofuran (450 ml) and chilled to 0C. A solution of dicyclohexylcarbodiimide (8~1 g), in tetra~
hydrofuran (50 ml) is added over a 0c5 hour period. The reaction is allowed to warm to 26 C
and stir for about 16 hours. The mixture is filtere~, and the iltrate concentrated under reduced pressure to a se~i-solid residué. The addition of ethyl acetate (50 ml) causes crystal-lization. The solids are collected and dried(6.9 g, melting point 150-151C).
The filtrate is washed with sodium bicarbonate, water, potassium bisulfate, and water (~wice~, and then dried over sodium sulfate and concentrated 30 until a second crop o crystals is obtained (2.6 g), melting point 131 135C.
~ 3~
B) (S?-3-~(Phenylacetyl)amino]-l-[(phenylmethyl)-ox~]-2-azetidinone To a cold solution (0C) of N~-(phenylacetyL)-N-[(phenylmethyl)oxy]-L-serinamide (6.88 g) in di.stilled tetrahydrofuran (300 ml), under nitrogen, is added triphenylphosphine (11.~0 g) followed by diethylazodicarboxylate (6,60 ml).
The solution is allowed to warm to 26C and stirred for twelve hours. After removal of solvent under reduced pressure the resulting residue is applied to a silica gel column (eluant ether/
hex~ne-~ether). Combination of fractions gives two batches; 1O3 g (pure) and 2~5 g (ca. 60% pure) (total yield ca~ 20 2 g)O The pure material is recrystallized from ethyl acetate/hexane to give solids; melting point 130-131C.
, Cl (S) l-Hydroxy-3-~(phenylacetyl)amino~-2-azetidino_ To an ethanolic (100 ml) solution o (S)-3-[(phenylacetyl)amino~ [(phenylmethyl) oxy~-2-azetidinone (0.8 g, contaminated with triphenylphosphine) is added 10~ palladi~n :
on charcoal catalyst (0.4 g) and the mixture is hydrogenated under ca. 1 atom pressure for one hour~ The reaction mixture is iltered through prewashed Celite and concentrated under reduced pressure to an oily residue. The product is partitioned between 50% sodium bicarbonate solution and et~yl acetateO The * Trade Mark aqueous layer is acidified with potassium bisulfate and extracted with ethyl acetate (three 50 ml portions). The combined extracts are dried over sodium sulfate and concentrated to a crystalline solid (ca. 200 mg~. Recrystalli2ation from met~anol/chloroorm a~fords an analytical sample, melting point 145-146C dec.
D~ (S)-2-Oxo-3-~(phenylacetyl)amino]-1-azet _inyl sulfate, ~Yridine salt 1 0 ~
(S)-l-Hydroxy-3-[(phenylacetyl)amino]-2-azetidinone (0 ol50 g) is dissol~ed in dry pyridine Clo ml) containing 4A molecular sieves. Pyridine 5ul~ur trioxide complex (0O216 g) is added and lS the solution is stirred under nitrogen for two houxs. After concentration under reduced p~essure, and vacuum drying, the product i5 purified on HP~20AG (25 ml). Elution with water and then 5% acetone/water, followed by lyophilization f the desired fractions affords the product (0.110 g) a~ a hygxoscopic powder;
~]D6= ~5.9 (c=0.645, water) Anal. Calc'd. for C16H17N3O6 2 C,. 4~.15; H, 4.74; N, 10~71; S, 8.34 Found:
C, 49.47; H, 4.67; N, 10~81; S, 8.25 .
~ `~ GC159 Example 5(S)-2-Oxo-3-[~ henylacetyl)amino]-l-azetidin~l sulfate, potassium salt -(S)-2-Oxo-3-[(phenylacetyl)amino]-1-azetidinyl sulfate, pyridine salt (1.5 g; see example 4) is dissolved in water and applied to a column containing 150 ml Dowex 50-X2K resin. Elution with 1500 ml double distilled water gives fi~e 300 ml fractions which are lyophilized. Fraction 1 contains 1.33 g of the title compound.
