NZ196055A - 2beta-chloromethyl-2alpha-methylpenam-3alpha-carboxylic acid sulphone,esters thereof,pharmaceutical compositions,and intermediates - Google Patents

2beta-chloromethyl-2alpha-methylpenam-3alpha-carboxylic acid sulphone,esters thereof,pharmaceutical compositions,and intermediates

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Publication number
NZ196055A
NZ196055A NZ196055A NZ19605581A NZ196055A NZ 196055 A NZ196055 A NZ 196055A NZ 196055 A NZ196055 A NZ 196055A NZ 19605581 A NZ19605581 A NZ 19605581A NZ 196055 A NZ196055 A NZ 196055A
Authority
NZ
New Zealand
Prior art keywords
acid
ester
compound
formula
solution
Prior art date
Application number
NZ196055A
Inventor
W J Gottstein
Original Assignee
Bristol Myers Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bristol Myers Co filed Critical Bristol Myers Co
Publication of NZ196055A publication Critical patent/NZ196055A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/28—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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 modified 2-carboxyl group
    • C07D499/32—Esters
    • 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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
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    • C07—ORGANIC CHEMISTRY
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    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/28—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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 modified 2-carboxyl group
    • C07D499/34—Thio-acid; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/28—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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 modified 2-carboxyl group
    • C07D499/34—Thio-acid; Esters thereof
    • C07D499/36—O-esters
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/66—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with alicyclic rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
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    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/70—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with hetero rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
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    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/86—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with only atoms other than nitrogen atoms directly attached in position 6 and 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
    • C—CHEMISTRY; METALLURGY
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    • C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, 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
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    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/897—Compounds with substituents other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, directly attached in position 2
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    • C07D519/06—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 containing at least one condensed beta-lactam ring system, provided for by groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00, e.g. a penem or a cepham system
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Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">New Zealand Paient Spedficaiion for Paient Number 1 96055 <br><br> AMENDED under Section Patents Act l&gt;53 v <br><br> 'Hip/sit. <br><br> of tie <br><br> ASSISTANT CO MM IS*vlP tiF.R OF PA-rp^ <br><br> 196 0 5 5 <br><br> Priority Date{s}: . s^.'. \; .^P. <br><br> Complete Specification Filed: $-9." Class: , hM*bA $&gt;. <br><br> Publication Date: ... i jQ.V. MQV. 198S <br><br> P.O. J quits H. Mo: ... .'AW • • <br><br> OS <br><br> Patents Form No. 5 <br><br> NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION <br><br> Chgi~uc_al_ conPoua) dS <br><br> ¥/WE BRISTOL-MYERS COMPANY, 345 Park Avenue, New York, New York, U.S.A. a Delaware Corporation, <br><br> hereby declare the invention, for which I/we pray that a patent may be granted to me/us, and the method by which it is to be performed, to be particularly described in and by the following statement <br><br> " 1 ~ (_ j/6 l( Ov-cd ^ ^ | &amp;) <br><br> 1A <br><br> 196055 <br><br> I. • Description: <br><br> The present invention relates to 2$-chloromethyl-2a-methylpenara-3a-carboxylic acid sulfone, a pharmaceutically acceptable salt or an easily hydrolyzed ester thereof which is useful as an inhibitor of 3-lactamases. <br><br> The presumed association between the resistance shown by f3-lactam antibiotics to certain bacteria and the ability of those bacteria to produce 8-lactamases has led to an intensive search for B-lactamase inhibitors. Clavulanic acid is an example of such a compound presently under intensive study. Another B-lactamase inhibitor has in its acid form the structure and is disclosed in U.S. Patent 4260598. <br><br> The compound having the structure <br><br> H H <br><br> O <br><br> COOH <br><br> is disclosed in U.S. Patents 4,036,847, 4,009,159, 3,993,646, 3,989,685 and 3,954,732. <br><br> -2- <br><br> 1960 5 5 <br><br> U.S. Patent 4,155,912 describes 2-penem-3-carboxylic acid compounds having the formula and esters and salts, and see also Farmdoc Abstracts 82090A, 10336B and 44337B. <br><br> The compound (under the number CP-45899) having the structure is an irreversibly acting S-lactamase inhibitor with excellent solution stability. It has weak antibacterial activity and potentiates the in vitro and in vivo activities of ampicillin versus g-lactamase-producing strains [A. R. English et al., Antimicrobial Agents and Chemotherapy, 14, 414-419 (1978) , Aswapokee et al., J. Antibiotics 31(12), 1238-1244 (Dec. 1978) and Derwent's Farmdoc Abstracts 89627A and 73866B] . <br><br> O <br><br> O <br><br> COOH <br><br> 1960 5 5 <br><br> -3- <br><br> It is disclosed by B. Baltzer et al., Mutual Pro- <br><br> f <br><br> Drugs of B-Lactam*Antibiotics and ^-Lactamase Inhibitors, J. Antibiotics, 33(10), 1183-1192 (1980) that the principle of combining 3-lactam antibiotic with a 3-lactamase inhibitor in a single molecule functioning as pro-drug for the two active components is illustrated by the linked esters 3 and 4 in which ampicillin and mecillinam, respectively, are combined with the 8-lactamase inhibitor penicillanic acid sulfone. It is shown that in man these esters are excellently absorbed from the gastro-intestinal tract and after absorption hydrolyzed with simultaneous liberation of the active components. As a result high blood and tissue levels of antibiotic and 6-lactamase inhibitor in a balanced ratio are attained. The advantages of "mutual pro-drugs" over simple combinations are discussed. <br><br> Esters 3 and 4 referred to therein have the structures <br><br> CH-C0-NH\ NH„ <br><br> HVy8 <br><br> J—N~ <br><br> 0/ <br><br> 0 0 t T <br><br> rfY <br><br> //■"—~C <br><br> CO <br><br> 0 <br><br> 1 <br><br> CHQ I 2 -co -0 <br><br> N-CH=N&lt; <br><br> &lt;7 <br><br> r <br><br> -N. <br><br> r <br><br> -N- <br><br> C0 <br><br> i <br><br> 0 0 <br><br> V P <br><br> CH <br><br> I 2 <br><br> -co-o <br><br> -4- <br><br> 1960 5 5 <br><br> It is stated in GB 2044255 published October 15, 1980 that the invention therein relates to hitherto unknown compounds of the general formula 1: <br><br> R-.—CH—CO—NH, 1 I « <br><br> H H <br><br> ?— <br><br> H <br><br> C—0—CH—A II I 0 R^ <br><br> in which stands for a phenyl, 4-hydroxyphenyl, 1,4-cyclohexadienyl or a 3-thienyl group; R2 represents a primary amino or a carboxy group; R^ is a hydrogen atom, or a lower alkyl, aryl or aralkyl radical, and A stands for a radical of a B-lactamase inhibitor containing a g-lactam ring as well as a carboxy group, A being connected via the carboxy group. <br><br> The new compounds are useful in the treatment of bacterial infections and are in particular strongly active against $-lactamase producing bacteria. See also Farmdoc Abstracts 60773C and 60776C. <br><br> Accordingly, the present invention provides the acid having the formula <br><br> 1 96 0 5 5 <br><br> 0 o <br><br> CHy <br><br> 1 3 tciOH <br><br> or a pharmaceutically acceptable salt of said acid or an easily hydrolyzed ester of said acid. <br><br> The pharmaceutically acceptable salts referred to above include nontoxic metallic salts such as sodium, potassium, calcium and magnesium, the ammonium salt and substituted ammonium salts, e.g. salts of such nontoxic amines as trialkylamines (e.g. triethylamine), procaine, dibenzylamine, N-benzyl-3-phenethylamine, 1-ephenamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N,N'-bis(dehydroabietyl)ethylenediamine, N-(lower)alky1-piperidine (e.g. N-ethylpiperidine) and other amines which have been used to form pharmaceutically acceptable salts of penicillins and cephalosporins. The most preferred salts are the alkali metal salts, i.e. the sodium and potassium salts, and the ammonium salt. <br><br> As used herein the term "physiologically hydrolyzed . esters" refers to those pharmaceutically acceptable esters known in the art to hydrolyze to the free acid form in vivo. Examples of suitable physiologically hydrolyzed esters include phenacyl, acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, <br><br> 1960 5 5 <br><br> -6- <br><br> phthalidyl(3-phthalidyl)3 indanyl(5-indanyl), methoxymethyl, benzoyloxymethyl, a-ethylbutyryloxymethyl, propionyloxy-methyl, valeryloxymethyl, isobutyryloxymethyl, 6-[(R)-2-amino-2-phenylacetamido] -333-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbonyloxymethyl and 6-[ (R)-2-amino-2-p-hydroxyphenylacetamido] -3 aj5-dime thy 1-7-oxo-4-thia-l-azabicyclo[3.2.0] heptane-2-carbonyloxymethyl. The preferred esters are the acetoxymethyl, pivaloyloxy-methyl, methoxymethyl, phthalidyl, 5-i*idanyl, 6-[(R)-2-amino-2-phenylacetamido]-3 ^-^-raethyl-^-oxo-^-thia-l-azabicyclof^. 2.0]heptane-2-carbonyloxymethyl and 6-[ (R)-2-amino-2-p-hydroxyphenylacetamido] -3,3-dimethyl-7-oxo -4 - thia-1 - az ab ic yc lo [ 3 • 2.0 ] hep t ane -2 -c arbony loxyme thy 1. <br><br> There is further provided by the present invention the process for the production as the desired product of the acid having the formula <br><br> o o <br><br> CH2C1 <br><br> "CH3 ^OOH <br><br> or a pharmaceutically acceptable salt of said acid which comprises the consecutive steps of a) catalytically hydrogenating9 as with a precious metal catalyst such as palladium, an ester having the formula <br><br> 190055 <br><br> Br, <br><br> CH2C1 <br><br> N- <br><br> CH. <br><br> QC C02R <br><br> wherein R"^ is benzyl or substituted benzyl and then b) subjecting the hydrogenated product to oxidation to produce said desired acid sulfone or salt thereof and then, if desired, <br><br> c) esterifying said acid or salt thereof to produce an easily hydrolyzed ester of said acid. <br><br> There is further provided by the present invention the process for the production as the desired product of the acid having the formula <br><br> O o <br><br> CH2C1 <br><br> 'CH. <br><br> -N <br><br> 3 <br><br> tOQH <br><br> or a pharmaceutically acceptable salt of said acid which comprises the consecutive steps of a) oxidizing, as with KMnO^, H2°2 or peroxide or peracid, an ester having the formula <br><br> Br. <br><br> 0 t <br><br> CHgCl <br><br> J " CH^ <br><br> N- <br><br> 'c-OCHgCCl^ 0 <br><br> -8- <br><br> 19G055 <br><br> to produce an ester sulfone having the formula <br><br> Br <br><br> ''/a <br><br> J <br><br> 0 0 <br><br> Z/ <br><br> \\ // ^CH2C1 <br><br> -N- <br><br> ;H3 <br><br> % <br><br> C-0CH«CC1_ n ^ 3 0 <br><br> and then b) reacting said ester sulfoxide with a metal in acid, as with zinc in glacial acetic acid, to produce said desired acid or salt and then, if desired, <br><br> c) esterifying said acid or salt thereof to produce an easily hydrolyzed ester of said acid. <br><br> ;,;"2 3bEC)982 ! <br><br> -9- <br><br> 196 0 5 5 <br><br> A wide variety of oxidants known in the art for the oxidation of sulfides to sulfones can be used. However, particularly convenient reagents for alkali metal permanganates, e.g. potassium permanganate, <br><br> and organic peracids, e.g. 3-chl°roPert&gt;en20ic acid. <br><br> Particularly useful protecting groups for are the benzyl group and substituted benzyl groups, especially <br><br> 4-nitrobenzyl. Benzyl and substituted benzyl groups can be removed conveniently by catalytic hydrogenation. In this case, a solution in an inert solvent of the compound of the formula A, wherein R"'" is benzyl or substituted benzyl, is stirred or shaken under an atmosphere of hydrogen, or hydrogen mixed with an inert diluent such as nitrogen or argon, in the presence of a catalytic amount of a hydrogenation catalyst. Convenient solvents for this hydrogenation are lower-alkanols, such as methanol; ethers, <br><br> such as tetrahydrofuran and dioxan; low molecular weight esters, such as ethyl acetate and butyl acetate; water; <br><br> and mixtures of these solvents. However, it is usual to choose conditions under which the starting material is soluble. The hydrogenation is usually carried out at a temperature in the range from about 0 to about 60°C. and at <br><br> 2 <br><br> a pressure in the range from about 1 to about 100 kg./cm. . The catalysts used in this hydrogenation reaction are the type of agents known in the art for this kind of transformation, and typical examples are the noble metals, such as nickel, palladium, platinum and rhodium. The catalyst is usually present in an amount from about 0.01 to about 2.5 weight-percent, and preferably from about 0.1 to about 1.0 weight-percent, based on the compound of formula A. It is often convenient to suspend the catalyst on an inert support; a particularly convenient catalyst is palladium suspended