CA1086718A - Process for preparing 6-triphenylmethylamino-2,2- dimethyl-3-(acetoxy or hydroxy) peram - Google Patents
Process for preparing 6-triphenylmethylamino-2,2- dimethyl-3-(acetoxy or hydroxy) peramInfo
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- CA1086718A CA1086718A CA330,404A CA330404A CA1086718A CA 1086718 A CA1086718 A CA 1086718A CA 330404 A CA330404 A CA 330404A CA 1086718 A CA1086718 A CA 1086718A
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- triphenylmethylamino
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Abstract
ABSTRACT OF THE DISCLOSURE
A process for the production of 6-triphenylmethyl-amino-2,2-dimethyl-3-acetoxypenam by reacting 6-triphenyl-methylamino-2,2-dimethylpenam-3-carboxylic acid, or a salt thereof, with lead tetraacetate in a reaction-inert organic solvent at a temperature in the range of about -30° to 80°C.
A process for the production of 6-triphenylmethyl-amino-2,2-dimethyl-3-acetoxypenam by reacting 6-triphenyl-methylamino-2,2-dimethylpenam-3-carboxylic acid, or a salt thereof, with lead tetraacetate in a reaction-inert organic solvent at a temperature in the range of about -30° to 80°C.
Description
~8~
This application is divided out of co-pending Application No. 261,354.
This invention relates to the production of in-termediates of use in the production of the novel anti-bacterial agents which are of value as animal feed supple-ments, described and claimed in said Application No.
261,354. More specifically, the novel intermediates are 6-triphenylmethylamino-2,2-dimethyl-3-acetoxy and 3-hydroxy penams.
For the sake of convenience, the compounds described herein are identified as derivatives o~ penam.
The term ~penam" has been defined in the J. Am. Chem. Soc~
75, 3293 (1953), as referring to the structure.
r~ ~: Penam Using this terminology r the well-known antibiotic penicillin G is designated as 6-~2-phenylacPtamido)-2/2 dimethylpenam-3--carboxylic acid. The hydrogen methyl phosphonate analog of penicillin G, Formula(Ib) below, wherein Rl is phenyl and Q i3 hydro~en, i5 deæignated as 6-(2-phenylacetamido)-
This application is divided out of co-pending Application No. 261,354.
This invention relates to the production of in-termediates of use in the production of the novel anti-bacterial agents which are of value as animal feed supple-ments, described and claimed in said Application No.
261,354. More specifically, the novel intermediates are 6-triphenylmethylamino-2,2-dimethyl-3-acetoxy and 3-hydroxy penams.
For the sake of convenience, the compounds described herein are identified as derivatives o~ penam.
The term ~penam" has been defined in the J. Am. Chem. Soc~
75, 3293 (1953), as referring to the structure.
r~ ~: Penam Using this terminology r the well-known antibiotic penicillin G is designated as 6-~2-phenylacPtamido)-2/2 dimethylpenam-3--carboxylic acid. The hydrogen methyl phosphonate analog of penicillin G, Formula(Ib) below, wherein Rl is phenyl and Q i3 hydro~en, i5 deæignated as 6-(2-phenylacetamido)-
2,2-dimethyl-3-(O-methylphosphono)penam. The corresponding d~methyl phosphonate is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-~oto dlmethylphosphono)penam and the corresponding diba~ic phosphonic acid is designated as 6-(2-phenylacetamido)-2,2-dimethyl-3-phosphonopenam.
It is an ob]ect of the present invention to .
' : .
.- , . . . . . . , , ~ .: . , ~
;'7~8 provide novel intermediates of u~e in ~he production of penam
It is an ob]ect of the present invention to .
' : .
.- , . . . . . . , , ~ .: . , ~
;'7~8 provide novel intermediates of u~e in ~he production of penam
3-pho~phonate~ which are valuable new antibact~rial agents useful a~ animal feed supplements. The said novel penam~ are tho~e of the F~rmula (I3 R ~HCONr ~ H3 (I) .' ~0 ,.
