CH520708A - Orally active alpha-carboxyarlylmethyl-penicillins - Google Patents

Abstract

Orally active alpha-carboxyarylmethyl-penicillins. N3A. Are prepared by treating 6-aminopenicillanic acid or a salt in an inert solvent with an arylmalonic acid ester. The reaction is carried out at temperatures between 0 and 50 degrees C at a pH 5 to 8.

Description

  

  
 



  Process for the production of esters of an α-carboxyaryl- or heteroaryl-methyl-penicillin
The present invention relates to a process for the manufacture of antibiotic agents and, more particularly, to an economically improved process for the manufacture of orally administrable arylmethylpenicillins having an α-carboxy ester group.



   The acylation of 6-aminopenicillanic acid by (1) acid chlorides and (2) simple or mixed acid anhydrides is described in U.S. Pat.



     3 270099, 3 142 673 and 3 173 916; acylation by (3) active derivatives of a substituted malonic acid to produce various esters of α-carboxy-arylmethylpenicillins is mentioned in British Patent No. 1,004,670. In addition, the production of such penicillins by acylation of 6-aminopenicillanic acid with aryl carboxy ketene esters is described in Swiss Patent No.



  501 669 mentioned.



   It has now been found that the acylation of 6-aminopenicillanic acid with a reactive derivative of an aryl-substituted malonic acid occurs easily and thus enables an economical production of the valuable esters of α-carboxyaryl-methylpenicillins, which are very valuable as orally administrable antibiotics are.



   The invention relates to a process for the preparation of esters of an α-carboxy-aryl or



  -heteroarylmethylpenicillins of the formula I.
EMI1.1
 wherein M is hydrogen, sodium, potassium or the cation of an amine. The inventive method is characterized in that a compound of the formula II
EMI1.2
  with an acylating agent of the formula
EMI2.1
 wherein X is chlorine, bromine or the radical -OCOR4, in which R4 is benzyl or lower alkyl., Rl is thienyl, furyl, pyridyl, phenyl or substituted phenyl, with the meaning of lower alkyl, chlorine, bromine, lower alkoxy, di-lower alkylamino or Trifluoromethyl for the phenyl substituent, and R2 isopropylphenyl or a group of the formula
EMI2.2
 means in which formulas Xt is chlorine, bromine, fluorine, lower alkoxy or lower alkyl,

   X2 is lower alkyl or chlorine or Xt and X2 together denote the methylenedioxy group, X5 denotes hydrogen, methyl, phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carboxy-lower alkyl or carbo-lower alkoxy-lower alkyl, X4 denotes nitro or di-lower alkyl-amino and also R2 is mono-substituted phenyl, with the meaning of phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carbo-lower alkoxy-lower alkyl or carboxy-lower alkyl for the phenyl substituent, or ac ac indanyl or substituted ac indanyl with the meaning of methyl, chlorine or bromine for the substituent; or R is acTetrahydronaphthyl or substituted ac is tetrahydronaphthyl with the meaning of methyl, chlorine or bromine for the substituent;

   or R2 1-lower alkoxy-2,2,2-trichloroethyl, or R2 1-lower alkoxy-2, 2,2-trifluoroethyl, (carbo-lower alkoxy) -lower alkoxymethyl, di (carbo-lower alkoxy) -lower alkoxymethyl, 3- [ 1- (Rs-substituted) -piperidyl], ¯ (CH2) m -NR5R ", -CH2CH (CH3) -NR5R6, -CH (CHS) -CH2NR5R6 or - (lower alkylene) -Y1, in which formulas m is a whole A number from 2 to 3, R5 is hydrogen, lower alkyl or benzyl, R is lower alkyl, lower alkanoyl, benzyl, phenyl or carbo-lower alkoxy, with the proviso that when R5 is hydrogen, R6 is lower alkanoyl or carbo-lower alkoxy, and Y is azetidino, aziridino, pyrrolidino , Piperidino, morpholino, thiomorpholino, N- (lower alkyl) -piperazino,

   Pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethyl-pyrrolidino, 1, 4,5,6-tetrahydropyrimidino, 4-methylpiperidino or 2,6-dimethylpiperidino, where each of the lower alkoxy, lower alkanoyl and lower alkyl radicals is 1 has up to 4 carbon atoms and the lower alkylene radical contains 1 to 3 carbon atoms, or R2 is the group of the formula
EMI2.3
 represents, in which Z is - (CH2) S- or (CH2) 4 or substituted derivatives of this group, the substituent being methyl, chlorine or bromine, or R2 is -phenylallyl or y- (substituted-phenyl) -allyl , in which the substituent is at least one chlorine, bromine and / or fluorine atom and / or at least one lower alkoxy, lower alkyl, nitro and / or methylenedioxy group,

   or y-phenylpropargyl or y- (substituted-phenyl-propargyl means in which the substituent is chlorine, bromine, lower alkoxy, lower alkyl or nitro, in an aqueous or anhydrous solvent system at temperatures from 0 to 500 ° C. and at a pH of about 5 to 8 condensed.



   Salts of the penicillin ester of the formula I in which M is a tri (lower alkyl) ammonium cation, for example, can be prepared by the process according to the invention. Compounds of the formula I in which R 1 is the phenyl radical and R 2 is either an isopropylphenyl radical or the radical of the formula can be prepared by the process according to the invention
EMI3.1
 In the latter case, the substituent X is preferably a lower alkyl group and the substituent X3 is preferably a hydrogen atom.



  Preferred meanings for X1 are lower alkyl, chlorine and lower alkoxy, where X1 can be, for example, the methyl or methoxy radical in the 2-position or a chlorine atom in the 4-position. If X is a lower alkyl radical, this can be, for example, a methyl radical in the 2-position or 4 position.



   Preferred compounds prepared by the process according to the invention in which R2 is a substituted phenyl radical are those in which R2 is the diphenyl radical. Preferred compounds prepared by the process according to the invention in which R2 is a group of the formula
EMI3.2
 are also those in which Rl has the meaning of a phenyl radical.



   The purity of the 6-aminopenicillanic acid is not critical for the successful implementation of the process according to the invention. You can use 6-aminopenicillanic acid in the pure form, but you can also use the partially pure form or the crude acid, as it is contained in fermentation broths. The use of water as a solvent favors the use of fermentation broths containing 6-aminopenicillanic acid from an economic point of view.



   The solvent system used can be those solvents or solvent mixtures which, when the process is carried out, do not undergo any noticeable reaction with either the starting materials or the end products. You can use aqueous as well as anhydrous solvents. When water is used as the solvent, there is of course a certain hydrolysis of the acid chloride starting product. With the correct selection of the reaction temperature, the pH values and the reaction time, the hydrolysis takes place rather slowly compared to the desired N-acylation reaction. Suitable solvents for the process according to the invention include: methylene chloride, benzene, chloroform, dioxane, water, acetone, tetrahydrofuran, diethyl ether and dimethyl ether.

  One can also use aqueous solvent systems, including those in which an emulsion is formed, e.g. B. Water- immiscible solvent with water. Solvents that easily form an emulsion with water are water-immiscible solvents such as e.g. B. benzene, n-butanol, methylene chloride, chloroform, methyl isobutyl ketone and lower alkyl acetates (such as ethyl acetate). The preferred water-immiscible solvent is methyl isobutyl ketone or ethyl acetate.



   When carrying out the process according to the invention, the pH range is 5 to 8, preferably 6 to 7. By adding a suitable acid acceptor, such as. B. an alkali or alkaline earth you can keep the pH at the neutral point. It is also possible, which is preferably carried out, to use a salt of 6-aminopenicillanic acid with an organic base so that the pH is close to the neutral point. Any organic base which salts with the 6-aminopenicillanic acid can be used. Suitable organic bases are e.g. B. tri-lower-alkylamines, dibenzylamine, N, N'-dibenzylethylenediamine, N-lower-alkylpiperidines, N-lower-alkyl-morpholines, N-benzyl ss-phenethylamine, N, N'-bis-dehydroabietylamine, dehydroabietylamine and l -Ephenamine. However, it is advantageous to use a tri-lower-alkylamine as the organic base, in particular triethylamine.

  Such bases have the advantage that they form salts with 6-aminopenicillanic acid which are soluble in many of the solvents mentioned above. They are particularly useful when using an anhydrous solvent system, such as. Methylene chloride are useful.



   According to the invention, the process is carried out at temperatures from 0 to 500.degree. However, it is preferred to use temperatures from about 0 to about 300 ° C to prevent degradation of the products.



   The preferred compounds used as acylating agents are the monoacid chlorides because they are much easier to prepare than the anhydrides.



   Malonic acid monoesters used as starting materials can be obtained by reacting the corresponding chlorocarbonyl ketene of the formula
EMI3.3
 with the corresponding alcohol of the formula R5OH, the substituents R and R2 being defined above. The reaction is preferably carried out at a 1: 1 molar ratio at temperatures from about -70 to about +300 ° C. It is preferable to work in a reaction-inert solvent in order to achieve better mixing and control of the reaction. Suitable solvents are e.g. B. diethyl ether, dimethyl ether, dioxane, methylene chloride and chloroform.

 

   The reaction mixture is then generally treated with water and a base, such as, for. B. sodium bicarbonate added. If the temperature of the reaction mixture is below the freezing point of water, it is heated to at least 0 ° C., either before or after the addition of water or the base. A sufficient amount of the base is added, generally 2 or 3 equivalents, to neutralize the hydrogen chloride formed as a by-product and to form the salt of the arylmalonic acid monoester. The mixture is then stirred for about half an hour and then the organic solvent is removed in vacuo at a temperature of less than 35.degree.

