US3169127A - Derivatives of penicillin amides - Google Patents
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- US3169127A US3169127A US157334A US15733461A US3169127A US 3169127 A US3169127 A US 3169127A US 157334 A US157334 A US 157334A US 15733461 A US15733461 A US 15733461A US 3169127 A US3169127 A US 3169127A
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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
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- the properties, particularly the antibiotic properties, of a given penicillin are determined to a large extent by the R group.
- the best known and most widely used penicillins, benzylpenicillin, phenoxymethylpenicillin, and, more recently, a-phenoxyethylpenicillin, wherein R represents the benzyl-, phenoxy-methyland a phenoxyethylradicals, while highly antagonistic toward gram positive microorganisms, are ineffective against the so-called antibiotic resistant strains of bacteria, that is, the penicillin or antibiotic resistant Staphylococci, and are readily destroyed by penicillinase.
- Antibiotic resistant bacteria, Staphylococci in particular are becoming the most important' cause of severe infections and deaths in hospitals today. Therefore, drugs which will combat the continuing rise in Staphylococci incidence and fatality are of immeasurable value to the medical profession.
- R is selected from the group consisting of straight-chain and branched-chain alkyl containing up to and including six carbon atoms; R is selected from the group consisting of R and R XR wherein R is selected fronrthe group consisting of straightand branchedchain alkylene containing two to three carbon atoms, inclusive; R is selected from the group consisting of straightand branched chain alkyl containing up to and including 4 carbon atoms; and X is selected from the group consisting of oxygen and sulfur.
- R and R may be alike or difi erent.
- novel compounds can exist in epimeric D and L forms derived respectively from the D- and L-precursor acids. It will be convenient to refer to these epimers as the D- and L-epimers. When a DL-precursor acid is used, a mixture of the D- and L-epimers is produced. Therefore, included within the purview of this invention are the D- and the L-epimers and mixtures thereof of the compounds of Formula 11 above, each of which exhibits substantial therapeutic activity.
- penicillinase the penicillin destroying enzyme elaborated by many microorganisms, and are also antagonistic toward other Gram-positive microorganisms.
- a-MethylmercaptoisobutyL a-Methylmercapto-n-butyla-n-Butyhnercaptocthyl calcium phosphate or animal feed stuff.
- the valuable products of this invention are remarkably effective in treating a number of infections, particularly those caused by antibiotic resistant Staphylococci, in poultry and animals including man.
- the pure material or mixtures thereof with other antibiotics can be employed.
- a non-toxic carrier that is, a carrier
- This may be either a pharmaceutical carrier, either a liquid or a solid, such as Water, aqueous ethanol, syrup, isotonic saline or glucose, starch, lactose, Either oral or parenteral administration is satisfactory.
- a pharmaceutical carrier either a liquid or a solid, such as Water, aqueous ethanol, syrup, isotonic saline or glucose, starch, lactose, Either oral or parenteral administration is satisfactory.
- the oral route is preferred.
- novel and valuable products of this invention are prepared by amidation of a simple or mixed anhydride of the appropriate penicillin with ammonia in a non-aqueous solvent.
- solvent such as chloroform, dimethylacetamide, tetrahydrofuran, methylisobutylketone and acetone, at a temperature of from about C. to about 50 C.
- an ammonium salt such as diammonium phosphate in an aqueous alkaline solution is used.
- the penicillin mixed anhydrides are readily prepared by treating an alkali metal salt, eg. the sodium or potassium salt, of the desired penicillin with an acid chloride of the second acid component in a suitable anhydrous solvent, such as chloroform, at from about -10 C. to about 50 C.
- a suitable anhydrous solvent such as chloroform
- they are prepared by the reaction of the penicllin acid with a carbodiirnide, preferably an aliphatic or alicyclic carbodiimide, e.g. 1,3-dicyclohexylcarbodiimide according to the well known procedures.
- the simple penicillin anhydrides are prepared by reacting the triethylammonium salt of the desired penicillin with thionyl chloride.
- novel penicillin precursors that is, the free acid form and alkali metal salts thereof of the compounds of Formula H, are prepared from G-aminopenicillanic acid by any of the several known methods for introducing an acyl substituent into a primary amine.
- They can, for example, be prepared by the acylation of 6-aminopenicillanic acid with the appropriate acid chloride, acid bromide, simple anhydride or mixed anhydride. Alternately, they can be prepared by the reaction of 6- aminopenicillanic acid with the appropriate acid precursor in the presence of a condensing agent, e.g., a carbodiimide, such as 1,3-dicyclohexylcarbocliimide.