R~R
and the pharmaceu~ically acceptable 8alt6 thereof wherein R and R are the same ~r different and are ~elected from the group con~isting of hydrogen and methyl;
Rl i~ selected from the group consi~ing of phenyl, phenoxy, 1,4-c~clohexadienyl, thienyl and phen~l mono~ub6tituted by a member ~elected from the g~oup c~n-sisting of hydroxy, and aminomethyl, and Q is selezted from the group consieting of hydrogen, amino, carboxy and ~ul~o: provided that:
when Rl i~ selected ~rom the group consisting of phenoxy and phenyl monoaubstituted by aminomethyl/ Q is hy~en;
when Q iR carboxy, Rl ls selected from the group con~isting of phenyl and thienyl;
and when Q i8 ~ulfo, Rl is phen~lO
Accordingly t~e present invention provide~ a proce~s for the production of 6-triphenylme~hylamino-2,2-dimethyl-3-acetoxypenam or the corresponding 3-hydroxy penam which ~.
compri~es the s~ep o~ reac~ing 6-triphenylmethylamino-2,2-di-methylpenam-3-carboxylic acid, o~ a 6alt thereof, with lead tetraacetate in a reaction-inert organia ~olvent at a temp-erature in the range of about -30 to 80aCo and in order ~o produce the hydroxy penam sub~e~uently hydrolyzing the product with alkali.
The n~vel compounds o~ the inven~ion are prep~red employing the well-Xnown 6-amin~penicillanic acid (6-APA) a8 starting material. The following flow sheet~ illustrate the proces~ o~ the lnvention and ways in which the antibi~tic compound can be pre~ared. In Flow Sheat .. , . , ; : . . ~
-~ ~1)8~;'7~1!31 the sequence of rea~ti.ons to form the compounds represented by the Formulae (IX), ~X~, ~XI) and ~XII) are outlined in a general manner.
. ' , : . :
,, ,~ , , ~ , ;, , - . :
.. ... . : - ~ . ~ . .
. , .. : . : :,. .. . .
~ ~8~7~
F ~_HEJET I
1 6-APA -~ 03CNH ~ CH3 H
~CH3 - --~ 03CNH ~ S ~ H3 OCOCH3 ~N~ H
(XIII) H / ~XIV~ H
03CNH ~ $ ~ ~ CH3 H~(CH3)2 03CNH ~ ~ ~ S ~ CHH3 COOH ~ ~ H ~
(II) ~ (III) CH3~ ~CH3 ~3CNH ~ ~ H3 N ~
(IX) ~ CH30 bR
NH2 ~ 'H3 (X) ¦ CH3 OR2 Rl) ;CHCONH~, ~H3 ~XI) ~ CH30 OR2 L~ R1CHCOWH ~ ~H3 --OR Note:
~XII) OCH3 . 0 = C6H5-R2 is hydrogen or methyl , . . . . , ;, , ., ~:
.,: , - ~lO~6 ~
If des1red c~nversion~ of t}le substi.tuents of the phosphono group~ can h~ ef~ected.
The synlthesis of the compounds of the invention as described above starts with the well-known intermediate 5 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 chlorotriphenyl-methane or the like. The 6-triphenylmethyl group in 6-triphenylmethylaminopenicillanic acid serves as a 6-amino protecting group in the subsequent reaction steps, as out-lined above, and is removed at the appropriate step to allow acylation of the 6-aminopenam-3-phosphonates as also shown above.
6-Triphenylmethylaminopenicillanic acld has now been found to undergo a novel reaction in the presence of lead tetraaceta~e to provide the novel intermediate 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam (XIII).
The novel reaction wi~h 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 about -30C. to 80~C. Bxamples of reaction-inert solvants which may be employed to carry out this novel process are N,N-dimethylformamide, N,N-dimethylacetamide, ben~ene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, chloroform, dichloromethane and the like.
Preferred reaction~inert solvents for the nove~.lead tetra-acetate .reaction are N,N-dimethylformamide and benzene.
While it i9 advantageous to carry ou^t said lead tetraacetate reactions under anhydrous conditions, ~rlgorous 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 u~e of such an inert atmosphere i5 not an essentlal condition. Ordinarily, the lead .. .. . . . . . . .. . ..
. ,. .: -. :~ ,: , : : . : . :
: ~ . ,, : . ,. - :
tetraacetate reagent is used in e~cess of the theoretically-requirecl amount to remove any water remaininy in the reaction mixture, or ormed as by~product, and to ensure ~ubstantial completion o~ the reaction. The 3-acetoxypenam products of the nove~ lead tetraacetate reaction are iso-lated by standard methods well known to those skilled in the art. For example, the reactio~ 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 i5 dried and solvent removed by evaporation. The resulting crude product may then be further purified by column chromatography or other methods known in the art.