Anal. Calc d- for Cll 11 2 6 2 C, 36.15; H, 3.86; N, 7.66; S~ 8.77; K,- 10.70 Found:
C~ 36014; H, 3.15; N, 7020; S, 9.81; K~ 14.01 Exam~le 6 (S)-2-Oxo-3-[(phenylacetyl)amino]-l-azetidinyl sulate, tetrabutylammonium salt _ (S)-2-Oxo--3-[(phenylacetyl)amino~ aæetidinyl sulfate, potassium salt ~93 mg, see exam~le S) i5 dissolved in water (5 ml) and tetrabutylal~nonium hydrogen sulfate (102 mg) is added. The solution is $haken for a few m,inutes, saturated with sodi~m chloride and extracted with methylene chloride (four times). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure to an oil (112 mg).
~nalO Calc d- for Cll~llN26SCl6H36N
C, 59085; H, 8.74; N, 7.75, S, 5091 Found:
C, 60025; M, 9.40; N, 7.13; S/ 5.51 * Trade Mark GCl59 Example 7(S)-2-Oxo-3-[(2-thienylacetyl)amino]-1-azetidinyl sulfate, potassi~m salt A solution of (3g)-3~ (phenylme~hyl)oxy]-carbonyl]amino]-2-oxo-1 azetidinyl sul~ate, tetrabutylammonium salt (l.O g; see example 3a) in dimethylformamide (.20 ml) containing lO~
palladium on charcoal. (0.5 g) is hydrogenated or six hours at 26C. The mixture is filtered to remove catalyst~ Hydroxybenzotriazole (0.261 g) is added, followed by thiopheneacetic acid (0.243 g) and finally dicyclohexylcarbodiimide DCC (0.352 g). The reaction mixture i5 stirred at 26C or about 16 hours, and then Goncentrated at 4QC un~er high vacuum. The residue is diluted with acetone (lO ml) and the resulting precipitate is filtered and washed with acetone (2 ml).
To the acetone filtrate is added potassium perfluorobutane sulfonate (0.867 g) in acetone (2 ml). T~e solution is treated with ether (approximately lO ml) and the precipitate is filtered and dried in hiyh vacuwm. Chromatography on EP ~O resin (water~5~ acetone/water) affords the product after lyophilization as a solid (51 mg). This material contains approximately 50% potassium perfluo.robutane sulfonate.
Anal. Calc'd. Eor CgH906N2S2K:
C, 31038; H, 2.63; N, 8.14; S, 18.62; K, 1~o55 Foundo C, 22.58; H, 1.30; N, 4~17; S, 14.63; K, 8G62 39~
In an attempt t.o further purify this material, the substance is dissolved in a small amount of acetone and ether is added. The precipitate is collected, dissolved i,n water and lyophilized.
The filtrate is e~aporated, dissolved in water and lyophilized. The precipitate yives 13 mg of 60% pure product and the filtrate yields 16 my of 44% pure product.
lG Example 8 (3S-trans~-3~[(-2,~imethoxybenzoyl)amino~-4-methvl 2~oxo l-a-zetidinvl sulfate, Pyridine (1:1~ salt A) (3S trans)-3r-[-(2,6 Dimethoxybenzoyl)amino~-4~
_ ____ methyl-l-t~henylmethyl)oxv~-2 azetidinone ' ' To a cold (~10C) solution of (3S~trans)-3-amino-4-methyl~l (phenylmethoxy)~2-azetidinone, toluenesulfonate (0O95 g; see example 2D) in methylene-chloride (50 ml) is added 2,6~d.imethoxy~
benzoyl chloride (0.60 g) and 4~dimethylamino pyridine (0.61 g). The reaction is stirred under nitro~en and allowed to rise to 26C over ~ive hours. The reaction mixture is concentrated to an oil and partitioned between ethyl aceta~e and aqueous hydrogen sulfate solution. The organic layer is washed with aqueous sodium bicarbonate, and brine, dried over sodium sulfate and concentrated to a foam (0.848 g).
GC15~ -B) (3S-trans)-3- L ( 2, 6-Dimethoxybenzoyl)amino]--l-hydroxy-4-methyl-2 azetidinone To a stirred solution of (3S-trans)-3-[(2,6-dLmethoxybenzoyl)aminoJ-4-methyl-1-[(phenylmethyl)oxyj-2-azetidinone ~0.848 g) in absolute ethanol (20 ml) under nltrogen is added 1,4-cyclohexadiene (8 ml) and ~reshly prepar~d palladium black (approximately 0.85 g). After one hour the reaction mixture is filtered and evapoxated to a solid (0.605 g).
