AT314081B - Process for the production of penicillins - Google Patents

Description

  

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   The invention relates to the production of new penicillins by acylation of new organosilane derivatives of 6-aminopenicillanic acid and hydrolysis or alcoholysis, whereby the corresponding penicillins with known antibiotic activity can be obtained. Silylated derivatives of 6-aminopenicillanic acid and their use for the production of semisynthetic penicillins with antibiotic activity are known. For example, the mono- and disilylation of 6-aminoenicillanic acid for the production of intermediates has been proposed and / or carried out, which intermediates can be easily acylated and then hydrolyzed or alcoholized to produce the corresponding antibiotic penicillins.

   Thus, von Glombitza in Annalen 673, [1964] p. 166, and in the patent literature, for example in US Pat. No. 3,249, 622 and Brit.
 EMI1.1
    No. nopenicillanic acid (6-APA) disclosed, wherein monochlorosilanes, aminosilanes and disilylamines (such as trimethylchlorosilane, trimethylsilyldiethylamine and hexamethyldisilazane) are used as silylating agents.



   In the known prior art, as illustrated by the publications cited, however, the possibility of using a monohydrocarbyldihalosilane or a trihalosilane (for example methyldichlorosilane or methyltrichlorosilane) for the production of organosilane derivatives of 6-aminopenicillanic acid is not indicated. This is apparently because the organosilane derivatives of 6-aminopeni- eillanic acid obtained would be assumed to contain reactive Si-Cl or Si-H groups which would also react in the subsequent acylation or would result in polymer mixtures that are insoluble in solvents and cannot be acylated.



   In the Austrian patent specification No. 249 862 a process for the preparation of penicillins is disclosed, wherein 6-aminopenicillanic acid with a dialkyldihalosilane and the amino group with an acid halide of a carboxylic acid of the general formula
 EMI1.2
 wherein R5 and R are alkyl, cycloalkyl, arylalkyl, aryl and heterocyclic groups with up to 12 carbon atoms and in the formulas (A) and (B) also represent hydrogen atoms and X is oxygen or sulfur, is reacted and the silicon radical is then with a reagent containing a hydroxyl group, e.g. B.



  Water or alcohol. In this patent specification, for example phenoxybutyric acid chloride and 3-phenyl-5-methylisooxazole-4-carboxyl chloride are given as acylating agents.



   However, it is nowhere disclosed that an acylating agent which contains an α-amino group can
 EMI1.3
 required acylating agent would not be possible.



   It has now surprisingly been found that the reaction products of 6-APA and dihydrocarbyldihalosilanes (e.g. dimethyldichlorosilane, methylphenyldichlorosilane and diphenyldichlorosilane) are acylated with functional derivatives of α-amino acids and their acylated products can also be hydrolyzed or alcoholized to give penicillins Reactions excellent yields and the penicillin end products can be obtained in excellent purity.



   The invention thus provides a process for the preparation of penicillins of the general formula
 EMI1.4
 wherein Ra is an acyl radical of an organic carboxylic acid, and its pharmaceutically acceptable salts by reacting 6-aminopenicillanic acid with an organic silicon derivative and acylation of the compound obtained, optionally in the crude reaction solution, which is characterized in that an organosilane derivative of 6-aminopenicillanic acid of the general formula

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 EMI2.1
 wherein R1 is hydrogen, alkyl, aryl or aralkyl; R is halogen, alkyl, aryl or aralkyl;

   W is hydrogen or a radical of the formula
 EMI2.2
 
 EMI2.3
 
R2 die25; p 0 or 1; and Y is halogen or a group of the formula
 EMI2.4
 mean, where in formula (II)
1. for m and p = 0, n is more than 1 and the two free valences form a cyclic connection with one another;
2. for n greater than 1, the sections A of the repeating groups B occur in random head-to-head, head-to-tail and tail-to-tail positions;
3. W is not hydrogen when n is 1 and Y corresponds to the formula (IV), and
4. m and p are always the same
 EMI2.5
 hydroxyl-free organic solvent and preferably in the presence of an acid acceptor, is acylated and then the acylated product is hydrolyzed or alcoholized and, if desired, the penicillin obtained in this way is converted into a salt.



   The acylated compounds of the above general formula are new compounds.



