DE2165990A1 - 6 or 7 (1'-cyclohexenylglycinamido)-penicillanic cephalosporanic or - desacetoxy cephalo sporadic acids - as antibiotics - Google Patents

Abstract

Cpds (I) and their salts and acetone complexes. (where A is derived from 6-APA, 7-ACA or 7-ADCA/amino desacetoxy cephalosporanic acid) by removal of NH2) are prepd. from 1-cyclohexenyl glycine (II) and 6APA, 7ACA or 7-ADCA. The prepn. of (II), from the aldehyde an alkali metal cyanide and ammonia followed by hydrolysis or from -cyclohexenyl acetic acid or nitrile by nitrosation and reduction (COOH) or by reduction and hydrolysis (CN) is also claimed.

Description

1-Cyclohexenylglycine and its method of elimination from patent ....... (patent application P 21 50 516.81 The invention relates to 1-cyclohexenylglycine and a method for its production.

1-Cyclohexenylglycine can be obtained by methods known per se, e.g.

by reacting 1-cyclohexene-1-aldehyde, with alkali metal cyanide and a Ammonia-forming material and subsequent hydrolysis are produced. These Reaction is conveniently carried out in a hydrophilic solvent, e.g. water, alcohols (e.g. methyl alcohol and ethyl alcohol), or their mixtures. she can generally be carried out at 0 to 80 ° C. However, preferably at one Temperature in the area before. 30 to 400C worked.

The alkali cyanide (e.g. sodium cyanide and potassium cyanide) and the ammonia supplying material (e.g. ammonium chloride and ammonium carbonate) are generally used used in an amount of 1 to 1.5 moles per mole of the 1-cyclohexene-1-aldehyde.

The reaction is generally in a time of 1 to 4 hours completed. When using aminonium chloride as the ammopiak-producing compound an aminonitrile compound is formed, while when using Ammonium carbonate a hydantoin compound is formed. The aminonitrile compound or the hydantoin compound can be isolated or subjected to hydrolysis without isolation will. The hydrolysis is generally carried out by treating the reaction product for example with hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or Barium hydroxide carried out. In the production of an aminonitrile compound, the hydrolysis expediently under acidic conditions, generally using a 3 to 12 normal acid. The reaction is convenient at a temperature in the range of about room temperature to 100oc. at Using the uydantoin compound, however, the reaction is expedient under alkaline conditions Conditionally and generally carried out at the reflux temperature.

The reaction can, if appropriate, also be carried out under increased pressure will. After completion of the reaction, the reaction mixture can be used without isolation as Starting material can be used, but it can also be done by methods known per se, e.g. single-gurig, phase transfer, recrystallization and chromatography, purified will.

l-Cy ^ lohexenylglycine can also be obtained via a l-cyclohexenyl compound of the general formula in which B is a protected or unprotected carboxyl group or cyano group. When B is an unprotected carboxyl group, the desired compound is obtained by nitrosating the compound (II) and then reducing it. When BB is a protected carboxyl group or cyano group, the desired compound is produced by nitration of the compound (II), followed by reduction and hydrolysis, which can be carried out in any order.

Protected carboxyl groups are, for example, alkyloxycarbonyl groups, e.g. methoxycarbonyl, ethoxycarbonyl, n- (or iso) -propoxycarbonyl, n-, iso-, s- or tert-butoxycarbonyl and n- or tert-amyloxycarbonyl, or a substituted one or unsubstituted phenoxycarbonyl group, e.g., phenoxycarbonyl, p-nitrophenoxycarbonyl or pentachlorophenoxycarbonyl or lower alkoxycarbonyloxycarbonyl groups, e.g. tert. -Butoxycarbonyloxycarbonyl and Xthoxycarbonyloxycarbonyl.

os D: he nitration is carried out in a manner known per se, for example by reacting the l-cyclohexenyl compound (II) with nitrites or nitrite esters in the presence of an acid (e.g. an inorganic acid such as hydrochloric acid or a organic carboxylic acid such as acetic acid) or a base (e.g. sodium hydride, equivalent Alkali alcoholates or alkali amides with sodium or potassium) carried out. Suitable Examples of nitrites are sodium nitrite and potassium nitrite. Suitable as a nitrite ester for example alkyl nitrites, e.g. methyl nitrite, ethyl nitrite, n-butyl nitrite, tert-butyl nitrite and isoamyl nitrite.

The reaction is generally carried out at a temperature of from 5 to 60.degree carried out. It runs smoothly in suitable solvents. Suitable as a solvent are for example alcohols, e.g. methanol and ethanol, aromatic hydrocarbons, e.g. benzene and xylene, halogenated hydrocarbons, e.g. chloroform and carbon tetrachloride, and ethers such as ethyl ether and tetrahydrofuran. The nitrosating agent is used in generally in an amount of about 1 to 1.2 moles per mole of 1-cyclohexenyl compound (II) is used, but is not limited to this range. The reaction is generally completed in about 0.5 to 2 hours.

The l-cyclohexenyl-o-nitrosoacetic acid compound prepared in this way is further reduced to its a-nitroso group into the amino group to convert. Reduction processes known per se can be used for this purpose without affecting the double bond of the l-cyclohexenyl group.

Reduction processes using, for example, are suitable of metals (e.g. iron, tin and zinc) or tin (IV) chloride in the presence of a Acid (e.g. hydrochloric acid) using an amalgam, e.g. B. aluminum amalgam, Hydrogen sulfide and its salts (e.g. sodium sulfide or sodium polysulfide) under acidic, neutral or alkaline conditions.

These reactions can take place in a solvent such as glacial acetic acid and Alcohols such as methanol and methanol.