on an inert support such as carbon. Addition <br><br> -10- <br><br> 1960 5 5 <br><br> ally it is usual to buffer the reaction mixture in order to operate at a pH in the range from about k to 9* a-nd preferably from 6 to 8. Borate and phosphate buffers are commonly used. The reaction typically takes about one hour. <br><br> There is further provided by the present invention the esters having the formula <br><br> R—CH—CO -NH <br><br> NHg o-. <br><br> or R <br><br> \ / <br><br> wherein R1 is hydrogen or hydroxy and <br><br> R2 is hydrogen, hydroxy, methyl, methoxy or chloro and <br><br> -11- <br><br> 1 960 5 $ <br><br> preferably the ester having the formula <br><br> \ t <br><br> CH-CO-NH. <br><br> NH, <br><br> A <br><br> CH3 <br><br> CH^ <br><br> C=0 <br><br> 0 <br><br> r <br><br> CHgCl <br><br> -N <br><br> CH, <br><br> €- <br><br> II <br><br> 0 <br><br> CH, <br><br> -0 <br><br> the ester having the formula <br><br> \ / <br><br> CH-CO-NH. <br><br> NH, <br><br> ;H5 <br><br> CHj <br><br> C=0 <br><br> 0 <br><br> r <br><br> -N <br><br> CHgCl <br><br> ''' CH, <br><br> 0 <br><br> 1 <br><br> CH, <br><br> €- <br><br> II <br><br> 0 <br><br> and and the process for producing such an ester which comprises the treatment with acid of a solution of a compound having the formula <br><br> -12- <br><br> L46c&gt;S$ <br><br> R—CH I <br><br> R6-C <br><br> 7 "I R'-C <br><br> H <br><br> t? <br><br> CO-NH <br><br> /? N <br><br> JS' CH2C1 -TCH3 <br><br> C-II <br><br> 0 <br><br> c=o <br><br> CH, <br><br> -0 <br><br> wherein R is <br><br> O, O. O. o <br><br> R is hydrogen, hydroxy, methyl, methoxy or chloro and R6 is alkyl, aralkyl or aryl, R7 is hydrogen, alkyl, aralkyl or aryl and R^ is alkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy or <br><br> R* <br><br> -N^ «-^R5 <br><br> wherein R and Rv are each hydrogen, alkyl, aralkyl or aryl or, when taken together with the nitrogen atom, are piperidino or morpholino with said treatment with acid preferably being carried out in an organic solvent such as acetone or chloroform or in aqueous or partly aqueous solution and preferably between pH 1 and pH 5 at room temperature. <br><br> -13- <br><br> 1960 5 5 <br><br> It is further preferred that, in the amino- <br><br> 12 "5 <br><br> protecting group, R is methyl, R is hydrogen and Jr is methoxy, ethoxy or methyl; this requires the use of methyl acetoacetate, ethyl acetoacetate or acetylacetone. <br><br> In the removal of the a-amino-protecting group it is preferred that use be made of a strong mineral acid such as hydrochloric acid or of formic acid. <br><br> There is further provided by the present invention as a novel intermediate an ester having the formula <br><br> Br s 2C1 <br><br> J <br><br> I <br><br> '*'ch3 <br><br> -or wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, and the process for its production which comprises heating, preferably at reflux, a compound having the formula <br><br> 0 <br><br> wherein R is benzyl or substituted benzyl and preferably p-nitrobenzyl, in an inert, anhydrous organic solvent, preferably dioxane, in the presence of large, and preferably <br><br> -14- <br><br> i960 <br><br> equimolar, amounts of a weak tertiary amine, preferably quinoline, and an acid chloride, preferably benzoyl chloride, until the reaction is substantially complete. <br><br> There is provided by the present invention in addition as a novel intermediate an ester having the formula <br><br> Br <br><br> O <br><br> I <br><br> &amp; #CH2C1 <br><br> nCf- <br><br> r wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, and the process for its production which comprises oxidizing a solution in an inert solvent, preferably methylene chloride, of a compound having the formula <br><br> Br <br><br> * <br><br> r <br><br> A-n- <br><br> CH C1 s s/ 2 <br><br> '// <br><br> :H3 <br><br> C-OR II 0 <br><br> wherein R is benzyl or substituted benzyl, and preferably p-nitrobenzyl, at about room temperature by the use of a peracid, preferably m-chloroperoxybenzoic acid. <br><br> -15- <br><br> 196 0 5 5 <br><br> There is further provided by the present invention as a novel intermediate the ester having the formula <br><br> Br <br><br> Y"*t ch2ci <br><br> *5 <br><br> C-OCHpCC H ^ <br><br> o <br><br> the process for its production which comprises oxidizing a solution in an inert solvent, preferably methylene chloride, of a compound having the formula <br><br> Br. <br><br> 0 <br><br> CHgCl <br><br> 'O- <br><br> CH^ <br><br> N- <br><br> C-OCHgCCl^ <br><br> 0 <br><br> at about room temperature by the use of an oxidizing agent such as KMnO^, HgOg or like peroxide or, preferably a peracid, preferably m-chloroperoxybenzoic acid. <br><br> "Skellysolve B" is a petroleum ether fraction of b.p. 6o°-68°C. consisting essentially of n-hexane ("Skellysolve" is a trade name of the Skelly Oil Co.). <br><br> The following examples are provided solely for the purpose of illustrating the preparation of representative compounds of the present invention and are not to be construed as limiting the invention. <br><br> 196055 <br><br> Example 1 <br><br> Preparation of Potassium 2S-Chloromethyl-2g-methylpenam-3a-carboxylate Sulfone (BL-P2013) <br><br> Br j <br><br> "r~f^ <br><br> t <br><br> Br, <br><br> ^ N <br><br> c02h a <br><br> rr <br><br> -n co2-ch2 <br><br> no. <br><br> Br co2-ch2 <br><br> a.ch-c1 TECHNO- O <br><br> -n- <br><br> '^02-CH2-^^-N0, <br><br> h, <br><br> V <br><br> ^o^&gt;CH2Cl <br><br> | CH: <br><br> Co2H <br><br> KMnO. <br><br> // <br><br> O. JO <br><br> .ch-cl <br><br> -f ^.CH2 <br><br> n- <br><br> co2K <br><br> _5 <br><br> (BL-P2013) <br><br> -17- <br><br> 196055 <br><br> 6a-Bromopenicillanic Acid S-Sulfoxide (_1) <br><br> 1. Dissolve 30 g (37.5 mmole) 6cr-bromopenicillanic acid N,N'-dibenzylethylenediamine salt [G. Cignarella et al., J. Org. Chem. 27, 2668 (1962) and E. Evrard, Nature 201, <br><br> 1124 (1964)] in 330 ml of methylene chloride. Agitate and cool to 0°C. <br><br> 2. Slowly add 13 ml (156 mmole) concentrated hydrochloric acid into the methylene chloride solution. The precipitation of dibenzylethylenediamine HC1 salt <br><br> (DBED'HCl) takes place within a minute. Stir the slurry at 0-5°C for 10 minutes. <br><br> 3. Filter to remove the DBED'HCl precipitate through a precoated diatomaceous earth ("Dicalite") filter. Wash the cake with 150 ml of methylene chloride. The filtration should be completed as quickly as possible. <br><br> Avoid holding the acidic methylene chloride solution for a prolonged period. There may be some filtration problems because of the fine nature of the precipitate. Addition of filter aid to the slurry may be helpful. <br><br> 4. Wash the combined methylene chloride filtrate and wash with 60 ml of cold water. Agitate 5 minutes and discard the aqueous phase. The pH of the wash is 2.0-2.3• <br><br> 5. The methylene chloride solution containing 6a-bromopenicillanic acid is concentrated under reduced pressure to a volume of 65-80 ml. Cool and stir the solution to 5°C. <br><br> -18- <br><br> 1960 5 5 <br><br> 6. With vigorous agitation cautiously add 13 ml (86.9 mmoles) of 40$ peracetic acid over a period of 30 minutes.- The reaction is exothermic. Maintain temperature between 15-l8°C with ice bath cooling. The sulfoxide begins to crystallize after 10 ml peracetic acid is added. Cool and stir the slurry at 0-5°C for two hours. <br><br> 7. Filter and wash the snow white cake with the following sequence: 10 ml 5°C water, then 10 ml 0-5°C methylene chloride, and finally wash with 15 ml of heptane. <br><br> 8. Dry the cake in 45°C air oven to constant weight, about 6-10 hours should be sufficient. Extended heating may generate a trace of pinkish color. The weight of 1^ is about 16.26 gm, 73-24$ yield. <br><br> 9. The reaction mix and final product may be monitored by TLC using 15 toluene/4 acetone/1 acetic acid (HAC) or 8 acetone/8 methanol/3 toluene/1 HAC solvent systems. The final product should be analyzed by KMR and IR. <br><br> p-Nitrobenzyl 6a-bromopenicillanate S-Sulfoxide (2) <br><br> To a solution of 12 g (0.04 mole) of 6a-bromopenicillanic acid s-sulfoxide in 100 ml of acetone was added 7.5 g (0.041 mole) of potassium 2-ethylhexanoate. The salt was collected by filtration, washed with cold acetone and air dried to yield a total of 10 grams. The crystalline potassium salt was dissolved in 75 ml of dimethylacetamide and 7.8 g (0.04 mole) of p-nitrobenzyl bromide was added. The solution was stirred at 23°C for 24 hours. The mixture was diluted with 500 ml of water and extracted with ethyl acetate. The ethyl acetate layer <br><br> -19- <br><br> 196 0 <br><br> was washed four times with water and dried over anhydrous magnesium sulfate. The solvent was evaporated at 35°C (15 mm) to an oil which crystallized. The light tan crystals of 2_ were slurried with ether and collected by filtration to yield 9 g (70$) mp 124-125°C dec. <br><br> Anal, calc'd for C^H^BrNgOgS: C, 41.98; H, 3-05; N, 6.52 <br><br> Pound: C, 42.00; H, 3-48; N, 6,98 <br><br> IR(KBr): l800(s), 1740(a), l6l0(w), 1520(s), 1450(m), 1350(s), 1060(m), 740(m) cm*1. H-NMR (60 mHz, DMS0): 51.22 (s,3H), 1.6 (s,3H), 4.67 (s,lH), 5.2 (d,Jvi-5 Hz,1H), 5.45 (s,2H), 5-68 (d,Jvl-5 Hz,lH), 7.5-8.5 (m,4H). <br><br> p-Nitrobenzyl 2P-chloromethyl-2a-methyl-6-bromopenam-3a-carboxylate (3_) <br><br> A solution of 5 g (0.012 mole) of p-nitrobenzyl 6a-bromopenicillanate S-sulfoxide (2) in 120 ml anhydrous dioxane was heated at reflux under nitrogen for 4 hours with 1.5 g (0.012 mole) of quinoline and 1.6 g (0.012 mole) of benzoyl chloride. The solution was diluted with 600 ml of water and extracted with ethyl acetate. The ethyl acetate extract was washed with 5$ sodium bicarbonate solution, 5$ phosphoric acid solution and finally with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to an oil at 35°C (15 mm). The oil crystallized and was collected, washed with ether, and finally with cold toluene to yield 2., 3.5 g (65$) mp 130-135°C dec. <br><br> Anal, calc'd for C-^H-^ClBrN^S: C, 40.06; H, 3-14; N, 6.23 <br><br> Found: C, 40.19; H, 3.12; N, 6.75 <br><br> IR(KBr): 1792(s), 1740(s), l6l0(w), 1520(s), 1353(s), 1280(m), 1025(w), 990(w), 750(w) cm"1. <br><br> NMR (60 mHz, BMSO): 5 1.45 (s,3H), 3-5-4.3 (m,2H),. 5.05 (s,lH), 5-42 (s,2H), 5.5(d,Jvl.5 Hz,lH), 5-62 (d,Jvl.5 Hz,1H), 7.5-8.5 (m,4H). <br><br> -20- <br><br> 1 96 0 <br><br> p-Nitrobenzyl 2P-Chloromethyl-2a-methylpenaiii-6a-carboxylate Sulfoxide (4_) <br><br> A solution of 1 g (0.0022 mole) of p-nitrobenzyl 33-chloromethyl-2a-methyl-6a-bromopenam-3a-carboxylate (2.) dissolved in 50 ml of methylene chloride was stirred with K73 mg of (0.0022 mole) of m-chloroperoxybenzoic acid. The solution was stirred at 23 °C for 3 hours. The methylene chloride was evaporated to 20 ml at 15 mm and 33 °C and the concentrated solution was diluted with 50 ml of heptane ("Skellysolve B"). The solvent was decanted and the residue was slurried with ether and QJ soon crystallized yield 250 mg, mp 136-137°C dec. <br><br> Anal. Calc'd for C^H^BrClNgOgS: C, 38.68; H, 3-02; N, 6.02 <br><br> Found: C, 39.14; H, 3-13; N, 5.96 <br><br> IR(KBr): l800(s), 1760(s), 1520(s), 1350(s), 1200(b), 1050(m), 830(w), 7^0(w) cm"*1. H-NMR (60 mHz, DMSO): 5 1.32 (s,3H), 3-8-4.5 (m,2H), 4.97 (s,1H), 5-25 (d,Jvl.5 Hz,iff),- 5.^5 (s,2H), 5.6 (d,J^1.5 Hz, 1H), 7.8-8.5 (m,4H). <br><br> Potassium 2ft-Chloromethyl-2a-methylpenam-3oc-carboxylate Sulfone (5) (BL-P2013) <br><br> To a solution of 7 g (0.015 mole) of p-nitrobenzyl 2P-chloromethyl-2a-methyl-6a-bromopenam-3ct-carboxylate sulfoxide (4J in 150 ml of ethyl acetate was added a suspension of 4 g of 30$ palladium on diatomaceous earth ("Celite") and 2.8 g of sodium bicarbonate in 150 ml of water. The mixture was hydrogenated for 3 hours at 50 psi. <br><br> -21- <br><br> 1960 5 5 <br><br> The catalyst was separated by filtration and the aqueous layer was separated and treated with 1.5 g of potassium permanganate in 50 ml of water. The mixture was stirred for 1 hour and 250 mg of sodium bisulfite was added. The mixture was filtered and the filtrate was adjusted to pH 2 with concentrated hydrochloric acid. The solution was lyophilized to give a white amorphous powder. The solid was extracted with ethyl acetate, evaporated to a volume of 20 ml and diluted with 100 ml of heptanes ("Skellysolve B"). White, hygroscopic, solid 2f3-chloromethyl-2a-methylpenam-3a-carboxylic acid sulfone was collected. The acid was dissolved in acetone and treated with solid potassium 2-ethylhexanoate. A crystalline white salt precipitated to give, after filtration, 170 mg of ^ mp &gt;140°C dec. <br><br> Anal, calc'd for CqE^CIKNO^^I^O: C, 28.27; H, 3-24; N, 4.12 <br><br> Found: C, 28.27; H, 3-69; N, 3-84 <br><br> IR(KBr): 1790(s), 1770(m), l620(s), l46o(m), 1370(s), 1310(s), 1200(s), 1140(s), 955(m), 740(m) cm"1. H-NMR (100 mHz, DgO): 81.68(s,3H), 3-2-3-9 (m,J*2 Hz, J~4 Hz, j*6.Ez,2H), 4.0-4.4 (m,2H), 4.3 (s,lH), 5-02 (d d, M Hz), J*2 Hz,lH). <br><br> Example 2 <br><br> Pivaloyloxymethyl 2B-Chloromethyl-2a-methylpenara-3a-carboxylate Sulfone <br><br> 28-Chloromethyl-2a-methylpenam-3a-carboxylic acid sulfone in dimethylformamide is treated with one equivalent of triethylamine and stirred to effect solution. Bromomethyl pivalate (1 equivalent) in dimethylformamide <br><br> -22- <br><br> i96 0 <br><br> is then added. The resulting mixture is stirred at room temperature. The mixture is then clarified by filtration and the filtrate poured into ice water. The separated solid is collected by filtration, washed with water and dried to give the title ester. <br><br> acetonyl and phenacyl esters of the same acid are prepared by substituting in the method above for the bromomethyl pivalate used therein an equimolar weight of chloromethyl acetate, chloromethyl methyl ether, Chloroacetone and phenacyl