  The remaining solution is extracted with ether, cooled to 10 to 150 C and then the pH is adjusted to about 2. The acidic solution is extracted with a suitable solvent, e.g. B. methylene chloride, then the extract is dried and the solvent is removed in vacuo.



   The aryl or heteroarylmalonic acid monoesters prepared in this way can be prepared by reaction with an excess of thionyl chloride, usually in the presence of an inert solvent, such as. B. benzene, diethyl ether or methylene chloride can be converted into their mono-acid chloride derivatives at temperatures from about 0 to about 80 "C by known methods.



   The required aryl-chloro-carbonyl ketenes or



  Heteroaryl-chlorocarbonyl ketenes can be prepared by reacting an aryl or heteroarylmalonic acid with a halogenating agent. The halogenating agent used is usually phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride or thionyl chloride, and the reaction temperatures are generally from about 0 to about 50 ° C. with a reaction time of about one to about 10 hours. The reaction is usually carried out in the presence of a solvent system, preferably in the presence of a reaction-inert solvent system. Suitable solvents are dialkyl ethers, such as. B. diethyl ether, dipropyl ether, mono- and dimethyl ethers of ethylene glycol and propylene glycol, methylene chloride and chloroform.



   The reaction time naturally depends on the reaction temperature and also on the nature of the starting products. For a given combination of starting materials, lower temperatures require longer reaction times than higher temperatures.



   The molar ratios of the starting materials, namely the aryl or heteroarylmalonic acid and the halogenating agent, can vary within wide limits; so e.g. up to 1:10 or higher, but at least stoichiometric amounts should be used for good yields, which is also generally preferred in practice. You can add the starting materials all at once to the reaction or also separately. If a separate addition is made, the order of addition is not critical. However, it appears that the reaction is less violent and fewer side reactions occur, as can be seen in particular from the color of the reaction mixture during the distillation if the aryl or. Heteroarylmalonic acid is added to the halogenating agent.

  If such working conditions are observed, the color of the reaction mixture generally changes from yellow to red. If the halogenating agent is added to the aryl or heteroarylmalonic acid, the reaction mixture changes color from yellow to black.



   The aryl- or heteroarylhalocarbonyl ketenes prepared in this way can be isolated from the reaction mixture by distillation in vacuo. Because of their high reactivity, these compounds are generally stored in a nitrogen atmosphere at low temperatures and with the exclusion of light.



   Acid anhydride derivatives of half-esters of Arylbzw. Heteroarylmalonic acid can be obtained by reacting the half-ester with a chloro-lower alkyl carbonate in the presence of an acid acceptor, such as. B. pyridine or a tri-lower-alkylamine can be prepared. Such reactions are described in J. Am. Chem. Soc. 75, 637-9 (1953) and J. Org. Chem. 22, 248 (1957).



  As is known to the person skilled in the art, other chlorine carbonates can be used instead of the chlorine-lower alkyl carbonates, such as. B. chlorobenzyl carbonate or chlorine phenyl carbonate.



   The a-carboxyarylmethylpenicillin ester or



  α-Carboxyheteroarylmethylpenicillin esters can be isolated by known methods. A typical method is based e.g. B. on the use of water as a solvent, adjustment of the pH of the reaction mixture to about 2 to 3 and extraction of the product with ethyl acetate. The ethyl acetate extract is then usually washed with water, the product is extracted therefrom with a 10 0 / above aqueous potassium bicarbonate solution and then it is extracted back into ethyl acetate. The ethyl acetate extracts are extracted again with water, the pH of the aqueous extract is adjusted to 2 to 3 and extracted back with ethyl acetate. The product can be isolated by removing the liquid substances.

  However, it is also possible to isolate the product in the form of an alkali or amine salt by adding the appropriate base, an inorganic or organic base, to the dry ethyl acetate extract.



   When using an aqueous emulsion as the solvent, it is advisable to isolate the product by extracting the reaction mixture after adjusting the pH to 2 with a suitable water-immiscible solvent. In this case, ethyl acetate has proven particularly useful. The extract can then be dried and evaporated to dryness. The product can then be converted into an amine or alkali salt by adding an appropriate base. One gives z. B.



     N-Sithylpiperidin or Kaliumäthylhexanoat to a solution of the ester in a suitable solvent, such as. B. ethyl acetate.



   Another valuable method is based on carrying out the acylation in an anhydrous solvent system; the implementation is z. B. carried out in methylene chloride, water is added to the reaction mixture and then the pH of the aqueous phase is adjusted to about 2-3. The aqueous phase is separated off, extracted with an anhydrous solvent, and the combined anhydrous solvent layers are then dried. By adding a suitable base, such as. B.

 

     The products can be precipitated from the anhydrous solvent in the form of their corresponding salts by using N-ethylpiperidine or by adding sodium or potassium 2-ethylhexanoate. However, it is also possible to remove the anhydrous solvent after drying by distillation at a low temperature, to take up the residue in a suitable solvent and then to precipitate the product from the solvent by adding an appropriate base. This last-mentioned second method allows a greater latitude with regard to the selection of the base. The appropriate solvent is determined by the solubility of the salt desired.



   The esters can be converted into the corresponding acids by known methods, such as. B.



  by weakly acidic or weakly alkaline hydrolysis or by enzymatic means with an esterase, such as. B. a liver homogenate.



   Preferred esters are those in which R2 is indanyl, 2-isopropyl-phenyl, dimethyl-substituted-phenyl or chlorine-substituted-tolyl. These esters, as well as other esters which can be prepared according to the invention, are antibiotics which are effective both in vivo and in vitro. B. extremely effective in treating a variety of sensitive gram-positive and gram-negative infections in animals and humans.



  For this purpose, the pure substances or mixtures of these substances with other antibiotics can be used. They can be administered alone or together with a pharmaceutical carrier which is appropriate for the desired route of administration. The new connections can e.g. B. be administered orally in the form of tablets containing such additives as starch, lactose, certain types of clay, etc .; however, they can also be present in capsules, alone or in a mixture with the same or equivalent additives. It is also possible to administer them orally in the form of elixirs or suspensions which contain taste-improving substances or colorings. They can be injected, e.g. B. intramuscular or subcutaneous.

  For this parenteral administration, it is best used in the form of a sterile, aqueous solution consisting of either water, isotonic saline, isotonic dextrose, or Ringer's solution. But you can also use non-aqueous solutions, such as. B. oils of vegetable origin (cottonseed oil, peanut oil, corn oil or sesame oil) or other non-aqueous vehicles that have no influence on the therapeutic effectiveness of the preparation and are non-toxic in the proportions or proportions in which they are used (glycerine, propylene glycol, Sorbitol). It is also possible to produce compositions of this type which are suitable for the preparation of solutions directly before administration. Such compositions can contain liquid diluents, such as. B. propylene glycol, diethyl carbonate, glycerin, sorbitol, etc.

  Buffering agents as well as local anesthetics and inorganic salts can be present to produce desired pharmacological properties.



   The oral and parenteral dosage levels of the compounds which can be prepared according to the invention are generally up to 200 mg / kg of body weight or 100 mg / kg of body weight per day.



   Many of the penicillin ester compounds which can be prepared according to the invention show an improved absorption when administered orally compared to the corresponding free acid or to the compounds in the form of alkali salts. They therefore represent convenient as well as effective dosage forms of α-carboxyarylmethyl penicillin.



   In addition, many of the esters described here, although they are inactive or have a relatively low activity against gram-negative organisms per se, are converted into the corresponding acid, namely into α-carboxybenzylpenicillin, upon parenteral injection in humans and animals.



   Preferred embodiments of the process according to the invention are described in the following examples.



   Example I.
The N-sithylpiperidine salt of a- [Carbo- (5-indanyloxy) -benzyl-penicillin
A mixture of 17.3 g (0.08 mol) of 6-aminopenicillanic acid in 125 ml of methylene chloride and 16.2 g of triethylamine (0.16 mol) is stirred in a bottle for 2 hours in a nitrogen atmosphere at room temperature. The mixture is then cooled to 0 ° C. (still in a slow stream of nitrogen) and 21.9 g (0.07 mol) of 2-phenyl-2 - (- indanyl-oxycarbonyl) acetyl chloride in 30 mm of methylene chloride are added as quickly as possible from a dropping funnel into the mixture mentioned, keeping the exothermic reaction temperature at less than 150 ° C. by cooling with an ice bath. The ice bath is removed and the mixture is stirred very vigorously for a further 11/2 hours.

  135 ml of water are then added to the mixture and the mixture is stirred for an additional 2 minutes. The pH is lowered from 8 to 2 by adding 6N hydrochloric acid (15 ml). Then the mixture is stirred vigorously for another 10 minutes and the organic layer separates. The acidic aqueous layer is extracted twice with 67 ml of methylene chloride each time, the methylene chloride layers are combined, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo at a temperature of less than 350 ° C. A slightly yellowish foam is obtained, which is dried to give crude penicillin. The yield is 34.4 g or 99 / o. 17 g (0.0344 mol) of the crude penicillin are dissolved in 40 ml of acetone and the mixture is cooled to 100.degree.