If B in the compounds prepared in this way is a protected Is carboxyl group or cyano group, these compounds are used to form the l-cyclohexenylglycine hydrolyzed. The hydrolysis can be carried out by methods known per se, for example by treatment the compound (il) with an inorganic acid such as hydrochloric acid and sulfuric acid or with an inorganic base such as sodium hydroxide and potassium carbonate will. These acids or bases are generally used in concentrations of 3 bis6-normally used, but you are not necessarily limited to this range. The reaction is generally carried out in an aqueous solution. By addition of alcohols such as methanol and ethanol can cause them to have a high concentration of the compound (II) to be carried out. The reaction temperature is generally from 40 to 100 ° C, expediently 70 to 1000C.

The l-cyclohexenylglycine prepared in the manner described has as such a relatively strong antibacterial effect and can therefore be used as a Fungicide can be used.

Since l-cyclohexenylglycine contains an asymmetric carbon atom, it is generally obtained as a racemate, which is optionally used for optical separation can be subjected to methods known per se. This can be, for example using optically active acids such as L-tartaric acid and D-camphorsulphonic acid, or optically active bases such as cinchonine. or by synthesizing the N-acyl compound of 1-cyclohexenylglycine and hydrolysis of the N-acyl compound with an enzyme, e.g.

Diastasis, happen.

i-Cyclohexenylglycine or its reactive derivatives can be mixed with 6-aminopenicillanic acid (6-APA), 7-aminocephalosporan acid (7-ACA) or 7-aminodeacetoxycephalosporan acid (7-ADCA) to form new and valuable antibacterial compounds of the general formula are reacted, in which A is a group which forms 6-aminopenicillanic acid, 7-aminocephalosporanic acid or 7-aminodeacetoxycephalosporanic acid upon introduction of an amino group.

The compounds (I) can, for example, with corresponding salts Alkali metals or alkaline earth metals, e.g. sodium, kailuin, calcium and aluminum, or organic amines, e.g.

Trimethylamine, triethylamine, tributylamine and pyridine form.

The compounds (I) can also be converted into acetone adducts of the general formula in which A has the meaning given above.

The conversion of l-cyclohexenylglycine to the compounds of the formula (1) is an acylation process in which the i-cyclohexenylglycine is usually in the form its reactive derivatives is used.

Examples of such derivatives are the acid halides, e.g. Acid chlorides and acid bromides, the acid azides and acid anhydrides, the mixed alkylphosphorus or alkyl carbonic anhydrides, active esters, e.g. corresponding esters with 4-substituted 2,5-oxazolidinedione, pentachlorophenol or N-hydroxysuccinimide. If required, condensation agents, e.g. cyclohexylcarbodiimide, phosphoryl chloride and ET, N'-carbonyl-bis-imidazole, be used. The amino group of 1-cyclohexenylglycine is preferably used, for example with hydrochloric acid, an organic aldehyde, o-nitfothiophenyl, a ß-diketone compound (e.g. acetylacetone or acetoacetic acid ester), azide or with a carbobenzoxy group, p-toluenesulfonyl group, phenylthiocarbonyl group, aryloxy group or phthalyl group, Isobornyloxycarbonyl group or ß-methylsul £ onylEthoxycarbonylgruppe protected.

6-APA, 7-ACA and 7-ADCA can be in the form of suitable salts or easily hydrolyzable esters can be used. When using easily hydrolyzable Esters, the reaction products are optionally subjected to hydrolysis in order to the desired compounds (I) or their salts are nu obtained.

6-APA, 7-ACA or 7-ADCA can be easily hydrolyzed as the corresponding Ester with. a silylating agent, e.g. Trimethylchlorosilane or trimethoxychlorosilane or a silenating agent, e.g. dimethyldichlorosilane and dimethoxydichioresilane, e.g. tri-n-butyltin oxide, triphenyl chloride, bis (p-methoxyphenyl) methyl chloride, Methoxymethyl chloride and ß-methylthioethyl chloride.

These reactions can be carried out in a solvent. However, precautions must be taken when using an easily hydrolyzable ester taken to prevent moisture from entering the reaction system. Suitable solvents are, for example, water, alcohols, see B.

Xthanol and methanol, acetone, dioxane, tetrahydrofuran, triethylamine, halogenated Hydrocarbons such as chlorobenzene, chloroform and methylene chloride and others organic solvents such as ethyl acetate, ether and acetonitrile. The reaction temperature is not essential, however, the reaction is often carried out under refrigeration or at room temperature carried out.

If, in the reaction according to the invention, an acid is used as a by-product is conveniently a basic reagent, for example an alkali such as alkali hydrogen carbonate Alkali carbonate or alkali hydroxide, or an organic amine, e.g. triethylamine or pyridine, present in the reaction system. In the case of an easily hydrolyzable one Ester, the product is hydrolyzed in the usual way and then by customary methods, z, B.

separated by concentration, phase transition and chromatography. If necessary, the product can be purified, for example by recrystallization will.

Of course, the isomeric forms of the compounds (I) also fall their mixtures within the scope of the invention.

The compounds (i) prepared in this way can by reaction be converted into their acetone adducts with acetone, which have a longer duration of action than the original compounds (I). In this reaction the acetone becomes preferably in an amount of more than 1 mole per mole of cyclohexenylglycine amide derivative (I) used. The reaction generally proceeds easily in a solvent, e.g. methylene chloride, dimethylformamide, water, chloroform and acetone. The pH the reaction mixture is preferably kept in a range of 5.5 to 9.5 and can be mixed with an inorganic alkali compound, e.g. sodium hydroxide, sodium carbonate, Potassium hydroxide and potassium carbonate, organic amines, e.g. triethylamine, or acids, e.g. hydrochloric acid and phosphoric acid. The reaction will take place at room temperature or at an elevated temperature.