` The intermediate 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam (XIII), thus obtained, may be directly converted to a-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-aoetic acid (II), or a salt thereof, by xeaction with about 2 equivalents of an alkali such as sodium hy-droxide or potaqsium hydroxide in an aqueous medium. This step i9 preferentially carried out under alkaline hydrolysis conditions at a temperature in the range of about 0 to 100C. It is also advantageous, but not essential, to employ an organic co-solvent in this process. Co~solvents which can be emploved are those which are miscible with ` water and will serve to dissolve the starting penam compound ~XIII). ~ypical examples of co-solvents which can be used are acetone, lower alkanols, such as methanol and ethanol; ethylene glycol; mono- and di(lower alkyl) ethers of ethylene glycol ~uch as 2-methoxyethanol and 1,2-dimethoxyethane; tetrahydrofuran; dioxane and acetonitrile. The reac~ion ha~ been ~ound to proceed through the novel intermediate (XIV), depicted below, to form said intermediate ~II). SCH3 ~6 ; ~ 3 (XIV) `:
, -, ~ . . . . .
. . .. : . . ~ . . . :. - . :- .
., .. . . ~ - . . .
8~7 iLi9 ~ ltexna~iv~ly, of course, said interrnediate (XIV) may be i~olated and further reacted to form compound (II) .
The isolation of the desired intermediate, ~-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid is readily accomplished by methods well known to those skilled in the art. For example, when the reaction is carried out in an aquaous medium containing co-solvent tetrahydrofuran, the co-solvent is removed by evaporation and the aqueous concentrate washed with ether to remove non-acidic by-products. The aqueous layer i~ 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.
15The further steps required for conversion o~
the intermediates of Formulae XII and XIV to the novel antibacterial compounds are described in co-pending Application No. 261,354.
The invention is illustrated by the fallowing ExampleS-Example 1 6-(Triphenylmeth~lamino)penicillanic acid To a stixred--suspension of 54 ~. (0.25 mole) of 6-amino penicillanic acid and 7~'ml. (0.$~ mole~ of triethylamine in 500 ml.
of chloro~orm (free of ethanol) at room temperat'u~3,~70,g.~0.25 mole) of chlorotriphenylmethane was added in portions ove~ a period o~ a few minutes. Stirring was continued ~or two days.
The volatile components were evaporated under reduced pressure, and the foamy residue taken up in ~00 ml. of water. The a~ueous mixture was washed twice wi-th 300 ml.
portions of diethyl ether, and then brought to pH 4.0 by the monitored addition of 4N hydrochloric acid. Organic matter was extracted with two 300 ml. portions of diethyl ether. ~he extracts were combinedl washed twice with ,, 200 ml. portions of water, once with 200 ml. of a ~aturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent affords 6-(triphenylmethylamlno)penicillanic acid as a yellow - , , , . . . ..: .
-. : - . . - . . . . .
~ . .. . . . . . .
.. ~ . . . ... . . . . .
- 1~8~;7 ~8--foam; yield 95 g. t88%); lH-nmr (CDC13) ppm (~):1.4 (s,3,~
CH3), 1.6 (s,3,~-CII3), 404(m,3,c-3, C-5, C-6 protons), 7.4(m,15~C6H5).
~ le 2 6-~Tri~henylamino-2,2~dimethyl-3-acetoxypenam A solution of 46 g~ (0.10 mole) o 6-(tri-phenylmethylamino)penicillanic acid and 425 ml. of benzene was heated under reflux in an apparatus which includes a Dean-Stark moisture trap. When no further water was collected in the trap, a stream of dry nitrogen was allowed to paRs through the solution while it cooled to room temperature. Lead tetraacetate-10% acetic aaid (64 g., 0.13 mole) was added in one portion, the mixture was stirred under nitrogen for 15 hours, and then filtered through a pad of diatomaceous earth (Celite). The filtrate was washed twice with 300 ml. portions of half-saturated 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 re9idue 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 ~ractions containing 6-triphenyl-methylamino-2,2-dimethyl-3-acetoxypenam. Evaporation of these combined fractions gave material which was approxi-mately 65~ pure; yield 11 g. (15%); H-nmr (CDC13) ppm 1.3 (9,3, ~CH3), 1.5 ~s,3,~-CH3), 2.0(s,3,C0~3), 3.3 ~d,l,NH), 4.4 (m,2,C-5,C-6 protons), 6.2 (s,l,C-3), 7.4 (m,15,C6H5). The product may be crystallized from an ether-methanol mixture.