  Then 3.96 g (0.035 mol) of N-ethylpiperidine are added to the mixture. This mixture is stirred for one minute and the white, crystalline salt which separates out is separated off by filtration, washed with acetone and finally dried. 17.9 g of 86% yield of this salt are obtained, which has a melting point of 143 to 1450 ° C. with decomposition.



   This salt is further purified by slurrying in acetone (10 g / 100 ml) at 40 ° C., cooling to room temperature, filtering and drying. 80 per cent of the salt can be recovered; the salt has a melting point of 149 to 151 "C. when decomposed.



   This salt is converted into the potassium salt as follows: 1.93 g (10.6 mmol) of potassium ethylhexanoate are added to a suspension of 5 g (8.2 mmol) of N-ethylpiperidine salt in 75 ml of ethyl acetate at room temperature. The mixture is then heated to 45 ° C. for 2 minutes, allowed to cool to room temperature and then cooled in an ice bath to 0 C. The potassium salt can be isolated by filtration, it is then washed with ethyl acetate and dried; , 2 g, 96.1% yield The product has a melting point of 198 to 1990 C with decomposition.

  Using sodium ethyl hexanoate, the sodium salt can be prepared in the same way; this has a melting point of 182 to 1840 C. with decomposition.



   Example 2
The N-ethyl piperidine salt of α - [Carbo (2-isopropylphenoxy)] benzylpenicilin
A mixture of 3.74 g (17.3 mmol) of 6-aminopenicillanic acid, 50 ml of methylene chloride and 3.5 g (35 mmol) of triethylamine is stirred vigorously at room temperature under nitrogen for 1 1/2 hours and then cooled to 0.degree. A solution of 4.3 g (14.4 mmol) of 2-phenyl-2- (2-isopropylphenoxycarbonyl) acetyl chloride in 5 ml of methylene chloride is then quickly added and the reaction mixture is stirred for a further hour at room temperature. Water is then added 20 times, the mixture is stirred for 2 minutes, cooled to 100 ° C. and the pH is adjusted to 2 by adding 6 normal hydrochloric acid.

  The mixture is stirred for a further 5 minutes, after which the methylene chloride layer separates, it is dried and evaporated to dryness, the crude penicillin being obtained, which is represented by a cream-colored foam; 4.4 g are obtained.



   550 mg (1.12 mmol) of crude penicillin in 1 ml of ethyl acetate are reacted with 147 mg of N-ethylpiperidine at room temperature. Stir for 2 minutes, then cool to 0 ° C., filter and dry to form the desired salt; the yield is 92%, 625 mg. The product has a melting point of 139 to 1400 C. The total yield of amine salt, based on the acid chloride used as the starting product, is 84.2%.



   The N-ethylpiperidine salt is converted into the potassium salt as follows:
100 ml of benzene are placed in a three-necked flask of 250 ml capacity and 50 ml of benzene are then distilled off. 3 g (5 mmol) of N-ethylpiridine salt are then added to the refluxing benzene and, after the addition, the mixture is cooled to room temperature. 3.2 ml of a 26% strength acetone solution of potassium ethyl hexanoate are then added to the mixture and the mixture is heated to 450 ° C. for 3 minutes. The mixture is again allowed to cool to room temperature, cooled further to 0 ° C., filtered and dried. The yield is 2.1 g, 78%; the product has a melting point of 180 to 1820 ° C. with decomposition. The sodium salt can be prepared in the same way, replacing sodium ethylhexanoate for potassium ethylhexanoate.

  The melting point of the sodium salt is 170 to 1720 C with decomposition, and the product was crystallized from isopropanol or ethyl acetate.



   Example 3
The following esters of α-carboxybenzyl penicilins can be prepared according to the procedure of Example 1 in the form of their N-ethylpiperidine salts.
EMI6.1




     R2 melting point
R2 Schenmelzpu in C 2,5-dimethylphenyl 144-150 2,4-dimethylphenyl 142144 2,3-dimethylphenyl 151-153 2,6-dimethylphenyl 150-151 3,4-dimethylphenyl 145-147 3, 5-dimethylphenyl 147-149 2-chloro-4-methylphenyl 144-145 4-chloro-2-methylphenyl 149-151 6-chloro-2-methylphenyl 153-154 R2 melting point
R2 melting pu in C 4-chloro-3-methylphenyl 141-142 2-methoxy-4-methylphenyl 150-152 3-methoxy-2-methylphenyl 150-152 4-indanyl 136-139 2- (5,6,7,8 -Tetrahydronaphthyl) 138-139 1- (5,6,7,8-tetrahydronaphthyl) 136139 4-chloro-3,5-dimethylphenyl 140-142 4-chloro-2,

   3 dimethylphenyl 144-147 3,4-methylenedioxyphenyl 146-148
Example 4
This example describes the preparation of a- [carbo- (2-isopropylphenoxy] -benzylpenicillin) from a fermentation broth which contains 6-aminopenicillanic acid.



   The fermentation broth, which has the 6-aminopeni cillanic acid, can by the method of
Example 1 of U.S. Patent No. 3,239,427 can be prepared by enzymatic hydrolysis of
Benzylpenicillin with Proteus rettgeri.



   1.5 l of the broth with 0.5 g of calcium chloride and 3 g of diatomaceous earth are added at room temperature 10
Minutes and then filtered. The clarified broth (1 liter) contains 5.4 g (0.024 mol)
6-aminopenicillanic acid. It is then placed in a rotary necked flask fitted with a well-functioning tube. Then add 10 g (0.0135
Moles) 2- (2-isopropylphenoxycarbonyl) acetyl chloride dropwise at room temperature for one
Hour to the broth. The pH of the mixture is maintained by the constant addition of 10% aqueous
Potash lye between 6.3 and 6.5. The mixture is then stirred for an additional hour at room temperature and a pH of 6.3 to 6.5, and finally the pH is adjusted by adding
6 normal hydrochloric acid to 2 one.



   The acidic solution is extracted 3 times with each
200 ml of ethyl acetate, washes the combined extracts with
Water, filtered and extracted the filtrate with
10% of the above aqueous potassium bicarbonate (500 ml). The aqueous layer is separated off, saturated with potassium chloride and extracted back twice with 200 ml of ethyl acetate each time. The combined ethyl acetate extracts are washed three times with 100 ml of water each time, the water extracts are combined and acidified by addition
6 normal hydrochloric acid to a pH of 2. A precipitate forms, which you can use twice each
75 ml of thenyl acetate extracted. The extract is dried with anhydrous sodium sulfate, filtered and finally evaporated to dryness in vacuo at 35.degree.



   5.4 g of a residue are obtained, which is represented by an oily foam. This is dissolved in 10 ml of ethyl acetate and 1.13 g (0.01
Mol) N-Ethylpiperidin at room temperature. A crystalline product separates out immediately. The mixture is cooled, then filtered and the product is washed with ethyl acetate and dried. 5.85 g, 40% yield, with a melting point of 146 to 1480 ° C. with decomposition are obtained.



   Example 5
This example is repeated, but with pH values of 3.0-3.3, 5-5.3 and 8.5-8.8 during the acylation and the desired product can also be obtained in this way. However, the yields are lower.



   Example 6
The potassium salt of a [Carbo- (2-isopropylphenoxy) -benzylpenicillin]
The pH of an aqueous suspension of 10.8 (0.05 mol) 6-aminopenicillanic acid in 500 ml of water is adjusted to 6.4 by adding 6 normal sodium hydroxide solution. 19 g (0.06 mol) of 2- (2-isopropylphenoxycarbonyl) acetyl chloride are added dropwise to this solution over the course of one hour at room temperature. The pH value is maintained at 6.3 to 6.5 by continuously adding 10% sodium hydroxide solution. The reaction mixture is stirred for 1.25 hours at room temperature and a pH of 6.3 to 6.5, and then the pH is adjusted to 2 by adding 6 normal hydrochloric acid. 500 ml of ethyl acetate are then added to the mixture and the mixture is stirred for a good 5 minutes.

  The ethyl acetate layer is separated off, concentrated to a volume of about 200 ml and then reacted with 0.07 mol of potassium ethylhexanoate. Concentrate the mixture further to a small volume, about 50 ml, add 100 ml fresh ethyl acetate and repeat concentration. This step is repeated again, then the crystalline salt is filtered off, washed with ethyl acetate and dried.



  The yield is 6.8 g, 25.4%.



   Example 7
Acylation of 6-aminopenicillanic acid in an aqueous emulsion
To a solution of 31.6 g (0.1 mol) of 2-phenyl 2- (2-isopropylphenoxycarbonyl) acetyl chloride in 250 ml of methyl isobutyl ketone is added in one portion at 25 C a solution consisting of 10.8 g (0, 05 mol) 6-aminopenicillanic acid and 100ml water and has a pH value of 6.4. Vigorous stirring is used and the pH is kept at 6 by constant addition of 10% aqueous sodium hydroxide solution.



   After 6 minutes, a further 250 ml of methyl isobutyl ketone are added, the emulsion is stirred and the pH is then adjusted to 2 by adding dilute hydrochloric acid. The solution is extracted three times with 200 ml of ethyl acetate each time, the combined extracts are washed with water and then dried with anhydrous sodium sulfate. The dry extract is evaporated to dryness, the residue is taken up in ethyl acetate and treated with 6.0 g of N-ethylpiperidine to form the corresponding salt, which can be separated off by filtration.

