AP398A - Carbapenems derivatives, their preparation and their use in pharmaceutical compositions. - Google Patents

Carbapenems derivatives, their preparation and their use in pharmaceutical compositions. Download PDF

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AP398A
AP398A APAP/P/1993/000480A AP9300480A AP398A AP 398 A AP398 A AP 398A AP 9300480 A AP9300480 A AP 9300480A AP 398 A AP398 A AP 398A
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Prior art keywords
hydroxyethyl
pyrrolidin
carboxy
ylthio
vas
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APAP/P/1993/000480A
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AP9300480A0 (en
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Michael John Betts
Gareth Morse Davies
Michael Lingard Swain
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Zeneca Ltd
Zeneca Pharma Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
    • C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
    • C07D477/20—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to carbapenems and provides a compound of the

Description

ANTIBIOTIC COMPOUNDS
The present invention relates to carbapenems and in particular to such compounds containing a carboxy substituted phenyl group. This invention further relates to processes for their preparation, to intermediates in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The compounds of this invention are antibiotics and can be used in the treatment of any disease that is conventionally treated vith antibiotics for example in the treatment of bacterial infection in mammals including humans.
Carbapenems vere first isolated from fermentation media in 1974 and vere found to have broad spectrum antibacterial activity.
Since this discovery substantial investigations have been made into nev carbapenem derivatives and many hundreds of patents and scientific papers have been published.
The first, and so far the only, carbapenem to be commercially marketed is imipenem (N-formimidoyl thienaraycin). This compound has a broad spectrum of antibacterial activity.
The present invention provides compounds vith a broad spectrum of antibacterial activity including against both Gram positive and negative, aerobic and anaerobic bacteria. They exhibit good stability to beta-lactamases. In addition representative compounds of this invention exhibit a very favourable duration of action.
The carbapenem derivatives referred to herein are named in accordance vith the generally accepted semi-systematic nomenclature:
BAD
ORIGINAL
Accordingly the present invention provides a conpound of the formula (I):
AP Ο Ο Ο 3 9 8
( . or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof vherein:
f is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R is hydrogen or C. .alkyl;
A”4*
R is hydrogen or C. .alkyl;
5
R and R are the same or different and are selected from hydrogen, halo, cyano, C^alkyl, nitro, hydroxy, carboxy, C^ ^alkoxy,
Cj ^alkoxycarbonyl, aminosulphonyl, Cj_^alkylaminosulphonyl, di-Cj alkylaminosulphonyl, carbamoyl, ^alkylcarbamoyl, di-Cj^ alkylcarbanoyl, trifluoromethyl, sulphonic acid, amino, ^alkylamino, di-Cj ^alkylamino, Cj_^alkanoylanino, C^_^alkanoyl(N-C^ ^alkyl)amino, ^alkanesulphonamido and _^alkylS(O)n- vherein n is zero, one or tvo:
vith the proviso that there is no hydroxy or carboxy substituent in a 3 position ortho to the link to -NR -.
Alkyl vhen used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
Preferably R^ is 1-hydroxyethyl.
R is hydrogen or C. .alkyl for example methyl, ethyl, ι-* 2 n-propyl, isopropyl or n-butyl. Preferably R is hydrogen or methyl 2 and in particular R is methyl.
R^ is hydrogen or Cj_*alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl. Preferably R^ is hydrogen.
BAD ORIGINAL Ά
AP Ο Ο Ο 3 9 8
- 3 4 5
R and R are the sane or different and are selected from hydrogen; halo for example fluoro, bromo or chloro; cyano; Cj ^alkyl for example methyl, ethyl, n-propyl, isopropyl or n-butyl; nitro; hydroxy; carboxy; C^_4alkoxy for example methoxy or ethoxy; C|_4alkoxycarbonyl for example methoxycarbonyl, ethoxycarbonyl and n-propoxycarbonyl; aminosulphonyl; Cj^aIkylaminosulphonyl for example methylaminosulphonyl and ethylaainosulphonyl; di-C^ *alkylaminosulphonyl for example di-methylaminosulphonyl, ( methylethylaminosulphonyl and di-ethylaminosulphonyl; carbamoyl;
C^^alkylcarbamoyl for example methylcarbamoyl or ethylcarbamoyl;
C di-C^_4alkylcarbamoyl for example dimethylcarbamoyl or diethylcarbamoyl; trifluoromethyl; sulphonic acid; amino;
Cj_4alkylamino for example methylamino or ethylamino; di-C^ ^alkylamino for example dimethylamino or diethylamino; C^^alkanoylamino for example acetamido or propionamido; C^_4alkanoyl(N-Cj ^alkyl)amino for example N-methylacetamido; C^^alkanesulphonamido for example methanesulphonamido; and C14alkylS(0)n- for example methylthio, methylsulphinyl or methylsulphonyl.
In a particular aspect a suitable class of compounds is that 4 5 in vhich R and R are the same or different and are selected from ' hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl,
¢. ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methylsulphonyl, methanesulphonamido or acetamido.
5
R and R may both be other than hydrogen but, in general, it 4 5 is particularly preferred that at least one of R and R is hydrogen.
•
Particularly preferred compounds are those in vhich R4 is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl and R^ is hydrogen.
The present invention covers all epimeric, diastereoisomeric and tautomeric forms of the compounds of the formula (I) vherein the absolute stereochemistry at the 5-position is as illustrated in
BAD ORIGINAL d
AP Ο Ο Ο 3 9 8 fornula (I). Vhen a bond is represented by a wedge, this indicates that in three dinensions the bond would be coning out of the paper and when a bond is hatched, this indicates that in three dinensions the bond would be going back into the paper. The conpounds of the fornula (I) have a number of other stereocentres, nanely: within the group R1 (when is 1-hydroxyethyl or 1-fluoroethyl); at the 6-position; at the 2
1-position (when R is Cj^alkyl); and at the 2' and 4' positions in the pyrrolidine ring:
(II)
Preferred compounds are those in which the beta-lactan ring protons are in trans configuration with respect to one another. Vhen R1 is 1-hydroxyethyl or 1-fluoroethyl it is preferred that the 8-substituent has the R-configuration. Thus a preferred class of compounds is that of the fornula (III):
and pharmaceutically acceptable salts and in vivo hydrolysable esters 2 3 4 5 thereof, wherein R , R , R and R are as hereinbefore defined.
Vhen R is ^alkyl for example methyl it is preferred that the compound is in the form of the IR configuration.
Preferred compounds are those in which the pyrrolidine ring has the following absolute stereochemistry at the 2'- and 4'positions:
BAD ORIGINAL ft
AP Ο Ο Ο 3 9 8 (
ζ*' (
A preferred class of compounds that of the formula (IV):
of the present invention is
COOH (IV) and pharmaceutically acceptable salts and in vivo hydrolysable esters 3 4 5 thereof vherein R , R , and R are as defined hereinbefore in formula (I).
Particularly preferred compounds vithin the formula (IV) are 3 4 5 those vherein R is hydrogen and R and R are the same or different and are selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, methanesulphonyl, trifluoromethyl, sulphonic acid, methylsulphlnyl, methanesulphonamido or acetamido.
Especially preferred compounds vithin the formula (IV) are 3 5 A those vherein R-5 and R3 are both hydrogen and R* is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl.
Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate, maleate and salts formed vith phosphoric and sulphuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine,
BAD ORIGINAL $
AP Ο Ο Ο 3 9 8
- 6 dibenzylamine, Ν,Ν-dibenzylethylamine or amino acids for example lysine. For the avoidance of doubt there may be one, tvo or three salt-forming cations dependent on the number of carboxylic acid functions and the valency of said cations.
Preferred pharmaceutically acceptable salts are sodium and potassium salts. Hovever, to facilitate isolation of the salt during preparation, salts vhich are less soluble in the chosen solvent may be preferred vhether pharmaceutically acceptable or not.
In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be Identified by administering, eg. intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include Cj_galkoxymethyl esters for example methoxymethyl, _galkanoyloxymethy1 esters for example pivaloyloxymethyl, phthalidyl esters, C^gcycloalkoxycarbonyloxyCj ^alkyl esters for example 1-cyclohexyloxycarbonyloxyethyl;
l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2onylmethyl; and C16alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention. Suitable in vivo hydrolysable ester forming groups for hydroxy include acetyl, propionyl, pivaloyl, ^alkoxycarbonyl for example ethoxycarbonyl and phenylacetyl.
Particular compounds of the present invention are:
(IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-hydroxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4/S)-2-(2-(3-carboxy-4-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-chlorophenylcarbaraoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic
BAD ORIGINAL
AP Ο Ο Ο 3 9 8 acid, (IR,5S,6S,8R,2'S,4'S)-2-(2- (3-carboxyphenylcarbaaoyl) pyrrolidin-4ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S) -2- (2- (3-carboxy-6-nethanesulphonylphenylcarbaaoy1) pyrrolidin-4-ylthio) -6-(1 -hydroxyethyl )-1 -aethylcarbapenea-3 carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2- (2- (3-carboxy-4-f luoropheny lcarbaaoyl) pyrrolidin-4-ylthio )-6-( 1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-fluorophenylcarbaaoyl)pyrrolidin-4-ylthio )-6-( 1-hydroxyethyl) -1-ae thy lcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2/S,4/S)-2-(2-(3-carboxy-2,4-difluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (1R,5S,6S,8R,2'S, 4'S )-2-(2-(3,4-dicarboxyphenylcarbaaoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl) - l-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2- (3-carboxy-4-hydroxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxyphenylcarbaaoyl)pyrrolidin4-ylthio)-6-( 1-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (IR, 5S, 6S, 8R, 2' S, 4' S) -2- (2- (2-carbaaoyl-3-carboxyphenylcarbaaoyl) pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-carbaaoylphenylcarbaaoyl) pyrrolidin-4-y lthio )-6-( 1-hydroxyethyl) -l-aethylcarbapenea-3-carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-carbaaoylphenylcarbaaoyl) pyrrolidin-4-ylthio )-6-(1-hydroxyethyl)-1-ae thy lcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-acetaaidophenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-acetamidophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic
BAD ORIGINAL
AP Ο Ο Ο 3 9 8 acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methylsulphonaaidophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenen-3carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-sulphophenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (IR, 5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-carbaaoylphenylcarbanoyl) ( pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-diaethylaninocarbonylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3carboxylic acid, (5R,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbaaoyl)pyrrolidin-4ylthio)-6-(l-hydroxyethyl)carbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-aethylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic ( acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-aethylphenylcarbaaoyl)( pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-methoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-aethoxyphenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-Bethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-methoxyphenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid,
BAD ORIGINAL ft
AP Ο Ο Ο 3 9 8
-9(1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4,6-diaethoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethoxycarbonylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-cyanophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-trifluoromethylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenea-3carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4,6-difluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-aethylsulphinylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenem-3carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethylsulphonylcarbaaoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-nethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-fluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2/S,4/S)-2-(2-(3-carboxy N'-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, and pharmaceutically acceptable salts and in vivo hydrolysable esters thereof.
Preferred compounds of the present invention are:
(IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methylphenylcarbamoyl)BAD ORIGINAL
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- ΙΟ pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-1-methylcarbapeneo-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-yltbio)-6-(1-hydroxyethyl)-1 -methylcarbapenem-3carboxylie acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbaaoyl)pyrrolidin-4ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid. (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-fluorophenylcarbamoyl)( pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenera-3-carboxylic acid, ( (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-fluorophenylcarbamoyl)pyrrolidin-4-yl thio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3,4-dicarboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid.
(IR,5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid. (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, and pharmaceutically acceptable salts thereof.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof
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- II for the therapeutic treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance vith standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition vhich comprises a compound of the formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this Invention may be formulated by means known in the art into the fora of, for example, tablets, capsules, aqueous or oily solutions or suspensions, emulsions, dispersible povders, suppositories and sterile injectable aqueous or oily solutions or suspensions.
The compounds of the present invention may be formulated as dry povder filled vials, vhich may contain the compound of the present invention alone or as a dry blended mixture. For example an acidic compound of the present invention may be dry blended vith an alkali metal carbonate or bicarbonate. Freeze dried formulations of compounds of the present invention, alone or as a mixture with standard excipients, are possible. Standard excipients include structure formers, cryoprotectants and pH modifiers, such as, mannitol, sorbitol, lactose, glucose, sodium chloride, dextran, sucrose, maltose, gelatin, bovine serum albumin (BSA), glycine, mannose, ribose, polyvinylpyrrolidine (PVP), cellulose derivatives, glutamine, inositol, potassium glutamate, erythritol, serine and other amino acids and buffer agents e.g. disodium hydrogen phosphate and potassium citrate.
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- 12 In addition to the coapounds of the present invention the pharaaceutical composition of this invention may also contain, or be co-administered vith, one or more knovn drugs selected froa other clinically useful antibacterial agents (for example other beta-lactams or aminoglycosides), inhibitors of beta-lactamase (for example clavulanic acid), renal tubular blocking agents (e.g. probenecid) and inhibitors of metabolising enzymes (for example inhibitors of dehydropeptidases, for example Z-2-acylamino-3-substituted propenoates 1 such as cilastatin) and N-acylated amino acids (for example see
(. EP-A-178911) vhich reduce adverse effects on the kidney.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule vhich contains betveen lOOrag and lg of the compound of this Invention.
A preferred pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example a sterile injectable containing betveen 1 and 50Z v/v of the compound of this invention.
r
Specific examples of compositions, vhich are constituted as a ( 1Z solution in vater, freeze dried and may be made up by adding 0.9Z aqueous sodium chloride solution to give the required concentration, preferably lmg-lOmg/ml, are as follovs:
Composition 1
Compound of Example 1
Composition 2
Compound of Example 1 Glycine
Further specific examples
50rag
50mg 3 lmg of compositions are as above, but
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- 13 vhere the compound of example 1 is replaced by any one of examples 2 to 37.
The pharmaceutical compositions of the invention vill normally be administered to man in order to combat infections caused by bacteria, In the same general manner as that employed for imipenem due allowance being made in terms of dose levels for the potency and duration of action of the compound of the present invention relative to f the clinical use of imipenem. Thus each patient vill receive a dally intravenous, subcutaneous or intramuscular dose of 0.05 to 5g, and
G preferably 0.1 to 2.5g, of the compound of this invention, the composition being administered 1 to 4 times per day, preferably 1 or 2 times a day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous Infusion over a period of time. Alternatively each patient vill receive a daily oral dose vhich is approximately equivalent to the daily parenteral dose. Thus a suitable daily oral dose is 0.05 to 5g of the compound of this invention, the composition being administered 1 to 4 times per day.
- In a further aspect the present invention provides a process for preparing the compounds of the formula (I) or a pharmaceutically ( acceptable salt or in vivo hydrolysable ester thereof vhich process comprises deprotecting a compound of the formula (V):
4 5 4 5 wherein R , R and R are as hereinbefore defined (R and R being optionally protected if appropriate); -COOR6 and -COOR? are carboxy or
3 9 protected carboxy; R is a group R or an amino protecting group; R is hydrogen or an amino protecting group; and Rl® is a group Rl, protected
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- 14 1-hydroxyethyl or protected hydroxymethyl; and vherein at least one protecting group is present; and thereinafter if necessary;
(i) forming a pharmaceutically acceptable salt, (ii) esterifying to form an in vivo hydrolysable ester.
Protecting groups may in general be chosen from any of the groups described in the literature or known to the skilled chemist as ( appropriate for the protection of the group in question, and may be (, introduced by conventional methods.
Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group vith minimum disturbance of groups elsewhere in the molecule.
The compounds of the formula (V) are novel and form another aspect of the invention.
Specific examples of protecting groups are given below for the sake of convenience, in vhich lover signifies that the group to vhich it is applied preferably has 1-4 carbon atoms. It vill be understood that these examples are not exhaustive. Vhere specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention.
A carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
Examples of carboxy protecting groups include straight or branched chain (l-12C)alkyl groups (eg isopropyl, t-butyl); lower alkoxy lower alkyl groups (eg methoxymethyl, ethoxymethyl,
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- 15 isobutoxymethyl); lover aliphatic acyloxy lover alkyl groups, (eg acetoxymethyl, propionyloxynethyl, butyryloxymethyl, pivaloyloxymethyl); lover alkoxycarbonyloxy lover alkyl groups (eg 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lover alkyl groups (eg p-methoxybenzyl, o-nitrobenzyl, £-nitrobenzyl, benzhydryl and phthalidyl); tri(lover alkyl)silyl groups (eg trimethylsilyl and t-butyldimethylsilyl); tri(lover alkyl)sllyl lover alkyl groups (eg trimethylsilylethyl); and (2-6C)alkenyl groups (eg allyl and ( vinylethyl).
1 Methods particularly appropriate for the removal of carboxyl protecting groups include for example acid-, base-, metal- or enzymically-catalysed hydrolysis.
Examples of hydroxyl protecting groups include lover alkenyl groups (eg allyl); lover alkanoyl groups (eg acetyl); lover alkoxycarbonyl groups (eg t-butoxycarbonyl); lover alkenyloxycarbonyl groups (eg allyloxycarbonyl); atyl lover alkoxycarbonyl groups (eg benzoyloxycarbonyl, £-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, £-nitrobenzyloxycarbonyl); tri lover alkylsilyl (eg trimethylsilyl, t-butyldimethylsilyl) and aryl lover alkyl (eg benzyl) groups.
c
Examples of amino protecting groups include formyl, aralkyl groups (eg benzyl and substituted benzyl, eg £-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenyImethyl); di-£-anisylmethyl and furylmethyl groups; lover alkoxycarbonyl (eg t-butoxycarbonyl); lover alkenyloxycarbonyl (eg allyloxycarbonyl); aryl lover alkoxycarbonyl groups (eg benzyloxycarbonyl, £-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, £-nitrobenzyloxycarbonyl; trialkylsilyl (eg trimethylsilyl and t-butyldimethylsilyl); alkylidene (eg methylidene); benzylidene and substituted benzylidene groups.
Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base-, metal- or
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APO00398
- 16 .
enzymically-catalysed hydrolysis, for groups such as £-nitrobenzyloxycarbonyl, hydrogenation and for groups such as o-nitrobenzyloxycarbonyl, photolytically.
Preferred protecting groups for carboxy and hydroxy groups in compounds of the foraula (I) are the groups allyl and j>-nitrobenzyl. A preferred method for removal of the allyl group is by palladium catalysis using tetrakis(triphenylphosphine)palladium and Meldrum's acid, in a dipolar aprotic solvent tetrahydrofuran mixture, such as dimethylsulphoxide/tetrahydrofuran or 1,3-dimethyl-2-oxo-tetrahydropyrimldine/tetrahydrofuran, or an alcohol/tetrahydrofuran mixture such as isopropanol/tetrahydrofuran or ethanol/tetrahydrofuran, preferably at ambient temperature. Alternatively, methylaniline may be used in place of Meldrum's acid, in dichioromethane. These conditions allov isolation of the product by precipitation of the sodium salt on the addition of a sodium salt such as sodium 2-ethylhexanoate.
A preferred method for removal of the £-nitrobenzyl group is hydrogenation using a palladium catalyst.
In another aspect of the present invention the compounds of the formulae (I) and (V) may be prepared by
a) reacting compounds of the formulae (VI) and (VII):
vherein R?, R^-Κ^θ are as hereinbefore defined and L is a leaving group, or
b) cycllsing a compound of the formula (VIII):
BAD ORIGINAL A (VIII)
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vherein R2, R^-R^ as hereinbefore defined and I^-R^ are independently selected fron C. ,alkoxy, aryloxy, di-C. .alkylamino and ll ”l3 diarylamino or any tvo of R -R represent o-phenylenedioxy;
13 or one of R -R is Cj^alkyl, allyl, benzyl or phenyl, and the other tvo values are independently selected from C^alkyl, trifluorornethyl or phenyl, vherein any phenyl group is optionally substituted vith Cj^alkyl or Cj^alkoxy:
and vherein any functional group is optionally protected and thereinafter if necessary:
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt;
(iii) esterifying to form an in vivo hydrolysable ester.
Suitably in the compound of the formula (VI) L is the reactive ester of a hydroxy group such as a sulphonate (for example C j _ 6alkanesulphonyloxy, tr i fluororaethanesulphonyloxy, benzenesulphonyloxy, toluenesulphonyloxy), a phosphoric ester (for example a diarylphosphoric ester such as diphenylphosphoric ester) or L is a halide (for example chloride). In an alternative L is a sulphoxide for example -SOCH-CH-NHCOCH3 vhich may be readily displaced. Preferably L is diphenylphosphoric ester (-OP(O)(OPh)?).
Compounds of the formula (VI) and their preparation are veil knovn in the carbapenem literature, for example see EP-A-126587, EP-A-160391, EP-A-243686 and EP-A-343499.
The reaction betveen the compounds of the formulae (VI) and (VII) is typically performed in the presence of a base such as an
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- 18 organic amine for example di-isopropylethylamine or an inorganic base for example an alkali metal carbonate such as potassium carbonate.
The reaction is conveniently performed at a temperature between -25°C and ambient, suitably at about -20*C. The reaction is generally performed in an organic solvent such as acetonitrile or dimethylformamide. The reaction is generally performed in a manner similar to that described in the literature for similar reactions.
The compounds of the formula (VII) are novel and form another aspect of the present invention.
The compounds of the formula (VII) may be prepared by the deprotection of a compound of the formula (IX):
(IX)
6 8 9 14 wherein R -R , R and R as hereinbefore defined and R is a protecting group, for example Cj^alkanoyl, C^galkoxycarbonyl or benzoyl. Preferred values for R1 are acetyl and t-butoxycarbonyl.
The compounds of the formula (IX) can be converted to the compounds of the formula (VII) by standard methods of deprotection, for example acetyl groups can be removed by basic hydrolysis in aqueous alkanol or alkenol for example allyl alcohol.
The compounds of the formula (IX) are novel and form another aspect of the present invention.
The compounds of the formula (IX) may be prepared by the reaction of an activated derivative of a compound of the formula (X), vhich may be formed in situ, vith a compound of the formula (XI):
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- 19 :-CX
COOH
(XI)
6 8 9 14 wherein R -R , R , R and R are as hereinbefore defined. Activated derivatives of the compound of the formula (X) Include acid halides, anhydrides and 'activated' esters such as lH-benzo[1,2,3] triazol-l-yl, pentafluorophenyl and 2,4,5-trichlorophenyl esters or the benzimidazol-2-yl ester of the thiocarboxylic acid corresponding to (X). The reaction of the compounds of the formulae (X) and (XI) is performed under standard methods, for example in the presence of Vilsmeier reagent (thus forming the reactive derivative of (X) in situ) at temperatures in the region -30°C to 25°C, preferably in the region -20eC to 5eC.
The compounds of the formulae (X) and (XI) are prepared by standard methods knovn to the skilled chemist such as the methods of the Examples hereinafter, the methods described in EP-A-126587 or by methods analogous or similar thereto.
Suitably, in the compounds of the formula (VIII), R^-R^ are independently selected from Cl-6 alkoxy such as methoxy, ethoxy, isopropoxy, n-propoxy or n-butoxy; aryloxy such as optionally phenoxy; di-C. .alkylamino such as dimethylamino or diethylamino;
ii 13 diarylamino such as diphenylamino or any tvo of R -R represent 11 13 o-phenylenedioxy. Preferably each of R -R have the same value and are C^^alkoxy for example methoxy, ethoxy, Isopropoxy or n-butoxy or are phenoxy.
The compounds of the formula (VIII) are cyclized under conventional conditions knovn in the art to form compounds of the formula (V). Typical conditions are heating in a substantially inert
BAD ORIGINAL ft organic solvent such as toluene, xylene or ethyl acetate at temperatures in the region 60-150°C. Typically the reaction is performed in an atmosphere of nitrogen and is carried out in the presence of a radical scavenger for example hydroquinone.
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- 20 The compounds of the formula (VIII) may be formed and cyclized in situ. The compounds of the formula (VIII) may conveniently be prepared by reacting compounds of the formulae (XII) and (XIII):
PRUR12R13 (XII) (XIII)
4 13 vherein R , and R -R are as hereinbefore defined.
Suitably the compound of the formula (XIII) is a phosphite or is the functional equivalent of such a compound.
The reaction betveen the compounds of the formulae (XII) and (XIII) is conveniently performed in an organic solvent such as toluene, xylene, ethyl acetate, chloroform, dichloromethane, acetonitrile or dimethylformamide. Typically the reaction is carried out at an elevated temperature for example 60-150°C.