   Preferably R 1 is hydrogen, lower. Alkyl (e.g. methyl). Phenyl, lower Alkylphenyl or benzyl and R is halogen (e.g. chlorine), lower. Alkyl (e.g. methyl or propyl), phenyl, lower. Alkylphenyl or benzyl, where the term "lower" as used herein means that the radical has 1 to 4 carbon atoms.



   The starting materials of the formula (II) which are acylated according to the invention and the corresponding compounds in which W denotes a hydrogen atom, n is 1 and Y corresponds to the formula (IV) are new compounds.



   The silenated 6-aminopenicillanic acid starting material of the formula (II) can be prepared by reacting 6-aminopenicillanic acid or a salt thereof with a di- or trihalosilane of the following formula
 EMI2.6
 

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 EMI3.1
 To achieve yield, the reaction can be continued until the salt formation of the corresponding hydrogen halide is practically complete or until practically all of the 6-aminopenicillanic acid has been converted.



  Preferably the 6-APA or the salt thereof and the compound of the formula (Va) are heated in the presence of an acid acceptor. The reaction is preferably carried out in solution. Suitable di- or trihalosilanes that can be used are, for example, dimethyldichlorosilane, methylpropyldichlorosilane, dimethyldibromosilane, dibutyldichlorosilane, diphenyldichlorosilane, methylphenyldichlorosilane, dibenzyldichlorosilane, methylsilosilane and methylbenzyldibrium.



   Different ratios of di- and trihalosilanes and acid acceptors can be used for reaction with 6-APA, with various new silenated products being obtained which have half or two silicone groups per APA group and in which one or both of the halogen atoms of the di- or trihalosilanes have reacted. For example, the following reactions can take place in which P is the remainder
 EMI3.2
 means, depending on the ratio of the reaction components used:
 EMI3.3
 
It is believed that the products containing more than one "P" unit (i.e., where n is greater than or equal to 1 in the preceding formula) are linear or cyclic dimers, trimers, or higher polymers.

   In such cases, the repeating 6-APA units of the respective groups may be statistical
 EMI3.4
 



   Although the silenated compounds have been successfully prepared using one-half to two moles of halosilane per mole of 6-APA, it is preferred to employ approximately equimolar ratios for maximum effect. Suitable acid acceptors are, for example, ammonia, organic amines, alkali metal carbonates and alkali metal carbonates. In general, it is preferred to add about two moles of an acid acceptor such as anhydrous ammonia or an amine such as triethylamine or diethylamine per mole of halogen

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 EMI4.1
 
 EMI4.2
 
 EMI4.3
 

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 EMI5.1
 (wherein R3 has the same meaning as in formula (V) above and is preferably an ethoxy radical);
3.
 EMI5.2
 (where R5 is hydrogen, lower

   Denotes alkyl or phenyl);
 EMI5.3
 (wherein q is an index from 1 to 5, preferably 2);
 EMI5.4
   (in which R has the same meaning as in formula (VII) above and R6 and R7 are hydrogen or halogen, R in this formula is preferably methyl and R and R are preferably chlorine in the 2- and 6-positions);
 EMI5.5
 
 EMI5.6
 means an index from 1 to 3 with the proviso that when r is 0, s is greater than 1, and when r is 1, s is less than 3.

   Preferably both R8 and R9 are hydrogen and r and s are both the same l); and
 EMI5.7
 
Illustrative examples of some of the acylating agents used particularly preferably are the following: phenoxyacetyl chloride, 2,6-dimethoxybenzoyl chloride, benzenesulfonyl chloride, 2-phenoxypropionyl chloride,
 EMI5.8
 
The acylation reaction is preferably carried out in the presence of an acid acceptor which can be the same or different from that which was used in the preparation of the silenated intermediate. Although a tertiary amine such as triethylamine is suitable for both reactions, it is preferable to use a weaker base such as N, N-dimethylaniline, pyridine or quinoline for the acylation reaction, since higher yields are often achieved with it.

   In the production of ct-aminopeni-

 <Desc / Clms Page number 6>

 In cillins, the acylation with α-amino acid halide hydrohalides is conveniently carried out in the absence of strong bases, such as the alkylamines. In practice it is preferred to inactivate any excess of strong amines that may still be present by adding a mineral acid salt of a weak amine, if, for example, 1 mole of dimethyldichlorosilane and an excess (e.g.

