IE43399B1 - Novel penam and thiazoline compounds - Google Patents

Description

This invention relates to novel intermediates for the production of antibacterial agents which are of value as animal feed supplements.

Patent Specification No. 43398 of which this is 5 a divisional, provides novel penam 3-phosphonates which are valuable new antibacterial agents useful as animal feed supplements. The said novel penams are those of the formula (I) and the pharmaceutically acceptable salts thereof, wherein 2 3 R and R are the same or different and are selected from the group consisting of hydrogen and methyl; R·'· is selected from the group consisting of phenyl, phenoxy, 1,4-cyclohexadienyl, thienyl and phenyl mono15 substituted by a member selected from the group consisting of hydroxy and aminomethyl, and Q is selected from the group consisting of hydrogen, amino, carboxy and sulfo; provided that: when R1 is selected from the group consisting of 2o phenoxy and phenyl monosubstituted by aminomethyl, Q is hydrogen; when Q is carboxy, R is selected from the group consisting of phenyl and thienyl; and when Q is sulfo, R^ is phenyl.

It is an object of this invention to provide novel 5 intermediates for the production of said compounds of formula (I). These novel intermediates are 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam, 6-triphenylmethylamino-2,2-dimethyl-3~hydroxypenam and a compound of the formula (II) and the salts thereof.

The novel compounds of the invention are prepared employing the well-known 6-aminopenicillanic acid (6-ARA) as starting material. The following flow sheet illus15 trates some of the processes by which the compounds of the invention can be prepared. 3 3 9 9 The synthesis of the' compounds of the invention as described above starts with the well-known intermediate 6-aminopenicillanic acid (6-APA). 6-APA is converted to 6-triphenylmethylaminopenicillanic acid by methods well known in the art, such as by reaction with chlorotriphenylmethane or the like. The 6-triphenylmethyl group in 6triphenylmethylaminopenicillanic acid serves as a 6-amino protecting group in the subsequent reaction steps,as out4 3 3 9 9 - 5 lined above, and is removed at a later stage of the process of Patent Specification No. 43398 to allow acylation of the 6-aminopenam-3-phosphonates. 6-Triphenylmethylaminopenicillanic acid or a salt thereof has now been found to undergo a novel reaction in the presence of lead tetraacetate to provide the novel intermediate 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam (XIII). The novel reaction with lead tetraacetate is carried out in a reaction-inert organic solvent, optionally in the presence of a tertiary amine such as pyridine, and at a temperature in the range of -30°C. to 80°C. Examples of reaction-inert solvents which may be employed to carry out this novel process are Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, chloroform, dichloromethane and the like. Preferred reaction-inert solvents for the novel lead tetraacetate reaction are Ν,Ν-dimethylformamide and benzene.

While it is advantageous to carry out said lead tetraacetate reactions under anhydrous conditions, rigorous exclusion of moisture is not essential since small amounts of water present will be consumed by the lead tetraacetate reagent. It is also preferred to carry out the reaction in the presence of an inert atmosphere such as that provided by the presence of nitrogen, argon or helium; however, the use of such an inert atmosphere is not an essential condition. Ordinarily, the lead tetraacetate reagent is used in excess of the theoreticallyrequired amount to remove any water remaining in the reaction mixture, or formed as by-product, and to ensure - 6 13399 substantial completion of the reaction. The 3-acetoxypenam product of the novel lead tetraacetate reaction is isolated by standard methods well known to those skilled in the art. For example, the reaction mixture may be filtered to remove insoluble material, and the filtrate washed with an aqueous solution of a neutralizing agent such as sodium, hydrogen carbonate. Excess neutralizing agent is removed by water washing and the organic layer is dried and solvent removed by evaporation. The result10 ing crude product may then be further purified by column chromatography or other methods known in the art.

The intermediate 6-triphenylmethylamino-2,2-dimethyl3-acetoxypenam (XIII), thus obtained, may be directly converted to a-triphenylmethylamino-5,5-dimethyl-3-thiazoline15 2-acetic acid (II), or a salt thereof, by reaction with about 2 equivalents of an alkali such as sodium hydroxide or potassium hydroxide in an aqueous medium. This step is preferably carried out under alkaline hydrolysis conditions at a temperature in the range of about 0° to 1OO°C. It is also advantageous, but not essential, to employ an organic co-solvent in this process. Co-solvents which can be employed are those which are miscible with water and will serve to dissolve the starting penam compound (XIII), Typical examples of co-solvents which can be Used are acetone, lower alkanols,. such as methanol and ethanol; ethylene glyeol; mono- and di(lower alkyl)ethers of ethylene glycol such as 2-methoxyethanol and 1,2dimethoxyethane; tetrahydrofuran; dioxane and acetonitrile. The reaction has been found to proceed through the novel intermediate (XIV), depicted below, to form said intermediate (II).

NH CH.

CH.

- -(XIV) OH Alternatively, of course, said intermediate (XIV) may be isolated and further reacted to form compound (II,.

