US3869449A - New penicillin esters, salts thereof, and methods for their preparation - Google Patents

New penicillin esters, salts thereof, and methods for their preparation Download PDF

Info

Publication number
US3869449A
US3869449A US243855A US24385572A US3869449A US 3869449 A US3869449 A US 3869449A US 243855 A US243855 A US 243855A US 24385572 A US24385572 A US 24385572A US 3869449 A US3869449 A US 3869449A
Authority
US
United States
Prior art keywords
ether
acid
formula
compounds
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US243855A
Other languages
English (en)
Inventor
Wagn Ole Godtfredsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leo Pharma AS
Original Assignee
Leo Pharmaceutical Products Ltd AS
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 Leo Pharmaceutical Products Ltd AS filed Critical Leo Pharmaceutical Products Ltd AS
Application granted granted Critical
Publication of US3869449A publication Critical patent/US3869449A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated 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

Definitions

  • R and R represent an alkyl radical having 1 1 References (mid from 1 to 6 carbon atoms, a cycloalkyl or cycloalkylal- UNITED STATES PATENTS kyl radical the cycloalkyl part having from 3 to 10 car- 3,669,978 0/1972 Deist .7 200/2391 bon atoms, or 1 nd R2 t gether ith the nitrogen 3,704,290 11/1972 Hou et a1 v 260/239.1 atom represent a heterocyclic ring with from 4 to 8 3.770.722 11/1973 Bright 260/239.1 carbon atoms; R represents radicals known from nat- FOREIGN PATENTS OR APPLICATIONS ural, biosynthetic, and semisynthetic penicillins; and 2.055.531 5/1971 Germany 260/239.1 pharmaceuncany acceptable salts thereof OTHER PUBLICATIONS Lund, Chemical Abstract 75: 49070k of Ger.
  • the new compounds are efficiently absorbed from the gastrointestinal tract and after the absorption they are rapidly transformed into the corresponding free penicillins and amidinopenicillanic acids, whereby a broad-spectrum infection can be combated.
  • the new penicillin esters have the general formula I:
  • R, and R represent an'alkyl radical having from 1 to 6 carbon atoms, a cycloalkylor cycloalkylalkyl radical the cycloalkyl part having from 3 to carbon atoms, or R and R together with thenitrogen atom represent a heterocyclic ring with from 4 to 8 carbon atoms.
  • R, and R which may be the same or different represent e.g.
  • radicals R and R may be further substituted with halogen atoms, an alkyl, hydroxy, alkoxy, alkylthio group, an acyl group, a carboxy, carbalkoxy, carbamyl, carbamido, cyano or sulfonyl group, or aminoor substituted amino group.
  • R represents radicals known from natural, biosynthetic and semisynthetic penicillins.
  • Such radicals are e.g. benzyl, phenoxymethyl, 2,6-dimethoxyphenyl, a-azidobenzyl, a-aminobenzyl, a-carboxybenzyl, a-phenoxyethyl, a-phenoxypropyl, 3-phenyl-5-methyl- 4-isoxazolyl, 3-(2-chlorphenyl)-5-methyl-4-isoxazolyl, 3-(2,6-dichlorophenyl)5-methyl-4-isoxazolyl, 3-(2- chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl, 2- ethoxy-l-naphtyl, Z-thienylmethyl, 3-thienylmethyl and a-(3-guanyll-ureido)-benzyl.
  • the salts of the new compounds are salts with inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, maleic acid, p-(N,N-dipropylsulfamyl)-benzoic acid and the like acids.
  • R R and R contain asymmetric carbon atoms the compounds of the invention will exist in different diastereoisomeric forms and the invention comprises all of these forms as well as mixtures thereof.
  • the form in which the compounds are obtained depends on which enantiomer of the starting materials and which method is used to make the compounds.
  • the mixtures of the diastereoisomers may be separated by fractional crystallization or other known methods.
  • the compounds of the invention are efficiently absorbed from the gastrointestinal tract and after the absorption they are rapidly transformed into the corresponding free penicillins and amidinopenicillanic acids, either spontaneously or under the influence of enzymes present in the body.
  • the new esters of the invention give rise to high concentrations of the corresponding free penicillins and amidinopenicillanic acids in the blood and tissues due to efficient absorption combined with rapid hydrolysis in the organism, whereby a broadspectrum infection can be combated, due to the fact that the amidinopenicillins possess strong antibacterial effect especially on gramnegative bacteria.
  • the compounds of formula (l) are well tolerated compounds which are administered in clinical practice either as such or, preferably, in the form of one of their salts mixed with carriers and/or auxiliary agents and in any suitable form of pharmaceutical presentation for oral use, such as tablets, pills or dragees, or can be filled in medical containers such as capsules, or as far as suspensions are concerned, filled into bottles.
  • Pharmaceutical organic or inorganic, solid or liquid carriers suitable for oral administration can be used to make up the composition.
  • Gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal fats and oils, gum, polyalkylene glycol, or other known carriers for medicaments are all suitable as carriers.
  • the preferred salt of the esters is the hydrochloride, but salts with other inorganic or organic acids may be used as mentioned above.