bromide, respectively. <br><br> Pivaloyloxymethyl 2B-Chloromethyl-2a-methylpenam-3g-carboxylate Sulfone BL-P2024 <br><br> The respective acetoxymethyl, methoxymethyl, <br><br> Example 3 <br><br> 0 P <br><br> o <br><br> II <br><br> + Nal + H20 + ClCH2-0-C-C(CH3)3 <br><br> acetone <br><br> (BL-P2013) <br><br> -23- <br><br> 1 96 0 <br><br> o o nV/ .vCH3 <br><br> /} N ^ <br><br> CH2C1 <br><br> o o <br><br> tt c02ch2-0-c-c(ch3)3 <br><br> (BL-P2024) <br><br> To a stirred suspension of 14.6g (0.0487 mol) <br><br> of BL-P2013 (5) in 200 ml of acetone was added 4 ml of a 10% aqueous solution of sodium iodide and the mixture was brought to reflux on the steam bath. To this refluxing suspension was added 14.8 ml (0.1 mol) of redistilled chloromethyl pivalate (B.P. 34°C at 7 mm Hg) all at once. The mixture was stirred at reflux for three hours and then cooled to room temperature (22°C). The crystalline solids were collected by filtration, washed with 3 x 30 ml of acetone and the combined filtrates were evaporated in an oil in vacuo at &lt;22°C. The oil was then taken up in 500 ml of ethyl acetate and washed once with water (200 ml) and once with saturated Na2SO^ while being stirred with 2 g. of decolorizing carbon with cooling (ice bath). After 20 minutes the mixture was filtered through a diatomaceous (Dicalite) pad with suction and the pad was washed with 4 x 100 ml of ethyl acetate. The combined filtrates were concentrated in vacuo at 22°C to an oil. The oil was then <br><br> -24- <br><br> 1960s concentrated further at about 22°C and &lt;1 mm Hg to remove most of the residual chloromethyl pivalate. The remaining oil was then triturated twice with 50 ml portions of n-pentane and then left over the weekend in the cold room (about 10°C) under n-pentane. The solid crystalline mass was then broken up to a solid powder under 40 ml of 4:1 mixture of ether-n-pentane. The product was then collected by filtration, washed with ether-pentane (1:1) <br><br> then pentane and air dried. After drying ija vacuo for four hours over P2°5 th®16 was obtained 13.37g. of pivaloyloxymethyl 26-chloromethyl-2a-methylpenam-3ct-carboxylate sulfone (about 75% yld) M.P. 93°-95°C. <br><br> Anal. Calcd. for C14H2QC1N07S: C, 44.03; H, 5.27; N, 3.67. <br><br> Found: C, 44.11; H, 5.08; N, 3.85. <br><br> Example 4 <br><br> Recrystallization of Potassium 2B-Chloromethyl-2a-methylpenam-3a-carboxylate Sulfone (BL-P2013) <br><br> To a mixture of 20 ml of n-butanol and one gram of BL-P2013 (5) was added water, one ml at a time, with shaking in a separatory funnel until a pale yellow solution was obtained. The clear solution was filtered through a fluted filter paper and the flask and filter paper washed with about 10 ml of 9:1 n-butanol-I^O and the combined filtrates were diluted with a further 20 ml of n-butanol. The resulting solution was placed in a round-buttomed flask on the roto-vap and evaporated under reduced pressure to approximately one half the original volume. The snow white crystalline product was collected by filtration, washed <br><br> i96 0 5 <br><br> with 6 x 10 ml of acetone and air dried. Yield 810 mg. <br><br> After vacuum drying 6 hours over P2°5 &lt;1 mm Hg. <br><br> there was obtained 800 mg M.P. 215°C (dec.) (80% yld). <br><br> Anal. Calcd. for CgHgClNC^SK'lI^O: C, 29.67; H, 3.39; N, 4.63 <br><br> Clf 10.94; K.F.H20, 5.56. Found: C, 29.23; H, 3.38; N, 4.49 CI, 10.74; K.F.HjO, 5.74. This recrystallization procedure produces a crystalline monohydrate differing from the starting material which is essentially anhydrous. <br><br> Example 5 <br><br> 0 0 <br><br> CH-0-C-C1 C12 v CICHg-O-C-Cl <br><br> 3 light =* . <br><br> +C1S05H <br><br> X 0 <br><br> T <br><br> CICHg-O-S-Cl <br><br> £ S <br><br> l 8 <br><br> See Chemical Abstracts 27* 2427 and 22, 382 ; and <br><br> GB 299064. <br><br> -26- <br><br> 19605 <br><br> o o ch.c1 <br><br> ' V/ 2 <br><br> CH. <br><br> "booK <br><br> ClS0,CHoCl 3 2 <br><br> o o <br><br> \ # <br><br> ^S^ch2CI <br><br> ''CH- <br><br> Nal acetone' <br><br> c-och2ci b 7 <br><br> 0 \U0 <br><br> -N <br><br> CHgCl <br><br> 'CH, <br><br> t-OCHgl 0 <br><br> 8 <br><br> 8 + <br><br> CH-CO-NH] <br><br> II <br><br> H <br><br> i <br><br> OCH^ <br><br> j pCHj <br><br> N- <br><br> COOK <br><br> 9 (U.S. Patent 3,316,247) <br><br> -M <br><br> 1960 5 5 <br><br> CH CO NH <br><br> r s^/ <br><br> .N. <br><br> CH^ CH^ <br><br> 0 <br><br> C=0 <br><br> 0 0 <br><br> CHgCl <br><br> _N- <br><br> S^/ <br><br> V/CH, <br><br> CH, <br><br> \ <br><br> ii <br><br> 0 <br><br> H* <br><br> CH CO NH <br><br> r <br><br> /&gt; o <br><br> .N. <br><br> CH5 <br><br> CHj <br><br> C=0 <br><br> 11 <br><br> J <br><br> o o <br><br> * * CHp01 <br><br> -N— <br><br> '^CH- <br><br> CH, <br><br> V ii <br><br> -28- <br><br> 196 0 <br><br> a) A solution of chloromethyl chlorosulfate (0.115 mol) in 40 ml. dichloromethane is added dropwise, keeping the reaction temperature "below 30°C., to a solution of compound 5. (0.1 mol) and potassium bicarbonate (0.3 mol) and tetrabutylammonium hydrogen sulfate (0.01 mol) in 200 ml. dichloromethane-rwater (1:1). At the end of the addition the mixture is stirred at room temperature for 30 minutes, the organic phase is separated and the aqueous phase is extracted with dichloromethane (50 ml.). The combined organic phases are dried (NagSO^) and evaporated in vacuo to give a residue which is dissolved in ether (150 ml.). Insoluble material is filtered off after adding diatomaceous earth and the filtrate is evaporated in vacuo to provide compound 7. <br><br> b) To a suspension of compound 5. (1-5 g.) in dimethylformamide (12 ml.) there is added 1.6 g. bis-chloromethyl sulfate and the mixture is stirred at room temperature for 45 minutes. After dilution with ethyl acetate (50 ml.) the mixture is washed with water and then aqueous sodium bicarbonate, dried and evaporated in vacuo to leave compound 7 as an oil. <br><br> c) To a solution of compound 5 (0.005 mol) in dimethylformamide (7-5 ml.) there is added triethylamine (0.007 mol) and chloroiodomethane (O.O^O mol) and the mixture is stirred at room temperature for four hours. <br><br> After dilution with ethyl acetate (30 ml.) the mixture is washed with water (3 x 10 ml.) followed by saturated aqueous sodium chloride (5 ml.), dried and evaporated in vacuo to leave compound 7 as an oil. <br><br> -29- <br><br> i96 0 <br><br> d) To a mixture of compound (0.15 mol) silver nitrate (0.15 mol) and silver oxide (7-5 g.) in acetonitrate (750 ml.) there is added chloroiodomethane (1.5 mol). <br><br> After stirring for 48 hours at room temperature, the silver salts are filtered off and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate (200 ml.) and the solution is washed with saturated aqueous sodium chloride, filtered, dried and evaporated in vacuo to give compound 7- <br><br> Compound 7 and other intermediates and final products of the present invention are purified, if desired, by column chromatography, as on "Sephadex" LH20 using chloroform-hexane, 65:35 as the eluent for example or by silica gel chromatography, e.g. using Mallinckrodt CC-7 and hexane-ethyl acetate, 3:2 or ethyl acetate-petroleum ether, 8:2 or 7:3 or 1:9 or 15:85 or ethyl acetate-n-hexane, 4:6 or 3:1 hexane-ethyl acetate, 3:1 or 1:1 or 1:4 or eyelohexane-ethyl acetate, 1:1. <br><br> Thin layer chromatography is also useful. <br><br> "Sephadex" is cross-linked dextran 2-(diethylamino) ethyl 2-[[2-(diethylamino)ethyl]diethylammonio]ethyl ether chloride hydrochloride epichlorhydrin (See Merck Index, Ninth Edition, item number 7337). <br><br> A solution of compound 7 (0.2 mol) and sodium iodide (0.3 mol) in acetone (150 ml.) is stirred at room temperature for 18 hours. The resulting suspension is cooled to about 0°C. and adjusted to about pH 7.2 by the addition of saturated aqueous sodium bicarbonate with stirring. After decolorizing by titration with 0.5 M aqueous sodium thiosulfate, water (150 ml.) is added dropwise to the stirred mixture to precipitate solid compound 8 which is collected by filtration, washed with acetone-water 1:1 (2 x 20 ml.), isopropanol (2 x 20 ml.) and ether (2 x 20 ml.) and dried. <br><br> 19605 <br><br> Ampicillin is converted to compound £ by the use of methyl acetoacetate in the procedures of U.S. <br><br> Patent 3,316,247. Then to a stirred solution of compound £ (0.57 mol) in dimethylformamide (1 liter) there is added at 5°C. 0.5 mol of compound 8. After stirring for 15 <br><br> minutes at 5°C. the reaction mixture is poured into an ice-cold mixture of ethyl acetate (4 liters) and saturated aqueous calcium chloride (2 liters) with stirring. The organic layer is separated, washed with saturated aqueous calcium chloride (2 x 500 ml.), filtered and evaporated to about one liter in vacuo to provide a concentrated solution of compound 10. To this concentrate there is added water (500 ml.) and n-butanol (500 ml.) and then, dropwise, 4 N hydrochloric acid with stirring until the ami no-protecting group is removed to provide a solution of compound 11. After the addition of the acid is finished ether (1 liter) and water (500 ml.) are added to the stirred mixture, the aqueous phase is separated and the organic phase is extracted with water (800 ml.). The combined aqueous extracts are washed with ether (1 liter) and then sodium chloride (640 g.) and dichloromethane (2 liters) are added and the mixture is stirred for 15 minutes. The organic phase is separated and the aqueous phase is extracted with dichloromethane (1 liter) and the combined organic extracts are dried (MgSO^) and evaporated to about 600 ml. under reduced pressure to give a concentrated solution of compound 11. Addition to the concentrate of 200 ml. 2-butanone followed by cooling precipitates solid 6-[ (R)-2-Amino-2-phenylacetamido"] -3.,3-dimethy 1-7- - <br><br> oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbonyloxymethyl 2 P-chlo rome thy 1 -2 -a-methylp enam-3&lt;*-c arboxylat e sulfone (11) which is collected by filtration. <br><br> -31- <br><br> 196 0 <br><br> Example 6 <br><br> 6-[(R)-2--Amino-2-p-hydroxyphenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbonyloxymethyl 2P-chloromethyl-2-a-methylpenam-3a-carboxylate sulfone having the formula <br><br> HO <br><br> V // <br><br> CH CO <br><br> NH, <br><br> -NH <br><br> 4 <br><br> 0 <br><br> ,N_ <br><br> CH^ CHj <br><br> C=0 <br><br> 0 0 <br><br> ^ O CH„C1 <br><br> JT~ <br><br> *CH^ <br><br> 't ii <br><br> 0 <br><br> CH, <br><br> is produced by substituting amoxicillin for the ampicillin used in the procedure of Example 5. <br><br> -32- <br><br> 196 0 <br><br> a) <br><br> Example 7 <br><br> + N-Bromosuccinimide a-azo-isobutyronitrile CC1„ <br><br> A <br><br> CHB-, <br><br> 12 <br><br> As taught by U.S. Patent 3,860,579, recrystallized phthalide (50 f 0.375 mol)- and recrystallized N-bromo-succinimide (0.375 mol) were refluxed by 4.5 hours in the presence of about 100 mgm a-azobutyronitrile in one liter CCl^. The mixture was cooled to about 15°C. and filtered to remove succinimide which was itself washed with about 100 ml. CCl^ and filtered. <br><br> The combined CCli phases were concentrated in vacuo to about 150 ml. giving solid 3-bromophthalide which was collected by filtration, washed with about 50 ml. CCl^ and air-dried to yield 54 g. which weighed 50 g. after recrystallization from boiling cyclohexane, m.p. 84°-86°C. <br><br> o o <br><br> V <br><br> !h <br><br> ch2c1 "CH^ <br><br> CHBr <br><br> 12 <br><br> C-OK II <br><br> 0 <br><br> DMF 22 °C. <br><br> 33- <br><br> 1960 5 5 <br><br> &lt;/—N <br><br> BL-P2036 *dl <br><br> 13 <br><br> To a stirred partial solution and partial suspension of compound 5. (BL-P2013; 2.3 0.0075 mol) in 20 ml. <br><br> dimethylformamide (DMF;. dried at least 3 weeks over 3A0 <br><br> molecular selves) was added 1.7 g. (0.008 mol) of <br><br> 3-bromophthallde (12) and the mixture was stirred 4 hours at 22°C. The resulting mixture was poured into a mixture of 200 ml. ice-cold water and 200 ml. ice-cold ethyl acetate (rinsing the flask with a little ethyl acetate) <br><br> and the mixture was shaken. Then the organic solvent phase was separated and washed with seven portions of ice-cold water (100 ml.). The ethyl acetate phase was washed once with saturated aqueous Na2S0^, dried in the cold over NagSO^, <br><br> filtered and evaporated to dryness in vacuo to leave as the residue an oil which was triturated twice with methylcyclo- <br><br> hexane (25 ml.), twice with "Skellysolve B" ("b.p. 60-68°C., <br><br> essentially n-hexane) (25 ml.) and four times with 25 ml. <br><br> n-hexane to 2.5 g. compound 13 as a nearly white solid after drying in air. This product was then dried over <br><br> Po0c at less than 1 mm Hg to give 2.5 g. compound 13, 2 0 ~ <br><br> m.p. 104°C. (dec.). Its estimated purity was 85-95$. <br><br> -34- <br><br> T96055 <br><br> Anal. Calcd. for C^H^CINO^S: <br><br> Found: <br><br> C, 51.61; H, 3.79; N, 3-77; CI, 9-53. <br><br> c, 52.59; H, 4.67; N, 3.21; <br><br> Cl, 7.73; K.F.H20, 0.27. <br><br> Example 8 <br><br> Pivaloyloxymethyl 2ft-Chloromethyl-2a-methylpenam.