- a condensing agent e.g., a carbodiimide, such as 1,3-dicyclohexylcarbocliimide.
- the -arninopenicillanic acid can be used in the form of the pure material dissolved or suspended in the solvent of choice, e.g., water, aqueous acetone, or in the form of a fermentation liquor or concentrate thereof.
- the solvent of choice e.g., water, aqueous acetone, or in the form of a fermentation liquor or concentrate thereof.
- G-aminopenicillanic acid with the desired acid chloride in the presence of an acid acceptor at a pH of from about 3.0 to about 9.0 and a temperature of from about 0 C. to about 50 C.
- a neutral to moderately alkaline pH level that is pH values of from about 6.0 to about 9.0 are favored since, under these conditions, a substantial yield of the desired product is produced.
- the preparation of the epimers or mixtures thereof of these novel products is most conveniently and preferably ccornplished by reacting 6-an1inopenicillanic acid with the appropriate modification, that is, with the DL- or with the D- or the L-component of the precursor acid or acid chloride.
- the epimcric penicillins can be separated from mixtures thereof by fractional crystallization, selective extraction, or selective precipitation of an insoluble salt of one epimer in the presence of the other.
- the amide derivatives of a given D- or L-epimer, or mixture thereof are prepared as described above.
- the L-epirners are somewhat more active than the D- epimers. Mixtures of the two epirners of a given penicillin amide appear to have activity at least equal to that expected from a summation of the individual activities.
- the Ot-flll-ZOXYZllkElIlOlC and ot-(alkoxyalkoxy)alkanoic acid reactants and the sulfur analogs thereof are prepared by reaction of the appropriate wbromoalkanoic acid with the proper sodium alcoholate or sodium thioalcoholate in accordance with known procedures.
- a preferred method of preparation utilizes the reaction of the appropriate ethyl-a-bromoalkanoate with the desired solid sodium alcoholate or thioalcoholate under anhydrous'conditions at about C. to about 200 C.
- the product is saponifled to the sodium or potassium salt and the acid re-. covered therefrom by acidification.
- the acid chloride is prepared by reaction of the acid with thionyl chloride according to procedures Well known in the art.
- the amides of the a x-(diallcoxy)alkyl-penicillins and the corresponding sulfur analogs that is, the compounds of Formula II wherein the hydrogen of the wcarbon atom is replaced by an XR group and wherein R is hydrogen as well as alkyl as defined above, also exhibit similar antagonisms toward the antibiotic resistantStaphylococci and Gram-positive microorganisms in general. They are, therefore, highly useful for treating infections caused by such microorganisms in poultry, animals and man.
- the parent penicillin precursors of these valuable products are conveniently prepared by the carbodiimide procedure described above and are converted to the amide by Procedures A or B.
- a,a-(dialkoxy)alkanoic acid reactants, and their sulfur analogs are prepared from the appropriate a,a-dihalo(chloro or bromo)alkanoic acid by reaction with an alkali metal salt of the alcohol or mercaptan having the desired R moiety.
- Primary and secondary amines representative of the above compounds are methylamine, dimethylamine, butylarnine, cyclohexylamine, (2-hydroxyethyl)amine, di-(Z-hydroxyet'nyl)amine, glycine, ti-alanine, piperazine, piperidine, 2-chloroethylamine, aniline, benzylamine, and cycloserine.
- Example 1 To a well stirred solution of 16 grams of 6-aminopenicillanic acid, 200 ml. of 3% sodium bicarbonate, 100 ml. of acetone and 2.5 m1. of 50% sodium hydroxide, a solution of 10 grams of DL-wmethoxy-n-butyryl chloride in 100 ml. of acetone is gradually added over a one hour period at C. The pH is maintained at 7.5 by the addition of sodium hydroxide. The mixture is stirred at room temperature for a half hour following completion of addition. 100 ml. of water is then added and the solution extracted with an equal volume of ether. The ether phase is discarded, the aqueous phase adjusted to pH 2.5 with phosphoric acid then extracted twice with 150 m1.
- PROCEDURE A 0.032 mole of triethylamine in 15 ml. of acetone is added to volume A at 05 C. and the mixture stirred for minutes.
- the mixture or" the amides of D- and L- x-methoxy-npropylpeniciliin is isolated by extraction with 2 x 75 ml. portions of methylisobutylketone and the combined extracts washed with 2 x volumes of 1% sodium bicarbonate solution and /4 volume of water. The solution is dried over anhydrous sodium sulfate then evaporated in vacuo to a heavy syrup. The product is precipitated by the addition of 75 ml. of n-hexane, the soii'd filtered, taken up in chloroform and reprecipitated as before by the addition of n-hexane. It is recovered by filtration and dried.