  • the compositions may contain other pharmaceutically active components which can appropriately be administered together with the ester in the treatment of the infectious diseases.
  • the compounds of the invention can be prepared by several methods.
  • a salt of a penicillin of the general formula ll is reacted with a compound of the general formula III in which formulae R is as defined above, X is a cation such as potassium, sodium, ammonium or trialkylammonium ion and Y represents a bromine atom, or iodine atom, an alkylsulphonyloxy group or an arylsulphonyloxy group, preferably in an inert organic solvent, e.g. dimethylformamide or acetone. and at room temperature or at slightly elevated temperatures,
  • X is a cation such as potassium, sodium, ammonium or trialkylammonium ion
  • Y represents a bromine atom, or iodine atom, an alkylsulphonyloxy group or an arylsulphonyloxy group, preferably in an inert organic solvent, e.g. dimethylformamide or acetone.
  • Section A Devoted to the Intermediates of Formula V and their Method of Making
  • This invention relates to once unknown derivatives of 6-aminopenicillanic acid, to pharmaceutically acceptable salts thereof, and to methods for the production of these same compounds.
  • the compounds of the invention have the general formula:
  • R and R represents the same or different substituents and each represents an aliphatic hydrocarbon radical, an aralkyl radical, a cycloalkyl radical, a cycloalkyl-alkyl radical, a heterocyclicically substituted alkyl radical; R and R together with the nitrogen atom represent a ring system; R and R together with the NC atoms represent a ring system; R can furthermore be hydrogen or have the same meaning'as R R represents a hydroxyl group, an esterified hydroxyl group, or a substituted or unsubstituted amino group radical.
  • R R and R represent an aliphatic hydrocarbon radical in which the carbon chain can be straight or branched, saturated or unsaturated, and may be interrupted by an oxygen or sulphur atom, such as methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tert. butyl, pentyl, hexyl, dodecyl allyl, butenyl, pentenyl, propargyl, methoxyethyl, ethoxyethyl, methylthioethyl and the like; an aralkyl radical, such as monoor bicyclic aralkyl radical, e.g.
  • R represents a hydroxyl group, a substituted hydroxyl group 0R in which R stands for an alkyl radical, aryl radical, aralkyl radical, an alkyl radical substituted with alkoxy, alkanoyl, aroyl, cyano, or a carbalkoxy group, e.g.
  • R further represents an acyloxymethyl radical the acyl part of which being an aliphatic, alicyclic, aromatic, ar-aliphatic or heterocyclic radical, such as acetyl, propionyl, butyryl, pivaloyl, cyclohexylacetyl, benzoyl, phenylacetyl, picolinyl, nicotinyl, furylacetyl, thienylacetyl etc., or R can represent an NR R radical, in which R and R are hydrogen, or have the same meanings as defined for R or together with the nitrogen atom form a ring in the same manner as defined for R R N.
  • the compounds of formula Ia may be isolated as such or in the form of a salt with a pharmaceutically acceptable acid, such as hydrochloric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc.
  • a pharmaceutically acceptable acid such as hydrochloric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, citric acid, tartaric acid, maleic acid, etc.
  • R stands for a hydroxyl group
  • the compounds of formula Ia may be isolated as the acid and as a salt thereof, preferably the alkali metal salts and the ammonium salts.
  • the invention comprises all possible isomeric forms of the compound of formula la.
  • the invention also comprises methods for the preparation of the above described compounds.
  • the compounds of formula Ia are prepared in two steps from amides of the general formula II:
  • Hal stands for halogen, preferably chlorine or bromine.
  • All well-known halogenating agents can be used, but it is preferable to use halogenating agents, which .throughout the course of the reaction form gaseous byproducts, such as phosgene or oxalyl chloride or bromide but also others, eg thionyl halides, may be used.
  • the reaction can be performed in inert, dry, organic solvents, e.g. ether or toluene, in which the amide halide in most cases will be insoluble and from which it can be isolated by filtration after the reaction is completed.
  • the compounds of formula III are hygroscopic and rather unstable and are therefore preferably used in the next step without purification.
  • R., has the meaning defined above.
  • the reaction is performed at low temperature and in inert organic solvents, which are dry and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the amide halide isinsoluble, e.g. ether, may be used as well.
  • the reaction is performed under cooling and in the presence of at least one equivalent of a tertiary amine. In the case where one equivalent of the tertiary amine is used, the reaction product will be isolated as the hydro halide, whereas the free amidines will be obtained when two or more equivalents of the tertiary amine are used.
  • the reaction time depends on the reactants, the temperature and the solvents used in the process.
  • R.,, stands for a hydroxyl group
  • the preparation of the trimethylsilyl ester of 6-aminopenicillanic acid is known from the literature.