The compounds (I) and their acetone adducts have a strong inhibitory nature Effect against gram-positive and grain-negative bacteria.

Compared to α-aminobenzylpenicillin and cephalosporin, they show one much stronger action against Escherichia coli. The compounds (I) are Easily absorbed by the small intestine in the case of oral administration and penetrate in the case of parenteral administration Administration quickly into the tissues with which they have good affinity.

The compounds (I) are therefore useful as antibacterial agents. For this purpose, they and their pharmaceutically acceptable acid addition salts (e.g. sodium and potassium salts) and their acetone adducts orally or parenterally as those or in the form of suitable preparations such as powders, granules, tablets or infection solutions mixed with pharmaceutically acceptable carriers, extenders, Diluents or adjuvants can be administered orally or parenterally. the Compounds (I), their salts and acetone adducts can be used to treat almost the same Diseases that are cured with α-aminobenzylpenicillin or cephalosporins, or diseases caused by Escherichia coli or the like are used will.

The dose of the compounds (Ij or their acetone adducts is different depending on the connections, the severity illness etc., but is generally in the range of about 5 to 500 mg / kg per day, preferably about 10 to 200 mg / kg per day.

The invention is further illustrated by the following examples. In these examples, parts are parts by weight, unless otherwise specified. Parts by weight relate to parts of space as grams to cubic centimeters.

Example 1 In a reactor from which the air is mixed with dry nitrogen has been displaced, 250 parts by volume are tert-butyl alcohol and then 12 parts metallic potassium given. The mixture is stirred vigorously and under dry conditions Refluxed nitrogen to completely dissolve the potassium. Become a solution 100 parts by volume of dry benzene are added. The mixture is cooled to 5 ° C. In the The same temperature is 33.6 parts of ethyl 1-cyclohexenyl acetate and then 35.2 parts Isoamyl nitrite added within 30 minutes. The ration mix is warming left to room temperature and then stirred for a further hour at room temperature. After dilution with 200 parts by volume of alcohol, the reaction mixture becomes 78 parts Zinc powder and then 250 parts by volume of concentrated hydrochloric acid dropwise with stirring added, the temperature being kept below 30 ° C. by cooling with ice.

The reaction mixture is filtered. The insoluble ones filtered off Components are washed with alcohol.

The washing liquid is combined with the filtrate. The mixture is concentrated under reduced pressure, whereupon about 150 parts of sodium hydrogen carbonate can be added. Here an oily substance is deposited, which is extracted with ether will. The ether is distilled off. 130 parts of an? OSdoigen are left behind aqueous sodium hydroxide solution and 130 parts by volume Ethyl alcohol given, whereupon it is concentrated at 70 ° C.

After 2 hours, the reaction mixture is used to remove the insoluble Substance filtered. The filtrate is adjusted to pH with concentrated hydrochloric acid of about 5.0, with 1-cyclohexenylglycine being deposited in the form of crystals. After cooling, the crystals are isolated, successively with water, alcohol and Ether washed and dried, whereby. 16 parts of 1-cyclohexenylglycine, melting point 24100 (dec.) Can be obtained.

Elemental analyzes: C H N Calculated for C8H13N02s 61.91 8.44 9.03 Found: 61.66 8.49 8.86 Infrared spectrum (KBr, cm-1): 3160, 2600, 1600, 1490, 1400, 1341, 1143, 1108, 718.

1-Cyolohexenylglycine can also be used in the same manner, depending on the use of 1-cyclohexenylglycine ethoxycarbonate anhydride instead of ethyl 1-cyclohexenyl acetate getting produced.

Example 2 To a cooled solution of 12 parts of metallic potassium In g50 parts by volume of tert-butanol are 24.2 parts of 1-cyclohexenylacetonitrile under flowing nitrogen and then added 35.2 parts isaamyl nitrite at 3000, whereupon the mixture is stirred for 2 hours, The reaction mixture is poured into ice water and extracted with 300 parts by volume of ether.

The aqueous layer is separated, washed with ether and washed with 19 parts by volume of acetic acid acidified, whereby an oily substance is deposited, which is extracted with ether. The extract is saturated with an aqueous Washed sodium chloride solution. The ethereal layer is dried and then concentrated, whereby crystals of 1-cyclohexenyl-a-nitroso-acetonitrile are obtained.

Aluminum amalgam, which is made from 10 parts of aluminum strips is with 200 parts by volume of a solution of 10% methyl alcohol in ether covered, whereupon in portions 100 parts by volume of an ethereal solution of the one described above Way prepared a-nitroso compound can be added. The mixture is over Left at night.

After removing the unreacted metal from the reaction mixture the filtrate is extracted with 6N hydrochloric acid. The extract is refluxed for 2 hours heated and then under reduced pressure to 1/3 of its original volume constricted.

The concentrate is neutralized with alkali, forming crystals deposit. The crystals become closer to each other with ethyl alcohol, ether and water washed and then dissolved in an aqueous sodium hydroxide solution. The solution is adjusted to the pH value of the isoelectric point of 1-cyclohexenylglycine with 1N hydrochloric acid set, whereby 9.5 parts of 1-cyclohexenylglycine with a melting point of 24100 (decomp.) can be obtained.

It is found that the compound obtained with the example 1 manufactured product is identical.

Example 3 A solution of 1.5 parts of that prepared according to Example 2 1-Cyclohexenyl-a-nitrosoacetonitrile in 20 parts by volume of ethyl alcohol is produced. 10 parts of zinc powder are added to the solution. whereupon 10 parts by volume of concentrated hydrochloric acid drop by drop with vigorous stirring be added, keeping the temperature at 1000. Then will Stirred for 30 minutes at room temperature.