 

   The corresponding 5 indanyl, 2,4-dimethylphenyl, 2-methyl-4-chlorophenyl, 3,4-dimethylphenyl and 4-indanyl esters are prepared in the same way by using the acid chloride of the corresponding phenylmalonic acid half-esters instead of isopropylphenyl ester.



   When the process described above is repeated using 2-phenyl-2- (2-isopropylphenoxycarbonyl) acetyl chloride, but with pH values between 3.5 and 8.0, the desired product is also obtained, but with a very high low yield.



   Example 8
The following compounds can be prepared by the method of Example 2 from the corresponding arylmalonic acid half-esters in the form of their N-ethylpiperidine salts.
EMI8.1




   R2 o-dimethylaminophenyl o-di-n-butylaminophenyl m-dimethylaminophenyl m-di-n, -propylaminophenyl p-methylethylaminophenyl p-methylisopropylaminophenyl 2,3-diethylphenyl 4,5-dimethyl-2-isopropylphenyl 2,6-dichlonphenyl 4-isopropylphenyl 3-chloro-2-fluorophenyl, 2-bromo-4-fluorophenyl,

   2-methoxy-4-methylphenyl 2-chloro-6-methoxyphenyl 3-methoxy-2-methylphenyl 2-methoxy-6-propylphenyl 6-chloro-2-methylphenyl 2-fluoro-4-methylphenyl 2-bromo-6-methylphenyl 2 -Bromo-4-t-butylphenyl 2-chloro-5-fluorophenyl 4-chloro-2-isopropylphenyl 2,6-diethylphenyl 2,4-di-n-propylphenyl 5-sithyl-3-methylphenyl 2-methyl-4-sec .-butylphenyl 3 methyl 4 -t-butylphenyl
R2 15 2,4,6-trimethylphenyl
2,6-dimethyl-4-ethylphenyl
6-chloro-5-indanyl 20
1,1,7-trimethyl-4-indanyl
1-indanyl 25 2-indanyl
6-methyl-5-indanyl
3-methyl-1-indanyl 30
2,2-dimethyl-1-indanyl
2,3-diethyl-1-indanyl 35 2-chloro-1-indanyl
3-bromo-1-indanyl
1-chloro-2-indanyl 40
1,5,6,7,8-tetrahydronaphthyl
2- (5,6,7,8-tetrahydronaphthyl) 45 1- (4-methyl-5,6,7,8-tetrahydronaphthyl
5-chloro-2,4-dimethylphenyl
2-chloro-3

   , 4-dimethylphenyl 60
2-chloro-4-isopropylphenyl
2-Isobutyl-4-fluorophenyl 55 6-Bromo-3,4-dimethylphenyl
4-chloro-2,6-dimethylphenyl 4-chloro-6-isopropyl-3-methylphenyl 60 4,6-dichloro-2-methylphenyl
5-methyl-4-indanyl 65 1-methyl-4-indanyl 1-methyl-5-indanyl
R2 7-methyl-5-indanyl 6-t-butyl-5-indanyl 1,1-dimethyl-4-indanyl 1,1,2-trimethyl-4-indanyl 5-chloro-4-indanyl 7-bromo-4- indanyl 2- (2,6-dimethyl-1,2,3,4-tetrahydronaphthyl) 1- (2-chloro-1,2,3,4-tetrahydronaphthyl) 2- (1-methyl-5,6,7, 8-tetrahydronaphthyl) 1- (4,4-dimethyl-5,6,7,8-tetrahydronaphthyl) 2- (1,6-dimethyl-5,6,7,8-tetrahydronaphthyl) 1- (2,4,6 -Trimethyl-5,6,7,8-tetrahydronaphthyl) 2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl) 1- (2-methyl-1,2,3,4 tetrahydronaphthyl)

   1- (3,4-dimethyl-1,2,3,4-tetrahydronaphthyl) 2- (6-methyl-1,2,3,4-tetrahydronaphthyl) 2- (n-isopropylanilino) ethyl 2- (Nn- Butylanilino) ethyl 2-methylbutylamino-1-propyl 2- (methylbutylamino) -1-propyl 3-aziridino-2-propyl 2- (1-bromo-1,2,3,4-tetrahydronaphthyl 2-dimethylaminoethyl 2-dibutylaminoethyl 2 - (2-Imidazolino) ethyl 2-piperidinoethyl 2-pyrrolidinoethyl 2-imidazoloethyl 2-morpholinoethyl 2-azetidinoethyl 2- (2,5-dimethylpyrrolidino) ethyl 2-aziridinoethyl 2-thiomorpholinoethyl
R2 2- (4-methylpiperidino) ethyl pyrrolidinomethyl aziridinomethyl (2-midazolino) methyl (1,4,5,6-tetrahydropyrimidino) methyl pyrrolidinomethyl piperidinomethyl 2-piperidino-1-propyl 2- (n-ethyl) piperazino -1-propyl <RTI

    ID = 9.9> 2-di- (n-propyl) -amino-1-propyl 3- (N-ethylanilino) -2-propyl 2- (N-methylanilino) -1-propyl 1-ethoxy-2,2,2 -trichloroethyl 1-butoxy-2,2,2-trichloroethyl 1-ethoxy-2,2,2-trifluoroethyl 1-isopropoxy-2,2,2-trichloroethyl dicarbomethoxyethoxymethyl 4-dimethylamino-2-methylphenyl 2-methyl-6-nitrophenyl 3-diethylaminopropyl 3-dibutylaminopropyl 3- (2-imidazolino) propyl 3-piperidinopropyl 3-pyrrolopropyl 2- (1,4,5,6-tetrahydropyrimidino) ethyl morpholinomethyl thiomorpholinomethyl 2-acetamidoethyl 2-butyraminoethyl 2- (ethyl) isopropyl ethyl 2- (2,6-dimethylpiperidino) ethyl 2- (N-methylanilino) ethyl 3-di- (n-butyl) amino-2-propyl
R3 3-Dimethylamino-2-propyl 2-pyrrolidino-1-propyl 2-thhlomorpholino-1-propyl 2- (imidazolino) -1-propyl 3

   -Imid azolidino2-propyl 3- (methylpropylamino) -propyl 3- (ethylisopropylamino) -propyl 3- (methylethylamino) -2-propyl 3 -imidazolo-2-propyl 3-pyrrolo-2-propyl 2-morpholino-1-propyl 3 - (2-Imid azolino) -2-propyl 3- (N-methylanilino) -propyl 2- (N-methyl) -piperazinoethyl 3-N-butylpiperazinopropyl 3 -Dimethylaminopropyl 3 -Di- (n-propyl) aminopropyl 3 - Di- (n-propyl) -amino-2-propyl 2-diethylamino-1-propyl 3-pyrrolidino-2-propyl 3 -piperidino-2-propyl 3-morpholino-2-propyl 2-methoxy-4- (2- carbomethoxy-vinyl) -phenyl 2,6-dimethoxy-4- (2-carboxyvinyl) -phenyl 2-chloro-3 - (2-carboxyvinyl) -phenyl 2- (2-carboxyvinyl) -6-nitro-4-biphenyl 2 , 4-dimethyl-6- (carboxymethyl) phenyl 4-t-butyl-2-biphenyl 3-methoxy-2-biphenyl, 2-isopropyl-4-methoxyphenyl 3 - (N-methylanilino) -2-propyl

   2- (Nn-propylanilino) -1-propyl 1-methoxy-2,2,2-trichloroethyl Re 1-butoxy-2,2,2-trifluoroethyl carbethoxyethoxymethyl 1 -t-butoxy-2,2,2-trichloroethyl 2- Nittophenyl 2-methyl-5-nitrophenyl 4-biphenyl 2-chloro-3-biphenyl 2-bromo-4-biphenyl 2-nitro-4-biphenyl 2-dimethylamino-5-biphenyl 2-carbomethoxymethylphenyl 4- (2-carboxyethyl) - phenyl 4- (2-carbethoxyethyl) -phenyl 4- (2-carboxyvinyl) -phenyl 2-methoxy-4- (2-carboxyvinyl) -phenyl 2-N, N-dibenzylaminoethyl 2-N-methyl-N-benzylaminoethyl 3 - N, N-dibenzylamino-2-propyl 5-dimethylamino-2-isopropylphenyl 2-N-methyl-N-formylaminoethyl 2-N-methyl-N-acetylaminoethyl 2-N- (n-butyl) -N- (formylaminoethyl 2- N- (n-Butyl) -N-acetylaminoethyl 3-N- (Isopropyl) -N-acetylaminopropyl <RTI

    ID = 10.12> 2-N-methyl-N-carbomethoxyaminoethyl 2-N-methyl-N-carbo- (isobutoxy) -aminoethyl 3 -N-formylaminopropyl 3-N-acetylaminopropyl 3 -N-carbo- (isobutoxy) aminopropyl y -Phenylpropargyl γ- (3,4-Dimethoxyphenyl) -propargyl 2-N- (n-butyl) -N-benzylaminoethyl 2-N- (n-butyl) -N-butyrylaminoethyl
R2 2-N-carbomethoxyaminoethyl 2-N-benzyl-N-carbomethoxyaminoethyl 2-N-benzyl-N-acetylaminoethyl 3-piperidyl
3- (1-methylpiperidyl)
3 - (1-n-Butylpiperidyl) 3- (1-Benzylpiperidyl) γ-phenylallyl γ- (4-chlorophenyl) allyl γ- (4-methoxyphenyl) allyl γ- (3,4-methylenedioxyphenyl) allyl γ- (2-nitrophenyl) allyl γ- (4-isopropoxy-3-methoxyphenyl) allyl γ- (3-fluorophenyl) allyl γ-

  ;- (2,4,5-Trichlorophenyl) -allyl y- (3-bromophenyl) -allyl r- (4-methylphenyl) -allyl γ- (2-chloro-4-methylphenyl) -allyl y- (2- Chlorophenyl) -propargyl y- (4-nitrophenyl) -propargyl y- (m-tolyl) -propargyl y- (4-isopropylphenyl) -allylγ- (2,5-dimethyl-4-methoxyphenyl) -allyl y- ( 3-methoxy-4-ethoxyphenyl) allyl y- (3-chloro-4-methoxyphenyl) allyl y- (3-methyl-6-nitrophenyl) allyl y- (2,6-dinitrophenyl) allyl y- (4 -n-butoxyphenyl) allyl
Example 9
The following penicillins can be prepared from the corresponding arylmalonic acid half-esters and 6-aminopenicillanic acid using the method of Example 1.
EMI11.1




   For each value of the substituent R2 given below, R1 denotes 2-thienyl '3-thienyl-, 2-pyrydyl, 2-furyl and o-tolyl; R4 represents a penicillanic acid residue.