When the above reaction is carrie~ out, but using`
N,N-dimethylormamide as solvent in place Oe benzene and with suitable modification of the above isolation proaedure, the title compound is obtained. When the reaction ls aarried out at 80C. for 15 minutes using benzene as solvent, or at -30~. ~or 120 hours in dichloromethane, the title compound is also obtained.
.. :. : ~ , ., ~ . .................... . .
: . , . , ~ . , - .:
867~
When one equivalent of pyridine (based on the starting 6-[~riphenylme~hylamino]penicillanic acid) is employed in the above procedures, the title compound is likewise obtained.
Example 3 o~i-Triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic Acid , " . . _ .
A solution of 6.37 g. (0.0135 mole) of 6-tri phenylmethylamino-2,2-dimethyl-3-acetoxypenam, 65 ml. of tetrahydrofuran, 13.5 ml. of water, and 13.5 ml. of 2~
aqueo~s 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 0C. for 30 minutes, the solids were removed by filtration and washed once with a small portion of ice-water and twlce with 20 ml. portions of diethyl ether. The crystalline sodium salt thu~ obtained was dissolved in a stirred mixture of 30 ml. of water and 50 ml~ of dichloro-methane and the pH adjusted to 4Ø 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%); mp.
180-182C; lH-nmr (CDC13) ppm t~):1.42 (s,3, CH3), 1.52 (s,3,CH3), 3.96 (d,J5 6=5 cps, 1,C-6~, 5.93 (q,J3 5=2.7, J5 6=5,1~C-5), 6.98 (d,J=2.7, l,C-3), 7.36 (m,15,C6H5).
When the above reaction is repeated but u~ing acetone as co-solvent in place of tetrahydro~uran and at a temperature of 0C. for 200 hours, the title compound is likewise obtained.
Similarly, when the reaction is carried out at 100C, ~or one hour using 2-methoxyethanol (methyl Cellosolve) as co-solvent, the title compound is obtained.
*penam numbering :: : , - , ...... ' ' , - . . i . .. ~ ~ .... ..
. ~ . .
' ~
~xample 4 ~ I'riphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid via 6-1'r~phenylmethylamino-2,2-dimethyl-3-hydroxypenam 5A. 6-Triphenylmethylamino-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 sodi~ hydroxide solution and the resulting mixture was stirred rapidly for 30 minutes at 25C. Ethyl ether (50 ml.) was then added with stirring and the layers were allowad to separate.
The aqueous layer was discarded and the organic layer was washed three times with 2 ml. portions of water, once with saturated aqueou3 sodium chloride solution, dried over anhydrous sodium sulfate and concen~rated in vacuo to obtain 1.6 g. of semisolid foam. The foam was dissolved in 3 ml. of chloroform and chromatographed on 40 g. o~ silica gel, eluting with chloroform. Seventy fractions, 5 ml. each were collected. Fractions 5-50 were ~ound 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 ln vacuo to obtain 250 mg. of 6-triphenylm~thylamino-2,2~dimethyl-3-hydroxypenam lH-nmr ~CDC13) ppm (~): 1.40 (s,3,CH3), 1.44 (s,3,CH3), 3.23 (d,l,NH), 4.3 (m, 2,C-5 and C-6), 5.13 (s,llC-3), 7.17-7.66 (m,15,C6H5).
B. ~-Triphenylmethylamino-5,5 dimethyl-3-thiazol ne-2-acetic acid, Sodium Salt. _ To a solution of 210 mg~ (0.49 millimoles) ~f 6-triphenylmethylamino-2,2-dimethyl-3-hydroxypenam in one milliliter of tetrahydrofuran was added 0.25 ml. of 2N
sodium hydroxide solution. The resultiny mixture was ~tirred 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 cry~talline residue. To thls was added .... . . .
: . ~, .. ~ . ~
- . . . .