The compounds of the formula (XII) may be prepared by a number of methods knovn in the art. For example the compounds of the formula (XII) may be prepared by the acylation of a compound of the formula (XIV):
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compound of the formula (XV):
Cl-CO-COOR7 (XV) wherein R is as hereinbefore defined.
The compounds of the formula (XIV) may be prepared by reacting compounds of the formulae (XVI) and (VII):
(XVI) c
Γ· s
10 wherein R and R are as hereinbefore defined. The compounds of the formula (XVI) are known in the art and may be reacted with the compounds of the formula (VII) under conventional acylation methods known in the art.
Compounds of the formulae (VII), (XII) and (XIV) are novel· and, as such, form another aspect of this invention.
The following biological test methods, data and Examples serve to illustrate the present invention.
Antibacterial Activity
The pharmaceutically acceptable carbapenem compounds of the
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- 22 present invention are useful antibacterial agents having a broad spectrum of activity in vitro against standard laboratory microorganisms, both Gram-negative and Gram-positive, vhich are used to screen for activity against pathogenic bacteria. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system. In particular the carbapenems of the present invention shov good stability to beta-lactamases and have a particularly good elimination half life in mammals. In general compounds shov significant improvement over imipenem.
(
The antibacterial properties of the compounds of the invention may also be demonstrated in vivo in conventional tests.
Carbapenea compounds have generally been found to be relatively non-toxic to varm-blooded animals, and this generalisation holds true for the compounds of the present invention. Compounds representative of the present invention vere administered to mice at doses in excess of those required to afford protection against bacterial infections, and no overt toxic symptoms or side effects attributable to the administered compounds vere noted.
o
.. The folloving results vere obtained for representative compounds on a standard in vitro test system using Diagnostic
Sensitivity Test. The antibacterial activity is described in terms of the minimum inhibitory concentration (MIC) determined by the 4 agar-dilution technique vith an inoculum size of 10 CFU/spot.
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1 1- ORGANISM | 1 1 1 MIC (ug/ml)
1 EXAMPLE 10 ceftriaxone
2 4
Enterobacter | cloacae 029 | I 0.06 0.03 0.03 0.01 0.06
1 Enterobacter | 1.00 1.00 0.50 0.25 32
cloacae 108 | 1 E. coli | TEH | I 0.03 0.02 0.02 0.01 0.03
1 S. aureus | 147N | 1 0.25 0.50 0.25 0.13 2.0
In the examples: (a) NHR spectra vere taken at 200MHz or 400MHz;
(b) Allyloxy means the propen-1-yloxy group -OCi^CH-CHj;
(c) THF means tetrahydrofuran;
(d) DHF means dimethylformamide;
(e) Meldrum's acid is 2,2-dimethyl-l,3-dioxane-4,6-dione.
(f) Evaporation of solvents vas carried out under reduced pressure;
(g) EtOAc means ethyl acetate;
(h) EEDQ means N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline;
(i) DHSO means dimethyl sulfoxide;
(j) DCCI means dicyclohexylcarbodiimide; and (k) The peak positions in NHR spectra taken in DMSO-dg and acetic acid-d^ vary depending on the ratio of DHSO to acetic acid.
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- 2« Example 1 (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5-hydroxyphenylcarbamoyl)pyrrolidin-4-yl-thio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, dlsodlum salt
To a solution of allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate (500 mg, 0.72 mM) and 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid,
829 mg, 5.75 mM) in a mixture of DMF (8 ml) and THF (4 ml), under an argon atmosphere, vas added tetrakis(triphenylphosphine)palladium (83 mg, 0.072 mM). The solution vas stirred, under argon vith protection from light, for 2 hours. The solution vas diluted vith diethyl ether (40 ml), and the resultant precipitate centrifuged, and the supernatant vas removed. The product vas washed by resuspension in ether followed by centrifugation, and finally dried under high vacuum. The crude product vas dissolved in vater (10 ml) and the pH adjusted to 6.8 vith NaHCO^. After filtration, the solution vas subjected to chromatography on Diaion CHP20P resin, and the fractions combined as appropriate to ( give the title product (66X). Nmr (DMSO-dg + acetic acid-d^): & 1.18 (d, 6H); 1.82 (m, part obscured, IH); 2.79 (m, IH); 3.03 (dd, IH); 3.22 (dd, IH); 3.38 (quintet, IH); 3.57 (dd, IH); 3.82 (quintet, IH); 3.99 (quintet, IH); 4.19 (dd + m, 2H); 7.13 (t, IH); 7.44 (t, IH); 7.65 (t, IH).
The starting materials vere prepared as follows:
Allyl 3-allyloxy-5-aminobenzoate
3-Hydroxy-5-nitrobenzoic acid (3.9 g, 21.3 mM) vas dissolved in DMF (55 ml), and anhydrous (11.78 g, 76.5 mM) added vith stirring. Allyl bromide (5.4 ml, 62.4 mM) vas run in, and the mixture stirred for 18 hours at ambient temperature. The solvent vas removed by evaporation, the residue treated vith vater, the pH vas adjusted to
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- 25 5.5, and product vas extracted into ethyl acetate. The combined extracts vere vashed vith aqueous NaH^PO^, vater, brine, and dried over MgSO^. The residue after evaporation vas subjected to chromatography on silica, eluting vith a mixture of petrol/EtOAc (10:1), to give allyl 3-allyloxy-5-nitrobenzoate (5.94 g, 90X). Nmr (CDCl^): δ 4.66 (dt,
2H); 4.87 (dt, 2H); 5.31-5.52 (m, 4H); 5.94-6.14 (m, 2H); 7.92 (m, 2H);
8.46 (t, IH).
Ms (CI): 264 (MH)+
The above ester (2 g, 7.6 mM) vas dissolved in ethyl acetate (15 ml), and added to a suspension of SnClj^H^ (13.7 g, 61 mM), heated under reflux, in ethyl acetate (35 ml) under argon. The mixture vas heated to reflux for 4 hours, cooled, and poured into a mix of 880 ammonia (20 ml) and vater (20 ml). The organic layer vas separated and three further extractions made vith ethyl acetate. The combined extracts vere vashed vith dilute ammonia solution, vater and brine, dried over MgSO^, and evaporated to give a yellov oil of allyl 3-allyloxy-5-aminobenzoate (1.53 g, 86Ϊ). Nmr (CDCl^): 6 3.60 (br,
2H); 4.53 (dt, 2H); 4.78 (dt, 2H); 5.25-5.44 (m, 4H); 5.96-6.12 (m,
2H); 6.43 (dt, IH); 7.00 (m, 2H).
Ms (CI): 233 (MH)+
Preparation of Side Chain Pyrrolidin-4-ylthioacetate
The cyclohexylamine salt of 4-acetylthio-l-allyloxycarbonyl2-carboxy-pyrrolidine (5.6 g, 15 mM) vas suspended in ethyl acetate, and shaken successively vith 2M HCl (20 ml and 10 ml), vater and brine, and the ethyl acetate layer dried over MgSO^. Evaporation gave the free acid. Vilsmeier reagent vas prepared by treatment of dimethylformamide (0.51 ml, 6.6 mM) in dichloromethane (20 ml) under argon vith oxalyl chloride (0.52 ml, 6 mM) in dichloromethane (5 al) for 30 minutes. 4-Acetylthio-l-allyloxycarbonyl-2-carboxypyrrolidine (1.64 g, 6 mM) in dichloromethane (7 ml) vas added to this in one portion, folloved by N-methylmorpholine (0.79 ml, 7.2 mM), in dichloroBAD ORIGINAL $
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- 26 methane (3 ml) and stirring continued for 30 minutes at -10°. After cooling to -20°, allyl 3-allyloxy-5-aminobenzoate (1.39 g, 5.9 mM) plus N-methylmorpholine (0.79 ml, 7.2 mM) dissolved in dichloromethane (15 ml) vere added dropvise. The temperature vas alloved to rise to 0°, and the reaction stored for 18 hours. After dilution vith dichloromethane (100 ml), the mixture vas vashed vith 2M HCl, H2O, and saturated NaHCOj, dried over MgSO^, and evaporated. Crude material vas purified by medium pressure chromatography on silica using a gradient of petrol in dichloromethane (3:1 to 2:1) to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4ylthioacetate as a gum (2.37 g, 81X). Nmr (CDCl^): A 2.32 (s, 3H);
2.58 (br, 2H); 3.39 (dd, IH); 4.03 (quintet, IH); 4.13 (dd, IH); 4.55 (t, part obscured, IH); 4.58 (dt, 2H) 4.68 (dt, 2H); 4.81 (dt, 2H);
5.23-5.49 (m, 6H); 5.84-6.15 (m, 3H); 7.36 (t, IH); 7.57 (t, IH); 7.66 (t, IH); 9.10 (br, IH).
Ms (+ve FAB): 489 (MH)+, 511 (M + Na)+
Conversion to Pyrrolidin-4-ylthlols (2S,4S)-4-Acetylthio-l-allyloxycarbonyl-2-(3-allyloxy-5allyloxycarbonylphenylcarbamoyl)pyrrolidine (1.89 g, 3.9 mM) vas dissolved in allyl alcohol (25 ml) and the solution flushed vith argon.
IM Sodium hydroxide (4 ml, 4 mM) vas added, the mixture stirred at ambient temperature for 2 hours, and then evaporated to dryness. The residue taken up in ethyl acetate (100 ml), vashed vith 2H HCl, vater,
NaHCOp brine, dried (MgSO^) and evaporated, to give (2S,4S)-1allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol as a gum (1.57 g, 762). Crude material vas used in the next stage.
Preparation of Protected Carbapenems
A solution of allyl (lR,5R,6S,8R)-6-(l-hydroxyethyl)l-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (1.5 g, 3 mM) vas dissolved in dry acetonitrile (18 ml) under argon, cooled to -20®,
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- 27 and diisopropylethylamine (0.63 ml, 3.6 mM) added, followed by dropwise addition of (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-yl-thiol (1.57 g, 3.5 mM) in acetonitrile (12 ml). The reaction mixture vas then stored at -20 for 3 days. Solvent vas evaporated, and the residue purified by medium pressure chromatography on silica with gradient elution (dichloromethane/ethyl acetate 40:60 to 70:30), to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxy-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio )-6-( 1-hydroxyethyl) -1methylcarbapenem-3-carboxylate as a gum (1.25 g, 60Z). Nmr (CDCl^): 6
1.23 (d, 3H); 1.35 (d, 3H); 2.65 (br, 2H); 3.26,3.31 (dd overlapping m, 2H); 3.46 (ra, IH); 3.79 (quintet, IH); 4.01 (dd, IH); 4.19-4.29 (m,
2H); 4.50-4.78 (ra, 9H); 5.19-5.46 (ra, 8H); 5.83-6.12 (m, 4H); 7.36 (br s, IH); 7.64 (m, 2H); 9.00 (br, IH).
Ms (+ve FAB): 696 (MH)+, 718 (M + Na)+
Allyl (IR,5R,6S,8R)-6-(1-hydroxyethyl)-1-methy1-2-diphenylphosphoryloxy-carbapenem-3-carboxylate vas prepared as follows.
To a solution of allyl (lR,5S,6S,8R)-6-(l-hydroxyethyl)l-methyl-2-oxocarbapenam-3-carboxylate (2.66 mMol) [prepared in situ from allyl 2-diazo-3-oxo-4-methyl-4-(3-(l-hydroxyethyl)-2-oxoazetidin4-yl)butanoate and rhodium octanoate: see for example EP-A-208889] and diisopropylethylamine (1.1 equivalents in acetonitrile, at O’C, under an argon atmosphere, vas added dropwise diphenyl chlorophosphate (1.1 equivalents). The solution vas stirred at ambient temperature for 30 minutes to form the corresponding 2-diphenylphosphoryloxycarbapenem.
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I Example | POSITION OF PHENYL SUBSTITUENT 1 1 -1 1 1 R1 „1....... 1 R2 1
I 1 2 1 .1________ 1 3 1 1 1 4 | 5 1 1_______ 1 8 1
1 2 I-------- 1 H 1--------1 | COOH I I I Cl --I------- 1 H I ..... --I------- 1 H I 1 He I 1 H I
3 1 1 H 1 1 | COOH 1 I I H 1 1 H I 1 1 ci I 1 | He I 1 H 1
4 1 1 H 1 1 | COOH I I 1 H 1 1 H 1 1 H I 1 | He I 1 H 1
5 1 1 H | 1 1 | COOH 1 | I H 1 1 H I 1 | so2ch, I 1 1 He I 1 H 1
6 1 1 H 1 1 | COOH 1 I 1 F 1 1 H 1 1 H I 1 | He I 1 H 1
7 1 1 H 1 1 | COOH 1 I 1 H 1 1 H I 1 1 F I 1 | Me I 1 H 1
8 1 1 v 1 1 | COOH 1 I I F 1 1 H I 1 1 H I 1 1 He I 1 H 1
9 1 1 H 1 1 | COOH I COOH 1 1 H I 1 1 H 1 He I 1 H 1
10 1 1 H I 1 1 | COOH 1 I I OH 1 1 H I 1 1 H I 1 | He I 1 H 1
11 1 1 H 1 1 | COOH I I I H 1 | COOH I 1 1 H I 1 | He I i Η 1
12 1 1 H 1 1 1 | COOH | 1 l_ H 1 1 H 1 1 1 H 1 1 | Me 1 _ 1 H 1
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- 29 POSITION OP PHENYL SUBSTITUENT
Example i-...... 1 2 1 .1....... 1 3 1 ..... 1 4 | 5 1 .1________ 1 6 1 1 1 1 k1 I...... 1 1 1 R2 _|____
13 1 H I | COOH | 1 H | conh2 I ι------- 1 H | I Me | _ |---- 1 M
14 1 1 H I 1 | COOH I 1 H 1 1 H 1 | conh2 I 1 Me I 1 1 M
15 1 | CONMe. | 1 2 | COOH I 1 H 1 1 H | 1 1 H 1 | He | 1 1 M
16 1 1 H | 1 | COOH I 1 H 1 | NHCOCH3 I 1 1 H 1 1 Me | 1 1 H
17 1 1 H I 1 | COOH | I NHCOCH3 1 1 H I 1 1 H I 1 | Me | 1 1 M I
18 1 1 H I 1 | COOH | 1 H 1 | NHSO2Me I 1 1 H I 1 | He I 1 1 H I
19 1 1 H I 1 | COOH I 1 H 1 | so3h 1 1 1 H I 1 | Me I 1 1 M
20 1 1 H I 1 | COOH I 1 H 1 1 H I 1 1 H 1 I M I 1 1 H I
21 1 1 H I 1 | COOH | 1 H 1 | CN I 1 ! H I 1 | He I 1 1 M I
22 1 1 H 1 | COOH | 1 H 1 | OMe I 1 1 H | 1 | He I 1 1 M I
23 1 1 H I 1 | COOH I 1 H 1 1 H I 1 | SOHe I 1 1 Me 1 1 M
24 1 1 H I 1 | COOH I 1 H 1 | SO2Me | 1 1 H I 1 f Me I 1 1 H I
25 1 1 H I 1 | COOH I 1 h 1 1 CP3 | 1 1 H 1 | He I 1 1 M I
26 1 1 H 1 1 | COOH 1 1 h 1 1 H 1 1 | OMe 1 1 | He 1 1 1 M 1
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- 30 POSITION OP PHENYL SUBSTITUENT
Example ι....... 1 2 1 _|....... 1 3 1 1 1 _l ___l 4 | 5 1 ........ 1 6 1 _|______ ”1 1 1 R1 1 1 ι l to
27 _ |----- 1 H | 1 | COOH I 1 1 I OHe 1 H I 1 1 H ..... 1 He I - |---- 1 H I
28 1 | ONe I 1 | COOH I 1 1 I H 1 1 H I 1 1 H I 1 1 He I 1 1 H I
29 1 1 H | 1 | COOH I 1 1 I H 1 1 H I 1 | He | 1 He I 1 1 H I
30 1 1 H 1 | COOH I 1 1 I Me 1 1 H I 1 1 H I 1 | He I 1 1 H I
31 1 1 H 1 1 | COOH I 1 1 I H 1 | He I 1 1 H I 1 , Me 1 1 1 H I
32 1 1 H I 1 | COOH 1 1 1 I H 1 | -COOHe I 1 1 H 1 | He I 1 1 H I
33 1 1 H I 1 | COOH I 1 1 I F 1 1 H I 1 1 ¥ I 1 | He I 1 1 H I
34 1 1 H I 1 | COOH I 1 1 I OHe 1 1 H I 1 | OHe I 1 | He I 1 1 H
35 1 1 H I 1 | COOH I 1 1 I H 1 1 H I 1 | CN | 1 He | 1 1 H |
36 1 1 H I 1 | COOH I 1 1 I H 1 1 F I 1 1 H I 1 He I 1 1 H I
37 1 1 H 1 1 | COOH 1 1 1 1 H 1 1 H 1 1 1 H 1 1 He 1 1 | He 1
Example 2 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, disodium salt vas prepared in the same general manner as Example 1 except that after the addition of the palladium catalyst the solution vas
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- 31 gently warned to dissolve the catalyst and vas stirred under argon vith protection fron light for 1 hour. A solution of sodiun 2-ethylhexanoate in THF vas added and the combined solutions poured into THF vith vigorous stirring. The resultant precipitate vas centrifuged and supernatant removed. The product vas vashed twice by resuspension in THF followed by centrifugation and finally dried under high vacuum to give the title product. Nmr (DMSO-dg + acetic acid-d^): & 1.17 (d, 6H); 1.85 (m, obscured, IH); 2.73 (m, obscured, IH); 2.95 (dd, 1H); 3.21 (dd, IH); 3.40 (m, IH); 3.54 (dd, IH); 3.78 (quintet, IH); 3.99 (t, IH); 4.11 (t, IH);
4.18 (dd, IH); 7.41 (d, IH); 7.75 (dd, IH); 8.06 (d, IH).
Ms (+ve FAB): 532/534 (MH)+, (Na salt)+; 554/556 (Na2 salt)*
The starting materials vere prepared as follovs:
2-Chloro-5-nltrobenzoic acid vas allylated essentially as in Example 1, except that the final extraction solvent vas toluene, to give allyl 2-chloro-5-nitrobenzoate. Nmr (CDCl^): δ 4.89 (dt, 2H); 5.33-5.51 (m, 2H); 5.96-6.15 (m, IH); 7.66 (d, IH); 8.27 (dd, IH); 8.72 (d, IH).
Ms (CI): 241/243 M+, 259/261 (M + NH^)+
Stannous chloride dihydrate vas refluxed in ethanol, under an argon blanket, to give a solution. The heat vas removed, and the above nitro compound in ethanol vas run in. Refluxing vas then continued for 3 hours, the mixture cooled, and solvents removed. The residue vas dissolved in ethyl acetate, and treated vith 880 ammonia until basic. The organic phase vas decanted from precipitated tin salts, and the slurry re-extracted similarly vith more solvent. Combined organic phases vere then vashed vith diluted ammonia, vater, and brine, before drying over MgSO^. Evaporation gave allyl 5-amino-2-chlorobenzoate. Nmr (CDCl^): δ 3.74 (br, 2H); 4.81 (dt, 2H); 5.27-5.47 (m, 2H); 5.93-6.13 (m, IH); 6.73 (dd, IH); 7.15 (d, IH); 7.24 (d, IH).
Ms (CI): 212/214 M+, 229/231 (M + NH4)+ bad origin^ &
APO 00 3 9 8
- 32 The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of dichloromethane/diethyl ether (100:0 to 95:5) to give (2S,4S)-l-allyloxycarbonyl-2-(3allyloxycarbonyl-4-chlorophenylcarbaaoyl)pyrrolidin-4-ylthioacetate.
Nmr (CDClg): 6 2.33 (s, 3H); 2.57 (br, 2H); 3.39 (dd, IH); 4.03 (quintet, IH); 4.13 (dd, IH); 4.55 (t, IH); 4.66 (dt, 2H) 4.83 (dt, 2H); 5.24-5.47 (m, 4H); 5.85-6.02 (m, 2H); 7.36 (d, IH); 7.70 (dd, IH); 7.92 (d, IH);
( 9.32 (br, IH).
( Ms (+ve FAB): 467/469 (MH)+, 489/491 (M + Na) +
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as in Example 1, purifying by chromatography using gradient elution from dichloromethane to ethyl acetate to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl4-chlorophenylcarbaraoyl)pyrrolidin-4-ylthio)-6-( l-hydroxyethyl)-lmethylcarbapenem-3-carboxylate. Nmr (CDCl^): & 1.24 (d, 3H); 1.36 (d,
3H); 2.65 (br, 2H); 3.25 (dd overlapping m, 2H); 3.48 (m, IH); 3.80 (quintet, IH); 3.98 (dd, IH); 4.20-4.31 (dd overlapping quintet, 2H); 4.52 (t, IH); 4.51-4.76 (m, 4H); 4.83 (dt, 2H); 5.20-5.47 (m, 6H); 5.85-6.11 (m, 3H); 7.39 (d, IH); 7.77 (dd, IH); 7.99 (d, IH); 9.05 (br, IH).
{ Ms (+ve FAB): 674/676 (MH)+, 696/698 (M + Na)+
Example 3 (IR,5S,6S,8R,2'S,4'S) -2-(2-(5-Carboxy-2-chlorophenylcarbamoyl) pyrrolidin-4-yl-thio)-6-(l-hydroxyethyl)-l-methylcarbapenera-3-carboxylic acid, disodium salt vas prepared using the technique of Example 2. Nmr (DMSO-dg + acetic acid-d*): δ 1.16 (d, 3H); 1.19 (d, 3H); 1.82 (m, obscured, IH); 2.70 (dd overlapping m, 2H); 3.22 (dd, IH); 3.35-3.60 (overlapping m, 3H); 3.95-4.08 (overlapping m, 2H); 4.16 (dd, IH); 7.57 (d, IH); 7.69 (dd, IH); 8.36 (d, IH).
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- 33 Ms (+ve FAB): 532/534 (ΜΗ)*, (Na salt)4-; 554/556 (Na2 salt)*
The starting naterials vere prepared as follovs:
4-Chloro-3-nitrobenzoic acid vas allylated essentially as in Example 1 above to give allyl 4-chloro-3-nitrobenzoate. Nmr (CDCl^): &
ζ 4.86 (d, 2H); 5.31-5.48 (m, 2H); 5.94-6.13 (m, 1H); 7.50 (d, 1H); 8.18 (dd, 1H); 8.52 (d, 1H).
o
Ms (CI): 241/243 M+, 259/261 (M + NH^)f
Reduction of the above nitro compound by the method of Example 2 gave allyl 3-amino-4-chlorobenzoate. Nmr (CDClg): δ 4.08 (br, 2H); 4.79 (dt, 2H); 5.25-5.44 (m, 2H); 5.92-6.11 (m, 1H); 7.30 (d, 1H); 7.38 (dd, 1H); 7.47 (d, 1H).
Ms (CI): 212/214 M+, 229/231 (M + NH4)+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of dichloromethane/diethyl ether (100:0 to 95:5) to give (2S,4S)-l-allyloxycarbonyl-2-(5l allyloxycarbonyl-2-chlorophenylcarbamoyl)pyrrolidin-4-ylthioacetate.
Nmr (CDC13): δ 2.32 (s, 3H); 2.56 (br, 1H); 2.66 (br, 1H); 3.43 (dd, 1H); 4.04 (quintet, 1H); 4.16 (dd, 1H); 4.61 (t, 1H); 4.66 (dt, 2H) 4.82 (dt, 2H); 5.21-5.45 (m, 4H); 5.84-6.11 (m, 2H); 7.45 (d, 1H); 7.77 (dd, 1H); 9.00 (d, 1H); 9.08 (br, 1H).
Ms (+ve FAB): 467/469 (MH)+, 489/491 (M + Na)+
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using gradient elution from dichloromethane to ethyl acetate to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-chloro phenylcarbamoyl) pyr rolidin-4-ylthio) -6- (1 -hydroxyethyl) - 1-methylcarbapenem-3-carboxylate. Nmr (CDClp: δ 1.23 (d, 3H); 1.36 (d, 3H); 2.65 bad original (br, 2H); 3.24 (dd overlapping m, 2H); 3.88 (quintet, IH); 4.08 (m, IH);
4.19-4.30 (dd overlapping quintet, 2H); 4.60 (t, IH); 4.67 (m, 4H); 4.82 (dt, 2H); 5.18-5.45 (m, 6H); 5.82-6.01 (m, 3H); 7.44 (d, IH); 7.76 (dd,
IH); 9.04 (d, IH); 8.98 (br, IH).