  • the trimethylsilylester of the amidine is preferably cleaved by a hydrolysis or an alcoholysis under mild conditions.
  • reaction products of formula Ia can be purified and isolated in usual manner and may be obtained either in free state or in the form of a salt.
  • the free acid can also be obtained from some of the esters by an enzymatic hydrolysis or a mild hydrogenolysis, and if the 6 free acid is the reaction product the esters and the amides can be prepared therefrom by methods known from the literature.
  • the compounds of formula I'Va are partly known compounds and may be prepared byesterification or amidation of -aminopenicillanic acid or a protected -aminopenicillanic acid, such as the 6-trityl derivative thereof.
  • the tritylgroup may be split off after the reaction under conditions not affecting the lactam ring. They can also be prepared by es'terification or amidation of the generally industrially used penicillins, whereafter the acyl side chain can be split off chemically or enzymatically under such conditions that the ester group or the amide group is not affected.
  • the starting material N-formyllhexamethyleneimine was prepared from hexamethyleneimine and chloral and had a boiling point of lll-l l2/1O mm Hg.
  • EXAMPLE 3a Pivaloyloxymethyl 6-( N,N-dimethylphenylacetamidino-N') penicillanate nitrate.
  • Cyanomethyl 6-aminopenicillanate was liberated from 4.7 g. of the p-toluenesulfonate according to the procedure of Example 1 and dissolved in 15 ml. of dry, alcohol-free chloroform. Dry triethylamine (3.1 ml.) was added and the solution was cooled to 30 C.. A solution of 1.7 g. crude amide chloride in 15 ml. of dry,
  • EXAMPLE 5a y-Phenylpropyl 6-[(hexahydro-1l-l-azepin-l-yl)- methylene-amine]-penicillanate hydrochloride A. 'y-Phenylpropyl 6-aminopenicillanate.
  • EXAMPLE 6a 6-[(Hexahydro-lH-azepin-1-y1)-methyleneamino]- penicillanic acid A solution of the amide chloride described in 6 1a (4.6 g) in dry, alcohol-free chloroform (20 ml.) was added slowly 5.18 a solution of trimethylsilyl 6- aminopenicillanate (7.2 g.) and triethylamine (3.5 ml.) 20
  • the compounds of formula V111 are described in the following Section B, or perhaps rather subsection.
  • the compounds which it describes are in places-described as the compounds of the invention or the like, but this is merely for convenience in designation and does not mean that they are among those compounds on which a patent is being sought in this application.
  • the suffix b has been appended to them.
  • the compounds of formula Vllb are those of formula V111 when R is hydrogen and R is hydrogen.
  • Section B as to the Compounds of Formula V111
  • This invention relates to a series of penicillin esters, to salts thereof and to methods of their preparation
  • the said penicillin esters have the general formula:
  • R and R are radicals known from bisynthetic, semi-synthetic and naturally occurring penicillins, such as alkyl, aryl or aralkyl radicals optionally substituted with hydroxy and etherified hydroxy, halogen, amino, azido, heterocyclic or spirocyclic radicals, for instance a benzyl radical, a phenoxymethyl radical, a dimethoxyphenyl radical, an alphaazidobenzyl radimethyl, trifluoromethyl, phenyl and benzyl radicals.
  • penicillins such as alkyl, aryl or aralkyl radicals optionally substituted with hydroxy and etherified hydroxy, halogen, amino, azido, heterocyclic or spirocyclic radicals, for instance a benzyl radical, a phenoxymethyl radical, a dimethoxyphenyl radical, an alphaazidobenzyl radimethyl, trifluoromethyl, phenyl and
  • the salts of the said compounds are salts with inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, fumaric acid, maleic acid and the like acids.
  • R and/or R contain asymmetric carbon atoms or when R is different from hydrogen and R different from R the compounds of the invention will exist in different epimeric forms and the invention comprises these epimers as well as mixtures thereof.
  • the form in which the compounds are obtained depends on which enantiomer of the starting materials and which method is used to make the compounds.
  • the mixtures of the epimeric forms may be separated by fractional crystallization or other known methods.
  • the compounds of formula radical, and other radicals containing one or two amino lllb are, f instance, methylene iodide, methylene groups.
  • R and R may represent the same or different mide, chloroidomethane, bismethanesulfonyloxy radicals but at least one of them shall contain an amino 25 methane or bis-toluenesulfonyloxymethane.
  • R a penicillin salt of formula 11b in which R, may be the same as, or different from, the first R thereby intermediate of formula lVb are obtained.
  • These can be converted into the compounds of the invention as described above.
  • the reactions are performed in inert organic solvents such as dimethylformamide or acetone and at room temperature or at slightly elevated temperatures.
  • the intermediates of formula lVb are not isolated but directly converted into the compounds of the invention.
  • the isolation of the reaction products is done in usual manner and if the epimers are to be separated this can be done, for instance, by means of fractional crystallization in suitable solvents.