-3g-carboxylate Sulfone <br><br> A mixture of 1 g. (0.0031 mole) of potassium 2 P-chloromethyl-2a-methylpenam-3a-carb oxylate sulfone hydrate and 1 g. of 3A molecular sieves was stirred in 15 ml. of dimethylacetamide for 2 hours at 23°. To this mixture was added 470 mg. (0.0031 mole) of pivaloyloxymethyl chloride and the stirring was continued for 18 hours. The molecular sieves were collected and the filtrate was diluted with 100 ml. of water and extracted with ethyl acetate. The ethyl acetate was washed nine times with water and dried over anhydrous magnesium sulfate. The solvent was removed at 30° (15 mm) to leave an oil which was chromatographed on silica using silicar CC-7 (methylene chloride 8, ethyl acetate 2) showing 1 spot Rf .5. The residue obtained crystallized from heptane ("Skellysolve B") to yield 100 mg. (M.P. 94-95°) of pivaloyloxymethyl 2P-chloromethyl-2a-methylpenam-3a-carboxylate sulfone. <br><br> Anal. Calcd.; C, 44.03; H, 5-27; N, 3.67. <br><br> Found : C, 44.20; H, 5.24; N, 3.63. <br><br> The NMR and IR spectra were consistent for structure. <br><br> -35- <br><br> 196055 <br><br> Example 9. <br><br> Sodium 2fi-Chloromethyl-2a-methylpenam-5a-carboxylate Sulfone <br><br> &lt;? <br><br> or <br><br> N - <br><br> V0. ^CHgCl . H+ <br><br> m <br><br> "CH- <br><br> /// <br><br> 6o2K <br><br> (306) <br><br> of <br><br> NaEH <br><br> (2) <br><br> V&gt;CH2C1 <br><br> ^ch5 <br><br> i <br><br> [Yf <br><br> — N k <br><br> /// <br><br> C02Na <br><br> CgHgClN05SNa <br><br> (289.67) <br><br> To a stirred solution of 500 mg. of BL-P2013 (potassium salt) in 5 ml. of HgO and 10 ml. of ethyl acetate was added 2N HC1 until pH 1 was obtained (done in an ice-bath with vigorous stirring). The mixture was then saturated with Na^SO^, the aqueous layer separated and the organic phase dried briefly in ice over Na^SO^, <br><br> filtered and treated dropwise with 50$ NaEH (sodium 2-ethylhexanoate) in anhydrous n-butanol until neutral to moist pH paper. Product did not crystallize upon scratching and was then concentrated jji vacuo to an oil which was dissolved in acetone (5 ml.), scratched - no crystals, ether added to cloud point - no cyrstals. Concentrated in vacuo on rotovap. to an oil which was dissolved in ethyl acetate -added one drop HgO - scratched - no crystals. Concentrated in vacuo and then residue was triturated with 5 ml. of n-butanol - 200 mg. of amorphous white powder obtained, ether washed - air dried - vacuum dried over P2°5 for hours. 180 mg. final yield of sodium 2p-chloromethyl-2a-methylpenam- <br><br> jja-carboxylate sulfone; dec. pt. &gt;100° indef. <br><br> Anal. Calcd. for CgH ClNO^SNa: C, 33-10; H, 3-13; N, 4.89 <br><br> Found: C, 33-20; H, 3-69; N, 4.44 K.F.H^O, 4.04 <br><br> -36- <br><br> '96055 <br><br> Example 10 <br><br> Potassium 2g-chloromethy1-2-methylpenam-3-carboxylate Sulfone (BL-P2013) <br><br> To 10 L of water, 130 g. (1.25 mole) of sodium hydrogen carbonate and 200 g. of 10 $ Pd on BaSO^ were added 272 g. (O.565 mole) of p-nitrobenzyl 6a-bromo-2(3-chloromethyl-2-methylpenam-3-carboxylate sulfone dissolved in 5 L of ethyl acetate. The mixture was hydrogenated at 40°C and 1 Kg .of pressure. After 5 hours, the hydrogen uptake became very slow and 200 g of 10$ Pd on BaSO^ <br><br> were added and the mixture hydrogenated until no further significant hydrogen absorption was perceptible. <br><br> The slurry was filtered through a diatomaceous earth ("Celite") pad, the pad was washed with water and the aqueous phase washed with 3 L of ethyl acetate. To the aqueous solution, 3 L of ethyl acetate were added and the pH of the mixture adjusted to 1.5 with 150 ml of 12 N HCl at 10°C. The organic phase was separated and the aqueous solution saturated with Na2S0^"10 H^O and extracted with 2 x 1 L of ethyl acetate. The combined extracts were dried with magnesium sulfate. The drying agent was removed and 260 ml of 2 N potassium 2-ethylhexanoic acid in butanol were added at 0°C. <br><br> After stirring 2 hours at 0°C, the potassium 2£-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) was collected and dried in a vacuum at room temperature. <br><br> Yield : 134.8 g (about 70$). <br><br> -37- <br><br> 196 0 5 5 <br><br> Example 11 <br><br> p-Nitrobenzyl 6g-Bromopenicillinate Sulfoxide t TEA + (101) <br><br> (296) <br><br> BrCH, <br><br> (216) <br><br> W <br><br> J <br><br> 0 <br><br> ft <br><br> N <br><br> C02CH2~&lt;A y— NO, <br><br> (431-28) <br><br> Procedure: <br><br> To 200 ml. of N,N-dimethylacetamide was added 44 g. (0.148 mole) of 6a-bromopenicillanic acid sulfoxide followed by 20.5 ml- (0.148 mole) of triethylamine and 38.2 g. (0.177 mole) of p-nitrobenzyl bromide. It was stirred at 22° for 20 hours. <br><br> The reaction mixture was poured into 1 liter HgO and extracted into 3 x 300 ml. of methylene chloride. The combined methylene chloride extracts were washed with 200 ml. of 5$ aqueous sodium bicarbonate solution and dried over sodium sulfate at 5° for half an hour. The solution was filtered and evaporated under vacuum to a residue. The <br><br> -38- <br><br> 1960 5 5 <br><br> residue was diluted with ether and the solid collected by filtration to yield 54 g. p-nitrobenzyl 6a-bromopenicillinate sulfoxide after drying. <br><br> 85$ yield. <br><br> nmr consistent for structure. <br><br> The yield for this step was the same as for the K-salt esterification. The advantage is there was no need to make the K-salt. (A step which goes in 85$ to 90$ yield). <br><br> Example 12 <br><br> Preparation of p-Nitrobenzyl 6a-Bromopenicillanate Sulfoxide <br><br> To 4.375 L of N,N-dimethylacetamide was added 873.0 g (2.95 moles) of 6a-bromopenicillanic acid (S) sulfoxide and then with stirring and while keeping the internal temperature below 35°C, 293 g (2.95 moles) of triethylamine followed by 764 g (3*54 moles) of p-nitrobenzyl bromide. The mixture was stirred then at room temperature for 5 hours and let stand overnight. <br><br> The reaction mixture was poured into 20 L of water and extracted with 3 x 7 L of methylene chloride. The combined organic extracts were washed 5 x 7 L of water and then with 7 L of 5$ aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. <br><br> The magnesium sulfate was filtered off and the solution evaporated to a crystalline residue; 4 L of diethyl ether were added and the crystals collected to yield after drying at room temperature 1171 g (92$) of p-nitrobenzyl 6a-bromopenicillanate sulfoxide. <br><br> Br 18.48$ (calculated 18.53$),^ (0.25$ Me OH) .+ 162°. <br><br> -39- <br><br> f 96 0 5 5 <br><br> Example 13 <br><br> Preparation of p-Nitrobenzvl 6a-Bromo-2P-chlorQmethyl- <br><br> 2-methylpenam-3-carboxylate Sulfone <br><br> To 16 L of acetic acid was added 364.6 g (0.812 mole) of p-nitrobenzyl 6a-bromo-2P-chloromethyl-2-methylpenam- <br><br> 3-carboxylate. To the solution so obtained and stirred at room temperature, a solution of 282 g (I.78 mole) of KMnO^ in 26 L of water was added dropwise over 3 hours. The mixture was then stirred at room temperature for 1 hour and H^Og (37$) was added dropwise until a colorless solution was obtained. 30 L of water were then added, the mixture stirred for 1 hour at roam temperature-and the crystalline precipitate was collected, washed with 3 x 5 L of water and with 2 x 2 L of ethanol and dried over vacuum at room temperature . <br><br> Yield: 297 g (76$) <br><br> Op (0.5$ CHgClg) + 75-9° <br><br> Example 14 <br><br> Preparation of BL-P2013 Free Acid y <br><br> 1—r V C] <br><br> □l_F® <br><br> cr *'co. <br><br> CH2C1 H^PO^ <br><br> V/C029K@ <br><br> *'CHj e <br><br> ^C02H <br><br> t960 55 <br><br> To a mixture of 25 ml of ethyl acetate and 10 ml of water was added 800 mg (0.00261 mole) of BL-P2013 potassium salt. After all of the solid had dissolved, the mixture was treated dropwise with 50$ aqueous phosphoric acid with vigorous shaking until no more material precipitated from the aqueous layer. The ethyl acetate layer was separated, then washed with satuated sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and washed with 10 ml of ethyl acetate. (The wash solvent was combined with the original filtrate). "Skellysolve B" was then added to the ethyl acetate to the cloud point (approx. 10 ml). The mixture was treated with 500 mg of activated carbon ("Darko KB") and filtered. The filtrate was diluted with 15 ml of "Skellysolve B", then seeded with crystals of BL-P2013 free acid. After approx. 3 hours at room temperature, the crystalline precipitate of free acid was collected and dried in vacuo (15 min) over P2°5 to 323 mg (46$) <br><br> m.p. slow decomp. over 100°. <br><br> Anal. Calcd... for CqH^qCINO^S: C, 35.89; H, 3.77; N,5,23, <br><br> CI, 13.25 <br><br> Found: C, 35-88, H, 3-91; N, 5-41; CI, 13-52 This product was found to be unstable when stored at 23°C. for seven days. <br><br> -41- <br><br> 1960 5 5 <br><br> Example 15 <br><br> 6a-Bromopenlcillanic Acid Sulfoxide <br><br> 0 <br><br> '6 *C0g£ <br><br> (c6h5ch2hhch2)? <br><br> Br <br><br> •&gt; <br><br> '^COgH <br><br> 2 <br><br> MW 800.64 <br><br> MW 296.14 <br><br> To 3 1 of methylene chloride was added 300 g <br><br> (0.75 mole) of 6a-bromopenicillanic acid N,N'-dibenzyl-ethylenediamine salt and this suspension was cooled to 5°. Then over a 15 min. period, with good stirring, 130 ml of conc. HCl was added dropwise. The slurry was stirred at 5° for 2 hours. It was then filtered through a ("Celite") pad of diatomaceous earth and the cake was washed with 3 x 250 ml of methylene chloride. <br><br> washed with 2 x 500 ml HgO and dried over sodium sulfate for 15 min. The sodium sulfate was removed by filtration and the filtrate evaporated under reduced pressure to approx. 750 ml. <br><br> stirring, 130 ml of 40$ peracetic acid was added dropwise such that the temperature was maintained at 5° to 12°. The addition was quite exothermic. At the end of the addition, the slurry was stirred at 5° for 2 hours and the product collected by filtration a$d washed with 100 ml of cold H20 (5°) and 100 ml of cold methylene chloride (5°). There was obtained 126 g (57$) of 6a-bromopenicillanic acid sulfoxide, m.p. 129°. The ir and nmr spectra were consistent for the desired product. <br><br> Anal. Calcd. for CgH1()BrN0^S: C, 32.44, H, 3-40; N, 4.73- <br><br> The combined methylene chloride solutions were <br><br> This solution was cooled to 5° and, with vigorous <br><br> Pound: a, 32.30; H, 3-35; N, 4.71; HgO, 2.18. <br><br> -42- <br><br> 1 96 0 5 <br><br> Potassium 6g-jBromopenicillanate Sulfoxide <br><br> 6 — <br><br> ''"C02H ^C02K <br><br> MW 334.24 <br><br> To 3 1 of acetone was added 126 g (0.43 mole) of 6a-bromopenicillanic acid sulfoxide and 162 ml of 50$ "by weight potassium 2-ethylhexanoic acid in n-butanol. <br><br> After stirring 1 hour at 22°, the product was collected by filtration, washed with 2 x 250 ml of acetone and dried. There was obtained 127 g (90$) of potassium 6a-bromo-penicillanate sulfoxide, m.p. 185°. 111116 ir and nmr spectra were consistent for the desired structure. <br><br> Anal. Calcd. for CgH^BrKNO^S: C, 28.75; H, 2.71; N, 4.19. <br><br> Pound: C, 29.03; H, 2.78; N, 4.04. <br><br> i <br><br> -43 <br><br> 1 96 0 5 <br><br> p-Nitrobenzyl 6a-Bromopenicillanate Sulfoxide 0 0 <br><br> + Rx + <br><br> Br <br><br> D x j- * <br><br> '*/C0gK <br><br> Br % <br><br> ■» <br><br> N. <br><br> r~ <br><br> MW 431.28 <br><br> *co2 c <br><br> '/ » <br><br> .NO, <br><br> To 1 1 of N,N-dimethylacetamide was added 145 g (0.43 mole) potassium 6a-bromopenicillanate sulfoxide, and, with stirring, there was then added 115 g (0.53 mole) of p-nitrobenzyl bromide at 22°. The mixture was stirred at 22° for 20 hours. <br><br> The reaction mixture was poured into 3 1 of HgO and extracted with 3 x 1500 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 2 x 500 ml of 5$ aqueous sodium bicarbonate solution and dried over sodium sulfate for 1/2 hour. The sodium sulfate was filtered off and the filtrate evaporated under reduced pressure to a residue to which 1 1 of diethyl ether was added causing the product to crystallize. The crystals were collected by filtration, washed with 2 x 100 ml of diethyl ether and dried to yield 162 g (87$) of p-nitrobenzyl 6a-bromopenicillanate sulfoxide, m.p. 111°. The ir and nmr spectra were consistent for the desired structure, Anal. Calcd. for C^H^BrNgOgS: C, 41.78; H, 3-51; N, 6.50. <br><br> Found: C, 41.66; H, 3*45; N, 6.85; H2O, 0.69. <br><br> -44- <br><br> 1960 5 5 <br><br> p-Nitrobenzyl 6a-Bromo-23-chloromethyl-2-methylpenam- <br><br> 3-carboxylate <br><br> 1r <br><br> Br <br><br> + <br><br> CH2C1 <br><br> ■&gt; <br><br> r' v <br><br> NO, <br><br> 2 <br><br> co2c <br><br> NO, <br><br> 2 <br><br> MW 449.71 <br><br> To 1 1 of p-dioxane was added to 70 g (0.16 <br><br> mole) of p-nitrobenzyl 6a-bramopenicillanate sulfoxide followed by 21.2 ml (0.10 mole) of benzoyl chloride and 21.8 ml (0.19 mole) of quinoline. The reaction mixture was refluxed for 4 hours and then cooled to 22°, poured into 2500 ml of HgO and extracted into 3 x 800 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml of 5$ aqueous sodium bicarbonate solution, 300 ml of 5$ aqueous phosphoric acl&lt;2~and 300 ml of HgO. The ethyl acetate solution was dried over sodium sulfate for 1/2 hour and the sodium sulfate was removed by filtration. The filtrate was evaporated under reduced pressure to a residue which was redissolved in 1 1. of ethyl acetate and again evaporated under reduced pressure to a residue. Then 1 1. of diethyl ether was added and the product collected by filtration to yield 41 g (57$) of p-nitrobenzyl 6a-bromo-2P-chloromethyl-2-methylpenam-3-carboxylate, m.p. 132°. The ir and nmr spectra were consistent for the desired structure. <br><br> Anal. Calcd. for C^H^BrClN^S: C, 40.06; H, 3-14; N, 6.23. <br><br> Found: C, 40.62; H, 3.11$ N, 6.13. <br><br> -45- <br><br> 196 0 5 5 <br><br> p-Nitrobenzyl 6a-Bromo-2P-chloromethyl-2-methylpenam-3-carboxylate Sulfoxide <br><br> (0.11 mole) of p-nitrobenzyl 6a-bromo-2f3-chloromethyl-2-methlypenam-3-carboxylate followed by 23 g (0.12 mole) of m-chloroperoxybenzoic acid. The solution was stirred at 22° for 2 hours and evaporated under reduced pressure to a wet residue. The residue was stirred with 4 1 of diethyl ether for 1 hour and allowed to stand at 10° for 20 hours. The product crystallized out and was collected by filtration, washed with 2 x 200 ml of diethyl ether and dried, yielding 39 g p-nitrobenzyl 6a-bromo-2£-chloromethyl-2-methylpenam-3-carboxylate sulfoxide (75$), m.p. 132°. The ir and nmr spectra were consistent for the desired structure. <br><br> Anal. Calcd. for C^H^BrClNgOgS: C, 38.69; H, 3-03; N, 6.07. <br><br> Pound: C, 38.98; H, 3.04; N, 5-84; H20, 0.35. <br><br> 0 <br><br> To 1200 ml of methylene chloride was added 51 g <br><br> -46- <br><br> 196 0 55 <br><br> Potassium 2g-Chloromethyl— 2-methylpenam-3-carboxylate -Siil fone (BL-P2013) <br><br> % <br><br> ~~0 <br><br> /S .CHaCl r to2cH^rv <br><br> NO, <br><br> o o <br><br> V^CHSC1 <br><br> /" <br><br> yo, <br><br> BL-P2013 MW 305.77 <br><br> CH- <br><br> ^~CO K <br><br> To 600 ml of H 0 was added 8 g of 30$ Pd on 2 <br><br> "Celite" and 16 g (O.19 mole) of sodium bicarbonate. <br><br> Then 32 g (O.69 mole) of p-nitrobenzyl 6a-bromo-23-chloromethyl-2-methylpenam-3-carboxylate sulfoxide was dissolved in 400 ml of ethyl acetate and added to the aqueous slurry. The mixture was hydrogenated on a Paar apparatus at 50 p.s.i. at 22° for 4 hours. The slurry was filtered through a thin "Celite" pad on a sintered glass funnel, the pad was washed with 2 x 50 ml HgO and the aqueous layer of the combined filtrate and washings was separated. The aqueous layer was washed with 200 ml of diethyl ether, then was cooled to 5° and, with stirring, a solution of 12 g. (.076 mole) of KMnO^ in 200 ml of H^O was added dropwise over a 1/2 hour period, keeping the pH between 7.5 and 8.0 by the addition of 40$ H^PO^. When the pink color persisted for 5 minutes, no more KMnO^ <br><br> solution was added. The reaction mixture was stirred with a small amount (approx. 