   B. 2.3 mol) of triethyl) amine were used in the silylation of one mole of 6-aminopenicillanic acid, the addition of 0.4 equivalents of dimethylaniline increases. 2HCI before acylation with phenylglycylchloride chlorohydrate, the total yield of anhydrous ampicillin D- (-) - <x-aminophenylacetamidopenicillanic acid from 70 to 83% of theory.



   In general, the same types of solvents can be used for the acylation of the silenated 6-APA-
Products that were used for their original presentation are used. The silenated penicillins obtained according to the invention become the corresponding ones on treatment with water or other compounds containing hydroxyl groups, such as, for example, an alcohol such as methyl or ethyl alcohol
Hydrolyzed or alcoholized penicillins, many of which are useful pharmaceutical compounds.



   Procedures (I) to (VI) relate to the preparation of silenated compounds which can be acylated according to the invention. i Procedure I: 40.5 g (0.40 mol) of triethylamine of a mixture of 43.2 g (0.20 mol) of 6-APA and 425 were placed in a 11-three-necked flask equipped with a stirrer, thermometer and drying tube ml of dry acetonitrile was added under a nitrogen atmosphere. At 10 ° to 150 ° C., 25.8 g (0.20 mol) of dimethyldichlorosilane were added dropwise and then the mixture was stirred at 45 ° C. for 1 hour.

   After cooling to 150 ° C., the insoluble material was filtered off, washed with acetonitrile and dried; 48.3 g (or 88% of theory) of triethylamine hydrochloride were thus obtained. Complete water solubility indicated the absence of unreacted 6-APA.



   To show that the -APA could be recovered, the clear pale yellow filtrate was added to 500 ml
Poured ice water and means! ml of 2.5N HCl adjusted to a pH of 3.9. After stirring for 1/2 hour, the white, crystalline 6-APA was filtered off, washed first with water and then with acetone; the dry weight was 40, 5 g or 94% of the starting material used; iodometric test gave 998 y / mg.



   Procedure II: If you work according to the procedure according to I, but use other anhydrous organic solvents instead of acetonitrile, soluble silenated derivatives of 6-APA are obtained, as shown below by the recovery of APA from the corresponding solutions .



   Table A.
 EMI6.1
 
<tb>
<tb> used <SEP> recovery
<tb> Solvent <SEP> reaction time <SEP> of <SEP> 6-APA
<tb> methylene chloride <SEP> 3 <SEP> h <SEP> 93% <SEP>
<tb> chloroform
<tb> (alcohol-free) <SEP> 1h <SEP> 85% <SEP>
<tb> Ethyl acetate <SEP> 2h <SEP> 82% <SEP>
<tb> Dioxane <SEP> 1 <SEP> h <SEP> 62% <SEP>
<tb> methyl isobutyl ketone <SEP> l <SEP> h <SEP> 77%
<tb>
 
Similarly, when using dimethylformamide, tetrahydrofuran and benzene as the reaction medium, 6-APA was recovered.



   Procedure III: A mixture of 43.2 g of 6-APA, 425 ml of methylene chloride and 40.5 g of triethylamine was treated with 25.8 g of dimethyldichlorosilane at 10 to 150 ° C. and the mixture was refluxed for 2 hours. An indicator showed that no free triethylamine remained. After stirring at 5 ° to 100 ° C. for 1/2 hour, the insoluble by-products were filtered off, washed with methylene chloride and dried. Of the 44 g obtained, only 0.4 g was unreacted 6-APA.



   After further triethylamine hydrochloride had been precipitated out by adding 250 ml of anhydrous ether and filtering, the filtrate was evaporated to dryness under reduced pressure at 250.degree. The residue, 57.3 g, was freed from the remaining triethylamine hydrochloride by dissolving in 290 ml of dry ethyl acetate, filtering and concentrating again to constant weight. 54.5 g or 1000/0 of theory were obtained. The total amount of triethylamine hydrochloride recovered was 53.9 g or 98% of theory.
 EMI6.2
 

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   This silenated 6-APA was at 200C in anhydrous solvents such as methylene chloride, chloroform,
Carbon tetrachloride, ethylene dichloride, ethyl acetate, tetrahydrofuran, dioxane, benzene, toluene, dimethyl sulfoxide, dimethylacetamide, dimethylformamide and acetonitrile are completely soluble, but poorly soluble in hexane and cyclohexane.