Insoluble constituents are filtered off from the reaction mixture and washed with ether. The filtrate is combined with the washing liquid. The mixture is concentrated under reduced pressure. Become a concentrate 10 Volume parts of concentrated hydrochloric acid are added, whereupon the mixture is refluxed for 1.5 hours heated and then adjusted to pH 5.0 with aqueous ammonia. Here will be 0.7 part of 1-cyclohexenylglycine was obtained.

Example 4 Under flowing nitrogen, 13.8 parts become metallic Sodium dissolved in 200 parts by volume of methyl alcohol, whereupon the methyl alcohol is distilled off wird0 The residue is suspended in 200 parts by volume of dry benzene. After cooling down the solution to 0 to 50C are 48.4 rIleile 1-cyclohexenylacetonitrile under vigorous Stirring added, whereupon 70.4 parts of isoamyl nitrite were added at the same temperature will. The solution is stirred for one hour at 1000, whereby the sodium salt the nitroso compound separates. The salt is dissolved in 200 parts by volume of water and the solution extracted with benzene. The benzene layer will continue using twice Extracts 200 parts of water each time. The aqueous layers are combined and shaken out with 200 parts of ether. The aqueous layer is separated and dropwise within 2 hours with vigorous stirring to a boiling aqueous solution Solution of 60 parts of sodium hydroxide in 200 parts by volume of water. Afterward The reaction solution is stirred for 3 hours, while the ammonia formed in this process is distilled off. The remaining solution becomes more concentrated to 170 parts by volume Hydrochloric acid neutralized, with α-nitroso-1-cyclohexenylacetic acid in the form of crystals with a melting point of 136-137 ° C.

The precipitate is mixed with 104 parts of zinc powder. To the received Mixture are stirred vigorously at a temperature not exceeding 3O added dropwise 320 parts by volume of concentrated hydrochloric acid, followed by a further 30 minutes is stirred. The unreacted zinc is filtered off. The filtrate is poured onto the Half of its original Concentrated in volume The concentrate is adjusted to pH 6 with an aqueous sodium hydroxide solution. The one here Crude crystals deposited are isolated and washed. The crystals are dissolved in an aqueous 1N sodium hydroxide solution. The pH of the solution becomes adjusted to about 5 with hydrochloric acid, with 1-cyclohexenylglycine in the form of crystals with a melting point of 241 ° C. This connection is the same as in the example 1 manufactured product identical.

Example 5 A solution of 4.4 parts of 1-cyclohexene-1-aldehyde in 8 Parts by volume of methanol becomes a solution of 2 parts of sodium cyanide and 2.36 parts Ammonium chloride given in 8 parts by volume of water. The mixture is 2 hours at room temperature stirred0 After this time, 20 parts by volume of water are added. The aminonitrile compound obtained is extracted with 20 parts by volume of benzene. The benzene layer is applied three times each 10 parts by volume of 6N hydrochloric acid extracted. The aqueous layer is refluxed for 2 hours heated. The resinous substance becomes. removed with activated charcoal and the filtrate up about 15 parts by volume and concentrated with concentrated aqueous ammonia (23% lg) adjusted to a pH of about 5.0, resulting in crude crystals / DL-1-cyclohexenylglycine precipitate0 The crystals are filtered off and dissolved in an aqueous 1N sodium hydroxide solution dissolved 0 Activated charcoal is added to the solution and the mixture is filtered. To the filtrate Ethanol is added (half the volume of the filtrate). The mixture is boiled, whereupon its pH is adjusted to about 5.0 with hydrochloric acid. Here are 1.1 parts DL-1-Cyclohexenylglycine in the form of colorless flakes with a melting point of 242 to 2430C obtain.

Infrared spectrum (KBr, cm-1): 3160, 2960, 1605, 1490, 1400, 1345, 1274, 1145, 720.

NM. Spectrum solvent: 1n-NaCD): 1.5-2.4 (multiplet, 8H) 3, o (Singlet, IH, -OH - COOH) 5.84 (Multiplet, IH, - CH = C -) Example 6 to one A solution of 13 parts of potassium eyanide becomes 11 parts of 1-cyclohexene-1-aldehyde and 38.4 parts Ammonium carbonate and 100 parts by volume of ethyl alcohol (5ig) are given. The mixture will Stirred for 2 hours at 60 to 650C. After this time, the ethyl alcohol is under distilled off under reduced pressure. The residue is acidified with dilute hydrochloric acid, whereby crystals are precipitated. 5 parts of the crystals are hydrolyzed, whereby 2.7 parts of 1-cylohexenylglycine are obtained. The melting point of a mixture this substance with the product prepared according to Example 1 is not lower than the melting point of the product prepared according to Example 1.

Example 7 1) A solution of 5 parts of 1-cyclohexenylglycine in 33.2 Volume parts of an aqueous sodium hydroxide solution is prepared. To the solution alternate between an aqueous 1N sodium hydroxide solution and chloroacetyl chloride given while the pH is kept in the alkaline range and cooled with ice is until the total amount of the aqueous sodium hydroxide solution 39.2 parts by volume and the total amount of chloroacetyl chloride reached 4.2 parts by volume.

The reaction mixture is allowed to stand and allow to warm to room temperature left and then stirred for 2 hours at room temperature, after adjusting to pH 8.0 the mixture is extracted with ether. The aqueous layer is made with 2N hydrochloric acid adjusted to pH 2.5. The suspension obtained is extracted three times with ether. The combined ether extracts are washed twice with aqueous saturated sodium chloride solution washed and then dried.