50 mg) of sodium bisulfite for 1/2 hour, and then the slurry was filtered through a "Celite" pad. The pad was washed with 2 x 50 ml of HgO. The <br><br> 196 055 <br><br> combined filtrate and washings were layered with 500 ml of ethyl acetate and, with stirring, the pH was adjusted to 1.5 hy the addition of 2 N HCl. The layers were separated and the aqueous layer was saturated with sodium sulfate• It was reextracted with 2 x 400 ml of ethyl acetate and the combined ethyl acetate extracts were dried over sodium sulfate for 1/2 hour at 5°. The sodium sulfate was removed by filtration and the filtrate evaporated under reduced pressure to a residue. That residue was dissolved in l€o ml of acetone and 160 ml of diethyl ether and 50$ by weight of potassium 2-ethylhexanoate in n-butanol was added until the solution was neutral to moist pH paper. The potassium salt of BL-P2013 crystallized out, was collected by filtration, washed with diethyl ether and dried. Yield 16 g potassium 2f3-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2013) (76$), m.p. 202°. The ir and nmr spectra were consistent for the desired structure. Anal. - Calcd. for CgH^ClKNO^: C, 31.42; H, 2.97; N, 4.58. <br><br> _ Found: C, 31.18; H, 2.98; N, 4.51s <br><br> ' h20, 0.93. <br><br> -38- <br><br> 1960 5 5 <br><br> Example l6 <br><br> Pivaloyloxymethyl 2ft-Chloromethyl--2-i]iethylpenam-3-carboxylate Sulfone (BL-P2024) <br><br> 0 0 " 0 ~ 0 <br><br> 0 0 <br><br> 0 <br><br> &gt;CH2C1 <br><br> ""CH3 . ^/COgK <br><br> HgCl CH^ <br><br> COgCHg 0000(01^) <br><br> BL-P2024 MW 381-83 <br><br> To a stirred suspension of 14.6 g (0.0487 mole) <br><br> of potassium 2f3-chloromethyl-2-methylpenam-3^carboxylate sulfone (BL-P2013) in 200 ml of acetone was added 4 ml of a 10$ aqueous solution of sodium iodide and the mixture was brought to reflux on the steam bath. To this reflux-ing suspension was added 14.8 ml. (0.1 mole) of redistilled chloromethyl pivalate (bp 34°C at 7 mm Hg) all at once. The mixture was stirred at reflux for three hours and then cooled to room temperature (22° C). The crystalline solids were collected by filtration, washed with 3 x 30 ml of acetone and the combined filtrates were evaporated to an oil under reduced pressure at &lt;22° C. The oil was then taken up in 500 ml of ethyl acetate and washed once with water (200 ml) and once with saturated NagSO^ solution (200 ml). The solution was then dried briefly over Na2S0^ while being stirred with 2 g of decolorizing carbon with cooling (ice bath). After 20 min. the mixture was filtered through a "Celite" pad and the pad washed with 4 x 100 ml of ethyl acetate. The combined filtrates were concentrated under reduced pressure at 22° C to an oil. The oil was then further concentrated at about 22° C and &lt;1 mm Hg to remove most of the residual chloromethyl pivalate. The remaining oil was then triturated twice with 50 ml portions of n-pentane and then left over the weekend at about 10° C <br><br> -49- <br><br> 196055 <br><br> under n-pentane. The resulting solid crystalline mass was then broken up to a powder under 40 ml of a 4:1 mixture of diethyl ether-n-pentane. The product was then collected by filtration, washed with diethyl ether-n-pentane (1:1) then n-pentane and air dried. After drying under high vacuum for four hours over P2°5 'fcliere was obtained 13.37 g pivaloyloxymethyl 2P-chloromethyl-2-methylpenam-3-carboxylate sulfone (BL-P2024) about (75$), m.p. 93° - 95° C . <br><br> -50- <br><br> 1960 55 <br><br> Purification of BL-P2024 <br><br> Approximately 3 6* crude BL-P2024 (obtained as described above) was dissolved in 5 ml. of ethyl acetate,• placed on a 4.5 x 40 cm. column of silica gel (Mallinckrodt CC-7), and eluted with 4:1 v/v CHgClg-ethyl acetate. The fractions containing a single spot at R^.0.84 (TLC on silica gel plates with 4:1 CHgClg-ethyl acetate, Ig detection) were combined and concentrated under reduced pressure to I.38 g. of a crystalline solid. A portion of this material (900 mg.) was dissolved in 5 ml. of ethyl acetate; the resulting solution was filtered, diluted almost to the cloud point with petroleum ether ("Skellysolve B") and then stored at room temperature for three days. The crystals which formed were collected by filtration, washed with petroleum ether and dried to give 560 mg., m.p. 100-101°., of purified BL-P2024. <br><br> Anal. Calcd. for C^H^Cl^S: C, 44.03; H, 5-27; N, 3.67 <br><br> Found: C, 44.11; H, 5-08; N, 3«85- <br><br> All temperatures in this application are given in degrees Centigrade. <br><br> 196 0 5 <br><br> Example 17 Preparation of BL-P2013 Ammonium Salt <br><br> 1. The free acid of BL-P2013 (250 mg.) dissolved in 20 ml. of acetone-methanol (1:1 by volume) was filtered to get a clear solution. <br><br> 2. Anhydrous ammonium solution was prepared by adding 1 ml. of ammonium hydroxide (30$, reagent grade) to 10 ml. of acetone-methanol (1:1 by volume) solvent and then 1 gm. of anhydrous magnesium sulfate was added to that solution with mild agitation and the mixture was filtered through a filter paper; the filtrate was designated "anhydrous ammonium solution." <br><br> 3. To the filtrate of Procedure 1, approximately 2 ml. of "anhydrous ammonium solution" was gradually added and mixed well. <br><br> 4. A 100 ml. portion of diethyl ether was mixed with the mixture from Procedure 3 to precipitate the ammonium salt of BL-P2013. <br><br> 5. The white ammonium salt was isolated from the solvent and washed with 2 portions of 50 ml. each of diethyl ether. <br><br> 6. The isolated powder was dried at 35° C vacuum oven for overnight. <br><br> 7. Analytical data were as follows: <br><br> Calculated $ C 33-7; H 4.6; N 9.8; <br><br> Found C 33-66; H 4.63; N 10.12; dry by KF <br><br> Microscopic Examination: crystalline substance <br><br> -52- <br><br> 1960 5 5 <br><br> Example 18 <br><br> Preparation of Non-hygroscopic Sodium Salt of BL-P2013 <br><br> 1. Dissolve 50 mg. of the free acid of BL-P2013 in 4 ml. of acetone-methanol (1:1 by volume) mixture. Filter to get a clear solution. <br><br> 2. Prepare sodium 2-ethylhexanoate solution by dissolving 40 mg. of sodium 2-ethylhexanoate in 10 ml. of acetone-methanol (1:1 by volume) mixture. <br><br> 3. To the filtrate of Procedure 1&gt; add the 10 ml. solution of Procedure 2 and mix well. <br><br> 4. A 10 ml. portion of diethyl ether was mixed with the mixture from Procedure 3 to precipitate the sodium salt of BL-P2013. <br><br> 5. The white salt was Immersed in the diethyl ether for 1-2 hours and then was isolated from the solvent and washed with 3 portions of 5 ml. each of diethyl ether. <br><br> 6. The isolated powder was dried at 30° C vacuum oven for overnight. <br><br> -53- <br><br> 1960 5 5 <br><br> Example 19 <br><br> Recrystallization of BL-P2Q13 <br><br> 0 0 <br><br> CHgCl Recryst. <br><br> )-aceton^ <br><br> fr <br><br> 'it <br><br> CH^ <br><br> HgO- <br><br> '"COgK-HgO <br><br> 0 <br><br> .CHgCl <br><br> '"'CH^ <br><br> N 1 <br><br> '* COgK-HgO <br><br> BL-P2013 (400 mg.) was dissolved in a minimum amount of acetone-HgO (1:1) "by volume and diluted with 10 ml. of acetone, filtered, then diluted with acetone to about 25 ml., scratched, and after 30 minutes the crystalline hydrate was collected by filtration, washed well with acetone, air dried and then vacuum dried at &lt;1 mm. Hg overnight. <br><br> Yield 280 mg. <br><br> Anal. Calcd. for CgHgClNOSK-HgO: C, 29.67; H, 3-39; N, 4.63; ...... - CI, 10.94; HgO, 5.55. <br><br> Found: C, 29-32; H, 3-32; N, 4.44; CI, 11.31; H20, 5-90. <br><br> -54- <br><br> 1960 5 5 <br><br> Example 20 <br><br> N,N' -DibenzylethylenerH ami ne Salt. of BL-P2013 BL-P2013 + 1/2 N,N'-Dibenzylethylene diamine diacetate <br><br> 306 mg. (0.001 ml) of BL-P2013 was dissolved in 7 ml. HgO and added to a solution of 180 mg. (0.0005mol) of N,N'-dibenzylethylenediamine diacetate in 7 ml. HgO. Hie mixture was stirred and the salt crystallized and after stirring approximately 1Q-15 minutes the salt was collected "by filtration and air dried to yield N,N'-dibenzylethylenediamine salt of BL-P2013 (300 mg). The material was recrystallized by dissolving it in approximately 10 ml. of boiling acetone and diluting with ether to the cloud point. 260 mg. of air dried and vacuum dried material was obtained. Anal. Calcd: C, 51.69; H, 5.42; N, 7-53; CI, 9-55-Found: C, 49-39; H, 5.49; N, 7.05; CI, 8.96; <br><br> H20, 1.23 (KF). <br><br> -55- <br><br> 196055 <br><br> Example 21 Chloromethyl Ester of BL-F2013 <br><br> + CICHg-O-SOgCl -+ (CH5CH2CH2CH2)4NifesOip <br><br> + 3 KHCO. <br><br> 3 <br><br> I CHgClg <br><br> I H*° <br><br> 0 0 <br><br> jCHgCl f <br><br> C-OCHgCl <br><br> (316.17) <br><br> -56- <br><br> 196055 <br><br> To a vigorously stirred mixture of 15*25 g (0.05 mol) of BL-P2013 (5), 15 g. (0.15 mol) KHCO^ and 1.7 g (0.005 mol) of tetrabutylammonium hydrogen sulfate (Aldrich Chem. Co.) in a mixture of 50 ml. water and 50 ml. CHgClg there was added dropwise a solution of 9-5 g (0.0575 mol) of CICHg-O-SOgCl in 40 ml. CHgClg. The temperature rose to 26° C. and after the addition (which took about 15 minutes) the mixture was stirred another 30 minutes. Because the product crystallized out more CHgClg (about 400 ml.) was added to obtain a solution. The separated CHgClg layer and a 50 ml. CHgClg wash were combined, dried over MgSO^ with stirring and 2 g of decolorizing carbon ("Darco KB") was added. After about 30 minutes the mixture was filtered, concentrated to about 50 ml. and isopropyl alcohol (150 ml.) was added. The rest of the CHgClg was then removed under reduced pressure. The resulting crystalline precipitate was collected by filtration, washed well with isopropyl alcohol and air-dried. <br><br> After vacuum drying at less than 1 mm. Hg there was obtained 8.5 g of chloromethyl 2f3-chloromethyl-2-methylpenam-3-carboxylate sulfone (J). M.p. 116° (dec., darkens above 100°C). <br><br> Anal. Calcd. for CoH^CloN0cS: C, 34.18; H, 3-51; N, 4.43; <br><br> 9 11 2 i? <br><br> CI, 22.43. <br><br> Found: C, 34.16; H, 3-45; N, 4.47; <br><br> """I"" : J21, 22.46; HgO, 0.33 (KF). <br><br> 'Estimated purity in the~90-95$ range. <br><br> -57- <br><br> 196055 <br><br> Iodomethyl Ester of BL-P2013 <br><br> .r- <br><br> 0 0 <br><br> ^ .OH CI <br><br> JL <br><br> r"//c <br><br> "s <br><br> C-0CH2C1 <br><br> Na I <br><br> a <br><br> 0 0 ^ &gt; <br><br> V"o <br><br> \ // &gt;CH2C1 <br><br> 8 <br><br> CH, <br><br> C-0CHoI ii 2 0 <br><br> To a stirred mixture of 5 g. (0.0159 mol) of the chloromethyl ester of BL-P2013 (7) in 25 ml. acetone was added 3 g. (0.02 mol) of sodium iodide. The resulting slurry was stirred for 17 hours and then cooled to about 0°C. Two drops of saturated aqueous KHCO^ were added and the mixture was slowly diluted dropwise with water over ten minutes until 50 ml. had been added. The slurry underwent a sudden color change from yellow to grey to purple to black and therefore the crystals were immediately collected by filtration and washed with cold acetone-water (1:2) and then isopropyl alcohol (3 x 10 ml), then diethyl ether and finally n-pentane and air-dried to yield 5-55 g- (91$ yield) of the iodomethyl ester of BL-P2013 (8J• M.p. 118° - 119°C. with decomposition. <br><br> Purity estimated at about 90$. <br><br> 6-[ (R)-2-Amino-2-phenylacetam1.do] -3 .,3-dime thy 1-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbonyloxymethyl 2P-chloromethyl-2-a-methylpenam-3cx-carboxylate sulfone (11) <br><br> -58- <br><br> 196 0 <br><br> 8' <br><br> \ // <br><br> ii <br><br> CH-CO-NHi <br><br> H <br><br> »^y&gt; <br><br> I N- <br><br> fs^A <br><br> COOK <br><br> OCKj <br><br> (A Dane salt of ampicillin; see U.S. Patent 3,316,247) <br><br> \ // <br><br> v-f <br><br> HC <br><br> 10 <br><br> CH CO NH <br><br> S <br><br> .N <br><br> H <br><br> •c^0 <br><br> OCH^ <br><br> J <br><br> 4 <br><br> o <br><br> .N. <br><br> CHj <br><br> C=0 <br><br> 0 0 <br><br> CV1 <br><br> -(H. <br><br> _N- <br><br> CH- <br><br> ii <br><br> 0 <br><br> CH, <br><br> -O <br><br> H <br><br> -59- <br><br> 1 96 0 <br><br> CH CO NH <br><br> /&gt; 0 <br><br> v/ <br><br> .N. <br><br> CH5 <br><br> CHj <br><br> C=0 <br><br> 11 <br><br> &lt;7 <br><br> * * CHoC1 _N — <br><br> ' CH-j ii O <br><br> CH, <br><br> -0 <br><br> To a stirred mixture cooled in an ice-bath of 5.46 g. (0.01 mol) of the indicated Dane salt of ampicillin £ (which was