- PROCEDURE B A solution of 6.03 mole of the potassium salts of D- and L-m-methoxy-n-propylpenicillin (prepared above) in 50 ml. of water is adjusted to pH 1.5 with dilute hydrochloric acid and extracted into 3 x 50 ml. volumes of ether. The combined ether extracts are then dried over anhydrous sodium sulfate and treated with an equimolar quantity of 1,3-dicyclohexyl carbodiimide dissolved in 100 ml. of ether. After 30 minutes at room temperature, a solution of 0.03 mole of diarnmonium phosphate (pi-l 7-8) is added and the mixture stirred for two hours atroom temperature and pH 7-8 and filtered.
- pi-l 7-8 diarnmonium phosphate
- Example 11 The procedure of Example I is repeated employing the 15 D and L-epimers of u-ethoxy-n-butyrylchloride in place of a-rnethoxy-n-butyrylchloride. The a-ethoxy-n-propylpenicillin thus obtained is then reacted according to Procedure A to give the amides of the D- and L-epimers of :x-ethoxy-n-propylpenicillin.
- Example HI A number of a-alkoxyalkyland a-alkylmercaptoalkyl penicillin amides are prepared according to Procedures A and B as mixtures of the D- and L-epirners from the corresponding penicillin prepared by the method of Ex- 7 ample 1. Such compounds are listed below together with the procedure employed for conversion of the penicillin to the amide.
- Additional penicillin amides of Formula II wherein R is R -'XR are prepared using suitable ot-(alkoxyall;oxy)alkanoic acids and ot-(alkylmercaptoalkylmercapto)-alkanoic acids as starting materials in place of u-(methoxyethoxy) propionic acid.
- Example V The procedure of Example I is repreated employing the L-eprmer of ot-methoxyh-butyryl chloride in place of the DL-epimeric mixture.
- the L-a-methoxy-n-propylpenicillin thus produced is converted to the amide by the method of Procedure A.
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Description
3,169,127 DERIVATHVES F PENICILLBI AMIDES Thomas A. Seto, Cretan, Conn, assignor to Chas. "Pfizer 8; Co., Inc, New York, NY, a corporation of Delaware No Drawing. Filed Dec. 6, I961, Ser. No, 157,334 14 Claims. (Ci. see-239.1
The properties, particularly the antibiotic properties, of a given penicillin are determined to a large extent by the R group. The best known and most widely used penicillins, benzylpenicillin, phenoxymethylpenicillin, and, more recently, a-phenoxyethylpenicillin, wherein R represents the benzyl-, phenoxy-methyland a phenoxyethylradicals, while highly antagonistic toward gram positive microorganisms, are ineffective against the so-called antibiotic resistant strains of bacteria, that is, the penicillin or antibiotic resistant Staphylococci, and are readily destroyed by penicillinase. Antibiotic resistant bacteria, Staphylococci in particular, are becoming the most important' cause of severe infections and deaths in hospitals today. Therefore, drugs which will combat the continuing rise in Staphylococci incidence and fatality are of immeasurable value to the medical profession.
It has been unexpectedly found that amide derivatives of a-alkoxyalkyl-and a-alkylmercaptoalkylpenicillins possess surprising activity against the antibiotic resistant Staphylococci both in Vitro and in vivo. The novel compounds of the present invention have Formula II:
wherein R is selected from the group consisting of straight-chain and branched-chain alkyl containing up to and including six carbon atoms; R is selected from the group consisting of R and R XR wherein R is selected fronrthe group consisting of straightand branchedchain alkylene containing two to three carbon atoms, inclusive; R is selected from the group consisting of straightand branched chain alkyl containing up to and including 4 carbon atoms; and X is selected from the group consisting of oxygen and sulfur. R and R may be alike or difi erent.
These novel compounds can exist in epimeric D and L forms derived respectively from the D- and L-precursor acids. It will be convenient to refer to these epimers as the D- and L-epimers. When a DL-precursor acid is used, a mixture of the D- and L-epimers is produced. Therefore, included within the purview of this invention are the D- and the L-epimers and mixtures thereof of the compounds of Formula 11 above, each of which exhibits substantial therapeutic activity.