   Re 1-methoxy-2,2,2-trichloroethyl 1-butoxy-2,2,2-trichloroethyl 1-ethoxy-2,2,2-trifluoroethyl 2-isopropylphenyl 2,6-dimethylphenyl 3-methyl-4-t -butylphenyl 4,5-dimethyl-2-isopropylphenyl 2,4-dimethyl-3-ethylphenyl 2,6-dichlorophenyl 2-dimethylaminoethyl 2-dibutylaminoethyl 2- (2-imidazolino) ethyl 2-piperidinoethyl 2-morpholinopropyl 3-thiomorpholinopropyl 2-pyrrolidinoethyl 2- (2-imidazolino) ethyl 2-pyrroloethyl 4-dimethylamino-2-methylphenyl 2 - (; b;

  ; thylbutylamino) ethyl 2-arizidinoethyl 2-chloro-5-methylphenyl 2-chloro-4-isopropylphenyl 4-chloro-2,3-dimethylphenyl 2-isobutyryl-4,6-dimethylphenyl 2-chloro-6-propylphenyl o-dimethylaminophenyl o-di-n-butylaminophenyl p-methylethylaminophenyl 2- (N-methylanilino) ethyl 2- (diisopropylaminoethyl
R2 3-diethylaminopropyl 2- (N-methyl) piperazinoethyl 2- (1,4,5,6-tetrahydropyrimidino) ethyl 3-imidazolopropyl 3-di-) n-propylamino) -2-propyl 3-pyrrolidino-2- propyl 3-diethylamino-2-propyl 3-morpholino-2-propyl 3-dimethylamino-2-propyl 3-diisopropylaminopropyl 2- (N-ethylanilino) ethyl 2-chloro-6-methoxyphenyl 2-ethoxy-3-methylphenyl 3- Pyrrolo-2-propyl 3- (2-imidazolino) -2-propyl 3-imidazolo-2-propyl 2-dimethylamino-1-propyl

   2-pyrrolo-1-propyl 2- (2,5-dimethylpyrrolidino-1-propyl arizidinomethyl piperidinomethyl (2-imidazolino) methyl (4-methylpiperidino) methyl pyrrolomethyl 2- (N-methylanilino) -1-propyl 2-nitrophenyl 4-methyl-2-nitrophenyl dicarbethoxyethoxymethyl carbethoxyethoxymethyl 4-indanyl 3-piperidinopropyl 3-pyrrolidinopropyl 3 - (methylethylamino) -2-propyl Re 1- (5,8-dimethyl-1,2,

   3, 4-tetrahydronaphthy1) 2- (1-methyl-1,2,3,4-tetrahydronaphthy1) 2- (1,2,3,4-tetrahydronaphthyl 1- (3-methyl-5,6,7,8- tetrahydronaphthyl 2-biphenyl 4-biphenyl 2-chloro-3-biphenyl 2-bromo-4-biphenyl 2-nitro-4-biphenyl 2-dimethylamino-5-biphenyl 2-t-butyl-4-methoxyphenyl 4-carbethoxymethylphenyl 2-carbomethoxyphenyl 4- (Carbo-n-butoxy) methylphenyl 4- (2-carbomethoxyethyl) phenyl 5-indanyl 1-methyl-4-indanyl 7-methyl-4-indanyl 1-methyl-5-indanyl 6-t-butyl 5-indanyl 6-chloro-4-indanyl 3-ethyl-1-indanyl 2-chloro-1-indanyl 1-chloro-2-indanyl 1-indanyl 2-indanyl 2-methyl-1-indanyl 2-methyl-2- indanyl 1- (5,6,7,8-tetrahydronaphthyl 2- (5,

   6,7,8-Tetrahydronaphthyl 2-N-methyl-N-acetylaminoethyl 2-N- (n-butyl) -N-acetylaminoethyl 3-N- (isopropyl) -N-acetylaminopropyl Re 2-N-methyl-N- carbomethoxyaminoethyl 2-N-methyl-N-carbo- (isobutoxy) -aminoethyl 4-carbomethoxymethylphenyl 4- (2-carboxyvinyl) phenyl 2-chloro-3- (2-carboxyvinyl) phenyl 2- (2-carboxyvinyl) -6 -nitro-4-biphenyl 3 -methyl-4- (2-carboxyethyl) -phenyl 4-t-butyl-2-biphenyl 3-methoxy-2-biphenyl 2-methyl-4-biphenyl 5-dimethylamino-2-isopropylphenyl 2 -N-methyl-N-formylaminoethyl y- (4-nitrophenyl) -allyl y- (3 -fluorophenyl) -allyl y- (4-methylphenyl) -allyl y- (2-chloro-4-methylphenyl) -allyl y- (3 -Methoxy-4-ethoxyphenyl) -allyl 2-N- (n-butyl) -N-carbomethoxyaminoethyl 3-N-formylaminopropyl 3-N-acetylaminopropyl 2-N, N-dibenzylaminoethyl 3-N-methyl-N-benzylaminopropyl

   3-piperidyl 3- (1-butylpiperidyl) 3- (1-benzylpiperidyl) y-phenylallyl y- (4-chlorophenyl) allyl y- (2-methoxyphenyl) allyl y- (3,4-dimethoxyphenyl) allyl y- (3-chloro-4-methoxyphenyl) -allyl y- (3-methyl-6-nitrophenyl) -allyl y- (2-nitro-4-chlorophenyl) -allyl y-phenylpropargyl Re y- (4-chlorophenyl) -propargyl y- (4-methoxyphenyl) -propargyl y- (4-nitrophenyl) -propargyl
Example 10
The following penicillins, in which the substituent Rj for each of the compiled R2 values is 3-furyl, 3-pyridyl, 4-pyridyl, p-tolyl, o-methoxyphenyl, p-methoxyphenyl, p-trifluoromethylphenyl, p-chlorophenyl-o-dimethylaminophenyl and means p-dimethylaminophenyl,

   can be prepared by the process of Example 4 from the corresponding arylmalonic acid half-ester and 6-aminopenicillanic acid.



  For the sake of convenience, only the values for R2 are listed below.



      Re 2-isopropylphenyl 1-methoxy-2,2,2-trichloroethyl 1-butoxy-2,2,2-trifluoroethyl dicarb ethoxyethoxymethyl carbethoxyethoxymethyl 1-isopropoxy-2,2,2-trichloroethyl 4,5-dimethyl-2-isopropylphenyl 2 , 6-dichlorophenyl 4-dimethylamino-2-methylphenyl 4-nitrophenyl 2-chloro-6-methoxyphenyl 3-methoxy-2-methylphenyl 5-fluoro-2-methoxyphenyl 2-isobutyl-4-fluorophenyl 4-chloro-2,3- dimethylphenyl 4-chloro-2,3-diethylphenyl 1- (5,6,7,8-tetrahydronaphthyl 2- (5,6,7,8-tetrahydronaphthyl 1-t-butoxy-2,2,2-trichloroethyl o-dimethylaminophenyl o-di-n-butylaminophenyl p-methylethylaminophenyl 2,

   3-dimethylphenyl
R2
2,4-di-n-propylphenyl
3-pyrrolopropyl aziridinomethyl pyrrolidinomethyl morpholinomethyl 2,6-dimethylphenyl 3-diisopropylamino-2-propyl 2-dimethylamino-1-propyl 3-aziridino-2-propyl 2- (N-methylanilino) -ethyl 3- (N-methylanilino) -propyl 2- (n-methylanilino) -1-propyl 3- (imidazolino) -2-propyl 1- (2-chloro-1,2,3,4-tetrahydronaphthyl) 1- (1,2,3,4-tetrahydronaphthyl 2- ( 1,2,3,4-Tetrahydronaphthyl 1-indanyl 2-chloro-1-indanyl 4-indanyl 5-indanyl 1 -methyl-5-indanyl 2-indanyl 1 -methyl-1 -indanyl 2-dimethylaminoethyl 2-piperidinoethyl 3- Morpholinopropyl 2-pyrrolidinoethyl 2-pyrroloethyl 2-di- (n-propyl) aminoethyl 3-diisopropylaminopropyl 3- (2-imidazolinopropyl) 3 - (2,5-dimethylpyrrolidino) propyl 3 - (4-methylpiperidino) -2-propyl

   
R2
2-morpholyno-1-propyl
2-thiomorpholino-1-propyl
2-imidazolo-1-propyl 2-butyramidoethyl 3-diethylaminoethyl 3-piperidinopropyl 2-pyrrolidinoethyl 2- (1,4,5,6-tetrahydropyrimidino) ethyl 2-diethyiamino 1-propyl 3-pyrrolidino-2-propyl 3-piperidino -2-propyl 3 -Di- (n-butyl) amino-2-propyl 3-dimethylamino-2-propyl 2-chloro-4-methylphenyl 2-methoxy-4-methylphenyl 4-biphenyl 2-chloro-3-biphenyl 2-Nitro-4-biphenyl 2-N-methyl-N-benzylaminoethyl 3-N, N-dibenzylamino-2-propyl 2-N-benzyl-N-acetylaminoethyl 3-piperidyl 3- (1-methylpiperidyl 3- (1- Benzylpiperidyl) y-phenylallyl r- (4-chlorophenyl) -allyl y- (2-methoxyphenyl) -allyl?