solvated with one molecule of isopropyl alcohol) in 60 ml. acetone there was added 4.08 g. (0.01 ml) of the iodomethyl ester of BL-P2013 (8J and the resulting nearly clear solution was stirred for five hours with the ice-bath removed after 30 minutes. Then most of the acetone was removed in vacuum on the roto-vap and the resulting concentrated solution was dissolved in 200 ml. cold ethyl acetate which was then washed with 2 x 50 ml. ice cold water and 2 x 100 ml. saturated aqueous Na2S0^. The ethyl acetate solution was then dried over NagSO^, filtered and most of the ethyl acetate was removed in vacuo on the roto-vap. The residue was triturated with 2 x 200 ml. dry diethyl ether and the resulting solids were collected by filtration to give 5-5 g. of 10 as a pinkish powder. This powder was <br><br> -60- <br><br> 1 96 0 5 <br><br> stirred in a mixture of 50 ml. water, 50 ml. n-butanol and 20 ml. ethyl acetate while 6n HCl was added dropwise to pH 2.5. Then occasionally a drop or two of HCl was added to keep the pH at 2.2 - 2.5 over 45 minutes. When the pH no longer drifted upward there was added to this mixture 100 ml. diethyl ether with good stirring. The aqueous phase was separated and combined with a second 25 ml. HgO extract of the organic layer. The aqueous solution was extracted once with 50 ml. diethyl ether and the ether was discarded. <br><br> The aqueous layer was then stirred vigorously under a layer of 100 ml. 2-butanone (methyl ethyl ketone) <br><br> while Na2S0^ was added to saturate the aqueous layer. The 2-butanone layer was separated, dried over NagSO^ <br><br> for 30 minutes in an ice-bath, filtered and concentrated in vacuo to near dryness. The residual oil was triturated to a solid with n-butanol, washed well with ether, then n-pentane, air-dried and then vacuum-dried over ?2®5 &lt;1 mm Hg pressure to yield 1.6 g. 6-[(R)-2-amino-2-phenylace- <br><br> tamido] -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3•2.0]heptane-2-carbonylmethyl 23-chloromethyl-2-a-methylpenam-3ci-carboxylate sulfone (11) in crude form. The IR and nmr spectra were consistent with structure 11 but not with high purity. <br><br> This solid product was estimated to contain at least 40$ and perhaps as much as 80$ 6-[(R)-2-amino-2-phenylace-tamido]3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]-heptane-2-carbonyloxymethyl 2£-chloromethyl-2-a-methyl-penam-3a-carboxylate sulfone. <br><br> -61- <br><br> 1960 5 5 <br><br> Example 22 <br><br> Improved Synthesis of BL-P2013 <br><br> This procedure simplifies production of BL-P2013 by eliminating the previous use of catalytic reduction. <br><br> Br <br><br> '*'&lt; <br><br> T <br><br> COOH <br><br> Step 1 <br><br> + CHgCCl^ + Dicyclohexylcarbodiimide OH <br><br> Pyridine <br><br> CH2C12 <br><br> Br <br><br> % <br><br> 0 <br><br> T <br><br> /y n ^ <br><br> ) c-ochgccl^ <br><br> 0 <br><br> (See page 633 of Cephalosporins and Penicillins, edited by Edwin H. Flynn, Academic Press, New York, 1972) <br><br> 6a-Bromopenicillanic acid sulfoxide (3J (30 g., 0.1 mol) was dissolved in 1 1. dry CHgClg followed by the addition of 16.2 ml. (0.2 mol) pyridine and 29.8 g. (0.2 mol) trichloroethanol. Then 20 g. (0.1 mol) of dicyclohexylcarbodiimide was added and the mixture was stirred at 22° for 16 hours. Dicyclohexylurea began <br><br> -62- <br><br> 1960 5 5 <br><br> to precipitate out; at the end it was removed by filtration, The filtrate was washed with 200 ml. of 5$ aqueous sodium bicarbonate, 200 ml. of 10$ phosphoric acid and 100 ml. of saturated aqueous sodium sulfate. The organic phase was dried over sodium sulfate at 5°C. for J&gt;0 minutes, filtered and evaporated to an oil. Diethyl ether was added and, <br><br> with scratching, the product 2^ crystallized out (27 g., 63$ yield). <br><br> Step 2 <br><br> Quinoline v <br><br> Br, <br><br> J <br><br> 0 * <br><br> rf <br><br> . CHgCl n/ <br><br> h CH^ <br><br> 7 <br><br> -N- <br><br> C-OCHgCCl^ <br><br> Compound 2_ (26.5 g*3 0.062 mol) was dissolved in 500 ml. p-dioxane and there was added 8.5 ml. (0.078 mole) benzoyl chloride and 8.75 ml. (O.o78 mole) quinoline. The solution was refluxed for four hours and then poured into 1100 ml. water and the product 3 was extracted into 2 x 400 ml. ethyl acetate. The ethyl acetate extracts were combined, successively washed with 200 ml. 5$ <br><br> aqueous sodium bicarbonate, 200 ml. 5$ phosphoric acid and 200 ml. saturated aqueous sodium.sulfate, dried over sodium sulfate at 5°C. for thirty minutes and evaporated to an oil (2.) which was used "as is" for the next reaction. <br><br> -63- <br><br> 196055 <br><br> Step 3 <br><br> KMn04+H202 <br><br> Br <br><br> in glacial acetic acid <br><br> o <br><br> Y"/t <br><br> ,ch2ci <br><br> :h5 <br><br> &lt;*&gt; <br><br> C-0CHoCC <br><br> n 2 <br><br> o <br><br> "S <br><br> Compound 2. obtained in the previous step was dissolved in 1 1. glacial acetic acid and, with stirring at 22°C., a saturated aqueous solution of KMnO^ was added dropwise until a pink color persisted (that is, a drop placed on a piece of filter paper gave a pink coloration). Then with cooling 30# H202 was added dropwise until a clear solution was obtained; some white precipitate was present. The solution was poured into 2.5 1. water and the product was extracted into 3 x 500 ml. ethyl acetate. The ethyl acetate was washed with 5$ aqueous sodium bicarbonate until neutral (that is, no more bubbling upon addition), dried over sodium sulfate and evaporated to leave as the residue. <br><br> -64- <br><br> 1960 5 5 <br><br> It was left at 10°C. for one day and then triturated with "Skellysolve B" to yield 9.1 g. solid 4_. The yield was 28# of theory for steps 2 and 3 combined. <br><br> Step 4 <br><br> i + © Zn in Acetic Acid + ©KEH <br><br> CH^ <br><br> 5 (BL-P2013) <br><br> COOK <br><br> (See U. S. Patent 4,164,497) <br><br> Zinc dust (3.75 g.) was slurried in 5 ml. glacial acetic acid and cooled to 5°C. To this mixture there was added a solution of 4 (3 g.; 0.0057 mole) in 15 ml. dimethylformamide and the resulting slurry was stirred at 5° for 2.5 hours. <br><br> The zinc was then filtered off and the pale yellow solution was poured into 80 ml. of 5# aqueous hydrochloric acid. That mixture was extracted with 3 x 25 ml. ethyl acetate. The combined ethyl acetate extracts were extracted with 3 x 20 ml. of 5# aqueous sodium bicarbonate, saving the ethyl acetate phase after separation. <br><br> -65- <br><br> 1960 5 5 <br><br> The bicarbonate extracts were combined, placed under a layer of ethyl acetate, adjusted to pH 1.5 by the addition of 2N HCl and saturated with sodium sulfate. The ethyl acetate was separated and the aqueous phase was extracted with 2 x 30 ml. ethyl acetate. <br><br> All of the ethyl acetate phases above were combined, dried over sodium sulfate and evaporated to an oil (which was the free acid form of BL-P2013) which was dissolved in about 20 ml. acetone to which 20 ml. diethyl ether was then added. Then 50# potassium 2-ethylhexanoate (KEH) in dry n-butanol was added to neutrality. The product 5. (BL-P2013) crystallized out. After stirring 0.5 hour at 22° it was collected by filtration to yield 650 mgm. of 5 (37# yield). <br><br> A 50 mgm. sample of 5 was dissolved in 0.5 ml. water and 20 mgm. N,N'-dibenzylethylenediamine (DBED) diacetate was added. The DBED salt of 5 crystallized out, was collected by filtration, washed with water and dried over 1*2^5 'under vacuum to yield N,N' -dibenzylethylenediamine 2P-chloromethyl-2-methylpenam-3-carboxylate sulfone (DBED salt of free acid 5.). <br><br> Another sample of 5 (450 mgm.) was dissolved in 3 ml. water to which was added a solution of 270 mgm. DBED diacetate in 2 ml. HgO. With scratching the DBED salt of 5 crystallized out (430 mgm.). Recrystallization from about 5 ml. boiling acetone yielded 270 mgm. <br><br> -66- <br><br> 1960 55 <br><br> Example 23 <br><br> 6-[ (R)-2-Amino-2-p-hydroxyphenylacetamldo] -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3-2.0]heptane-2-carbonyloxymethyl 23-chloromethyl-2-a-methylpenam-3a-carboxylate sulfone having the formula <br><br> -NH, <br><br> /) 0 <br><br> .N. <br><br> CKj <br><br> CHj <br><br> C=0 <br><br> J? <br><br> 0 0 <br><br> .CH2C1 <br><br> J* — <br><br> *CH, <br><br> ii <br><br> 0 <br><br> CH, <br><br> is produced by substituting the corresponding Dane salt of amoxicillin for the ampicillin used in the procedure of Example 21. <br><br> - 67 - <br><br> 196055 <br><br> BIOLOGICAL DATA <br><br> The product of Example 1, Compound 5&gt; having the structure ch2CI <br><br> will be referred to below as BL-P2013. <br><br> Although at best a very veak antibacterial agent itself, BL-P2013 inhibits ^-lactamases and protected ceforanide and amoxicillin from destruction by 0-lactamase-producing bacteria in vitro and in vivo when used in combination vith those two agents. Ceforanide has the formula <br><br> 3 -'v i ch2NH2 <br><br> 'CH CGN&amp; <br><br> /s\ <br><br> N N <br><br> CH„S <br><br> NJ. " I <br><br> CH2C02H <br><br> (78-(o-aminomethylphenylacetamido)-3-(l-carboxymethyltetrazol-5-yl-thiomethyl)-3-cephem-4-carboxylic acid). <br><br> -68- <br><br> 1960 5 5 <br><br> Table 1 <br><br> Antibacterial Activity of the New Sulfone <br><br> MIC <br><br> (mcg/ml) <br><br> Organism <br><br> BL-P2013 <br><br> Ampicillin <br><br> S. pneumoniae <br><br> A-9585 <br><br> 16 <br><br> 0.004 <br><br> S. pyogenes <br><br> A-9604 <br><br> 63 <br><br> 0.004 <br><br> S. aureus <br><br> A-9537 <br><br> &gt;125 <br><br> 0.16 <br><br> S. aureus + 50% serum <br><br> A-9537 <br><br> &gt;125 <br><br> 0.06 <br><br> S. aureus Pen-Res <br><br> A—9606 <br><br> &gt;125 <br><br> &gt;125 <br><br> S. aureus Meth-Res <br><br> A15097 <br><br> &gt;125 <br><br> 125 <br><br> S. faecalis <br><br> A20688 <br><br> &gt;125 <br><br> 0.13 <br><br> E. coli <br><br> A15119 <br><br> &gt;125 <br><br> 1 <br><br> E. coli <br><br> A20341-1 <br><br> &gt;125 <br><br> &gt;125 <br><br> K. pneumon iae <br><br> A15130 <br><br> &gt;125 <br><br> 125 <br><br> K. pneumoniae <br><br> A20468 <br><br> &gt;125 <br><br> &gt;125 <br><br> P. mirabilis <br><br> A—9900 <br><br> &gt;125 <br><br> 0.13 <br><br> P. vulgaris <br><br> A21559 <br><br> &gt;125 <br><br> 125 <br><br> P. morganii <br><br> A15153 <br><br> &gt;125 <br><br> &gt;125 <br><br> P. rettgeri <br><br> A21203 <br><br> &gt;12 5 <br><br> 4 <br><br> S. marcescens <br><br> A20019 <br><br> &gt;125 <br><br> 16 ; <br><br> E. cloacae <br><br> A-9659 <br><br> &gt;125 <br><br> 63 <br><br> E. cloacae <br><br> A-9656 <br><br> &gt;125 <br><br> &gt;125 <br><br> P. aeruginosa <br><br> A—9843A <br><br> &gt;125 <br><br> &gt;125 <br><br> P. aeruginosa <br><br> A21213 <br><br> &gt;125 <br><br> &gt;125 <br><br> -69- <br><br> 1960 5 5 <br><br> Table 2 <br><br> Anti-Bacteroides Activity of Ceforanide and Amoxicillin Alone and in Combination with BL-P2013 <br><br> Beta- <br><br> MIC imcg/ml) * <br><br> Organism lact-amase <br><br> Ceforanide <br><br> Ceforanide +BL-P2013 (1:1) <br><br> BL-P 2013 <br><br> Amoxicillin +BL-P2013 (1:1) <br><br> Amoxi-cillir <br><br> B. fragilis <br><br> A21916 <br><br> + <br><br> 63 <br><br> 2 <br><br> &gt;125 <br><br> 2 <br><br> 8 <br><br> A22053 <br><br> + <br><br> 32 <br><br> 4 <br><br> 63 <br><br> 2_ <br><br> 8 <br><br> A22021 <br><br> + <br><br> 32 <br><br> 2 <br><br> 32 <br><br> _2_ <br><br> 4 <br><br> A21875 <br><br> + <br><br> 32 <br><br> £ <br><br> 63 <br><br> 2 <br><br> 8 <br><br> A22534 <br><br> + <br><br> &gt;125 <br><br> 32 <br><br> 125 <br><br> 16 <br><br> &gt;125 <br><br> A22697 <br><br> + <br><br> 63 <br><br> a <br><br> 63 <br><br> 2_ <br><br> 8 <br><br> A22693 <br><br> + <br><br> 63 <br><br> 4 <br><br> 63 <br><br> 2_ <br><br> 16 <br><br> A22694 <br><br> + <br><br> 125 <br><br> 16 <br><br> 63 <br><br> 2 <br><br> 16 <br><br> A22695 <br><br> + <br><br> &gt;125 <br><br> _1_6_ <br><br> 32 <br><br> 4_ <br><br> 125 <br><br> A22696 <br><br> + <br><br> &gt;125 <br><br> _32_ <br><br> 63 <br><br> £ <br><br> &gt;125 <br><br> A22533 <br><br> + <br><br> &gt;125 <br><br> _32_ <br><br> 32 <br><br> 32 <br><br> &gt;125 <br><br> A22535 <br><br> + <br><br> &gt;125 <br><br> 125 <br><br> 11 <br><br> &gt;125 <br><br> A22792 <br><br> + <br><br> &gt;125 <br><br> £ <br><br> 32 <br><br> £ <br><br> 125 <br><br> A22793 <br><br> + <br><br> 32 <br><br> £ <br><br> 32 <br><br> 2 <br><br> 8 <br><br> A22794 <br><br> + <br><br> 32 <br><br> 4 <br><br> 32 <br><br> 2 <br><br> 8 <br><br> A22795 <br><br> + <br><br> 63 <br><br> 32 <br><br> 4 <br><br> 16 <br><br> A22797 <br><br> + <br><br> 63 <br><br> 63 <br><br> 2 <br><br> 16 <br><br> A22798 <br><br> + <br><br> 32 <br><br> 4 <br><br> 63 <br><br> 2_ <br><br> 8 <br><br> B. theta-iotaomic-ron A2227" <br><br> + <br><br> 125 <br><br> 4 <br><br> 63 <br><br> 2 <br><br> 16 <br><br> A2227S <br><br> + <br><br> 125 <br><br> £ <br><br> 63 <br><br> 4 <br><br> 16 <br><br> -70- <br><br> 1960 5 5 <br><br> Table 2 - cont'd. <br><br> Anti-Bacteroides Activity of Ceforanide and Amoxicillin Alone and in Combination with BL-P2013 <br><br> Beta- <br><br> MIC (mcg/ml)* <br><br> Organism lact-amase <br><br> Ceforanide <br><br> Ceforanide +BL-P2013 (1:1) <br><br> BL-P 2013 <br><br> Amoxicillin +BL-P2013 (1:1) <br><br> Amoxicillin <br><br> Bacteroides species <br><br> A2093^ <br><br> + <br><br> 32 <br><br> 4 <br><br> 32 <br><br> 2 <br><br> 8 <br><br> A21959 <br><br> + <br><br> 63 <br><br> 4 <br><br> 32 <br><br> 2 <br><br> 16 <br><br> A2092S <br><br> + <br><br> 63 <br><br> 4 <br><br> 32 <br><br> 2 <br><br> 16 <br><br> A21954 <br><br> + <br><br> 63 <br><br> 16 <br><br> 63 <br><br> 2 <br><br> 16 <br><br> A20932 <br><br> + <br><br> 63 <br><br> 16 <br><br> 63 <br><br> _ 4_ <br><br> 8 <br><br> A2093( <br><br> + <br><br> 125 <br><br> 8 <br><br> 125 <br><br> 4 <br><br> 32 <br><br> A20933 <br><br> + <br><br> 63 <br><br> 4 <br><br> 32 <br><br> 2 <br><br> 