The isolation of the desired intermediate, a-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid is readily accomplished by methods well known to those skilled in tbe art. For example, when the reaction is carried out in an aqueous medium containing co-solvent tetrahydrofuran, the co-solvent is removed by evaporation and the aqueous concentrate washed with ether to remove non-acidic byproducts. The aqueous layer is chilled and the precipitate that forms is removed and washed thoroughly to obtain the carboxylate salt. This may be dissolved in water, acidified to effect precipitation of the desired acid (II) which can then be isolated by filtration.

The intermediate of formula II has the ability to form carboxylate salts which can be of use in their isolation and purification. The salts can be prepared by standard techniques, such as contacting the acidic and basic components, usually in a 1:1 molar ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate.

They are then recovered by filtration, by precipitation with i non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents which are suitably employed in salt formation belong to both the organic and inorganic types, and they include ammonia, 3 3 9 » - 8 organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Representative examples Of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine; secondary amines, Such as diethyiamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N,N dimethylaniline, N-ethylpiperidine, N10 methylmorpholine and l,5-diazabicyclo[4.3.o] non-5-ene; hydroxides, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates, such as potassium carbonate and sodium carbonate; and bicarbonates, such as sodium bicarbonate and potassium bicarbonate; sodium 2-ethylhexanoate and potassium 2-ethylhexanoate.

The following Examples illustrate the invention. Example 1 relates to the preparation of an intermediate.

Example 1 6-(Triphenylmethylamino)penicillanic Acid To a stirred suspension of 54 g. (0.25 mole) of 6aminopenicillanic acid and 70 ml. (0.50 mole) of triethylamine in 500 ml. of chloroform (free of ethanol) at room temperature, 70 g. (0.25 mole) of chlorotriphenylmethane was added iri portions over a period of a few minutes. Stirring was continued for two days. The volatile components were evaporated under reduced pressure, and the foamy residue taken up in 400 ml. of water. The aqueous mixture was washed twice with 300 ml. portions of diethyl ether, and then brought to pH 4.0 by the monitored addi- 9 tion of 4N hydrochloric acid. Organic matter was extracted with two 300 ml. portions of diethyl ether. The extracts were combined, washed twice with 200 ml. portions of water, once with 200 ml. of a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent affords 6-(triphenylmethylamino)penioillanic acid as a yellow foam; yield 95 g. (83%); ^H-ninr (CDClg) ppm (δ): 1.4 (s, 3, a-CH^), 1.6 (s, 3, β-ΟΗ^), 4.4 (m, 3, c-3, C-5, C-6 protons), 7.4 (m, 15, ccH_). o 5 Example 2 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam A solution of 46 g. (0.10 mole) of 6-(triphenylmethylamino)penicillanic acid and 425 ml. of benzene was heated under reflux in an apparatus which includes a DeanStark moisture trap. When no further water was collected in the trap, a stream of dry nitrogen was allowed to pass through the solution while it cooled to room temperature.

Lead tetraacetate-10% acetic acid (64 g., 0.13 mole) was added in one portion, the mixture was stirred under nitrogen J or 15 hours, and then filtered through a pad of diatomaceous earth (Celite—Registered Trade Mark). The filtiate was washed twice with 300 ml. portions of halfsaturated aqueous sodium hydrogen carbonate, twice with water, and dried over anhydrous sodium sulfate. Evaporation of the volatile components furnished 15 g. of a brown foam. This residue was subjected to chromatography through a column containing 350 g. of silica gel. Eluting the column with chloroform .afforded some initial undesired material, but this was followed by fractions containing 6-tri phenyImethylamino-2,2-dimethyl~3-acetoxypenam. Evaporation of these combined fractions gave material which was approximately 65% pure; yield 11 g. (15%); Hnmr (CDClj) ppm (6): 1.3 (s, 3, a-CH/, 1.5 (s, 3, β-CHp, 3 3 a η - 10 2.0 (s, 3, COCttf), 3.3 (d, 1, NH), 4.4 (m, 2, C-5, C-6 protons), 6.2 (s, 1, C-3), 7.4 (m, 15, CgH^). The product may be crystallized from an ether-methanol mixture.

When the above reaction is carried out, but using Ν,Ν-dimethylformamide as solvent in place of benzene and with suitable modification of the above isolation procedure, the title compound is obtained. When the reaction is o carried out at 80 C. for 15 minutes using benzene as solvent, or at -30°C. for 120 hours in dichloromethane, the title compound is also obtained.

When one equivalent of pyridine (based on the starting 6-[triphenyImethylamino]penicillanic acid) is employed in the above procedures, the title compound is likewise obtained.