  When treating a solution of 5 g of this dimethylsilane derivative in 50 ml of dry ethyl acetate
 EMI7.1
 
Starting material used 6-APA.



   Iodometric test found 884 y / mg.



   The silenized 6-APA has a density of 1.23 g / ml. It is amorphous and has no particular melting point. It contains about one silicon atom per 6-APA nucleus, as shown by NMR and Si content by X-ray fluorescence. The polymer structure of the silenated 6-APA was determined by molecular weight determinations,
Viscosity measurements and NMR spectra confirmed. The molecular weight determinations showed that the polymer consisted of about four units of a monomer prepared from dimethylsilane and 6-APA in the same ratio. Methylene chloride solutions of the silenated 6-APA had a viscosity that increased with increasing concentration of the solute, indicating a polymeric structure.



   NMR determinations on samples of solid, silenated 6-APA showed a 1: 1 ratio of silenylmethylene to 6-APA-methylene. The main silenylmethyl peaks in the NMR spectrum of the silenation reaction mixtures as well as the solid silenated 6-APA can be attributed to the COO-Si-NH bonds, which also indicates polymeric structure. In addition to the head-to-tail bonds mentioned above, NMR peaks corresponding to the head-to-head and tail-to-tail bonds-COOSi-0-c-0 and -NHSiNH-were shown.



   Procedure IV: According to a procedure similar to that described under I, a mixture of 21.6 g (0.1 mole) 6-APA, 213 ml methylene chloride and 20.3 g (0.20 mole) triethylamine with 15.7 g ( 0, 10 moles)
Treated methylpropyldichlorosilane with cooling. After gently refluxing for 2 hours and cooling to 150 ° C., the insoluble material was filtered off and washed with methylene chloride. Dissolving the triethylamine hydrochloride by stirring in water gave 0.4 g of unreacted 6-APA.



   Recovery of the 6-APA from the clear, pale yellow methylene chloride solution by pouring it into water,
Filtering and washing the white product with acetone gave 18.8 g of 6-APA or 87% recovery; iodometric test gave 993 y / mg.



   Procedure V: According to the procedure described in procedure IV, but with equimolar
Amounts of other halosilanes used in place of methylpropyldichlorosilane became soluble
Derivatives of 6-APA are obtained as shown by recovery from solution as described below:

   
 EMI7.2
 
<tb>
<tb> used <SEP> recovery
<tb> halosilane <SEP> reaction time <SEP> from <SEP> 6-APA
<tb> methyldichlorosilane <SEP> l <SEP> h <SEP> 84% <SEP>
<tb> Phenylmethyldichlorosilane <SEP> 2 <SEP> h <SEP> 88%
<tb> Methyltrichlorosilane <SEP> l <SEP> h <SEP> 52% <SEP>
<tb> Diphenyldichlorosilane <SEP> 3h <SEP> 78%
<tb>
 
Procedure VI: 25.3 g (0.1 mol) of diphenyldichlorosilane were added dropwise at 10 to 150 ° C. to a mixture of 21.6 g of 6-APA, 213 ml of methylene chloride and 20.3 g of triethylamine and the mixture was refluxed for 3 hours cooked. After cooling to 100 ° C., the insoluble by-products were filtered off and washed with methylene chloride.

   Removal of the triethylamine hydrochloride from the dry solid by dissolving it in cold water left 1.6 g of unreacted 6-APA.



   The clear methylene chloride solution was evaporated to dryness under reduced pressure at 20 ° to 250 ° C. The residue, 46.0 g, was freed from triethylamine hydrochloride by dissolving in 200 ml of dry ethyl acetate, filtering and concentrating to constant weight, 39.4 g. This product was a pale yellow, friable solid with a chlorine content of 0.33 sol.



   Elemental analysis:
 EMI7.3
 
H found: C 59.77 H 5, 41 N 6, 10'lo.



   The product was soluble at 200C in anhydrous solvents including CHCl 2, tetrahydrofuran, acetone, benzene and dimethylformamide.