  • amino groups are present in the R and R radicals, these amino groups are preferably protected during the reactions or are replaced by groups which can be converted to amino groups as a last step of the synthesis.
  • Z is selected from groups which are capable of being converted to an amino group by means of methods mild enough to avoid destruction of the molecule at the ester group or at the lactam ring.
  • 2, is a benzyloxycarbonyl-amino radical, a p-halo-, p-nitro-, or p-methoxy-benzyloxy-carbonylamino radical, a B,B,,8-trichloro-ethoxycarbonyl-amino or an allyloxycarbonyl-amino radical; or 2,, is a sulphur containing radical, such as a tritylsulphenyl-amino or arylsulphenylamino radical, ie an o-nitrophenylsulphenylamino radical; 2;, may also be a tritylamino radical, a-
  • tertiary butoxycarbonyl-amino radical or a radical obtained by reacting the free amino group with a B-dicarbony] compound such as acetylacetone, an acetoacetic ester or benzoylacetone to form enamines or Schiff bases.
  • a B-dicarbony] compound such as acetylacetone, an acetoacetic ester or benzoylacetone to form enamines or Schiff bases.
  • any group represented by 2 which can be converted by reduction, by mild acid hydrolysis or by other mild reactions known per se, into an amino group will be suitable, since experiments have shown that the esters of formula lb formed by the reaction in question are stable under such conditions.
  • the conversion of 2,, into an amino group can be effected by different procedures depending on what 2;, stands for.
  • Catalytic hydrogenation will be preferred when 2,, stands for benzyl-oxycarbonyl-amino and re lated derivatives thereof, and for trityl-amino.
  • This hydrogenation is preferably performed at room temperature and at atmospheric or slightly elevated pressure in a solvent which may be a non-reducible organic solvent or a mixture thereof with water.
  • the preferred catalysts are noble metal catalysts such as palladium or platinum or RaneyNickel, but other catalysts can also be used.
  • Electrolytic reduction can also be used in these cases.
  • 2, stands for a B,B,B-trichloroethoxycarbonylamino radical
  • reduction with zinc in acetic acid is preferred.
  • a mild acid hydrolysis is preferred in the case where 2,, stands for a sulphur-containing radical, an enamine or a Schiff base, for instance at a pH of about 2 in a diluted solution of hydrogen chloride preferably in aqueous tetrahydrofurane.
  • An acid hydrolysis for instance with hydrochloric acid, acetic acid, p-toluenesulfonic acid or trifluoroacetic acid can also be used for elimination of the trityl and tert.butoxycarbonyl radical.
  • lf 2 is an azido or a nitro group or a hydrogen atom, especially a bromime atom, these groups may be transformed into the free amino group in a known manner, the azido and the nitro group by a catalytic hydrogenation with a noble metal catalyst or with Raney-Nickel or by an electrolytic reduction, and the halogen atom by an amination, for instance with hexamethylenetetramine.
  • radicals R and R contain a free hydroxy group it can be protected during the reaction by generally known methods, e.g. by etherification or acylation.
  • the compounds of the invention can also be prepared from 6-aminopenicillanic acid which, in the form of a salt, reacts with the compounds of formula lllb to form an ester of the following formula Vlb:
  • R is as defined above.
  • the amino groups are preferably, but not necessarily, protected for instance with a triphenylmethyl radical and the process can be performed under reaction conditions similar to those described above for the reaction between compounds of formulae llb and llb.
  • 117 is, however, phosphorus pentachloride, because the reaction in this case can be performed at low temperature increasing the stability of the intermediate formed, which presumably is an imino halide.
  • the reaction can be performed in different solvents, but the preferred are chloroform and methylene chloride.
  • the intermediate is not isolated but is treated with an excess ofa primary alcohol to form an imino ether.
  • the reaction temperature and the reaction time depend on the alcohol used; in most cases temperatures from 20C to 20C will be convenient.
  • the esters of 6-aminopenicillanic acid can be isolated from the reaction mixture as such or in the form of a salt with an inorganic or organic acid such as the hydrochloride or the tosylate.
  • Y and Y in the compounds of formula lIlb can be the same or different. If Y is substantially more reactive than Y the reaction will be a two-step process and the first reaction product will be an a-Y ester of 6-amino-penicillanic acid or a protected 6-aminopenicillanic acid. Both these esters and the above described corresponding esters of formula Vb are such compounds which also constitute a part of this invention. It is evident that they are especially valuable intermediates for the preparation of compounds of the invention in which R and R are different.
  • esters of o-aminopenicillanic acid in free or protected form can be reacted with a salt of a penicillin of formula llb whereby, if necessary after elimination of of a protecting group on the amino group, a compound of the following formula Vllb is obtained:
  • the lR-spectrum (CHCl shows strong bands at: 2110,1780, 1690 and 1510 cm