~V15 ~ 8 0.5 ml. of D2O followed by 1 drop of dilute hydrochloric acid to ad]ust the p~ to about 7. T~e resul~iny mixture was stirred for several minuteS after which the solid material was allowed to settle and the liquid drawn o~f with a micropipette. The resulting crystals were dried ln vacuo, then dissol~ed in perdeutro-dimethylsulfoxide.
The 1H-nmr spectrum was identical to that of an authentic specimen of ~he sodium salt of ~-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid. lH-nmr (DMSO-d6) ppm (~); 1.22 (s,3,CH3), 1.32(s,3,CH3), 3.45 (d,l,C-6 )
R~R
and the pharmaceu~ically acceptable 8alt6 thereof wherein R and R are the same ~r different and are ~elected from the group con~isting of hydrogen and methyl;
Rl i~ selected from the group consi~ing of phenyl, phenoxy, 1,4-c~clohexadienyl, thienyl and phen~l mono~ub6tituted by a member ~elected from the g~oup c~n-sisting of hydroxy, and aminomethyl, and Q is selezted from the group consieting of hydrogen, amino, carboxy and ~ul~o: provided that:
when Rl i~ selected ~rom the group consisting of phenoxy and phenyl monoaubstituted by aminomethyl/ Q is hy~en;
when Q iR carboxy, Rl ls selected from the group con~isting of phenyl and thienyl;
and when Q i8 ~ulfo, Rl is phen~lO
Accordingly t~e present invention provide~ a proce~s for the production of 6-triphenylme~hylamino-2,2-dimethyl-3-acetoxypenam or the corresponding 3-hydroxy penam which ~.
compri~es the s~ep o~ reac~ing 6-triphenylmethylamino-2,2-di-methylpenam-3-carboxylic acid, o~ a 6alt thereof, with lead tetraacetate in a reaction-inert organia ~olvent at a temp-erature in the range of about -30 to 80aCo and in order ~o produce the hydroxy penam sub~e~uently hydrolyzing the product with alkali.
The n~vel compounds o~ the inven~ion are prep~red employing the well-Xnown 6-amin~penicillanic acid (6-APA) a8 starting material. The following flow sheet~ illustrate the proces~ o~ the lnvention and ways in which the antibi~tic compound can be pre~ared. In Flow Sheat .. , . , ; : . . ~
-~ ~1)8~;'7~1!31 the sequence of rea~ti.ons to form the compounds represented by the Formulae (IX), ~X~, ~XI) and ~XII) are outlined in a general manner.
. ' , : . :
,, ,~ , , ~ , ;, , - . :
.. ... . : - ~ . ~ . .
. , .. : . : :,. .. . .
~ ~8~7~
F ~_HEJET I
1 6-APA -~ 03CNH ~ CH3 H
~CH3 - --~ 03CNH ~ S ~ H3 OCOCH3 ~N~ H
(XIII) H / ~XIV~ H
03CNH ~ $ ~ ~ CH3 H~(CH3)2 03CNH ~ ~ ~ S ~ CHH3 COOH ~ ~ H ~
(II) ~ (III) CH3~ ~CH3 ~3CNH ~ ~ H3 N ~
(IX) ~ CH30 bR
NH2 ~ 'H3 (X) ¦ CH3 OR2 Rl) ;CHCONH~, ~H3 ~XI) ~ CH30 OR2 L~ R1CHCOWH ~ ~H3 --OR Note:
~XII) OCH3 . 0 = C6H5-R2 is hydrogen or methyl , . . . . , ;, , ., ~:
.,: , - ~lO~6 ~
If des1red c~nversion~ of t}le substi.tuents of the phosphono group~ can h~ ef~ected.
The synlthesis of the compounds of the invention as described above starts with the well-known intermediate 5 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 chlorotriphenyl-methane or the like. The 6-triphenylmethyl group in 6-triphenylmethylaminopenicillanic acid serves as a 6-amino protecting group in the subsequent reaction steps, as out-lined above, and is removed at the appropriate step to allow acylation of the 6-aminopenam-3-phosphonates as also shown above.
6-Triphenylmethylaminopenicillanic acld has now been found to undergo a novel reaction in the presence of lead tetraaceta~e to provide the novel intermediate 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam (XIII).