   On treating a solution of 10 g of this silenated 6-APA derivative in 50 ml of methylene chloride with 50 ml of cold water, 6-APA crystallized; 3.75 g were obtained, corresponding to 72% of the 6-APA obtained as starting material; iodometric test gave 976 y / mg.

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 EMI8.1
 

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 drips. After gently refluxing for 1 h, the mixture was cooled to 100 ° C. under nitrogen and 13 ml of a 3.1N solution of dimethylaniline dihydrochloride in methylene chloride were added to inactivate the excess ammonia.



   At 00C, 41.9 g of D- (-) - phenylglycyl chloride hydrochloride were added in portions over 20 minutes. After stirring at 0 ° C. for a further 15 minutes, the reaction mixture was poured into 1200 ml of ice water and, as described in Example 1, converted into anhydrous ampicillin; Yield zo the theory; biological test
987 y / mg.



    Example 3: 6- (1-aminocyclohexanecarboxamido) penicillanic acid
As described in Procedure HI, a methylene chloride solution of silenated 6-APA was prepared from 0.20 moles of APA. Without filtering off the triethylamine hydrochloride, the mixture was 16.6 g
Treated pyridine and then 40.7 g (0.25 mol) of 1-amino-1-cyclohexanecarboxylic acid chloride hydrochloride were added in portions over 20 min at 00C. After stirring at 0 ° C. and finally at 20 ° C. for 1 hour, the reaction mixture was poured into 400 ml of water, filtered and the pH was adjusted to 5.4 by adding dilute sodium hydroxide solution.



   After stirring overnight at 200 ° C., the product was filtered, washed and dried; the yield
Dihydrate was 59.0 g or 78% of theory; iodometric test showed a purity of 95%. Water content according to the Karl Fischer method 8, 650/0.



   When carrying out the process according to Example 3, but using equivalent amounts of others
Acylating agent instead of 1-aminocyclohexanecarboxylic acid chloride hydrochloride, a number of penicillin derivatives were obtained and from these the corresponding penicillins, as indicated in Table B below:

   
Table B.
 EMI9.1
 
<tb>
<tb> <SEP> acylating agents used <SEP> endpenicillins
<tb> 1- <SEP> aminocycopentane carbon <SEP> - <SEP> 6- <SEP> (1- <SEP> aminocycopentane carbox- <SEP>
<tb> acid chloride chlorhydrate <SEP> amido) penicillanic acid
<tb> 2-amino-1,2,3,4-tetrahydro- <SEP> 6- (2-amino-1,2,3,4-tetrahydro-
<tb> 6-methoxy-2-naphthoic acid- <SEP> 6-methoxy-2-napthamido) <SEP> chloride chlorohydrate <SEP> penicillanic acid
<tb> 2-Amino-1, <SEP> 2, <SEP> 3, <SEP> 4-tetrahydro- <SEP> 6- <SEP> (2-Amino-1, <SEP> 2, <SEP> 3 , <SEP> 4-tetrahydro-
<tb> 7-ethoxy-2-naphthoic acid <SEP> - <SEP> 7-ethoxy-2-naphthamido) <SEP> chlorohydrate <SEP> penicillanic acid
<tb> 2-Amino-4-phenyl-2-indan- <SEP> 6- (Indan <SEP> -2-amino-4-phenylcarboxylic acid chloride chlor-2-carboxamido)

  -penicillic anhydrate <SEP> acid
<tb> 2-Amino-3-phenoxy-2-indan-<SEP> 6- (indan-2-amino-3-phenoxycarboxylic acid chloride chlor- <SEP> 2-carboxyamido) <SEP> -penicillic anhydrate <SEP> acid
<tb> 2-Amino-4-butyl-2-indane <SEP> 6- (indan-2-amino-4-butylcarboxylic acid chloride chlor- <SEP> 2-carboxamido) <SEP> -penicillic anhydrate <SEP> acid
<tb> 1-Amino-7-methyl-1-indan-<SEP> 6- (indan-1-amino-7-methylcarboxylic acid chloride chlorohydrate <SEP> 1-carboxamido) <SEP> -penicillanic acid
<tb>
 
 EMI9.2
 methylaniline was added and then 24.2 g (0.14 mol) of 2-amino-2-carboxyindanoic acid chloride hydrochloride in small amounts for 20 minutes at OOC. The mixture was allowed to warm to room temperature and stirred for an additional 15 minutes.