  • the lR-spectrum (KBr) shows strong bands at: 17701790 (broad) and 1690 em
  • the mixture is diluted with ethyl acetate 500 ml.) and ether (500 ml.), filtered, and the filtrate washed with water- (3 X 250 ml.), 0.5 M aqueous sodiumbic'arbonate (l00,ml.), and water (2X 100 ml.).
  • Example lb B performed asde'scribed in Example lb B.
  • the aqueous phase is separated and freeze-dried to afford-the desired compound as a colourless amorphous powder.
  • the IR-spectrum (KBr) shows strongbands at'1.780, 1 690,.15 15, 1495, 1292, 1240, 1205. and 977 cm.
  • the NMR-spectrum (CD OD) shows peaks at 1.45 (S), 1.48 (s) 1.53 (s), 1.60 (s),-4.47 (s), 4.57 (s),-4.'65 (s), 5.17 (s), 5..405.80 (m), 5.95 (s), 6.907.80 (m) g and 7.55. (s), .TMS beingused as internal reference.
  • the crude material is purified by dry column chromatography on silica gel (cycloheXane ethyl acetate 7:3) and'th e pure chloromethyl benzylpenicillinate thus obtained is crystallized from ether'z' petroleum ether to yield colourless crystals with m .p 92 -"93, C..
  • TMS is used as internal reference.
  • the IR-spectrum (CHCl shows strong bands at 2130, 1785, 1668, 1510, 1295 and 980 cm
  • the NMR-spectrum (CDCl shows peaks at 8 1.47 (s), 1.52 (s), 1.63 (s), 3.63 (s), 4.42 (s), 4.48 (s), 5.13 (s), 5.40-5.90 (m), 5.88 (s), 7.33 (s), and 7.43 (s). (TMS being used as internal standard).
  • EXAMPLE 4 b A. Bis(6B-phenylacetamido-penicillanoyloxy)- methane To a stirred suspension of potassium benzylpenicilli-' nate (22.3 g.) in dimethylformamide 1 10 ml.) is added chloroiodomethane (5.3 g. After stirring for 48 hours at room temperature the mixture is diluted with ethyl 3-(o-chlorophenyl) -5- I acetate (330 ml.) and extracted with water (2 X 60 ml.), 2% aqueous sodium bicarbonate (60 ml.) and water (2 X 60 ml.).
  • the organic phase is dried and evaporated to dryness in vacuo to yield the desired compound as an amorphous powder.
  • the lR-spectrum (CHCI shows strong bands at 1780, 1675, 1505, 1290, 1135 and 982 cm.
  • the aqueous phase is separated and the pH adjusted to 7.5 by addition of sodium bicarbonate.
  • the aqueous phase is extracted with ether (25 ml.).
  • the organic phase is separated, dried and evaporated to dryness in vacuo to yield a mixture of the desired compound and quinoline.
  • EXAMPLE 5b A. Bis-(6/3-amino-penicillanoyloxy)-methane To a solution of PCl (1.28 g.) in dry, alcohol-free Cl-lCl (30 ml.) is added quinoline (1.46 ml.) with stirring. The solution is cooled to -l0 C. and bis-(6B- phenylacetamido-penicillanoyloxy)-methane (1.36 g.) is added. After stirring for minutes at 10 C. n-
  • propyl alcohol (6.6 ml.) is added. The temperature is kept at -10 C. for a further 15 minutes. Then the mixture is poured into water (50 ml.) and petroleum ether 1 10 ml.) is added.
  • R represents a hydrogen atom
  • the intermediates of formula Vlll can be used directly in the next step, and if R represents a protective group this is first removed, e.g. by hydrogenation or hydroly- SIS.
  • R and R have the meanings defined before, and R stands for O or S to yield the compounds of formula l.
  • the amides of formula IX can by welbknown methods be transferred into reactive derivatives such as acid amide halides, acid amide dialkyl sulphate complexes or acid amide acetals.
  • the acid amide halides used are preferably the chlorides or bromides, and they can be prepared by treating the amides with halogenating agents. It is preferred to use halogenating agents which throughout the reaction form gaseous by-products, such as phosgene, oxalyl halides, or thionyl halides, but also others may be used.
  • the reaction can be performed in inert, dry, organic solvents, e.g.
  • amide halide in most cases will be insoluble and from which it can be isolated by filtration after the reaction is completed.
  • the acid amide halides are hygroscopic and rather unstable and are therefrom preferably used in the next step without purification.
  • the acid amide dialkyl sulphate complexes can be prepared by treating the amides with dialkyl sulphate, preferably dimethyl sulphate, under well-known conditions.
  • dialkyl sulphate preferably dimethyl sulphate
  • acid amide dialkyl sulphate complexes with sodium lower alcoholates, e.g. sodium methoxide, acid amide acetals of the general formula lXa:
  • R1 N-cn(oR IXa R2 6 2 in which R and R have the meanings defined above and R, is a lower alkyl group, are formed, which acetals may also be used in the next step.
  • a reactive derivative in form of an acid thioamide alkyl halide complex can be formed by treatment with alkyl halides, eLg. lower-alkyl iodide. This reaction is well known from the chemical literature.
  • reaction conditions for the reaction between the amide derivative and the compound of formula VIII depend on the reaction components used in the process.
  • the reaction temperature depends on the reaction components.
  • the reaction is performed in inert organic solvents, for instance ether.
  • reaction is also performed in inert organic solvents, which are dry'and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the starting materials are insoluble, e.g. ether, may be used as well.
  • inert organic solvents which are dry'and free from traces of alcohols, preferably chloroform, in which the reaction components are soluble, but solvents in which the starting materials are insoluble, e.g. ether, may be used as well.