  ;- (3,4-methylenedioxyphenyl) allyl y- (4-nitrophenyl) allyl
Example 11
According to the method of Example 2, α-carboxypenicillin esters in which the aryl group, R1 for each of the given meanings of R3 is m-tolyl, m-methoxyphenyl, m-trifluoromethylplienyl, o-isopropylphenyl, o-chlorophenyl, o-bromophenyl, m- Bromophenyl, m-chlorophenyl, o-butoxyphenyl, o-buty.lphenyl, o-diethylaminophenyl, p-di- (n-propyl) -aminophenyl, o-dibutylaminophenyl and m-dimethylaminophenyl means prepared from the corresponding starting compounds.



   re
1-methoxy-2,2,2-trichloroethyl
1-ethoxy-2,2,2-trifluoroethyl dicarbethoxymethyl carbethoxyethoxymethyl dicarbomethoxyethoxymethyl 2-isopropylmethyl .o-dimethylaminophenyl m-di-n-propylaminophenyl 3,4-dimethylphenyl 2,6-di-n-propylphenyl 4,5-dimethyl-2- isopropylphenyl 2s6 -dichlorophenyl 2-nitrophenyl 4-dimethylamino-2-methylphenyl 2-methoxy-4-methylphenyl 4-chloro-2-methylphenyl 4-fluoro-3 -methylphenyl 2-bromo-4-t-butylphenyl 4-chloro-2, 3-dimethylphenyl 1 - (5,6,7,

   8-Tetrahydronaphthyl 1- (1,2,3,4-tetrahydronaphthyl) 1-indanyl 2-indanyl 4-indanyl 5-indanyl 5-methyl-4-indanyl 1 -methyl-5-indanyl 6-chloro-5-indanyl 2 -Piperidinoäthyl 2-Morpholinoäthyl 3-Pyrrolidinoäthyl Re
3-pyrrolopropyl
2- (1,2,4,5,6-tetrahydropyrimidino) ethyl 3 -pyrrolidinopropyl 2-dibitylaminoethyl 2-pyrroloethyl 2-imidazoloethyl 2-azetidinoethyl 3-dimethylaminopropyl 2- (5,6,7,8-tetrahydronaphthyl) 1- (1-methyl-1,2,3,4-tetrahydronaphthyl) (imidazolino) methyl piperidinomethyl 2-pyrrolidino-1-propyl 2-morpholino-1-propyl 2-pyrrolo-1-propyl 3-imidazolo-2-propyl 3 - (2-Imidazolino) -2-propyl 2- (methylethylamino) ethyl 3- (methylethylamino) -2-propyl 2- (diethylamino) -1-propyl 3 -pyrroleJ.dino-2-propyl 3-diethylamino-2- propyl 3-moipholino-2-propyl 3

   Dimethylamino-2-propyl 3-piperidinopropyl 2- (n-methylanilino) -ethyl 3- (N-methylanilino) -2-propyl 3 -azaridinopropyl 3 - (N-methylpiperazino) -propyl 3 - (2-imidazolino) -propyl 2-N-isopropyl-N-formylaminoethyl 2-N- (n-butyl) -N-acetylaminoethyl 2-N-methyl-N-carbomethoxyaminoethyl
R2 2-N- (n-butyl) -N-carbomethoxy-aminoethyl 3-N-acetylaminopropyl 2-N-methyl-N-benzylaminoethyl 3 -N, N-dibenzylaminopropyl 3-piperidyl 3- (1-benzylpiperidyl) y- Phenylallyl y- (4-chlorophenyl) -allyl 7- (4-methoxyphenyl) -alWl?

  ;- (3,4-Methylenedioxyphenyl) allyl 4-biphenyl 2-bromo-4-biphenyl 2-nitro-4-biphenyl 2-dimethylamino-5-biphenyl 4- (carbo-n-butoxy) methylphenyl 4- (2 -Carbomethoxyethyl) -phenyl 4-carbomethoxymethylphenyl 2-methoxy-4- (2-carbomethoxyvinyl) -phenyl 2-chloro- (2-carboxyvinyl) -phenyl 3-methyl-4- (2-carboxyethyl) -phenyl 3-methoxy-2 -biphenyl 2-isopropyl-4-methoxyphenyl 5-dimethylamino-2-isopropylphenyl 2-N-ethyl-N-acetylaminoethyl-γ- (3-fluorophenyl) -allyl y-phenylpropargyl y- (2-chlorophenyl) -propargyl γ - (3-methoxyphenyl) propargyl
Example 12 α-Carbo (2-isopropylphenoxy) benzylpenicillin anhydride method
A stirred solution of 2.5 g of mono- (2-isopropylphenyl) phenylmalonate in 10 ml of acetone is cooled to 0 ° C. in an ice bath.

  Then 1.27 g of anhydrous triethylamine are added dropwise over the course of 15 minutes, followed by 900 mg of dry chloroethyl carbonate. A precipitate is formed immediately, which consists of triethylamine hydrochloride. A solution of 1.8 g of 6-aminopenicillanic acid in a solution of sodium bicarbonate (20 ml of a 50% solution) and 5 mol of acetone is then added all at once to the mixed anhydride. The mixture is stirred for half an hour at 0 C, then extracted three times with 50 ml of ether each time and acidified to a pH of 1.0 with concentrated hydrochloric acid. The acidic solution is extracted three times with 50 ml of ethyl acetate each time, the extracts are combined, washed back with water, further with saturated salt solution and dried over anhydrous sodium sulfate.

  The solvent is removed under reduced pressure to give the product in the form of a yellow oil; the yield is 940 mg, 21.6 / o.



   This product is converted into the crystalline N-ethylpiperidine salt by dissolving it in ethyl acetate and adding a slight excess of N-ethylpiperidine. The salt is isolated, washed with ethyl acetate and then dried.



   The following penicillins can be prepared from the corresponding starting materials in the same way.
EMI16.1




  R1 R2 R1 (C1-COOR ') Phenyl 5-Indanyl Ethyl Phenyl 4-Indanyl Isobutyl Phenyl 2-Isopropylphenyl Benzyl Phenyl 3,4-Dimethylphenyl Ethyl Phenyl -CH2-CH2-N (n-C3H7) 2 n-Propyl Phenyl -CH2 -CH2-Morpholino n-Propyl 3-Thienyl 5-Indanyl Ethyl R1 R2 R1 (Cl-COOR ') 3-Thienyl 2-Isopropylphenyl Ethyl 3-Thienyl 2-Methoxy-4-methylphenyl Ethyl 3-Thienyl -CH2-Piperidino Ethyl 3 -Thienyl H2-CH2CH2-N (CH3) 2 ethyl 3-thienyl -CH2-imidazolo ethyl o-chlorophenyl 5-indanyl ethyl p-methoxyphenyl 5-indanyl ethyl p-trifluoromethylphenyl 5-indanyl ethyl p-dimethylaminophenyl 5-indanyl ethyl Chlorophenyl 2-isopropylphenyl ethyl 2-thienyl 5-indanyl n-propyl 2-thienyl 4-chloro-2-methylphenyl n-propyl 2-pyridyl 5-indanyl ethyl 4-pyridyl 5-indanyl ethyl 2-furyl 5-indanyl ethyl 4- Pyridinl -CH2CH2-N (n-C3H7) 2 benzyl 4-pyridyl 2-isopropylphenyl

   Ethyl phenyl 2-biphenyl 7 ethyl phenyl 3-methoxy-2-biphenyl ethyl phenyl 2-nitro-4-biphenyl ethyl phenyl 4- (2-carbomethoxyethyl) -phenyl methyl phenyl 2-methoxy-4- (2-carbomethoxyvinyl) phenyl methyl 3 thienyl 2-biphenyl methyl p-chlorophenyl 2-biphenyl methyl 4-pyridyl 2-biphenyl methyl thienyl 2-t-butyl-4-methoxyphenyl methyl p-methoxyphenyl 2-t-butyl-4-methoxyphenyl methyl 4-pyridyl 2-t -Butyl-4-methoxyphenyl methyl phenyl 2-N, N-dibenzylaminoethyl ethyl CO2 H2O 50 90 R1 R2 R1 (Cl-COOR ') phenyl 3 <1-benzylpiperidyl) ethyl phenyl 3-N-acetylaminopropyl ethyl phenyl;

  ;, - phenylalyl methyl phenyl y-phenylpropargyl methyl
Example 13
Potassium salt of α-carbo (2-biphenyloxy) -benzylpenicillin α-carbo- (2-biphenyloxy) -phenylacetic acid
90.0 g (0.5 mol) of phenylmalonic acid, 85 g (0.5 mol) of d-phenylphenol, 0.8 ml of N, N-dimethylformamide, 725 ml of isopropyl ether and 59.5 g (0.05 mol) of thionyl chloride combined, stirred and refluxed on a steam bath for 2 hours. The mixture is cooled to room temperature and then washed 3 times with 50 ml of water each time and extracted 3 times with 100 ml of saturated aqueous sodium bicarbonate solution each time.