     After pouring the amber-colored solution into 200 ml of ice water and filtering the mixture, the filtrate was adjusted to a pH of 5.8 with dilute sodium hydroxide solution. After stirring for 16 hours, the white product was filtered off, washed with water and acetone and then dried; Yield 18.6g
 EMI9.3
 

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 Elemental analysis: calculated for C18H21O4N3S: C57.58H5.64N11.19%, found: C 57.46 H5.82 N11.38%.



    Example 5: Ampicillin
 EMI10.1
 
Hold; iodometric test gave 1004 y / mg.



   Elemental analysis: calculated for C H igO S: C 55.00 H 5, 48 N 12.03%, found: C 55.28 H 5, 75 N 12.03%.



   Example 6: Penicillin V (Phenoxymethylpenicillin)
23 g (0.20 mol) of methyldichlorosilane were added dropwise at 10 to 150 ° C. to a mixture of 43.2 g of 6-APA, 425 ml of methylene chloride and 40.5 g of triethylamine and the mixture was refluxed for 1 hour. After cooling to 100 ° C. and filtering off the triethylamine hydrochloride, the solution was treated with 26.7 g of N, N-dimethylaniline, after which the solution of 34.0 g (0.20 mol) of phenoxyacetyl chloride in 100 ml of methylene chloride was added over 20 minutes at 00 ° C. The mixture was stirred at 200 ° C. for 1 1/2 hours.



   After pouring the clear red solution into 800 ml of ice water containing 80 g of sodium bicarbonate, the layers were separated and the methylene chloride layer was extracted again with water. By acidifying the
 EMI10.2
   Hydrochloric acid 95%.



   Example 7: 6- (1-Aminocyclohexanecarboxyamido) -penicillanic acid
A methylene chloride solution of methyl hydrogen silane derivative of 6-APA was prepared as described in Example 6. Without filtering, the mixture was treated with 17.4 g of pyridine and 40.7 g of 1-amino
 EMI10.3
 and 200 ml of isopropyl alcohol, 39.2 g in the form of the dihydrate was obtained; biological test gave 888 y / mg.



   Example 8: Dicloxacillic acid [3- (2,6-dichlorophenyl) -5-methylisoxazole penicilin]
A methylene chloride solution of the methyl hydrogen silane derivative of 6-APA was prepared as described in Example 6. After filtering, the solution was treated with 26.7 g of N, N-dimethylaniline, and then a solution of 58.2 g (0.20 mol) of 3- (2,6-dichlorophenyl) -5-methylisoxazole-4-carbonyl chloride in 80 ml of methylene chloride were added over 15 minutes at 00C. The mixture was allowed to warm to room temperature and stirred for an additional hour.



     After pouring the reaction mixture into 500 ml of ice water and separating the layers, the dried methylene chloride layer was treated with 700 ml of hexane to crystallize the product. The dicloxacillic acid obtained after drying was 67 g or 71% of theory.



    Example 9a: Silenated ampicillin.HCl
A 14.2 g (0.05 mole) sample of solid, silenated 6-APA, prepared as described in Procedure III.
 EMI10.4
 The temperature was allowed to rise to 180 ° C. for 15 minutes at -30 ° C. and the mixture was stirred for 1 1/2 hours.



   The insoluble product was collected by centrifugation and decanted under dry nitrogen and finally washed sequentially with methylene chloride, ethyl acetate and methylene chloride. The resulting light yellow powder was stirred in anhydrous ether, collected by filtration under dry nitrogen and dried in a vacuum distillator at room temperature. The product was 17.7 g or 80% of the
 EMI10.5
 ; Example 9b: ampicillin
22.1 g (0.05 mol) of solid, silenated ampicillin HCl, prepared as described in Example 9a, were added to a mixture of 260 ml of ice water and 140 ml of methylene chloride. After stirring for 5 minutes, the two phase mixture was clarified by filtration and the layers were separated.