The ether solution is distilled, whereby crystals are formed, which are recrystallized from benzene ether. 4.5 parts by volume of N-chloroacetyl-1-cyclohexenylglycine are thereby obtained obtained from melting point 137 to 140000 Elemental analysis: C H N Cl Calculated for C10H14NO3Cl: 51.84 6.09 6.04 15.30 Found: 51.78 5.86 5.83 15.52 Infrared spectrum (KBr, cm-1): 3360, 2650, 1730, 1625, 1545, 1410, 1255, 1210, 1155, 1010, 885, 7850 2.) A suspension of 1 part of the N-chloroacetyl-1-cyclohexenylglycine prepared in this way water is produced in 25 parts by volume. 4.5 parts by volume become a suspension added aqueous 1N sodium hydroxide solution, a homogeneous solution being obtained will. The solution becomes a solution of 5 parts of diastase in 40 parts by volume of water The mixture is added to pH 7.2 with an aqueous 1N sodium hydroxide solution set and then stirred at 3700 for 115 hours. The reaction mixture becomes Removal of deposits filtered. The filtrate is brought to pH with 2N hydrochloric acid 2.5 adjusted and then extracted with ethyl acetate.

The ethyl acetate extract is mixed with a saturated sodium chloride solution washed, dried and concentrated, crystals separating out. By three times Recrystallization from ethyl acetate gives 0.2 parts of D (-) - N-chloroacetyl-I cyclohexenylglycine obtained from melting point 137 to 13800 in the form of colorless powdery crystals0 [α] D = -1360 (EtOH 0 = 1.0) Elemental analysis: C H N Cl Calculated for C10H14NO3Cl: 51.84 6.09 6.04 15.30 Found: 52.03 5.71 5.97 15.30 3) A suspension of 0.1 part of D (-) - N-chloroacetyl-1-cyclohexenylglycine in 4 parts by volume of 6N hydrochloric acid is refluxed for 15 minutes0 The reaction mixture becomes af about 1 volume The concentrate is adjusted to pH 5.0 with aqueous 7N ammonia, whereby crystals separate out. The crystals are washed with cold water and dried, leaving 0.03 parts of D (-) - 1-cyclohexenylglycine, melting point 224 to 2250C can be obtained.

[α] D = -147.7 (1N-HCl, C = 1.0%) 4) The one obtained in the section (2) aqueous layer is adjusted to pH 5.0 with an aqueous 1N sodium hydroxide solution and concentrated under reduced pressure. The concentrated solution is at 20 parts of the ion exchange resin "Amberlite IR-120B" (manufacturer Rohm & Haas Co.) adsorbed. The resin is filtered off and washed with 500 parts by volume of water, whereupon is extracted with aqueous 1.5N ammonia. The extract is concentrated, whereby Cut off the crystals. 0.15 part of L (+) - 1-cyclohexenylglycine is obtained as the product.

[α] D = + 147 ° (1N-HCl, C = 1.0%) Example 8 A solution of 0.63 Parts of sodium 1-cyclohexenyl glycinate and 0.42 parts of methyl acetoacetate in 40 parts by volume Methanol is stirred at 60 ° C. for 3 hours. The reaction solution is concentrated and the enamine compound obtained is well dried and chloroform is dry in 25 parts by volume solved. The solution is cooled to -20 ° C, whereupon a solution of 0.49 parts of isobutyl chlorocarbonate chloroform is added in 10 parts by volume within 5 minutes.

The mixture is 2 hours at a temperature in the range of -20 Stirred to -8 ° C. Then at -10 C a solution containing 0.78 parts of 6-aminopenicillanic acid, Contains 0.4 parts of triethylamine and 30 parts by volume of chloroform, added, on what 2 hours at -5 to + 5 ° C is stirred. The reaction mixture is concentrated and the residue in a solution of 0.75 parts of sodium hydrogen carbonate in 50 parts by volume Dissolved in water. After washing with ether, the aqueous layer is isolated and adjusted to pH 2.5 with 2N hydrochloric acid. The layer is left for 30 minutes at room temperature stirred and the separated oily substance extracted twice with ether. the The ether layer is discarded and the aqueous layer with sodium hydrogen carbonate adjusted to pH 4.0 and then freeze-dried. The raw product obtained is purified by column chromatography, 0.3 parts of 6- (1'-cycloxenylglcinamido) penicillanic acid can be obtained from the eluate obtained with water-ethanol (4: 1).

Infrared spectrum (KBr, cm-1): 3400, 3350, 1775, 1685, 1600, 1530, 1510, 1200.

Below are the minimum growth inhibitory concentrations of 6- (1'-Cyclohexenylglycinamido) penicillanic acid called.

(γ / ml) Staphylococcus aureus 209P 0.2 Bacillus subtilis 0.2 Sarcina lutea 0§2 Escherichia coli 0.5 Proteus morganii Eb54 1 example 9 In a reactor from which the air has been displaced with nitrogen 5.2 parts of dry 6-aminopenicillanic acid and 51 parts by volume of dry methylene chloride given, whereupon it is stirred well. 7.3 parts by volume of triethylamine are added to the mixture and 3.4 parts by volume of N, N-dimethylaniline. Then 6.9 parts by volume of rimethylchlorosilane added dropwise to the mixture at a temperature of 0 to 500, whereupon the Reaction mixture is stirred for 30 minutes at 1000 * The reaction mixture is then left to warm and stirred for 2.5 hours at room temperature. After addition of 5.05 parts of 1-cyclohexenylglycine chloride hydrochloride at a temperature of 0 to 5 ° C becomes 30 minutes at 0 to 10 ° C, 1.5 hours at 10 to 15 ° C and 1.5 hours stirred at 15-1700.