  The combined aqueous extracts are washed twice with 25 ml of ether each time, then acidified with 6 normal hydrochloric acid to a pH value of 3.0 and extracted again 3 times with 50 ml of ether each time. The ether extracts are washed twice with 15 ml of water each time, followed by 15 ml of saturated aqueous water twice each time. Salt solution, and finally dried over anhydrous sodium sulfate and evaporated to dryness. 90.3 g of α-carbo (2-biphenyloxy) phenylacetic acid are obtained.



   Acid chloride = the a-carbo (2-biphenyloxy) -phenyl-acetic acid
45.0 g (0.135 mol) of a-carbo- (2-biphenyloxy) -phenylacetic acid, 450 ml of methylene chloride, 0.1 ml of anhydrous N, N-dimethylformamide and 16.66 g (0.14 mol) of thionyl chloride are in placed in a dry vessel equipped with a condenser and a drying tube, and then refluxed the mixture for 3 hours. The methylene chloride solvent is removed in vacuo, an additional 200 ml of the solvent are added and the evaporation is repeated, 48.0 g of a yellow oil being obtained.



   α-Carbo- (2-biphenyloxy) -benzylpenicillin
A slurry of 29.16 g (Q, 135 mol) of 6-aminopenicillanic acid in 800 ml of methylene chloride is stirred vigorously and then 27.27 g (0.27 mol) of triethylamine are added to this mixture at room temperature. After stirring for 2 hours, the mixture is filtered, cooled to 5 ° C. and 48.0 g (0.135 mol) of the acid chloride of α-carbo- (2-biphenyloxy) phenylacetic acid in 200 ml of methylene chloride are added at such a rate Reaction mixture that the temperature does not rise to more than 10 C. The mixture is then stirred for one hour, diluted with 400 ml of water, the pH is adjusted to 2 and everything is mixed thoroughly. The methylene chloride phase is separated off, dried over sodium sulfate and evaporated to dryness.

  The residue is taken up in ethyl acetate 300 times, the solution is washed three times with 150 ml of water each time and extracted three times with 150 ml of saturated aqueous sodium bicarbonate solution each time. The aqueous extract is washed with ethyl acetate and then in the presence of 300 ml of fresh ethyl acetate on its own; Acidified pH 2.0.



   The suspension is mixed thoroughly, the ethyl acetate phase is separated off and washed in sequence three times with 150 ml of water each time and then three times with 150 ml of saturated salt solution. It is then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.



   The residue is dissolved in 400 ml of ethyl acetate and 12.0 g are added. N-ethylpiperidine to the solution. The mixture is inoculated and left to stand overnight. The product obtained is filtered, washed with ethyl acetate and air-dried; 37.5 g with a melting point of 131 to 133 ° C. are obtained with decomposition.



   The product obtained is converted into the potassium salt by adding potassium 2-ethylhexanoate (16 ml of an ethyl acetate solution containing 0.283 g / ml) to a slurry of the N-ethylpiperidil salt (10 g) in 100 mol of dry benzene. The mixture becomes clear, it is heated in a steam bath to 45 (D, inoculated and allowed to stand at room temperature. The precipitated product is filtered off and washed with ether. 5.97 g are obtained.



   Example 14
The processes described above are repeated using the following phenol derivatives instead of o-phenylphenyl: butylated hydroxyanisole 4Xarbomethoxyethylphenol
4-Carboethoxymethylphenol 4-: arbo43ethoxyme.thylphenol
For the production of the half-ester of malonic acid. with the phenol derivatives mentioned, phosphorus oxychloride is used rather than thionyl chloride.

 

   The following esters can be obtained in this way in the form of their N-ethylpiperidine salts (NEP): Penicillins as NEP salts Melting point in Cα -carbo- (2-t-butyl-4-methoxyphenoxy) - 148-152 benzylpenicillin (decomposition )?

  ; -Carbo- (4-carbomethoxyethylphenoxy) -94-96 benzylpenicillin (decomposition) penicillins as NEP salts, melting point in 0 aXarbo44-carbethoxymethylphenoxy) - 104-106 benzylpenicillin (decomposition) a-Carbo- (4-carbolmethoxymetbyl- 89-92 phenoxy) benzene penicillin (decomposition)
The esters listed in the table can be converted into their corresponding sodium or potassium salts by the method described above using sodium or potassium 2-ethylhexanoate.



   Example 15
Following the procedure of Example 2, the
Products of Examples 3 and 8 to 12 converted into their corresponding sodium and potassium salts.



   Example 16
Following the procedure of Examples 1 to 3 and 8 to 12, but replacing N-ethylpiperidine with an appropriate amine, the following are obtained
Salts of the compounds described: N-methylpipe ridin, triethylamine, tributylamine, N, N-dibenzyläthy Ienediamine, procaine and dibenzylamine.



   Preparation A
Malonic acids
The following arylmalonic acids, which have not previously been described in the literature, can be prepared according to the method of Wallingford et al., J. Chem. Soc. 63, 2D56-2059 (1964). The process is based on the condensation of an alkyl carbonate, usually a diethyl carbonate, with an equimolecular amount of the desired ethylarylacetate in the presence of an excess (4 to 8 times) of sodium ethylate with continuous removal of the alcohol formed as a by-product from the reaction mixture.



  The esters produced in this way are hydrolyzed to the corresponding acid by known processes.
EMI19.1




   R1 o-methoxyphenyl m-methoxyphenyl p-methoxyphenyl o-trifluoromethylphenyl * m-trifluoromethylphenyl p-trifluoromethylphenyl olsopropylphenyi 3-furyl 3-pyridyl 4-pyridyl o-butoxyphenyl o-dimethylaminophenyl-p-dimethylaminophenyl-p-diethylaminophenylmethyl-dimethylaminophenyl-dimluorine from o-trifluorobenzonitrile by the following procedure of Corse et al, J. Am. Chem. Soc. 70, 2841 (1948): (a) Conversion of the nitrile into o-trifluoromethylacetophenone by a Grignard reaction with methyl magnesium iodide, followed by hydrolysis; (b) Reaction of acetophenone with sulfur and morpholine at 1350 C for 16 hours, followed by treatment with glacial acetic acid and hydrochloric acid.



   Preparation B
Phenylchlorocarbonyl ketene (1) 46 g of phosphorus pentachloride are added to 20 g of phenylmalonic acid in 100 ml of ethyl ether. A violent reaction occurs. The reaction mixture is refluxed for 4 hours and then the ether is partially removed by heating on a steam bath. The reaction mixture turns black when about half of the ether is removed.



  The remaining ether is removed in a vacuum at about 100 mmHg. The residue is distilled in vacuo and the fraction collected, which has a boiling point of 75 to 900 ° C. at a pressure of 1.5 to 4 mmHg. The product is a yellow liquid and it is distilled again at 740 ° C. and 1.5 mm. It shows a distinct peak in the infrared region of the spectrum at 4.69.



   The procedure is repeated, but 10 g of phenylmalonic acid are used instead of 20 g. If phosphorus pentachloride is added, the reaction is less violent. The same product is obtained.



   (2) 23 g of phosphorus pentachloride are added to a stirred solution of 10 g of phenylmalonic acid in 50 ml of ethyl ether at an initial temperature of 0 to 5 C for 5 minutes. The temperature rises to 13 ° C. during the addition. The mixture is refluxed for 5 hours and then left to stand at room temperature overnight. After removing the ether at 20 mmHg, a dark concentrate is obtained, which is distilled in vacuo and gives the desired product. This has a boiling point of 80 to 880 C at 1.5 to 2.5 mm and a boiling point of 74 "C at 0.2 mm.



   (3) Over a period of 2 minutes, 10 g of phenylmalonic acid are added to a stirred solution of 46 g of phosphorus pentachloride in 100 ml of ethyl ether. The mixture is stirred for 4 hours at room temperature, then refluxed for 4 hours and left to stand overnight at room temperature. The excess of the phosphorus pentachloride is filtered off and the ether is removed by distillation at ordinary pressure. The color of the reaction mixture gradually changes from dark yellow to red. The residue is distilled in vacuo and a product is obtained which has a boiling point of 83 to 860 ° C. at 1.5 mm. The product is a yellow liquid.