Example 3 (x-Triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic Acid A solution of 6.37 g (0.0135 mole) of 6-triphenylmethylamino-2,2-dimethyl-3-acetOxypenam, 65 ml - of tetra20 hydrofuran, 13.5 ml. of water, and 13.5 ml. of 2N aqueous sodium hydroxide was stirred at room temperature for 60 hours. The reaction mixture was concentrated under reduced pressure to about one-third of the original volume, and the aqueous concentrate washed three times with 50 ml. portions of diethyl ether. Precipitation occurred during the washing process. After allowing the mixture to stand at 0°C. for 30 minutes, the solids were removed by filtration and washed once with a small portion of ice-water and twice with 20 ml.· portions of diethyl ether. The crystaliO line sodium salt thus obtained was dissolved in a stirred mixture of 30 ml. of water and So ml. of dichloromethane - 11 and the pH adjusted to 4.0. The organic phase was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford nearly colorless crystals of the title compound: yield 3.45 g. (59%); m.p. 180—182°C; ^H-nmr (CDCl^) ppm (fi): 1.42 (s, 3, CHg), 1.52 (s, 3, CH ), 3.96 (d, Jg g = 5 cps. 1, C-6)* , 5.93 (q, Jg g = 2.7, J3 θ=5, 1, C-5)*, 6.98 (d, J=2.7, 1, C-3)*, 7.36 (m, 15, C‘H ). *penam numbering When the above reaction is repeated but using acetone as co-solvent in place of tetrahydrofuran and at a temperature of 0°C. for 200 hours, the title compound is likewise obtained.

Similarly, when the reaction is carried out at 100°C. for one hour using 2-methoxyethanol (methyl Cellosolve) as co-solvent, the title compound is obtained.

Cellosolve is a Registered Trade Mark.

EXAMPLE 4 a-Triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid via 6-Triphenylmethylamino-2,2-dimethyl-3-hydroxypenam A. 6-TriphenyImethylamino-2,2-dimethyl-3-hydroxypenam To a solution of 1.7 g. (0.0036 moles) of 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam in 10 ml. of tetrahydrofuran was added 2.0 ml. of 2N sodium hydroxide solution and the resulting mixture was stirred rapidly for 30 minutes at 25°C. Ethyl ether (50 ml.) was then added with stirring and the layers were allowed to separate. The aqueous layer was discarded and the organic layer was washed three times with 2 ml. portions of water, once with saturated aqueous sodium chloride solution, 3 3 9 9 - 12 dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 1.6 g. of semisolid foam. The foam was dissolved in 3 ml. of chloroform and chromatographed on 40 g. of silica gel, eluting with chloroform. Seventy fractions, 5 ml. each, were collected. Fractions 5—50 were found to contain starting material and fractions 53— 70 were found to contain only one compound, more polar than the starting material upon thin-layer chromatography. Fractions 53—70 were combined and evaporated in vacuo to obtain 250 mg. of 6-triphenyImethylamino-2,2-dimethy1-3hydrojcfpenam. H-nmr (CDCl^) ppm (δ): 1.40 (s, 3, CH-j)» 1.44 (s, 3, CH3), 3.23 (d, 1, lii), 4.3 (m, 2, C-5 and C-6), 5.13 (s, 1, C-3), 7,17—7.66 (m, 15, C^), B. re-Triphenylmethylamino-5,5-dimethyl-3-thiazoline-215 acetic acid, Sodium Salt To a solution of 210 mg. (0.49 millimoles) of 6triphenylmethylamino-2,2-dimethyl-3-hydroxypenam in one milliliter of tetrahydrofuran was added 0.25 ml. of 2N sodium hydroxide solution. The resulting mixture was stirred at room temperature for one hour, after which 5 ml. of ether and 0.3 ml. of deuterium oxide were added.

The lower, aqueous, layer was removed and concentrated in vacuo to obtain a crystalline residue. To this was added 0.5 ml. of D^O followed by 1 drop of dilute hydrochloric acid to adjust the pH to about 7. The resulting mixture was stirred for several minutes after which the solid material was allowed to settle and the liquid drawn off with a micropipette. The resulting crystals were dried in vacuo, then dissolved in perdeutero-dimethylsulfoxide.

The '‘H-nmr spectrum was identical to that of an authentic specimen of the sodium salt of α-triphenylmethylamino-5,54 3 3 9 9 - 13 dimethyl-3-thiazoline-2-acetic acid. ^H-ninr (DMSO-dg) ppm (¢): 1.22 (s, 3, CHg), 1.32 (s, 3, CHg), 3.45 (d, 1, C-6*), 4.68 (m, 1, C-5*), 6.68 (d, 1, C-3*), 7.07— 7.42 (m, 15. C.H_), b □ penam numbering

Claims (5)

1. CLAIMS:1. 6-Triphenylmethylamino-2,2-dimethyl-3-acetoxypenam

2. 6-Triphenylmethylamino-2,2-dimethyl-3-hydroxypenam,

3. A compound of the formula (II) and the salts thereof.

4. A process for the production of 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam which comprises 10 the step of reacting 6-triphenylmethylamino-2,2-dimethylpenam-3-carboxylic acid, ar a salt thereof, with lead tetraacetate in a reaction-inert organic solvent at a temperature in the range of -30° to 80°C. 5. The process according to claim 4 wherein said 15 reaction-inert organic solvent is a member of the group consisting of N,N-dimethylformamide and benzene.

5. A process for the production of a compound of formula (II) or a salt thereof, which comprises the step of reacting 6-triphenylmethylamino-2,2-dimethyl~3-aeetoxypenam under alkaline hydrolysis conditions at a temperature in the range of 0° to 100°C.