Ms (+ve FAB): 674/676 (MH)+, 696/698 (M + Na)+
Example 4 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, disodium salt vas prepared using the technique of Example 2 except that a mixture of DMSO and THF vas used. Nmr (DMSO-dg + acetic acid-d^): δ 1.18 (d, 6H); 1.94 (m, obscured, IH); 2.85 (m, IH); 3.10 (dd, IH); 3.23 (dd, IH); 3.40 (quintet, IH); 3.66 (dd, IH); 3.89 (quintet, IH); 3.99 (t, IH); 4.21 (dd, IH); 4.27 (t, IH); 7.46 (t, IH); 7.71 (d, IH); 7.86 (d, IH); 8.27 (s, IH). Ms (+ve FAB): 498 (MH)+, (Na salt)+; 520 (Na2 salt)*
The starting materials vere prepared as follovs:
3-Nitrobenzoic acid vas allylated essentially as in Example 1, except that the final extraction solvent vas diethyl ether, to give allyl 3-nitrobenzoate. Nmr (CDCl-j): δ 4.88 (d, 2H); 5.33-5.49 (m, 2H);
5.96-6.17 (m, IH); 7.66 (t, IH); 8.41 (td, 2H); 8.88 (t, IH).
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, gave allyl 3-aminobenzoate. Nmr (CDC13): δ 3.38 (br, 2H); 4.79 (dt, 2H); 5.24-5.44 (m, 2H); 5.93-6.09 (m, IH); 6.86 (dm, IH); 7.21 (t, IH); 7.37 (t, IH); 7.45 (dt, IH).
Preparation of Side Chain Pyrrolidin-4-ylthioacetate (2S,4S)-4-Acetylthio-l-allyloxycarbonyl-2-carboxypyrrolidine (2.54 g, 9.3 mM), allyl 3-aminobenzoate (1.5 g, 8.5 mM), and 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline (2.72 g, 11 mM) vere
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- 35 dissolved in toluene (50 al) and stirred for 18 hours at ambient temperature. The reaction mixture vas diluted vith ethyl acetate (150 ml) and vashed vith 2M HCl (3 by 30 al), vater, saturated NaHCO^, and brine. Drying over MgSO^ and evaporation gave (2S,4S)-4-acetylthio-lallyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbaaoyl)pyrrolldine as a gum (3.7 g, 100Z) in a state sufficiently pure for further vork. Nmr (CDCl^): 6 2.32 (s, 3H); 2.60 (br, 2H); 3.40 (dd, IH); 4.03 (quintet, IH); 4.13 (dd, IH); 4.57 (t, IH); 4.66 (da, 2H); 4.82 (dt, 2H); 5.23-5.46 (a, 4H); 5.86-6.12 (a, 2H); 7.41 (t, IH); 7.82 (d, IH); 7.91 (d, IH); 8.07 (t, IH); 9.18 (br, IH).
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenea phosphate as Example 1, purifying by chromatography using gradient elution from dichloromethane to ethyl acetate/dichloromethane 1:1, to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2(3-allyloxycarbonylphenylcarbaraoyl)pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDCl^): δ 1.24 (d, 3H); 1.36 (d, 3H); 2.64 (br, 2H); 3.26,3.28 (dd overlapping a, 2H); 3.48 (m, IH); 3.81 (quintet, IH); 4.01 (dd, IH); 4.22-4.32 (a, 2H); 4.54 (t,
IH); 4.62-4.75 (a, 4H); 4.82 (m, 2H); 5.19-5.45 (a, 8H); 5.82-6.10 (a,
4H); 7.41 (d, IH); 7.81 (d, IH); 7.92 (dm, IH); 8.11 (t, IH); 8.98 (br, IH).
Ms (+ve FAB): 640 (MH)+, 662 (H + Na)+
Example 5 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-6-methanesulphonylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid disodiua salt vas prepared from the appropriate protected carbapenea as described in Example 1. Nmr (DHSO-dg + acetic acid-d*): δ 1.20 (d,
6H); 1.99 (quintet, IH); 2.75 (m, part obscured, IH); 2.87 (dd, IH); 3.22 (s, 3H); 3.25 (dd, part obscured, IH); 3.44 (quintet, IH); 3.62 (dd, IH); 3.75 (quintet, IH); 4.03 (quintet, IH); 4.16-4.23 (m, 2H); 7.90 (dd, IH); 8.17 (d, IH); 9.00 (d, IH).
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AP Ο Ο Ο 3 9 8
- 36 Ms (+ve FAB): 554 (MH)+, 576 (Na salt)*, 598 (Na2 salt)*
The starting materials vere prepared as follovs:
4-Methanesulphonyl-3-nitrobenzoic acid vas allylated essentially as in Example 1, except that crude product vas purified by chromatography over silica, eluting vith a gradient of dichloromethane to dichloromethane/diethyl ether 9:1, to give allyl 4-methanesulphonyl3-nitrobenzoate. Nmr (CDCl-j): 6 3.45 (s, 3H); 4.90 (dt, 2H); 5.30-5.49 (m, 2H); 5.96-6.12 (m, IH); 8.29 (d, IH); 8.40-8.46 (m, 2H).
Reduction as in Example 1, except that the solvent vas methanol, gave allyl 3-amino-4-methanesulphonylbenzoate. Nmr (CDCl^): 6 3.07 (s, 3H); 4.82 (dt, 2H); 5.05 (br, 2H); 5.29-5.44 (m, 2H); 5.95-6.11 (m, IH);
7.46 (m, 2H); 7.81 (d, IH).
Ms (+ve FAB): 256 (MH)+, 273 (M + NH*)*
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of dichloromethane/diethyl ether (100:0 to 90:10), to give (2S,4S)-l-allyloxycarbonyl-2-(5allyloxycarbonyl-2-methanesulphonylphenylcarbamoyl)pyrrolidin-4ylthioacetate. Nmr (CDC13): 6 2.31 (s, 3H); 2.41 (m, IH); 2.80 (m, IH); 3.11 (s, 3H); 3.51 (dd, IH); 4.00-4.18 (a, 2H); 4.53 (dd, IH); 4.65 (2m,
2H) 4.87 (dt, 2H); 5.23-5.47 (m, 4H); 5.83-6.13 (m, 2H); 7.93 (dd, IH);
8.03 (d, IH); 9.09 (br s, IH).
Ms (+ve FAB): 511 (MH)+, 533 (M + Na)+
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using gradient elution from dichloromethane through to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl2-methanesulphonylphenylcarbamoyl)-pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDC13): 6 1.21 (d,
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AP Ο Ο Ο 3 9 8
- 37 3H); 1.35 (d, 3H); 2.43 (η, ΙΗ); 2.75 (br, 1H); 3.08 (s, 3Η); 3.23 (dd overlapping n, 2H); 3.55 (dd, IH); 3.85-4.08 (, 2H); 4.19-4.28 (n, 2H); 4.53-4.68 (m, 5H); 4.86 (dt, 2H); 5.17-5.47 (m, 6H); 5.79-6.12 (n, 3H);
7.92 (dd, IH); 8.00 (d, IH); 9.16 (br s, IH); 10.14 (br, IH).
Ms (+ve FAB): 718 (MH)+, 740 (M + Na) + j' Example 6 ζ (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-fluorophenylcarbamoyl)pyrrolidin4-yl-thlo)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid
To a solution of allyl (lR,5S,6S,8R,2'S,4'S)-2-(l'allyloxycarbonyl-2'-(3-allyloxycarbonyl-4-fluorophenylcarbaraoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate (199 mg, 0.3 mH) and 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid, 259 mg, 1.8 mN) in DMF (1.5 ml), under an argon atmosphere, vas added tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mM) in THF (0.1 ml). The solution vas stirred under argon for 2 hours and tetrakis(triphenylphosphine) palladium (5 mg, 0.0045 mM) in THF (0.1 ml) vas added. After ( ' stirring for 30 minutes, THF (3 ml) and ether (9 ml) vere added, the resultant solid filtered off, vashed vith ether (9 ml), and dried under high vacuum to give the title product (72 mg, 49X). Nrar (DMSO-dg + acetic acid-d^): 6 1.30 (d, 6H); 2.00 (m, part obscured, IH); 2.91 (m, part obscured, IH); 3.13 (dd, IH); 3.36 (dd, IH); 3.55 (dq, IH); 3.73 (dd, IH); 3.95 (m, IH); 4.12 (m, IH); 4.29 (dd, IH); 4.34 (dd, IH); 7.40 (dd, IH); 7.98 (m, IH); 8.32 (dd, IH).
Ms (+ve FAB): 494 (MH)+, 516 (M + Na) +
The starting materials vere prepared as follovs:
Allyl 5-amino-2-fluorobenzoate
2-Fluoro-5-nitrobenzoic acid (4.16 g, 22.5 mM) vas dissolved in DMF (45 ml), and anhydrous K2 CO3 (4·65 8» 33·7 “H) added vith stirring.
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- 38 Allyl bromide (2.38 ml, 28.1 mM) vas run in, the mixture vas stirred for 18 hours at ambient temperature before being poured into vater (450 ml) and extracted vith diethyl ether (3 x 100 ml). The combined extracts vere dried over MgS04, and evaporated to give a yellov oil (5.4 g). The oil vas purified by chromatography on silica, eluting vith a mixture of ethyl acetate/hexane (12.5:87.5), to give allyl 2-fluoro-5-nitrobenzoate (4.64 g, 92X). Nmr (CDClj): δ 4.89 (d, 2H); 5.30-5.50 (m, 2H); 5.90-6.10 (m, IH); 7.32 (t, IH); 8.38-8.46 (m, IH); 8.86 (dd, IH).
Ms (El): 226 (MH)+; (CI): 225 M+, 243 (M + NH4) +
The above ester (2.47 g, 10.97 mM) vas dissolved in methanol (40 ml), and stannous chloride dihydrate (9.89 g, 43.76 mM) in cone HCI (9 ml) vas added to the stirred solution vhlle maintaining the temperature betveen 5° and 15°. The mixture vas then stirred overnight at ambient temperature before being poured into vater (200 ml) and neutralized vith solid NaHCOj (17.6 g) to pH6. The mixture vas extracted vith chloroform (3 x 200 ml), the combined extracts vere dried over MgSO4, and evaporated to give allyl 5-amino-2-fluorobenzoate (2.09 g, 98X) as a yellov oil. Nmr (CDClj): δ 3.60 (br s, 2H); 4.82 (dt, 2H); 5.25-5.48 (m, 2H); 5.93-6.12 (m, IH); 6.78 (ddd, IH); 6.93 (dd, IH); 7.20 (dd, IH).
Ms (El): 195 M+; (CI): 196 (MH)+; 213 (M + NH4) +
The above amine vas condensed vith the proline acid as in Example 1. The product vas purified by chromatography on silica using ethyl acetate/hexane (42.5:57.5) to give (2S,4S)-l-allyloxycarbonyl2-(3-allyloxycarbonyl-4-fluorophenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): δ 2.32 (s, 3H); 2.50-2.70 (br s, 2H); 3.40 (d, IH); 3.98-4.20 (m, 2H); 4.56 (t, IH); 4.67 (dt, 2H); 4.84 (dt, 2H); 5.20-5.50 (a, 4H); 5.83-6.12 (m, 2H); 7.10 (dd, IH); 7.80-7.89 (m, IH); 7.93 (dd, IH); 8.90-9.40 (br s, IH).
Ms (+ve FAB): 451 (MH)+, 473 (M + Na)+
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- 39 Conversion to Pyrrolidln-4-ylthiol (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-fluorophenyl carbamoyl)-pyrrolidin-4-ylthioacetate (1.33 g, 2.96 mM) vas dissolved in allyl alcohol (30 ml) and the solution flushed vith argon. IM Sodium hydroxide (3.1 ml, 3.1 mM) vas added, the mixture stirred at ambient temperature for 30 minutes, treated vith acetic acid (0.3 ml), stirred for a further 5 minutes, and then evaporated to dryness. The residue vas taken up in ethyl acetate (60 ml), vashed vith saturated aq. NaHCO^ (60 ml), brine, dried (MgSO^) and evaporated, to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-fluorophenylcarbamoyl)pyrrolidin-4ylthiol as a gum (1.07 g, 892). The crude material vas used as such in the next stage.
The thiol vas condensed vith carbapenem phosphate as in Example 1, and product purified by chromatography on silica, eluting vith ethyl acetate/dichloromethane (75:25) to give allyl (1R,5S,6S,8R,2S',4S')2-(l-allyloxycarbonyl-2-(3-carboxy-4-fluorophenylcarbamoyl)-pyrrolidin-4ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDCl^): δ 1.24 (d, 3H); 1.35 (d, 3H); 2.40-2.80 (br, 2H); 3.24-3.28 (m, 2H); 3.40-3.58 (br, IH); 3.80 (dq, IH); 3.99 (dd, IH); 4.19-4.33 (m, 2H); 4.53 (t, IH); 4.59-4.77 (m, 4H); 4.77-4.88 (m, 2H); 5.17-5.50 (m, 6H);
5.80-6.13 (m, 3H); 7.10 (dd, IH); 7.82-7.95 (m, IH); 8.00 (dd, IH); 8.70-9.20 (br s, IH).
Ms (+ve FAB): 658 (MH)+
Example 7 (lR,5S,6S,8R,2'S,4'S)-2-(2-(5-Carboxy-2-fluorophenylcarbamoyl)pyrrolidin-4-yl-thio)-6-(l-hydroxyethyl)-i-raethylcarbapenem-3-carboxylic acid vas prepared from the appropriate protected carbapenem as in Example 6. Nmr (DMSO-dg + acetic acid-d^): δ 1.30 (d, 6H); 1.84 (m, IH); 2.80-2.93 (m, 2H); 3.36 (dd, IH); 3.58 (m, IH); 3.66 (dd, IH); 3.81 (m, IH); 4.09( dq, IH); 4.21 (m, IH); 4.31 (dd, IH); 7.56 (dd, IH); 8.07 (m, IH); 8.90 (d, IH).
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- 40 Ms (+ve FAB): 494 (MH)+, 516 (M + Na) +
The starting materials vere prepared as follows:
Allyl 3-amino-4-fluorobenzoate , 4-Fluoro-3-nitrobenzoic acid vas allylated as in Example 6 to give allyl 4-fluoro-3-nitro benzoate. Nmr (CDClj): 6 4.87 (dt, 2H);
C 5.48-5.32 (m, 2H); 5.95-6.14 (m, IH); 7.40 (dd, IH); 8.30-8.38 (m, IH);
8.76 (dd, IH).
Ms (El): 225 M+; (CI): 225 M+, 243 (M + NH4) +
The above vas reduced essentially as in Example 2, except that methanol vas used as solvent to give allyl 3-amino-4-fluorobenzoate. Nmr (CDClj): 6 3.70 (br, 2H); 4.79 (dt, 2H); 5.25-5.44 (m, 2H); 5.96-6.09 (m, IH); 7.02 (dd, IH); 7.41-7.54 (m, 2H).
Ms (El): 195 M+; (CI): 196 (MH)+ r
The above amine vas condensed vith the proline acid as in (
Example 1, purifying the product by chromatography on silica using ethyl acetate/hexane (50:50) as eluent, to give (2S,4S)-l-allyloxycarbonyl2-(5-allyloxycarbonyl-2-fluorophenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): & 2.33 (s, 3H); 2.62 (br, 2H); 3.40 (dd, IH); 3.98-4.20 (m, 2H); 4.60 (t, IH); 4.67 (dt, 2H); 4.82 (dt, 2H); 5.2-5.5 (m, 4H); 5.8-6.15 (m, 2H); 7.16 (dd, IH); 7.83 (ddd, IH); 8.97 (dd, IH); 9.27 (br, IH).
Ms (El): 451 (MH)+; (CI): 451 (MH)+
The above thioacetate vas deacetylated to thiol, condensed vith carbapenem phosphate as in Example 6, and the product purified by chromatography (eluting vith ethyl acetate) to give allyl (lR,5S,6S,8R,2'S,4/S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl2-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1BAD ORIGINAL
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- «1 methylcarbapenem-3-carboxylate. Nmr (DMSO-dg + acetic acid-d^): & 1.90 (m, part obscured, IH); 2.78 (m, IH); 3.22 (dd, IH); 3.26 (m, IH); 3.52 (m, IH); 3.83-4.03 (m, 2H); 4.09 (dd, IH); 4.22 (m, IH); 4.53 (m, IH);
4.53-4.65 (m, 4H); 4.80 (dt, 2H); 5.05-5.43 (m, 6H>; 5.73-=5.98 (m, 2H); ~
5.98-6.09 (m, IH); 7.38 (dd, IH); 7.78 (br s, IH); 8.49 (m, IH); 8.62 (d, IH).
Ms (+ve FAB): 658 (MH)+, 680 (M + Na)+
Example 8 (IR, 5S, 6S, 8R, 2' S, 4' S) -2- (2- (3-Carboxy-2,4-dif luorophenyl carbamoylpyrrolidin-4-ylthio) -6- (1-hydroxyethyl) - l-methylcarbapenem-3carboxylic acid, vas prepared from the appropriate protected carbapenera as in Example 7. Nmr: (DMSO-dg + acetic acid-d^): 6 1.29 (d, 6H); 1.94-1.99 (ra, part obscured IH); 2.81-3.07 (a, IH); 3.05 (dd, IH); 3.37 (dd, IH); 3.56 (m, IH); 3.75 (dd, IH); 3.92 (q, IH); 4.10 (dq, IH); 4.29-4.38 (a, 2H); 7.22 (t, IH); 8.07 (m, IH).
Ms (+ve FAB): 512 (MH)+, 534 (H + Na)+
The starting materials vere prepared as follovs:
Allyl 3-amino-2,6-difluorobenzoate
2,6-Difluoro-3-nitrobenzoic acid vas allylated as in Example 6 to give allyl 2,6-difluoro-3-nitrobenzoate. Nmr (CDC13): 4.90 (dt, 2H);
5.33-5.50 (m, 2H); 5.95-6.03 (m, IH); 7.09-7.27 (ddd, IH); 8.22-8.27 (ddd, IH).
Ms (EI): 244 (MH)+; (CI): 261 (H + ΝΗ^)+
The above ester vas reduced as in Example 2, except that methanol vas used as the solvent, to give allyl
3-amino-2,6-difluorobenzoate. Nmr (CDC13): 64.86 (dt, 2H); 5.27-5.49 (m, 2H); 5.95-6.09 (m, IH); 6.77-6.86 (m, 2H).
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- 42 MS (El): 213 Μ+; (CI): 214 (ΜΗ) +
The above amine vas condensed vith the proline acid as in Example 1, purifying by chromatography and eluting vith ethyl acetate/hexane (40:60), to give (2S,4S)-l-allyloxycarbonyl-2(3-allyloxycarbonyl-2,4-difluorophenylcarbaraoyl)pyrrolidin-4ylthioacetate. Nmr (CDC13): 6 2.32 (s, 3H); 2.60 (br, 2H); 3.40 (dd, IH); 3.95-4.19 (ra, 2H); 4.57 (t, IH); 4.67 (dt, 2H); 4.86 (dt, 2H); 5.20-5.50 (m, 4H); 5.81-6.13 (ra, 2H); 6.95 (ddd, IH); 8.4 (ddd, IH); 9.2 (br, IH).
MS (+ve FAB): 469 (MH)+
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as in Example 6. The product vas purified by chromatography on silica, eluting vith ethyl acetate, to give allyl (IR,5S,6S,8R, 2S',4S')-2-(l-allyloxycarbonyl-2-(3-carboxy-2,4-difluoro phenylcarbamoyl) pyrrolidin-4-ylthio )-6-(1 -hydroxyethyl) -1 -methylcarbapenem-3-carboxylate. Nmr (CDClj): 6 1.26 (d, 3H); 1.36 (d, 3H); 1.80 (d, IH); 2.62 (br, 2H); 3.19-3.36 (m, 2H); 3.44 (dd, IH); 3.08 (q, IH)j 4.05 (dd, IH); 4.19-4.33 (m, 2H); 4.50-4.80 (m, 5H); 4.86 (dt, 2H); 5.17-5.50 (m, 6H); 5.82-6.10 (ra, 3H); 6.95 (dt, IH); 8.38 (dt, IH); 9.00 (br, IH).
Ms (+ve FAB): 676 (MH)+, 698 (M + Na)+
Example 9 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3,4-Dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, trisodium salt vas prepared using the technique of Example 2 except that a mixture of DMSO and THF vas used. Nmr (DMSO-dg + acetic acid-d^):
1.18 (d, 6H); 1.84 (ra, part obscured, IH); 2.78 (m, IH); 3.02 (dd, IH);
3.23 (dd, IH); 3.40 (quintet, IH); 3.58 (dd, IH); 3.83 (quintet, IH); 4.00 (quintet, IH); 4.20 (dd overlapping m, 2H); 7.92 (dd, IH); 8.17 (d, IH); 8.33 (d, IH).
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- 43 Ms (+ve FAB): 542 (MH)+, (Na salt)*; 564 (Na2 salt)*
The starting material vas prepared as follows:
2-Carboxy-4-nitrobenzoic acid vas allylated according to the procedure of Example 1 to give allyl 2-allyloxycarbonyl-4-nitrobenzoate. Nmr (CDClg): δ 4.85 (dt, 4H); 5.29-5.47 (m, 4H); 5.91-6.12 (m, 2H); 7.88 (d, IH); 8.38 (dd, IH); 8.63 (d, IH).
Reduction of the above nitro compound by the method of Example 2, and purifying by medium pressure chromatography on silica using a gradient of dichloromethane/diethyl ether (100:0 to 90:10), gave allyl
2-allyloxycarbonyl-4-amino-benzoate. Nmr (CDCl^): 83.94 (br, 2H); 4.71-4.80 (m, 4H); 5.22-5.42 (m, 4H); 5.88-6.10 (m, 2H); 6.69 (dd, IH); 6.75 (d, IH); 7.74 (d, IH).
The above amine vas condensed vith proline acid as Example 1, purifying by medium pressure chromatography on silica using a gradient from dichloromethane to 20X diethyl ether in dichloromethane, to give (2S,4S)-l-allyloxycarbonyl-2-(3,4-diallyloxycarbonylphenylcarbamoyl) pyrrolidin-4-ylthioacetate. Nmr (CDCl-j): δ 2.32 (s, 3H); 2.59 (br, 2H); 3.37 (dd, IH); 4.03 (quintet, IH); 4.12 (dd, IH); 4.56 (t, IH); 4.67 (d, 2H); 4.77 (t, 4H); 5.25-5.42 (m, 6H); 5.84-6.11 (a, 3H); 7.79 (m, 3H);
9.52 (br, IH).
The above thioacetate vas deacetylated to thiol, vhich vas condensed vithout further purification vith carbapenem phosphate as Example 1, finally purifying by medium pressure chromatography on silica, using dichloromethane/ethyl acetate 3:2 as eluant, to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3,4-diallyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate. Nmr (CDCIj): δ 1.24 (d, 3H); 1.35 (d, 3H); 2.62 (br, 2H); 3.26 (dd overlapping m, 2H); 3.47 (br, IH); 3.81 (quintet, IH); 3.97 (dd, IH); 4.19-4.29 (overlapping m, 2H); 4.53 (t, IH); 4.62-4.82 (m, 8H); 5.19-5.44 (m, 8H); 5.84-6.07 (m, 4H); 7.82 (s, 3H); 9.30 (br, IH).
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- 44 Example 10 (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-hydroxyphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid vas prepared using the technique of Example 1, except that the crude acid vas of sufficient purity, and did not require chromatography. Nmr (DMSO-dg + acetic acid-dj: & 1.17 (d, 6H); 1.95 (m, obscured, 1H); 2.87 (m, obscured, IH); 3.17 (dd, IH); 3.25 (dd, IH); 3.42 (dt, IH); 3.75 (dd, IH); 3.99-4.05 (m, 2H); 4.22 (dd, IH); 4.33 (t, IH); 6.76 (d, IH); 7.56 (dd, IH); 7.97 (d, IH).
Ms (+ve FAB): 492 (MH)+, 514 (M + Na)+
The starting materials vere prepared as follovs:
2-Hydroxy-5-nitrobenzoic acid vas allylated essentially as in Example 1, except that the final extraction solvent vas diethyl ether, to give allyl 2-allyloxy-5-nitrobenzoate. Nmr (CDClj): δ 4.82 (m, 4H); 5.26-5.55 (m, 4H); 5.97-6.13 (m, 2H); 7.49 (d, IH); 8.41 (dd, IH); 8.52 (d, IH).