In addition to their unexpected and significant activity against the antibiotic resistant Staphylococci, the novel products of this invention are resistant to destruction by Hafiz? Patented Feb. 9, l65
penicillinase, the penicillin destroying enzyme elaborated by many microorganisms, and are also antagonistic toward other Gram-positive microorganisms.
The in vitro and especially the in vivo antagonism of these valuable products toward the resistant Staphylococci is indeed surprising and unexpected since the acid forms of these novel penicillins, the compounds of Formula II wherein the carboxarnide group is replaced by a carboxy group or an alkali metal salt thereof, possess little or no activity against the resistant Staphylococci. The in vivo activity is all the more surprising in view of the absence of in vivo activity in benzylpenicillin amide. Furthermore, chemical modification of the penicillin molecule has, up until the discovery of the present class of compounds, resulted in significant activity against the resistant Staphylococci only through modification of the acyl side chain. Previous attempts to impart new antibiotic properties to the penicillins (Cooper, J. Am. Chem. Soc. 70, 3966 (1948) and Holysz et al., J. Am. Chem. Soc. 72, 4760 (1950)) via amide formation have resulted in conflicting data as to the in vivo efiicacy of such amides. Repetition of the prior art experiments has confirmed the findings of Holysz et al. (loc. cit) that amide formation of penicillins e.g, benzylpenicillin, imparts no in vivo activity to the penicillin. It has been found that conversion of penicillins to their amide derivatives does not, in general, impart or enhance in vivo activity against the resistant strains of Staphylococci. Indeed, enhancement of such activity by amide formation appears to be the exception rather than the rule. The penicillin amides are generally somewhat less active against the Grampositive microorganisms than are the parent acids.
The in vitro antimicrobial activity of a variety of a-alkoxyalkylpenicillin amides and a-alkylmercaptoalkylpenicillin amides against the antibiotic resistant strains of Staphylococcus aureus 376, 400 and K are listed in- Table I along with similar data for the amides of benzylpenicillin and phenoxymethylpenicillin. The minimal inhibitory concentrations (MIC) are reported in terms of meg/ml.
TABLE I [In Vitro Data (mcg./rnl.)]
Antibiotic Resistant S. aureus Strains Penicillin Amide HG) i- M onerocamera:
a-lsobutoxyethyL a-n-PropylmercaptoethyL a-Methylmercaptoethyl wlsopropylmercaptoethyl a-Bntoxyctliyl Phenoxymethyl. Benzyl a-Meth ylmercapto-n-arn yl. a-MethylmercaptoisobutyL a-Methylmercapto-n-butyla-n-Butyhnercaptocthyl calcium phosphate or animal feed stuff.
ares,
terms of nag/kg. and compared with P13 values obtained with the amide of phenoxymethylpenicillin.
TABLE II [PDnt Values (mg./kg.)]
The valuable products of this invention are remarkably effective in treating a number of infections, particularly those caused by antibiotic resistant Staphylococci, in poultry and animals including man. For this purpose the pure material or mixtures thereof with other antibiotics can be employed. man and animals, a non-toxic carrier, that is, a carrier In order to do this for administration to which is non-toxic when administered in a quantity sufficient to provide the required dosage of the desired penicillin is selected. This may be either a pharmaceutical carrier, either a liquid or a solid, such as Water, aqueous ethanol, syrup, isotonic saline or glucose, starch, lactose, Either oral or parenteral administration is satisfactory. However, because of ease of administration the oral route is preferred.
The novel and valuable products of this invention are prepared by amidation of a simple or mixed anhydride of the appropriate penicillin with ammonia in a non-aqueous solvent. solvent such as chloroform, dimethylacetamide, tetrahydrofuran, methylisobutylketone and acetone, at a temperature of from about C. to about 50 C. Alternatively, an ammonium salt, such as diammonium phosphate in an aqueous alkaline solution is used.
The penicillin mixed anhydrides are readily prepared by treating an alkali metal salt, eg. the sodium or potassium salt, of the desired penicillin with an acid chloride of the second acid component in a suitable anhydrous solvent, such as chloroform, at from about -10 C. to about 50 C. Alternatively, they are prepared by the reaction of the penicllin acid with a carbodiirnide, preferably an aliphatic or alicyclic carbodiimide, e.g. 1,3-dicyclohexylcarbodiimide according to the well known procedures.
The simple penicillin anhydrides are prepared by reacting the triethylammonium salt of the desired penicillin with thionyl chloride.
It should be noted that, in preparing the penicillin amides from an alkali metal salt or triethylammonium salt, it is not necessary to isolate the intermediate products, e.g. the penicillin acids and anhydrides, as is demonstrated more fully below. It is far more convenient from a practical standpoint to use the intermediate in the form of the solution in which it is prepared.