16 <br><br> A20927-] <br><br> 0.5 <br><br> 1 <br><br> 63 <br><br> 0.13 <br><br> 0.13 <br><br> A2093! <br><br> — <br><br> 2 <br><br> 2 <br><br> 125 <br><br> 0.13 <br><br> 0.13 <br><br> good synergism marginal synergism <br><br> ♦Minimum inhibitory concentration (MIC) determined by the agar dilution method using 50X dilutions of 24 hour cultures as inocula dispensed by the Steer's inoculator. Assay medium composed of Brucella Agar plus 5% laked sheep blood and 10 mcg/ml vitamin K. <br><br> -71- <br><br> 1960 5 5 <br><br> Table 3 <br><br> Therapeutic Efficacy of Amoxicillin in Combination with BL-P2013 in Mice Experimentally Infected with a Beta-Lactaxnase Strain of Staphylococcus aureus <br><br> Organism <br><br> Challenge (No. of Organisms) <br><br> PD^q/Treatment (mg/kg) <br><br> Amoxicillin (A) IM PO <br><br> BL-P2 013 (B) IM PO <br><br> A+B (1:1) IM PO <br><br> S. aureus A-9606 <br><br> 5 x 108 5 x 108 7 x 108 <br><br> &gt;800 &gt;800 &gt;800 &gt;800 &gt;800 <br><br> &gt;50 &gt;200 &gt;50 &gt;200 &gt;50 <br><br> 6.3 44 19 77 9.6 <br><br> Treatment schedule: Drugs administered 0 and 2 hours postinfection. <br><br> Table 4 <br><br> Blood levels of BL-P2013 and its Pivaloyloxymethyl Ester (BL-P2024) After Oral Administration to Mice <br><br> Compound <br><br> Dose (mg/kg) <br><br> Blood 15 30 Minutes <br><br> Level <br><br> 60 After <br><br> (yg/ml) <br><br> 90 120 150 Adminis tration <br><br> Half-life (min.) <br><br> Assay Organism <br><br> 100 <br><br> 4.5 <br><br> 5.1 <br><br> 3.9 <br><br> 2.3 <br><br> 1.5 <br><br> 0.8 <br><br> 50 <br><br> E. coli A-9675 <br><br> BL-P2013 <br><br> 100 <br><br> 4.6 <br><br> 4.1 <br><br> 3 <br><br> &lt;2.6 <br><br> &lt;2.6 <br><br> &lt;2.6 <br><br> - <br><br> S. aureus A-9606 <br><br> 200 <br><br> 7.4 <br><br> 9.8 <br><br> 7.1 <br><br> 4.1 <br><br> 2.8 <br><br> &lt;2.6 <br><br> 50 <br><br> S. aureus A-9606 <br><br> 100 <br><br> 12.8 <br><br> 12.9 <br><br> 9.7 <br><br> 7.2 <br><br> 5.5 <br><br> 4.2 <br><br> 70 <br><br> E. coli A-9675 <br><br> BL-P2024 <br><br> 100 <br><br> 13.1 <br><br> 12 <br><br> 8 <br><br> 5.7 <br><br> 3,8 <br><br> &lt;2.5 <br><br> 60 <br><br> S. aureus A-9606 <br><br> 200 <br><br> 14.7 <br><br> 14.4 <br><br> 9.8 <br><br> 8.7 <br><br> 5.1 <br><br> &lt;2.5 <br><br> 60 <br><br> S• aureus A-9606 <br><br> Values represent averages of two to four tests. <br><br> Table 5 <br><br> Blood Levels and Half-Life of BL-P2024 After Oral Administration of Various Doses to Mice <br><br> Compound <br><br> Dose (mg/kg) <br><br> Blood Level (ug/ml) 15 30 60 90 120 <br><br> Minutes After Administration <br><br> 150 <br><br> t 1/2 (min.) <br><br> 25 <br><br> 5.9 <br><br> 6.2 <br><br> 3.6 <br><br> 1.9 <br><br> 1.3 <br><br> 0.7 <br><br> 40 <br><br> BL-P2024 <br><br> 50 <br><br> 7.7 <br><br> 9.5 <br><br> 6.3 <br><br> 4.7 <br><br> 3.5 <br><br> 2.3 <br><br> 60 <br><br> 100 <br><br> 12.3 <br><br> 12.2 <br><br> 9.4 <br><br> 7.2 <br><br> 5.7 <br><br> 4.6 <br><br> 85 <br><br> 200 <br><br> 14.7 <br><br> 14.4 <br><br> 9.8 <br><br> 8.7 <br><br> 5.1 <br><br> &lt;2.5 <br><br> 60 <br><br> BL-P2024 was suspended in Tween-CMC-water. <br><br> Values are averages of 2 experiments for 25 and 50 mg/kg doses, 5 to 6 experiments for the 100 mg/kg dose, and 2 to 3 experiments for the 200 mg/kg dose. <br><br> Assay organism: E. coli A9675 for all doses except for 200 mg/kg of BL-P2024 <br><br> (S. aureus. A9606) . <br><br> Table 6 <br><br> Therapeutic Efficacy of Amoxicillin in Combination with BL-P2013 . in Mice Experimentally Infected with 0-Lactamase Producing Strains of S. aureus and E. coli <br><br> PDgo/Treatment (mg/kg) <br><br> Organism <br><br> (No. of <br><br> Amoxicillin:BL-P2013 <br><br> BL-P <br><br> Organisms) <br><br> Amoxicillin 4:1 <br><br> 2:1 <br><br> 1:1 <br><br> 1 <br><br> :2 <br><br> 1: <br><br> 4 <br><br> 2013 <br><br> S. aureus <br><br> 7 <br><br> x <br><br> 10° <br><br> &gt;200 <br><br> &gt;200 :&gt;50 <br><br> 44:22 <br><br> 33:33 <br><br> 38 <br><br> :76 <br><br> 25 <br><br> :100 <br><br> &gt;200 <br><br> A9606 <br><br> 2 <br><br> x <br><br> 109 <br><br> &gt;800 <br><br> 33:17 <br><br> 14:14 <br><br> 10 <br><br> : 20 <br><br> &gt;200 <br><br> S. aureus <br><br> 4 <br><br> x <br><br> 108 <br><br> &gt;200 <br><br> 132:66 <br><br> 78:39 <br><br> 44:44 <br><br> &gt;200 <br><br> A15091 <br><br> 5 <br><br> x <br><br> 108 <br><br> &gt;800 <br><br> 114:57 <br><br> 100:100 <br><br> 66 <br><br> :132 <br><br> &gt;200 <br><br> S. aureus <br><br> 6 <br><br> x <br><br> 108 <br><br> &gt;200 <br><br> 174:44 <br><br> 44:22 <br><br> 25:25 <br><br> 22 <br><br> :44 <br><br> 19 <br><br> :76 <br><br> 174 <br><br> A20379 <br><br> 5 <br><br> x <br><br> 108 <br><br> &gt;200 <br><br> 50:25 <br><br> 43:43 <br><br> 35 <br><br> :70 <br><br> &gt;200 <br><br> E. coli <br><br> 5 <br><br> x <br><br> 105 <br><br> &gt;200 <br><br> 25:6.3 <br><br> 11:5.5 <br><br> 11:11 <br><br> &gt;200 <br><br> A20649 <br><br> 6 <br><br> x <br><br> 105 <br><br> &gt;2%° <br><br> 20:5 <br><br> 8:4 <br><br> 6:6 <br><br> 10 <br><br> :20 <br><br> 63 <br><br> :25 <br><br> &gt;200 <br><br> E. coli <br><br> 7 <br><br> x <br><br> 105 <br><br> &gt;200 <br><br> 6:1.5 <br><br> 6:3 <br><br> 5:5 <br><br> &gt;200 <br><br> A21223 <br><br> 6 <br><br> x <br><br> 105 <br><br> &gt;200 <br><br> 8:2 <br><br> 6:3 <br><br> 6:6 <br><br> 4 <br><br> : 8 <br><br> 3. <br><br> 5:14 , <br><br> &gt;200 <br><br> 7 <br><br> x <br><br> 105 <br><br> &gt;200 <br><br> 7:3.5 <br><br> &gt;200 <br><br> Continued <br><br> Therapeutic Efficacy of Amoxicillin in Combination with BL-P2013 in Mice Experimentally Infected with 0-Lactamase Producing Strains of S. aureus and E. coli <br><br> Challenge (No. of Organisms) <br><br> PD^g/Treatment (mg/kg) <br><br> Organism <br><br> Amoxicillin Amoxicillin 4:1 <br><br> :BL-P2013 2:1 1:1 <br><br> 1:2 1:4 <br><br> BL-P 2013 <br><br> E. coli <br><br> 8 x 105 <br><br> &gt;200 <br><br> 8:2 <br><br> 6:3 3:3 <br><br> 4:8 4:16 <br><br> &gt;200 <br><br> A9675 <br><br> 7 x 105 <br><br> &gt;100 <br><br> 10:2.5 <br><br> 6:3 7:7 <br><br> 2.5:5 <br><br> &gt;100 <br><br> 6 x 105 <br><br> &gt;400 <br><br> 13:3.3 <br><br> 6:3 5:5 <br><br> 5:10 <br><br> &gt;200 <br><br> Treatment schedule: Drugs were administered orally at 0 and 2 hours post-infection. <br><br> Drugs were suspended in TCMC. <br><br> • • • • <br><br> LO LO <br><br> o sO <br><br> Table 7 <br><br> Therapeutic Efficacy of Amoxicillin in Various Combinations with the Pivaloyloxymethyl Ester (BL-P2024) of BL-P2013 in Mice Experimentally Infected with p-Lactamase Producing Strains of S. aureus and E. coli <br><br> Organism <br><br> Challenge (No. of Organisms) <br><br> Drug- . Vehicle <br><br> PDgg/Treatment (mg/kg) a <br><br> Amoxicillin <br><br> Amoxicillin:BL-P2024 4:1 2:1 1:1 <br><br> BL-P 2024 <br><br> S. aureus <br><br> 5 x 108 <br><br> TCMC <br><br> &gt;.800 <br><br> 66:33 57:57 <br><br> &gt;200 <br><br> A15091 <br><br> S. aureus <br><br> 5 x 108 <br><br> TCMC <br><br> &gt;800 <br><br> 12:6 9:9 <br><br> 200 <br><br> A20379 <br><br> E. coli <br><br> 9 x 105 <br><br> 50% <br><br> &gt;100 <br><br> 12:12 6:3 3:3 <br><br> &gt; 25 <br><br> A9675 <br><br> DMSO <br><br> E. coli <br><br> 7 x 105 <br><br> 50% <br><br> &gt;100 <br><br> 10:2.5 7:3.5 4:4 <br><br> &gt; 25 <br><br> A9675 <br><br> DMSO <br><br> E. coli <br><br> 7 x 105 <br><br> TCMC <br><br> &gt;100 <br><br> 8:2 6:3 5:5 <br><br> &gt; 25 <br><br> A9675 <br><br> E. coli <br><br> 6 x 105 <br><br> TCMC <br><br> &gt;400 <br><br> 9*2:2.4 7:3.5 7:7 <br><br> &gt;200 <br><br> A9675 <br><br> a Mice treated orally at 0 and 2 hours post-infection. <br><br> k Amoxicillin:BL-P2024 combinations were soluble in 50% DMSO. Amoxicillin was soluble in TCMC (aqueous Tw^Jp-carboxym^^ylcellulose) whereas BL-P2024 wq^administer^ as a suspension in that vehicle. <br><br> Table 8 <br><br> Oral Mouse Blood Levels of BL-P2036 and BL-P2013 or BL-P2024 <br><br> Test Number 1 <br><br> Compound <br><br> Dose (mg/kg) <br><br> Blood Levels (mcg/ml) <br><br> 15 30 60 90 120 150 Minutes After Administration <br><br> BL-P2036 <br><br> 25 <br><br> 1.7 (1.3-2.3) <br><br> 2.3_ (2-2.6) <br><br> 0.9 <br><br> (0.6-1.3) <br><br> &lt;0.6 <br><br> &lt;0.6 <br><br> &lt;0.6 <br><br> BL-P2036 <br><br> 50 <br><br> 2.8 (1.6-4.8) <br><br> 3.3 (2-5.3) <br><br> 2.5 (1.2-5.3) <br><br> 1.3 (0.7-2.4) <br><br> 0.8 (0.5-1.5) <br><br> &lt;0.6 <br><br> BL-P2036 <br><br> 100 <br><br> 3.6 <br><br> (2.6-4.9) <br><br> , 3.9 (2.9-5.1) <br><br> 3.2 (2.4-4.4) <br><br> 2 <br><br> (1.5-2.7) <br><br> 1.5 (1.1-2.1) <br><br> 0.8 (0.7-1.0) <br><br> BL-P2013 <br><br> 25 <br><br> 1.3 (1.1-1.6) <br><br> 1.4 (1.2-1.6) <br><br> 1.0 (0.8-1.2) <br><br> &lt;0.6 <br><br> &lt;0.6 <br><br> &lt;0.6 <br><br> BL-P2013 <br><br> 50 <br><br> 2.2 <br><br> (1.8-2.7) <br><br> 2.6 (2.1-3.2) <br><br> 1.9 (1.4-2.6) <br><br> 1.5 (1.1-2.1) <br><br> 1.1 (0.8-1.4) <br><br> 0.8 (0.5-1.3) <br><br> BL-P2013 <br><br> 100 <br><br> 3.4 <br><br> (2.1-5.4) <br><br> 4.5 (3.6-5.7) <br><br> (3.4-4.6) <br><br> 3.6 (2.5-5) <br><br> 2.7 (1.7-4.3) <br><br> 2.1 (1.4-3.2) <br><br> Compounds prepared In Tween-CMC-HgO <br><br> Values In parentheses are 95# confidence limits. <br><br> Assay Organism: E. coli a9675 <br><br> (pH = 6.69 0.1# inoculum) <br><br> Test Number 2 <br><br> Compound <br><br> Dose <br><br> (mgAg) <br><br> Blood Levels (mcg/ml) <br><br> 15 30 60 90 120 150 Minutes After Administration <br><br> BL-P2024 <br><br> 25 <br><br> ^•7 <br><br> (2.6-5.5) <br><br> 4.3 (3-6.2) <br><br> (0.9-5-8) <br><br> 0.8 (0.4-1.8) <br><br> &lt;0.6 <br><br> &gt;0.6 <br><br> BL-P2024 <br><br> 50 <br><br> 5 <br><br> (0.8-33-3) <br><br> 4.5 (1.5-13.4) <br><br> *&gt;9 (2.4-9.8) <br><br> 3.6 (3.1-4.1) <br><br> 2.6 (1.5-4.3) <br><br> 1.7 (0.9-3.1) <br><br> BL-P2024 <br><br> 100 <br><br> 8.3 <br><br> (5.5-12.6) <br><br> 9.5 (5.2-17.5) <br><br> 7.8 (4.2-14.3) <br><br> 4.8 (3-4-6.7) <br><br> (2^2-6.8) <br><br> (2.8-5) <br><br> BL-P2036 <br><br> 25 <br><br> 3.6 (2.2-5.9) <br><br> 3.3 (2.2-4.7) <br><br> 2.1 (1.6-2.8) <br><br> 1.4 (0.7-2.8) <br><br> 0.8 (0.4-1.7) <br><br> &lt;0.6 <br><br> BL-P2036 <br><br> 50 <br><br> 4.0 (3-5.3) <br><br> 3.6 <br><br> (1.4-9) <br><br> 2 2 <br><br> (1.4-3.7) <br><br> 2.1 (1.3-3.6) <br><br> 1.5 (O.6-3.6) <br><br> 1.0 (0.5-2.4) <br><br> BL-P2036 <br><br> 100 <br><br> 4.9 (3.7-6.5) <br><br> 6.5 (3.7-11.5) <br><br> 4.5 (3.4-5.9) <br><br> 2.8 (2.2-3.6) <br><br> 1.9 (1-3.7) <br><br> 1.3 (0.4-4) <br><br> Compounds prepared in 5# Propylene Glycol &amp; Tween-CMC-HgO Values in parentheses are 95$ confidence limits. <br><br> Assay Organism: E. coli A9^75 <br><br> (pH = 6.6, 0.1# inoculum) <br><br> Test Number 3 <br><br> Compound <br><br> | Dose j (mgAg) <br><br> Blood Levels (mcg/ml) <br><br> 15 30 60 90 120 150 Minutes After Administration <br><br> BL-P2013 <br><br> 25 <br><br> 1.4 (1.1-1.9) <br><br> 2.0 <br><br> (1.5-2.6) <br><br> 1.4 (0.9-2.1) <br><br> 1.2 (0.6-2.3) <br><br> ■ , &lt; 1.2 <br><br> &lt;1.2 <br><br> BL-P2013 <br><br> 50 <br><br> 4.6 (3-6.9) <br><br> 5.5 <br><br> (3-10.1) <br><br> 3.6 (2-6.4) <br><br> 3.1 (1.7-5.7) <br><br> (028-5) <br><br> 1.1 (0.8-1.5) <br><br> BL-P2013 <br><br> 100 <br><br> 6.8 (4.8-9.6) <br><br> 11.5 (7.3-18) <br><br> 6.4 <br><br> (3.2-12.8) <br><br> 4.2 (2.1-8.6) <br><br> 3.3 _ (1.4-7.6) <br><br> 2'§ <br><br> (0.7-8.9) <br><br> BL-P2036 <br><br> 25 <br><br> 4.3 (2.9-6.5) <br><br> 4.5 <br><br> (2.2-9.2) <br><br> 3.5 (1.7-7.2) <br><br> 2*5 0 (1.3-4.8) <br><br> 2.2 <br><br> (1-4.9) <br><br> 2.0 (1-3.7) <br><br> BL-P2036 <br><br> 50 <br><br> 4.6 (2.3-9.2) <br><br> 4.8 (3.3-7.1) <br><br> 3-5 (1.8-7) <br><br> 2.2 (1.2-4) <br><br> 1.9 (1.2-3) <br><br> 1.8 (0.3-4.6) <br><br> BL-P2036 <br><br> 100 <br><br> (3.1-16.2) <br><br> 6.7 (3.6-12.3) <br><br> 5.8 (3.9-8.5) <br><br> 4.3 (3-6) <br><br> 4 <br><br> (2.8-5.6) <br><br> S'7 <br><br> (1.8-4) <br><br> Compounds prepared in 5# Propylene Glycol &amp; Tween-CMC-H20. Values in parentheses are 95# confidence limits. <br><br> Assay Organism: E. coll A9675 <br><br> (pH = 6.6, 0.1# inoculum) <br><br> -80- <br><br> 19605 <br><br> The compounds of the present invention are thus useful, given orally and parenterally, for enhancing the effectiveness of (J-lactam antibiotics against 8-lactamase producing bacteria. On a weight basis, the dosage is from one-fifth to five times, and preferably equal to, that of the B-lactam antibiotics. As an example, the compounds of the present invention as shown above when used in a 1:1 ratio markedly improved the activity of ceforanide and amoxicillin against p-lactamase producing strains of anaerobic Bacteroides such as B. fragilis, B. thetaiotaomicron and other species of that genus and also against resistant Staphylococcus aureus. The compounds of the present invention are given either in admixture with or concomitantly with the B-lactara antibiotic with the dosage within the indicated ratio to the known. and customary dosage of the antibiotic. <br><br> Thus, the ability of the compounds of the present invention to enhance the effectiveness of a B-lactam antibiotic against certain 8-lactamase-producing bacteria makes them valuable for co-administration with certain B-lactam antibiotics in the treatment of bacterial infections in mammals, particularly man. In the treatment of a bacterial infection, a compound of the present invention can be co-mingled with the B-lactam antibiotic, and the two agents thereby administered simultaneously. Alternatively, a compound of the present invention can be administered as a separate agent during a course of treatment with a B-lactam antibiotic. <br><br> -81- <br><br> 196055 <br><br> When using a compound of the present invention or salt thereof, to enhance the antibacterial activity of a. 3-lactam antibiotic, it can be administered alone, or preferably, in formulation with standard pharmaceutical carriers and diluents. A compound of the present invention which is in the acid form or as a pharmaceutically-acceptable salt thereof, can be administered orally or parenterally; a compound of the present invention in the form of an ester which is readily hydrolyzable in vivo, is best administered orally. Parenteral administration includes intramuscular, subcutaneous, intraperitoneal and intravenous administration. <br><br> When a compound of the present invention is used in the presence of a carrier or diluent, said carrier or diluent is chosen on the basis of the intended mode of administration. For example, when considering the oral mode of administration, the compound can be used in the form of tablets, capsules, lozenges, troches, powders, <br><br> syrups, elixirs, aqueous solutions and suspensions, and the like, in accordance with standard pharmaceutical practice. <br><br> The proportional ratio of active ingredients to carrier will naturally depend on the chemical nature, solubility, <br><br> stability and potency of the active ingredients, as well as the dosage contemplated. However, these pharmaceutical compositions will likely contain from about 5% to about 80% of carrier. In the case of tablets for oral use, <br><br> carriers which are commonly used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are commonly used in tablets- For oral administration in capsule form, useful diluents are lactose and high molecular weight <br><br></p> </div>