The novel reaction wi~h 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 about -30C. to 80~C. Bxamples of reaction-inert solvants which may be employed to carry out this novel process are N,N-dimethylformamide, N,N-dimethylacetamide, ben~ene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, butyl acetate, chloroform, dichloromethane and the like.
Preferred reaction~inert solvents for the nove~.lead tetra-acetate .reaction are N,N-dimethylformamide and benzene.
While it i9 advantageous to carry ou^t said lead tetraacetate reactions under anhydrous conditions, ~rlgorous 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 u~e of such an inert atmosphere i5 not an essentlal condition. Ordinarily, the lead .. .. . . . . . . .. . ..
. ,. .: -. :~ ,: , : : . : . :
: ~ . ,, : . ,. - :
tetraacetate reagent is used in e~cess of the theoretically-requirecl amount to remove any water remaininy in the reaction mixture, or ormed as by~product, and to ensure ~ubstantial completion o~ the reaction. The 3-acetoxypenam products of the nove~ lead tetraacetate reaction are iso-lated by standard methods well known to those skilled in the art. For example, the reactio~ 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 i5 dried and solvent removed by evaporation. The resulting crude product may then be further purified by column chromatography or other methods known in the art.
` The intermediate 6-triphenylmethylamino-2,2-dimethyl-3-acetoxypenam (XIII), thus obtained, may be directly converted to a-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-aoetic acid (II), or a salt thereof, by xeaction with about 2 equivalents of an alkali such as sodium hy-droxide or potaqsium hydroxide in an aqueous medium. This step i9 preferentially carried out under alkaline hydrolysis conditions at a temperature in the range of about 0 to 100C. It is also advantageous, but not essential, to employ an organic co-solvent in this process. Co~solvents which can be emploved are those which are miscible with ` water and will serve to dissolve the starting penam compound ~XIII). ~ypical examples of co-solvents which can be used are acetone, lower alkanols, such as methanol and ethanol; ethylene glycol; mono- and di(lower alkyl) ethers of ethylene glycol ~uch as 2-methoxyethanol and 1,2-dimethoxyethane; tetrahydrofuran; dioxane and acetonitrile. The reac~ion ha~ been ~ound to proceed through the novel intermediate (XIV), depicted below, to form said intermediate ~II). SCH3 ~6 ; ~ 3 (XIV) `:
, -, ~ . . . . .
. . .. : . . ~ . . . :. - . :- .
., .. . . ~ - . . .
8~7 iLi9 ~ ltexna~iv~ly, of course, said interrnediate (XIV) may be i~olated and further reacted to form compound (II) .
The isolation of the desired intermediate, ~-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid is readily accomplished by methods well known to those skilled in the art. For example, when the reaction is carried out in an aquaous medium containing co-solvent tetrahydrofuran, the co-solvent is removed by evaporation and the aqueous concentrate washed with ether to remove non-acidic by-products. The aqueous layer i~ 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.
15The further steps required for conversion o~
the intermediates of Formulae XII and XIV to the novel antibacterial compounds are described in co-pending Application No. 261,354.
The invention is illustrated by the fallowing ExampleS-Example 1 6-(Triphenylmeth~lamino)penicillanic acid To a stixred--suspension of 54 ~. (0.25 mole) of 6-amino penicillanic acid and 7~'ml. (0.$~ mole~ of triethylamine in 500 ml.
of chloro~orm (free of ethanol) at room temperat'u~3,~70,g.~0.25 mole) of chlorotriphenylmethane was added in portions ove~ a period o~ a few minutes. Stirring was continued ~or two days.
The volatile components were evaporated under reduced pressure, and the foamy residue taken up in ~00 ml. of water. The a~ueous mixture was washed twice wi-th 300 ml.
portions of diethyl ether, and then brought to pH 4.0 by the monitored addition of 4N hydrochloric acid. Organic matter was extracted with two 300 ml. portions of diethyl ether. ~he extracts were combinedl washed twice with ,, 200 ml. portions of water, once with 200 ml. of a ~aturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent affords 6-(triphenylmethylamlno)penicillanic acid as a yellow - , , , . . . ..: .
-. : - . . - . . . . .
~ . .. . . . . . .
.. ~ . . . ... . . . . .