The novel penicillin precursors, that is, the free acid form and alkali metal salts thereof of the compounds of Formula H, are prepared from G-aminopenicillanic acid by any of the several known methods for introducing an acyl substituent into a primary amine.
They can, for example, be prepared by the acylation of 6-aminopenicillanic acid with the appropriate acid chloride, acid bromide, simple anhydride or mixed anhydride. Alternately, they can be prepared by the reaction of 6- aminopenicillanic acid with the appropriate acid precursor in the presence of a condensing agent, e.g., a carbodiimide, such as 1,3-dicyclohexylcarbocliimide.
They can also be prepared by the method of Shcehan et al., Journal of the American Chemical Society, 81, 3089 (1959) which utilizes D-penicillamine and t-butyl phthal- The reaction is conducted in a reaction-inert 7 imidomalonaldehydate as starting materials for a series of reactions. Substitution of the phenoxyacetyl chloride utilized by Sheehan et al., by, for example,
in the reaction sequence produces the potassium salt of the desired penicillin.
The -arninopenicillanic acid can be used in the form of the pure material dissolved or suspended in the solvent of choice, e.g., water, aqueous acetone, or in the form of a fermentation liquor or concentrate thereof.
It is preferred to utilize the reaction of G-aminopenicillanic acid with the desired acid chloride in the presence of an acid acceptor at a pH of from about 3.0 to about 9.0 and a temperature of from about 0 C. to about 50 C. A neutral to moderately alkaline pH level, that is pH values of from about 6.0 to about 9.0 are favored since, under these conditions, a substantial yield of the desired product is produced.
When prepared in this manner thenovel peni cillins are obtained as their sodium or potassium salts. They are readily converted to the acid form by acidification with a mineral acid, such as sulfuric or hydrochloric acid, and are recovered by extraction, filtration or centrifugation of the precipitated acid.
The preparation of the epimers or mixtures thereof of these novel products is most conveniently and preferably ccornplished by reacting 6-an1inopenicillanic acid with the appropriate modification, that is, with the DL- or with the D- or the L-component of the precursor acid or acid chloride. The epimcric penicillins can be separated from mixtures thereof by fractional crystallization, selective extraction, or selective precipitation of an insoluble salt of one epimer in the presence of the other. The amide derivatives of a given D- or L-epimer, or mixture thereof are prepared as described above. T
The L-epirners are somewhat more active than the D- epimers. Mixtures of the two epirners of a given penicillin amide appear to have activity at least equal to that expected from a summation of the individual activities.
The Ot-flll-ZOXYZllkElIlOlC and ot-(alkoxyalkoxy)alkanoic acid reactants and the sulfur analogs thereof are prepared by reaction of the appropriate wbromoalkanoic acid with the proper sodium alcoholate or sodium thioalcoholate in accordance with known procedures. A preferred method of preparation utilizes the reaction of the appropriate ethyl-a-bromoalkanoate with the desired solid sodium alcoholate or thioalcoholate under anhydrous'conditions at about C. to about 200 C. The product is saponifled to the sodium or potassium salt and the acid re-. covered therefrom by acidification. The acid chloride is prepared by reaction of the acid with thionyl chloride according to procedures Well known in the art.
The amides of the a x-(diallcoxy)alkyl-penicillins and the corresponding sulfur analogs, that is, the compounds of Formula II wherein the hydrogen of the wcarbon atom is replaced by an XR group and wherein R is hydrogen as well as alkyl as defined above, also exhibit similar antagonisms toward the antibiotic resistantStaphylococci and Gram-positive microorganisms in general. They are, therefore, highly useful for treating infections caused by such microorganisms in poultry, animals and man. The parent penicillin precursors of these valuable products are conveniently prepared by the carbodiimide procedure described above and are converted to the amide by Procedures A or B. The necessary a,a-(dialkoxy)alkanoic acid reactants, and their sulfur analogs are prepared from the appropriate a,a-dihalo(chloro or bromo)alkanoic acid by reaction with an alkali metal salt of the alcohol or mercaptan having the desired R moiety.