  • the reaction is performed under cooling and in the presence of at least one equivalent of a tertiary amine, for example trimethylamine, triethylamine, N,N- diisopropylethylamine or N-methylmorpholine.
  • the reaction product will be obtained as a salt when an acid amide halide is used, and as the free esters of formula I when the dialkyl sulphate complexes and thioamide alkyl halide complexes are used.
  • the reaction time depends on the reactants, the temperature and the solvents used in the process.
  • a compound of the above formula V1 is reacted with a compound of the above formula VII under the same conditions as described above for the reaction between the compounds of formula IV and formula VII to yield a compound of formula X:
  • EXAMPLE 1 6-[ (Hexahydrol H-azepinl -yl )-methyleneamino]- penicillanovloxvmethvl benzvlnenicillinatp
  • a suspension of sodium 6-[(hexahydro-IH- azepin-l-yl)-methyleneamino]-penicillanate (3.5 g.) in dimethylformamide (50 ml.) was added chloromethyl benzylpenicillinate (3.8 g.). After stirring at room temperature for 65 hours, the mixture was diluted with ethyl acetate (200 ml.) and washed with water (3 X 25 ml.).
  • the organic phase was extracted with dilute hydrochloric acid (pl-l 2.5).
  • the aqueous phase was separated and made alkaline by adding sodium bicarbonate.
  • the oil which separated was taken up in ethyl acetate and the solution was dried and evaporated to dryness in vacuo to yield the desired compound as an amorphous powder.
  • the NMR-spectrum (CDCl showed peaks at 8 1.47 (s), 1.65 (s), 1.58 (m), 3.37 (m), 3.63 (s), 4.38 (s),'4.40 (s), 5.08 (dd), 5.4 5.8 (m), 5.87 (s), 6.20 (d), 7.32 (s) and 7.59 ((1) ppm.
  • TMS was used as internal reference.
  • the IR-spectrum (CHCI showed strong bands at 1773, 1673 and 1630 cm".
  • the starting materials used in the above example are prepared in the following manner: 6-[(Hexahydro-lH-azepin-l-yl)-methyleneamino]- penicillanic acid dihydrate.
  • A. l-Hexamethyleneiminecarboxaldehyde dimethyl acetal was prepared from the N-formylhexamethyleneimine-dimethyl sulfate complex by reaction with sodium methoxide according to the method of Bredereck et al. (Chem. Ber. 101,41 (1968). The boiling point was 83 -84C./12 mm Hg.
  • the IR-spectrum (KBr) showed strong bands at: 1785, 1770, 1655,1547,1303, 1139,1118 and 712 cm.
  • EXAMPLE 2 6-[(Hexahydro-1 H-azepin- 1 -y1)-methyleneamino]- penicillanoyloxymethyl benzylpenicillinate, hydrochloride.
  • EXAMPLE 3 6-[(I-1exahydro-ll-l-azepin-lyl)-methyleneamino]- penicillanoyloxymethyl phenoxymethylpenicillinate.
  • This compound was obtainedas described in Example l by using chloromethyl phenoxymethylpenicillinate instead of chloromethyl benzylpenicillinate.
  • EXAMPLE 4 6-[(1-lexahydro-lI-l-azepin-l-yl)-methyleneamino]- penicillanoyloxymethyl phenoxymethylpenicillinate, hydrochloride.
  • the organic phase was extracted with dilute hydrochloric acid (pH -2.5).
  • the aqueous phase was separated and made alkaline by adding sodium bicarbonate.
  • the oil which separated was taken up in ethyl acetate and the solution was dried and evaporated to dryness in vacuo to yield the desired compound as a yellow oil.
  • EXAMPLE 7 A. 6-Amino-penicillanoyloxymethyl benzylpenicillinate. A
  • TMS was used as internal reference.
  • EXAMPLE 8 By following the procedure described in Example 1 and by replacing the chloromethyl benzylpenicillinate with the chloromethyl esters of 3-(2-chloro-6- fluorophenyl)-5-methyl-4-isoxazolylpenicillin and D(-)-a-azidobenzylpenicillin, respectively, the follow- 'ing compounds were prepared: 6-[(hexahydro-1H- EXAMPLE 9 6-[(Hexahydro-lH-azepin-l-yl)-methyleneamino]- penicillanoyloxymethyl D(-)-a-aminobenzylpenicillinate, dihydrochloride.
  • Example II Following the procedure described in Example I the above compound was prepared from sodium 6-[(N- ethyl-N-isopropylamino)-methyleneamino]- penicillanate and chloromethyl 3-(o-chlorophenyl)-5- methyl-4-isoxazolylpenicillinate. The compound was isolated as an amorphous powder.
  • Chloromethyl 3-(o-chlorophenyl)-5-methvl-4-isoxazolylpenicillinate was prepared in analogy with chloromethyl benzylpenicillinate (cfr. Example 1). The compound was isolated as an amorphous powder.
  • This compound was prepared from sodium 6- [(hexahydro-l-(2H)-azocinnyl)-methyleneamino]- penicillanate and chloromethyl benzylpenicillinate following the procedure described in Example I. It was obtained as an amorphous powder.
  • a penicillin ester of the formula I H H R1 l E 2 N-CH l L 5 O C N CH H H CH R com. S 5 5 I li B (1% N----CH V Q in which R and R together with the nitrogen atom to which they are attached represent hexahydroazepinyl; R represents a member selected from the group consisting of benzyl, phenoxymethyl, 3-(2'-chloro-6'- fluorophenyl)-5-methyl-4-isoxazolyl,D(-)-alphaazidobenzyl, D(-)-alpha-aminobenzyl and 3-(0- chlorophenyl)-5-methyl-4-isoxazolyl; and pharmaceutically acceptable, non-toxic salts thereof.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US243855A 1971-05-05 1972-04-13 New penicillin esters, salts thereof, and methods for their preparation Expired - Lifetime US3869449A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1335871 1971-05-05