- 1~8~;7 ~8--foam; yield 95 g. t88%); lH-nmr (CDC13) ppm (~):1.4 (s,3,~
CH3), 1.6 (s,3,~-CII3), 404(m,3,c-3, C-5, C-6 protons), 7.4(m,15~C6H5).
~ le 2 6-~Tri~henylamino-2,2~dimethyl-3-acetoxypenam A solution of 46 g~ (0.10 mole) o 6-(tri-phenylmethylamino)penicillanic acid and 425 ml. of benzene was heated under reflux in an apparatus which includes a Dean-Stark moisture trap. When no further water was collected in the trap, a stream of dry nitrogen was allowed to paRs through the solution while it cooled to room temperature. Lead tetraacetate-10% acetic aaid (64 g., 0.13 mole) was added in one portion, the mixture was stirred under nitrogen for 15 hours, and then filtered through a pad of diatomaceous earth (Celite). The filtrate was washed twice with 300 ml. portions of half-saturated 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 re9idue 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 ~ractions containing 6-triphenyl-methylamino-2,2-dimethyl-3-acetoxypenam. Evaporation of these combined fractions gave material which was approxi-mately 65~ pure; yield 11 g. (15%); H-nmr (CDC13) ppm 1.3 (9,3, ~CH3), 1.5 ~s,3,~-CH3), 2.0(s,3,C0~3), 3.3 ~d,l,NH), 4.4 (m,2,C-5,C-6 protons), 6.2 (s,l,C-3), 7.4 (m,15,C6H5). The product may be crystallized from an ether-methanol mixture.
When the above reaction is carrie~ out, but using`
N,N-dimethylormamide as solvent in place Oe benzene and with suitable modification of the above isolation proaedure, the title compound is obtained. When the reaction ls aarried out at 80C. for 15 minutes using benzene as solvent, or at -30~. ~or 120 hours in dichloromethane, the title compound is also obtained.
.. :. : ~ , ., ~ . .................... . .
: . , . , ~ . , - .:
867~
When one equivalent of pyridine (based on the starting 6-[~riphenylme~hylamino]penicillanic acid) is employed in the above procedures, the title compound is likewise obtained.
Example 3 o~i-Triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic Acid , " . . _ .
A solution of 6.37 g. (0.0135 mole) of 6-tri phenylmethylamino-2,2-dimethyl-3-acetoxypenam, 65 ml. of tetrahydrofuran, 13.5 ml. of water, and 13.5 ml. of 2~
aqueo~s 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 0C. for 30 minutes, the solids were removed by filtration and washed once with a small portion of ice-water and twlce with 20 ml. portions of diethyl ether. The crystalline sodium salt thu~ obtained was dissolved in a stirred mixture of 30 ml. of water and 50 ml~ of dichloro-methane and the pH adjusted to 4Ø 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%); mp.
180-182C; lH-nmr (CDC13) ppm t~):1.42 (s,3, CH3), 1.52 (s,3,CH3), 3.96 (d,J5 6=5 cps, 1,C-6~, 5.93 (q,J3 5=2.7, J5 6=5,1~C-5), 6.98 (d,J=2.7, l,C-3), 7.36 (m,15,C6H5).
When the above reaction is repeated but u~ing acetone as co-solvent in place of tetrahydro~uran and at a temperature of 0C. for 200 hours, the title compound is likewise obtained.
Similarly, when the reaction is carried out at 100C, ~or one hour using 2-methoxyethanol (methyl Cellosolve) as co-solvent, the title compound is obtained.
*penam numbering :: : , - , ...... ' ' , - . . i . .. ~ ~ .... ..
. ~ . .
' ~
~xample 4 ~ I'riphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid via 6-1'r~phenylmethylamino-2,2-dimethyl-3-hydroxypenam 5A. 6-Triphenylmethylamino-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 sodi~ hydroxide solution and the resulting mixture was stirred rapidly for 30 minutes at 25C. Ethyl ether (50 ml.) was then added with stirring and the layers were allowad to separate.