The substitution of ammonia by a primary or secondary amine of the formula RNli or R'R"NH where R and R" are selected from the group consisting of lower alliyl, hy-clroxy (lower) alkyl, a-carboxy (lower) alkyl, Bcarboxy, (lower) allryl, halo (lower) alkyl, alicyclic, aryl, substituted aryl, benzyl, R and R when taken together represent a 5- and 6-membered ring which may contain a hetero atom, produces valuable isotelic products having a greater or lesser solubility in water than the unsubstituted amide. Primary and secondary amines representative of the above compounds are methylamine, dimethylamine, butylarnine, cyclohexylamine, (2-hydroxyethyl)amine, di-(Z-hydroxyet'nyl)amine, glycine, ti-alanine, piperazine, piperidine, 2-chloroethylamine, aniline, benzylamine, and cycloserine.
The following examples are provided to further illustrate in detail methods for the procedure of the present invention. They are, however, not to be construed as limiting the invention in any way.
Example 1 To a well stirred solution of 16 grams of 6-aminopenicillanic acid, 200 ml. of 3% sodium bicarbonate, 100 ml. of acetone and 2.5 m1. of 50% sodium hydroxide, a solution of 10 grams of DL-wmethoxy-n-butyryl chloride in 100 ml. of acetone is gradually added over a one hour period at C. The pH is maintained at 7.5 by the addition of sodium hydroxide. The mixture is stirred at room temperature for a half hour following completion of addition. 100 ml. of water is then added and the solution extracted with an equal volume of ether. The ether phase is discarded, the aqueous phase adjusted to pH 2.5 with phosphoric acid then extracted twice with 150 m1. of methylisobutylketone. The combined methylisobutylketone extracts are then extracted with 100 ml. of water and divided into two equal volumes, A and B. Volume A is dried over anhydrous sodium sulfate and the resulting dry solution of DL-ot-methoxy-npropylpenicillin used in Procedure A below. To volume B 60 ml. of water is added and the pH adjusted to.6.5 by the addition of N potassium hydroxide. The aqueous phase is separated and freeze-dried to give a mixture of the D- and L-epimers of the potassium salt of ot-methoxy-npropylpenicillin as a powder. The product is used in procedure B below.
PROCEDURE A 0.032 mole of triethylamine in 15 ml. of acetone is added to volume A at 05 C. and the mixture stirred for minutes. A solution of 0.032 mole of ethylchlorocarbonate in 30 ml. of dry acetone is added and, after 10 minutes agitation, the mixture cooled to 50 C. A solution of 0.03 mole of diammonium phosphate in ml. of 3% sodium bicarbonate, chilled to 5 (1., is then slowly added to-the mixed anhydride. The mixture is allowed to reach room temperature and is then stirred for minutes.
The mixture or" the amides of D- and L- x-methoxy-npropylpeniciliin is isolated by extraction with 2 x 75 ml. portions of methylisobutylketone and the combined extracts washed with 2 x volumes of 1% sodium bicarbonate solution and /4 volume of water. The solution is dried over anhydrous sodium sulfate then evaporated in vacuo to a heavy syrup. The product is precipitated by the addition of 75 ml. of n-hexane, the soii'd filtered, taken up in chloroform and reprecipitated as before by the addition of n-hexane. It is recovered by filtration and dried.
PROCEDURE B A solution of 6.03 mole of the potassium salts of D- and L-m-methoxy-n-propylpenicillin (prepared above) in 50 ml. of water is adjusted to pH 1.5 with dilute hydrochloric acid and extracted into 3 x 50 ml. volumes of ether. The combined ether extracts are then dried over anhydrous sodium sulfate and treated with an equimolar quantity of 1,3-dicyclohexyl carbodiimide dissolved in 100 ml. of ether. After 30 minutes at room temperature, a solution of 0.03 mole of diarnmonium phosphate (pi-l 7-8) is added and the mixture stirred for two hours atroom temperature and pH 7-8 and filtered. The filtrate is extracted with 2 X /3 volumes of chloroform. The combined extracts are washed with dilute (1%) sodium bicarbonate and water, then dried with anhydrousd sodium sulfate, evaporated to a heavy syrup, and the amides precipitated by the addition of n-hexane. I [The product is identical to that obtained in Procedure 5 PROCEDURE C Procedure A above is repeated but with replacement of the sodium bicarbonate-diammonium phosphate solution by a saturated solution of ammonia in isopropanol (a 10% excess of ammonia is used). The product, iso- 10 lated according to the method of Procedure A, is identical to that obtained in Procedure A.
Example 11 The procedure of Example I is repeated employing the 15 D and L-epimers of u-ethoxy-n-butyrylchloride in place of a-rnethoxy-n-butyrylchloride. The a-ethoxy-n-propylpenicillin thus obtained is then reacted according to Procedure A to give the amides of the D- and L-epimers of :x-ethoxy-n-propylpenicillin.