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, and NaHCOj solution vas used to basify, gave allyl 2-allyloxy-5-aminobenzoate. Nmr (CDClj): δ 3.23 (br, 2H); 4.53 (dt, 2H); 4.79 (d, 2H); 5.21-5.49 (m, 4H); 5.93-6.14 (m, 2H);
6.80 (m, 2H); 7.16 (d, IH).
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of dichloromethane/diethyl ether (100:0 to 85:15) to give (2S,4S)-l-allyloxycarbonyl-2-(4allyloxy-3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthioacetate.
Nmr (CDClj): δ 2.33 (s, 3H); 2.56 (br, 2H); 3.39 (dd, IH); 4.01 (quintet, IH); 4.13 (dd, IH); 4.52 (t, IH); 4.60 (dt, 2H) 4.66 (m, 2H); 4.81 (dt, 2H); 5.23-5.51 (m, 6H); 5.85-6.13 (m, 3H); 6.91 (d, IH); 7.76 (dd, IH);
7.81 (d, IH); 8.97 (br, IH).
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- 45 The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using gradient elution from dichloromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(4-allyloxy-3allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl) -1methylcarbapenem-3-carboxylate. Nmr (CDClj): δ 1.24 (d, 3H); 1.36 (d,
3H); 2.57 (br, 2H); 3.25, 3.28 (dd overlapping quintet, 2H); 3.47 (br,
C IH); 3.78 (quintet, IH); 4.01 (dd, IH); 4.18-4.27 (dd overlapping m, 2H);
4.51 (t, IH); 4.58-4.79 (ra, 6H); 4.79 (dt, 2H); 5.19-5.51 (m, 8H);
(. 5.83-6.12 (m, 4H); 6.93 (d, IH); 7.79 (dd, IH); 7.85 (d, IH); 8.88 (br,
IH).
Ms (+ve FAB): 696 (HH)+, 718 (M + Na)+
Example 11 (lR,5S,6S,8R,2'S,4'S)-2-(2-(3,5-Dicarboxyphenylcarbaraoyl)pyrrolidin4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid vas prepared using the technique of Example 1, except that the crude acid r vas of sufficient purity, and did not need chromatography. Nmr (DMSO-d^ + acetic acid-d^): δ 1.15 (d, 6H); 1.77 (m, part obscured,
-- IH); 2.69 (m, part obscured, IH); 2.85 (m, part obscured, IH); 3.19 (dd, IH); 3.33-3.51 (m, 2H); 3.71 (quintet, IH); 3.94 (quintet, IH);
4.03 (t, IH); 4.15 (dd, IH); 8.18 (t, IH); 8.45 (d, 2H).
Ms (+ve FAB): 520 (MH)+, 542 (M + Na)+
The starting materials vere prepared as follovs:
3-Carboxy-5-nitrobenzoic acid vas allylated essentially as in Example 1 to give allyl 3-allyloxycarbonyl-5-nitrobenzoate. Nmr (CDClj): δ 4.89-4.93 (m, 4H); 5.33-5.50 (ra, 4H); 5.97-6.17 (m, 2H);
9.00 (t, IH); 9.04 (d, 2H).
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Reduction of the above nitro compound by the method of Example 2 gave allyl 3-allyloxycarbonyl-5-aminobenzoate. Nmr (CDCl^): δ 3.91 (br, 2H); 4.80-4.84 (m, 4H); 5.26-5.45 (m, 4H)t 5.96-6.11 (m, 2H); 7.53 (d, 2H); 8.09 (t, 1H).
The above amine vas condensed vith proline acid as Example 1, ( to give (2S,4S)-l-allyloxycarbonyl-2-(3,5-diallyloxycarbonylphenylcarbamoyl)pyrrolidin-4-yl-thioacetate. Nmr (CDCl^): δ 2.33 (s, 3H); f 2.60 (br, 2H); 3.40 (dd, 1H); 4.03 (quintet, 1H); 4.14 (dd, 1H); 4.58 (t, 1H); 4.65-4.70 (m, 2H); 4.83-4.87 (m, 4H); 5.24-5.47 (m, 6H); 5.84-6.16 (m, 3H); 8.39 (d, 2H); 8.45 (t, 1H); 9.36 (br, 1H).
The above thioacetate vas deacetylated to thiol, and condensed vith carbapenem phosphate as Example 1, to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3,5-diallyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1methylcarbapenem-3-carboxylate. Nmr (CDCl^): δ 1.23 (d, 3H); 1.35 (d, 3H); 2.63 (br, 2H); 3.25, 3.29 (dd overlapping m, 2H); 3.49 (br, 1H);
(quintet, 1H); 3.98 (dd, 1H); 4.19-4.30 (m, 2H); 4.55 (t, 1H)j 63-4.78 (ra, 4H); 4.84 (d, 4H); 5.19-5.45 (m, 8H); 5.84-6.12 (m, 4H); 46 (s, 3H); 9.18 (br, 1H).
Ms (+ve FAB): 724 (MH)+, 746 (M + Na)+
Example 12 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid.
To a solution of 4-nitrobenzyl (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-allyloxycarbonylphenylcarbaraoyl)-l-(4-nitrobenzyloxycarbonyl)pyrrolidin-4ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenera-3-carboxylate (10 g, 12 mM) and Heldrum's acid (5.2 g, 36 mM) in THF (70 ml), under an atmosphere of argon and vith the exclusion of light, vas added tetrakis(triphenylphosphine)palladium (1.4 g, 1.2 mM). The mixture
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- 47 vas stirred at ambient temperature for 30 minutes. The mixture vas diluted vith ethyl acetate (230 ml) and added to a solution of sodium bicarbonate (1.5 g) in distilled vater (200 ml). 102 Pd-charcoal (4 g) vas added and the mixture hydrogenated inan atmosphere of hydrogen for 3 hours. The catalyst vas filtered, the filtrate extracted vith ethyl acetate (2 x 100 ml) and ether (2 x 100 ml), and the aqueous layer concentrated under reduced pressure to about 250 ml. This solution vas ( split into tvo and each sample purified by passage through a 1 litre
HP20SS column using vater as eluent. The pure fractions vere collected
C and freeze-dried giving the title compound as a pale yellov solid (3.5 g). Nmr (DMSO-dg + acetic acid-d^, positions sensitive to exact solvent ratio): δ 1.19 (d, 6H); 1.94 (dt, IH); 2.97 (dt, IH); 3.13 (dd, IH); 3.25 (dd, IH); 3.42 (dt, IH); 3.68 (dd, IH); 3.94 (quintet, IH);
4.02 (quintet, IH); 4.22 (dd, IH); 4.32 (t, IH); 7.46 (t, IH); 7.73 (dt, IH); 7.88 (dm, IH); 8.27 (t, IH).
Ms (+ve FAB): 498 (Na salt), 520 (di-Na salt).
The starting material vas prepared as follovs;
r
3-Nitrobenzoic acid (50 g, 0.3 M) vas allylated by a similar method to ( that described in Example 1. Solid KjCO^ (θ^.7 g, 0.6 M) vas added to the acid in dry DMF (700 ml) vith stirring. There vas a slight exotherm and the mixture became thick. Allyl bromide (38.8 ml, 0.45 M) vas added over 30 minutes and the mixture vas left stirring overnight. After filtration through diatomaceous earth, the solution vas evaporated to dryness under reduced pressure and the residue partitioned betveen ether and aqueous NaHCOj. The ether layer vas vashed vith dilute HCl, brine and vater, dried and evaporated giving a yellov oil (62g). Nmr (DMSO-dg): δ 4.85-4.92 (m, 2H); 5.27-5.5 (m,
2H); 5.97-6.2 (m, IH); 7.85 (t, IH); 8.37-8.42 (dt, IH); 8.48-8.54 (dq, IH); 8.64 (t, IH).
Without further purification this oil vas reduced to allyl 3-aminobenzoate (53 g) using stannous chloride and the method described in example 6. Nmr (CDCl^): δ 3.6 (broad, 2H); 4.77-4.82 (dt, 2H);
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- 48 5.24-5.44 (η, 2H); 5.96-6.1 (m, 1H); 6.83-6.88 (a, IH); 7.17- 7.25 (η, IH); 7.35-7.47 (a, 2H).
The above allyl 3-aminobenzoate (26.6 g, 0.15 M) vas condensed vith 4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (55.2 g, 0.15 M) by suspension in toluene (750 al) and addition of EEDQ (44.5 g, 0.18 M). The mixture vas stirred overnight, diluted vith EtOAc (2 1) and vashed vith dilute HCl, vater and brine. The EtOAc phase vas dried and evaporated, and the residue
V recrystallised from ethanol giving (2S,4S)-4-acetylthio-l-(4nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine (67.7 g). Nmr (DMSO-dg): δ 1.93 (quintet, IH); 2.9 (ra, IH); 3.35 (m, IH); 3.91-4.14 (ra, 2H); 4.49 (quintet, IH); 4.81 (dd, 2H); 5.22 (dd, 2H); 5.2-5.44 (m, 2H); 5.95-6.10 (m, IH); 7.47 (d, 2H); 7.66 (t, 2H); 7.8-7.93 (m, 2H); 8.18-8.3 (m, 2H); 10.31 (s, IH).
The above thioacetate (52.7 g, 0.1 M) vas converted to the thiol by dissolving it in degassed allyl alcohol (1 1) and adding aqueous NaOH (2H, 50 ml) at 0°C. After 3 hours aqueous HCl (2 H, 52.5 ml) vas added, the solvent evaporated and the residue partitioned betveen EtOAc and brine. The EtOAc phase vas dried over MgSO^, filtered and evaporated. The thiol vas used without further purification.
A solution of 4-nitrobenzyl (lR,5R,6S,8R)-6-(l-hydroxyethyl)l-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (59.68 g,
0.1 H) in acetonitrile (500 ml) and methylene chloride (120 ml) vas cooled to -15°C and ethyl diisopropylamine (52.5 ml) vas added slowly.
(2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol (0.1 M), in acetonitrile (400 ml) vas added under argon and the mixture left overnight. The solvent vas evaporated and the residue subjected to chromatography on silica, eluting vith methylene chloride, EtOAc and acetonitrile, giving
4-nitrobenzyl (lR,5R,6S,8R,2'S,4'S)-2-(l-(4-nitrobenzyloxycarbonyl)-2(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxy-
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- 49 ethyl)-l-methylcarbapenem-3-carboxylate as a yellov solid (52.6 g).
Nmr (DMSO-d6+CD3OD): & 1.26 (d, 3H); 1.35 (d, 3H); 2.2-2.4 (m, IH);
2.7-2.95 (m, IH); 3.28-3.40 (m, 2H); 3.54-3.63 (m, IH); 3.8 (t, IH); 4.01-4.1 (q, IH); 4.21-4.33 (a, 2H); 4.61 (dd, lH);-4.73 (d, 2H); 5.17-5.45 (m, 6H); 5.93-6.11 (m, IH); 7.37-8.22 (complex pattern of doublets and double doublets, 12H).
( Example 13 ( The deprotection and hydrogenation vere carried out by a similar method to that described in example 12, except that 4-nitrobenzyl (IR,5S,6S,8R,2zS,4/S)-2-(2-(3-allyloxycarbonyl-5-carbamoylphenylcarbamoyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate (0.44 g) vas used.
After the hydrogenation, the aqueous layer vas vas freeze-dried, vithout HP20SS chromatography, to give (lR,5S,6S,8R,2'S,4'S)-2-(2(3-carboxy-5-carbamoylphenylcarbamoyl)pyrrolidin-4-ylthio)-6(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, as a pale yellov solid (125 mg). Nmr (DMSO-dg + acetic acid-d^): 6 1.9 (d, 6H); 1.98-2.06 (m, IH); 2.85-2.98 (ra, IH); 3.16- 3.21 (m, IH); 3.26 (dd, IH); 3.43 (quintet, IH); 3.74 (dd, IH); 3.91-3.97 (ra, IH); 4.0 (t, IH); 4.23 (dd, IH); 4.39 (t, IH); 8.24 (t, IH); 8.33 (t, IH); 8.44 (t, IH).
The starting material vas prepared as follovs:
5-Nitroisophthalic acid (5g) vas converted to the mono allyl ester using one equivalent of allyl bromide (2 ml) using a similar method to that described in example 1. The required acid (2.7 g) vas extracted from the organic phase vith aqueous NaHCOg. The organic layer contained the di-allyl ester (2.7 g). The mono acid, 3-allyloxycarbonyl-5-nitrobenzoic acid, vas obtained as a vhite solid. Nmr (CDC13): 4.87 (d, 2H); 5.3-5.5 (q, 2H); 5.97-6.15 (m, IH);
9.01 (t, 3H).
Ms (CI): 252 (MH)+
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- 50 DCCI (1.3 g) vas added to a solution of the above acid (1.5 g) and N-hydroxysuccinimide (0.76 g) in methylene chloride (50 ml) and the mixture stirred at ambient temperature for 2 hours. A vhite solid vas filtered and the solution evaporated to dryness. The active ester vas purified on silica gel eluting vith methylene chloride then it vas dissolved in methylene chloride and treated vith ammonia gas at 5°C. The vhite solid vhich precipitated vas 3-allyloxycarbonyl-5nltrobenzamide (1.1 g). Nmr (DMSO-dg): δ 4.9 (dt, 2H); 4.88-4.93 (m, 2H); 6.03-6.11 (m, IH); 7.83 (broad s, IH); 8.55 (broad s, IH); 8.75 (t, IH); 8.84 (t, IH); 8.94 (t, IH).
Ms (CI): 268 (M + ΝΗή)+
3-Allyloxycarbonyl-5-nitrobenzaraide (1 g) vas reduced vith SnCl2 by a similar method to the reduction in example 12, giving 3-allyloxycarbonyl-5-aminobenzamide (0.5 g). Nmr (DMSO-dg):
4.78 (dt, 2H); 5.2-5.8 (broad, 2H); 5.26-5.45 (m, 2H); 5.91-6.13 (m, IH); 7.22 (broad s, IH); 7.27 (t, IH); 7.33 (t, IH); 7.59 (s, IH).
Ms (CI): 221 (MH)+ (2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (0.75g) vas converted to the acid chloride and reacted vith
3- allyloxycarbonyl-5-aminobenzamide (0.45 g) by a similar method to that described in example 12. The crude product vas subjected to chromatography on silica gel, eluting vith EtOAc and giving
4- acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-5 carbamoylphenylcarbamoyl)pyrrolidine (0.58 g). Nmr (DMSO-dg): δ 1.92-2.06 (m, IH); 2.3 (s, 3H); 2.79-2.83 (m, IH); 3.38 (dd, IH); 3.97-4.12 (m, 2H); 4.49 (dd, IH); 4.83 (dt, 2H); 5.19 (dd, 2H); 5.25-5.43 (m, 2H); 5.97-6.11 (m, IH); 7.31 (broad s, 2H); 7.54 (d, 2H); 8.04 (d, 2H); 8.12 (t, IH); 8.26 (t, IH); 8.31 (t, IH); 10.0 (s, IH).
The thiol vas generated from the above thioacetate by the method described in example 12.
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- 51 A solution of 4-nitrobenzyl (lR,5R,6S,8R)-6-(l-hydroxyethyl)l-methyl-2-diphenylphosphoryloxycarbapenern-3-carboxylate (0.6 g) and (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-5aminocarbamoylphenylcarbamoyl)pyrrolidin-4-ylthiol (0.48 g) in acetonitrile (20 ml) vas reacted by a similar method to that as described in example 12. Purification vas by flash chromatography, eluting vith EtOAc then 5X MeOH/EtOAc, giving 4-nitrobenzyl (IR,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-5-carbamoylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate as a yellov solid (0.44 g).
Nmr (DMSO-dg): δ 1.19-1.22 (d, 6H); 2.0-2.11 (a, IH); 2.8-2.92 (a, IH); 3.32 (dd, IH); 3.42-3.62 (m, 2H); 3.92-4.2 (a, 2H); 4.31 (broad d, IH);
4.53 (q, IH); 4.84 (d, 2H); 4.98-5.46 (a, 6H); 5.98-6.14 (a, IH);
7.42- 8.52 (complex pattern of doublets and double doublets, 11H).
Example 14
The deprotection and hydrogenation vas carried out by a similar method to that described in example 12, except that p-nitrobenzyl (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-allyloxycarbonyl-6carbamoylphenylcarbamoyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate vas used. After the hydrogenation, the aqueous layer vas freeze-dried to give (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-carbamoylphenylcarbamoyl)pyrrolidin-4-yl thio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid. Nmr (DMSO-dg + acetic acid-d*): δ 1.3-1.38 (2xd,
6H); 2.0-2.11 (m, IH); 2.85-2.96 (m, IH); 3.09 (dd, IH); 3.37 (dd, IH);
3.53 (quintet, IH); 3.79 (dd, IH); 3.94 (t, IH); 4.16 (t, IH); 4.33 (dd, IH); 4.43 (t, IH); 7.87 (dd, IH); 7.97 (d, IH); 9.12 (d, IH).
Ms (+ve FAB): 541 (Na salt), 563 (di-Na salt).
The starting material vas prepared as follovs:
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- 52 Nitroterephthalic acid (6.33 g) in methylene chloride (75 ml) and THF (15 ml) vas converted to the mono acid chloride using oxalyl chloride (2.63 ml), DHF (2.55 ml) and N-methylmorpholine (7.95 ml) at -10°C. After 1 hour the solvents vere removed and, vithout further purification, the product vas dissolved in allyl alcohol (20 ml) and THF (10 ml) and stirred overnight at ambient temperature. The solvents vere removed and the residue partitioned betveen EtOAc and aqueous ( NaHCO^· Acidification of the NaHCO^ solution and extraction vith EtOAc gave the product, 4-allyloxycarbonyl-2-nitrobenzoic acid (6.8 g).
Γ Nmr.(CDClj): 6 4.89 (d, 2H); 5.31-5.49 (ra, 2H); 5.95-6.15 (a. IH); 7.94 (d, IH); 8.36 (dd, IH); 8.54 (d, IH). Vithout purification, this acid vas converted by the method above to the acid chloride vhich vas dissolved in THF (100ml) at 0°C. Ammonia gas vas bubbled into the solution until the reaction vas completed. The solution vas partitioned betveen EtOAc and vater, and the product from the organic fraction purified on silica, eluting vith methylene chloride folloved by EtOAc. The product (4 g), containing a small impurity, vas reduced vith SnCl2 by a similar method to that in example 12 giving 4-allyloxycarbonyl-2-aminobenzamide. Nmr (DMSO-dg): & 4.79 (d, 2H); 5.22-5.46 (m, 2H); 5.91-6.13 (ra, IH); 7.02 (dd. IH); 7.37 (d, IH); 7.61 ( (d, IH).
(2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxypyrrolidine (1.58g) vas converted to the acid chloride by suspension in methylene chloride (25 ml) and addition of oxalyl chloride (1.52 ml).
A fev drops of DMF vere added. After 2 hours the solvents vere evaporated and the acid chloride, dissolved in methylene chloride (10 ml), vas added under argon to a solution of 4-allyloxycarbonyl-2-aminobenzamide (0.52 g) in THF (10 ml) and methylene chloride (5 ml) containing N-methylmorpholine (0.38 ml) at 0°C. The reaction vas left overnight and partitioned betveen methylene chloride and dilute aqueous HCl. The methylene chloride fraction vas vashed vith vater, brine and dried. Purification vas by silica chromatography, eluting vith increasing concentrations of EtOAc in methylene chloride, giving (2S, 4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxycarbonyl-6-carbamoylphenylcarbamoyl)pyrrolidine (0.84 g).
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- 53 Nmr (CDClg): δ 2.25 (quintet, IH); 2.29 (s, 3H); 2.83 (a, IH); 3.53 (dd, IH); 4.02 (quintet, IH); 4.2 (dd, IH); 4.49 (dd, IH); 4.85 (d, 2H); 5.23-5.46 (n, 2H); 5.97-6.13 (η, IH); 7.31-7.5 (broad, 2H); 7.57 (d, IH); 7.75 (dd, IH); 7.81-7.95 (broad, 2H),· 9.27 (d, IH).
The thiol vas generated from the above thioacetate by a similar method to that described in example 12.
A solution of 4-nitrobenzyl (1R,5R,6S,8R)-6-(1-hydroxyethyl)l-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate and (2S,4S)1-(4-nitrobenzyloxycarbonyl)-2-(2-carbamoyl-5-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol in acetonitrile (20 ml) were reacted as described in example 12, giving 4-nitrobenzyl (lR,5R,6S,8R,2'S,4'S)-2(1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxy3-carbonyl-6-carbamoylphenylcarbamoyl)pyrrolidin-4-ylthio)-6(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate as a yellov foam (1.24 g). Nmr 1.23-1.35 (m, 6H); 2.2-2.38 (m, IH); 2.77-2.93 (a, IH);
3.27 (dd, IH); 3.28-3.42 (m IH); 3.65-3.92 (m, 2H); 4.17- 4.35 (a, 3H);
4.53 (t, IH); 4.83 (d, 2H); 4.92-5.44 (m, 6H); 5.93-6.11 (m, IH); 6.22-6.58 (broad, 2H); 7.35- 8.23 (complex pattern of doublets and double doublets, 10H); 9.20 (d, IH).
Example 15
The deprotection and purification vere carried out by a similar method to that described in example 2 (chromatography of the final product vas on an HF20SS column) except that allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(2-dimethylaminocarbonyl3-allyloxycarbonylphenylcarbanioyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate vas used. The appropriate aqueous fractions from the column vere freeze-dried to give (lR,5S,6S,8R,2'S,4'S)-2-(2-(2-dimethylaminocaΓbonyl-3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-( l-hydroxyethyl)-l-methylcarbapenem-3carboxylic acid. Nmr (DMSO-dg + acetic acid-d4, mixture of rotamers): δ 1.17 (d, 6H); 1.75 (m, 2H); 2.65,2.72 (2 x s, overlapping m, 4H);
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- 54 3.00,3.01 (2 χ s, overlapping m, 4H); 3.17 (dd, IH); 3.41 (quintet,
IH); 3.55 (a, 2H); 3.96 (a, 2H); 4.15 (dd, IH); 7.43 (t, IH); 7.68 (a, IH); 8.20-8.40 (2 x d, IH).
The starting material vas prepared as follows:
2-Dimethylaminocarbonyl-3-nitrobenzoic acid (1 g) vas ( to the allyl ester by a similar method to that described in example 1 for the formation of allyl 3-allyloxy-5-aminobenzoate giving ( allyl 2-dimethylaminocarbonyl-3-nitrobenzoate (0.88 g).
Nmr (DMSO-d6): δ 2.45 (s, 3H); 2.97 (s, 3H); 4.79 (dd, 2H); 5.28-5.47 (ra, 2H); 5.9-6.1 (m, IH); 7.81 (t, IH); 8.28-8.4 (dq, 2H).
Ms (CI): 279 (MH)+
The allyl ester (0.44 g) vas reduced vith SnClj by a similar method to the reduction described in example 1, giving allyl
2-dimethylaminocarbonyl-3-aminobenzoate (0.41 g) as a clear red oil.
Nmr (CDClj): δ 2.24 (s, 3H); 3.06 (s, 3H); 3.64 (broad, 2H); 4.68 (dd, 2H); 5.17-5.37 (m, 2H): 5.82-6.02 (m, IH); 6.83 (dd, IH); 7.09-6.85 (m, IH); 7.37 (dd, IH).
Ms (CI): 249 (MH)+
Allyl 2-dimethylaminocarbonyl-3-aminobenzoate (0.39 g,
1.4 mM) vas condensed vith (2S,4S)-4-acetylthio-l-alloxycarbonyl-2carboxypyrrolidine (0.42 g, 1.54 mM) using a similar method to the EEDQ method described in example 12, giving (2S,4S)-l-allyloxycarbonyl-2-(2dimethylaminocarbonyl-3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-yl thioacetate (0.84 g). Nmr (CDClj, mixture of rotamers): δ 2.32 (s, 3H); 2.38 (br m, part obscured, IH); 2.38 (br m, part obscured,
IH); 2.74,2.76 (2 x s overlapping br m, 4H); 3.11,3.14 (2 x s, 3H);
3.36-3.45 (m, IH); 3.98-4.14 (m, 2H); 4.50 (dd, IH); 4.56-4.79 (m, 4H);
5.16-5.44 (m, 4H); 5.93-6.06 (m, 2H); 7.45 (t, IH); 7.81-7.86 (m, IH);
8.33-8.41 (2 x d, IH); 8.60 (br, IH).
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- 55 Ms (CI): 504 (ΜΗ) +
The thiol vas generated fro· the above thioacetate by a similar method to that described in example 12.