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US05/554,423 Division US4554160A (en) 1971-05-05 1975-03-03 Penicillin esters, salts thereof and methods for their preparation

Publications (1)

Publication Number Publication Date
US3869449A true US3869449A (en) 1975-03-04

Family

ID=10021514

Family Applications (1)

Application Number Title Priority Date Filing Date
US243855A Expired - Lifetime US3869449A (en) 1971-05-05 1972-04-13 New penicillin esters, salts thereof, and methods for their preparation

Country Status (10)

Country Link
US (1) US3869449A (enrdf_load_stackoverflow)
JP (1) JPS5541240B1 (enrdf_load_stackoverflow)
CA (1) CA1112569A (enrdf_load_stackoverflow)
DE (1) DE2221912A1 (enrdf_load_stackoverflow)
DK (1) DK140481B (enrdf_load_stackoverflow)
FR (1) FR2135339B1 (enrdf_load_stackoverflow)
GB (1) GB1335718A (enrdf_load_stackoverflow)
NL (1) NL7205957A (enrdf_load_stackoverflow)
SE (1) SE417098B (enrdf_load_stackoverflow)
ZA (1) ZA722545B (enrdf_load_stackoverflow)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4181659A (en) * 1976-04-15 1980-01-01 Leo Pharmaceutical Products Ltd. A/S Bis-penicillanoyloxy-alkanes
US4244951A (en) * 1979-05-16 1981-01-13 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4309347A (en) * 1979-05-16 1982-01-05 Pfizer Inc. Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide
US4323499A (en) * 1981-01-05 1982-04-06 Pfizer Inc. 6-(2-Aryl-2-(1,1-dioxopenicillanoyloxy-methoxycarbonyl)acetamido penicillanic acids
US4340539A (en) * 1980-01-21 1982-07-20 Bristol-Myers Company Derivatives of 6-bromo penicillanic acid
US4342772A (en) * 1979-02-13 1982-08-03 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) β-Lactam compounds, antibacterial compositions thereof and method of use
US4345071A (en) * 1976-06-29 1982-08-17 Leo Pharmaceutical Products, Ltd. A/S Derivatives of penicillanic acid
US4377524A (en) * 1979-05-16 1983-03-22 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4407751A (en) * 1979-02-13 1983-10-04 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Processes for preparing β-lactams
US4432903A (en) * 1980-09-08 1984-02-21 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4488994A (en) * 1980-09-08 1984-12-18 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4508723A (en) * 1977-05-17 1985-04-02 Ciba Geigy Corporation 6-Azaoligocycloalkylmethyleneaminopenam compounds
US4540687A (en) * 1981-09-09 1985-09-10 Pfizer Inc. Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds
US4582829A (en) * 1981-09-09 1986-04-15 Pfizer Inc. Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds
US6642377B1 (en) * 1999-07-30 2003-11-04 Eisai Co., Ltd. Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL59257A (en) * 1979-02-13 1983-09-30 Rech Applications Therap 6-(n-(cyclic amino-substituted methylene)amino)penicillanates and salts thereof,their production and pharmaceutical compositions containing them
DE3051044C2 (enrdf_load_stackoverflow) * 1979-06-19 1989-03-30 Leo Pharmaceutical Products Ltd. A/S (Loevens Kemiske Fabrik Produktionsaktieselskab), Ballerup, Dk

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3669978A (en) * 1970-05-28 1972-06-13 American Home Prod Process for the production of semi-synthetic penicillin intermediate
US3704290A (en) * 1970-12-09 1972-11-28 American Home Prod 6-(1 - substituted aminocycloalkane-carboxamido)-penicillanic acid and salts
US3770722A (en) * 1971-10-04 1973-11-06 Pfizer 6 - (alpha - (aryl substituted)acylamino-acylamino)penicillanic acidsand derivatives thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3669978A (en) * 1970-05-28 1972-06-13 American Home Prod Process for the production of semi-synthetic penicillin intermediate
US3704290A (en) * 1970-12-09 1972-11-28 American Home Prod 6-(1 - substituted aminocycloalkane-carboxamido)-penicillanic acid and salts
US3770722A (en) * 1971-10-04 1973-11-06 Pfizer 6 - (alpha - (aryl substituted)acylamino-acylamino)penicillanic acidsand derivatives thereof