20 Example HI A number of a-alkoxyalkyland a-alkylmercaptoalkyl penicillin amides are prepared according to Procedures A and B as mixtures of the D- and L-epirners from the corresponding penicillin prepared by the method of Ex- 7 ample 1. Such compounds are listed below together with the procedure employed for conversion of the penicillin to the amide.
- Penicillin: Procedure u-Methoxyethyl A cx-Methoxy-B-methylpropyl A ot-Ethoxyethy1 A d-lsobutoxyethyl A a-Methoxy-n-butyl B wEthoXy-n-butyl B a-(n-ButOKy)-n-propyl A a-Methoxy-n-pentyl A Ot-(Il-PIOPOXY)-Il-PIOPY1 A a-Isopropoxy-n-propyl A a-Methoxy-fifi-dimethylpropyl A a-Ethoxy-n-pentyl A a-Ethoxyn-heptyl C aIs0butOxy-n-propyl A a-Ethoxy-n-hexyl A at-Butoxy) -n-propyl A a-n-Hexoxy-n-heptyl A ot-li iethoxy-n-methylbutyl B u-Isopropoxy-,8methylpropyl A cx-n-Amyloxy-n-hexyl A a-Methylmercapto-n-propyl A ct-iithylmercaptoen-propyl A a-Methylmercapto-fi-methylpropyl A ot-Isopropylmercapto-n-propyl A a-n-Amyloxyethyl C u-Tsoamyloxyethyl C lx-Methoxy-n-amyl A a-Hexoxy-n-propyl a- A a-Methylmercapto-n-butyl B a-Methylmercapto-n-heptyl B 0 a-Methylmercapto-n-pentyl B a-n-Fropylmercapto-n-heptyl B a-Butylmercapton-propyi A or-isoamylmercapto-n-propyl B tx-Ethylmercaptoethyl A 5 u-lsobutylmercaptoethyl A Example I V u-(Methoxyethoxy)-ethylpenicillin is prepared by the method of Example I and is converted to the amide by Procedure B.
Additional penicillin amides of Formula II wherein R is R -'XR are prepared using suitable ot-(alkoxyall;oxy)alkanoic acids and ot-(alkylmercaptoalkylmercapto)-alkanoic acids as starting materials in place of u-(methoxyethoxy) propionic acid.
Penicillin DL- Ethoxyethoxy) ethyl a-(n-Propoxyethoxy ethyl o- Butoxyethoxy) ethyl OC-(I1-PIOPOXYH-PIOPOXY) ethyl a- Methoxyethoxy) -n-propyl oc- Methoxyethoxy -n-butyl a- Methoxyethoxy) -n-pentyl o:- Methoxyethoxy) -,8-methylpropyl OL- (Methoxy-n-prop oxy) ethyl u- Isopropoxyethoxy) ethyl Cr.- Methylmercaptoethylmercapto) ethyl oc- Ethylmercaptoethylmercapto) -n-propyl oz-( n-Propylmercapto-n-propylmercaptio -n-b utyl oc- (n-Butylmercaptoethylrnercapto) ethyl a- Methoxyis opropoxy ethyl a- Metbylmercap toiso pro pylmercapto ethyl a- (n-Butoxyisopropoxy) ethyl Ot- Methoxyisopropoxy) -B-methylbutyl oc- Methoxyisopropoxy) ethyl a- (Ethoxyisopropoxy) ethyl 0t- Ethoxyisopropoxy -n-propyl a- Me thylmercaptoisopropylmercapto) ethy UL- Eth oxyethoxy -n heptyl a- Methoxyethoxy) -n-hexyl w Me thylmercaptomethylmercapto -n-hexyl Ot- Ethylmercap toethylmercapto -n-heptyl It should be noted that in those preparations wherein R represents the isopropylene moiety, a mixture of two products is obtained. In these products the branched methyl group of the isopropylene moiety may lie on the first or second carbon of the alkylene moiety.
, Example V The procedure of Example I is repreated employing the L-eprmer of ot-methoxyh-butyryl chloride in place of the DL-epimeric mixture. The L-a-methoxy-n-propylpenicillin thus produced is converted to the amide by the method of Procedure A.
Similarly, additional epimeric amides are prepared en1- ploying the methods of Example I and Procedure A.
Penicillin amide tion Serial No. 80,524, filed January 4, 1961 and now abandoned.
(a L) What is claimed is: 1. A compound having the formula:
chain alkyl having from 1 to 4 carbon atoms; and X is selected from the group consisting of oxygen and sulfur.