A solution of allyl (lR,5R,6S,8R)-6-(l-hydroxyethyl)-lmethyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (0.73 g,
1.47 mM) and (2S,4S)-l-allyloxycarbonyl)-2-(2-dimethylaminocarbonyl3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol in acetonitrile (12 ml) vere reacted by a similar method to that described in the 'preparation of protected carbapenem' step in example 1, giving allyl (IR,5R,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(2-dimethylaminocarbonyl3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-raethylcarbapenem-3-carboxylate as a vhite solid (0.63 g).
Nmr (CDClj, mixture of rotamers): δ 1.24 (d, 3H); 1.35 (2 x d, 3H);
1.98 (br, IH); 2.34 (br, IH); 2.73 (s, 3H); 3.11,3.13 (2 x s, 3H);
3.22-3.46 («, 3H); 3.66-3.85 (B. IH); 4.00-4.26 (m, 3H); 4.50 (t, IH);
4.62-4.80 («» 6H); 5.08-5.46 (m, 6H); 5.83-6.06 (m, 3H); 7.46 (td, IH);
7.86 (d, IH); 8.29 (m, IH); 8 .55 (br, IH).
Ms (CI): 711 (MH)+
Example 16 (lR,5S,6S>8R>2'S,4zS)-2-(2-(3-Carboxy-5-acetamidophenylcarbamoyl)pyrrolidln-4-ylthiol-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, dipotassium salt.
To a solution of 4-allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-(4nitrobenzyloxycarbonyl)-2-(3-carboxy-5-acetamidophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylate (0.4 g, 0.53 mmol) in DMF (20 ml) vere added Meldrum's acid (0.2 g, 1.39 mmol) and tetrakis triphenylphosphine palladium (40 mg, 0.035 mmol). The reaction mixture vas stirred for one hour, at ambient temperature. A solution of IM potassium phosphate buffer (20 ml) and
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- 56 zinc povder (0.5 g) vere added to the solution and after one hour, at ambient temperature, the reaction mixture vas filtered over diatomaceous earth and the pH of the filtrate adjusted to 7.5 vith solid potassium carbonate. The solution vas filtered, concentrated under reduced pressure and the resulting residue purified by reverse phase chromatography (Nucleosil C18), vith vater as eluant, to give, after freeze drying, the title compound (78 mg, 28X). Nmr (DMSO-dg + acetic acid-d4): δ 1.15 (d, 3H); 1.17 (d, 3H); 1.74 (m, IH); 2.06 (s, 3H); 2.66 (m, IH); 2.84 (m, IH); 3.20 (dd, IH); 3.40 (m, 2H); 3.70 (m, IH) j 3.97 (m, 2H); 4.16 (dd, IH); 7.92 (s, IH); 7.94 (s, IH); 8.19 (s, IH).
The starting material vas prepared as follovs:
A solution of (2S,4S)-4-acetylthio-2-carboxy-l-(4-nitrobenzyloxycarbonyl)pyrrolidine (1 g, 1.8 mmol) and EEDQ (0.53 g, 3 mmol) in chloroform (70 ml) vas stirred at ambient temperature for 1 hour. 3-Acetamido-5-aminobenzoic acid (0.53 g, 2.7 mmol) and diisopropylethylamine (0.7 ml, 4 mmol) vere then added to the reaction mixture, vhich vas stirred for 2 hours, at ambient temperature. After evaporation of the solvent, the crude compound vas purified by chromatography on HP20SS using methanol/vater (80:20) as the eluant. Partial evaporation of the solvents and lyophilisation gave (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-acetaraidophenylcarbamoyl)pyrrolidin-4-ylthioacetate (lg, 67X).
(2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-5acetamidophenylcarbamoyl)pyrrolidin-4-ylthioacetate vas dissolved in a mixture of methanol (60 ml) and vater (20 ml) and the pH of the solution vas adjusted to 11 vith a IH aqueous solution of NaOH. After 30 minutes at ambient temperature, the reaction mixture vas neutralised vith methanol, evaporated and purified by chromatography on HP20SS, using methanol/vater (80:20) as the eluant. Evaporation and lyophilisation gave (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3carboxy-5-acetamidophenylcarbaraoyl)pyrrolidin-4-ylthiol (0.68 g. 74X). Nmr (DMSOdg + acetic acid-d4): δ 2.05 (s, 3H); 2.05 (m, IH); 2.75
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- 57 (η, 1H); 3.20-3.80 (η, 2H); 4.00 (η, 1H); 4.42 (η, 1H); 5.40 (br s,
2H); 7.45-8.30 (m, 7Η).
To a solution of 4-nitrobenzyl (lR,5S,6S,8R)-6-’(l-hydroxy- “ ethyl)-l-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate (0.6 g,
1.2 mmol) in DMF (12 ml) vere added sequentially diIsopropylethylamine (0.6 ml, 3.4 mmol), (2S,4S)-l-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy5-acetamidophenylcarbamoyl)pyrrolidin-4-ylthiol (0.6 g, 1.2 mmol), tri-n-butylphosphine (0.6 ml, 2.4 mmol) and vater (0.1 ml, 5.5 mmol). The reaction mixture vas stirred overnight, at 4°C, evaporated to dryness and the residue vas purified by chromatography on HP20SS resin, using acetonitrile/vater (40:60) as the eluant. Evaporation and lyophilisation gave allyl (lR,5R,6S,8R,2S',4'S)-2-(l-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-acetamidophenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate (0.8 g, 88X). Nmr (DMSO-dg + acetic acid-dj: & 1.15 (d, 3H); 1.17 (d, 3H), 2.05 (s, 3H); 2.17 (m, IH); 2.81 (m, IH); 3.26 (dd, IH); 3.36 (td, IH); 4.56-4.74 (a, 2H); 5.02-5.73 (m, 4H); 5.91 (m, IH);
7.47 (d, IH); 7.68 (d, IH); 7.85-7.99 (m, 3H); 8.20-8.29 (m, 2H).
Example 17 (IR,5S,6S,8R,2z S,4'S)-2-(2-(4-Acetamido-3-carboxyphenylcarbaaoyl)pyrrolidln-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenera-3-carboxylic acid, dipotassium salt.
The title compound vas prepared from 4-allyl (1R,5S,6S,8R, 2zS,4zS)-2-(l-(4-nitrobenzyloxycarbonyl)-2-(4-acetamido-3-carboxyphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl) -1-methy lcarbapenem-3-carboxylate (diisopropylethylamine salt) using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-dj: δ 1.14 (d, 3H); 1.16 (d, 3H); 1.75 (a, IH); 2.07 (s, 3H); 2.73 (m, IH); 2.96 (dd, IH);
3.21 (dd, IH); 3.39 (m, IH); 3.54 (dd, IH); 3.78 (m, IH); 3.96 (m, IH); 4.08 (t, IH); 4.18 (dd, IH); 7.69 (dd, IH); 8.18 (d, IH); 8.42 (d, IH).
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- 58 MS (+ve FAB): 571 (MH)+, (K salt)
The starting material vas prepared as follovs:
(2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(4-acetamido-3carboxyphenylcarbamoyl)pyrrolldin-4-ylthioacetate vas prepared from 2-acetamido-5-aminobenzoic acid using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-d^): 6 1.95 (m, IH); 2.12 , (s, 3H); 2.34 (s, 3H); 2.77 (m, IH); 3.32 (m, IH); 3.93-4.50 (m, 3H);
5.04-5.32 (m, 2H); 7.47-8.42 (m, 7H).
(2S,4S)-1-(4-Nitrobenzyloxycarbonyl)-2-(4-acetamido-3carboxyphenylcarbamoyl)pyrrolidin-4-ylthiol vas prepared from (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(4-acetamido-3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthioacetate using a similar method to that of example 16.
Allyl (IR,5R,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl )-2-(4-acetamido-3-carboxyphenylcarbamoyl)pyrrolidin-4-ylthio)( 6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate (diisopropylethylamine salt) vas prepared from (2S,4S)-l-(4-nitrobenzyloxycarbonyl)-2' (4-acetamido-3-carboxyphenylcarbaraoyl)pyrrolidin-4-ylthiol and allyl (IR,5R,6S,8R)-6-(1-hydroxyethyl)-1-methyl-2-diphenylphosphoryloxycarbapenera-3-carboxylate using a similar method to that of example 16. Nmr (CDC13) 6: 1.14-1.80 (m, 23H); 2.17 (s, 3H); 2.67 (m, IH);
3.00-3.30 (m, 3H); 3.35-3.90 (ra, 4H); 3.90-4.40 (m, 3H); 4.40-4.75 (ra, 3H); 5.00-5.75 (m, 4H); 5.70-6.10 (m, IH); 7.38-8.65 (ra, 7H).
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- 59 Example 18 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenea-3carboxylic acid dlpotasslum salt.
The title compound vas prepared from allyl (IR, 5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5methylsulphonaraidophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl )- 1-methylcarbapenem 3-carboxylate using a similar method to that of example 16. Nmr (DMSOdg + acetic acid-d^): 6 1.16 (d, 3H); 1.17 (d, 3H); 1.74 (m, IH); 2.64 (m, IH); 2.81 (dd, IH); 3.01 (s, 3H); 3.20 (m, IH); 3.40 (m, 2H); 3.68 (m, IH); 3.96 (m, 2H); 4.17 (dd, IH); 7.54 (s, IH); 7.82 (s, IH); 8.00 (s, IH).
MS (+ve FAB): 607 (M+H)+ for monopotassium salt; 645 (M+H)+ for dipotassium salt.
The starting material vas prepared as follovs:
(25.45) -1-(4-(Nitrobenzyloxycarbonyl)-2-(3-carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthioacetate vas prepared from 3-amino-5-methylsulphonamidobenzoic acid using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-d^): 6 2.00 (m, IH); 2.30 (s, 3H); 2.84 (m, IH); 2.95 (s, 3H); 3.20-3.51 (m, IH); 3.83-4.20 (ra, 2H); 4.30-4.58 (m, IH); 5.20 (ra, 2H); 7.48-8.22 (m, 7H).
(25.45) -1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthiol vas prepared from (2S, 4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthioacetate using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-d^): 6 2.10 (m, IH);
2.78 (m, IH); 2.99 (s, 3H); 3.43 (m, IH); 3.68 (m, IH); 4.05 (m, IH);
4.42 (m, IH); 5.13-5.32 (m, 3H); 7.50-8.82 (m, 7H).
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- 60 Allyl (lR,5R,6S,8R,2'S,4'S)-2-(l-(4-nitrobenzyloxycarbonyl)2-(3-carboxy-5-methylsulphonamidophenylcarbamoyl)pyrrolidin-4-ylthio)6- (1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate vas prepared. from (2S, 4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-methylsulphonamidophenylcarbaooyl)pyrrolidin-4-ylthio and allyl (lR,5R,6S,8R)-6-(lhydroxethyl)-l-methyl-2-diphenylphosphoryloxycarbapenem-3carboxylate using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-d4): δ 1.20 (d, 3H); 1.22 (d, 3H); 1.96 (m, IH); 2.83 (m, IH); 3.00 (s, 3H); 2.26-3.57 (m, 3H); 3.87-4.28 (m, 4H); 4.42-4.76 (m, 3H); 5.08-5.42 (ra, 4H); 5.92 (m, IH); 7.22-8.22 (m, 7H).
Example 19 (1R,5S,6S,88,2'S,4'S)-2-(2-(3-Carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, dlsodium salt.
To a stirred solution of 4-nitrobenzyl (1R,5S,6S,8R,2'S,4'S)2-(1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylat e (0.5 g, 0.56 mmol) in DMF (5 ml) and vater (5 ml) vas added a solution of IM sodium phosphate buffer (5 ml) followed by zinc povder (1 g). The reaction mixture vas stirred for 1 hour and the pH of the solution vas adjusted to 8 by adding a saturated aqueous solution of sodium hydrogen carbonate. After filtration over diatomaceous earth, the filtrate vas concentrated and purified by subjecting to preparative chromatography (Nucleosil C-18), using vater as the eluant.
Concentration and lyophilisation of the required fractions gave the title compound (44 mg, 122). Nmr (DMSO-dg + acetic acid-d4): δ 1.15 (d, 3H); 1.16 (d, 3H); 1.78 (m, IH); 2.73 (ra, IH); 2.92 (m, IH); 3.21 (dd, IH); 3.40 (m, IH); 3.48 (m, IH); 3.75 (m, IH); 3.97 (m, IH); 4.03 (m, IH); 4.18 (ra, IH); 7.93 (S, IH); 8.11 (s, IH); 8.29 (s, IH).
MS (-ve FAB): 576 (M-H)~ for monosodiura salt; 598 (M-H) for disodium salt.
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- 61 The starting material vas prepared as follovs:
(25.45) -1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthioacetate vas prepared from 3-amino-5sulphobenzoic acid using a similar method to that of example 16.
Nmr (DMSO-dg + acetic acid-d*): 6 1.97 (m, IH); 2.30 (s, 3H); 2.80 f (m, IH); 3.37 (m, 1H)j 3.86-4.15 (m, 2H); 4.46 (ra, IH); 5.05-5.28 (m, 2H); 7.46-9.25 (m, 7H).
r (25.45) -1-(4-Nitrobenzyloxycarbonyl)-2-(3-carboxy-5sulphophenylcarbamoyl)pyrrolidin-4-ylthiol vas prepared from (2S,4S)-1(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolldin-4-ylthioacetate using a similar method to that of example 16. Nmr (DMSO-dg + acetic acid-d4): δ 1.25 (d, 3H); 1.27 (d, 3H); 2.07 (ra, IH); 2.70 (ra, IH); 3.4 (m, IH); 3.67 (m, IH); 3.99 (m, IH);
4.49 (m, IH); 5.07-5.30 (m, 2H); 7.47-8.40 (ra, 7H).
4-Nitrobenzyl (IR,5S,6S,8R,2'S,4'S)-2-(1-(4-nitrobenzyloxy carbonyl)-2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthio)-6(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate vas prepared from (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(3-carboxy-5-sulphophenylcarbamoyl)pyrrolidin-4-ylthiol and 4-nitrobenzyl (lR,5R,6S,8R)-6-(lhydroxyethyl)-l-methyl-2-diphenylphosphoryloxycarbapenem-3-carboxylate using a similar method to that of example 1. Nmr (DMSO-d., + acetic o acid-d4): δ 1.20 (d, 3H); 1.21 (d, 3H); 1.96 (m, IH): 2.77 (m, IH); 3.18-3.47 (m, 2H); 3.66-4.90 (ra, 6H); 5.04-5.50 (m, 4H); 7.30-8.35 (m, 11H).
Example 20 (5R,6S,8R,2^,4^)-2-(2 - (3-Carboxyphenylcarbamoyl) pyrrolidin-4ylthio)-6-(l-hydroxyethyl)carbapenem-3-carboxylic acid, disodium salt.
To a stirred solution of allyl (5R,6S,8R,4'S)-2-(lallyloxycarbonyl)-2-(3-allyloxycarbonylphenylcarbamoyl)BAD ORIGINAL ft
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-62pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl )carbapenem-3-carboxylate (0.185 g, 0.296 mmol) in CHgCl^ (4 ml), at ambient temperature, vere added sequentially N-methylaniline (0.190 g, 1.776 mmol), vater (4 ml), sodium bicarbonate (100 mg) and te£rakis(trlphenylphosphine)palladium -------(34 mg, 0.029 mmol). After 10 minutes the aqueous phase vas separated and injected onto a C18 preparative HLPC column giving the title compound (43 mg, 271). Nmr (DMSO-dg + acetic acid-d^): 1.16 (d, 3H);
1.81 (m, IH); 2.64 (m, IH); 2.84 (m, IH); 3.26 (m, 3H); 3.4 (m, IH);
3.67 (m, IH); 3.94 (m, 2H); 4.12 (m, IH); 7.42 (t, IH); 7.65 (d, IH);
7.83 (d, IH); 8.27 (s, IH).
The starting allyl (5R,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidin-4-yl-thio)-6(l-hydroxyethyl)carbapenem-3-carboxylate vas prepared in 67X yield using a similar procedure to that described in example 1, by reacting (2S,4S) l-allyloxycarbonyl-2-(3-allyloxycarbonylphenylcarbamoyl)pyrrolidine-4-thiol, described in example 4, vith allyl (5R,6S,8R)-6-(1-hydroxyethyl)-2-diphenylphosphoryloxycarbapenem-3carboxylate (EP-A-126780 and EP-A-208889).
Example 21 (IR,5S,6S,8R, 2' S,4'S)-2-(2-(3-Carboxy-5-cyanophenylcarbamoylpyrrolidln-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, disodium salt
To a solution of allyl (IR,5S,6S,8R,2'S,4'S)-2-(1-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate (358 mg, 0.54 mM) and 2,2-dimethyl-l,3-dioxane-4,6-dione (388 mg, 2.7 mM) in a mixture of DMF (8 ml) and THF (4 ml), under an argon atmosphere, vas added tetrakis(triphenylphosphine)palladium (62 mg, 0.054 mN). The solution vas stirred, under argon vith protection from light, for 1.75 hours, and solvent removed by evaporation. The residue vas dissolved in a mixture of THF (6 ml) and DMF (2 ml), and a solution of sodium 2-ethylhexanoate (295 mg, 1.77 mM) in THF (4 ml) vas added, folloved by
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- 63 diethyl ether (20 ml). The resultant precipitate vas centrifuged, and supernatant removed. The product vas vashed tvice by resuspension in a mixture of THF (4 ml) and diethyl ether (10 ml), then diethyl ether (20 ml) folloved by centrifugation. Crude product vas dissolved in vater (20 ml) and the pH adjusted to 7.4 vith NaHCOj. After filtration, the solution vas chromatographed on HP20SS resin, and fractions combined as appropriate to give the title product (206 mg, 70Z). Nmr (DMSO-dg + acetic acid-d^): δ 1.17 (d, 6H); 1.95 (m, part obscured, 1H); 2.83 (m, IH); 3.09 (dd, IH); 3.25 (dd, IH); 3.41 (quintet, IH); 3.64 (dd, IH); 3.88 (quintet, IH); 4.02 (quintet, IH); 4.22 (dd, IH); 4.31 (t, IH); 8.00 (s, IH); 8.28 (t, IH); 8.46 (t, IH).
Ms (+ve FAB): 523 (MH)+, (Na salt)
The starting materials vere prepared as follovs:
3-Cyano-5-nltrobenzoic acid
3-Amino-5-nitrobenzoic acid (3.64 g, 20 mM) vas dissolved in concentrated hydrochloric acid (20 ml), diluted vith vater (75 ml), cooled to 0°, and added over 30 minutes to a solution of NaN02 (1.38 g, 20 mM) in vater (10 ml). The pH vas adjusted to 6.2 vith saturated NajCOj solution. A mixture of CuS0^.5H20 (10 g, 42 mH) in vater (40 ml) and KCN (10 g, 154 mM) in vater (20 ml) vas heated to 65s, the solution of diazonium salt added over 15 minutes, and the mixture refluxed for 40 minutes. After cooling, and acidifying vith 2M hydrochloric acid, the organics vere extracted into ethyl acetate (2 x 200 ml). The combined extracts vere vashed vith aqueous Na^PO^, vater, brine, and dried over Na2S0^. Evaporation gave 3-cyano-5nitrobenzoic acid (3.6 g, 94Z).
Nmr (DMSO-dg): δ 8.69 (t, IH); 8.80 (t, IH); 8.97 (t, IH).
Ms (-ve FAB): 191 (M - H)~
Ir (nujol): v 2220 cm”^
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- 64 3-Cyano-5-nitrobenzoic acid vas allylated essentially as in Example 1, except that the chromatographic purification used a mixture of petrol/ethyl acetate (5:1), to give allyl 3-cyano-5-nitrobenzoate. Nmr (DMSO-dg): δ 4.91 (dt, 2H); 5.39-5.53 (m, 2H); 5.99-6.19 (m, IH); 8.78 (t, IH); 8.81 (t, IH); 9.04 (t, IH).
Ms (+ve FAB): 202 M+; 232 (M + NH4)+; (both for amino compound by ammonia reduction) c
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-5-cyanobenzoate, mp 112-113°. Nmr (DMSOdg): δ 4.79 (dt, 2H); 5.25-5.45 (m, 2H); 5.94-6.13 (m overlapping br, IH); 7.10 (t, IH); 7.37 (t, IH); 7.48 (t, IH).
Ms (+ve FAB): 202 M+; 232 (M + NH4) +
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of dichloromethane/ethyl acetate (19:1 to 9:1) to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxyC carbonyl-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): δ 2.33 (s, 3H); 2.59 (br, 2H); 3.38 (dd, IH); 3.97-4.17 (m, ' 2H); 4.56 (t, IH); 4.69 (d, 2H); 4.84 (d, 2H); 5.26-5.48 (ra, 4H); 5.856.14 (ra, 2H); 8.03 (br s, IH); 8.18 (t, IH); 8.29 (br s, IH); 9.69 (br, IH).
Ms (+ve FAB): 458 (MH)+; 480 (M + Na)+
The above thioacetate vas deacetylated as Example 1, to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthiol. Nmr (CDClj): δ 1.90 (d, IH); 2.52 (br, IH); 2.65 (br, IH); 3.34-3.52 (ra, 2H); 4.07 (dd, IH); 4.54 (t,
IH); 4.69 (d, 2H); 4.84 (d, 2H); 5.27-5.47 (m, 4H); 5.87-6.11 (ra, 2H);
8.01 (S, IH); 8.21 (t, IH); 8.28 (s, IH); 9.56 (br, IH).
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- 65 The above thiol vas condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient of dichloromethane/ethyl acetate (3:2 to 2:3) to give allyl (1R,5S,6S,8R,2'S,4'S)2 - (1 - al ly loxycar bonyl -2-(3 -ally loxycarbonyl - 5 - cyanophenylcar banoy 1) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-me thylcarbapenem-3carboxylate. Mar (CDCl^): δ 1.27 (d, 3H); 1.35 (d, 3H); 2.67 (v br, 2H); 3.21-3.33 (overlapping!·, 2H); 3.53 (br, IH); 3.83 (quintet, IH);
3.93 (dd, IH); 4.20-4.31 (overlapping m, 2H); 4.54 (t, IH); 4.63-4.86 ( (m, 6H); 5.21-5.47 (ra, 6H); 5.82-6.11 (m overlapping br, 3H); 8.05 (t,
IH); 8.33 (br s, IH); 8.37 (br s, IH); 9.35 (br, IH).
Ms (+ve FAB): 665 (MH)+; 687 (M + Na)+
Example 22 (1R,5S,6S,8R, 2'S,4'S)-2-(2-( 3 -Car boxy-5 -me thoxyphenylcarbaraoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-me thylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 21. Nmr (DMSO-dg + acetic acid-d^): δ 1.17 (d, 3H); 1.18 (d, 3H); 1.83 (m, part obscured, IH); 2.76 (quintet, IH); 2.98 (dd, IH);
3.22 (dd, IH); 3.39 (quintet, IH); 3.56 (dd, IH); 3.81 (s overlapping ra, 4H); 4.00 (quintet, IH); 4.15,4.18 (t overlapping dd, 2H); 7.22 (t, IH); 7.58 (t, IH); 7.84 (t, IH).
Ms (-ve FAB): 505 (M - H)~, (Na salt)
The starting materials vere prepared as follows:
3-Hydroxy-5-nitrobenzoic acid vas methylated essentially as the allylation step of Example 1, except that the allyl bromide vas replaced by dimethyl sulfate, and purification by chromatography vas unnecessary, to give methyl 3-methoxy-5-nitrobenzoate. Nmr (CDCl^)! δ
3.94 (s, 3H); 3.97 (s, 3H); 7.87 (t, IH); 7.90 (t, IH); 8.44 (t, IH).
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- 66 The above ester (3.45 g, 16 mM) vas dissolved in THF (100 ml), treated vith IH NaOH (25 ml), and stirred at ambient temperature for 5 hours. After removal of the solvent, the residue vas treated vith vater (50 ml), acidified vith 2M sulfuric acid, and extracted vith ethyl acetate (3 x 60 ml). The combined organic extracts vere vashed vith aqueous NaHjPO^ brine, and dried over MgSO^. Evaporation gave 3methoxy-5-nitrobenzoic acid, vhich vas allylated essentially as in Example 1, except that the chromatographic purification used a mixture ( of petrol/ethyl acetate (6:1), to give allyl 3-methoxy-5-nitrobenzoate.
Nmr (CDClj): 6 3.95 (s, 3H); 4.87 (dt, 2H); 5.31-5.48 (m, 2H); 5.956.15 (m, IH); 7.89 (t, IH); 7.92 (t, IH); 8.46 (t, IH).