The reaction mixture is poured into 144 parts by volume of cold water and stirred at 0 to 5 ° C for 30 minutes. After adding 0.7 parts of kieselguhr tCelitefl the mixture is filtered and washed with cold water. The filtrate is with the wash liquid combined and the aqueous layer separated and washed with ethyl acetate washed. The aqueous layer is separated and adjusted to pH with sodium bicarbonate 4.0 adjusted, with 6- (i'-Cyclohexenylglycinamido) penicillanic acid as a white precipitate is obtained.

Example 10 A solution of 0.51 parts of sodium D (-) - 1-cyclohexenylglycine and 0.37 parts of methyl acetoacetate in 30 parts by volume of methyl alcohol is added for 2 hours 600C stirred. The reaction solution is concentrated to obtain an enamine compound will. After cold drying, the enzyme compound is dry in 25 parts of the room Dissolved chloroform A solution of 0.5 part of isobutyl chlorocarbonate is added to the solution given in 10 parts by volume of chloroform at -20 ° C, followed by 2 hours at one temperature from -15 to -8 ° C is stirred. After adding a solution of 0.63 part of 6-aminopenicillanic acid and 0.3 parts of triethylamine in 30 parts by volume of chloroform at the above temperature is stirred for 2 hours at a temperature of 2 to 500.

The reaction mixture is concentrated and the residue in a solution of 1 part of sodium hydrogen carbonate dissolved in 100 parts by volume of water. The solution will be adjusted to pH 2.6 with 2N hydrochloric acid and stirred for 30 minutes. The reactor mixture is extracted with ether and the aqueous layer is adjusted to pH 4.0 0 and then purified by chromatography, 0.2 parts of 6- [D (-) - α-amino-1'-cyclohexenyl-acetoamido] penicillanic acid.

[α] D = + 225.2 ° (1n-HCl, C = 0.55%) infrared spectrum (KBr, cm-1): 1780, 1690, 1605, 1510, 1390, 1310, 1245, 1127.

Rf value: 0.6 (solvent: n-butyl alcohol-acetic acid water mixture 3: 1: 1).

Example 11 In a reactor from which the air is displaced with nitrogen becomes 5.2 parts dry 6-aminopenicillanic acid and 51 parts by volume dry Methylene chloride, 6.8 parts by volume of triethylamine and 3.36 parts by volume of N, N-dimethylaniline given, whereupon it is stirred. 3.1 parts of dimethyldichlorosilane are added to the mixture at a Temperature from 10 to 1500 was added dropwise within 20 minutes. The reaction mixture is then left to warm and stirred at 250C for 1.5 hours. The received Solution are 5.05 parts of 1-cyclohexenylglycyl chloride hydrochloride at one temperature from 0 to 500 added within 45 minutes, followed by 15 minutes at 00 to 50C, 1.5 hours at 5 to 1000 and 1.5 hours at 1000 is stirred.

The reaction mixture is poured into 144 parts by volume of cold water, whereupon the mixture is stirred at 5 to 1000 for 15 minutes. The reaction mixture is filtered after the addition of 0.7 part of silica gel "Celite".

The filter cake is washed with cold water. The washing liquid is combined with the filtrate obtained in the manner described above. To the watery Layer are given 20 parts by volume of ethyl acetate. A solution of 5.62 parts by volume of diphenylsulfonic acid in 15 parts by volume of water drop by drop with one Temperot-ur from 00 to 50C added dropwise, while the pHr '# ert with an aqueous 5N sodium hydroxide solution is kept at 1.5.

The diphenyl sulfonate of 6- (1-cyclohexenylglycineamido) penicillanic acid is used here failed.

The reaction mixture is stirred at 500 ° for 6 hours and filtered. The filter cake is mixed with 30 parts by volume of cold water with a pH of 1.5 to 2.0, and washed with 30 parts by volume of ethyl acetate. He will then twice washed with 6 parts by volume of ethyl acetate, whereupon the filter cake sucked off well will. Here, 15 parts of the diphenyl sulfonate of 6- (1-cyclohexenylglycineamido) penicillanic acid are used obtain. The salt is suspended in 17 parts by volume of 85% isopropyl alcohol. To Addition of 17 parts by volume of triethylamine to the mixture is this 45 minutes at 60 Stirred up to 700C, whereby a precipitate separates out. The precipitation is done with heating filtered off and three times with 5 parts by volume of 85% isopropyl alcohol washed and then dried over phosphorus pentoxide under reduced pressure, taking 2.0 parts of 6- (1-cyclohexenylglycineamido) penicillanic anhydride as a white Powder can be obtained. This product shows characteristic in the infrared spectrum Absorption bands at 3340 cm-1 (-NH-), 1760 cm-1 (ß-lactam carbonyl), 1690 cm (amidocarbonyl), 1600 cm-1 (carboxylate) and 1510 cm-1 (amide).

The minimum growth-inhibiting concentration is 0.2 µg / ml for Staphylococcus pyogenes var. aureus and 0.8 µg / ml in Escherichia coli.