2. The compound represented by the-formula of claim 1 wherein R is alkyl containing 1 to 6 carbon atoms, R is methyl and X is oxygen.
3. The compound represented by the formula of ciaim 1 wherein R is alkyl containing 1 to 6 carbon atoms, R is ethyl and X is oxygen.
4. The compound represented by the formula of claim 1 where R is methyl, R is allryl containing-1 to 6 carbon atoms and X is oxygen.
5. The compound represented bythe formula of claim 1 wherein R is ethyl, R is aliryl containing 1 to 6 carbon atoms and X is oxygen.
6. The compound represented by the formula of claim 1 wherein R is alkyl containing 1 to 6 carbon atoms, R is methyl and X is sulfur.
7. The compound represented by the formula of claim 1 wherein R is alkyl containing 1 to 6 carbon atoms, R is R X-R R is ethylene, R is alkyl containing 1 to 4 carbon atoms X is oxygen.
8. The amide of oz-methoxy-n-propylpenicillin.
9. The amide of ct -n-amyloxyethylpenicillin.
10. The amide of a-ethoxy-n-propylpenicillin.
11. The amide of a-(methoxyethoxy)-n-propylpenicil- 12.' The amide of a-rnethyirnercapto-n-propy1peniciliin. 13. The amide of a-methoxyfimethylpropylpenicillin. 14. The amide of a-isobutoxyethyipenicillin.
References Cited in the file of this patent UNITED STATES PATENTS 2,562,410 Eehrens et a1 July 31, 1951 2,593,852 Cooper Apr. 22, 1952 2,623,876 Behrens et al Dec. 30, 1952 2,941,995 Doyle et al Tune 21, 1960
Claims (1)
1. A COMPOUND OF THE FORMULA:
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US157334A US3169127A (en) | 1961-12-06 | 1961-12-06 | Derivatives of penicillin amides |
FR883867A FR1720M (en) | 1961-01-04 | 1962-01-04 | Penicillin derivatives. |
BE612271A BE612271A (en) | 1961-01-04 | 1962-01-04 | New penicillins. |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US157334A US3169127A (en) | 1961-12-06 | 1961-12-06 | Derivatives of penicillin amides |
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US3169127A true US3169127A (en) | 1965-02-09 |
Family
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US157334A Expired - Lifetime US3169127A (en) | 1961-01-04 | 1961-12-06 | Derivatives of penicillin amides |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3301849A (en) * | 1963-09-04 | 1967-01-31 | Bristol Myers Co | 6-(alpha-phenoxyalkanoylamino) thiopenicillanic acid |
US3306893A (en) * | 1962-12-04 | 1967-02-28 | Lepetit Spa | Phenoxymethylpenicillin carbo-terbutoxymethoxyamide |
US3352850A (en) * | 1960-02-16 | 1967-11-14 | Beecham Group Ltd | Synthetic penicillins |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2562410A (en) * | 1949-05-03 | 1951-07-31 | Lilly Co Eli | Oxy-penicillins |
US2593852A (en) * | 1949-11-16 | 1952-04-22 | Bristol Lab Inc | Penicillin amides |
US2623876A (en) * | 1948-02-09 | 1952-12-30 | Lilly Co Eli | Mercapto-penicillins |
US2941995A (en) * | 1957-08-02 | 1960-06-21 | Beecham Res Lab | Recovery of solid 6-aminopenicillanic acid |
-
1961
- 1961-12-06 US US157334A patent/US3169127A/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2623876A (en) * | 1948-02-09 | 1952-12-30 | Lilly Co Eli | Mercapto-penicillins |
US2562410A (en) * | 1949-05-03 | 1951-07-31 | Lilly Co Eli | Oxy-penicillins |
US2593852A (en) * | 1949-11-16 | 1952-04-22 | Bristol Lab Inc | Penicillin amides |
US2941995A (en) * | 1957-08-02 | 1960-06-21 | Beecham Res Lab | Recovery of solid 6-aminopenicillanic acid |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3352850A (en) * | 1960-02-16 | 1967-11-14 | Beecham Group Ltd | Synthetic penicillins |
US3306893A (en) * | 1962-12-04 | 1967-02-28 | Lepetit Spa | Phenoxymethylpenicillin carbo-terbutoxymethoxyamide |
US3301849A (en) * | 1963-09-04 | 1967-01-31 | Bristol Myers Co | 6-(alpha-phenoxyalkanoylamino) thiopenicillanic acid |
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