Ms (CI): 237 H+; 255 (M + NH4) +
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-5-methoxybenzoate. Nmr (DMSO-dg): δ 3.72 (s, 3H); 4.50 (v br, 2H); 4.75 (dt, 2H); 5.25-5.43 (m, 2H); 5.95-6.11 (m, IH); 6.47 (t, IH); 6.75 (t, IH); 6.93 (t, IH).
f Ms (CI): 208 (HH)+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of petrol/ethyl acetate (5:2 to 2:1) to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl5-methoxyphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): δ 2.32 (s, 3H); 2.59 (br, 2H); 3.38 (dd, IH); 3.85 (s, 3H); 4.02 (quintet, IH); 4.15 (dd, IH); 4.55 (t, IH); 4.68 (d, 2H); 4.81 (d, 2H); 5.22-5.46 (m, 4H); 5.83-6.13 (ra, 2H); 7.35 (t, IH); 7.58 (br s, IH);
7.64 (t, IH); 9.12 (br, IH).
Ms (+ve FAB): 463 (HH)+; 485 (H + Na)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient of dichlororaethane/ethyl acetate (60:40 to 45:55) to give
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- 67 allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDCl^): δ 1.25 (d, 3H); 1.37 (d, 3H); 2.64 (v br, 2H); 3.21-3.33 (overlapping m, 2H); 3.48 (br, IH); 3.80 (quintet, IH); 3.85 (s, 3H); 4.01 (dd, IH); 4.19-4.29 (overlapping n, 2H); 4.53 (t, IH); 4.62-4.83 (m, 6H); 5.20-5.45 (m, 6H); 5.84-6.11 (m overlapping br, 3H); 7.25 (t, IH); 7.63 (m, 2H); 8.90 (br, IH).
Ms (+ve FAB): 670 (MH)+; 692 (M + Na) +
Example 23 (IR,5S,6S,8R,2'S,4'S)-2-(2-(5-Carboxy-2-methanesulphinylphenylcarbamoyl)pyrrolidin-4-yl-thio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxyllc acid, disodium salt vas prepared as a mixture of diastereoisomers at the sulfoxide centre, using the technique of Example 21. Nmr (DMSO-dg + acetic acid-d^): δ 1.18 (d, 6H); 1.87 (m, part obscured, IH); 2.64-2.91, 2.82, 2.84 (m overlpping 2 x s, 5H); 3.21 (dd, IH); 3.40 (quintet, IH); 3.52 (dd, IH); 3.71 (quintet, IH); 4.01 (quintet, IH); 4.01 (m, IH), 4.18 (dd, IH); 7.83 (t, IH); 7.94 (td, IH); 8.45 (d, IH).
Ms (+ve FAB): 560 (MH)+, (Na salt); 582 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
4-Hethanesulphinyl-3-nitrobenzoic acid
4-Methylthio-3-nitrobenzoic acid (4.36 g, 20 mM) vas dissolved in acetic acid (200 ml), and treated at ambient temperature vith H202 (2.5 ml, 302, 22 mM). After stirring at ambient temperature for 4 days, excess peroxide vas decomposed vith sodium metabisulfite, and solvent evaporated. The residue vas purified by chromatography on silica, eluting vith methanol, to give 4-methanesulphinyl-3nitrobenzoic acid (4.1 g, 892), mp 238-239·. Nmr (DMSO-dg): δ 2.90 (s,
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- 68 3H); 8.29 (d, IH); 8.56 (dd, IH); 8.68 (d, IH).
Ms (-ve FAB): 229 (M - H)“
The above acid vas allylated essentially as in Example 1, except that the chromatographic purification vas unnecessary, to give allyl 4-methanesulphinyl-3-nitrobenzoate, mp 119-121*. Nmr (DMSO-dg): & 2.91 (s, 3H); 4.91 (dt, 2H); 5.29-5.50 (m, 2H); 5.99-6.18 (m, IH); 8.34 (d, IH); 8.61 (dd, IH); 8.69 (d, IH).
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-4-methanesulphinylbenzoate. Nmr (CDCl^): & 2.92 (s, 3H); 4.82 (dt, 2H); 5.17 (br, 2H); 5.28-5.46 (m, 2H); 5.966.11 (ra, IH); 7.30 (dd, IH); 7.41 (m, 2H).
Ms (El): 223 (M - O)+; 239 M+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of hexane/ethyl acetate (3:2 to 1:1) to give (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl2-methanesulphinylphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (DMSO-dg at 100°): & 1.98 (m, IH); 2.32 (s, 3H); 2.73 (s, 3H); 2.86 (m, part obscured, IH); 3.36 (m, IH); 3.91-4.10 (overlapping m, 2H); 4.48 (dd, IH); 4.53 (ra, 2H); 4.86 (d, 2H); 5.11-5.49 (m, 4H); 5.80-5.97 (m, IH); 6.01-6.15 (ra, IH); 8.09 (s, 2H); 8.35 (s, IH).
Ms (+ve FAB): 495 (MH)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from ethyl acetate to ethyl acetate/isopropanol (98:2) to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5allyloxycarbonyl-2-raethanesulphinylphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (DMSO-dg, mixture of rotamers): 6 1.18 (d, 6H); 1.99 (br, IH); 2.80 (s overlapping m, 5H); 3.25 (solvent overlapping m, 2H); 3.54 (m, IH);
BAD original
AP Ο Ο Ο 3 9 8
- 69 3.90-4.18 (m, 3H); 4.15 (dd, 1H); 4.55 (m, 4Η); 4.85 (d, 2H); 5.06 (d, IH); 5.14-5.46 (a, 6H); 5.79-6.13 (a, 3H); 7.80-8.05(a, 2H)j 8.12 (a, IH); 10.10 (a, IH).
Ms (+ve FAB): 702 (MH) +
Example 24
I (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5-methanesulphonyl( phenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, disodiua salt vas prepared using the technique of Example 21. Nmr (DMSO-dg + acetic acid-d^): & 1.16 (d, 3H)j 1.18 (d, 3H); 1.75 (quintet, IH); 2.63 (a, IH); 2.79 (dd, IH); 3.20 (s overlapping m, 4H); 3.38 (m, 2H); 3.64 (quintet, IH); 3.95 (a, 2H); 4.14 (dd, IH); 8.09 (t, 1H); 8.44 (m, 2H).
Ms (-ve FAB): 574 (M - H)~, (Na salt)
The starting materials vere prepared as follovs:
3-Methylthio-5-nitrobenzoic acid (
3-Amlno-5-nitrobenzoic acid (1.82 g, 10 mM) vas dissolved in concentrated sulphuric acid (1.9 ml), diluted vith vater (10 ml), and cooled to 5°. A solution of NaNO? (0.7 g, 10 mM) in vater (3 al) vas added and the mixture stirred for 30 minutes. The cold solution of diazoniua salt vas added to a slurry of thiomethylcopper(I) at 3°, and the mixture stirred for 45 minutes. Organics vere extracted into ethyl acetate (5 x 60 ml), and the combined organic layers vashed vith aqueous NaHjPO^, vater, brine, and dried over Na2S04· Evaporation gave 3-methylthio-5-nitrobenzoic acid (1.77 g, 83%). Nmr (DMSO-dg): 6 2.63 (s, 3H); 8.10 (t, IH); 8.21 (t, IH); 8.32 (t, IH); 13.68 (br, IH).
Ms (-ve FAB): 213 (M - H)‘
BAD ORIGINAL ft
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- 70 The above acid vas allylated essentially as in Example 1, except that the chromatography eluant vas a mixture of petrol/ethyl acetate (6:1), to give allyl 3-methylthio-5-nitrobenzoate. Nmr (CDClj): 6 2.60 (s, 3H); 4.87 (dt, 2H); 5.32-5.49 (m, 2H); 5.93-6.07 (m, IH); 8.20 (m, 2H); 8.57 (t, IH).
Ms (El): 253 M+ f Allyl 3-methylsulphonyl-5-nitrobenzoate
Allyl 3-methylthio-5-nitrobenzoate (1.12 g, 4.4 mM) vas dissolved in methanol (30 ml), and cooled to 2°. A solution of potassium peroxymonopersulfate ^KHSOg.KHSO^.i^SO^, 8.13 g, 13.2 mM) in vater (25 ml) vas added slovly, and stirring continued for 4 hours. The mixture vas diluted vith vater (60 ml) and extracted vith ethyl acetate (3 x 100 ml). The combined organic extracts vere vashed vith vater, brine, and dried over ^280^. Crude product vas purified by chromatography on silica using a gradient of petrol/ethyl acetate (3:1 to 2:1) to give allyl 3-methylsulphonyl-5-nitrobenzoate (0.74 g, 59%).
C Nmr (DMSO-dg): δ 3.44 (s, 3H); 4.94 (dt, 2H); 5.32-5.53 (m, 2H); 6.016.25 (ra, IH); 8.78 (t, IH); 8.89 (t, IH); 8.91 (t, IH).
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-5-methanesulphonylbenzoate. Nmr (DMSOdg): δ 3.15 (s, 3H); 4.80 (dt, 2H); 5.26-5.47 (ra, 2H); 5.95-6.15 (tn overlapping br, 3H); 7.29 (t, IH); 7.47 (t, IH); 7.51 (t, IH).
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient of hexane/ethyl acetate (2:1 to 1:1) to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl5-methanesulphonylphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): δ 2.34 (s, 3H); 2.48 (ra, IH); 2.62 (m, IH); 3.17 (s, 3H); 3.41 (dd, IH); 4.03 (quintet, IH); 4.15 (dd, IH); 4.58 (dd, IH); 4.71 (d, 2H); 4.84 (dt, 2H); 5.27-5.47 (m, 4H); 5.88-6.14 (m, 2H); 8.23 (br s, 2H); 8.37 (t, IH); 9.69 (br, IH).
BAD ORIGINAL ft
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- 71 Ms (+ve FAB): 511 (MH)+; 533 (M + Na) +
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient of dichloromethane/ethyl acetate (55:45 to 20:80) to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methanesulphonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDClj): & 1.24 (d, 3H); 1.36 (d, 3H); 2.54 (br, IH); 2.66 (br, IH); 3.12 (s, 3H); 3.19-3.22 (overlapping m, 2H); 3.54 (br, IH); 3.87 (quintet, IH); 3.94 (dd, IH); 4.25,4.29 (quintet overlapping dd, 2H); 4.55 (t, IH); 4.654.80 (ra, 4H); 4.85 (d, 2H); 5.20-5.46 (m, 6H)j 5.86-6.12 (m overlapping br, 3H); 8.31 (br, IH); 8.43 (br, IH); 8.52 (br, IH); 9.40 (br, IH).
Ms (+ve FAB): 718 (MH)+; 740 (M + Na)+
Example 25 (lR,5S,6S,8R,2'S,4/S)-2-(2-(3-Carboxy-5-trifluoromethylphenylcarbaraoyl) pyrrolidin-4-ylthio)-6- (1-hydroxyethyl) -1-methylcarbapenem-3-carboxylic acid, disodium salt vas prepared using the technique of Example 2. Nmr (DMSO-dg + acetic acid-d4): & 1.16 (d,
6H); 1.92 (m, part obscured, IH); 2.77 (m, part obscured, IH); 3.00 (dd, IH); 3.21 (dd, IH); 3.37 (quintet, IH); 3.59 (quintet, IH); 3.80 (quintet, IH); 3.97 (quintet, IH); 4.20 (ra, 2H); 7.91 (br s, IH); 8.27 (br s, IH); 8.44 (br s, IH).
Ms (-ve FAB): 542 (M - H)~, (acid); 564 (M - H)~, (Na salt)
The starting materials vere prepared as follovs:
3-Nitro-5-trifluoromethylbenzoic acid vas allylated essentially as in Example 1, except that the product vas sufficiently pure for use vithout chromatography, to give allyl 3-nitro-5-trifluoromethylbenzoate. Nmr (DMSO-dg): δ 4.91 (dt, 2H); 5.30-5.51 (rn, 2H);
BAD ORIGINAL
A %
AP Ο Ο Ο 3 9 8
- 72 5.99-6.20 (m, 1H); 8.58 (br s, 1H); 8.77 (br s, 1H); 8.84 (t, 1H).
Ms (CI): 275 M+; 293 (M + NH*) +
Reduction of the above nitro compound by the method of Example 2 gave allyl 3-amino-5-trifluoromethylbenzoate, sufficiently pure for use without chromatography. Nmr (DMSO-dg): & 4.78 (dt, 2H); 5.24-5.43 (m, 2H); 5.93-6.13 (m, 1H); 7.08 (t, 1H); 7.27 (br s, 1H);
7.44 (t, 1H).
Ms (CI): 245 M+; 263 (M + NH*)+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/diethyl ether (9:1) to give (2S,4S)-l-allyloxycarbonyl2-(3-allyloxycarbonyl-5-trifluoromethylphenylcarbamoyl)pyrrolidin-4ylthioacetate. Nmr (CDCl^): δ 2.33 (s, 3H); 2.59 (m, 2H); 3.39 (dd, 1H); 4.04 (quintet, 1H); 4.14 (dd, 1H); 4.58 (t, 1H); 4.62 (dt, 2H); 4.85 (dt, 2H); 5.23-5.48 (m, 4H); 5.84-6.15 (m, 2H); 8.03 (br s, 1H);
8.23 (br s, 2H); 9.60 (br, 1H).
Ms (+ve FAB): 501 (MH)+; 523 (M + Na)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate/dichloromethane (9:1) to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-trifluoromethylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (DMSO-dg + acetic acid-d*): δ 1.21 (d, 6H); 2.05 (br, 1H); 2.85 (br, 1H); 3.29 (dd, 1H);
3.44 (dd, 1H); 3.51 (quintet, 1H); 3.93 (br, 1H); 4.05-4.18 (m, 2H);
4.27 (dd, 1H); 4.43-4.71 (overlapping m, 5H); 4.85 (d, 2H); 5.16-5.46 (ra, 6H); 5.70-6.16 (m, 3H); 7.94 (br s, 1H); 8.37 (br s, 1H); 8.53 (br s, 1H).
BAD ORIGINAL fi
AP Ο Ο Ο 3 9 8
- 73 Ms (+ve FAB): 708 (MH)+; 730 (M + Na) +
Example 26 (IR,5S,6S,8R,2'S,4'S)-2- (2-(5-Carboxy-2-methoxyphenylcarbamoyl )pyrrolidin-4-ylthio) -6-( 1-hydroxyethyl) -l-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 1. Nmr (DMSO-dg + acetic acid-d^): δ 1.20 (d, 6H); 1.93 (m, part obscured, IH); 2.86 (quintet, IH); 3.02 (dd, IH); 3.26 (dd, 1H);
3.44 (quintet, IH); 3.68 (dd, IH); 3.84 (quintet, IH); 3.95 (s, 3H);
4.03 (quintet, IH); 4.22 (dd, IH); 4.34 (t, IH); 7.13 (d, IH); 7.78 (dd, IH); 8.25 (d, IH).
Ms (+ve FAB): 528 (MH)+, (Na salt); 550 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
4-Methoxy-3-nitrobenzoic acid vas allylated essentially as in Example 1, except that the product vas sufficiently pure for use vithout chromatography, to give allyl 3-nitro-4-methoxybenzoate. Nmr (CDClj): δ 4.03 (s, 3H); 4.83 (dt, 2H); 5.29-5.46 (m, 2H); 5.93-6.14 (m, IH); 7.14 (d, IH); 8.24 (dd, IH); 8.52 (d, IH).
Ms (CI): 237 M+; 255 (M + NH4)+
Reduction of the above nitro compound by the method of Example 2 gave allyl 3-amino-4-methoxybenzoate sufficiently pure for use vithout chromatography. Nmr (CDClj): δ 3.72 (br, 2H); 3.90 (s,
3H); 4.77 (dt, 2H); 5.24-5.43 (m, 2H); 5.95-6.10 (m, IH); 6.79 (d, IH); 7.41 (d, IH); 7.50 (dd, IH).
Ms (CI): 208 (MH)+
The above amine vas condensed vith proline acid as Example 4, except that the material vas purified by chromatography on silica, bad original
AP Ο Ο Ο 3 9 8
- 74 using a gradient from dichloromethane to dichloromethane/diethyl ether (4:1), giving (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2methoxyphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDCl^): 62.33 (s, 3H); 2.51 (br, IH); 2.66 (br, IH); 3.41 (dd, IH); 3.93 (s, 3H);
4.01 (quintet, IH); 4.17 (dd, IH); 4.55 (t, IH); 4.64 (d, 2H); 4.80 (dt, 2H); 5.18-5.44 (ra, 4H); 5.81-6.14 (m overlapping br, 2H); 6.91 (d, IH); 7.84 (dd, IH); 8.90 (br, IH); 9.01 (d, IH).
Ms (+ve FAB): 463 (MH)+; 485 (M + Na)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1methylcarbapenem-3-carboxylate. Nmr (CDCl^): 6 1.23 (d, 3H); 1.36 (d, 3H); 2.52 (br, IH); 2.66 (br, IH); 3.22 (dd, IH); 3.28 (quintet, IH);
3.44 (dd, IH); 3.83 (quintet, IH); 3.93 (s, 3H); 4.09 (m, IH); 4.194.31 (overlapping m, 2H); 4.53 (t, IH); 4.65 (a, 4H); 4.81 (d, 2H); 5.19-5.45 (m, 6H); 5.83-6.11 (m, 3H); 6.91 (d, IH); 7.83 (dd, IH); 8.79 f (br, IH); 9.04 (d, IH).
f Ms (+ve FAB): 670 (MH)+; 692 (M + Na)+
Example 27 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Nmr (DMSO-dg + acetic acid-d^): 6 1.17 (d, 6H); 1.83 (m, part obscured, IH); 2.75 (quintet, IH); 2.97 (dd, IH); 3.23 (dd, IH); 3.40 (quintet, IH); 3.56 (dd, IH); 3.82 (s + m, 4H); 3.99 (quintet, IH); 4.12 (t, IH); 4.19 (dd, IH); 7.09 (d, IH); 7.75 (dd, IH); 7.95 (d, IH).
Ms (+ve FAB): 528 (MH)+, (Na salt); 550 (MH)+, (Na2 salt)
BAD ORIGINAL $
AP Ο Ο Ο 3 9 8
- 75 The starting aaterials vere prepared as follovs:
2-Methoxy-5-nitrobenzoic acid vas allylated essentially as in Example 1, except that the product vas sufficiently pure for use vithout chromatography, to give allyl 2-methoxy-5-nitrobenzoate. Nmr (CDClj): δ 4.03 (s, 3H); 4.85 (dt, 2H); 5.30-5.49 (m, 2H); 5.95-6.14
Γ (m, IH); 7.08 (d, IH); 8.48 (dd, IH); 8.72 (d, IH).
C Ms (CI): 238 (MH)+; 255 (M + NH4) +
Reduction of the above nitro compound by the method of Example 2 gave allyl 5-amino-2-methoxybenzoate sufficiently pure for use vithout chromatography. Nmr (CDClj): δ 3.39 (br, 2H); 3.83 (s,
3H); 4.80 (dt, 2H); 5.23-5.47 (ra, 2H); 5.94-6.13 (m, IH); 6.83 (d, 2H); 7.18 (t, IH).
Ms (CI): 208 (MH)+
The above amine vas condensed vith proline acid as Example 4, * except that the material vas purified by chromatography on silica, using a gradient from dichioromethane to dichloromethane/diethyl ether (4:1), giving (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4methoxyphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDClj): δ 2.32 (s, 3H); 2.58 (br, 2H); 3.39 (dd, IH); 3.89 (s, 3H); 4.02 (quintet,
IH); 4.13 (dd, IH); 4.53 (t, IH); 4.66 (dt, 2H); 4.80 (dt, 2H); 5.235.48 (m, 4H); 5.84-6.13 (m, 2H); 6.94 (d, IH); 7.80 (m, 2H); 8.94 (br, IH).
Ms (CI): 463 (MH)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichioromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1BAD ORIGINAL
AP Ο Ο Ο 3 9 8
- 76 methylcarbapenem-3-carboxylate. Nmr (CDClj): δ 1.25 (d, 3H); 1.36 (d, 3H); 2.65 (br, 2H); 3.25 (dd, IH); 3.28 (quintet, IH); 3.47 (br, IH); 3.79 (quintet, IH); 3.89 (s, 3H); 4.01 (dd, IH); 4.18-4.29 (overlapping a, 2H); 4.51 (t, IH); 4.66 (a, 4H); 4.79 (dt, 2H); 5.19-5.46 (β, 6H); 5.84-6.11 (π, 3H); 6.95 (d, IH); 7.79-7.87 (a, 2H)j 8.70 (br, IH).
Ms (+ve FAB): 670 (MH)+; 692 (M + Na) +
Example 28 (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-2-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Mir (DMSO-dg + acetic acid-d^): δ 1.18 (d, 6H); 1.85 (m, part obscured, IH); 2.66-2.86 (overlapping m, 2H); 3.21 (dd, IH); 3.41 (quintet, IH); 3.52-3.72 (overlapping m, 2H); 3.82 (s, 3H); 3.99 (quintet, IH); 4.08 (dd, IH);
4.17 (dd, IH); 7.17 (t, IH); 7.45 (dd, IH); 8.41 (dd, IH).
Ms (+ve FAB): 528 (HH)+, (Na salt); 550 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
2-Hydroxy-3-nitrobenzoic acid vas methylated essentially as the allylation step of Example 1, except that the allyl bromide vas replaced by methyl iodide, and purification by chromatography vas unnecessary, to give methyl 2-methoxy-3-nitrobenzoate. Nmr (DMSO-dg): δ 3.88 (s, 3H); 3.90 (s, 3H); 7.44 (t, IH); 8.04 (dd, IH); 8.12 (dd,
IH).
Ms (CI): 212 (HH)+; 229 (M + NH4) +
The above ester (3.45 g, 16 mM) vas hydrolysed by essentially the method of Example 22, except that the solvent vas DHSO in place of THF, to give 2-methoxy-3-nitrobenzoic acid. Nmr (DMSO-dg): δ 3.89 (s, 3H); 7.40 (t, IH); 8.01 (dd, IH); 8.06 (dd, IH).
BAD ORIGINAL $
AP Ο Ο Ο 3 9 8
- 77 Ms (CI): 215 (Μ + ΝΗ4) +
The above nitro acid vas allylated essentially as in Example 1, except that the product vas sufficiently pure for use vithout chromatography, to give allyl 2-methoxy-3-nitrobenzoate. Nmr (CDCIj): δ 4.00 (s, 3H); 4.86 (dt, 2H); 5.31-5.50 (m, 2H); 5.96-6.16 (m, IH);
7.27 (d, IH)ϊ 7.92 (dd, IH); 8.06 (dd, IH).
f Ms (CI): 238 (MH)+; 255 (M + NH4)+
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-2-methoxybenzoate sufficiently pure for use vithout chromatography. Nmr (CDCIj): δ 3.86 (s, 3H); 3.92 (br,
2H); 4.82 (dt, 2H); 5.26-5.49 (m, 2H); 5.96-6.16 (m, IH); 6.91 (dd,
IH); 7.00 (t, IH); 7.23 (dd, IH).
Ms (CI): 208 (HH)+; 225 (M + NH4)+
The above amine vas condensed vith proline acid as Example 4, f to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-2-methoxyphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDCIj): δ 2.30 (s, 3H); 2.53 (br, IH); 2.65 (br, IH); 3.41 (dd, IH); 3.86 (s, 3H); 4.04 (quintet, IH); 4.16 (dd, IH); 4.58 (t, IH); 4.66 (d, 2H); 4.83 (dt,
2H); 5.20-5.47 (ra, 4H); 5.83-6.13 (m overlapping br, 2H); 7.16 (t, IH); 7.60 (dd, IH); 8.57 (dd, IH); 9.15 (br, IH).
Ms (+ve FAB): 463 (MH)+; 485 (M + Na)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-2methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-lmethylcarbapenem-3-carboxylate. Nmr (CDCIj): δ 1.24 (d, 3H); 1.35 (d, 3H); 2.53 (br, IH); 2.68 (br, IH); 3.24 (dd, IH); 3.28 (quintet, IH);
BAD ORIGINAL
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- 78 3.43 (br, IH); 3.80 (quintet, IH); 3.83 (s, 3H); 4.12 (m, IH); 4.194.29 (overlapping a, 2H); 4.57 (t, IH); 4.64 (n, 4H); 4.83 (d, 2H); 5.18-5.48 (m, 6H); 5.81-6.14 (η, 3H); 7.17 (t, IH); 7.61 (dd, IH); 8.56 (dd, IH); 9.02 (br, IH).