Example 12 In a reactor from which the air is displaced with nitrogen becomes 5.2 parts dry 6-aminopenicillanic acid and then 51 parts by volume given dry methylene chloride. After adding 6.8 parts by volume and uriethylamine 3.36 parts by volume of N, N-dimethylaniline, the mixture is stirred, whereupon 3.1 parts of dimethyldichlorosilane be added dropwise at 10 to 1500 within 20 minutes. The reaction mixture is left to warm and stirred for 1.5 hours at 250C. The here obtained Solution become 5.05 parts of 1-cyclohexenylglycine chloride hydrochloride within 45 Added at 0 ° C to 5 ° C for minutes. The mixture is 15 minutes at 0 to 5 ° C, 1.5 Stirred at 5 to 1000 hours and at 1000 for 1.5 hours. The reaction mixture is poured cold water into 144 parts by volume and then stirred at 5 to 1000 for 15 minutes. After adding 0.7 part of "Celite" kieselguhr, the mixture is filtered. The filter cake is washed with cold water and the filtrate is combined with the washing liquid. The aqueous layer is washed with ethyl acetate. At a temperature of 0 until 50C the aqueous layer is adjusted to H 4.0 with sodium bicarbonate, whereby 6- (1'-Cyclohexenylglycinamido) -penicillanic acid is obtained as a white precipitate.

EXAMPLE 13 0.72 parts of sodium cyclohexenylglycinate are added to 20 parts by volume of methanol solved. 0.47 parts of methyl acetoacetate are added to the solution. The mixture will Stirred for 2 hours at 50 ° C and then evaporated to dryness. The The enamine compound is immediately dissolved in 25 parts by volume of chloroform. At -15 ° C a solution of 0.55 parts of isobutyl chlorocarbonate in 10 parts by volume of chloroform added. The mixture is stirred at -8 ° C. for 90 minutes.

Then a solution of 1.08 parts of 7-aminocephalosporan acid and 0.41 parts of triethylamine in 30 parts by volume of chloroform within 10 minutes -50C was added dropwise, whereupon the mixture is stirred at a temperature of 0 ° to 500 ° for 2 hours.

The mixture is concentrated and the residue in 100 parts by volume of a Dissolved 1% aqueous sodium hydrogen carbonate solution. The solution is made with 2N hydrochloric acid adjusted to p, 2.5, stirred for 30 minutes and extracted with ether.

The aqueous layer is adjusted to PE 3.8 with sodium hydrogen carbonate and then concentrated, 7- (1'-Cyclohexenylglycinamido) -cephalosporanic acid being obtained will.

Example 14 In a mixture of 20 parts by volume of ethyl acetate and 1.64 Parts of triethylamine 2.16 parts of 7-aminocephalosporanic acid are suspended. To the Suspension are 0.87 parts of trimethylsilyl chloride at a temperature of 0o to 1000 given. The temperature is gradually increased. At room temperature this will be Mixture stirred for a further 3 hours.

While cooling with ice, add 1.05 parts of quinoline and then a solution of 1.68 parts of 1-cyolohexenylglycine chloride in 20 parts by volume of ethyl acetate added to the reaction mixture. The mixture is stirred for 3 hours at room temperature.

The reaction mixture is concentrated and then in 160 parts by volume of a Dissolved 1% aqueous sodium hydrogen carbonate solution. The solution is made with ether g wash and the watery Layer with 2N hydrochloric acid to pH 3.8 set and then narrowed. The concentrate is purified by column chromatography purified, with 7 = (1 1-Cyclohexenyiglycinamido) -cephalosphoransäure of the melting point 195 to 2000C (decomp.).

Rf value: 0.25 (n-BuOH: H2O: tetrahydrofuran = 3: 1: 1) 0.57 (n-BuOH: H2O: acetic acid = 3: 1: 1).

Elemental analysis: C H N S Calculated for C18H23N3SO6.H2O: 50.57 5.89 9.82 7.50 Found: 50.24 5.74 9.83 7.54 UV spectrum (in H20): 258 u Example 15 1.8 parts of sodium 1-cyclohexenylglycinate are suspended in 40 parts by volume of ethyl alcohol. 1.45 parts of ethyl acetoacetate are added to the suspension. The mixture is 3 hours heated to reflux at 650C. The ethyl alcohol is distilled off from the reaction mixture, which is then dried. The residue (enamine compound) is in 50 parts by volume Dissolved chloroform. The solution becomes a solution of 1.36 parts by volume isobutyl chlorocarbonate added chloroform in 10 parts by volume at a temperature of -15 to -10 ° C, whereupon Is stirred for 2 hours at the same temperature. The resulting mixture is a solution of 2.14 parts of 3-deacetoxy-7-aminocephalosporanic acid and 1.1 parts Triethylamine was added dropwise in 100 parts by volume of chloroform at -50C, whereupon the mixture 2 hours at a temperature of -5 to OOC is stirred.

The reaction mixture is concentrated and the residue in an aqueous Solution of 2 parts of sodium hydrogen carbonate dissolved in 100 parts by volume of water and then extracted with ethyl acetate. The aqueous layer is diluted with 2N hydrochloric acid PH adjusted to 2.5 and stirred for 30 minutes.

The aqueous solution is extracted with ethyl acetate and the aqueous Layer adjusted to pH 4.5 and concentrated. The concentrate will purified by chromatography, giving 3-deacetoxy-7- (1'-cyclohexenylglycineamido) -cephalosporanic acid is obtained.

Example 16 In 25 parts by volume of dry methylene chloride, 1.1 Parts of 7-aminodeacetoxycephalosporanic acid suspended. The suspension will be 1.1 Parts of dry triethylamine and then 0.63 parts of N, N-dimethylaniline were added. The mixture is stirred well. While cooling with ice-water, it becomes 0.65 parts Dimethyldichlorosilane added dropwise at 1000.