The aqueous layer was discarded and the organic layer was washed three times with 2 ml. portions of water, once with saturated aqueou3 sodium chloride solution, dried over anhydrous sodium sulfate and concen~rated in vacuo to obtain 1.6 g. of semisolid foam. The foam was dissolved in 3 ml. of chloroform and chromatographed on 40 g. o~ silica gel, eluting with chloroform. Seventy fractions, 5 ml. each were collected. Fractions 5-50 were ~ound 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 ln vacuo to obtain 250 mg. of 6-triphenylm~thylamino-2,2~dimethyl-3-hydroxypenam lH-nmr ~CDC13) ppm (~): 1.40 (s,3,CH3), 1.44 (s,3,CH3), 3.23 (d,l,NH), 4.3 (m, 2,C-5 and C-6), 5.13 (s,llC-3), 7.17-7.66 (m,15,C6H5).
B. ~-Triphenylmethylamino-5,5 dimethyl-3-thiazol ne-2-acetic acid, Sodium Salt. _ To a solution of 210 mg~ (0.49 millimoles) ~f 6-triphenylmethylamino-2,2-dimethyl-3-hydroxypenam in one milliliter of tetrahydrofuran was added 0.25 ml. of 2N
sodium hydroxide solution. The resultiny mixture was ~tirred 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 cry~talline residue. To thls was added .... . . .
: . ~, .. ~ . ~
- . . . .
~V15 ~ 8 0.5 ml. of D2O followed by 1 drop of dilute hydrochloric acid to ad]ust the p~ to about 7. T~e resul~iny mixture was stirred for several minuteS after which the solid material was allowed to settle and the liquid drawn o~f with a micropipette. The resulting crystals were dried ln vacuo, then dissol~ed in perdeutro-dimethylsulfoxide.
The 1H-nmr spectrum was identical to that of an authentic specimen of ~he sodium salt of ~-triphenylmethylamino-5,5-dimethyl-3-thiazoline-2-acetic acid. lH-nmr (DMSO-d6) ppm (~); 1.22 (s,3,CH3), 1.32(s,3,CH3), 3.45 (d,l,C-6 )
4.68 (m,l,C-5 ), 6.68 ~d,l,C-3 ), 7.07-7.48 (m,15,C6H5).
*penam numbering . . .
*penam numbering . . .
Claims (3)
1. A process for the production of 6-triphenylmethyl-amino-2,2-dimethyl penam of the formula:
wherein R is hydrogen or acetyl which comprises the step of reacting 6-triphenylmethylamino-2,2-dimethyl penam-3-carboxy-lic acid, or a salt thereof, with lead tetraacetate in a reaction-inert organic solvent at a temperature in the range of about -30° to 80°C. and if required in order to produce a compound wherein R is hydrogen hydrolyzing the product with alkali.
wherein R is hydrogen or acetyl which comprises the step of reacting 6-triphenylmethylamino-2,2-dimethyl penam-3-carboxy-lic acid, or a salt thereof, with lead tetraacetate in a reaction-inert organic solvent at a temperature in the range of about -30° to 80°C. and if required in order to produce a compound wherein R is hydrogen hydrolyzing the product with alkali.
2. The process according to claim 1, wherein said reaction-inert solvent is a member of the group consisting of N,N-dimethylformamide and benzene.
3. A compound of the formula wherein R is as defined in claim 1 whenever obtained by the process of either of claims 1 and 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA330,404A CA1086718A (en) | 1975-10-06 | 1979-06-22 | Process for preparing 6-triphenylmethylamino-2,2- dimethyl-3-(acetoxy or hydroxy) peram |
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61963475A | 1975-10-06 | 1975-10-06 | |
| US619,634 | 1975-10-06 | ||
| US05/680,423 US4031077A (en) | 1975-10-06 | 1976-04-26 | Antibacterial 3-phosphono penams |
| CA261,354A CA1094548A (en) | 1975-10-06 | 1976-09-16 | Antibacterial phosphonopenams and a process for the production |
| CA330,404A CA1086718A (en) | 1975-10-06 | 1979-06-22 | Process for preparing 6-triphenylmethylamino-2,2- dimethyl-3-(acetoxy or hydroxy) peram |
| US680,423 | 1984-12-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1086718A true CA1086718A (en) | 1980-09-30 |
Family
ID=27425941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA330,404A Expired CA1086718A (en) | 1975-10-06 | 1979-06-22 | Process for preparing 6-triphenylmethylamino-2,2- dimethyl-3-(acetoxy or hydroxy) peram |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1086718A (en) |
-
1979
- 1979-06-22 CA CA330,404A patent/CA1086718A/en not_active Expired
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