Ms (+ve FAB): 670 (MH)+; 692 (M + Na)+
Example 29 (lR,5S,6S,8R,2'S,4'S)-2-(2-(5-Carboxy-2-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenera-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Nmr (DMSO-dg + acetic acid-d^): δ 1.19 (d, 6H); 1.88 (m, part obscured, IH); 2.31 (s, 3H); 2.77 (dt, IH); 2.93 (dd, IH); 3.22 (dd, IH); 3.42 (quintet, IH); 3.57 (dd, IH); 3.77 (quintet, IH); 4.01 (quintet, IH); 4.16 (t, IH); 4.19 (dd, IH); 7.35 (d, IH); 7.69 (dd, IH); 8.39 (d, IH).
Ms (+ve FAB): 512 (MH)+, (Na salt); 534 (MH)+, (Na2 salt); 556 (M + Na)+, (Na2 salt);
The starting materials vere prepared as follows:
4-Methyl-3-nitrobenzoic acid vas allylated as in Example 1, except that purification by chromatography vas unnecessary, to give allyl 4-methyl-3-nitrobenzoate. Nmr (DMSO-dg): δ 2.59 (s, 3H); 4.84 (dt, 2H); 5.27-5.47 (ra, 2H); 5.96-6.16 (m, IH); 7.67 (d, IH); 8.16 (dd, IH); 8.44 (d, IH).
Ms (El): 222 (MH)+
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, gave allyl 3-amino-4methylbenzoate sufficiently pure for use vithout chromatography. Nmr (DMSO-dg): δ 2.10 (s, 3H); 4.74 (dt, 2H); 5.15 (br, 2H); 5.22-5.43 (a, 2H); 5.93-6.12 (m, IH); 7.04 (d, IH); 7.11 (dd, IH); 7.28 (d, IH).
BAD ORIGINAL
AP Ο Ο Ο 3 9 8
- 79 Ms (CI): 192 (ΜΗ)+; 209 (Μ + ΝΗ4)*
The above amine vas condensed vith proline acid as Example 4, purifying by chromatography using a gradient from dichloroaethane to dichloromethane/diethyl ether (9:1), to give (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-methylphenylcarbamoyl)pyrrolidin-4ylthioacetate. Nmr (DMSO-dg, mix of rotamers): δ 1.97 (quintet, IH);
2.26 (s, 3H); 2.34 (s, 3H); 2.80 (br, IH); 3.30 (br, IH); 3.93-4.08 (br m, 2H); 4.53 (br, 3H); 4.80 (dt, 2H); 5.10-5.44 (m overlapping br, 4H); 5.78-6.13 (m overlapping br, 2H); 7.38 (d, IH); 7.72 (dd, IH); 7.94 (br, 0.5H); 8.01 (br, 0.5H); 9.61 (br, 0.5H); 9.67 (br, 0.5H).
Ms (CI): 447 (MH)+; 464 (M + NH4)*
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/ethyl acetate (1:1), to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (DMSO-dg + acetic acidd^, mix of rotamers): δ 1.16 (d, 3H); 1.18 (d, 3H); 1.98 (quintet, IH);
2.27 (s, 3H); 2.86 (br, IH); 3.27 (dd, IH); 3.33 (t, IH); 3.56 (quintet, IH); 3.95 (quintet, IH); 4.02 (dd, IH); 4.15 (quintet, IH); 4.27 (dd, IH); 4.48-4.70 (overlapping m, 5H); 4.80 (d, 2H); 5.10-5.45 (m overlapping br, 6H); 5.81-6.14 (m overlapping br, 3H); 7.38 (d, IH);
7.75 (dd, IH); 8.01 (br, 0.5H); 8.07 (br, 0.5H); 9.60 (br, IH).
Ms (+ve FAB): 654 (MH)+; 676 (M + Na)+
Example 30 (IR, 5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-4-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Nmr (DMSO-dg + |w»·BAD ORK5IHM, A
AP Ο Ο Ο 3 9 8
- 80 acetic acid-d^): δ 1.15 (d, 3H); 1.16 (d, 3H); 1.78 (dt, IH); 2.48 (s, 3H); 2.60 (dt, IH); 2.90 (dd, IH); 3.21 (dd, IH); 3.39 (quintet, IH);
3.49 (dd, IH); 3.73 (quintet, IH)j 3.99 (quintet, IH); 4.03 (t, IH);
4.17 (dd, IH); 7.23 (d, IH); 7.70 (dd, IH); 8.12 (d, IH).
Ms (+ve FAB): 512 (MH)+, (Na salt); 534 (HH)+, (Na2 salt); 556 (M + Na)+, (Na2 salt)
The starting materials vere prepared as follovs:
2-Methyl-5-nitrobenzoic acid vas allylated as in Example 1, except that purification by chromatography vas unnecessary, to give allyl 2-methyl-5-nitrobenzoate. Nmr (DMSO-dg): δ 2.65 (s, 3H); 4.84 (dt, 2H); 5.28-5.47 (m, 2H); 5.99-6.18 (m, IH); 7.65 (d, IH); 8.31 (dd, IH); 8.57 (d, IH).
Ms (CI): 222 (MH)+; 099 (M + NH4) +
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, gave allyl 5-amino-2methylbenzoate sufficiently pure for use vithout chromatography. Nmr (DMSO-dg): δ 2.33 (s, 3H); 4.73 (dt, 2H); 5.18 (br, 2H); 5.23-5.44 («, 2H); 5.93-6.12 (m, IH); 6.68 (dd, IH); 6.95 (d, IH); 7.12 (d, IH).
Ms (CI): 192 (MH)+; 209 (M + NH4) +
The above amine vas condensed vith proline acid as Example 4, purifying by chromatography using a gradient from dichloromethane to dichloromethane/diethyl ether (9:1), to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-methylphenylcarbamoyl)pyrrolidin-4ylthioacetate. Nmr (DMSO-dg, mix of rotamers): δ 1.91 (br m, IH); 2.33 (s, 3H); 2.76 (br ra, IH); 3.28 (s overlapping m, 4H); 4.00 (br m, 2H); 4.38 (t, IH); 4.51 (br, 2H); 4.78 (dt, 2H); 5.01-5.46 (m overlapping br, 4H); 5.68-6.16 (m overlapping br, 2H); 7.27 (d, IH); 7.72 (dd, IH); 8.11 (br, 0.5H); 8.05 (br, 0.5H); 10.17 (br, IH).
SAD ORIGINAL
AP Ο Ο Ο 3 9 8
Ms (+ FAB): 447 (ΜΗ)+; 469 (Μ + Na) +
The above thioacetate vas deacetylated and condensed vith carbapenea phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/ethyl acetate (1:1), to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-4-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl) -l-methylcarbapenem-3-carboxylate. Nmr (DMSO-dg + acetic acidd4): 6 1.19 (d, 6H); 1.92 (br, part obscured, IH) j 2.48 (s, 3H); 2.79 (br, IH); 3.25 (dd, IH); 3.32 (t, IH); 3.54 (quintet, IH); 3.91 (br m, IH); 4.01 (quintet, IH); 4.12 (dd, IH); 4.25 (dd, IH); 4.45 (m, IH); 4.50-4.68 (ra, 4H); 4.78 (dt, 2H); 5.18-5.45 (m, 6H); 5.70-6.13 (m overlapping br, 3H); 7.25 (d, IH); 7.76 (dd, IH); 8.12 (br m, IH).
Ms (+ve FAB): 654 (MH)*; 676 (M + Na)+
Example 31 (IR,5S,6S,8R,2'S,4z S)-2-(2-(3-Carboxy-5-methylphenylcarbamoyl)pyrrolidln-4-ylthlo)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, disodium salt
Allyl (1R,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenera-3-carboxylate (3 g, 4.59 mM) and 2,2dimethyl-l,3-dioxane-4,6-dione (3.97 g, 27.6 mM) vere dissolved in a mixture of DMSO (15 ml) and THF (5 ml), under an argon atmosphere, and tetrakis(triphenylphosphine)palladium (531 mg, 0.46 mM) vas added. The solution vas stirred, under argon vith protection from light, for 1 hour. A solution of sodium 2-ethylhexanoate (1.53 g, 9.22 uH) in THF (5 ml) vas added, folloved by THF (250 ml). The resultant precipitate vas filtered, under an argon blanket to exclude moisture, and vashed successively vith small portions of THF (tvice), and diethyl ether. Crude product and NaHCOj (1.5 g) vere dissolved in vater (100 ml), and the solution chromatographed on HF20SS resin using a gradient elution
BAP ORIGINAL
AP Ο Ο Ο 3 9 8
- 82 from vater to vater/acetonitrile (9:1). Appropriate fractions vere combined and freeze-dried to give (1R,5S,6S,8R,2'S,4'S)-2-(2-(3carboxy-5-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, disodium salt. Nmr (DMSOdg + acetic acid-d4): δ 1.13 (d, 3H); 1.15 (d, 3H); 1.76 (dt, IH); 2.32 (s, 3H); 2.68 (dt, IH); 2.87 (dd, IH); 3.18 (dd, IH); 3.36 (quintet, IH); 3.45 (dd, IH); 3.71 (quintet, IH); 3.95 (quintet, IH); 4.02 (t, IH); 4.14 (dd, IH); 7.49 (s, IH); 7.65 (s, IH); 8.05 (s, IH).
{ Ms (+ve FAB): 512 (MH)+, (Na salt); 534 (MH)+, (Na2 salt); 556 (M +
Na)+, (Na2 salt)
The starting materials vere prepared as follovs:
3-Methyl-5-nitrobenzoic acid
3,5-Dimethylnitrobenzene (30 g, 0.198 M) vas heated vith stirring to 80® in a mixture of pyridine (400 ml) and vater (250 ml). KMnO4 (62.7 g, 0.396 M) vas added in portions over 0.75 hours, and heating continued at 85-90® for 1.75 hours. The hot solution vas filtered through celite, vashing vith hot vater (150 ml). The pink filtrates vere decolourised vith a fev drops of sodium metabisulfite, and evaporated to dryness. The residue vas dissolved in vater (250 ml), and extracted vith diethyl ether (2 x 90 ml). The aqueous layer vas acidified (concentrated hydrochloric acid), and extracted vith ethyl acetate (3 x 120 ml). Combined organic extracts vere vashed vith NaH2F04 solution, brine, and dried over MgSO4. Crude product vas eluted through a pad of silica, using a mixture of ethyl acetate/dichloromethane/acetic acid (25:25:1), to give 3-methyl-5nitrobenzoic acid (14.5 g, 40X), mp 171-172*. Nmr (DMSO-dg): δ 2.51 (s, 3H); 8.17 (s, IH); 8.30 (t, IH); 8.42 (t, IH); 13.58 (br, IH).
Ms (CI): 181 (MH)+
3-Hethyl-5-nitrobenzoic acid vas allylated as in Example 1, except that purification by chromatography vas unnecessary, to give
BAD ORIGINAL
AP Ο Ο Ο 3 9 8
- 83 allyl 3-methyl-5-nitrobenzoate. Nmr (CDCl^): & 2.53 (s, 3M); 4.87 (dt, 2H); 5.31-5.48 (a, 2H); 5.99-6.13 (m, IH); 8.20 (s, IH); 8.23 (s, IH); 8.68 (s, IH).
Ms (CI): 222 (MH)+
Reduction of the above nitro compound by the method of Example 1, gave allyl 5-aaino-3-methylbenzoate sufficiently pure for use without chromatography. Nmr (CDCl-j): δ 2.30 (s, 3H); 3.46 (br,
2H)J 4.78 (dt, 2H); 5.23-5.45 (m, 2H); 5.93-6.12 (m, IH); 6.68 (t, IH);
7.17 (t, IH); 7.27 (t, IH).
Ms (CI): 192 (MH)+; 220 (M + C2H5)+
The above amine vas condensed vith proline acid as Example 4, purifying by chromatography using hexane/ethyl acetate (3:1) as eluant, to give (2S,4S)-1-allyloxycarbonyl-2-(3-allyloxycarbony1-5-methylphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nmr (CDCl^): δ 2.33 (s, 3H); 2.39 (s, 3H); 2.58 (br, 2H); 3.29 (dd, IH); 4.02 (quintet, IH); 4.13 (dd, IH); 4.56 (t, IH); 4.68 (dm, 2H); 4.82 (dt, 2H); 5.23-5.44 (ra, 4H); 5.86-6.12 (ra, 2H); 7.63 (s, IH); 7.85 (s, IH); 7.85 (s, IH); 9.09 (br, IH).
Ms (+ FAB): 447 (MH)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient of dichloromethane/ethyl acetate (3:2 to 2:3), to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5raethyIphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylate. Nmr (CDC13): δ 1.23 (d, 3H); 1.35 (d, 3H); 2.38 (s, 3H); 2.63 (br, 2H); 3.23 (dd, IH); 3.27 (quintet, IH); 3.46 (br, IH); 3.78 (quintet, IH); 4.00 (dd, IH); 4.24 (overlapping a, 2H); 4.51 (t, IH); 4.59-4.63 (a, 4H); 4.79 (d, 2H); 5.17-5.42 (a, 6H); 5.826.09 (a, 3H); 7.61 (s, IH); 7.73 (s, IH); 7.99 (s, IH); 8.87 (br, IH).
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AP Ο Ο Ο 3 9 8
- 84 Ms (+ve FAB): 654 (MH) +
Example 32 (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-Carboxy-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-1-aethylcarbapenem-3-carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Nmr (DMSO-dg + acetic acid-d^): & 1.18 (d, 6H); 1.92 (br, part obscured, IH); 2.81 (ra, IH); 3.03 (dd, IH); 3.23 (dd, IH); 3.41 (quintet, IH); 3.61 (m, IH); 3.90 (s overlapping ra, 4H); 4.00 (quintet, IH); 4.21 (overlapping m, 2H); 8.25 (t, IH); 8.50 (m, 2H).
Ms (+ve FAB): 556 (MH)+, (Na salt); 578 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
3-Methoxycarbonyl-5-nitrobenzoic acid vas allylated as in Example 1, except that purification by chromatography vas unnecessary, to give allyl 3-methoxycarbonyl-5-nitrobenzoate. Nmr (DMSO-dg): δ 3.97 (s, 3H); 4.91 (dt, 2H); 5.31-5.51 (m, 2H); 6.00-6.19 (m, IH); 8.75 (t, IH); 8.81 (d, 2H).
Ms (El): 265 M+
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, gave allyl 3-amino-5methoxycarbonylbenzoate sufficiently pure for use vithout chromatography. Nmr (DMSO-dg): δ 3.79 (br, 2H); 3.92 (s, 3H); 4.82 (dt, 2H); 5.26-5.46 (a, 2H); 5.94-6.14 (ra, IH); 7.53 (ra, 2H); 8.07 (t, 1H).
Ms (CI): 236 (MH)+; 253 (M + NH4) +
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient froa dichloromethane to
BAD ORIGINAL
AP Ο ο Ο 3 9 8
- 85 dichloronethane/diethyl ether (9:1), to give (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthioacetate. Nnr (CDClj): δ 2.33 (s, 3H); 2.60 (br,
2H); 3.40 (dd, IH); 3.94 (s, 3H); 4.04 (quintet, IH); 4.14 (dd, IH); 4.58 (t, IH); 4.68 (dm, 2H); 4.85 (dt, 2H); 5.25-5.47 (m, 4H); 5.856.16 (a, 2H); 8.36 (t, IH); 8.43 (m, 2H); 9.40 (br, IH).
Ms (+ FAB): 491 (MH)+; 513 (M + Na)+ (2S,4S)-1-Allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthioacetate (1.2 g, 2.4 mM) vas dissolved in THF (50 ml) under an argon atmosphere, and aqueous methylamine (33Z v/v, 0.51 g, 5.4 mH) vas added. Stirring vas continued for 3 hours, and solvent removed. The residue vas treated vith 211 hydrochloric acid and extracted vith ethyl acetate. The organic solution vas vashed vith vater, brine, aqueous NaHCOj and dried over MgSO^. Removal of solvents gave (2S,4S)-l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-ylthiol (1.02 g, 93Z). The thiol vas condensed vithout further purification vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichioromethane to dichloromethane/ethyl acetate (1:1), to give allyl (lR,5S,6S,8R,2/S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5-methoxycarbonylphenylcarbamoyl)pyrrolidin-4-yl thio)-6-(1hydroxyethyl)-l-methylcarbapenera-3-carboxylate. Nmr (CDClj): δ
1.24 (d, 3H); 1.37 (d, 3H); 2.64 (br, 2H); 3.26 (dd overlapping quintet, 2H); 3.48 (br, IH); 3.86 (quintet, IH); 3.94 (s overlapping m, 4H); 4.25 (quintet, IH); 4.29 (dd, IH); 4.56 (t, IH); 4.69 (m, 4H);
4.86 (dm, 2H); 5.19-5.46 (m, 6H); 5.85-6.13 (m, 3H); 8.46 (m, 3H); 9.18 (br, IH).
Ms (+ve FAB): 698 (MH)+; 720 (M + Na)+
Example 33 (lR,5S,6S,8R,2'S,4,S)-2-(2-(5-Carboxy-2,4-difluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3s-»’BAD ORIGINAL
AP Ο Ο Ο 3 9 8
- 86 carboxylic acid, disodium salt vas prepared using the technique of Example 2. Nmr (DMSO-dg + acetic acid-d^): 6 1.20 (d, 6H); 1.96 (a, part obscured, IH); 2.81 (a, IH); 3.14 (dd, IH); 3.27 (dd, IH); 3.43 (quintet, IH); 3.73 (m, IH); 3.91 (quintet, IH); 4.04 (quintet, IH);
4.23 (dd, IH); 4.43 (t, 2H); 7.29 (t, IH); 8.54 (t, IH).
Ms (+ve FAB): 534 (MH)+, (Na salt); 556 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
2,4-Difluoro-5-nitrobenzoic acid
2,4-Difluorobenzoic acid (5 g, 0.031 M) vas dissolved in concentrated sulfuric acid (30 ml), and cooled to 0°. The mixture vas stirred, and fuming nitric acid (d 1.567 g/ml, 1.91 ml, 0.047 M) added dropvise, keeping the temperature belov 5°. After stirring for 3 hours, the mix vas poured onto ice, and organics extracted into dichioromethane (2 x 75 ml). The combined organic layers vere vashed vith vater, dried (MgSO^), and evaporated to give 2,4-difluoro-5-nitrobenzoic acid (3.9 g, 61X). Nmr (DMSO-dg): & 7.18 (t, IH); 8.88 (t,
IH); 9.93 (br, IH).
Ms (-FAB): 202 (M - H)
2,4-Difluoro-5-nitrobenzoic acid vas allylated as in Example 1, except that the reaction time vas only 1.5 hours, the DMF vas stirred over IR-120-H ion exchange resin before use, and purification by chromatography vas unnecessary, to give allyl 2,4-difluoro-5-nitrobenzoate. Nmr (CDClj): δ 4.88 (dt, 2H); 5.31-5.50 (m, 2H); 5.93-6.13 (m, IH); 7.13 (t, IH); 8.80 (dd, IH).
Ms (El): 265 M+
Reduction of the above nitro compound by the method of Example 2, except that the solvent vas methanol, gave allyl 5-amino2,4-difluorobenzoate, sufficiently pure for use vithout chromatography.
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AP Ο Ο Ο 3 9 8
- 87 Nmr (CDC13): 6 3.61 (br, 2H); 4.81 (dt, 2H); 5.26-5.48 (a, 2H); 5.926.12 (a, 1H); 6.83 (t, 1H); 7.38 (dd, 1H).
Ms (CI): 214 (MH)*; 231 (M + NH4)*
The above aalne vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/diethyl ether (9:1), to give (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2,4-difluorophenylcarbamoyl)pyrrolidin4-ylthioacetate. Nmr (CDClj): δ 2.33 (s, 3H); 2.63 (br, 2H); 3.39 (dd, 1H); 4.04 (quintet, 1H); 4.14 (dd, 1H); 4.59 (t, 1H); 4.66 (dt, 2H); 4.83 (dt, 2H); 5.22-5.49 (m, 4H); 5.84-6.13 (a, 2H); 6.94 (t, 1H); 8.82 (t, 1H); 9.22 (br, 1H).
Ms (+ FAB): 469 (MH)*; 491 (M + Na)*
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/ethyl acetate (1:1), to give allyl (lR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2,4-difluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1hydroxyethyl)-l-methylcarbapenem-3-carboxylate. Nmr (CDClj): δ
1.25 (d, 3H); 1.38 (d, 3H); 2.62 (br, 2H); 3.24 (dd overlapping quintet, 2H); 3.45 (dd, 1H); 3.88 (quintet, 1H); 4.03 (dd, 1H); 4.25 (quintet, 1H); 4.29 (dd, 1H); 4.57 (t, 1H); 4.68 (a, 4H); 4.82 (dm,
2H); 5.21-5.48 (a, 6H); 5.85-6.10 (m, 3H)j 6.94 (t, 1H); 8.85 (t, 1H);
9.12 (br, 1H).
Ms (+ve FAB): 676 (MH)*; 698 (M + Na)*
Example 34 (IR,5S,6S,8R,2'S,4'S)-2-(2-(5-Carboxy-2,4-dimethoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3carboxylic acid, disodium salt vas prepared using the technique of Example 2. Nmr (DMSO-dg + acetic acid-d*): δ 1.20 (d, 6H); 1.95 (a,
BAD QRJQWL
AP Ο Ο Ο 3 9 8
- 88 part obscured, IH); 2.87 (dt, IH); 3.08 (dd, IH); 3.26 (dd, IH); 3.41 (quintet, IH); 3.71 (dd, IH); 3.87 (quintet, part obscured, IH); 3.91 (s, 3H); 3.96 (s, 3H); 4.03 (quintet, IH); 4.21 (dd, IH); 4.39 (t, 2H);
6.76 (s, IH); 8.44 (s, IH).
Ms (+ve FAB): 558 (MH)+, (Na salt); 580 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
2.4- Dimethoxy-5-nitrobenzoic acid
A solution of sodiua methoxide vas prepared by dissolving sodiua metal (1.42 g, 0.062 M) in methanol (40 ml) vith cooling. Allyl
2.4- difluoro-5-nitrobenzoate (5 g, 0.021 M) vas added and the mixture vas stirred for 2 hours. A solution of NaOH (2 g, 0.05 H) in vater (10 ml) vas added, and the mixture stirred at ambient temperature foT 16 hours. Solvent vas evaporated, the residue dissolved in vater (50 ml), and extracted vith diethyl ether (40 ml). The aqueous layer vas acidified vith sulfuric acid, and the precipitate filtered and dried to give 2,4-dimethoxy-5-nitrobenzoic acid (4.23 g, 91Z). Nmr (CDClj): δ 4.07 (s, 3H); 4.16 (s, 3H); 6.62 (s, IH); 8.81 (s, IH).
Ms (CI): 228 (MH)+; 245 (M + NH4)+
2,4-Dimethoxy-5-nitrobenzoic acid vas allylated as in Example 1, except that purification by chromatography vas unnecessary, to give allyl 2,4-dimethoxy-5-nitrobenzoate. Nmr (CDClj): δ 4.02 (s, 3H); 4.04 (s, 3H); 4.79 (dt, 2H); 5.26-5.46 (m, 2H); 5.93-6.13 (m, IH); 6.54 (s, IH); 8.63 (s, IH).
Ms (+ FAB): 268 (MH)+; 290 (H + Na)+
Reduction of the above nitro compound by the method of Example 1, gave allyl 5-amino-2,4-dimethoxybenzoate. Nmr (CDClj): δ
3.25 (br, 2H); 3.87 (s, 3H); 3.90 (s, 3H); 4.76 (dt, 2H); 5.22-5.46 (m, 2H); 5.93-6.12 (m, IH); 6.47 (s, IH); 7.29 (s, IH).
BAD ORIGINAL ft
AP Ο Ο Ο 3 9 β
- 89 Ms (CI): 238 (ΜΗ)*
The above amine vas condensed vith proline acid as Example 4, purifying by chromatography using a gradient from dichloromethane to dichloromethane/diethyl ether (4:1), to give (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2,4-dimethoxyphenylcarbamoyl)pyrrolidin4-ylthioacetate. Nmr (CDCip: & 2.32 (s, 3H); 2.49 (br, IH); 2.64 (br, IH); 3.40 (dd, IH); 3.91 (s, 3H); 3.93 (s, 3H); 4.00 (quintet, IH);
4.17 (dd, IH); 4.53 (t, IH); 4.64 (d, 2H); 4.77 (dt, 2H); 5.19-5.46 (m,
4H); 5.80-6.14 (m overlapping br, 2H); 6.49 (s, IH); 8.69 (br, IH);
8.81 (s, IH).