   Preparation B
The procedure of Preparation B-3 is repeated, but using the appropriate malonic acid derivative in place of the phenylmalonic acid, to give the following compounds.
EMI20.1




      Rt 2-thienyl 3-thienyl 2-furyl o-tolyl m-tolyl p-tolyl o-methoxyphenyl m-methoxyphenyl p-methoxyphenyl o-trifluoromethylphenyl p-trifluoromethylphenyl m-trifluoromethylphenyl o-isopropylphenyl 3-furyl 2-pyridyl 3-pyridyl 4 -Pyridyl o-bromophenyl o-chlorophenyl p-chlorophenyl m-chlorophenyl Rt o-butoxyphenyl o-dimethylaminophenyl o-diethylaminophenyl m-dimethylaminophenyl p-dimethylaminophenyl
Preparation C
Esters of Arylcarboxyketenen general manufacturing method
0.1 mol of the corresponding alcohol R2OH is added to a solution of 0.1 mol of the corresponding aryl halocarbonyl ketene in methylene chloride (sufficient to produce a clear solution and generally from about 5 to 10 ml per g of the ketene). The reaction mixture is in a nitrogen atmosphere

   left and stirred for a period of 20 minutes to 3 hours. Care must be taken that no moisture is present. The temperature can range from about -70 to about -20 "C.



   Then 200 ml of water are added to the reaction mixture followed by 3 equivalents of sodium bicarbonate. The mixture is warmed to 0 C and stirred for half an hour in order to form a heavy emulsion. The methylene chloride is removed in vacuo at a temperature of less than 35 ° C. and the aqueous solution that remains is extracted with ether. The ether extract is backwashed with water (made alkaline by adding sodium bicarbonate, pH 8), dried over anhydrous sodium sulfate, and evaporated to give unreacted alcohol.



   The basic aqueous solution is cooled to 10 C, the pH is adjusted to 2.0 by adding dilute hydrochloric acid and extracted with methylene chloride.



  The extract is dried over anhydrous sodium sulfate and evaporated to dryness, the malonic acid half-ester remaining.



   The esters obtained in this way are generally used without further purification for the preparation of the α-carboxyarylpenicillin esters described here.

 

   Preparation D
Acid chlorides of arlymalonic acid half-esters
General manufacturing method
A solution of malonic acid half ester in methylene chloride (about 10 ml / g of the ester) and thionyl chloride (one equivalent) is carefully refluxed for 3 hours. The methylene chloride and other volatiles are removed by evaporation in vacuo, leaving the acid chloride. The acid chlorides obtained in this way can be used further without purification.



   Preparation E
Aminoisopropanols
The aminoisopropanols listed below can be prepared by reacting propylene oxide with the corresponding amine. The method generally comprises the reaction of the propylene oxide with an aqueous solution of the amine in a closed tube and with a molar ratio of 1.0 to 1.4. The sealed tube is shaken and left to stand overnight, then heated for 6 hours at 80 "C and a further 4 hours at 95" C. The reaction vessel is then cooled, the contents are removed and the aminoisopropanol can be salted out by adding potassium carbonate .



   If the product is liquid, it is separated off, dried with solid potassium hydroxide and then distilled in vacuo. If the product is solid, it is filtered off and recrystallized from a suitable solvent.



      NRsR dimethylamino diethylamino di-n-propylamino diisopropylamino di-n-butylamino 1, 4,5,6-tetrahydropyrimidino n-ethylpiperazino piperidino pyrrolidino pyrrolo morpholino thiomorpholino imidazolino imidazolidino
Preparation F
2-aminopropanols
The following 2-aminopropanols have the formula
EMI21.1
 wherein NRsR6 means di-lower alkyl-amino or a heterocyclic group. These compounds can be prepared by the method of Moffet, Org. Syn., Coll. Vol.

 

  IV, page 834. This process involves the reduction with lithium aluminum hydride of the corresponding ester of the formula
EMI21.2
 By reacting the desired amine with ethyl a-bromopropionate, this ester can be prepared by the method of Moffet, Org. Syn., Coll. Vol. IV, page 466.



      -NR5R, di- (n-propyl) -amino di- (n-butyl) -amino di-isopropylamino 1,4,5,6-tetrahydropyrimidino N-methylpiperazino N-n-butylpiperazino piperidino morpholino thiomorpholino pyrrolo imidazolino imidazolidino

 

Claims (1)

PATENT CLAIM Process for the preparation of esters of an α-carboxy-aryl or heteroarylmethylpenicillin of the formula I. EMI21.3 wherein M is hydrogen, sodium, potassium or the cation of an amine, characterized in that a compound of the formula II EMI22.1 with an acylating agent of the formula III EMI22.2 where X is chlorine, bromine or the radical -OCOR4, in which R4 is benzyl or lower alkyl, R1 is thienyl, furyl, pyridyl, phenyl or substituted phenyl, with the meaning of lower alkyl, chlorine, bromine, lower alkoxy, di-lower alkylamino or trifluoromethyl for the phenyl substituent, and R2 isopropylphenyl or a group of the formula EMI22.3 means. in which formulas Xt is chlorine, bromine, fluorine, lower alkoxy or lower alkyl, X2 is lower alkyl or chlorine, or X1 and X2 together are the methylenedioxy group, X3 is hydrogen, methyl, phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carboxy-lower alkyl or carbo-lower alkoxy is lower alkyl, X4 is nitro or di-lower alkyl-amino and Re is also mono-substituted phenyl, with the meaning of phenyl, carboxyvinyl, carbo-lower alkoxyvinyl, carbo-lower alkoxy-lower alkyl or carboxy-lower alkyl for the phenyl substituent, or Re ac indanyl or substituted ac is indanyl, with the meaning of methyl, chlorine or bromine, chlorine or bromine for the substituent; or Re ac is tetrahydronaphthyl or substituted ac tetrahydronaphthyl, with the meaning of methyl, chlorine or bromine for the substituent; or Re 1-lower alkoxy-2,2,2-trichloroethyl, 1-lower alkoxy-2,2,2-trifluoroethyl, (carbo-lower alkoxy) -lower alkoxymethyl, -Di (carbo-lower alkoxy) -lower alkoxymethyl, 3iC1- (R, - substituted) -Pipendyl], - (CH2) m -NR5R ", -CH2CH (CH3) -NR5R6, -CH (CHS) -CH2-NRsRG or - (lower alkylene) -Y1, in which formulas m is an integer of 2 to 3, R5 is hydrogen, lower alkyl or benzyl, R6 is lower alkyl, lower alkanoyl, benzyl, phenyl or carbo-lower alkoxy, with the proviso that when Re is hydrogen, R5 is lower alkanoyl or carbo-lower alkoxy, and Y, azetidino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, N- (lower alkyl) -piperazino, pyrrolo, imidazolo, 2-imidazolino, 2,5-dimethyl -pyrrolidino, 1,4,5,6-tetrahydropyrimidino, 4-methylpiperidino or 2,6-dimethylpiperidino; wherein each of the lower alkoxy, lower alkanoyl and lower alkyl radicals has 1 to 4 carbon atoms and the lower alkylene radical contains 1 to 3 carbon atoms, or Re is the group of the formula EMI22.4 represents, in which Z is - (CH2) S- or - (CH2), or substituted derivatives of this group, the substituent being methyl, chlorine or bromine, or Re y-phenylallyl or y- (substituted-phenyl) - Allyl means in which at least one chlorine, bromine and / or fluorine atom and / or at least one lower alkoxy, lower alkyl, nitro and / or methylenedioxy group is present as a substituent, or y-phenylpropargyl or y- (substituted-phenyl) - propargyl means in which the substituent is chlorine, bromine, lower alkoxy, Lower alkyl or nitro is condensed in an aqueous or anhydrous solvent system at temperatures from 0 to 500 C and at a pH of 5 to 8. SUBCLAIMS 1. The method according to claim, characterized in that the acylating agent has the following formula EMI22.5 2. The method according to dependent claim 1, characterized in that the reaction is carried out in an anhydrous solvent system in the presence of an acid acceptor, preferably a tri-lower alkyl-amine. 3. The method according to claim or dependent claim 1, characterized in that the solvent system is an aqueous solvent system. 4. The method according to dependent claim 2, characterized in that the solvent is methylene chloride and the tri-lower-alkylamine is triethylamine. 5. The method according to claim or dependent claim 1 or 3, characterized in that Re is phenyl and Re is 2-isopropylphenyl. 6. The method according to claim or dependent claim 1 or 3, characterized in that R, is phenyl and Re is the following formula EMI23.1 in which Xj and X2 are lower alkyl and X3 is hydrogen. 7. The method according to claim or dependent claim 1 or 3, characterized in that Re is phenyl and Re is the following formula EMI23.2 in which Xj is chlorine, X2 is lower alkyl and X3 is hydrogen. 8. The method according to claim or dependent claim 1 or 3, characterized in that Re is phenyl and Re is the following formula EMI23.3 in which Xt is lower alkoxy, X2 is lower alkyl and X8 is hydrogen. 9. The method according to claim or dependent claim 1 or 3, characterized in that Re is phenyl and Re is the following formula EMI23.4 in which Z is - (CH2) S- or - (CH2) 4-. 10. The method according to claim or dependent claim 1 or 3, characterized in that Re is phenyl and Re is biphenyl. 11. The method according to dependent claim 6, characterized in that X2 is 2-methyl and X2 is 4-methyl. 12. The method according to dependent claim 7, characterized in that X1 is 4-chlorine and X is 2-methyl. 13. The method according to dependent claim 8, characterized in that Xt is 2-methoxy and X2 is 4-methyl. 14. The method according to dependent claim 9, characterized in that Z is the group - (CH2) 3-. 15. The method according to claim or one of the dependent claims 1 to 4, characterized in that a compound of the formula I is prepared in which M is a tri (lower alkyl) ammonium cation.