C) (3S-trans )!-3- [ ( 2,6-Dimethoxybenzoyl)amino]-4~
met~l 2 oxo-l-azetidinYl sulfate vridine (1 1) salt ~ P~
To a solution of (3S-trans)-3 [(2,6~dimethoxy-, .
benzoyl)amino]~l-hydroxy-4-methyl-2 azetidinon~
(0.6~ g) in dry pyridine ~20 ml) under nitrogen is added 4A molecular sieves (approximately 3 ml) a~d pyridine-sulfur trioxide complex (1.35 g)O
After three hours the reaction mixture is flltered Z0 and the filtrate concentrated and applied to an ~P-20AG resin column (acetone/water)O The desired fractions are lyophilized to afford the title compound (0.19~ g) as a powder.
Anal. Calc d- for 18 21 3 8 C, 48.21; H, 4.94; N, 9.37; S, 7.15 Found:
C, 48.23; H, 4.94; N~ 9.37; S, 7~10 Examples 9-69 .
Following ~he procedure of example 3, but substituting the carboxylic acid lis-ted in column I for (Z)-2-amino a ~ (methoxyimino)-4-thiazole-acetic acid, yields the potassium salt of the compound 1isted in column II.
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" GC159 Example 70 2-Oxo-3-methox -3-[( henvlacet~l)amino]-l-P _ ~ _ azetidinyl sulfate,-pyridine salt A) 3-Methox -3-[( hen lacet 1)amino]-l-[( hen 1-Y P ~ ~ P Y
methyl)ox~]~2-azetidinone To a solution of (S)-3-~(phenylacetyl)a~ino]-l-~(phenylmethyl)oxy]-2~azetidinone (lmM; see example 4B) in freshly distilled tetrahydrouran (10 ml) at -78C is added via syringe a solution of lithium methoxide (3mM1 in dry methanol (5 ml).
After 5 minutes, t-butyl hypochlorite tl30 ~1) is added and the mixture is stirred at ~78C
for 30 mi~utes. The reaction mixture is pouxed into 0.5 ~ monobasic potassium phosphate ~uffer and extracted with two 100 ml portions of methylene chloride. The combined organic extracts are dried over sodium sulfate and concentrated to an oily residue~ The title compound is isolated by column chromatograp~y as a racemateO
B) ~o- ne~
azetidinvl sul~a~e, PYridine salt Following the hydrogenolysis and sulfation procedures described in example 4, parts C and D, but utilizing 3-methoxy-3-~(phenylacetyl)amino]-l-[tphenylmethyl)oxy] 2-azetidinone in place of (S)-3 ~(phenylacetyl)amino~ l~[(phenylmethyl)oxy]-2-azetidinone, yield~ the title compoundO
" GC159 Example 70 2-Oxo-3-methox -3-[( henvlacet~l)amino]-l-P _ ~ _ azetidinyl sulfate,-pyridine salt A) 3-Methox -3-[( hen lacet 1)amino]-l-[( hen 1-Y P ~ ~ P Y
methyl)ox~]~2-azetidinone To a solution of (S)-3-~(phenylacetyl)a~ino]-l-~(phenylmethyl)oxy]-2~azetidinone (lmM; see example 4B) in freshly distilled tetrahydrouran (10 ml) at -78C is added via syringe a solution of lithium methoxide (3mM1 in dry methanol (5 ml).
After 5 minutes, t-butyl hypochlorite tl30 ~1) is added and the mixture is stirred at ~78C
for 30 mi~utes. The reaction mixture is pouxed into 0.5 ~ monobasic potassium phosphate ~uffer and extracted with two 100 ml portions of methylene chloride. The combined organic extracts are dried over sodium sulfate and concentrated to an oily residue~ The title compound is isolated by column chromatograp~y as a racemateO
B) ~o- ne~
azetidinvl sul~a~e, PYridine salt Following the hydrogenolysis and sulfation procedures described in example 4, parts C and D, but utilizing 3-methoxy-3-~(phenylacetyl)amino]-l-[tphenylmethyl)oxy] 2-azetidinone in place of (S)-3 ~(phenylacetyl)amino~ l~[(phenylmethyl)oxy]-2-azetidinone, yield~ the title compoundO
Claims (28)
1. A process for the preparation of a .beta.-lactam having the formula I:
I
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl, which comprises either a) cyclising a compound of the formula:
wherein A is a nitrogen protecting group, X is a leaving group and R3, R4 and Y have the meaning stated above, by treatment with a base to provide a compound of the formula:
and then removing the protecting group A to provide a compound of formula I; or b) cyclising a compound of the formula:
to provide a compound of the formula and then removing the protecting group A to provide a compound of formula I; or c) deprotecting a compound of the formula:
to remove the protecting group A and thus provide a compound of formula I.