Ms (+ FAB): 493 (MH)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate, to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2,4dimethoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1methylcarbapenem-3-carboxylate. Nmr (CDCl^): δ 1.22 (d, 3H); 1.36 (d, 3H); 2.48 (br, IH); 2.65 (br, IH); 3.23 (dd, IH); 3.28 (quintet, IH);
3.43 (dd, IH); 3.80 (quintet, IH); 3.91 (s, 3H); 3.92 (s, 3H); 4.09 (dd, IH); 4.24 (quintet, IH); 4.27 (dd, IH); 4.51 (t, IH); 4.66 (m,
4H); 4.77 (dt, 2H); 5.20-5.45 (m, 6H); 5.83-6.11 (m overlapping br,
3H); 6.49 (s, IH); 8.45 (br, IH); 8.82 (s, IH).
Ms (+ve FAB): 700 (MH)+
Example 35 (lR,5S,6S,8R,2'S,4'S)-2-(2-(5-carboxy-2-cyanophenylcarbamoyl) pyrrolidin-4-yl thio)-6-(1-hydroxyethyl)-1-me thy lcarbapenem-3carboxylic acid, disodlum salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO. Nmr (DMSO-dg + acetic acid-d^): δ 1.17 (d, 6H); 1.83 (m, part obscured, IH); 2.62-2.79
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- 90 (overlapping η, 2Η); 3.18 (dd, IH); 3.41 (quintet, IH); 3.66 (quintet, IH); 3.98 (quintet, IH); 4.07 (dd, IH); 4.17 (dd, IH); 7.79 (·, 2H); 8.67 (s, IH).
Ms (+ve FAB): 523 (MH)*, (Na salt); 545 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
4-Cyano-3-nitrobenzolc acid
4-Chloro-3-nitrobenzoic acid (5.84 g, 29 mM), cuprous cyanide (5.2 g, 58 mM), cuprous chloride (0.96 g, 9.7 mM), and quinoline (6.9 ml, 58 mM) vere heated under an argon atmosphere at 180’ for 3.5 hours. After cooling, the mixture vas dissolved in concentrated hydrochloric acid (60 ml), diluted vith water (80 ml), and extracted vith ethyl acetate (3 x 100 ml). The combined organic layers vere vashed vith aqueous NaHjPO^, brine, and dried over MgSO^. Crude product vas purified by chromatography on silica, eluting vith a mixture of dichloromethane/acetic acid (98:2), to give 4-cyano-3-nitrobenzoic acid (2.65 g, 48%). Nmr (DMSO-dg): 6 8.31 (d, IH); 8.41 (dd, IH); 8.68 (d, IH).
Ms (El): 192 M+
The above nitro acid vas allylated essentially as in Example 1, purifying the crude product by chromatography on silica, using an eluant of hexane:ethyl acetate (6:1), to give allyl 4-cyano-3-nitrobenzoate. Nmr (CDC13): 6 4.93 (dt, 2H); 5.37-5.50 (m, 2H); 5.97-6.13 (m, IH); 8.03 (d, IH); 8.46 (dd, IH); 8.94 (d, IH).
Ms (CI): 221 (MH)*; 250 (M + NH4)*
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-4-carbamoylbenzoate, recrystallised from ethyl acetate/petrol, mp 149-150°. Nmr (DMSO-dg): δ 4.77 (dt, 2H); 5.25-5.43 (rn, 2H); 5.96-6.11 (m, IH); 6.72 (br, 2H); 7.04 (dd, IH);
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- 91 7.25 (br, IH); 7.35 (d, IH); 7.63 (d, IH); 7.87 (br, IH).
Ms (El): 220 M+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using hexane/ethyl acetate (1:1) to give (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-carbamoylphenylcarbaaoyl)pyrrolldin-4-ylthioacetate. Nmr (CDC1^, mix of rotamers): 6
2.25 (quintet, IH); 2.28 (s, 3H); 2.82 (br, IR); 3.52 (dd, IH); 4.13 (t, IH); 4.20 (br m, IH); 4.52 (dd, IH); 4.61 (br, 2H); 4.85 (d, 2H); 5.01-5.48 (m overlapping br, 4H); 5.66-6.12 (m overlapping br, 2H);
6.55 (br, IH); 6.89 (br, IH); 7.64 (br m, IH); 7.79 (br m, IH); 9.30 (br m, IH); 11.68 (br, 0.5H); 12.06 (br, 0.5H).
Ms (+ve FAB): 476 (MH)+ (2S, 4S)-1-Allyloxycarbonyl-2-(5-allyloxycarbonyl-2-cyanophenylcarbamoyl)pyrrolidin-4-ylthioacetate
DMF (0.2 ml, 2.5 mM) vas dissolved in acetonitrile (10 ml), cooled to -5®, and treated vith oxalyl chloride (0.2 ml, 2.3 mM).
After stirring for 30 minutes, a solution of (2S,4S)-l-allyloxycarbonyl-2-(5-allyloxycarbonyl-2-carbamoylphenylcarbamoyl)pyrrolidin-4ylthioacetate (1 g, 2.1 mM) in acetonitrile (15 ml) vas added, folloved hy pyridine (0.38 ml, 4.6 mM). After 15 minutes, the mixture vas diluted vith ethyl acetate (200 ml), vashed vith hydrochloric acid (2M, 20 ml), vater, aqueous NaHCOj, and brine, and dried over Na2S04. Crude product vas purified by chromatography using a gradient from dichloromethane to ethyl acetate to give (2S,4S)-l-allyloxycarbonyl-2-(5allyloxycarbonyl-2-cyanophenylcarbamoyl)pyrrolidin-4-ylthioacetate (0.9 g, 93X). Nmr (CDCLj): 6 2.32 (s, 3H); 2.63 (br, 2H); 3.46 (dd, IH); 4.06 (quintet, IH); 4.16 (dd, IH); 4.64 (t, IH); 4.71 (dt, 2H); 4.85 (dt, 2H); 5.22-5.47 (m, 4H); 5.87-6.14 (m, 2H); 7.67 (d, IH); 7.87 (dd, IH); 8.96 (d, IH); 9.42 (br, IH).
Ms (4-ve FAB): 458 (MH) + ; 480 (M + Na) + bad original
AP Ο Ο Ο 3 9 8
- 92 The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-2methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1methylcarbapenem-3-carboxylate. Nmr (CDCl^): 6 1.24 (d, 3H); 1.35 (d, 3H); 2.60 (br, 2H); 3.25 (dd overlapping quintet, 2H); 3.52 (br, IH); 3.88 (quintet, IH); 4.02 (dd, IH); 4.25 (quintet, IH); 4.28 (dd, IH); 4.55-4.74 (m, 5H); 4.85 (dt, 2H); 5.18-5.468 (m, 6H); 5.83-6.11 (m, 3H); 7.65 (dt, IH); 7.87 (dd, IH); 9.00 (br s, IH); 9.25 (br, IH).
Ms (+ve FAB): 665 (MH)+; 687 (M + Na)+
Example 36 (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-fluorophenylcarbamoyl)pyrrolldin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DHSO. Nmr (DMSO-dg + acetic acid-d4): 6 1.20 (d, 6H); 1.99 (dt, IH); 2.91 (dt, IH); 3.26 (dd overlapping m, 3H); 3.42 (quintet, IH); 3.74 (dd, IH); 3.96 (quintet, IH); 4.04 (quintet, IH); 4.22 (dd, IH); 4.41 (t, IH); 7.43 (do, IH);
7.81 (dd, IH); 8.00 (t, IH).
Ms (+ve FAB): 516 (MH)+, (Na salt); 538 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
3-Fluoro-5-nitrobenzoic acid
A vigorously stirred slurry of nitrosonium tetrafluoroborate (3.53 g, 30.2 mM) in acetonitrile (50 ml) under an atmosphere of argon vas cooled in an ice bath, and 3-amino-5-nitrobenzoic acid (5.0 g, 27.5 mN) vas added in three portions. The temperature vas then alloved to rise to ambient, and the mixture vas stirred for 48 hours. 1,2-DiBAD ORIGINAL &
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- 93 chlorobenzene (50 ml) vas added, and acetonitrile distilled from the mixture at reduced pressure. The mixture vas then heated to 170° for 30 minutes, vhen gas evolution had ended. After cooling, the mix vas poured into dichloromethane (200 ml), and extracted vith NaHCOj solution. After back vasbing the aqueous phase vith dichloromethane, it vas acidified (2M hydrochloric acid), and organics extracted vith ethyl acetate (2 x 100 ml). The combined organic layers vere vashed vith brine, and dried over MgSO^. Crude product vas purified by chromatography on silica, eluting vith a gradient from dichloromethane/acetic acid (99:1) to dichloromethane/isopropanol/acetlc acid (80:20:1), to give 3-fluoro-5-nitrobenzoic acid (3.26 g, 64X). Nmr (DMSO-dg): δ 8.14 (dm, IH); 8.37 (dt, IH); 8.46 (m, IH).
Ms (El): 185 M+
Allyl 3-fluoro-5-nitrobenzoate
3-Fluoro-5-nitrobenzoic acid (3 g, 16.2 mM), £-toluenesulfonic acid (1.54 g, 8.1 mM), and allyl alcohol (50 ml) vere heated to reflux, passing the distillate through 3A molecular sieves, for 16 hours. After cooling, the mixture vas neutralised vith triethylamine, and solvent removed. The residue vas dissolved in ethyl acetate, vashed vith 2M hydrochloric acid, aqueous NaHCOj, and brine, and dried over MgSO^. Crude product vas purified by chromatography on silica, using a gradient elution from dichloromethane to ethyl acetate/dichloromethane (3:1), to give allyl 3-fluoro-5-nitrobenzoate. Nmr (CDC13): δ 4.89 (dt, 2H); 5.33-5.49 (m, 2H); 5.95-6.15 (m, IH); 8.11 (ra, 2H); 8.70 (t, IH).
Ms (CI): 226 (MH)+; 253 (M + C2H5)+
Reduction of the above nitro compound by the method of Example 1 gave allyl 3-amino-5-fluorobenzoate. Nmr (CDCl^): δ 3.89 (br, 2H); 4.79 (dt, 2H); 5.25-5.45 (m, 2H); 5.92-6.12 (m, IH); 6.54 (dt, IH); 7.07-7.15 (m, 2H).
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- 94 Ms (CI): 196 (ΜΗ)+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient from dichioromethane to dichloromethane/diethyl ether (85:13) to give (2S,4S)-l-allyloxycarbonyl-2- (3-allyloxycarbonyl-5-fluorophenylcarbamoyl)pyrrolidin-4ylthioacetate. Nmr (CDClj): 6 2.33 (s, 3H); 2.59 (br, 2H); 3.48 (dd, IH); 4.03 (quintet, IH); 4.13 (dd, IH); 4.56 (t, IH); 4.68 (dt, 2H);
4.82 (dt, 2H); 5.25-5.46 (a, 4H); 5.86-6.11 (a, 2H); 6.47 (da, IH);
7.72 (t, IH); 7.87 (dt m, IH); 9.38 (br, IH).
Ms (+ve FAB): 451 (MH)+; 473 (M + Na)+
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichioromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-5fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenera-3-carboxylate. Nmr (CDClj): 6 1.24 (d, 3H); 1.36 (d, 3H); 2.63 (br, 2H); 3.26 (dd, IH); 3.29 (quintet, IH); 3.48 (br, IH); 3.81 (quintet, IH); 3.97 (dd, IH); 4.27 (dd overlapping m, 2H); 4.54 (t,
IH); 4.62-4.76 (m, 4H); 4.81 (dt, 2H); 5.20-5.46 (m, 6H); 5.85-6.10 (m overlapping br, 3H); 7.48 (dt, IH); 7.83 (br s, IH); 7.88 (dt, IH);
9.18 (br, IH).
Ms (+ve FAB): 658 (MH)+; 680 (M + Na)+
Example 37 (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-N'-methylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, disodium salt vas prepared using the technique of Example 2, except that the DMF vas replaced by DMSO, and product vas purified by chromatography on a CHP20P column, eluting vith vater. Nrar (DMSO-dg + acetic acid-d^, run at 50°): & 1.12 (d, 3H); 1.18 (d, 3H);
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AP000398
- 95 1.67 (br, IH); 2.13 (br, IH); 3.02 (dd, IH); 3.17 (dd, IH); 3.28 (s overlapping a, 5H); 3.65 (br, 1H); 3.98 (quintet overlapping a, 2H); 4.12 (dd, IH); 7.58 (d, IH); 7.91 (d, IH); 7.98 (a, IH).
Ms (+ve FAB): 512 (MH)+, (Na salt); 534 (MH)+, (Na2 salt)
The starting materials vere prepared as follovs:
Allyl 3-aethylaminobenzoate
Allyl 3-aminobenzoate (5 g, 28.2 mN) vas dissolved in triethyl orthoformate (50 ml) and trifluoroacetic acid (5 drops) vas added. The soluiton vas stirred and refluxed up through 3A molecular sieves for 5 hours. Solvent vas removed, and the residue dissolved in ethanol (50 ml), folloved by the addition of acetic acid (8.08 ml) and sodium cyanoborohydride (6.85 g, 0.108 M) in several portions. The mixture vas stirred at ambient temperature for 16 hours, and solvent removed. The residue vas dissolved in diethyl ether, vashed vith vater, brine, and dried over MgSO^. Crude product vas purified by chromatography on silica, eluting vith a gradient from dichloromethane to dichloromethane/ethyl acetate (95:5), to give allyl 3-methylaminobenzoate (0.93 g, 17X). Nmr (CDCIj): 6 2.88 (s, 3H); 4.81 (dt, 2H); 5.23-5.45 (ra, 2H); 5.94-6.13 (m, IH); 6.83 (dd, IH); 7.25 (dd, IH); 7.33 (t, IH); 7.43 (dm, IH).
Ms (CI): 192 (MH)+
The above amine vas condensed vith proline acid as Example 1, purifying by chromatography using a gradient from dichloromethane to dichloromethane/diethyl ether (4:1) to give (2S,4S)-1-allyloxycarbonyl2-(3-allyloxycarbonyl-N' -me thylphenylcarbaaoyl)pyrrolidin-4-yl thioacetate. Nmr (CDCIj, mixture of rotamers): & 1.93 (m, IH); 2.32 (s, 3H); 2.48 (m, part obscured, IH); 3.28, 3.31 (2 x s, 3H); 3.40 (quintet, IH); 3.76 (m, IH); 4.01 (m, IH); 4.24 (m, IH); 4.50-4.74 (m, 2H); 4.86 (d, 2H); 5.18-5.48 (m, 4H); 5.84-6.13 (ra, 2H); 7.38-7.68 (m, 2H); 7.90-8.11 (m, 2H).
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- 96 Ms (+ve FAB): 447 (MH)+; 469 (M + Na) +
The above thioacetate vas deacetylated and condensed vith carbapenem phosphate as Example 1, purifying by chromatography using a gradient from dichloromethane to ethyl acetate to give allyl (IR,5S,6S,8R,2'S,4'S)-2-(l-allyloxycarbonyl-2-(3-allyloxycarbonyl-N'methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3 -carboxylate. Nmr (CDClg, mixture of rotamers): 6 1.20 (2 x d, 3H); 1.34 (2 x d, 3H); 1.87 (br, IH); 2.30 (br, IH); 3.29, 3.31 (2 x s, overlapping m, 6H); 4.05-4.30 (m, 4H); 4.50-4.81 (m, 5H); 4.96 (d, 2H); 5.20-5.48 (ra, 6H); 5.85-6.13 (m, 3H); 7.39-7.68 (m, 2H); 7.91-8.11 (m, 2H).
Ms (+ve FAB): 654 (MH)+; 676 (M + Na)+
RP36750
18DEC92
RML/MB
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R«*jng now par rj·:::: r.1rxrnl<<J *ix) •vcrtaincd my/our s··.J .··-'aiton and in *’hat manner the sjr;: is C’ be periormei1 Qjte declare that whir 5/we claim ii · —

Claims (2)

1. A compound of the formula (I):
or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof wherein:
rI is 1-hydroxyethyl, 1-fluoroethyl or hydroxymethyl;
R is hydrogen or C. .alkyl;
R is hydrogen or C. ,alkyl;
4 5
R and R are the same or different and are selected from hydrogen, halo, cyano, CMalkyl, nitro, hydroxy, carboxy, Cj ^alkoxy, C^_4alkoxycarbonyl, aminosulphonyl, Cj_4alkylaminosulphonyl, di-C^ ^alkylaminosulphonyl, carbamoyl, Cj_4alkylcarbamoyl, di-C^_4 alkylcarbamoyl, trifluoromethyl, sulphonic acid, amino, Cj ^alkylamino, di-C^_4alkylaraino, C14alkanoylaraino, C^_4alkanoyl(N-Cj_4alkyl)amino,
C^_4alkanesulphonamido and -S(O)n'
two: vith the proviso that there is no position ortho to the link to -NR 2. A compound according to 3. A compound according to is hydrogen or methyl. 4. A compound according to is methyl. 5. A compound according to is hydrogen.
)j_4alkyl wherein n is zero, one or hydroxy or carboxy substituent in a claim 1 wherein R^ is 1-hydroxyethyl.
either claim 1 or claim 2 wherein R either claim 1 or claim 2 wherein R any one of claims 1 to 4 wherein R
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- 2 6. A compound according to any one of claims 1 to 5, of the formula (IV):
4 5
7. A compound according to claim 6 wherein R and R are the same or different and selected from hydrogen, fluoro, chloro, hydroxy, carboxy, cyano, nitro, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, trifluoromethyl, sulphonic acid, methylsulphinyl, methylsulphonyl, methanesulphonamido or acetamido.
8. A compound according to either claim 6 or claim 7 wherein at
4 5 least one of R and R is hydrogen.
9. A compound according to claim 6 wherein R is hydrogen, carboxy, fluoro, chloro, methyl, methoxy, cyano, sulphonic acid or methoxycarbonyl and R^ is hydrogen.
10. A compound according to claim 1 vhich is (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-hydroxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-chlorophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid,
BAD ORIGINAL S
AP Ο Ο Ο 3 9 8
- 3 (lR,5S,6S,8R,2'S,4'S)-2-(2-( 3 -c arboxypheny lcar bamoy 1) pyrrolidin- 4 ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-( 3 -carboxy-6-methanesulphonylphenylcarbamoyl)pyrrolidin-4-ylthio) -6- (1-hydroxyethyl)-l-methylcarbapenem-3carboxylie acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl )-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-fluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl )-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2,4-difluorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR, 5S, 6S, 8R, 2 'S, 4 'S) -2- (2- (3,4-dicarboxyphenylcarbamoyl) pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-hydroxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-nethylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxyphenylcarbamoyl)pyrrolidin4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (1R,5S,6S,8R,2'S,4'S)-2-(2-(2-carbamoyl-3-carboxyphenylcarbamoyl) pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenera-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2- (3-carboxy-5~acetamidophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-acetaaidophenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1 -hydroxyethyl) -l-methylcarbapenem-3-carboxylic acid,
BAD original
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-4(IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-n»ethylsulphonaraidophenylcarbamoyl) pyrrolidin-4-ylthio) - 6- (1-hydroxyethyl) - l-methylcarbapenem-3carboxyllc acid, (IR,5S,6S,8R,2' S, 4' S) -2-(2-(3-carboxy-5-sulphophenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-me thylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-carbamoylphenylcarbamoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4' S) -2-(2-(3-carboxy-2-dimethylarainocarbonylphenylcarbamoyl) pyrrolidin- 4-ylthio )-6-(1 -hydroxyethyl) -1 -methylcarbapenem-3carboxylic acid, (5R, 6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)carbapenem-3-carboxylic ac id, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-methyIphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-raethylphenylcarbamoyl)pyrrolidin-4-ylthio )-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-2-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4 ' S) -2-(2-(3-carboxy-4-methoxyphenylcarbaraoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenera-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-me thoxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-me thylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-methoxyphenylcarbamoyl)pyrrolidin-4-ylthio) -6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4,6-dimethoxyphenylcarbamoyl)BAD ORIGINAL
AP Ο Ο Ο 3 9 8
-5pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethoxycarbonylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-cyanophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenea-3-carboxylic acid, (IR, 5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-trifluoromethylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4,6-difluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(l-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-methylsulphinylphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-aethylcarbapenem-3carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methylsulphonylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-fluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-cyanophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy Ν'-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1 vhich is (lR,5S,6S,8R,2/S,4/S)-2-(2-(3-carboxy-5-methylphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid,
BAD ORIGINAL
AP Ο Ο Ο 3 9 8
- 6 (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-aethoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-methoxyphenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-aethylcarbapenem-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-methoxycarbonylphenylcarbanoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-aethylcarbapenem-3carboxylic acid, (IR,5S,6S,8R,2' S,4'S)-2-(2-(3-carboxy-5-cyanophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-aethylcarbapenem-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-chlorophenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-aethylcarbapenea-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenem-3-carboxylic acid.
(IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-4-fluorophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl )-l-aethylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-6-fluorophenylcarbaaoyl) pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-l-nethylcarbapenen-3-carboxylic acid, (lR,5S,6S,8R,2'S,4'S)-2-(2-(3,4-dicarboxyphenylcarbamoyl)pyrrolidin-4ylthio)-6-(1-hydroxyethyl)-l-methylcarbapenem-3-carboxylic acid. (lR,5S,6S,8R,2'S,4'S)-2-(2-(3,5-dicarboxyphenylcarbamoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, (IR,5S,6S,8R,2'S,4'S)-2-(2-(3-carboxy-5-sulphophenylcarbaaoyl)pyrrolidin-4-ylthio)-6-(1-hydroxyethyl)-1-methylcarbapenea-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition vhich comprises a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier.
BAD ORIGINAL ft
AP Ο Ο Ο 3 9 β
13. A process for preparing a compound according to claim 1 vhich comprises deprotecting a compound of the formula (V):
2 4 5 4 5 vherein R , R and R are as defined in claim 1 (R and R being optionally protected if appropriate); -COOR^ and -COOR? are carboxy or 8 3 protected carboxy; R is a group R (as defined in claim 1) or an amino
9 10 protecting group; R is hydrogen or an amino protecting group; and R is a group R1 (as defined in claim 1), protected 1-hydroxyethyl or protected hydroxymethyl; and vherein at least one protecting group is present;
and thereinafter if necessary;
(1) forming a pharmaceutically acceptable salt, (ii) esterifying to form an in vivo hydrolysable ester.
14. A compound of the formula (V) as defined in claim 13.
15. A process for preparing a compound according to claim 1 or a compound of the formula (V) as defined in claim 13 vhich comprises:
a) reacting compounds of the formulae (VI) and (VII):
vherein R^, R^-R^ are as defined in claim 13 and L is a leaving group,
BAD ORIGINAL
AP Ο Ο Ο 3 9 8 or
b) cyclising a conpound of the formula (VIII):
(DoonJ’ (VIII) wherein R^, R4-R^® are as hereinbefore defined and R^-R^ are independently selected from C. ,alkoxy, aryloxy, di-C. ^-alkylamino and 11/13 1-0 diarylamino or any two of R -R represent o-phenylenedioxy;
11 13 or one of R -R is C^alkyl, allyl, benzyl or phenyl and the other two values are independently selected from Cj_4alkyl, trifluoromethyl or phenyl, wherein any phenyl group is optionally substituted vith Cj ^alkyl or C^alkoxy;
and wherein any functional group is optionally protected and thereinafter if necessary:
(i) removing any protecting groups;
(ii) forming a pharmaceutically acceptable salt;
(iii) esterifying to form an in vivo hydrolysable ester.
16. A compound of the formula (I), as defined in claim 1, in the form of a non-pharmaceutically acceptable salt.
17. A compound of the formula (VII) or (VIII) as defined in claim 15.
18. A compound of the formula (IX), (XII) or (XIV):
(IX)
BAD ORIGINAL ft (in)
AP Ο Ο Ο 3 9 8
Coot1 wherein R2 and R^-R1® are as protecting group.
defined in claim 13 and R*4 is a
APAP/P/1993/000480A 1992-02-04 1993-01-21 Carbapenems derivatives, their preparation and their use in pharmaceutical compositions. AP398A (en)

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US20020042408A1 (en) 2002-04-11
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US5478820A (en) 1995-12-26
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