The reaction mixture is stirred for 2 hours at room temperature. Afterward 1.1 parts of powdered D (-) 1 -cyclohexenylglycine chloride hydrochloride are used added in portions at a temperature below 10 ° C. The mixture is at 1 hour 1000, 1.5 hours at 10 to 1500 and 1.5 hours at 15 to 1700. It will then poured ice water into 30 parts by volume. The solution is adjusted to 1.3 and Stirred for 15 hours, after which 1.0 part of "Celite" kieselguhr is added. The mixture is stirred for a further 10 minutes and then filtered. The filtrate is made with In-KOH adjusted to p11 4-, 7 and freeze-dried, leaving 3.0 parts of a pale yellowish Powder can be obtained. The powder is subjected to thin layer chromatography, where the solvent is a mixture of acetic acid, n-butanol and water (1: 3: 1) is used. This product turns out to be a mixture of four different compounds.

2.0 parts of the powder are added to 20 parts by volume of water, whereupon the pH value is adjusted to 6.9 with an aqueous 1N potassium hydroxide solution. The solution obtained is on a column of the ion exchange resin "Amberlite XAD II "(manufacturer Rohm & Haas Co., USA). The one with 10% ethyl alcohol fraction obtained (positive in the ninhydrin reaction and palladium chloride reaction ) is freeze-dried, leaving 0.85 parts of 7- (D (-) 1'-cyclohexenylglycineamido) desacetoxycephalosporanic acid can be obtained in the form of white feather-like crystals. This product shows in the infrared spectrum characteristic absorption bands at 1770 cm-1, 1G90 cm 1600 cm 1 (wide) and 1520 cm 1.

Example 17 A from 6.0 parts of 6- (1'-Cyclohexenylglycinamido) -penicillanic acid, 1.1 parts of water, 4.9 parts by volume of triethylamine and 35 parts by volume of acetone solution is stirred for 16 hours at room temperature. The reaction mixture obtained is poured into 50 parts by volume of ice water.

At the same time, 2N hydrochloric acid is added. The mixture is 2 hours stirred in a pH range of 2.5 to 3.0 while cooling with ice. the Precipitation is washed with cold hydrochloric acid (pH 2.5) and in a vacuum desiccator dried over phosphorus pentoxide, with 6- 2'-dimethyl-4 '"cyclohexenyl) -5'-oxo ~ 1' -imidazolidinyl7penicillanic acid is obtained in the form of a white powder. That The infrared spectrum of this product shows an absorption corresponding to the ß-lactam ring at 1785 cm1 and an absorption corresponding to the Y-lactam ring at 1720 cm3 Elemental analysis: C H N Calculated for C19H27N304S: 57.99 6.92 1068 8.15 Found: 57.50 6.99 10.65 7.60 Example 18 3.5 parts of 7- (D (-) 1-cyclohexenylglycineamido) desacetoxycephalosporanic acid are used in 25 parts by volume of acetone suspended.

1.5 parts by volume of triethylamine are added to the suspension.

The mixture is stirred at room temperature for 20 hours and then filtered. The filtrate is concentrated under reduced pressure and the acetone is distilled off. 25 parts by volume of ice water are added to the residue while cooling with ice and is stirred, the mixture is adjusted to pH 3.0 with 1N hydrochloric acid, whereby a precipitate separates.

The mixture is stirred for 2 hours while cooling with ice. The precipitate is filtered off, washed with cold water and then with acetone and dried over phosphorus pentoxide in a vacuum desiccator, with 2.4 parts of le 7-LZ'2'-imethyl-rC '- (D (-)? "- cyclohexene-imidazolidinyl-7-de-acetoxycephalosporanic acid can be obtained as a white powder.

This product shows characteristic absorption in the infrared spectrum at 1785 cm 1 (ß-lactam carbonyl) and 1700 cm 1 (wide) (imidazolidinone ring -CO). The absorption bands of the amide at 1680 and 1520 cm are missing.

Example 19 In 8 parts by volume of dry dimethylformamide, 2.0 Parts of 7- (D - (-) 1'-cyclohexenylglycineamido-cephalosporanic acid are dissolved mixed with 0.7 parts by volume of triethylamine. Then 0.5 part of methylchloromethyl sulfide added dropwise at 1000. The mixture is stirred for 4 hours at room temperature and then filtered. The filtrate is concentrated for some time under reduced pressure and then poured ice water into 400 parts by volume. After setting the mixture on PH 7.0, the insoluble constituents are filtered off, with 2 parts by volume of ice water washed and dried in a vacuum desiccator over P205. Here the crude 7- (D (-) 1'-cyclohexenylglycineamido) -cephalosporanic acid methylsulfenylmethyl ester obtained as a pale yellowish powder. The powder is dissolved in 10 parts by volume of acetone. The solution is stirred for 16 hours at room temperature. The acetone is reduced under The pressure is distilled off and the syrupy residue is added to 20 parts by volume of ice water, whereupon it is stirred for some time.

The mixture is then adjusted to pH 3.0 with 1N HCl.

The precipitated crystals are filtered off and washed with ice water and dried over phosphorus pentoxide in a vacuum desiccator, 0.4 parts 7- [2 ', 2'- Dimethyl-4 '- (D (-) - 1 "-cyclohexenyl) -5'-oxo-1'-imidazolidinyl] cephalosporanic acid can be obtained as a white powder.

Claims (3)

P a t e n t a n s p r ü c h e 1) 1-Cyclohexenylglycine. 2) Process for the preparation of 1-cyclohexenylglycine characterized in that that 1-cyclohexene-1aldehyde is supplied with an alkali metal cyanide and an ammonia Reacts compound and hydrolyzes the reaction product. 3) Process for the preparation of 1-cyclohexenylglycine, characterized in that compounds of the general formula in which B is a carboxyl group, a protected carboxyl group or cyano group, nitrosated, the nitrosation product in cases in which B is an unprotected carboxyl group, reduced and in cases in which B is a protected carboxyl group or cyano group, reduced and hydrolyzed in any order.