I
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl, which comprises either a) cyclising a compound of the formula:
wherein A is a nitrogen protecting group, X is a leaving group and R3, R4 and Y have the meaning stated above, by treatment with a base to provide a compound of the formula:
and then removing the protecting group A to provide a compound of formula I; or b) cyclising a compound of the formula:
to provide a compound of the formula and then removing the protecting group A to provide a compound of formula I; or c) deprotecting a compound of the formula:
to remove the protecting group A and thus provide a compound of formula I.
2. The process of claim 1 (a) wherein the cyclisation is carried out in the presence of a base.
3. The process of claim 2 wherein the base is potassium carbonate.
4. The process of claim 1 (a) wherein there is present an organic solvent.
5. The process of claim 4 wherein the solvent is acetone.
6. The process of claim 1 (a) which is carried out by heating under reflux conditions.
7. The process of claim 1 (a) which is carried out by heating with potassium carbonate in acetone under reflux conditions.
8. The process of claim 1 (a) wherein the leaving group X is a methanesulfonyloxy group.
9. The process of claim 1 (b) wherein the cyclisation is carried out by means of triphenylphosphine and diethylazodicarboxylate.
10. The process of claim 1 (a), (b), or (c) wherein the protecting group is t-butoxycarbonyl which is removed by treatment with trifluoroacetic acid.
11. The process of claim 1 (a), (b) or (c) wherein the protecting group is benzyloxycarbonyl which is removed by catalytic hydrogenation.
12. The process of claim 11 wherein the catalytic hydrogenation is carried out by means of palladium on charcoal.
13. The process of claim 1 (a), (b) or (c) wherein the protecting group is o-nitrophenylsulfenyl which is removed by treatment with p-toluenesulfonic acid in combination with p-thiocresol.
14. The process of claim 1 wherein R3 and R4 are hydrogen.
15. The process of claim 1 wherein R3 is hydrogen and R4 is methyl.
16. The process of claim 1 wherein R3 is methyl and R4 is hydrogen.
17. A .beta.-lactam having the formula I:
I
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl, when prepared by the process of claim 1.
I
wherein R3 and R4 are the same or different and each is hydrogen or alkyl and Y is benzyl or pivaloyl, when prepared by the process of claim 1.
18. A .beta.-lactom, as defined in claim 17, when prepared by the process of claim 2 or 3.
19. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 4 or 5.
20. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 6 or 7.
21. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 8.
22. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 9.
23. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 10.
24. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 11 or 12.
25. A .beta.-lactam, as defined in claim 17, when prepared by the process of claim 13.
26. A .beta.-lactam, as defined in claim 17, wherein R3 and R4 are hydrogen, when prepared by the process of claim 14.
27. A .beta.-lactam, as defined in claim 17, wherein R3 is hydrogen and R4 is methyl, when prepared by the process of claim 15.
28 A .beta.-lactam, as defined in claim 17, wherein R3 is methyl and R4 is hydrogen, when prepared by the process of claim 16.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/202,830 US4337197A (en) | 1980-10-31 | 1980-10-31 | O-sulfated β-lactam hydroxamic acids and intermediates |
| US202,830 | 1980-10-31 | ||
| CA000388104A CA1179339A (en) | 1980-10-31 | 1981-10-16 | O-SULFATED .beta.-LACTAM HYDROXAMIC ADIDS |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000388104A Division CA1179339A (en) | 1980-10-31 | 1981-10-16 | O-SULFATED .beta.-LACTAM HYDROXAMIC ADIDS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1193272A true CA1193272A (en) | 1985-09-10 |
Family
ID=25669462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000461837A Expired CA1193272A (en) | 1980-10-31 | 1984-08-24 | O-sulfated beta-lactam hydroxamic acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1193272A (en) |
-
1984
- 1984-08-24 CA CA000461837A patent/CA1193272A/en not_active Expired
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