Claims (3)

<div class="application article clearfix printTableText" id="claims"> <p lang="en"> -82-<br><br> 196055<br><br> polyethylene glycols. When aqueous suspensions are required for oxral use, the active ingredients are combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For parenteral administration, which includes intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredients are usually prepared, and the pH or the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic.<br><br> Although the prescribing physician will ultimately decide the dosage to be used in a human subject, the ratio of the daily dosages of a compound of the present invention, or salt thereof, and the B-lactam antibiotic will normally be in the range from about 1:5 to 5:1, and preferably about 1:1. Additionally, the daily oral dosage of each component will normally be in the range from about 10 to about 200 mg. per kilogram of body weight and the daily parenteral dosage of each component will normally be about 10 to about 100 mg. per kilogram of body weight. These figures are illustrative only, however, and in some cases it may be necessary to use dosages outside these limits.<br><br> This invention is capable of industrial application.<br><br> -83-<br><br> WHAT WE CLAIM IS:<br><br> 1. The acid having the formula o o<br><br> cooh or a pharmaceutically acceptable salt of said acid or a physiologically hydrolyzable ester of said acid.<br><br> 2. An ester of claim 1 selected from the group consisting of the phenacyl, acetoxymethyl, pivaloyloxymethyl, a-acetoxyethyl, a-acetoxybenzyl, a-pivaloyloxyethyl, 3-phthalidyl, 5-indanyl, methoxy-methyl, benzoyloxymethyl, a-ethylbutyryloxymethyl, propionyloxymethyl, valeryloxymethyl, isobutyryloxy-methyl, 6-1(r)-2-amino-2-phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo [3.2.0] -heptane-2-carbonyloxy-methyland 6-[(R)-2-amino-2-p-hydroxyphenylacetamido] -3, 3-dimethyl-7-oxo-4-thia-l-azabicycloI3.2.0] heptane-2-carbonyloxymethyl esters.<br><br> 3. The ester of Claim 2 which is the 6-[(R)-2-amino-2-phenylacetamido] -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo 13.2.0] heptane-2-carbonyloxyme thy 1 ester.<br><br> 4. The ester of Claim 2 which is the 6-[(R)-2-amino-2-p-hydroxyphenylacetamido] -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carbonylmethyl ester.<br><br> --84-<br><br> 1960 5 5<br><br> 5. An ester having the formula<br><br> R—CH—CO -NH<br><br> NHg<br><br> 'C<br><br> :H3 *3<br><br> °* 0<br><br> ^ 0"N Y CHgCl r<br><br> 4<br><br> o<br><br> -N<br><br> t<br><br> C-<br><br> II<br><br> 0<br><br> CH.<br><br> C=0<br><br> 0<br><br>
1<br><br> CH,<br><br> or R<br><br> ,2 .<br><br> O.' O-. O"' O"<br><br> wherein R"*" is hydrogen or hydroxy and<br><br> R is hydrogen, hydroxy, methyl, methoxy or chloro.<br><br> -85-<br><br> 6. A process for the preparation of the compounds as claimed in claims 1-4 which comprises the consecutive steps of a) catalytically hydrogenating an ester having the formula<br><br> X CH_C1<br><br> rrfi<br><br> \ N K 1<br><br> /- CO,R<br><br> O 2<br><br> wherein is benzyl or substituted benzyl and then b) subjecting the hydrogenated product to oxidation to produce said desired acid sulfone or salt thereof and then, if desired,<br><br> c) esterifving said acid or salt thereof to produce a physiologically hydrolyzable ester of said acid.<br><br> 7. The process according to claim 6 wherein hydrogenation is carried out with a palladium catalyst.<br><br> 8. The process according to claim 6 wherein oxidation is carried out with an alkali metal permanganate or an organic peracid.<br><br> f w<br><br> .21 JUNS984<br><br> -86-<br><br> | O &lt; n q tr i/uujj<br><br> 9. A process for the preparation of the compounds as claimed in claims 1-4 vhich comprises the consecutive steps of a) oxidizing, as with KMnO^, or like peroxide or peracid, an ester having the formula<br><br> Br ° .CHgCl<br><br> % ^.s v"» CHj<br><br> U<br><br> C-OCHgCCl^ 0<br><br> to produce an ester sulphone having the formula<br><br> 0 0<br><br> Br \\ // /V1<br><br> J—]N—%<br><br> 0 C-OCHgCCl^<br><br> 0 and then b) reacting said ester sulphone with a metal in acid, as with zinc in glacial acetic acid, to produce said desired acid or salt and then, if desired,<br><br> c) esterifying said acid or salt thereof to produce a physiologically hydrolyzable ester of said acid.<br><br> -87-<br><br> 10. A process for the preparation of the compounds as claimed in claim 5 which comprises the treatment with acid of a solution of a compound having the formula wherein B is or<br><br> R*<br><br> H*'-V \ 1<br><br> \\ J— (wherein B is hydrogen or hydroxy and<br><br>
2<br><br> R is hydrogen, hydroxy, methyl, methoxy or chloro) and R6 is alkyl, aralkyl or aryl, R7 is hydrogen, alkyl, aralkyl or aryl and R"^ is alkyl, aralkyl, aryl, alkoxy, aralkoxy, or aryloxy or<br><br> -88-<br><br> \96055<br><br>
3-*"<br><br> ^ wherein R and R are each hydrogen, alkyl, aralkyl or aryl or, when taken together with the nitrogen atom, are piperidino or morpholino and said treatment with acid is earned out in an organic solvent or in aqueous or partly agueous 5 solution at room temperature.<br><br> 11. The process of claim 10 wherein R6 is methyl,<br><br> 7 3<br><br> R' is hydrogen and R is methoxy, ethoxy or methyl.<br><br> 12. The process of claim 10 wherein the reaction is carried out in acetone or chloroform.<br><br> 10 13. The process of any one of claims 10-12 wherein the reaction is carried out at a pH between 1 and 5.<br><br> 14. A pharmaceutical composition for enhancing the effectiveness of ^-lactam antibiotics against B-lactamase-producing bacteria, comprising as active<br><br> 15 ingredient the free acid or pharmaceutically acceptable salt of a compound as claimed in claim 1 in the presence of a carrier or diluent.<br><br> 15. An antibacterial composition comprising as active ingredient an ester as claimed in any of claims 2-5.<br><br> 2 0 16. An antibacterial composition comprising as active ingredients the ^-lactamase -inhibiting free acid or pharmaceutically acceptable salt of the acid of claim 1 , in admixture with a ^-lactam antibiotic in the presence of a carrier or diluent.<br><br> -89-<br><br> i o ^ n h R<br><br> • I / O U J J<br><br> 4 * fc<br><br> 17. The composition of claim 16 wherein the B-lactam antibiotic is ceforanide, ampicillin or amoxicillin.<br><br> Of<br><br> 18. The composition of claims 16 -and- 17 wherein the ratio of active ingredients is from 1:5 to 5:1 by weight.<br><br> or<br><br> 19. The composition of claims 16 and 17 -wherein the ratio of active ingredients is about 1:1 by weight.<br><br> 20. The,method of enhancing the effectiveness of B-lactam antibiotics for treatment of non-human mammals against #-lactamase-producing bacteria, caiprising administering a free acid or pharmaceutically acceptable salt of a compound as claimed in claim 1.<br><br> in non-human maitmals<br><br> 21. The method of treating infectious diseases/which comprises administering an antibacterially effective amount of an ester as claimed in any of claims 2-5.<br><br> in non-human mammals<br><br> 22. The method of treating infectious diseases/which comprises co-administering an antibacterially effective amount of the free acid or pharmaceutically acceptable salt of the acid as claimed in claim 1 with a B-lactam antibiotic.<br><br> 23. The method of claim 22 wherein the B-lactam antibiotic is ceforanide, ampicillin or amoxicillin.<br><br> 24. The method of claim 22 or 23 wherein the ratio of active ingredients administered is from 1:5 to 5:1 by weight.<br><br> 25. The method of claim 22 or 23 wherein the ratio of active ingredients is about 1:1 by weight.<br><br> -90-<br><br> 1960 5 5<br><br> 26. An ester having the formula<br><br> Br*<br><br> (y<br><br> •S\&gt;^H2C1<br><br> T0R<br><br> wherein R is benzyl or p-nitrobenzyl.<br><br> 27. An ester having the formula<br><br> Br<br><br> ch2c1<br><br> 'ch.<br><br> "C-OR<br><br> wherein R is benzyl, p-nitrobenzyl or 3,3,3-trichloroethyl<br><br> 28. The ester of Claim 27 wherein R is 3,3,3-trichloroethyl.<br><br> 29. The ester having the formula<br><br> K<br><br> /~N<br><br> o o xs' ach_ci<br><br> \/ 2<br><br> 'CH.<br><br> C-OCH CC1_ II 2 y<br><br> -91-<br><br> JCM]<br><br> r-. , -■ r r<br><br> ✓ \J w' sj<br><br> 30. A process for the preparation of fe compound as claimed in claim 26 which comprises heating a compound having the forzmla wherein R is benzyl or p-nitrobenzyl in an inert,<br><br> anhydrous organic solvent, in the presence of large, equimolar, amounts of k weak tertiary amine, and an acid chloride, until the reaction is substantially complete.<br><br> 10<br><br> H<br><br> 31. A process ^or the preparation of a compound as claimed in claim 27 or 2B which comprises oxidizing a solution, in an inert solvent, of a compound having the formula wherein R is benzyl, p-rii-rdbenzyl or 3, 0,3-trichloroethyl at about i \ r / /<br><br> room temperature by the use of a peracid.<br><br> -91-<br><br> 196055<br><br> 30. A process for the preparation of a compound as claimed in claim 26 which comprises heating a compound having the fornula wherein R is benzyl or p-nitrobenzyl in an inert,<br><br> anhydrous organic solvent, in the presence of large, equimolar, amounts of a weak tertiary amine, and an acid chloride, until the reaction is substantially complete.<br><br> 31. A process for the preparation of a compound as claimed in claim 2 7 or 28 which comprises oxidizing a solution, in an inert solvent, of a compound having the formula wherein R is benzyl, p-nitrobenzyl or 3, 3, B-trichloroethyl at about rocm temperature by the use of a peracid.<br><br> 0<br><br> II<br><br> 0<br><br> -92-<br><br> 19G055<br><br> 32. A process for the preparation of a compound as claimed in claim 29 vhich comprises o&gt;:idizing a solution, in an inert solvent, of a compound having the formula at about room temperature by the use of an oxidizing agent such as KMnO^, ^2°2 °r like Peroxide or a peracid.<br><br> 33. Compounds as claimed in claim 1 as particularly described herein.<br><br> 34. A process for producing compounds as claimed in claim 1 substantially as herein described with reference to the examples.<br><br> 35. A pharmaceutical composition as claimed in claim 14 substantially as herein described.<br><br> 36. An antibacterial composition as claimed in claim 15 substantially as herein described.<br><br> 37. An antibacterial composition as claimed in claim 16 substantially as herein described.<br><br> II<br><br> 0<br><br> </p> </div>
NZ196055A 1980-01-21 1981-01-20 2beta-chloromethyl-2alpha-methylpenam-3alpha-carboxylic acid sulphone,esters thereof,pharmaceutical compositions,and intermediates NZ196055A (en)

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US4406887A (en) * 1981-10-13 1983-09-27 Bristol-Myers Company Method for treating resistant bacteria including anaerobes
JPS58185589A (en) * 1982-04-23 1983-10-29 Taiho Yakuhin Kogyo Kk Penicillin derivative and preparation thereof
US4496484A (en) * 1983-04-22 1985-01-29 Taiho Pharmaceutical Company, Limited Penicillin derivatives
EP0232966B1 (en) * 1986-01-17 1997-10-08 Beecham Group Plc Process for the preparation of penem compounds and intermediates for this preparation
JP2603082B2 (en) * 1987-09-07 1997-04-23 大塚化学株式会社 Method for producing penicillanic acid derivative

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US4241050A (en) * 1978-09-01 1980-12-23 Pfizer Inc. Penam 1,1-dioxides as beta-lactamase inhibitors
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YU92483A (en) 1983-12-31
FR2482103A1 (en) 1981-11-13
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KR840002214B1 (en) 1984-12-03
YU14481A (en) 1983-10-31
IE51078B1 (en) 1986-10-01
YU45556B (en) 1992-05-28
ATA23381A (en) 1982-11-15
GR73512B (en) 1984-03-08
ES8204436A1 (en) 1982-05-01
AT371469B (en) 1983-06-27
FR2482103B1 (en) 1983-03-25
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ZA81306B (en) 1982-02-24
ES8501405A1 (en) 1984-12-01
ES498717A0 (en) 1982-05-01
AU6651481A (en) 1981-07-30
FI67553B (en) 1984-12-31
ES508347A0 (en) 1984-12-01
FR2491071B1 (en) 1984-04-27
YU44195B (en) 1990-04-30
YU217583A (en) 1986-06-30
PT72373B (en) 1982-07-23
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FI810121L (en) 1981-07-22
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AU3183384A (en) 1984-11-29
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