   To the aqueous layer was added 38 ml of ethyl acetate, and then an aqueous solution containing 12 g of naphthalenesulfonic acid was added dropwise at 100 ° C. while a dilute sodium hydroxide solution was added at the same time to maintain the pH at 1.5. After stirring overnight, the white crystalline product was collected by filtration and washed well with cold water and finally with ethyl acetate, with ampicillin

 <Desc / Clms Page number 11>

 when its 6-naphthalinsulfonic acid salt was obtained, yield 19.5 g or 70% of theory.



   Example 10: Ampicillin
22.1 g (0.05 mol) of solid, silenated ampicillin HCl, prepared as described in Example 9a, in 88% yield from 6-APA, were added to a mixture of 260 ml of ice water and 140 ml of methylene chloride.



  After stirring for 5 minutes, the two phase mixture was clarified by filtration and the layers were separated. Biopest of the aqueous phase showed 9.9 g ampicillin or 57% of theory.
 EMI11.1
 let flow. After cooling to 150 ° C. under nitrogen, the insoluble by-products were filtered off, washed with methylene chloride and dried. Of the 36.1 g obtained, only 0.03 g was unreacted 6-APA.



   After evaporation of the filtrate to dryness under reduced pressure at 20 to 270 ° C., the residue was freed from remaining triethylamine hydrochloride by dissolving in 500 ml of dry ethyl acetate, filtering and concentrating to a constant weight of 57.3 g. The total recovery of triethylamine hydrochloride was quantitative (54.7 g).



   The product was an almost colorless, friable solid with a chlorine content of 0.25%. The average molecular weight was 1660 (corresponding to a polymer with 5 units), as was determined by lowering the freezing point in dimethyl sulfoxide. b) Production of "phenylmethyl-silenated 6- (1-aminocyclohexanecarboxamido) -penicillanic acid-HCl
A sample of 33.4 g (0.10 mol) of "phenylmethylsilenated APA" was dissolved in 230 ml of methylene chloride under dry
 EMI11.2
 



   230 ml of absolute ether was added and the product was collected by decantation under dry nitrogen and then washed with two portions of methylene chloride-ether (1: 3). The white powder obtained was washed with ether and dried in vacuo; Yield 44.2g.



   X-ray fluorescence showed the product to contain 12.90/0 N, N-dimethylaniline HCl and an Si content of 5.2% compared to a theoretical value of 4.90/0 calculated for this mixture , exhibited. NMR showed that the Si-methyl groups are predominantly bound in 0-Si-N bonds, suggesting a head-to-tail polymer structure. c) Treatment of a sample of this material in methylene chloride with water and adjustment of the pH value of the aqueous layer to 5.4 with sodium hydroxide solution gave ss- (1-aminocyclohexanecarboxyamido) -penicillanic acid dihydrate.

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Claims (1)

PATENT CLAIMS: EMI11.3 EMI11.4 in which represents an acyl radical of an organic carboxylic acid, and its pharmaceutically acceptable salts by reacting 6-APA with an organic silicon derivative and acylating the compound obtained, optionally in the crude reaction solution, characterized in that an organosilane derivative of 6-aminopenicillanic acid of the general formula <Desc / Clms Page number 12> EMI12.1 wherein R1 is hydrogen, alkyl, aryl or aralkyl; R2 is halogen, alkyl, aryl or aralkyl; W is hydrogen or a radical of the formula EMI12.2 wherein R1 and R2 have the meanings given above and X is halogen; m 0 or 1; n is an index from 1 to 25; p 0 or 1; and Y is halogen or a group of the formula EMI12.3 mean, where in formula (II) 1. for m and p = 0, n is more than 1 and the two free valences form a cyclic compound with one another; 2. for n greater than 1, the sections A of the repeating groups B in statistical head-to-head, Head-to-tail and tail-to-tail positions occur; 3. W is not hydrogen when n is 1 and Y corresponds to the formula (IV), and 4. m and p are always the same or a reaction solution containing this compound (II) with a reactive derivative of an organic carboxylic acid Rb-CO-OH (where Rb-CO denotes an acyl group, Rb being an amino group on the a-carbon atom for If the organosilane derivative of 6-aminopenicillanic acid to be acylated contains an alkyl, aryl or aralkyl group both as R1 and R2), preferably in an organic solvent free from hydroxyl groups and preferably in the presence of an acid acceptor, and then the acylated product is hydrolyzed or alcoholysed and, if desired, the penicillin thus obtained is converted into a salt. EMI12.4