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4181659A (en) * 1976-04-15 1980-01-01 Leo Pharmaceutical Products Ltd. A/S Bis-penicillanoyloxy-alkanes
US4345071A (en) * 1976-06-29 1982-08-17 Leo Pharmaceutical Products, Ltd. A/S Derivatives of penicillanic acid
US4508723A (en) * 1977-05-17 1985-04-02 Ciba Geigy Corporation 6-Azaoligocycloalkylmethyleneaminopenam compounds
US4840944A (en) * 1979-02-13 1989-06-20 Leo Pharmaceutical Products Ltd. Antibacterial beta-lactams, pharmaceuticals thereof and methods of using them
US4342772A (en) * 1979-02-13 1982-08-03 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) β-Lactam compounds, antibacterial compositions thereof and method of use
US4407751A (en) * 1979-02-13 1983-10-04 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) Processes for preparing β-lactams
US4244951A (en) * 1979-05-16 1981-01-13 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4309347A (en) * 1979-05-16 1982-01-05 Pfizer Inc. Penicillanoyloxymethyl penicillanate 1,1,1',1'-tetraoxide
US4377524A (en) * 1979-05-16 1983-03-22 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4340539A (en) * 1980-01-21 1982-07-20 Bristol-Myers Company Derivatives of 6-bromo penicillanic acid
US4488994A (en) * 1980-09-08 1984-12-18 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4432903A (en) * 1980-09-08 1984-02-21 Pfizer Inc. Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide
US4323499A (en) * 1981-01-05 1982-04-06 Pfizer Inc. 6-(2-Aryl-2-(1,1-dioxopenicillanoyloxy-methoxycarbonyl)acetamido penicillanic acids
US4540687A (en) * 1981-09-09 1985-09-10 Pfizer Inc. Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds
US4582829A (en) * 1981-09-09 1986-04-15 Pfizer Inc. Antibacterial 6'-(2-amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl penicillanate 1,1-dioxide compounds
US6642377B1 (en) * 1999-07-30 2003-11-04 Eisai Co., Ltd. Process for the preparation of basic antibiotic-inorganic acid addition salts and intermediate oxalates

Also Published As

Publication number Publication date
DK140481B (da) 1979-09-10
DE2221912A1 (de) 1972-11-16
FR2135339A1 (enrdf_load_stackoverflow) 1972-12-15
SE417098B (sv) 1981-02-23
JPS5541240B1 (enrdf_load_stackoverflow) 1980-10-22
NL7205957A (enrdf_load_stackoverflow) 1972-11-07
ZA722545B (en) 1973-01-31
GB1335718A (en) 1973-10-31
CA1112569A (en) 1981-11-17
FR2135339B1 (enrdf_load_stackoverflow) 1975-06-20

Similar Documents

Publication Publication Date Title
US3869449A (en) New penicillin esters, salts thereof, and methods for their preparation
US3697507A (en) Esters of {60 -aminobenzylpenicillin
US5608082A (en) Compounds useful as antiproliferative agents and GARFT inhibitors
CY1205A (en) Penicillin derivatives
US4229443A (en) Derivatives of penicillanic acid
SE445644B (sv) 7beta-amino-3-cefem-3-amino-4-karbonsyra-foreningar som mellanprodukter for framstellning av 7beta-amino-3-cefem-3-ol-4-karbonsyra-foreningar
NO811740L (no) Dioksydforbindelser, fremgangsmaate til deres fremstilling og deres anvendelse
US3658802A (en) Cephalosporine derivatives and process
IE47080B1 (en) New derivatives of amidino penicillanic acid
US3850908A (en) Aminoacyloxymethyl esters of penicillins
US4492692A (en) Cephalosporin derivatives
US3833580A (en) 3-morpholino-n6-cyclohexylcarbonyl sydnonimine
US3546211A (en) Polycyclic b-lactams
DE2636962C2 (enrdf_load_stackoverflow)
US3864331A (en) Acyloxymethyl esters of {60 -aminopenicillins
US4554160A (en) Penicillin esters, salts thereof and methods for their preparation
US3719668A (en) Semi-synthetic penicillin esters
US4576939A (en) Penem derivatives
US3951957A (en) Chloromethyl ester of penicillins
US3660575A (en) Esters of alpha-aminobenzylpenicillin in dosage unit form
US3819643A (en) Esters of 6-amino penicillanic acid
US4345071A (en) Derivatives of penicillanic acid
EP0128718B1 (en) Process for 6-(aminomethyl)penicillanic acid 1,1-dioxide and derivatives thereof
JPS62198687A (ja) ２β−置換チオメチルペニシリン誘導体
US3847913A (en) Cephalosporanic acid esters